http://connection.asco.org RSS feeds for ASCO Connection – professional networking for ASCO’s worldwide oncology community 60 http://connection.asco.org/Magazine/Article/ID/3520/Tissue-Acquisition-for-Personalized-Therapy-Merits-and-Drawbacks.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3520 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3520&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3520/Tissue-Acquisition-for-Personalized-Therapy-Merits-and-Drawbacks.aspx IntroductionBy Al B. Benson III, MD, FACP, FASCOFeinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern UniversityPersonalized medicine embodies the concept of delivering the right care at the right time. An individualized approach to provide value-based, high-quality cancer care incorporates team medicine requiring patient access to comprehensive services offered by nurses, multispecialty oncology clinicians, psychologists, social workers, nutritionists, financial counselors, genetic counselors, and pathologists, as important examples. Many now prefer the term “precision medicine,” with the additional emphasis on choosing the tests that are most likely to benefit patients, whether for diagnostic, toxicity assessment, efficacy, or surveillance purposes.Advances in developmental therapeutics have introduced an evolving portfolio of targeted agents across a spectrum of diseases, which, by definition, challenges the clinician to precisely select those individuals most likely to benefit from a molecularly driven strategy. The quest to identify particular markers to predict which patients are most likely to obtain disease control from a given targeted therapy has been elusive for many of the targeted therapies now available. Tumor heterogeneity and the complexity of molecular pathways exemplify the many obstacles that have hindered the development of precise predictive markers linked to treatment efficacy. To further address these challenges, it will be increasingly important to include pathologists and other laboratory scientists, as well as imaging biomarker experts, as critical members of the medical team with routine access to patients’ tissues, particularly for inclusion in tumor banks for future research purposes and for correlative studies in developmental therapeutic clinical trials.In this issue of ASCO Connection’s Current Controversies in Oncology series, Dr. Lillian Siu discusses the acceptance of research biopsies by patients, the importance of obtaining these biopsies, and the limitations of developing less-invasive techniques to develop biomarkers. Dr. Luis Diaz offers insights as to the drawbacks of obtaining human biopsies and the limitations imposed on the analyses of these tissues, including sample characteristics and tumor heterogeneity, as well as novel approaches that may preclude the need for actual tissue biopsies to obtain individual biologic information. As science evolves, the goal is to fuse the bench and the bedside to more precisely offer predictably effective therapeutics for the individual patient over time by members of a truly comprehensive medical team.Dr. Benson is a Professor of Medicine at Feinberg School of Medicine and Associate Director for Clinical Investigations at the Robert H. Lurie Comprehensive Cancer Center. He serves on the Editorial Boards of ASCO Connection and ASCO University®.Tissue Acquisition for Personalized Cancer Therapy: Current Standard and Future OutlookBy Lillian L. Siu, MDPrincess Margaret Cancer Centre, University of Toronto, CanadaPersonalized cancer medicine: “No Tissue, No Marker, No Trial”We have entered the personalized cancer medicine era whereby we are increasingly utilizing information gathered from molecular characteristics of tumor tissue to complement histopathology, in order to enhance diagnostic, prognostic, or predictive evaluations.1 The quote, “no tissue, no marker, no trial,” by Dr. James Doroshow, Director of the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, bears a clear message.2 The acquisition of tumor tissue to perform validated biomarker assays that help distinguish responders from nonresponders, or provide proof of mechanism, has become a fundamental component of high-impact clinical trials using molecularly targeted agents.Acceptance of research biopsies by patientsTumor biopsies, typically using a needle with or without image guidance, enable a direct assessment of biomarkers at the tissue and individual tumor cell levels to confirm the presence or absence of a genetic aberration, to assess target engagement or inhibition, or to identify mechanisms of resistance. As with all invasive procedures, tumor biopsies carry risks, but the frequencies are relatively low, ranging from 5% to 7% overall and less than 1% for major complications in the hands of experienced drug development programs.3,4 The ethics of mandatory research tumor biopsies for correlative studies in clinical trials have been the subject of many deliberations,5,6 especially when the results do not personally affect the clinical care of the trial participants. Most groups have emphasized the importance of providing trial participants a clear understanding of the rationale, risks and benefits of such procedures, so patients can make an informed and voluntary decision.5,6 We have previously surveyed 325 clinic patients who had prior diagnostic but not research biopsies; 48% of the respondents would not be deterred from enrolling into a clinical trial that mandates tumor biopsies for research purposes only.7Post-diagnostic tumor re-biopsiesThe scenario in which tumor biopsies are performed to procure tissue to measure a biomarker that can be used to guide clinical management is distinct from that in which biopsies are performed solely for exploratory research. An obvious example for the first scenario is tissue procurement to detect KRAS mutation in advanced colorectal cancer to avoid ineffective therapy with anti–epidermal growth factor receptor monoclonal antibodies. A less clear-cut example would involve tumor biopsy to select patients whose tumors harbor an unvalidated predictive biomarker of promise, based on preclinical data, for matching to an investigational agent. Although such tumor biopsies seem to fall somewhere between research and diagnostic procedures in their risk-benefit ratio, physicians should exert equal rigor in obtaining informed consent from their patients.Current status of tumor biopsies compared with other alternativesThere are emerging interests to develop less-invasive techniques, such as circulating free nucleic acids (cfNA), to replace the need for tumor biopsies for molecular profiling.8 Until the samples offered by cfNA are validated to be as sensitive as tissue samples and representative of the global status of the cancer genomic landscape in patients, there are several key reasons why tumor biopsies should remain a gold standard at the present time: Tumor biopsies provide tissue for histopathologic confirmation of the diagnosis, to evaluate basic morphologic features such as tumor grade, and to perform relevant immunostains for prognostic and predictive purposes (e.g., estrogen receptor in breast cancer).Examination of tumor tissue enables the evaluation of heterogeneity in gene copy or gene/protein expression at the cellular level, especially in the context of histologic heterogeneity, which is not possible by cfNA.cfNA are not always detectable, and even when detectable, the concordance between genomic aberrations present in tumor specimens and in blood-based samples must be demonstrated for the latter to be an acceptable substitute. In a recent study of 84 patients with advanced solid tumors, a comparison of somatic mutations detected using the Sequenom OncoCarta genotyping panel (v1.0) between matched plasma and formalin-fixed paraffin-embedded archival tumor tissue of primary and/or metastatic sites revealed an overall concordance of only 60% (25 of 42 detected mutations).9Assays that evaluate cfNA are limited by their sensitivity of detection. Ease of detection is related to the frequency of the somatic alterations in the analyzed regions of cancer-related genes. Although sensitivity can be increased by novel techniques that enable amplification and deep sequencing of selected genomic regions, these methods need further optimization before transitioning from research to diagnostic laboratories for routine clinical application.10Likewise, the specificity of assays to differentiate tumor from germ-line cfNA can be a challenge and may require comparative analysis of constitutional nucleic acids to minimize false-positive results.The ability to detect, diagnose, and monitor disease using blood-based biomarkers brings promise to a new paradigm that may eventually obviate the need for invasive procedures such as tumor biopsies. Current efforts should be focused on optimizing these procedures to improve their sensitivity, specificity, reliability, and validity such that they can be implemented in aregulatory-approved setting and applied in clinical practice.Dr. Siu is a Professor of Medicine at the University of Toronto and the Director of the Phase I Clinical Trials Program at the Princess Margaret Cancer Centre. She is a member of the ASCO Board of Directors.ReferencesTran B, Dancey JE, Kamel-Reid S, et al. J Clin Oncol. 2012;30:647-60. PMID: 22271477.Doroshow JH. Vision of Molecular Targeted Therapies in Colon Cancer in 2012. Presented at: 2012 Gastrointestinal Cancers Symposium; January 21, 2012; San Francisco, CA.Dowlati A, Haaga J, Remick SC, et al. Clin Cancer Res. 2001;7:2971-6. PMID: 11595684.Overman MJ, Modak J, Kopetz S, et al. J Clin Oncol. 2013;31:17-22. PMID: 23129736.Olson EM, Lin NU, Krop IE, et al. Nat Rev Clin Oncol. 2011;8:620-5. PMID: 21808265.Peppercorn J, Shapira I, Collyar D, et al. J Clin Oncol. 2010;28:2635-40. PMID: 20406927.Agulnik M, Oza AM, Pond GR, et al. J Clin Oncol. 2006;24:4801-7. PMID: 17050865.Schwarzenbach H, Hoon DS, Pantel K. Nat Rev Cancer. 2011;11:426-37. PMID: 21562580.Perkins G, Yap TA, Pope L, et al. PLoS One. 2012;7:e47020. PMID: 23144797.Forshew T, Murtaza M, Parkinson C, et al. Sci Transl Med. 2012;4:136ra68. PMID: 22649089.Alternatives to Tissue Acquisition for Personalized Therapy: Viable Options or Scientific Parlor Trick?By Luis A. Diaz, Jr., MDThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsMany of the major advances in targeted therapy in oncology have relied on the acquisition of tumor tissue prior to initiating therapy or following the onset of resistance. The availability of tissue for molecular analyses has been instrumental in understanding the primary mechanism of action of agents like trastuzumab, imatinib, panitumumab, erlotinib, crizotinib, and vemurafenib, where the molecular partner for predicting response has been defined (i.e., HER2/neu amplification, mutant KIT, mutant KRAS and mutant EGFR, ALK rearrangements, and mutant BRAF, respectively). Likewise, access to tumor tissue following clinical resistance has helped define mechanisms of secondary resistance to these targeted agents, often in the very pathway or gene that defined their responsiveness. So it seems obvious, if not mandatory, that all drug development should require pre- and post-treatment biopsies to ascertain the molecular genotype to guide the therapeutic phenotype.Drawbacks of the biopsy approachAs with many things in translational medicine, several barriers exist to bridging the bench to the bedside. In terms of tissue acquisition, there are four major barriers that require real consideration. The first two relate to clinical topics, physician and patient opposition, and procedural toxicity. When samples are available from a cancer surgery, the availability of tissue is not an issue. However, biopsies as part of a clinical trial are complicated by physician and patient reluctance, especially since these biopsies will often not influence the outcome of the patient at hand. Biopsies are an inconvenience from a scheduling perspective, increase the cost of patient care, and are another uncomfortable, invasive procedure for patients. Furthermore, biopsies are not without complications. A recent review of the investigative biopsy experience at the MD Anderson Cancer Center, by Overman et al., reported a complication rate for thoracic biopsies of 17.1% and 1.6% for abdominal/pelvic sampling.1There are also technical barriers to tissue acquisition that require discussion: sample characteristics and tumor heterogeneity. Following a biopsy, the majority of tumor tissue is preserved in formalin-fixed paraffin-embedded blocks (FFPE), which crosslinks DNA to the point that a large fraction of archived FFPE samples have been reported to be inadequate for molecular analysis,2 which is why freezing is the ideal choice for preserving tumor tissue. In each of these blocks of tumor tissue, the amount of tumor is dependent on the tumor cellularity (% tumor) and the size of the section of tumor. Some tumors have a high percentage of tumor cellularity (colon cancer, sarcomas, renal cell carcinomas) while other tumors have poor tumor cellularity because of necrotic tissue or stromal contamination (pancreatic cancer, glioblastoma). This is further compounded by low tissue amounts present from fine-needle aspirates and core needle biopsies, which provide a very small amount of tumor tissue for analysis in comparison to surgically resected tumors.Tumor heterogeneity also proves to be problematic. Tumors themselves are heterogeneous, with different areas of the same tumor showing different genetic profiles (intratumoral heterogeneity); likewise, heterogeneity exists between metastases within the same patient (intermetastatic heterogeneity). A biopsy or tissue section from one part of a solitary tumor will miss the molecular intratumoral as well as intermetastatic heterogeneity. Taken together, the quality of the molecular information derived from any biopsy depends on how well the sample accounts for tumor cellularity, method of preservation, molecular and tissue heterogeneity, and quantity of tissue available for analysis.Despite these limitations, tissue remains the “gold standard” for molecular analyses largely because of the abundance of tumor material in a sample and the clonal nature of cancer, where the key driver mutations are consistent even in multiple subclones throughout tumors and their metastases.Novel approachesRecent developments in digital genomics have resulted in the emergence of novel approaches that may be able to circumvent the issues with tissue biopsies for personalized therapy. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) can provide the same genetic information available in a tissue biopsy necessary to interrogate key companion diagnostics, and accessing the blood stream has clear advantages. For one, both of these are sources of fresh DNA, unhampered by preservatives. Sampling the blood from a needle stick is virtually noninvasive and therefore avoids the dangers of biopsies. Furthermore, blood can be drawn at any time during the course of therapy and allow for dynamic monitoring of molecular changes in the tumor rather than relying on a static time point.What molecular information can be derived from CTCs and ctDNA? CTCs are shed from the tumor(s) into the circulation, and single-cell analysis of CTCs has demonstrated the potential of evaluating DNA and RNA for mutations, rearrangements, and expression changes. These analyses are still investigational tools but will likely be available for clinical use in the near future.ctDNA are small fragments of DNA released into the circulation during tumor cell turnover. This is a normal homeostatic process for most tumors and virtually all advanced cancers shed detectible levels of ctDNA in the blood.3 These fragments are identified by the mutations present within them. In other words, these fragments are components of the cancer’s genome and therefore contain the same genetic defects as the tumor or tumors themselves. These defects span the types of genomic alterations identified in tumor and include point mutations (KRAS),4 rearrangements,5 amplifications (HER2), and even aneuploidy.6 Moreover, interrogating plasma from patients can account for molecular heterogeneity since the circulation is a collecting pool for ctDNA fragments from all of the tumors in a patient’s body.7The evaluation of CTCs and ctDNA for genetic alterations present in the tumor tissue are, in reality, a liquid biopsy. The purpose of this test will be to identify the molecular profile of a tumor through a simple blood collection. While much of the current data for CTCs and ctDNA are investigational, the sensitivity of these liquid biopsies for patients with stage IV disease, at least for ctDNA, appears to be approaching > 99%.3,7 Future studies will determine the viability of these tests for clinical use, but at this point they do provide an alternative to tissue biopsies and are an option, especially in clinical trials, for serial collections for determinations of molecular resistance or genotyping for eligibility in a clinical trial.Dr. Diaz is an Associate Professor of Oncology at Johns Hopkins. He is a member of ASCO’s Scientific Program Committee in the Developmental Therapeutics—Experimental Therapeutics Track.ReferencesOverman MJ, Modak J, Kopetz S, et al. J Clin Oncol. 2013;31:17-22. PMID: 23129736.Tol J, Koopman M, Cats A, et al. N Engl J Med. 2009;360:563-72. PMID: 19196673. Diehl F, Schmidt K, Choti MA, et al. Nat Med. 2008;14:985-90. PMID: 18670422. Holdhoff M, Schmidt K, Donehower R, et al. J Natl Cancer Inst. 2009;101:1284-5. PMID: 19641175. Leary RJ, Kinde I, Diehl F, et al. Sci Transl Med. 2010;2:20ra14. PMID: 20371490. Leary RJ, Sausen M, Kinde I, et al. Sci Transl Med. 2012;4:162ra154. PMID: 23197571. Diaz LA Jr, Williams RT, Wu J, et al. Nature. 2012;486:537-40. PMID: 22722843.The views and opinions expressed in Current Controversies in Oncology are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. virginia.anderson Mon, 22 Apr 2013 18:46:29 GMT f1397696-738c-4295-afcd-943feb885714:3520 http://connection.asco.org/Magazine/Article/ID/3444/Intraoperative-Radiation-Therapy-IORT-for-Early-Stage-Breast-Cancer.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3444 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3444&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3444/Intraoperative-Radiation-Therapy-IORT-for-Early-Stage-Breast-Cancer.aspx Introduction By Hope S. Rugo, MD University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center Can we forgo whole-breast radiation in women with very early-stage breast cancer? This question has been addressed with two major research approaches. First is the question of whether we could identify a group of patients who could entirely forgo radiation due to very low risk of local recurrence. Indeed, recent data has demonstrated that older women with hormone receptor–positive breast cancer, taking hormone therapy, and with clear surgical margins have similar survival to women who added whole-breast radiation to their treatment plan, although there was a small increase in the risk of local recurrence. The second question is whether we can limit the extent of radiation, and therefore shorten the treatment time and reduce exposure of normal tissue. In this article, two experts debate the use of intraoperative radiation therapy (IORT), discussing both the risks and merits of this approach. While Dr. Benjamin Smith feels that the data are encouraging but still immature, Dr. Michael Alvarado feels that there is ample evidence that, in carefully selected patients, IORT should be offered as an alternative to standard radiation. This interesting question is of great importance to our patients, who could avoid five weeks of daily radiation with its associated time commitment and toxicity, but clearly remains controversial. Learning to do less rather than more, when more has been the standard, is always a greater challenge than learning to do more. This seems counterintuitive, but we tend to believe that the current standard is the best and are often reluctant to believe that in some settings, less is equally effective. Of course, a rigorous approach to studying this question and solid data is necessary. Read on, and see what you think! Dr. Rugo is a Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. She serves on the ASCO Connection Editorial Board and is an Associate Editor for Cancer.Net, ASCO’s patient information website. IORT: More Convenient, Comparably Effective By Michael D. Alvarado, MD University of California, San Francisco Helen Diller Family Comprehensive Cancer Center Local control of early-stage breast cancer has improved dramatically as a result of less-invasive surgical strategies that combine breast-conserving surgery (BCS) followed by whole-breast external beam radiation (WB-EBRT).1,2 Nonetheless, 21% of North American women who undergo BCS do not complete the recommended radiation therapy, partially because of cost and inconvenience.3 Researchers have continued searching for opportunities to improve effectiveness and patient tolerability of both surgical and radiation interventions. Accelerated shortened courses of radiation may provide a solution for ensuring that women complete breast irradiation by offering a more convenient and comparably effective alternative. Numerous observational studies, as well as randomized trials, have demonstrated that local recurrence in the conserved breast is confined to the index quadrant more than 90% of the time. Therefore, targeting the local tumor bed with focused radiotherapy may be sufficient in a majority of early-stage breast cancers. The recently developed technique of intraoperative radiation therapy (IORT) delivered at the time of BCS has shown promising results as a form of partial-breast irradiation. TARGIT-A trial This technique has been tested in more than 3,000 patients in the TARGIT-A trial, an international randomized controlled trial, and in close to 2,000 patients in the ELIOT trial.4,5 Utilizing intraoperative radiotherapy with electrons (ELIOT), Veronesi et al. reported outcomes for 1,822 patients who underwent BCS and IORT. At 36 months mean follow-up, the local recurrence was 2.3%, while local toxicity for liponecrosis and fibrosis was 4.2% and 1.8%, respectively. Vaidya et al. published initial results from the TARGIT trial for 2,232 patients randomly assigned to either standard external beam radiation or intraoperative radiation with the Intrabeam device, which utilizes soft x-rays. At four years, the local recurrence for both arms was statistically equivalent (0.95% vs. 1.2% respectively). The frequency of any complications or local toxicity was similar in both arms. Of course, longer follow-up is needed to confirm these initial results, keeping in mind that even in the event of a slightly higher local recurrence in the IORT arms, they would not be considered negative trials. TARGIT-A accrued 2,000 patients exponentially in years five to 10—1,200 in the last two—which explains the median follow-up. Follow-up was available for 99% of patients. The trial was overpowered (585 needed for noninferiority), therefore, four-year results are available.6 Phase II studies utilized the 20 Gy dose as a boost.7 Shared decision-making Allowing patients to choose between two non-equivalent therapeutic options is common practice in breast cancer treatment. In this setting, patients are often making trade-offs between risk of recurrence and quality of life.8 When making a decision between mastectomy and BCS, women are concerned about the risk of recurrence, the need for radiation, and side effects from radiation.9 These factors lead some women to choose mastectomy over BCS followed by conventional WB-EBRT. If BCS is offered with IORT, women may choose BCS over mastectomy, preferring the convenience and reduced side effects of IORT even if it meant a slightly higher risk for local recurrence. When considering what treatment options should be offered as the field moves forward, the preferences of the patients, who are key stakeholders, should be taken into consideration. These preferences, in addition to clinical trial data and resource considerations, should drive health care innovation. IORT trials are demonstrating that less-aggressive interventions are effective for women with lower-risk tumors. This is a significant achievement for women and much-needed progress in the ability to tailor treatments for women with early-stage breast cancer. If we can safely accomplish the same outcome in a more efficient, more convenient, and less invasive manner, the medical community should be the first to consider early adoption of this new technique. Dr. Alvarado is an Associate Professor of Surgery at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. References 1. Clarke M, Collins R, Darby S, et al. Lancet. 2005;366:2087-106. PMID: 16360786. 2. Darby S, McGale P, Correa C, et al. Lancet. 2011;378:1707-16. PMID: 22019144. 3. Tuttle TM, Jarosek S, Habermann EB, et al. Cancer. 2012;118:2004-13. PMID: 21952948. 4. Vaidya JS, Joseph DJ, Tobias JS, et al. Lancet. 2010;376:91-102. PMID: 20570343. 5. Veronesi U, Orecchia R, Luini A, et al. Breast Cancer Res Treat. 2010;124:141-51. PMID: 20711810. 6. Armitage P, Berry G. Statistical Methods in Medical Research, Third Edition. 1994. 7. Vaidya JS, Baum M, Tobias JS, et al. Int J Radiat Oncol Biol Phys. 2011;81:1091-7. PMID: 20951505. 8. Alvarado M, Connolly J, Oboite M, et al. Patient preference for choosing intra-operative or external-beam radiotherapy following breast conservation. Eur Cancer J Suppl. 2010;8:126-7. 9. Katz SJ, Lantz PM, Janz NK, et al. J Clin Oncol. 2005;23:5526-33. PMID: 16110013. IORT: More Evidence Required By Benjamin D. Smith, MD The University of Texas MD Anderson Cancer Center Intraoperative radiation therapy (IORT) for breast cancer represents the ultimate in patient convenience and, understandably, has generated considerable enthusiasm. To date, however, the only published, randomized trial to evaluate IORT is the Targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer (TARGIT-A) trial.1 This ambitious, international effort enrolled more than 2,000 patients who were randomly assigned to IORT followed by selective whole-breast irradiation compared to standard whole-breast irradiation. The cumulative incidence of in-breast tumor recurrence at four years was 1.2% in patients who received intraoperative radiation and 0.95% in patients who received only standard whole-breast irradiation (p = 0.41). At first read, these results appear to strongly support the use of IORT. Questions remain This trial began on March 24, 2000, the data were locked for analysis on May 2, 2010, and the results were published shortly thereafter on July 10, 2010. Strangely, for a trial of this magnitude, the median follow-up was not specified in the abstract or text. However, one can deduce from the published table (Table 6 in Vaidya JS et al.1) that the median follow-up for the overall cohort at the time of data lock was 25.3 months. A back-of-the-envelope calculation reveals that, if accrual were relatively evenly distributed over the decade during which this trial was open, then median follow-up for the study cohort should be about five years, rather than two years as reported. Even if accrual was skewed toward later years, it is difficult to simulate a scenario in which a trial that is accruing patients over a decade could have a median follow-up of just two years. This issue raises a concern that many patients enrolled on this study could have been lost to follow-up after two years of treatment, but this issue is not discussed by the study authors. If many patients on a trial were lost to follow-up, this would generate additional uncertainty regarding the true outcome experienced by the average patient, especially if loss to follow-up is due to the patient having an oncologic event. In the face of uncertainties regarding follow-up from a phase III study, review of the long-term results of the phase II study that preceded the phase III study can be illuminating. However, uniquely in the case of TARGIT-A, the authors embarked on the phase III trial without any phase II data demonstrating the safety and oncologic outcomes of IORT as a sole radiation treatment modality. These shortcomings—unusually short follow-up and lack of applicable phase II data—provoke uncertainty regarding the conclusion endorsed by the TARGIT-A authors that “intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks.” Review of other experiences with IORT In light of the limitations of the TARGIT-A trial, review of other experiences with IORT can be enlightening. The European Institute of Oncology has conducted a large, prospective randomized trial of IORT with electrons (ELIOT) compared to standard whole-breast radiation. While not yet published, results presented in May 2012 at the Groupe Européen de Curiethérapie and the European Society for Radiotherapy (GEC-ESTRO) Meeting in Spain indicated that patients randomly assigned to ELIOT experienced a significantly increased risk of in-breast tumor recurrence.2 No randomized trials evaluating IORT have been conducted in the United States. Memorial Sloan-Kettering Cancer Center has reported a phase II experience with IORT that resulted in a five-year in-breast tumor recurrence risk of 7.7%,3 which is higher than recently reported results with standard whole-breast radiation.4 Long-term results from a University of North Carolina (UNC) phase II trial are awaited, although short-term results are already concerning for excess risk of in-breast tumor recurrence.5 Given these lingering uncertainties about the TARGIT-A results, coupled with potentially unfavorable outcomes in the ELIOT trial and modest control rates in the Memorial and UNC experiences, it is my opinion that IORT remains best confined to the investigational setting. Dr. Smith is an Assistant Professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center. He currently serves on the Journal of Clinical Oncology Editorial Board and is a past recipient of the Conquer Cancer Foundation of the American Society of Clinical Oncology’s Career Development Award. References 1. Vaidya JS, Joseph DJ, Tobias JS, et al. Lancet. 2010;376:91-102. PMID: 20570343. 2. Orecchia R. ELIOT trials in Milan: results. Radiother Oncol. 2012;103(Suppl 2):S4 (Abstract 10). 3. Beal K, Sacchini V, Zelefsky M, et al. 5 year update on intraoperative radiation therapy for breast cancer. Int J Radiat Oncol Biol Phys Suppl to Annual Meeting. 2011:S241-S242 (Abstract 2061). 4. Arvold ND, Taghian AG, Niemierko A, et al. J Clin Oncol. 2011;29:3885-91. PMID: 21900114. 5. Kimple RJ, Klauber-DeMore N, Kuzmiak CM, et al. Ann Surg Oncol. 2011;18:939-45. PMID: 21061074. ascoadmin Tue, 26 Feb 2013 01:08:34 GMT f1397696-738c-4295-afcd-943feb885714:3444 http://connection.asco.org/Magazine/Article/ID/3404/Surgical-Margins-for-Breast-Cancer.aspx#Comments 2 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3404 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3404&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3404/Surgical-Margins-for-Breast-Cancer.aspx Experts debate how to achieve both clear margins and the best cosmesis Introduction Anees B. Chagpar, MD, MSc, MA, MPH, FACS, FRCS(C) Breast Center—Smilow Cancer Hospital at Yale-New Haven and Yale University School of Medicine In a past column on ASCOconnection.org, I talked about a debate that had occurred in our tumor board in which a patient had a margin <1 mm from ink. While “technically negative,” it was a little too close for comfort for me; the surgeon whose case it was, however, argued based on evidence from the NSABP B-06 trial that if a tumor did not touch ink, outcomes were equivalent to the alternative of mastectomy—at least for survival. It brought up how we interpret data—and the difference between what we know and what we think we know; or as the comedian Stephen Colbert would put it, between “truth” and “truthiness.” We like to think that what we do is “evidence-based,” but we can almost always find data to support any position we wish to take. My two good friends, Dr. Mel Silverstein and Dr. Mike Dixon, have duked out the margins debate in many public forums and settle the score here once and for all. Here is what we know for sure: (1) obtaining negative margins reduces local recurrence rates; (2) there is no consensus on what constitutes an adequate negative margin (although many would be happy with >1 mm); (3) radiation therapy continues to play a role in breast-conserving surgery (although there may be exceptions in tiny areas of estrogen receptor-positive ductal carcinoma in situ excised with widely clear margins); (4) there are ways to take out large segments of breast tissue without compromising cosmesis (although taking out less may yield excellent cosmetic outcomes without needing a contralateral symmetry procedure); and finally, (5) for the record, Mel is not a Republican (not that it matters). Dr. Chagpar is Director of the Breast Center at Smilow Cancer Hospital, Assistant Director for Diversity and Health Equity at Yale Comprehensive Cancer Center, Program Director of the Yale Interdisciplinary Breast Fellowship, and an Associate Professor in the Department of Surgery at Yale University School of Medicine. She currently serves on ASCO’s International Affairs Committee and is a columnist for ASCOconnection.org. Less Is More J. Michael Dixon, BSc, MBChB, MD, FRCS, FRCS(Ed), FRCP(Hon) Western General Hospital Edinburgh More than 20 years after randomized trials demonstrated that breast-conserving surgery followed by post-operative radiotherapy has the same outcome as mastectomy, there still remains controversy as to how much of the breast should be excised when performing breast-conserving surgery. The aim of breast-conserving surgery is to excise the cancer to clear margins.1,2 The controversy surrounds what constitutes a clear margin. The margin width is the distance from the cancer to the ink painted on the surface of the excision specimen. In surveys of surgeons and radiation oncologists, no one margin width was endorsed by more than 50% of respondents.3-5 Thus, there is no consensus, and one consequence of this is that given a distance to the nearest margin of 1 mm, some surgeons and oncologists will accept this whereas others advise re-excision to achieve a wider margin. A major problem in the published literature is that there are large numbers of single-center series that have all used different margin widths to define what constitutes complete excision.6 This allows any individual surgeon to quote a paper that supports his or her personal view. The first review of surgical margins was conducted by Eva Singletary, MD, and published in the American Journal of Surgery in 2002.7 What Dr. Singletary established was that leaving disease at margins was unacceptable and significantly increased local recurrence rates. She established that wider margins did not reduce local recurrence rates and concluded that some of the best local recurrence rates were in series that had used a 1- to 2-mm margin width. This was endorsed by a more recent comprehensive review and meta-analysis of 21 retrospective studies.8 This analysis included 14,571 patients with breast cancer and demonstrated that a positive margin was associated with an odds ratio for local recurrence of 2.42. If the margin width was <1 mm this increased local recurrence by 1.8 times. There was, however, no statistical difference in local recurrence rates associated when comparing margin widths of >1 mm, >2 mm, and >5 mm when studies were adjusted for the use of radiation boost and endocrine therapy. The finding of this comprehensive meta-analysis was that a 1-mm negative margin is as good as a wider margin if patients receive optimal adjuvant therapy. The conclusion was that there is no justification for demanding margins greater than 1 mm. Some have found difficulty in believing that recurrence rates are not reduced when margins are wider. This is in part because detailed whole-breast studies have shown disease extending 2 to 3 cm from the edge of the primary cancer.9 What a “clear 1-mm margin” indicates is not that there is no residual disease in the breast, but that any residual tumor burden is low and will be controlled with radiotherapy. Although mastectomy is offered to many patients, and patients choose it in the belief that this reduces local recurrence rates, mastectomy does not eliminate local recurrence. Randomized trials comparing mastectomy alone with breast-conserving surgery and radiotherapy have in fact shown similar local recurrence rates with both breast-conserving surgery followed by radiotherapy and mastectomy.10 Systemic treatment reduces local recurrence The rates of local recurrence after breast-conserving surgery continue to fall.8 In NSABP B-06, the 20-year recurrence rate was 14.3%,1 whereas the NSABP trials conducted in the 1990s showed 10-year local recurrence rates ranging between 3.5% to 6.5%.11 One of the major reasons for this is that systemic treatment reduces local recurrence significantly. In-breast recurrence was reduced in NSABP B-14 from 14.7% in the placebo group to 4.3% in patients receiving tamoxifen,12 and in NSABP B-13, which included patients with ER-negative tumors, there was a 10-year recurrence rate of 13.4% in the no-treatment group compared with 2.6% in patients receiving chemotherapy.13 Studies from Edinburgh in more than 1,300 patients have confirmed that local recurrence rates do not fall with increasing margin width. In breast tumors, recurrence rates also did not increase when front and back margins were less than 1 mm, provided that full thickness of breast tissue was taken and radiotherapy boost was delivered. There were in fact no local recurrences at five years in patients who had a positive deep margin even though pectoral fascia was not removed routinely. Importance of cosmetic outcome It is important to limit the amount of breast tissue removed during breast-conserving surgery because the single most important factor affecting cosmetic outcome is the volume of breast tissue removed.14 Wider excisions remove more tissue and so produce significantly poorer cosmetic outcomes. There is a direct correlation between cosmetic outcome and psychological well-being—anxiety and depression scores, body image, sexuality, and self-esteem are reported as being significantly better in patients with excellent or very good cosmetic results; only patients who get a good cosmetic outcome gain the full benefits of breast-conserving surgery.15 The evidence shows that wider margins have no benefit in breast-conserving surgery. Wider margins have an adverse effect on the cosmetic outcome. Surgeons must abandon their obsession with wide margins and accept 1 mm as sufficient. Such a change will reduce health care costs, reduce the number of women having re-excisions, improve cosmetic outcomes, and thus significantly benefit patients. Dr. Dixon is a Professor of Breast Surgery and Consultant Surgeon, Edinburgh Breast Unit, Western General Hospital Edinburgh, UK. He currently serves on the editorial boards of Breast Cancer Management and Annals of Surgical Oncology and is Co-Chair of the Miami Breast Cancer Conference. References Fisher B, Anderson S, Bryant J, et al. N Engl J Med. 2002;347:1233-41. PMID: 12393820. Veronesi U, Cascinelli N, Mariani L, et al. N Engl J Med. 2002;347:1227-32. PMID: 12393819. Vallasiadou K, Young OE, Dixon JM. Br J Surg. 2003;90:44. Azu M, Abrahamse P, Katz SJ, et al. Ann Surg Oncol. 2010;17:558-63. PMID: 19847566. Taghian A, Mohiuddin M, Jagsi R, et al. Ann Surg. 2005;241:629-39. PMID: 15798465. Morrow M, Harris JR, Schnitt SJ. N Engl J Med. 2012; 367:79-82. PMID: 22762325. Singletary SE. Am J Surg. 2002;184: 383-93. PMID: 12433599. Houssami N, Macaskill P, Marinovich ML, et al. Eur J Cancer. 2010;46:3219-32. PMID: 20817513. Holland R, Veling SH, Mravunac M, et al. Cancer. 1985;56:979-90. PMID: 2990668. Morris AD, Morris RD, Wilson JF, et al. Cancer J Sci Am. 1997;3:6-12. PMID: 9072310. Anderson SJ, Wapnir I, Dignam JJ, et al. J Clin Oncol. 2009;27:2466-73. PMID: 19349544. Fisher B, Dignam J, Bryant J, et al. J Natl Cancer Inst. 1996;88:1529-42. PMID: 8901851. Fisher B, Dignam J, Mamounas EP, et al. J Clin Oncol. 1996;14:1982-92. PMID: 8683228. Dixon JM. “Breast-conserving surgery: the balance between good cosmesis and local control,” in A Companion to Specialist Surgical Practice: Breast Surgery. Ed. Dixon JM. Edinburgh: Elsevier, 2009. Al-Ghazal SK, Blamey RW. Breast. 1999;8:162-8. PMID: 14731434. More Is Better Melvin J. Silverstein, MD Hoag Memorial Hospital Presbyterian; Keck School of Medicine, University of Southern California In 1999, my colleagues and I published a paper in the New England Journal of Medicine showing that patients with ductal carcinoma in situ (DCIS) treated by excision alone had a very low local recurrence rate (about 5% at 10 years), if clear margins of 10 mm or more were achieved.1 Following that paper and the presentation of those data at numerous meetings, word spread that I no longer used radiation therapy (even for invasive cancer), that I required 10-mm margins for all cases or I returned to the operating room for re-excision or mastectomy, and that I voted Republican. None of those were true. But somehow, erroneously, I became the guru for 10-mm margins without breast irradiation for all patients with breast cancer, both noninvasive and invasive. So, let me set the record straight. I always recommend breast irradiation for patients with invasive cancer receiving breast-conserving therapy and for about half of my patients with DCIS. The exception, which follows NCCN guidelines,2 are patients with DCIS with small, well-excised, low-grade lesions (low University of Southern California/Van Nuys Prognostic Index scores).3-5 Moreover, I routinely accept 1 mm as a clear margin, and I do not require re-excision, if radiation therapy is going to be used. While I intuitively prefer wider margins, I’m willing to accept narrow but clear margins. With that said, can I prove that wider margins are better? I admit that in 2001, while giving the Keynote Lecture at the American Society of Breast Surgeons Annual Meeting, I did say, “Margins are like money. More is better.” I still feel that way, but Mike Dixon is right. I cannot prove that 2 mm is better than 1 mm, nor that 3 mm is better than 2 mm. I cannot prove an incremental benefit because the precise measurement of margin width was not common until recently, and the prospective, level I evidence that would be required to prove an incremental benefit simply does not exist. Nevertheless, wider margins make sense, and most surgeons and radiation oncologists would prefer a wider margin, if there were no cosmetic cost. For patients with DCIS treated with excision alone (no radiation therapy), wider margins correlate with less residual disease and a lower local recurrence rate.6-8 Those benefits may not be so apparent for patients with invasive cancer because the value of wider surgical margins is blunted by both radiation therapy and the addition of other adjuvant treatments. I do not want wider margins at significant cosmetic cost. What I do want is wider margins and better cosmesis. I want both. In support of that, and dating back to the 1980s and the Van Nuys Breast Center, I have always been a champion of oncoplastic breast conservation. I have always trained residents and breast fellows to believe that the appearance of the breast after breast preservation is important and that it should be equal or better than before the initial excision, if possible. Gains from wider excisions In an attempt to understand what is gained by wider excision, my colleagues and I recently analyzed 100 consecutive excisions using a simple ellipse and compared those cases with 100 consecutive excisions using an oncologically designed reduction mammoplasty, in which a larger amount of tissue could be removed while achieving a better cosmetic result.9 The data are outlined in the Table below: In this series, when compared with a conventional elliptical excision, oncoplastic reduction routinely produced larger specimens, wider margins, a lower percentage of close or transected margins, and a lower re-excision rate. Oncoplastic reduction achieved all these benefits while routinely producing better cosmetic results. When wider margins = better cosmesis   Fig. 1: Preoperative (L); Two years postoperative (R): A patient with a large upper central left breast carcinoma treated with neoadjuvant chemotherapy and wide segmental resection, using a split reduction excision, followed by radiation therapy. Complete excision with wide margins as well as excellent cosmesis were achieved. Figure 1 shows a woman with a large upper central left breast cancer. She would have been deformed with a standard excision, or, more likely, she would have been treated with a mastectomy and her reconstruction compromised by post-mastectomy radiation therapy. The use of neoadjuvant chemotherapy followed by an oncoplastic split reduction excision and radiation therapy yielded widely clear margins and a far superior cosmetic result (a win-win: wider margins and better cosmesis). Her long-term survival will be equivalent to standard lumpectomy or mastectomy, and she will be a far happier patient. A reduction excision offers additional benefits. When clear margins are achieved during the first operative procedure, re-excision or conversion to mastectomy is eliminated, resulting in substantial cost savings and the elimination of the additional psychic trauma of a second procedure. The removal of excess breast tissue from the contralateral breast, while achieving symmetry, also appears to lower the overall risk of a future contralateral breast cancer.10,11 I cannot prove to you that wider excision leads to a lower local recurrence rate when radiation therapy and modern adjuvant treatment is given, although I believe that it does, in a small fraction of patients; but it clearly leads to fewer re-excisions and fewer mastectomies. However, if wider excisions affect your cosmetic results negatively, then I agree, you should not be doing wider excisions. Perhaps you should not be doing breast surgery. After all, it is 2013. Dr. Silverstein is Director of the Hoag Breast Program at Hoag Memorial Hospital Presbyterian, and Clinical Professor of Surgery at the Keck School of Medicine, University of Southern California. He has served on ASCO’s Scientific Program Committee. References Silverstein MJ, Lagios M, Groshen S, et al. New Engl J Med. 1999;340:1455-61. PMID: 10320383. Carlson RW, Allred DC, Anderson BO, et al. NCCN Clincal Practice Guidelines in Oncology: Breast Cancer. 2008; nccn.org. Silverstein MJ. Am J Surg. 2003;186:337-43. PMID: 14553846. Silverstein MJ, Buchanan C. Breast. 2003;12:457-71. PMID: 14659122. Silverstein MJ, Lagios M. J Natl Cancer Inst Monogr. 2010;41:193-96. PMID: 20956828. Silverstein M. Women’s Health. 2008;4: 565-77. PMID: 19072459. Silverstein MJ. “Margin width as the sole predictor of local recurrence in patients with ductal carcinoma in situ of the breast,” in Silverstein MJ, Recht A, Lagios M, eds. Ductal Carcinoma in Situ of the Breast. 2nd ed. Philadelphia: Lippincott, Williams and Wilkins; 2002. Silverstein MJ, Lagios M, Lewinsky B, et al. Breast Cancer Res Treat. 1997;46:23. Kopkash K, Savalia N, Silverstein MJ. A Comparison of Breast Conservation Methods: Ellipse Verses Reduction Excision. Submitted American Society of Breast Surgeons Annual Meeting 2013. Boice J, Persson I, Brinton L, et al. Plast Reconst Surg. 2000;106:755-62. PMID: 11007385. Brinton L, Persson I, Boice J, et al. Cancer. 2001;91:478-83. PMID: 11169929. The views and opinions expressed in Current Controversies in Oncology are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. ascoadmin Thu, 20 Dec 2012 19:30:57 GMT f1397696-738c-4295-afcd-943feb885714:3404 http://connection.asco.org/Magazine/Article/ID/3355/Clinical-Trials-Predictive-Factors-and-Endpoints-Current-and-Future-Challenges.aspx#Comments 3 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3355 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3355&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3355/Clinical-Trials-Predictive-Factors-and-Endpoints-Current-and-Future-Challenges.aspx Introduction Hope S. Rugo, MD University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center In the article that follows, Dr. Anthony Provenzano discusses some of the more challenging problems facing clinical research in this decade. An overarching theme is the inexact process of drug evaluation and approval, which is closely associated with a lack of predictive factors that would help truly individualize cancer care. Indeed, recent and ongoing studies have highlighted the importance of treatment in the neoadjuvant setting as a pathway to drug approval, a concept now embraced by regulatory agencies. Using a backbone of standard chemotherapy for breast cancer, the ISPY2 multicenter trial is testing the addition of a series of novel agents to paclitaxel with serial biopsies and assessment of pathologic response at the time of surgery. This approach offers the potential to determine predictive biomarkers in real time, without starting with predetermined single (and therefore more limited) markers. ISPY2 is the largest of many trials utilizing this general approach and has taken the novel approach of partnering with pharmaceutical companies through the Foundation of the National Institute of Health. Along with new and hopefully more efficient mechanisms of evaluating novel therapeutics, it is critical to involve the patient as a partner in decision making and provide the tools to navigate increasingly complex therapeutic options. Each treatment decision is associated with toxicity and cost; goals of therapy need to be clearly defined as each new therapy adds complexity to therapy. Indeed, we need to hold drug development to a high standard, including an assessment of efficacy that is meaningful to those suffering from the disease under study, and a careful and prioritized exploration for predictive biomarkers. Looking forward, it does indeed appear that oncology requires more of a Renaissance approach—the simple country doctor just won’t do. Dr. Rugo is a Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. She serves on the ASCO Connection Editorial Board and is an Associate Editor for Cancer.Net, ASCO’s patient information website. The Cross Roads of Clinical Trials, The Promise of Personalized Medicine, and Surrogate Endpoints: “To Boldly Go Where No Man Has Gone Before...”Anthony F. Provenzano, MDLawrence Medical Associates, P.C., Lawrence Hospital Center We are at the crossroads where the clinical trial process, the promise of personalized medicine, and surrogate endpoints (perceived clinical benefit) have finally intersected. All three must be reconciled so they can be translated into true clinical benefit. Furthermore, these algorithms must coexist within an economic environment that will allow for the continual and efficient allocation of research funding. These goals can be further realized through the strategic collaboration of scientific cross-disciplines, such as biomedical engineering, computer science, physics, and other scientific disciplines that have contributed recently to improvements in diagnosis and treatment of cancer.1 Clinical trial process Only one in every 10 new molecular therapeutic agents that enters clinical development receives U.S. FDA approval.2 Phase I/II/III models have been used to test drugs commonly in the metastatic setting before they are used in operable disease. In the era of personalized medicine, we may need criteria other than Response Evaluation Criteria in Solid Tumors (RECIST) to assess true drug benefit in both the primary (neoadjuvant and adjuvant) and metastatic setting. In the preoperative setting, the use of phase 0 (window of opportunity) trials can help to facilitate the drug development process and help target select patients in subsequent clinical trials.3 We are still left with the problem of how best to validate markers and assess response criteria in an integrated fashion. This is where the aforementioned collaborative approach could expedite the process, perhaps with the aid of complex computer models that could predict how these different parameters should be weighted. The promise of personalized medicine Marker identification and response do not guarantee true clinical benefit, even though RECIST criteria may be losing ground to other surrogates such as metabolic imaging. Nonetheless, the holy grail of drug assessment will be the discovery of a valid subset of markers at each stage of tumor “evolution” whose phase 0 response to a cocktail of drugs will be not only predictive but prognostic. We are not even remotely close to this realization (except, of course, in Star Trek reruns with Mr. Spock and Dr. McCoy in command). Surrogate endpoints A surrogate endpoint can be either an intermediate clinical endpoint or a biomarker.4 Two conditions must be fulfilled to qualify as an intermediate endpoint: strong association between the surrogate and true endpoint from a patient perspective, and hazard ratios of the effect of treatment on the surrogate and true endpoint must be comparable. As oncologists, we must be able to translate for our patients the meaning of true clinical benefit as a balance between patient- and tumor-centered outcomes.5 Overall survival (OS) and quality of life (QOL) are endpoints suitable for patients with either early or advanced disease. Progression-free survival (PFS) and time to progression (TTP) are endpoints used for patients with advanced disease. PFS measures the time from a patient’s random assignment to a treatment until either the disease progresses or the patient dies from his or her cancer. OS is the time from random assignment to death from any cause. PFS measures the effect of only one drug until disease progression. OS is diluted by subsequent treatments. PFS captures tumor shrinkage or stabilization. Surrogate endpoints bring ambiguity. Statisticians, for instance, censor deaths when calculating TTP but count them as events for PFS. In addition, some investigators use these two surrogates interchangeably when they are clearly different. Progression-free survival, examined We measure PFS by new lesions, increased size of the target measurable lesions by RECIST, clear increase in nontarget disease, and increase in signs or symptoms of disease without quantitative change in measurements. The advantages of PFS as an endpoint are shorter duration of studies, the effect of only the study drug is measured, subsequent treatment has less effect on the outcome, and it is advantageous for phase II studies. The disadvantages are more measurement errors, the frequency of assessments may introduce bias, and it is more difficult to measure or reproduce measurements.5 PFS is defined as time to first progression or death from any cause if disease progression did not occur, and cannot evaluate treatment strategy beyond first progression.4 Few studies have found associations between PFS and QOL.6-8 Panitumumab in metastatic colorectal cancer and sunitinib in metastatic renal cell carcinoma are two of them. Initial approval and later revocation by the FDA of bevacizumab in the treatment of metastatic breast cancer were based upon smaller increase in PFS and a higher incidence of adverse events without improvement in OS or QOL.9,10 Is the increased PFS with maintenance bevacizumab in ovarian cancer worth it, since patients are asymptomatic and being followed with serial CTs and CA125s?11 What if the duration of therapy is so long to achieve that small PFS benefit but is associated with a longer period of side effects?12 When is watchful waiting better than maintenance therapy?13 Patients are fearful of watchful waiting but, on the other hand, do we really spend enough time learning from patient-reported outcomes?14 We know that PFS is a surrogate for OS in metastatic colorectal cancer but not for many other cancers.15 Insurers know this as well. Will economic issues drive not only the approval process but also the discontinuation process for expensive drugs? Future considerations PFS is subjective, and other biologic surrogates not confounded by how progression is defined and measured are needed.16 During stable disease, for example, how does the tumor microenvironment change and what effect do stem cells have on this complex entity we call “stable disease”? These interactions with “measurable” disease are not assessed by RECIST. We should probably coin a new acronym: TWOTRT (time without treatment-related toxicity). Intraperitoneal (IP) chemotherapy for ovarian cancer does not lead to significant increase in PFS or OS, and yet neurotoxicity can last for more than 12 months beyond the end of treatment.17 When patients are asked about acceptable minimal survival benefits, 46% reported greater than 12 months, 17% reported 10 to 12 months, and 10% reported 1 to 2 months.18 How can we improve the correlation of true clinical benefit with our perceived notions of benefit based upon surrogacy? We need ways to better predict projected life span before a diagnosis of cancer is made. We need better ways to predict noncancer-related mortality after a diagnosis of cancer is made. We need better ways to standardize QOL assessments before and after diagnosis. New surrogate endpoints are required in the rapidly changing world of genomic (personalized) medicine—even though we are far from realizing that Spockian achievement. Embedded in surrogates such as PFS and OS are inherent biologic variables that defy a way to achieve accurate measurements. A new collaboration with basic and applied science across disciplines is necessary to expedite the discovery process and make it more efficient and cost effective.We must be able to answer our patients’ simple questions, such as, “How long do I have to live?”, “Will this treatment help me?”, and “How will this medicine make me feel? Is it worth it?” We must answer them without having the patient resort to a medical dictionary or cling to farfetched hopes that seem more connected to science fiction than reality. The fictitious Dr. McCoy once said (and I paraphrase): “I’m a doctor—not a moon shuttle conductor, bricklayer, psychiatrist, mechanic, engineer, scientist, physicist, magician, miracle worker, flesh peddler, or veterinarian.” Contrary to this sentiment, I believe we sometimes must wear other hats in order to make progress. Dr. Provenzano is the Chief of Medical Oncology and Director of Oncology at Lawrence Medical Associates, P. C., and Lawrence Hospital Center in New York, and a Clinical Assistant Professor at New York Medical College. He currently serves on the Editorial Board of Cancer.Net, ASCO’s patient information website. Technical assistance provided by Henry H. Cheung. References 1. Provenzano AF. Simone’s OncOpinion on Clinical Trials(12/25/08). Oncology Times. 2009:31:3-4. 2. Kola I, Landis J. Nat Rev Drug Disc. 2004;3:711-5. PMID: 15286737. 3. Kalinsky K, Hershman DL. J Clin Oncol. 2012;30:2573-5. PMID: 22565006. 4. Chibaudel B, Bonnetain F, Shi Q, et al. J Clin Oncol. 2011;29:4199-204. PMID: 21969501. 5. Fallowfield LJ, Fleissig A. Nat Rev Clin Oncol. 2011;9:41-7. PMID: 22009075. 6. Siena S, Peters M, Van Cutsem E, et al. Br J Cancer. 2007;97:1469-74. PMID: 18040272. 7. Odom D, Barber B, Bennett L, et al. Int J Colorectal Dis. 2011;26:173-81. PMID: 21190026. 8. Motzer RJ, Hutson TE, Tomczak P, et al. N Engl J Med. 2007;356:115-24. PMID: 17215529. 9. Miller K, Wang M, Gralow J, et al. N Engl J Med. 2007;357:2666-76. PMID: 18160686. 10. Jones A, Ellis P. BMJ. 2011;343:d4946. PMID: 21816748. 11. Hensley ML. J Clin Oncol. 2011;29:1230-2. PMID: 21383287. 12. Ozols RF. J Clin Oncol. 2003;21:2451-3. PMID: 12829660. 13. Ciuleanu T, Brodowicz T, Zielinski C, et al. Lancet. 2009;374:1432-40. PMID: 19767093. 14. Basch E. Ann Oncol. 2009;20:1905-6. PMID: 19934250. 15. Minasian LM, O’Mara AM, Reeve BB, et al. J Clin Oncol. 2007;25:5128-32. PMID: 17991932. 16. Mayfield E. Life Raft Group. www.liferaftgroup.org/news_sci_articles/pfs_benefit.html. Accessed August 14, 2012. 17. Wenzel LB, Huang HQ, Armstrong DK, et al. J Clin Oncol. 2007;25:437-43. PMID: 17264340. 18. Sheik-Yousouf A, Gandhi S, Dukhovny S, et al. Eur J Cancer Suppl. 2010;8:77 (abstr 63). ascoadmin Tue, 30 Oct 2012 00:06:10 GMT f1397696-738c-4295-afcd-943feb885714:3355 http://connection.asco.org/Magazine/Article/ID/3304/HPV-Vaccinations-for-Males-Time-to-Support-Universal-Voluntary-Vaccination.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3304 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3304&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3304/HPV-Vaccinations-for-Males-Time-to-Support-Universal-Voluntary-Vaccination.aspx Introduction: Head and Neck Squamous Cell Cancer and HPV: A Different Animal Antonio Jimeno, MD, PhD University of Colorado Cancer Center and Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Human papillomavirus (HPV) types 16 and 18 are the etiologic cause of an increasing percentage of head and neck squamous cell cancer (HNSCC).1,2 This subtype of HNSCC typically affects younger, healthier patients, who have a potentially longer time at risk for recurrence than the “classic” patient with HNSCC. The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only targeted drug for HNSCC.3,4 HPV-positive and HPV-negative HNSCC have a different biology5; while HPV-positive HNSCC seems to have higher susceptibility to radiation and DNA-targeting agents than HPV-negative HNSCC, data are starting to emerge questioning the role of EGFR inhibitors in HPV-positive HNSCC. A retrospective study showed that patients who are HPV-positive have worse outcomes after cetuximab plus radiation compared to cisplatin and radiation.6 Investigators recently presented the results of the randomized phase III SPECTRUM trial that evaluated the safety and efficacy of panitumumab (a fully human monoclonal antibody targeting EGFR) combined with platinum- based chemotherapy compared with chemotherapy alone in patients with relapsed or metastatic HNSCC.7 Patients with HPV-negative HNSCC had improved outcomes when treated with panitumumab compared with chemotherapy alone, whereas no improvement was observed in patients with HPV-positive tumors. This may be secondary to lower expression of EGFR in HPV-positive HNSCC,8,9 but the precise reason is unknown. This dual problem (increasing incidence and potentially lower efficacy of existing therapies) highlights the need for further action in both implementing prevention strategies and researching novel treatment approaches that reflect this changing landscape. Dr. Jimeno is an Associate Professor of Medicine/Oncology and Otolaryngology, Director of the Head and Neck Cancer Medical Oncology Program, and Director of the Cancer Stem Cell-directed Clinical Trials Program at the University of Colorado Cancer Center and Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology. He has been an ASCO member since 2003. References Gillison ML, Koch WM, Capone RB, et al. J Natl Cancer Inst. 2000;92:709-20. Kreimer AR, Clifford GM, Boyle P, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:467-75. Bonner JA, Harari PM, Giralt J, et al. N Engl J Med. 2006;354:567-78. Vermorken JB, Mesia R, Rivera F, et al. N Engl J Med. 2008;359:1116-27. Agrawal N, Frederick MJ, Pickering CR, et al. Science. 2011;333:1154-7. Koutcher LD, Sherman E, Carlson D, et al. 2010 ASTRO Annual Meeting. Abstract 133. Stoehlmacher-Williams J, Villanueva C, Foa P, et al. J Clin Oncol. 2012;30 (suppl; abstr 5504). Reimers N, Kasper HU, Weissenborn SJ, et al. Int J Cancer. 2007;120:1731-8. Kumar B, Cordell KG, Lee JS, et al. J Clin Oncol. 2008;26:3128-37. HPV Vaccination for Males: Clinical Trials and Social Tribulations Gregory A. Masters, MD, FACP Helen F. Graham Cancer Center In debating the societal value of a medical intervention, one must consider multiple angles. Thus considered, I believe it is time to support universal vaccination of both boys and girls (young men and women) against the human papillomavirus (HPV) for the following reasons: 1) The sexually transmitted virus HPV is associated with, and probably causes many types of, morbid and potentially fatal cancer; 2) We have a highly effective vaccine for the prevention of HPV infection in both males and females; 3) Although we must acknowledge the need for prospective research to substantiate the hypothesis that HPV vaccination can prevent HPV-associated cancers and reduce overall mortality, it is up to us as cancer care leaders to educate and opine on the value of these interventions so that primary care physicians and individual patients can make an appropriate choice regarding participation in these vaccination programs, and so the public and government representatives can make informed decisions on public funding of this care. HPV has been implicated as a cause of many virally induced diseases: genital warts, recurrent respiratory papillomatosis, and numerous malignancies, including those of the cervix, vagina, vulva, penis, anus, oral cavity, and oral pharynx. This virus is currently thought to be the most common sexually transmitted disease, with 20 million people infected in the United States, and 6.2 million new infections annually.1 Exposure to this virus is nearly ubiquitous among sexually active individuals. Increasing sexual activity is associated with a higher risk of HPV infection. The prevalence of HPV among girls and women is 26.8%.1 Infections often occur soon after the onset of sexual activity. Specific sexual behavior may influence the transmission of HPV and thus affect sites of infection and subsequent malignancy.2 Studies suggest that HPV prevalence in the oral pharynx is three times higher in men than women,3 so their risk of oral pharynx cancer may be higher. HPV subtypes 16 and 18 are strongly implicated in most cervical cancers, most anal cancers, many penile cancers, and some oropharynx cancer. Up to 70% of cervical cancer cases are associated with these viral subtypes.4 Recent data suggests that the incidence of HPV-associated oropharynx cancer is on the rise, accounting for only 16% of oral cancers in the 1980s compared with 72% of these cancers diagnosed between 2000 and 2004.5 Two vaccines have been developed that demonstrate activity in controlling viral infection and decreasing viral associated morbidity from HPV. The two vaccines in clinical use include the bivalent vaccine HPV2 (Cervarix®, GlaxoSmithKline), effective against oncogenic HPV types 16 and 18, and a quadrivalent vaccine HPV4 (Gardasil®, Merck), effective against HPV types 6, 11, 16, and 18. These vaccines have shown significant efficacy in reducing HPV-associated disease such as genital warts and premalignant lesions. One study of HPV4 showed a 90% reduction in development of external genital lesions in male patients without prior infection who received the vaccine.6 Because of the morbidity, both physical and psychologic, that this virus causes, FDA approval was granted in 2006 for the HPV vaccine in females to prevent cervical cancer. The vaccine was approved for use in males in 2009 to prevent genital warts. Reflecting the FDA approval, both the American Academy of Pediatrics and the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices have updated their recommendations for HPV vaccination to include boys and young men. These clinical guidelines now include a recommendation for HPV vaccination in boys and men age 11 to 26, in addition to previous recommendations for vaccination of girls and women age 11 to 26. Clinical trial evidence supporting the reduction in invasive cancer incidence or mortality has not yet been shown, in part because of the significant lag time associated with the development of malignancy from initial HPV infection. Nonetheless, it is reasonable to assume that reducing HPV infection rates will ultimately lead to fewer cancers and thus a reduced mortality from HPV-associated malignancies. The magnitude of that benefit can still be debated. Public education needed Despite these benefits, public acceptance of the HPV vaccine has been slow, and adherence to the clinical guidelines impotent. This has been a subject of debate, with discussion involving clinicians and scientists with a scientific background in infectious disease, public health, and oncology, as well as political candidates, who may or may not be well educated and informed on the topic. This has not served the public well. The focus on government mandates has been a distraction: we should not support government mandates in this area. Few people want to be told what they have to do in health-related activities, and required vaccination would not be realistic with our limited resources to enforce such a mandate. Rather, progress will be best achieved through education. The barriers we face in moving forward with a more universal HPV vaccination program include both social and financial barriers, but the potential benefits of HPV vaccination in males include societal benefits, such as herd immunity, decreased morbidity and mortality, and lower societal cost for the care of HPV-related diseases. Should ASCO take a position on HPV vaccination in males? If so, how can we implement such a strategy? And what can we as clinicians do to help our patients most effectively? These are ongoing questions that will need to be addressed in this debate. This is an issue that is not going away soon. The public health impact of HPV infection and the potential benefits of HPV vaccination will continue to occupy headlines until an appropriate strategy has been developed that maximizes our ability to control infection and reduce morbidity and mortality from this preventable disease. We oncologists spend a lot of time treating patients with advanced disease: redirecting some of our efforts to earlier interventions that can prevent morbidity and mortality may have a greater societal impact and may be a more cost-effective strategy. Dr. Masters is a lung cancer specialist and Director of Medical Oncology Fellowship at Helen F. Graham Cancer Center. An ASCO member since 1996, he currently serves on the Cancer Communications Committee and as Chair of the Test Materials Development Committee. References Dunne EF, Unger ER, Sternberg M, et al. JAMA. 2007;297:813-9. D’Souza G, Kreimar A, Viscidi R, et al. N Engl J Med. 2007;356:1944-56. Gillison ML, Broutian T, Pickard RK, et al. JAMA. 2012;307:693-703. Schiffman M, Castle PE, Jeronimo J, et al. Lancet. 2007;370:890-907. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. J Clin Oncol. 2001;29:4294-301. Giuliano AR, Palefsky JM, Goldstone S, et al. N Engl J Med. 2011; 364:401-11. The views and opinions expressed in Current Insights in Oncology are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. Do you have a suggestion for a future Current Controversies in Oncology topic? Please send an email to ascoconnection@asco.org. ascoadmin Wed, 29 Aug 2012 21:14:28 GMT f1397696-738c-4295-afcd-943feb885714:3304 http://connection.asco.org/Magazine/Article/ID/3255/Adjuvant-Chemotherapy-for-Soft-Tissue-Sarcoma-Is-It-Indicated.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3255 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3255&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3255/Adjuvant-Chemotherapy-for-Soft-Tissue-Sarcoma-Is-It-Indicated.aspx Introduction Robert G. Mennel, MD, FACP Texas Oncology–Baylor Charles A. Sammons Cancer Center Sarcoma makes up a true minority of malignancies. In adults, sarcomas make up only 1% to 2% of all cancers; in children, sarcomas account for approximately 7% of all of pediatric malignancies. There are also approximately 60 different diseases that are included under this diagnosis of sarcoma. The large high-grade sarcomas have a poor cure rate with surgery alone. Metastatic soft tissue sarcoma is rarely cured. Taking all of the facts together, you can see why effective adjuvant chemotherapy is indicated for a large high-grade sarcoma. The rarity of sarcomas and the great variation of the diseases included under this diagnosis would predict that well-designed studies would be difficult to enroll sufficient numbers of patients to give results that reach significance. This has been the case. The pediatric population has fared better than the adults, since they have at least one disease—rhabdomyosarcoma—for which clearly designed studies1 have been completed, demonstrating the clear-cut benefit for adjuvant chemotherapy. In 1997, the first meta-analysis was published, which showed an advantage for adjuvant chemotherapy for large high-grade soft tissue sarcomas.2 This analysis was updated in 20083 and showed that soft tissue sarcomas treated with adjuvant chemotherapy had a reduction in the risk of death with a hazard ratio of 0.77 (95% CI 0.64-0.93; p=0.01). The absolute risk reduction of death was 6% for adjuvant chemotherapy (95% CI 2%-11%: p=0.003), or 40% versus 46%. The assumption is that the major advantage for adjuvant chemotherapy is for large, high-grade sarcomas of the extremities, although specific data points were not included in the studies to allow an accurate subgroup analysis to answer this point. In this issue of ASCO Connection, Dr. Alberto Pappo and Dr. Margaret von Mehren outline these studies and enumerate the difficulty that the clinician caring for a patient with a soft tissue sarcoma faces in making a decision about employing adjuvant chemotherapy. They also discuss the hope for the future, namely definable targets that can be exploited for higher cure rates in our patients with large high-grade sarcomas. They allude to the problem that this hoped-for therapy has to confront, namely a very disrupted genome in soft tissue sarcomas.4 This genomic disaster may make the discovery of the important targets very difficult. When new agents are found to target these important pathways, the paucity of patients will make the study of these agents using the randomized trial model very difficult. Therefore, in soft tissue sarcomas, should we perform different types of studies to prove the effectiveness of these new drugs? Dr. Mennel is a medical oncologist and hematologist at Texas Oncology-Baylor Charles A. Sammons Cancer Center. He currently serves on ASCO’s Cancer Education Committee, Integrated Media and Technology Committee, and the ASCO Connection Editorial Board. References 1. Raney RB, Anderson JR, Barr FG, et al. J Pediatr Hematol Oncol. 2001;23:215-20. 2. Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350:1647-54. 3. Pervaiz N, Colterjohn N, Farrokhyar F, et al. Cancer. 2008;113:573-81. 4. Helman LJ, Meltzer P. Nat Rev Cancer. 2003;3:685-94. The Role of Chemotherapy in the Treatment of Pediatric Soft Tissue Sarcomas Alberto S. Pappo, MD St. Jude Children’s Research Hospital Soft tissue sarcomas account for about 7% of all cancers in patients under age 20, and rhabdomyosarcoma is the most common histologic diagnosis in this population, with an expected 350 cases per year in the United States. Historically, when treated with local measures alone (such as surgery and radiotherapy), rhabdomyosarcoma was curable in less than 30% of cases.1,2 The observations that selected chemotherapy agents were active against this disease3,4 prompted the formation of the Intergroup Rhabdomyosarcoma Study Group in 1972 (IRSG; now known as the Soft Tissue Sarcoma Committee of the Children’s Oncology Group [COG]). Since its inception, more than 5,000 patients have been treated in a series of prospective randomized trials. These trials have increased cure rates to over 70% and have identified clinical and biological factors that accurately predict outcome, facilitating the development of risk-based therapies (see Table 1).5,6 Patients with high-risk disease, as well as some patients with intermediate-risk disease, continue to fare poorly. Novel therapies are desperately needed for these patients.TABLE 1. Therapeutic Regimens for Pediatric Soft Tissue Rhabdomyosarcoma, According to Risk Group  Risk Group (Percent of cases)  Characteristics  Therapy  Expected 5-year failure-free survival  Low (35%)  Embryonal tumors Localized disease at favorable sites and grossly resected disease at unfavorable sites  VA±C±RT  95%  Intermediate (50%)  Embryonal tumors Unresected disease at unfavorable sites Alveolar tumors All localized disease  VAC± an experimental arm±RT  65%  High (15%)  Embryonal and alveolar tumors Metastatic disease  VAC±I,D,E,V,Ir±RT  30% .telerik-reTable-1 { border-width: 0px; border-style: none; border-collapse: collapse; font-family: Tahoma; } .telerik-reTable-1 tr.telerik-reTableHeaderRow-1 { margin: 10px; padding: 10px; color: #3F4D6B; background: #D6E8FF; text-align: left; font-size: 10pt; font-style: normal; font-family: Tahoma; text-transform: capitalize; font-weight: bold; border-spacing: 10px; line-height: 14pt; vertical-align: top; } .telerik-reTable-1 td.telerik-reTableHeaderFirstCol-1 { padding: 0in 5.4pt 0in 5.4pt; color: #3a4663; line-height: 14pt; } .telerik-reTable-1 td.telerik-reTableHeaderLastCol-1 { padding: 0in 5.4pt 0in 5.4pt; color: #3a4663; line-height: 14pt; } .telerik-reTable-1 td.telerik-reTableHeaderOddCol-1 { padding:0in 5.4pt 0in 5.4pt; color: #3a4663; line-height: 14pt; } .telerik-reTable-1 td.telerik-reTableHeaderEvenCol-1 { padding:0in 5.4pt 0in 5.4pt; color: #3a4663; line-height: 14pt; } .telerik-reTable-1 tr.telerik-reTableOddRow-1 { color: #666666; background-color: #F2F3F4; font-size: 10pt; vertical-align: top; } .telerik-reTable-1 tr.telerik-reTableEvenRow-1 { color: #666666; background-color: #E7EBF7; font-size: 10pt; vertical-align: top; } .telerik-reTable-1 td.telerik-reTableFirstCol-1 { padding: 0in 5.4pt 0in 5.4pt; } .telerik-reTable-1 td.telerik-reTableLastCol-1 {padding:0in 5.4pt 0in 5.4pt;} .telerik-reTable-1 td.telerik-reTableOddCol-1 { padding: 0in 5.4pt 0in 5.4pt; } .telerik-reTable-1 td.telerik-reTableEvenCol-1 { padding:0in 5.4pt 0in 5.4pt; } .telerik-reTable-1 tr.telerik-reTableFooterRow-1 { background-color: #D6E8FF; color: #4A5A80; font-weight: 500; font-size: 10pt; font-family: Tahoma; line-height: 11pt; } .telerik-reTable-1 td.telerik-reTableFooterFirstCol-1 { padding: 0in 5.4pt 0in 5.4pt; border-top: solid gray 1.0pt; text-align: left; } .telerik-reTable-1 td.telerik-reTableFooterLastCol-1 { padding:0in 5.4pt 0in 5.4pt; border-top:solid gray 1.0pt; text-align:left; } .telerik-reTable-1 td.telerik-reTableFooterOddCol-1 { padding: 0in 5.4pt 0in 5.4pt; text-align: left; border-top: solid gray 1.0pt; } .telerik-reTable-1 td.telerik-reTableFooterEvenCol-1 { padding: 0in 5.4pt 0in 5.4pt; text-align: left; border-top: solid gray 1.0pt; } V, vincristine; A, actinomycin D; C, cyclophosphamide; I, ifosfamide; D, doxorubicin, E, etoposide; Ir, irinotecan; RT, radiotherapy In contrast to rhabdomyosarcoma, the remaining 60% of soft tissue sarcomas in pediatrics, known as nonrhabdomyosarcoma soft tissue sarcomas, are more prevalent in older patients, and, prior to 2007, only three prospective trials that accrued fewer than 200 patients had been conducted in the U.S.7-9 Since then, however, COG has developed and completed a prospective trial (ARST0332) that will provide the most comprehensive information to date regarding the biology, clinical course, and treatment of these patients. The unprecedented progress that we have witnessed in the past 30 years reinforces the importance of enrolling patients in well-designed prospective clinical trials. Current efforts to better understand the genetic features that drive tumor growth of soft tissue sarcomas are expected to lead to studies that explore novel targeted agents in combination with standard therapies for these diseases. Dr. Pappo, of St. Jude Children’s Research Hospital, specializes in pediatric melanoma, soft tissue sarcomas, and pediatric gastrointestinal stromal tumors. He currently serves on the Editorial Boards of the Journal of Clinical Oncology and Cancer.Net. References 1. Flamant F, Hill C. Cancer. 1984;53:2417-21. 2. Neifeld JP, Maurer HM, Godwin D, et al. J Pediatr Surg. 1979;14:699-703. 3. Wilbur J. Cancer Chemother Rep. 1974;58:281-4. 4. Pratt CB, Hustu HO, Fleming ID, et al. Cancer Res. 1972;32:606-10. 5. Pappo AS, Shapiro DN, Crist WM. Pediatr Clin North Am. 1997;44:953-72. 6. Raney RB, Anderson JR, Barr FG, et al. J Pediatr Hematol Oncol. 2001;23:215-20. 7. Pappo AS, Devidas M, Jenkins J, et al. J Clin Oncol. 2005;23:4031-8. 8. Pratt CB, Pappo AS, Gieser P, et al. J Clin Oncol. 1999;17:1219. 9. Pratt CB, Maurer HM, Gieser P, et al. Med Pediatr Oncol. 1998;30:201-9. The Role of Adjuvant Chemotherapy in the Treatment of Adult Soft Tissue Sarcomas Margaret von Mehren, MD Fox Chase Cancer Center Soft tissue sarcomas (STS) account for about 1% of all cancers in adults, with an annual incidence of 11,280 for all age groups.1 Unlike pediatric sarcomas, in which rhabdomyosarcoma accounts for the majority of cases, there is a tremendous heterogeneity of histologies diagnosed in adult patients. Increasingly, differences in tumor biology are being elucidated, challenging our practice of grouping these tumors as one entity when evaluating therapeutic agents. Gastrointestinal stromal tumor (GIST) is the clearest example of biologic data leading to a completely different treatment paradigm; the use of tyrosine kinase inhibitors targeting KIT and PGFRA has resulted in improved overall survival in the adjuvant and metastatic disease settings.2,3 Trials testing the benefit of chemotherapy in patients with metastatic sarcoma have demonstrated some evidence for tumor response and progression-free survival benefit. The highest response rates have been achieved with doxorubicin and ifosfamide,4 and thus these agents have been utilized in trials assessing therapy in the adjuvant setting.5 Unlike the outcomes in rhabdomyosarcoma, trials evaluating the benefit of adjuvant treatment have had varying results for progression-free and overall survival. Meta-analyses have been performed to better understand outcomes. An analysis published in 2008 included 1,953 patients from published clinical trials.6 This study documented statistically significant odds ratios (OR) in favor of adjuvant chemotherapy for local recurrence (OR 0.73 [95% CI 0.56-0.94; p=0.02]), distant and overall recurrence (OR 0.67 [95% CI 0.56-0.82; p=0.0001]). When analyzing survival, doxorubicin alone was not statistically significant (OR 0.84 [95% CI 0.68-1.03; p=0.09]) but doxorubicin combined with ifosfamide was (OR 0.56 [95% CI 0.36-0.85; p=0.01]). This study did not include the most recent adjuvant study completed by the EORTC evaluating doxorubicin and ifosfamide versus observation in resected grade 2 and 3 extremity tumors. When included in a meta-analysis by other investigators, the analysis identified only a recurrence-free survival benefit at 10 years, but no benefit for overall survival.7 Finally, a meta-analysis of retrospective data from the French Sarcoma Group, which included histologic grade as a variable in the analysis, identified a significant benefit for adjuvant chemotherapy for improved metastasis-free and overall survival at five years (HR 0.7 [95% CI 0.6-0.9; p=0.01] and HR 0.6 [95% CI 0.5-0.8; p=0.0002], respectively) was observed, but only in patients with grade 3 tumors.8 Trying to make a clinical judgment on the benefits of adjuvant chemotherapy using evidence-based clinical trial results is challenging. The trials analyzed have used varying regimens and doses of chemotherapies and have enrolled different patient populations. Increasingly, biologic data is underscoring that these diseases we have labeled soft tissue sarcoma are a very heterogeneous group, and it is not feasible to conduct individual trials for each individual histology. Smaller histology-specific international trials are needed in the metastatic disease setting to provide information for potential therapies that might be considered in the adjuvant setting. To date, our studies have demonstrated that 1) the benefit of adjuvant therapy for intra-abdominal tumors other than GIST is very limited and not recommended, and 2) for extremity and trunk tumors, factors suggesting a poorer prognosis should be considered on an individual basis, such as size and histologic grade. Dr. von Mehren is a medical oncologist at Fox Chase Cancer Center, where she serves as the Director of Sarcoma Oncology. An ASCO member since 1995, she has previously served on the Scientific Program Committee. References 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society, 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf. Accessed 4 May 2012. 2. Pisters PW, Colombo C. J Surg Oncol. 2011;104:896-900. 3. Caram MV, Schuetze SM. J Surg Oncol. 2011;104:888-95. 4. Singer S, Maki RG. O’Sullivan B. “Soft Tissue Sarcomas,” in DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology, 8th Edition, edited by DeVita VT, Lawrence TS, and Rosenberg SA. Philadelphia: Lippincott Williams & Wilkins, 2011. 5. Patrikidou A, Domont J, Cioffi A, et al. Curr Treat Options Oncol. 2011;12:21-31. 6. Pervaiz N, Colterjohn N, Farrokhyar F, et al. Cancer. 2008;113:573-81. 7. O’Connor JM, Chacón M, Petracci FE, et al. J Clin Oncol. 2008;26(May 20 suppl; abstr 10526). 8. Italiano A, Delva F, Mathoulin-Pelissier S, et al. Ann Oncol. 2010;21:2436-41. ascoadmin Mon, 02 Jul 2012 14:54:07 GMT f1397696-738c-4295-afcd-943feb885714:3255 http://connection.asco.org/Magazine/Article/ID/3197/PSA-Screening-for-Prostate-Cancer-A-Debate-on-Implications-of-the-PLCO-Trial.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3197 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3197&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3197/PSA-Screening-for-Prostate-Cancer-A-Debate-on-Implications-of-the-PLCO-Trial.aspx Introduction David L. Graham, MD Carle Physicians Group We live in the prostate-specific antigen (PSA) era. The explosion in use of the PSA test as a screen for prostate cancer since the 1980s has brought us to the point that its use can nearly be defined as ubiquitous. If it is not ubiquitous yet, many clinicians would argue that it should be. Despite this, no consensus of recommendations for its use exists among the main oncology and public health organizations. Part of the reason for this may lie in the expectations for screening tests. Previous requirements for a screening test included a test that was easy to perform at a reasonable cost, and which enabled an intervention leading to an effect on the outcome related to that disease. Gold-standard outcomes for screening studies have generally been disease-specific survival. The inherent difficulty in demonstrating these criteria in a screening test for prostate cancer is that we have never had to evaluate a screen for a disease that autopsy prevalence studies would suggest, depending on the age group being screened, is present in 40% to 60% of the screened patients. In addition, the relatively low lethality rate of prostate cancer—14% by summarized American Cancer Society data of 2007–2011—makes the impact of screening potentially more difficult to determine. Large studies have demonstrated conflicting data regarding the effect of PSA screening. Updated data on the impact of PSA screening on prostate cancer-specific mortality from the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial have been recently published. In this column, Dr. William Catalona and Dr. Derek Raghavan discuss the merits and critiques of the study and present their opinion on screening strategies for prostate cancer. Dr. Graham is the Medical Director for Multispecialty Clinical Research Services at Carle Physicians Group, in Urbana, Illinois, and currently serves on ASCO’s Integrated Media and Technology Committee. Follow Dr. Graham on Twitter @davidgrahammd and read his commentary on ASCOconnection.org. No Level 1 Evidence Indicates PSA Screening Improves Overall Survival Derek Raghavan, MD, PhD, FACP Levine Cancer Institute The very sad aspect of the debate on PSA and screening for prostate cancer is that it seems to epitomize the epithet, “Often wrong, but never in doubt.” The discussion has repeatedly been mis-focused in current medical literature on whether the various PSA screening studies were well-executed or flawed, and this has led to the conclusion that the data published somehow misrepresent the utility of PSA as a screening tool. These are not issues that help us to understand the situation. Principles of effective screening and analysis of trials Before focusing on the specifics of prostate cancer, it is important to understand several key points that relate to any program of cancer screening or cancer survival analysis: For any cancer-screening program to be useful, it must (by definition) improve overall survival, not just disease-specific survival.1 Another potentially useful role for cancer-screening programs is the reduction of the morbidity of treatment. These well-tested and established criteria have frequently been met for other cancers—specifically, mammography in breast cancer, colonoscopy for colorectal cancer, and Pap smears for cervical cancer, among others. In a parallel situation, many years ago, annual chest x-rays were tested as a means of improving survival for lung cancer, failed the test, and were dropped from clinical practice. There is no reason why the bar should be lowered specifically to validate PSA as a screening test when the only improvement in survival has been tumor-specific survival, and no study has shown an overall survival benefit. It is not appropriate to design a clinical trial and then to negate the trial because it doesn’t show the expected results. Even if a randomized trial has design flaws, the presence of those flaws does not prove the opposite result from that demonstrated by the trial. If a screening study demonstrates that screening improves overall survival, that observation does not necessarily imply that all of the improvement in survival is due to the test—in other tumors (and in prostate cancer), changes in diagnostic and staging techniques, introduction of adjuvant therapies (e.g., breast cancer), changes in health practices (e.g., smoking cessation vis-à-vis lung cancer), salvage therapies, novel chemotherapy and targeted therapeutics, and even improved palliative care can contribute to improved survival. Furthermore, in any clinical population, health-seeking behavior is often associated with improved outcomes—thus, the typical patient who seeks screening tests also practices better dietary habits, exercises, and seeks medical attention for other conditions more promptly. In the evaluation of any randomized clinical trial, focusing only on disease-specific survival can introduce a dangerous bias of interpretation. An example is the Veterans Administration study from 40 years ago, in which patients with advanced prostate cancer were treated with high-dose estrogens in an attempt to gain control of their disease while a second group was randomly allocated to treatment with placebo.2 There was clear evidence of improved cancer-specific survival in the estrogen-treated group, but overall survival was identical; when the study was analyzed in detail, it became clear that high-dose estrogens reduced deaths from prostate cancer in the short term, but this reduction was offset by an increase in deaths from cerebrovascular and cardiovascular disease, created by the therapeutic effect of high-dose estrogens. As a consequence, this modality was dropped from our therapeutic armamentarium. By definition, using a test for a symptomatic person (e.g., a man with symptoms of prostatism) is not screening; screening is the use of a test to detect an illness in a patient with no symptoms or signs of that disease. Thus, the many clinical anecdotes about life-saving interventions in men presenting with nonspecific urological symptoms are not relevant to a discussion of screening of asymptomatic populations. Should we be screening asymptomatic white males for prostate cancer using PSA? Many randomized trials have addressed this question. Unfortunately, in all of these studies, there is a paucity of information regarding black men and men with positive family histories of prostate cancer, and we simply don’t have enough information to answer the question for these population groups. Given that outcomes (adjusted for age and socioeconomic status) in this group are inferior to the rest of the community, my own view is that we must emphasize education and provide structured approaches to screening black males, and any males with a positive family history, until clear information is available to resolve the issue. However, much more information is available regarding prostate screening in asymptomatic white males. Despite the significant design and execution flaws enumerated by Dr. Catalona, which should not be ignored, the PLCO trial did not demonstrate an overall survival benefit from PSA-driven prostate screening, even after 13 years of follow up.3 Randomized trials of screening for other cancers, by their nature, suffer from irregularities of follow-up and confounding factors (e.g., crossover, prior testing, and failure to adhere to the planned protocol); however, as noted above, in many tumors, these studies have shown an overall survival benefit from screening. The two key European studies, ERSPC4 and Goteborg,5 have both demonstrated tumor-specific survival benefits, but no improvement in overall survival. While one could argue that it is too early for survival benefit to have been demonstrated in prostate cancer (a disease with a long, natural history often occurring in elderly males) in any of these studies, I view that as exactly the reason why routine PSA screening should not be introduced into the general population. Analyzing the statistics Many have claimed that there has been a reduction in cause-specific deaths from prostate cancer since the introduction of PSA screening. I’m not sure that is true. For example, the U.S. government SEER statistics include the disclaimer, “includes only invasive cancers unless otherwise specified.” In other words, more than 50% of the cases (those that are less aggressive) identified from screening activities are being omitted, which stacks the deck in favor of routine PSA screening. By contrast, using total patient numbers generated from respected American Cancer Society publications, the figures are quite different. In 1981, in the United States, there were 20,790 deaths from prostate cancer6; in 1989, 25,943 deaths7; in 2012, it is projected that there will be 28,170 deaths.8 This is hardly the pattern of major progress from a screening activity! The U.S. population has not swelled that quickly, but the denominator of cases of low-risk disease, identified by random and enthusiastic PSA testing, certainly has grown quickly. If the PSA believers really want to improve their data, why not add benign prostatic hyperplasia (BPH) to their denominator and improve their risk-benefit ratio even more? At present, there is a cacophony of noise from the advocates of routine PSA screening, acknowledging that perhaps we overtreat men with prostate cancer, and noting the flaws in the extant PSA tools, leading to their conclusion that we should now use risk-adapted, age-adapted, PSA-density, or velocity-adapted algorithms of screening. They may well have the right idea, and perhaps that is exactly the correct approach to developing a strategy to save lives. However, as in all other domains of medicine, and particularly those that potentially will cost billions of dollars to the community that is struggling to rationalize health expenditure, I challenge them to prove their hypotheses, and to do so this time with well-designed and well-executed clinical trials. We should educate our population about the entity of prostate cancer, emphasizing symptoms, risk factors, and available treatments, define programs for black men and men with positive family histories, and take a much more rational approach to addressing this vexed problem, absent rhetoric and hype. Dr. Raghavan is President of Levine Cancer Institute, Carolinas HealthCare System, and a Professor of Medicine at the University of North Carolina. He has served on ASCO task forces related to cost of care, access to care, and health disparities, and received an ASCO Statesman Award in 2010. References 1. Kramer BS, Croswell JM. Annu Rev Med. 2009;60:125–37. 2. Blackard CE. Cancer Chemother Rep. 1975;59:225–7. 3. Andriole GL, Crawford ED, Grubb RL 3rd, et al. J Natl Cancer Inst. 2012;104:125–32. 4. Schröder FH, Hugosson J, Roobol MJ, et al. N Engl J Med. 2009;360:1320–8. 5. Hugosson J, Carlsson S, Aus G, et al. Lancet Oncol. 2010;11:725–32. 6. Silverberg E. CA Cancer J Clin. 1981;31:13–28. 7. Silverberg E, Lubera JA. CA Cancer J Clin. 1989;39:3–20. 8. Siegel R, Naishadham D, Jemal A. CA Cancer J Clin. 2012;62:10–29. What’s Wrong with PLCO: Drawbacks and Implications for PSA Screening William J. Catalona, MD Northwestern University Feinberg School of Medicine Overall mortality: Not the primary endpoint Dr. Raghavan’s focus on overall mortality and his example of administering toxic doses of estrogens to patients with advanced prostate cancer is more relevant to treatment trials than to screening trials. As with other cancer-screening programs, a key feature of the prostate cancer debate is reduction in cancer-specific mortality. Although overall mortality is an important outcome, the adoptions of other larger cancer programs (e.g., breast and colon cancer) were based on reductions of cancer-specific mortality. The primary endpoint of the randomized clinical trials of prostate cancer screening was prostate cancer-specific mortality (PCSM), not overall mortality. These trials cannot address the overall mortality issue at early follow-up. Overall mortality has a much lower statistical power in screening trials due to statistical noise from deaths due to other causes. In accepted screening programs for other tumors, screening has not been shown to modify overall mortality. Dr. Raghavan attributes the observed age-adjusted decreases in PCSM to causes other than PSA testing; however, there is simply no other mechanism that can reasonably account for the dramatic drop in age-adjusted PCSM since the introduction of PSA. The PLCO trial The design of the PLCO trial was flawed from the beginning, and its findings mislead and misinform. As a result, the popular and medical media have reported faulty information, the public is confused, and physicians are in the awkward position of having discussions with patients based upon unfounded recommendations. Enumerating the flaws PLCO1–3 has by far the most flaws of the large, randomized controlled trials of PSA-based screening for prostate cancer. At least 43% of participants had undergone prior screening before they enrolled in PLCO,1 and 4% to 5% had undergone biopsy. This removed many high-risk tumors from the study population. This is reflected in the modest differences in high-grade and advanced-stage prostate cancer between the screening and control arms that are substantially less than those observed in ERSPC4 or Goteborg.5 Thus, in PLCO, PCSM events are fewer and occur later than they would without prescreening. The most important flaw in PLCO is that at least 52% of controls were screened during the trial (“contamination”). This may, in fact, be an underestimate, because PLCO investigators estimated contamination based on surveys sent every one to two years to random 1% subsets of controls. Controls also may have been screened, biopsied, and treated during the follow-up phase of the trial. Therefore, there was no pure control group, and many controls benefitted from “opportunistic” screening. Consequently, while ERSPC (≈15% contamination; 20% PCSM benefit) and Goteborg (≈3% contamination; 44% PCSM benefit) compared active screening to minimal opportunistic screening; PLCO compared formalized screening in 85% to opportunistic screening in ≥52%. This high contamination rate reduced differences in PCSM between the study arms. As there was no organized screening in PLCO after the screening phase, the two arms become even more similar, further decreasing differences that would have occurred with continued longitudinal screening. At the outset, PLCO powered the study to demonstrate a 20% reduction in PCSM with screening. The study investigators planned for non-compliance in their power calculations, expecting 90% compliance in the screening arm and 20% contamination in the control arm, but got 86% and 52%, respectively. To maintain the same level of power would require twice the benefit anticipated to reach statistical significance. Thus, PLCO cannot be informative about whether longitudinal PSA-based screening reduces PCSM. PLCO should not be interpreted as a “negative study” showing that screening does not work; it simply is unable to say anything about whether screening significantly reduces PCSM. PLCO’s protocol (screening for six years with PSA using a >4 ng/mL cutoff plus digital rectal examination for four years) is not representative of current screening methods. Prostate cancer risk-assessment tools now widely used for decision-making, such as baseline PSA, PSA velocity, percent-free PSA, etc., were not used in PLCO, and, therefore, the results are not relevant to present-day screening.6 PLCO did not require men with abnormal screening results to undergo biopsy; rather, the men and their physicians decided what further evaluation, if any, would occur. Only ≈40% with abnormal results underwent biopsy within one year, which compromised early detection and treatment. PLCO included men up to age 74. Since death from prostate cancer often occurs >13 years after diagnosis, older men have more competing risks and are less likely to demonstrate a PCSM benefit. In Goteborg, with their shorter screening interval and lower PSA cutoffs, less contamination and longer follow-up, PCSM benefits occurred largely in younger men. This was also the case in ERSPC. PLCO’s results not only conflict with ERSPC and Goteborg but also are internally inconsistent. PLCO reported a higher PCSM in the screening arm, but that rate was 25% lower in men who had undergone ≥2 PSA tests at baseline than in those not tested. In a subset analysis, screened subjects with minimal comorbidity had a 44% lower PCSM.2 PLCO recently updated the mortality results (up to 13 years in 57%).3 The screening arm had a higher prostate-cancer detection rate but a lower rate of advanced and high-grade tumors. Nevertheless, despite its more favorable tumor features, the screening arm still had a 9% higher PCSM. PLCO also re-examined subsets of their participants grouped by age, comorbidity, and pretrial PSA testing.3 On their second subset analysis, they changed the comprehensive Charlson Index they used in their first analysis in favor of a more restrictive index that excluded patients with congestive heart failure, peripheral vascular disease, connective-tissue disease, hemiplegia, HIV, renal disease, and dementia. Using the new definition, they reported no PCSM benefit in any of the subgroups; nevertheless, using the comprehensive definition used previously, there remained a significant 27% lower PCSM in screened subjects with minimal comorbidity. Regardless, the study was not powered to examine this issue, and post hoc subset analyses should be interpreted with caution. PLCO investigators speculate that the PCSM benefits of ERSPC were due to differences in the treatments offered to patients in the screening versus the control arms (i.e., screening-arm patients were more likely to receive radical prostatectomy). Their premise is that treatment at a university hospital is always better, and in at least one ERSPC center, patients were more frequently treated at a university. Because screen-detected prostate cancer is generally diagnosed earlier, it is more frequently amenable to radical prostatectomy. In ERSPC, the choice of therapy was affected more by other factors than by trial arm, with the trial arm having only a minor role in treatment choice (e.g., χ2 of 8 of a total χ2 of 2,428).7 PSA level, age, and tumor stage were the most important factors for treatment choice, and the study arm was not associated with treatment after correction for age, PSA level, and tumor characteristics. Moreover, in Goteborg (having the greatest PCSM benefit), men with localized disease in the two study arms received similar treatment. PLCO has not reported an analysis of their patients treated in the community versus academic centers or adjusted for surgical volume; thus, it is unknown how treatment differences affected PLCO results. Benefits of PSA screening During the PSA era, the United States has seen a >75% reduction in the rate of advanced prostate cancer at diagnosis and a >42% reduction of age-adjusted PCSM (Figure 1),8 with similar patterns occurring in other countries where PSA screening is widespread.9 Screening has not been adequately studied in high-risk populations such as black men (only 4% of PLCO subjects were black), who have 50% higher prostate-cancer incidence and 200% higher PCSM, and whose outcomes have improved during the PSA era.7 Statistical modeling teams estimated 45% to 70% of this benefit is directly attributable to PSA screening.10 ERSPC and Goteborg provide valid level 1 evidence that PSA screening reduces PCSM, whereas PLCO is noninformative on this issue. In a comprehensive evaluation of randomized controlled trials on prostate cancer screening, Allan et al. concluded, “The best evidence demonstrates prostate cancer screening will reduce prostate cancer mortality. It is time for the debate to move beyond this issue...”11 Many men not wanting to suffer or die from prostate cancer would prefer to accept the risks of screening to have the opportunity for early diagnosis when the tumor is still curable. Nearly all urologists and most internists support PSA screening of appropriately selected men.12 At present, PSA is the best test available for early diagnosis, and, in fact, no other way to identify prostate cancer in its curable stages is now available. To deny the opportunity for informed decision-making needlessly places men in harm’s way, and it would be unconscionable to implement that denial based upon flawed science. Dr. Catalona, a surgical oncologist and prostate cancer specialist, is a professor in the Department of Urology at Northwestern Feinberg School of Medicine and Director of the Clinical Prostate Cancer Program at the Robert H. Lurie Comprehensive Cancer Center. References 1. Andriole GL, Crawford ED, Grubb RL 3rd, et al. N Engl J Med. 2009;360:1310–9. 2. Crawford ED, Grubb R 3rd, Black A, et al. J Clin Oncol. 2011;29:355–61. 3. Andriole GL, Crawford ED, Grubb RL 3rd, et al. J Natl Cancer Inst. 2012;104:125–32. 4. Schröder FH, Hugosson J, Roobol MJ, et al. N Engl J Med. 2009;360:1320–8. 5. Hugosson J, Carlsson S, Aus G, et al. Lancet Oncol. 2010;11:725–32. 6. Loeb S, Carter HB, Catalona WJ, et al. Eur Urol. 2012;61:1–7. 7. Wolters T, Roobol JM, Steyerberg EW, et al. Int J Cancer. 2010;126:2387–93. 8. Age-adjusted U.S. mortality rates by cancer site: all ages, all races, male, prostate 1992–2008. Mortality source: US Mortality Files, National Center for Health Statistics, CDC. http://www.seer.cancer.gov/faststats/selections.php. Accessed 4 February 2012. 9. Bouchardy C, Fioretta G, Rapiti E, et al. Int J Cancer. 2008;123:421–9. 10. Etzioni R, Tsodikov A, Mariotto A, et al. Cancer Causes Control. 2008;19:175–81. 11. Allan GM, Chetner MP, Donnelly BJ, et al. Canad Urol Assoc J. 2011;5:416–21. 12. Sternberg S. US News Health. 28 October 2011. http://health.usnews.com/top-doctors/articles/2011/10/28/survey-of-top-doctors-finds-widespread-support-for-psa-screening. Accessed 23 February 2012. ascoadmin Tue, 17 Apr 2012 15:25:25 GMT f1397696-738c-4295-afcd-943feb885714:3197 http://connection.asco.org/Magazine/Article/ID/3149/Insights-into-Smoldering-Asymptomatic-Multiple-Myeloma.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3149 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3149&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3149/Insights-into-Smoldering-Asymptomatic-Multiple-Myeloma.aspx Introduction By William N. Hait, MD, PhD Johnson & Johnson Pharmaceuticals Research & Development Soon we will know our susceptibility to all diseases, but will have no idea what to do about it. Genotypic changes plus a life of environmental exposures may (or may not) lead to progression to serious disease. In certain instances, we can track progression and intervene appropriately. Oncologic diseases offer an important opportunity for potentially more effective approaches to therapy, i.e., the treatment of pre-malignances (“cancer interception,” a phrase coined by Dr. Elizabeth Blackburn of the University of California, San Franciso). Multiple myeloma is a life-threatening disease characterized by end-organ damage, including intensely painful fractures of the bone (a feeling described by one of my patients as “stubbing your toe but it never goes away”). Pre-myelomas are identified by clonal expansion of plasma cells, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Dr. Robert Kyle’s excellent review describes the diagnosis and prognosis of these pre-malignant conditions and makes thoughtful recommendations regarding management. Ideally, prevention of disease would entail minimal morbidity and would target those individuals at greatest risk. MGUS and SMM progress to MM at a predictable rate based on characteristics described by Dr. Kyle’s group that include the quantity of the M-spike and degree of marrow plasmacytosis.1 Therefore, a group of patients at high risk for progressing to a fatal disease can be diagnosed and potentially treated. Might these patients have been spared the morbidity and mortality of multiple myeloma and its treatment by earlier therapeutic intervention? There are reasons to suspect that early intervention, i.e., the treatment of pre-malignancies, will be more effective. For example, a BCR-ABL inhibitor such as imatinib is highly effective when used to treat chronic myelogenous leukemia (CML) in chronic phase.2 However, as CML progresses to accelerated phase and on to blast crisis, this well-tolerated medication loses almost half of its efficacy.3 To make cancer interception a reality, much preparatory work needs to be done. Identification of practical regulatory endpoints, such as valid surrogates of clinical benefit and metrics for payor acceptance, remain important opportunities for further progress. Dr. Kyle wisely opines that patients with SMM at low risk for progression should be carefully observed, and those who are at the highest risk should not be treated outside of a clinical trial. Preliminary studies with “imids” and dexamethasone are encouraging.4,5 Recently, anti-interleukin 6 monoclonal antibodies (e.g., siltuximab) have been developed and are undergoing investigation in patients with high-risk SMM, tracked using a newly developed circulating myeloma cell kit. Shakespeare wrote in Hamlet, “Disease desperate wrought by desperate measures are relieved or not at all.” In contrast, the predecessors to disease should require less desperation and greater concentration by the biomedical research community. Careful characterization of premalignant conditions exemplified by the work of Dr. Kyle’s group is essential if we are to make cancer interception a reality. Dr. Hait, a medical oncologist, is Senior Vice President and Worldwide Therapeutic Area Head of Oncology at Johnson & Johnson Pharmaceuticals Research & Development, LLC. He currently serves on ASCO’s Cancer Research Committee. References 1. Kyle RA, Remstein ED, Therneau TM, et al. N Engl J Med. 2007;356:2582-90. 2. Druker BJ, Talpaz M, Resta DJ, et al. New Engl J Med. 2001;344:1031-7. 3. Druker BJ, Sawyers CL, Kantarjian H, et al. N Engl J Med. 2001;344:1038-42. 4. Detweiler-Short K, Hayman S, Gertz MA, et al. Am J Hematol. 2010;85:737-40. 5. Mateos M-V, López-Corral L, Hernández M, et al. Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment. ASH Annual Meeting Abstracts. 2011:Abst 991. Insights into Smoldering (Asymptomatic) Multiple Myeloma (SMM) By Robert A. Kyle, MD Mayo Clinic Smoldering (asymptomatic) multiple myeloma (SMM) is defined by the presence of a monoclonal (M) protein level ≥ 3 g/dL and/or ≥ 10% monoclonal plasma cells in the bone marrow, but no evidence of end-organ damage.1 End-organ damage (“CRAB”) consists of hypercalcemia (C), renal insufficiency (R), anemia (A), or bone lesions (B) due to the plasma cell proliferative disorder. SMM must be differentiated from monoclonal gammopathy of undetermined significance (MGUS) because of its greater risk of progression to multiple myeloma (MM) or a related disorder. The risk of progression to symptomatic MM is approximately 10% per year for SMM compared to 1% per year for MGUS. MGUS and disease progression MGUS is found in 3% of the white population age 50 or older. It is more common in men (4.0%) than in women (2.7%). The prevalence increases to 5% in persons age 70 or older and to 7.5% among those age 85 or older. The size of the M protein is modest, with more than 60% having an M protein < 1.0 g/dL. Uninvolved immunoglobulins are reduced in less than one-third of patients.2 The prevalence of MGUS in black patients is approximately twice that of the white population, and the prevalence in Japanese patients is approximately two-thirds that of the white population.3,4 This was confirmed in patients from Ghana, where the prevalence was 5.8% in 917 men age 50 years or older.5 In contrast, the prevalence of MGUS in Nagasaki, Japan, was 2.4% in patients age 50 older.6 It should be pointed out that MGUS precedes virtually all cases of MM.7 It is impossible to know whether a patient with MGUS will remain stable or progress to a plasma cell malignancy such as MM, Waldenström macroglobulinemia, or AL amyloidosis. Predictors of progression include the size of the serum M protein at the time of recognition of MGUS. The risk of progression 10 years after the recognition of MGUS was 6% for those with an M-protein level of 0.5 g/dL or less in contrast to 24% for those with an M protein of 2.5 g/dL. At 20 years, the risk of progression in a patient with an M protein of 1.5 g/dL was 1.9 times the risk of progression with an initial value of ≤ 0.5 g/dL, while the risk of progression with an M protein of 2 g/dL initially was 4.6 times the risk of progression with an initial value of 0.5 g/dL. Patients with an IgM or an IgA monoclonal protein have an increased risk of progression compared to those with an IgG protein. The number of bone marrow plasma cells in the bone marrow is also an important factor. The presence of an abnormal serum free light chain ratio (FLC) is found in about one-third of patients with MGUS. The risk of progression in these patients was higher than in patients with a normal FLC ratio (hazard ratio = 3.5). This was independent of the level and type of serum M protein.8 Risk factors consisting of an elevated serum M protein ≥ 1.5 g/dL, an IgA or an IgM monoclonal protein, and an abnormal FLC ratio had a risk of progression at 20 years of 58% (high risk), compared with only 5% when none of these risk factors were present. It must be kept in mind that death from cardiovascular disease, cerebrovascular events, non-plasma cell malignancies or other causes unrelated to the plasma-cell proliferative process are much more common than death from a plasma cell disorder during long-term follow-up. Patients with MGUS should not be treated but should be tested again in four to six months to exclude the possibility of an evolving MM. I believe that patients with low-risk MGUS may be reevaluated every two years, whereas those with high-risk MGUS should be followed annually or until they develop an unrelated condition that significantly limits life expectancy. Distinguishing SMM from MM requiring therapy SMM is a more advanced premalignant stage than MGUS. Just as in MGUS, there is no evidence of CRAB (no end-organ damage) related to the plasma-cell proliferative process. However, patients with SMM may fulfill the usual diagnostic criteria of MM such as a serum M spike ≥ 3 g/dL, 10% or more plasma cells in the bone marrow, reduction of uninvolved immunoglobulins in the serum, and monoclonal light chains in the urine. Thus, SMM must be distinguished from MM requiring therapy. Approximately 10% to 20% of patients with newly diagnosed MM actually have SMM. In a group of 276 patients who fulfilled the criteria for SMM, the median age of 64 (with only 3% younger than 40) and 62% male were similar to that in MM.1 The serum M protein at diagnosis ranged from 0.5 to 5.4 g/dL with 11% of the patients having an M spike of ≥ 4 g/dL. IgG was the most common (74%), while 22.5% had IgA, 0.5% had an IgD monoclonal protein and biclonal gammopathies were found in 3%. Kappa was the most common light chain at 67%, with lambda in the remaining 33%. Reduction of uninvolved immunoglobulins occurred in 83%. A monoclonal light chain was found in the urine in 53% but was < 0.1 g/24h in 84%. The most common proportion of bone marrow plasma cells was in the 15% to 19% category. Only 10% had fewer than 10% plasma cells in the bone marrow, while 10% had 50% or more bone marrow plasma cells. During follow-up, 85% of patients with SMM died. During this period, symptomatic MM developed in 57%, while AL amyloidosis was recognized in 2%. The median time to progression (TTP) was 4.8 years. The median survival of the patients who developed MM was 3.4 years, which was similar to that of MM during the same period. Deaths from non-myeloma disorders, including cardiovascular and cerebrovascular disease as well as non-plasma cell cancers, were 18% at five years, 26% at 10 years, 30% at 15 years, and 35% at 20 years. The overall survival of SMM was 60% at five years, 34% at 10 years, and 20% at 15 years (median, 6.3 years). Risk of progression The risk of progression of SMM to MM was 10% per year for the first five years, 3% per year for the next five years, and then 1% to 2% per year for the next decade (Figure 1).1 This is in contrast to MGUS, which has a risk of progression of approximately 1% per year following recognition throughout more than 25 years of follow-up.9 The risk of progression to active MM or AL amyloidosis at 10 years was 55% for patients with an initial plasma cell level of 10% to 14%, compared to progression in 70% of the patients who had more than 50% plasma cell infiltration of the bone marrow. At 10 years, the risk of progression to active MM or AL amyloidosis was 57% in patients with an initial M protein of 2 g/dL and 70% in those with an M protein of 5 g/dL. On multivariate analysis, the size of the serum M protein and the number of bone marrow plasma cells were the most significant independent risk factors for progression. The cumulative probability of progression at 15 years was 87% in patients with ≥ 10% plasma cells and ≥ 3 g/dL of M protein compared to 70% for those with ≥ 10% plasma cells and < 3 g/dL of M protein, and only 39% for the patients with < 10% plasma cells and ≥ 3 g/dL of M protein. The median TTP was two years in the first group, eight years in the second group, and 19 years in those with fewer than 10% bone marrow plasma cells and ≥ 3 g/dL of monoclonal protein. At five years of follow-up, 66% of patients with IgA experienced disease progression, compared to 46% with IgG. At 10 years, 77% of patients with IgA experienced disease progression, compared to 62% with IgG. In addition to the size of the M protein and number of bone marrow plasma cells, an FLC ratio of ≤ 0.125 or ≥ 8 was an independent risk factor for progression. Incorporating the FLC ratio into the risk model, the five-year progression rates in those with bone marrow plasma cells ≥ 10% and a serum M protein ≥ 3 g/dL was 76%, while those with bone marrow plasma cells ≥ 10% but a serum M protein < 3 g/dL was 51%. The risk of progression was only 25% for those with a serum M protein ≥ 3 g/dL, bone marrow plasma cells < 10%, and an FLC ratio of > 0.125 to < 8.10 Treatment of patients with SMM I believe that patients with SMM should be observed for evidence of progression and not treated unless they are part of a clinical trial. The blood tests should be repeated two to three months after the initial recognition to exclude the possibility of an evolving MM. It has been suggested that there are two types of SMM—an evolving SMM characterized by progressive increase of the serum M protein until symptomatic MM develops and a non-evolving SMM in which the M protein is stable and then abruptly increases when symptomatic MM develops.11 If stable, testing should be repeated every four to six months for the first year and if still stable, reevaluate at six- to 12-month intervals. Efforts to treat patients with SMM have been reported. In a series of 29 eligible patients with SMM, 34% had a partial response to thalidomide. The median TTP to symptomatic myeloma was 35 months. The median TTP was 61 months for those achieving a partial response, 39 months for those with a minimal response (MR), and nine months for those whose disease failed to respond.12 Mateos et al. reported that 118 patients with SMM at high risk of progression were randomly assigned to lenalidomide and dexamethasone or no treatment. Four patients experienced disease progression in the lenalidomide/dexamethasone regimen, compared to 28 of 61 (46%) in the placebo arm. The three-year overall survival was 98% in the treated patients, compared to 82% for placebo.13 In my opinion, the key is to recognize the patients with SMM at the highest risk for progression and then treat them in a clinical trial with a regimen active for multiple myeloma and with as few side effects as possible. One would like to identify those patients who are at a 90% risk of progression at two years and treat them in a randomized clinical trial. Dr. Kyle is a Professor of Medicine, Laboratory Medicine, and Pathology at Mayo Clinic and has been an ASCO member since 1968. An internationally recognized expert in hematologic malignancies, he was the first to describe monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. In 2007, Dr. Kyle was presented with the David A. Karnofsky Memorial Award, ASCO’s highest scientific honor. References 1. Kyle RA, Remstein ED, Therneau TM, et al. N Engl J Med. 2007;356:2582-90. 2. Kyle RA, Therneau TM, Rajkumar SV, et al. N Engl J Med. 2006;354:1362-9. 3. Cohen HJ, Crawford J, Rao MK, et al. Am J Med. 1998;104:439-44. [Erratum. Am J Med. 1998;105:362.] 4. Landgren O, Gridley G, Turesson I, et al. Blood. 2006;107:904-6. 5. Landgren O, Katzmann JA, Hsing AW, et al. Mayo Clin Proc. 2007;82:1468-73. 6. Iwanaga M, Tagawa M, Tsukasaki K, et al. Mayo Clin Proc. 2007;82:1474-9. 7. Landgren O, Kyle RA, Pfeiffer RM, et al. Blood. 2009;113:5412-7. 8. Rajkumar SV, Kyle RA, Therneau TM, et al. Blood. 2005;106:812-7. 9. Kyle RA, Therneau TM, Rajkumar SV, et al. Mayo Clinic Proc. 2004;79:859-66. 10. Dispenzieri A, Kyle RA, Katzmann JA, et al. Blood. 2008;111:785-9. 11. Rosiñol L, Bladé J, Esteve J, et al. Br J Haematol. 2003;123:631-6. 12. Detweiler-Short K, Hayman S, Gertz MA, et al. Am J Hematol.2010;85:737-40. 13. Mateos M-V, López-Corral L, Hernández M, e tal. Smoldering Multiple Myeloma (SMM) At High-Risk of Progression to Symptomatic Disease: A Phase III, Randomized, Multicenter Trial Based On Lenalidomide-Dexamethasone (Len-Dex) As Induction Therapy Followed by Maintenance Therapy with Len Alone Vs No Treatment. ASH Annual Meeting Abstracts. 2011;Abst 991. ascoadmin Tue, 21 Feb 2012 18:28:25 GMT f1397696-738c-4295-afcd-943feb885714:3149 http://connection.asco.org/Magazine/Article/ID/3098/Evaluating-Risks-Benefits-of-Hormone-Therapy-for-Women-at-High-Risk-for-or-with-a-History-of-Breast-Cancer.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3098 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3098&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3098/Evaluating-Risks-Benefits-of-Hormone-Therapy-for-Women-at-High-Risk-for-or-with-a-History-of-Breast-Cancer.aspx Introduction Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Breast cancer is the most common malignancy diagnosed in women.1 The adoption of screening guidelines and advances in adjuvant therapy have led to significant improvements in survival for these women. As a result, an increasing number of premenopausal women survive breast cancer and subsequently experience debilitating menopausal symptoms. These include urogenital complaints (recurrent urinary tract infections, urinary urgency, vaginal dryness, and dyspareunia), vasomotor symptoms (hot flashes and night sweats), and central symptoms (insomnia, memory loss, and mood alterations) that may detract from the woman’s overall sense of well-being and interfere with her daily activities. Clinical trials in women with a history of breast cancer have identified moderately effective therapies for vasomotor symptoms, including selective serotonin and norepinephrine reuptake inhibitors and gabapentin.2 Topical lubricants improve vaginal dryness and decrease sexual concerns for some women with urovaginal symptoms. Hormone replacement therapy (HRT), either estrogen alone or combination estrogen/progesterone, is the most effective means to treat these symptoms and protects against the accelerated bone loss that may occur with treatment-induced menopause. However, the results from the Women’s Health Initiative study and others outline the potential harm of HRT.3,4 Healthy postmenopausal women with a uterus treated with combination estrogen and progesterone have an increased risk of breast cancer and breast cancer mortality. Postmenopausal women with a prior hysterectomy treated with a short to moderate duration of estrogen alone have an overall decrease in the risk of developing breast cancer. For women with a history of breast cancer, there is limited data. It is unclear whether estrogen for a short duration at a low dose, or estrogen in concert with tamoxifen, are reasonable recommendations for women with debilitating menopausal symptoms. In the feature that follows, the authors discuss the available data regarding the use of hormone replacement therapy for women at high risk for breast cancer as well as for those women with a history of breast cancer. While there is conflicting data from previously published trials, HRT in women with prior breast cancer requires careful evaluation of the risks and benefits and patient understanding of the available data. References 1. Siegel R, Ward E, Brawley O, et al. CA Cancer J Clin. 2011;61:212-36. 2. Loprinzi CL, Sloan J, Stearns V, et al. J Clin Oncol. 2009;27:2831-7. 3. Chlebowski RT, Anderson GL, Gass M, et al. JAMA. 2010;304:1684-92. 4. Stefanick ML, Anderson GL, Margolis KL, et al. JAMA. 2006;295:1647-57. Dr. Von Roenn is a Professor of Medicine at Northwestern University’s Feinberg School of Medicine, member of the Robert H. Lurie Comprehensive Cancer Center, and Medical Director of Northwestern Memorial Hospital’s Home Hospice Program. She serves on ASCO’s Cancer Education Committee and Professional Development Committee and is on the ASCO Connection Editorial Board. A Favorable Approach to the Use of Hormone Therapy Julia A. Files, MD Mayo Clinic, Phoenix Sandhya Pruthi, MD Mayo Clinic, Rochester A majority of breast cancers diagnosed occur in postmenopausal women and are hormone receptor-positive. Epidemiologic studies and one of the largest randomized controlled trials conducted in women have shown an increase in breast cancer risk following five years of combined estrogen-progestin (E+P) therapies compared to placebo and estrogen (E) alone.1,2 More recently, a large prospective study on hormone therapy (HT) and breast cancer risk also showed that breast cancer risk was greater among users of combination hormone therapy than users of estrogen-only formulations. Risk was also greater if the hormone therapy was initiated around the time of menopause rather than later in life.3 The North American Menopause Society recommends that HT be offered at the lowest effective dose for the shortest duration possible to women who are experiencing moderate to severe menopausal symptoms.4 Women at high risk for the development of breast cancer (those with a personal or family history of breast cancer, Gail Model > 1.66%, or personal history of precancerous breast lesion or BRCA mutation) may request systemic HT for management of moderate to severe menopausal symptoms. Physicians face the dilemma posed by the goal of minimizing risk of disease while trying to preserve quality of life. If HT is prescribed, it requires that the physician engage the patient in collaborative decision-making to choose the therapy that provides the most acceptable risk versus benefit for the individual patient. Risks for women with a BRCA mutation Recently, there has been discussion surrounding the use of HT and future risk of breast cancer in women with a BRCA mutation. Risk-reducing salpingo-oophorectomy is associated with decrease in overall mortality as well as breast and ovarian cancer-specific mortality, but may result in an exacerbation of moderate to severe menopausal symptoms.5 Several studies looking at short-term HT (systemic E+P and E alone) use in patients who have a BRCA mutation have not found an increase in breast cancer risk and the use may even be associated with a decrease in risk.6,7 Further, a study of women with a BRCA mutation who had undergone bilateral prophylactic oophorectomy and subsequent use of short-term HT reported that HT did not negate the breast cancer risk reduction following this procedure.8 Women with a prior diagnosis The decision to use HT in women with a prior diagnosis of breast cancer is more complex. Although observational studies and randomized trials of hormone therapy in breast cancer survivors have shown conflicting results, the use of systemic HT in women with a previous diagnosis of breast cancer (especially combined E+P) cannot be endorsed.1,9,10 Genitourinary atrophy (GUA) is a consequence of estrogen deficiency and is often worsened by the administration of aromatase inhibitors. Many women with a history of breast cancer suffer significant symptoms associated with GUA.11 Several recent overviews on the management of urogenital atrophy in women with a history of breast cancer have highlighted treatment with low-dose vaginal 17 B-estradiol (vaginal estradiol tablets 10 ug or vaginal estradiol ring) after appropriate disclosure to the patient.12 Appropriate dosing of local estrogen therapy is critical as although estrogen administered vaginally are associated with delivery of a lower dose over a year, it can lead to systemic levels equal to those achieved by oral or transdermal products. The lowest effective dose for achieving resolution of clinical symptoms without systemic effect is the goal. Best results may be achieved through the use of a low-dose vaginal estrogen tablet once a week in combination with daily use of vaginal lubricants and/or moisturizers. The long-term safety of these preparations are not known, and it may not be possible to ever design a large enough study that will be able to effectively evaluate vaginal preparations and breast cancer risk or recurrence. In addition, a critical factor to note is that many women discontinue or are non-compliant with their anti-estrogen therapies due to negative quality-of-life symptoms. In the large chemoprevention trials (STAR, MAP.3), low-dose vaginal estrogen preparations were allowed on study for management of symptoms associated with GUA.13,14 The decision to initiate low-dose vaginal estrogen needs to be individualized and made jointly with the oncologist.11,12 The role of HT in women with a prior diagnosis of breast cancer should be limited to local therapy for the treatment of GUA. In summary, the evidence at present does not support the use of systemic estrogen in patients with a diagnosis of breast cancer. The decision to use low-dose local vaginal estrogen in women at high risk or with a history of breast cancer should be done on an individualized basis and be made collaboratively with the patient, understanding the benefits and risks as well as taking into account the impact on quality of life. References 1. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350:1047-59. 2. Rossouw JE, Anderson GL, Prentice RL, et al. JAMA. 2002;288:321-33. 3. Beral V, Reeves G, Bull D, et al. J Natl Cancer Inst. 2011;103:296-305. 4. Santen RJ, Allred DC, Ardoin SP, et al. J Clin Endocrinol Metab. 2010;95(7 Suppl 1):s1-s66. 5. Domchek SM, Friebel TM, Singer CF, et al. JAMA. 2010;304:967-75. 6. Eisen A, Lubinski J, Gronwald J, et al. J Natl Cancer Inst. 2008;100:1361-7. 7. Domchek SM. J Clin Oncol. 2011;29:(suppl; abstr 1501). 8. Rebbeck TR, Friebel T, Wagner T, et al. J Clin Oncol. 2005;23:7804-10. 9. von Schoultz E, Rutqvist LE. J Natl Cancer Inst. 2005;97:533-5. 10. Holmberg L, Iversen OE, Rudenstam CM, et al. J Natl Cancer Inst. 2008;100:475-82. 11. Files JA, Ko MG, Pruthi S. Mayo Clin Proc. 2010;85:560-6; quiz 566. 12. Pruthi S, Simon JA, Early AP. Breast J. 2011;17:403-8. 13. Vogel VG, Costantino JP, Wickerham DL, et al. JAMA. 2006;295:2727-41. 14. Goss PE, Ingle JN, Alés-Martinez JE, et al. N Engl J Med. 2011;364:2381-91. Dr. Files is an Assistant Professor of Medicine and a physician in the Women’s Health Internal Medicine Division at Mayo Clinic, Phoenix, Arizona. Her research interest is women’s health. Dr. Pruthi is an Associate Professor of Medicine and a consultant in the Department of Medicine, the Division of General Internal Medicine, and the Breast Diagnostic Clinic at Mayo Clinic, Rochester, Minnesota. Her research interests include breast diseases and women’s health. Caution: Menopausal Hormone Therapy after Breast Cancer Rowan T. Chlebowski, MD, PhD Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Deepu Madduri, MD Harbor-UCLA Medical Center Any consideration of menopausal hormone therapy in patients with breast cancer for climacteric symptom management should begin with a clear understanding of the potential risk of breast cancer recurrence and premature death, as breast cancer safety for any hormonal approach in this setting is not established.1,2 Based on randomized clinical trial settings, hormone therapy regimens commonly used in women without breast cancer differ in their effects on breast cancer incidence. For postmenopausal women with a uterus, combined estrogen plus progestin increases breast cancer incidence,3 delays diagnosis,3,4 and nearly doubles breast cancer mortality.5 In contrast, estrogen alone in postmenopausal women with prior hysterectomy, at least for moderate duration use, reduces breast cancer incidence.6,7 It is unknown how these findings relate to hormone therapy use and recurrence risk in women with diagnosed breast cancer. Risks outweigh benefits for those with early-stage breast cancer The adverse influence of estrogen deprivation on climacteric symptoms and sexual dysfunction from breast cancer therapy are well recognized.1,8,9 While systemic hormone therapy is effective for climacteric symptom management, use in randomized clinical trial settings results in adverse breast cancer outcome. The HABITS trial (Hormonal Replacement after Breast Cancer—Is It Safe?) randomly assigned 434 women with early-stage breast cancer who had climacteric symptoms to either physician-directed hormone therapy or no such therapy. The trial was stopped early when hormone therapy more than doubled recurrence risk (HR: 2.4, 95% CI [1.3-4.2]).10 A parallel study, the Stockholm Trial, randomly assigned 378 patients with early-stage breast cancer to one of several defined hormone therapy regimens or no hormone therapy. As hysterectomy was common in this population, 73% received either estradiol alone or a “spacing out” estradiol regimen involving 14 days of progestin per 91-day cycle. Although events were limited (11 vs. 13, respectively), recurrences were not increased on hormone therapy.11 Unfortunately, such combination regimens with fewer days of progestin exposure are reported less effective in abrogating estrogen-associated endometrial cancer risk.12 Finally, the LIBERATE trial randomly assigned 3,148 women with early-stage cancer therapy and vasomotor symptoms to the hormonal agent tibolone, which reduces climacteric symptoms and increases bone density but not breast density, or no hormonal therapy. Recurrence risk was substantially increased (HR: 1.4, 95% CI [1.14-1.70]), especially in the tibolone group also receiving aromatase inhibitors (HR: 2.4, 95% CI [1.01-5.0]).13 While observational, largely retrospective reports of menopausal hormone therapy and breast cancer recurrence have reported safety, major design limitations, including frequent absence of balanced restaging at hormone therapy initiation and reports based on retrospective clinical experiences, preclude reliable conclusions.14 Managing urogenital systems For sexually active women with breast cancer, sexual dysfunction associated with vaginal dryness represents a difficult management problem.1,15 Simple non-hormone–based intervention, including vaginal lubricants, moisturizers, and dilator use, should be the initial approach.16 Vaginal lubricants not containing hormones have proven effective in randomized clinical trials for some women, but others may need local estrogen therapy for relief.17,18 However, a commonly prescribed sustained-release estradiol vaginal ring (Estring®) results in absorption sufficient to change lipid profile comparable to full-dose oral estrogens.19 An approach with potentially lower estrogen absorption would be non-hormonal lubricant inter-vaginally and a titrated-down dose of intermittent estrogen cream on the more sensitive external genitalia.1 Given the adverse signals regarding aromatase inhibitor use and estrogen addition from the LIBERATE trial,13 postmenopausal women with limiting symptoms related to vaginal atrophy should be switched to tamoxifen if local estrogen therapy is being considered. Unlike an aromatase inhibitor, tamoxifen reduces breast cancer recurrence risk in both low- and high-estrogen environments.20 While there is concern regarding endometrial cancer with combination estrogen plus tamoxifen, in the IBIS-I prevention trial endometrial cancers were not increased with that combination compared to tamoxifen alone,21 and in the Italian Tamoxifen Prevention Trial tamoxifen influence on breast cancer was not blocked by menopausal hormone therapy.22 Managing vasomotor symptoms For vasomotor symptoms, several selective serotonin reuptake inhibitors, including venlafaxine, provide substantial relief in approximately half of users.16,23 Mindfulness training holds exciting potential for coping with hot flash symptoms in the future. Since distress to climacteric symptoms reflects both the physical symptom severity and the women’s psychological reactions to them,24 a recent randomized trial evaluated mindfulness training-based stress reduction on hot flash distress. In the trial, while hot flash frequency did not differ among the randomization group (measured by skin temperature monitoring), the mindfulness training group had significantly better quality of life, subjective sleep quality, and lower anxiety and perceived stress.25 Premenopausal women with a BRCA1/2 mutation For premenopausal women with a BRCA1/2 mutation managed with prophylactic salpingo-oophorectomy, safety had been reported for systemic hormone therapy regarding breast cancer risk.26,27 However, caution is still advised as largely retrospective experiences involve short duration exposure and very few breast cancer events.28 In summary, regardless of the severity of climacteric symptoms, consideration of systemic combined hormone therapy must be cautiously approached given the substantial increase in recurrence risk seen with its use in randomized clinical trial settings. While local vaginal estrogen regimens are effective for women with vaginal dryness, their safety with respect to recurrence risk has not been established. Non-hormone–based therapies provide an attractive alternative warranting further study. References 1. Kwan KW, Chlebowski RT. Clin Breast Cancer. 2009;9:219-24. 2. Melisko ME, Goldman M, Rugo HS. J Cancer Surviv. 2010;4:247-55. 3. Chlebowski RT, Hendrix SL, Langer RD, et al. JAMA. 2003;289:3243-53. 4. Chlebowski RT, Anderson G, Pettinger M, et al. Arch Intern Med. 2008;168:370-7. 5. Chlebowski RT, Anderson GL, Gass M, et al. JAMA. 2010;304:1684-92. 6. Stefanick ML, Anderson GL, Margolis KL, et al. JAMA. 2006;295:1647-57. 7. LaCroix AZ, Chlebowski RT, Manson JE, et al. JAMA. 2011;305:1305-14. 8. Hickey M, Saunders C, Partridge A, et al. Ann Oncol. 2008;19:1669-80. 9. Panjari M, Bell RJ, Davis SR. J Sex Med. 2011;8:294-302. 10. Holmberg L, Iverson OE, Rudenstam CM, et al. J Natl Cancer Inst. 2008;100:475-82. 11. von Schoultz E, Rutqvist LE. J Natl Cancer Inst. 2005;97:533-5. 12. Furness S, Roberts H, Marjoribanks J, et al. Cochrane Database Syst Rev. 2009;(2):CDOOO402. 13. Kenemans P, Bundred NJ, Foidart JM, et al. Lancet Oncol. 2009;10:135-46. 14. Col NF, Kim JA, Chlebowski RT. Breast Cancer Res. 2005;7;R535-40. 15. Hill EK, Sandbo S, Abramsohn E, et al. Cancer. 2011;117:2643-51. 16. Carter J, Goldfrank D, Schover LR. J Sex Med. 2011;8:549-59. 17. Bygdeman M, Swahn M. Maturitas. 1996;23:259-63. 18. Nachtigall LE. Fertil Steril. 1994;61:178-80. 19. Naessen T, Rodriguez-Macias K, Lithell H. J Clin Endocrinol Metab. 2001;86:2757-62. 20. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2011;378:771-84. 21. Cuzick J, Forbes JF, Sestak I, et al. J Natl Cancer Inst. 2007;99:272-82. 22. Veronesi U, Maisonneuve P, Rotmensz N, et al. J Natl Cancer Inst. 2007;99:727-37. 23. Pachman DR, Jones JM, Loprinzi CL. Int J Womens Health. 2010;2:123-35. 24. Santoro N, Sherman S. New interventions for menopausal symptoms. Bethesda, MD: National Institutes of Health, U.S. Dept. of Health and Human Services, 2006. 25. Carmody JF, Crawford S, Salmoirago-Blotcher E, et al. Menopause. 2011;18:611-20. 26. Rebbeck TR, Friebel T, Wagner T, et al. J Clin Oncol. 2005;23:7804-10. 27. Eisen A, Lubinski J, Gronwald J, et al. J Natl Cancer Inst. 2008;100:1361-7. 28. Chlebowski RT, Prentice RL. J Natl Cancer Inst. 2008;100:1341-3. Dr. Chlebowski is a Professor in Residence at David Geffen School of Medicine at UCLA, Chief of the Division of Medical Oncology/Hematology at Harbor-UCLA Medical Center, and an investigator at the Los Angeles Biomedical Research Institute. He is a member of the Journal of Clinical Oncology Editorial Board and has served on various ASCO committees, including the Breast Cancer Risk Reduction Expert Panel. Dr. Madduri is a Fellow in the Division of Medical Oncology/Hematology at Harbor-UCLA Medical Center. ascoadmin Tue, 20 Dec 2011 17:34:29 GMT f1397696-738c-4295-afcd-943feb885714:3098 http://connection.asco.org/Magazine/Article/ID/3035/Development-of-Vaccines-for-Solid-Tumors-Can-We-Do-It.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=3035 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=3035&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/3035/Development-of-Vaccines-for-Solid-Tumors-Can-We-Do-It.aspx By Jedd D. Wolchok, MD, PhD Memorial Sloan-Kettering Cancer Center The notion of a vaccine to prevent or control solid tumors is inherently attractive based on the success of prophylactic immunization against a wide variety of infectious pathogens and the perceived specificity and low toxicity of vaccine monotherapy. To get the “low-hanging fruit” out of the way immediately, let’s deal with malignancies caused by viral infections, which have effective and approved vaccines available (human papillomavirus [HPV] and hepatitis B virus [HBV]). These represent evidence that “yes, we can do it” as prophylactic immunization against oncogenic HPV and HBV will certainly decrease the incidence of these malignancies. However, these represent relatively easy targets for the immune system as the antigens are inherently foreign and therefore highly immunogenic. For the average solid tumor, most of what the immune system “sees” is a spectrum of self antigens, which are shared with the normal tissue counterpart and subject to immunologic ignorance and tolerance. The challenges to cancer immunologists are to: 1) devise strategies to overcome ignorance and tolerance and/or 2) identify antigenic targets that are not routinely expressed on normal tissues (cancer testis antigens, neo-antigens from fusion proteins [BCR-ABL], mutational antigens). Enhancing the immunogenicity of self antigens Enhancing the immunogenicity of self antigens can be envisioned to occur through a variety of mechanisms. One is to use an altered form of the antigen. My research team and others have explored this strategy using xenogeneic or cross-species immunization, in which an orthologue from another species is used for vaccination.1 An example is the use of human tyrosinase DNA in dogs with metastatic melanoma. Dog tyrosinase is 90% identical to human, yet the 10% difference appears to be sufficient to suggest to the dog’s immune system that this is non-self. This strategy has led to the licensure of the tyrosinase DNA vaccine by the U.S. Department of Agriculture as the first therapeutic cancer vaccine in the United States.2,3 Studies using mouse antigen–based vaccines are currently being conducted to establish if a similar strategy is useful in humans. Another strategy to enhance immunogenicity against self antigens on cancer is to express the antigen in a viral vector, such as a poxvirus, adenovirus, or alphavirus backbone.4,5 The viral proteins in the vector may provide immunologic “help” due to their inherent immunogenicity, and the viral polymerases may have imperfect fidelity, leading to the production of altered antigens with improved immune responses resulting from the creation of improved epitopes. Currently, a poxvirus-based prostate cancer vaccine is being investigated in late-stage clinical trials after initial studies suggested that overall survival is improved with the use of such a vaccine.6 Vaccines also may be combined with other immune modulators to enhance potency. The success of sipuleucel-T for prostate cancer attests to the utility of a cell-based product to improve immunity to prostatic acid phosphatase (PAP), a self antigen. This product, recently licensed by the FDA, is based on expression of PAP fused to granulocyte-macrophage colony-stimulating factor (GM-CSF).7 The fusion protein is incubated with autologous peripheral blood mononuclear cells as a source of antigen-presenting cells. A variety of other strategies, including the use of cytokines, double-stranded RNA, and pathogen-derived materials, are currently undergoing investigation for their ability to act as immunologic adjuvants for cancer vaccines. “Holy grail” of cancer antigen identification The “holy grail” of cancer antigen identification is the use of a target derived from an oncoprotein. This would be a way of directly addressing cells that specifically harbor a mutated oncogene. If a specific mutation responsible for contributing to malignant transformation was identified, it clearly would be an excellent choice as a potential target for a cancer vaccine. For example, attention has been paid to the V600E mutation in BRAF given its strong association with cutaneous melanoma. Investigators are exploring the sequence to see if the specific mutation allows for enhanced binding to major histocompatibility complex (MHC) molecules compared with the wild-type BRAF protein. Vaccines targeting HER2/neu are based on such a principle if alterations of HER2 could induce immunity to this functionally important, over-expressed self antigen. Oncogenic fusions such as BCR/ABL also are attractive vaccine targets since the precise area of the fusion represents a non-self neo-antigen not expressed by the normal cell counterpart.8 There is also a class of proteins known as cancer/testis (C/T) antigens which, as the name implies, are only expressed on normal spermatozoa and a variety of malignancies. Transcription silencing occurs in other adult normal tissues; they are not subject to peripheral tolerance given the immunologically privileged nature of the testis. Two of these C/T antigens are MAGE-A3 and NY-ESO-1, which are both being studied in clinical trials for a variety of malignancies.9 The development of a successful preventive or therapeutic cancer vaccine for solid tumors clearly is an important goal. We have learned much about what prevents immunity to antigens on cancer and some novel strategies have emerged to address them. We can envision therapeutic vaccines as part of a more complex therapeutic program, including the use of more global immune modulators, such as CTLA-4 blocking antibodies.10 Routine use of combination approaches, which introduce additional possibilities for toxicity, likely will be problematic in the preventive setting where healthy but at-risk patients will be the population. In this setting, the urgency is to identify more immunogenic antigens specifically related to the malignant phenotype. Dr. Wolchok is a medical oncologist and melanoma specialist at Memorial Sloan- Kettering Cancer Center. He is a member of the Journal of Clinical Oncology Editorial Board and serves on the Grants Selection Committee for the Conquer Cancer Foundation of ASCO. Dr. Wolchok was the lead author on an abstract selected for the 2011 ASCO Annual Meeting Plenary Session—Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma (Abstract LBA5). References Naftzger C, Takechi Y, Kohda H, et al. Proc Natl Acad Sci U S A. 1996;93:14809-14. Bergman PJ, Camps-Palau MA, McKnight JA, et al. Vaccine. 2006;24:4582-5. Epub 2005 Aug 24. Bergman PJ, McKnight J, Novosad A, et al. Clin Cancer Res. 2003;9:1284-90. Kim CJ, Prevette T, Cormier J, et al. J Immunother. 1997;20:276-86. Avogadri F, Merghoub T, Maughan MF, et al. PLoS ONE. 2010;5:pii: e12670. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. J Clin Oncol. 2010;28:1099-105. Kantoff PW, Higano CS, Shore ND, et al. N Engl J Med. 2010;363:411-22. Jain N, Reuben JM, Kantarjian H, et al. Cancer. 2009;115:3924-34. Gnjatic S, Nishikawa H, Jungbluth AA, et al. Adv Cancer Res. 2006;95:1-30. Hodi FS, O’Day SJ, McDermott DF, et al. N Engl J Med. 2010;363:711-23. Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. ascoadmin Tue, 13 Sep 2011 00:56:22 GMT f1397696-738c-4295-afcd-943feb885714:3035 http://connection.asco.org/Magazine/Article/ID/2928/International-Perspectives-on-Breast-Cancer-Surveillance-for-Childhood-Cancer-Survivors.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=2928 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=2928&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/2928/International-Perspectives-on-Breast-Cancer-Surveillance-for-Childhood-Cancer-Survivors.aspx IntroductionSmita Bhatia, MD, MPH City of Hope Comprehensive Cancer Center Women exposed to chest radiation during childhood or adolescence for an unrelated cancer are at an increased risk of breast cancer. Overall, childhood cancer survivors are at a 13- to 55-fold increased risk compared with an age- and sex-matched general population. The absolute excess risk ranges from 18.6-79 per 10,000 person-years, and the cumulative incidence from 12%-26% after 25-30 years from radiation exposure.1-4 The risk of breast cancer has been found to increase as early as eight years from radiation exposure and continues to increase with time from exposure.1 The cumulative incidence of breast cancer by age 40-45 ranges from 13%-20%.1,2,4 The median age at diagnosis of breast cancer is 36, at least 25 years earlier than that observed in the general population. The risk is strikingly similar to that observed for women with a BRCA gene mutation, where, by age 40, the cumulative incidence of breast cancer ranges from 10%-19%,5 and is substantially higher than the risk for women in the general population (1% at a comparable age).6 Because of the similarity in risk of breast cancer between women receiving chest radiation and those with a BRCA mutation, it is logical to assume that similar recommendations, in terms of age at initiation, frequency of screening, and screening modalities should apply to the former group. Although currently available evidence is insufficient to demonstrate a survival benefit from the initiation of breast cancer surveillance in women treated with chest radiation for childhood cancer, interventions to promote detection of small and early-stage tumors may improve prognosis, particularly for those who may have more limited treatment options because of prior exposure to radiation or anthracyclines.7 In the feature that follows, clinicians from the United Kingdom (U.K.) and United States (U.S.) briefly discuss how breast cancer surveillance recommendations for this high-risk population were developed and implemented within their countries, with special reference to common and unique access issues and barriers within the respective health care systems. The perspectives presented underscore the need for more research, on both sides of the pond, to expand the evidence base, better understand the benefits and harms of the various breast cancer surveillance options, and to test interventions aimed at overcoming individual-, provider-, and system-level barriers. Dr. Bhatia is the first holder of Ruth Ziegler Chair in Population Sciences. In addition, she holds several positions at City of Hope National Medical Center, including Chair, Department of Population Sciences, Associate Director for Population Research at the Comprehensive Cancer Center, and Director of the Center for Cancer Survivorship. She is a member of the ASCO Cancer Survivorship Committee and has served on the Cancer Prevention Committee and the Journal of Clinical Oncology Editorial Board. She is the Associate Chair of the Children’s Oncology Group.Developing and Implementing Breast Cancer Surveillance Recommendations in the U.K. Gill Levitt, BSc, MRCP, MRCPCH Great Ormond Street Hospital for Children Roderick Skinner, MB, ChB The Newcastle Upon Tyne Hospitals NHS Foundation Trust In 2003, the U.K. Department of Health (DH) and the National Health Service (NHS) Breast Cancer Screening Programme released a recommendation for female Hodgkin lymphoma survivors treated with chest radiation prior to age 36.8 Initiation of screening begins at age 25 or eight years after radiation, whichever occurs last. Annual MRI is recommended for those age 25-29. At age 30, a baseline two-view mammogram is assessed. If the mammogram shows predominantly fatty tissue, then the woman has annual mammography until age 49. For women with dense breast tissue at baseline mammography, an annual breast MRI is combined with mammography. If the breast tissue becomes predominantly fatty prior to age 50, screening continues with annual mammography alone. Once a survivor is 51, the screening recommendation follows the average risk (general population) guideline consisting of mammography every three years. Concurrent with the release of the above recommendations, the DH set up a retrospective national notification and screening program for the approximately 5,000 women who were treated from 1962 onwards for Hodgkin lymphoma with supra-diaphragmatic radiation prior to age 36.8 The DH, working with the cancer network lead clinicians and regional cancer registries, identified eligible women and notified them by mail of their risk of breast cancer and invited them back to the lymphoma clinic for a single visit. At the clinic visit, the above recommendation for breast cancer screening was discussed and breast cancer screening tests ordered if desired. The new surveillance recommendations were made public by the press. Access and participation Through the U.K. NHS, there is universal access to the recommended breast cancer screening, according to the protocol described above. However, this access does not include other women treated with chest radiation for other cancers (e.g., non-Hodgkin lymphoma, Wilms tumor, sarcoma) during their pediatric or young-adult years. U.K. investigators have undertaken preliminary investigations to evaluate uptake and potential facilitators and barriers of breast cancer surveillance recommendations following the 2003 U.K. DH notification. Howell et al reported that only 58% (243/417) of eligible women in the Greater Manchester and Cheshire Cancer Network, the largest cancer network in England, responded to the notification and attended the lymphoma clinic visit.9 Among eligible women in the Weston Park Hospital, Sheffield area, 76% (77/101) attended a lymphoma clinic visit.10 Fifty-six of these women were interviewed before risk counseling and again following screening and results (50 patients).11 Absolom et al found that 64% learned more about late effects, 76% were reassured about their health, and that women were generally keen to take advantage of screening and experienced relatively little distress. To date, there are no published data on the national uptake of breast cancer surveillance from this notification exercise. Since 2003, there has not been another national effort to notify patients or general practitioners. New initiatives Two current initiatives seek to improve the care of children and young people treated for cancer in England. The National Institute for Health and Clinical Excellence (NICE) has published Improving Outcomes Guidance with quality standards against which cancer centers are now judged by regular peer review.12 The second is the DH-funded National Cancer Survivorship Initiative, which aims to improve the lives of those living with and beyond cancer, including appropriate care for cancer survivors as well as surveillance for later consequences of cancer and its treatment. This initiative has recommended that all patients receive a summary of the treatment they received and a care plan to outline the risk for specific late adverse effects of treatment and planned surveillance to facilitate earlier detection. It is anticipated that prospective provision of such information soon after completion of treatment will improve follow-up and surveillance uptake rates. Although Hodgkin lymphoma survivors are recognized to be at particularly high risk of breast cancer following radiotherapy and have a national surveillance program in place, other patient groups who received irradiation involving breast tissue are not included in the program. While less evidence is available than for Hodgkin lymphoma survivors, it appears logical to suggest similar surveillance for these survivors.9 Dr. Levitt is a Consultant in Pediatric Oncology at Great Ormond Street Hospital for Children NHS Trust. Her research and patient care interests include the treatment and late effects of treatment for childhood malignant disease in particular solid tumours. Dr. Skinner is a pediatric oncologist at Royal Victoria Infirmary. His professional interests include the late side-effects of treatment for cancer and leukemia in children, as well as bone marrow transplantation and aplastic anemia in children. Developing and Implementing Breast Cancer Surveillance Recommendations in the U.S. Kevin C. Oeffinger, MD Memorial Sloan-Kettering Cancer Center In 2002, the Institute of Medicine charged the Children’s Oncology Group (COG) with development of comprehensive clinical practice guidelines for long-term follow-up care of childhood cancer survivors.13,14 Based upon the available evidence and an assessment of the potential benefits and harms of different breast cancer surveillance options, COG recommended in 2003 that women treated for a pediatric cancer with moderate- to high-dose chest radiation (> 20 Gy) initiate annual screening mammography at age 25 or eight years after the radiation, whichever occurs last. In 2008, the recommendations were revised to also include an annual breast MRI.15 These recommendations have been adopted as the standard of care in the U.S. and are consistent with those of the American Cancer Society.16 Because a national or regional method to notify women of their risk of breast cancer does not exist in the U.S., dissemination efforts have largely been undertaken through posting of the COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers on a publicly available website.17 COG investigators have also contributed to efforts to increase clinician awareness of the risk of breast cancer in women treated with chest radiation through multiple avenues, including primary care-based journals, continuing medical education monographs, and through national and regional meetings. Access and participation There is no national health plan in the U.S.; universal access to breast cancer surveillance methods is not available. Instead, the cost of surveillance is either covered through private health insurance plans, public assistance programs (e.g., Medicaid, Medicare), or paid by the individual. Notably, 22.8% of U.S. women age 25-34 and 19.8% of U.S. women age 35-44 are currently without any form of health insurance.18 Many others are underinsured. Most private health insurance plans include coverage of breast MRI in this population of women; however, some insurers and Medicaid require a pre-authorization letter stating that the woman has a lifetime risk of breast cancer of 20% or more. For women without health insurance or with inadequate insurance, the cost of breast MRI generally prohibits the use of this mode of screening. Uptake of COG breast cancer surveillance recommendations is also challenged by the fact that adult survivors of pediatric cancer in the U.S. are not followed at a cancer center, but rather by a primary care physician or obstetrician/gynecologist, most of whom are unaware of the substantially heightened risk of breast cancer among these women.19-21 In 2005-2006, Childhood Cancer Survivor Study (CCSS) investigators interviewed women in the U.S. and Canada, age 25-50 years, who had survived pediatric cancer and whose treatment included chest radiation.22 Of those younger than 40 years, 47% had never had a mammogram or other breast imaging study. The most common barriers among younger women were their lack of awareness of the risk or the lack of recommendation for screening from their primary physician. Only 53% of women age 40-50 were being regularly screened. Less than 3% reported ever having a breast MRI. New initiatives These data have motivated increased efforts to develop effective interventions to educate providers and survivors about the need for breast cancer surveillance in this high-risk group. In a prospective feasibility study conducted among a random sample of 72 Hodgkin lymphoma survivors in the CCSS who were at increased risk for breast cancer and had not had a screening mammogram within the prior two years, distribution of a one-page survivorship care plan with breast cancer surveillance recommendations prompted 41% to complete a mammogram.23 These data informed an ongoing randomized clinical trial through the CCSS that is testing the effectiveness of a mail- and telephone-based intervention aimed at communicating with women about risk and the COG recommendation. In 2010, the Patient Protection and Affordable Care Act (PPACA) was signed into U.S. law. PPACA will prohibit denial of coverage based upon preexisting conditions, such as a history of childhood cancer. Thus, the PPACA may provide coverage for breast cancer surveillance for many cancer survivors who are currently unable to access the recommended screening tests. In addition, since many of these women have chronic diseases related to their cancer therapy,24the PPACA may influence the type of health care and preventive services available for these women.25 The effect of PPACA is yet to be determined, but offers the potential to improve access to breast cancer surveillance among women in this high-risk group. Dr. Oeffinger is a primary care physician and Director of the Adult Long-Term Follow-Up Program at Memorial Sloan-Kettering Cancer Center. He is a member of the ASCO Cancer Survivorship Committee and has served on the Journal of Clinical Oncology Editorial Board. He also serves on the Late Effects and Outcomes Steering Committee of the Children’s Oncology Group and the Survivorship Research Task Force for the American Association for Cancer Research. References Bhatia S, Yasui Y, Robison LL, et al. J Clin Oncol. 2003;21:4386-94. Kenney LB, Yasui Y, Inskip PD, et al. Ann Intern Med. 2004;141:590-7. Ng AK, Bernardo MV, Weller E, et al. Blood. 2002;100:1989-96. Taylor AJ, Winter DL, Stiller CA, et al. Int J Cancer. 2007;120:384-91. Easton DF, Ford D, Bishop DT. Am J Hum Genet. 1995;56:265-71. Fay MP, Pfeiffer R, Cronin KA, et al. Stat Med. 2003;22:1837-48. Tabár L, Duffy SW, Vitak B, et al. Cancer. 1999;86:449-62. United Kingdom Department of Health; Cancer Policy Team. Increased risk of breast cancer after radiotherapy for Hodgkin’s Disease: Patient Notification Exercise. London: Department of Health, 2003. NHS Breast Screening Programme. Accessible at http://www.cancerscreening.nhs.uk/breastscreen/. Howell SJ, Searle C, Goode V, et al. Br J Cancer. 2009;101:582-8. Greenfield DM, Wright J, Brown JE, et al. Br J Cancer. 2006;94:469-72. Absolom K, Greenfield D, Ross R, et al. Breast. 2007;16:590-6. Improving Outcomes Guidance National Institute for Health and Clinical Excellence (NICE) Accessible at http://guidance.nice.org.uk/CSGCYP. Hewitt M, Weiner S, Simone JV, eds. Childhood Cancer Survivorship: Improving Care and Quality of Life. Washington, DC: National Academies Press; 2003. Landier W, Bhatia S, Eshelman DA, et al. J Clin Oncol. 2004;22:4979-90. Henderson TO, Amsterdam A, Bhatia S, et al. Ann Intern Med. 2010;152:444-55; W144-54. Saslow D, Boetes C, Burke W, et al. CA Cancer J Clin. 2007;57:75-89. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer. 2008; Version 3.0. Accessible at http://www.survivorshipguidelines.org. Martinez ME, Cohen RA. Health insurance coverage: Early release of estimates from the National Health Interview Survey, January–June 2010. National Center for Health Statistics. December 2010. Accessible at http://www.cdc.gov/nchs/nhis.htm. Nathan PC, Greenberg ML, Ness KK, et al. J Clin Oncol. 2008;26:4401-9. Oeffinger KC, Mertens AC, Hudson MM, et al. Ann Fam Med. 2004;2:61-70. Oeffinger KC, Robison LL. JAMA. 2007;297:2762-4. Oeffinger KC, Ford JS, Moskowitz CS, et al. JAMA. 2009;301:404-14. Oeffinger KC, Hudson MM, Mertens AC, et al. Pediatr Blood Cancer. 2011;56:818-24. Oeffinger KC, Mertens AC, Sklar CA, et al. N Engl J Med. 2006;355:1572-82. Laiteerapong N, Huang ES. JAMA. 2010;304:899-900. Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. elyse.blye Thu, 02 Jun 2011 16:55:43 GMT f1397696-738c-4295-afcd-943feb885714:2928 http://connection.asco.org/Magazine/Article/ID/2857/Active-Cancer-Treatment-during-PregnancyTwo-perspectives-on-timing-and-drug-choice.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=2857 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=2857&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/2857/Active-Cancer-Treatment-during-PregnancyTwo-perspectives-on-timing-and-drug-choice.aspx Introduction Antonio C. Wolff, MD Sidney Kimmel Comphrensive Cancer Center at Johns Hopkins April 2011 issue: While breast cancer is relatively uncommon in young adults, women increasingly delay pregnancy and childbirth into their fourth decade of life, and sometimes into their 40s. Consequently, we have seen and expect to continue to see an increase in the frequency of breast cancer diagnosed during pregnancy. Much of the available data on disease management and maternal/child outcomes are retrospective, anecdotal, and/or self-reported to various registries. Still, a consistent pattern has emerged over the years, i.e., a coordinated and experienced multidisciplinary health care team is critical to ensure the most optimal outcome for mother and child. In this column, Dr. Jennifer Litton and Dr. Michael Perry write brief commentaries identifying some of the challenges imposed by this clinical scenario. Despite the limitations in our knowledge, a consistent pattern emerges: breast cancer outcome appears similar to that observed in nonpregnant patients with breast cancer; pregnancy termination is rarely needed; and most children appear to be doing well long-term, with only a small number born with congenital malformation or requiring special-needs care. While hopeful and optimistic, these data must be viewed with some caution in view of the ascertainment bias inherit to their method of collection. We now know that optimal evaluation of breast masses and staging are possible with an emphasis on imaging studies that limit or avoid radiation exposure such as ultrasound and magnetic resonance imaging, and that surgical intervention for diagnosis and treatment is safe in most cases despite limited data on the use of sentinel node technique during pregnancy. If appropriate, preoperative or postoperative chemotherapy with agents like cyclophosphamide, doxorubicin, and 5-fluorouracil is feasible during pregnancy, while the use of taxanes, trastuzumab, colony-stimulating factors, and radiation therapy should preferentially be delayed until after delivery. A more challenging clinical scenario is the less-common occurrence of pregnancy in women with metastatic disease; decisions about pregnancy termination are difficult, very personal, and must take into account the mother’s safety. Obstetricians, primary care, and cancer care providers should expect to meet this clinical scenario with increasing frequency. For the sake of our patients and their families, we must all be prepared to act in a coordinated fashion. Dr. Wolff is an Associate Professor of Oncology in the Breast Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Dr. Wolff is a member of the Journal of Clinical Oncology and ASCO Connection Editorial Boards, Co-Chair of the ASCO-CAP HER-2 and Hormone Receptor Testing in Breast Cancer Panels, past Chair of the ASCO Clinical Practice Guidelines Committee, and an ASCO Statesman Award recipient. Breast Cancer and Pregnancy Jennifer K. Litton, MD The University of Texas M. D. Anderson Cancer Center Treating a pregnant patient with breast cancer is a challenging and emotional situation for both the patient and the health care provider. Health care providers have often felt that in order to treat the mother appropriately, they had to recommended pregnancy termination. However, over the past several years, emerging data from case series and cooperation between cancer treatment centers have demonstrated experience in treating pregnant patients with breast cancer optimally while maintaining a viable pregnancy and delivering a healthy infant.1-3 This has led to multiple publications and expert opinions regarding the care of these patients. The data that are available, due to the nature of this situation, can never be level I evidence. We will never randomize patients to becoming pregnant during breast cancer or not. Therefore, sharing experience and outcomes in this clinical situation is paramount. As women increasingly are delaying childbearing, the incidence of breast cancer diagnosed during pregnancy is rising, and oncologists are expected to face this situation with increasing frequency in the future.4 The oncologist must effectively counsel each patient as to her individual risk of recurrence, survival, and toxicity in order to help support her decision regarding her pregnancy. The patient Mounting evidence has demonstrated that treating the mother in the second trimester with an anthracycline-based regimen can be both effective and safe.1,5 Additionally, there is building evidence (with now at least 40 reports in the literature) of taxanes being given safely during pregnancy.6 Older methotrexate-containing regimens, such as cyclophosphamide/methotrexate/fluorouracil (CMF), should be avoided, as methotrexate is a known abortifacient. Biologicals, such as trastuzumab, have recently been deemed unsafe during pregnancy by the FDA. Much of the older data and case series that demonstrated worse outcomes for the pregnant patient with breast cancer did not specify the treatments used or extent of delays of initiation of therapy. More recent case series detailing treatment during pregnancy have shown outcomes similar to nonpregnant patients.7-9 Assembling a multidisciplinary team that can effectively communicate throughout the treatment is essential to providing optimal care for the patient while monitoring the progress of the fetus. Several publications have outlined treatment plans, which include involving the medical oncologist, surgeon, radiation oncologist, and maternal-fetal specialist.10-11 At our institution, prior to each dose of chemotherapy administered, an ultrasound to evaluate fetal growth, fluid, and placental integrity is completed. We also use ultrasound to evaluate the tumor response to preoperative chemotherapy regimens. Radiation can be given in a timely fashion after the completion of chemotherapy, surgery, and delivery of the fetus. The child The long-term data of the children exposed to chemotherapy in utero are accumulating. Few prospectively collected data regarding the children exist. However, there are now multiple self-reporting registries emerging.1,12-13 To date, there is growing evidence that when anthracycline chemotherapy is given to patients after the first trimester, there is no increase in birth defects. At this point, there are no specific recommendations for follow-up health care for these children. These registries and cohorts will need to be continually followed over the next several decades, as the children become adults and have children of their own. The collaboration between institutions to provide this information is ongoing and necessary. Although there is no—and will never be—level I evidence in this challenging clinical situation, the mounting data reported show efficacy and safety when treating women during pregnancy with chemotherapy and surgery. Not offering treatment during pregnancy has the potential of causing significant harm to the patient, and thus the fetus, as delay of therapy may cause further tumor spread both locally and distally, decreasing the overall chance for cure. Jennifer K. Litton, MD, is an Assistant Professor in the Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center. Her research interests include pregnancy and breast cancer, genetic testing, the treatment of young patients with breast cancer, and oncofertility. References Hahn KM, Johnson PH, Gordon N, et al. Cancer. 2006;107:1219-26. Loibl S, von Minckwitz G, Gwyn K, et al. Cancer. 2006;106:237-46. Van Calsteren K, Heyns L, De Smet F, et al. J Clin Oncol. 2010;28:683-9. Andersson TM, Johansson AL, Hsieh CC, et al. Obstet Gynecol. 2009;114:568-72. Mir O, Berveiller P, Rouzier R, et al. Ann Oncol. 2008;19:1814-5. Mir O, Berveiller P, Goffinet F, et al. Ann Oncol. 2010;21:425-6. Beadle BM, Woodward WA, Middleton LP, et al. Cancer. 2009;115:1174-84. Murphy C, Mallam D, Stein S, et al. J Clin Oncol. 2010;28:15s (suppl; abstr 1589). Litton JK, Warneke CL, Hahn K, et al. Proc Breast Cancer Symp. 2010; abstr 105. Amant F, Deckers S, Van Calsteren K, et al. Eur J Cancer. 2010;46:3158-68. Litton JK, Theriault RL. Oncologist. 2010;15:1238-47. Cardonick E, Dougherty R, Grana G, et al. Cancer J. 2010;16:76-82. Avilés A, Neri N. Clin Lymphoma. 2001;2:173-7. Chemotherapy in Pregnancy Michael C. Perry, MD, MACP Ellis Fischel Cancer Center, University of Missouri School of Medicine The frequency of cancer in women of childbearing age is fortunately uncommon; nevertheless, the simultaneous occurrence is an extraordinarily difficult situation for the patient, her family, and the physician, requiring enough face-to-face discussion to ensure that everyone understands all the issues and is as comfortable with the options as possible. Cancer is the leading cause of death in childbearing women, with the most common malignancies being breast, cervix, ovary, leukemia, lymphoma, melanoma, and thyroid. After a histologic diagnosis has been confirmed, a modified staging approach is used, avoiding ionizing radiation in favor of ultrasound. This may, of necessity, result in understaging. An accurate estimation of the due date is critical as some malignancies can be reasonably predicted to pursue a slower course, with therapy delayed until after birth. Pharmacokinetic factors If therapy is considered to be necessary, then pregnancy-associated physiologic changes may change drug pharmacokinetics and require alternate dosing and schedules. The expected increase in cardiac output and plasma volume increases plasma flow and glomerular filtration rate. This, in turn, results in a lowering of the serum creatinine, and pregnancy may amplify the renal excretion of chemotherapeutic agents. The expected increase in total body water and plasma volume can increase the distribution volume for water-soluble drugs, decreasing peak drug concentrations and prolonging half lives. Amniotic fluid also serves as a pharmacologic third space for drugs such as methotrexate, delaying elimination and increasing toxicity. Pregnancy may also be associated with increased serum levels of certain proteins that may affect plasma concentration and distribution of drugs with low lipid solubility and increased affinity for plasma proteins. An enhancement in hepatic blood flow and hepatic oxidation may occur, which, along with the increased renal excretion, may result in increased drug clearance from the body. A decrease in gastrointestinal motility can affect oral drug distribution, especially late in pregnancy. Other changes include placental transfer, changes in fetal pharmacokinetics, and placental excretion. Risk factors Chemotherapy drugs administered in the first week after conception probably produce an “all or nothing” effect—a spontaneous abortion or a normal fetus. In the second and third trimesters, drugs may impair fetal growth and development. Neuronal growth in the brain continues during this period with possible microcephaly, mental retardation, and impaired learning. Risk factors have been assigned to all drugs based upon the level of risk a drug poses to the fetus during pregnancy. These categories are A, B, C, D, and X. Multiple factors influence the probability of teratogenesis: timing of exposure, dose, frequency of administration, and duration of exposure, as well as individual and genetic susceptibility. This brief review does not permit a separate listing of each drug, but the antimetabolites are particularly devastating when given in the first trimester, with less deleterious effects from alkylating agents. To summarize: in the setting of a malignancy in a pregnant woman, a firm diagnosis is required, with a reasonable attempt at staging without ionizing radiation, then a long, thoughtful discussion with the patient about her wishes and possibilities. Knowledge of the physiological changes that accompany pregnancy is critical and the choice of drugs essential. Michael C. Perry, MD, MACP, is Deputy Director of the Ellis Fischel Cancer Center, where he is Chair of the Scientific Peer Review Committee, as well as the Nellie B. Smith Chair of Oncology. He is also Director of the Division of Hematology and Medical Oncology at the University of Missouri. A past member of ASCO’s Board of Directors, Dr. Perry currently serves on the FDA Oncology Drug Advisory Committee. Reference Hartley MS, and Doll DC. “Chemotherapy in Pregnancy.” The Chemotherapy Sourcebook 5th edition. Michael C. Perry, ed. Philadelphia: Lippincott Williams & Wilkins, 2011. Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. CurrentControversies@asco.org Mon, 28 Mar 2011 14:51:34 GMT f1397696-738c-4295-afcd-943feb885714:2857 http://connection.asco.org/Magazine/Article/ID/2770/Bevacizumab-in-the-Treatment-of-Advanced-Ovarian-Cancer.aspx#Comments 6 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=2770 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=2770&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/2770/Bevacizumab-in-the-Treatment-of-Advanced-Ovarian-Cancer.aspx Introduction Jonathan S. Berek, MD, MMS Stanford University School of Medicine Editor-in-Chief, ASCO Connection January 2011 issue: Two randomized trials of primary chemotherapy with bevacizumab ([Gynecologic Oncology Group] GOG 0218 and ICON7) were presented and discussed at the 2010 Annual Meetings of ASCO, the European Society for Medical Oncology (ESMO), and the International Gynecologic Cancer Society (ICGS). These trials demonstrate a modest progression-free survival advantage in patients treated with bevacizumab concurrently with standard carboplatin and paclitaxel chemotherapy and then as maintenance therapy. Overall survival data are not yet available. Based on these data, targeting vascular endothelial growth factor (VEGF) in epithelial ovarian cancer is a valid strategy, and the development of other drugs that involve this pathway is important. The goal will be to discover similar agents that have an even better cost/benefit ratio and can be given by mouth. Drugs in this class will likely play an important role in the treatment of the disease. Taken together, several questions should be considered. Do these results justify approval of the agent for this purpose? Does the cost vs. benefit of the drug warrant approval? If not, should the drug be approved for use in other situations, e.g., treatment of persistent or relapsed disease? My colleagues, Robert Burger, MD, and Maurie Markman, MD, discuss these issues.   Bevacizumab Should Be Available as Part of Standard Primary Treatment Robert A. Burger, MD, FACS Fox Chase Cancer Center Strategies to target the fundamental processes of ovarian cancer disease progression are critical. Angiogenesis is one such process, and VEGF its central promoter. Bevacizumab, a VEGF neutralizing monoclonal antibody, has demonstrated single agent activity in phase II ovarian cancer trials.1,2 Two positive international cooperative group phase III studies of bevacizumab in front-line therapy have been reported in 2010: GOG 0218 (doubleblind, placebo-controlled)3-5 and ICON7 (open-label).6,7 Both demonstrated that, in comparison to women randomized to six cycles of carboplatin/paclitaxel alone, those randomized to chemotherapy in combination with bevacizumab followed by bevacizumab maintenance up to a pre-specified number of cycles (16 and 12, respectively) conferred a statistically significant prolongation of progression-free survival, the primary endpoint. The majority of participants had advanced disease (all in GOG 0218, 82% in ICON7). The experimental regimens were well tolerated, with adverse events similar to previous phase III trials for metastatic non-gynecologic malignancies. Gastrointestinal perforation and fistula rates were less than 3% in the experimental groups. There was no apparent difference in the rates of febrile neutropenia, arterial thrombo-embolic events, or wound healing complications. The only cumulative effects were hypertension requiring treatment (23% and 18% for GOG 0218 and ICON7, respectively) and proteinuria (less than 1% grade 3); hypertension was manageable in the vast majority of cases. Overall survival data have yet to mature—at this point there is no evidence of a benefit. For GOG 0218, unblinding to treatment assignment was permitted at the time of disease progression. The ultimate analysis of overall survival may be limited by a “cross-over” effect in the use of bevacizumab or other anti-VEGF agents for the management of recurrent disease. The potential benefit What is the potential clinical benefit to patients with advanced ovarian cancer? In GOG 0218 the hazard of disease progression was reduced by 28%, and for the 465 patients with stage III (residual tumor implants after initial surgery greater than 1 cm) or stage IV disease enrolled to ICON7, by 32%. This effect is consistent with results of previous advanced ovarian cancer phase III trials for which statistically significant improvements in overall survival were observed, but these trials were not vulnerable to a cross-over effect.8-11 In June 2010, the Gynecologic Cancer Intergroup reiterated its consensus statement from 200512 that progression-free survival is “most often the preferred primary endpoint for front-line ovarian cancer clinical trials” (including maintenance trials) because of the potential impact of multiple recurrence regimens on overall survival, and indeed there are over a dozen preferred active therapies listed by the National Comprehensive Cancer Network13—including bevacizumab. Those who argue against the incorporation of bevacizumab into front-line therapy often do so based on monetary cost. Although this is an important public health issue for patients with advanced ovarian cancer benefitting from prolonged therapy, our responsibility as oncologists is to offer the most clinically effective care available. Is integration of bevacizumab into front-line therapy appropriate in all cases of advanced ovarian cancer? It is too early to tell. For example, there is no level I evidence for use in patients receiving intraperitoneal (IP) chemotherapy (although the current GOG phase III IP trial incorporates bevacizumab in all three regimens) or for use in patients receiving neo-adjuvant chemotherapy prior to surgical cytoreduction. Will all patients receiving bevacizumab in front-line therapy benefit? The answer is clearly “no,” but just as it is also “no” for platinum/taxane-based chemotherapy itself. We clearly need to build on this experience, and there are many unanswered questions. Can molecular tumor or host characteristics predict benefit? What is the optimal duration of therapy in front-line treatment beyond a pre-specified number of cycles? For now, however, based on two independent lines of level I evidence, to deny the option of front-line bevacizumab to women with advanced ovarian cancer would be discriminatory. References Burger RA, Sill MW, Monk BJ, et al. J Clin Oncol. 2007;25:5165-71. Cannistra SA, Matulonis UA, Penson RT, et al. J Clin Oncol. 2007;25:5180-6. Burger RA, Brady MF, Bookman MA, et al. J Clin Oncol. 2010;28:18s (suppl; abstr LBA1). Burger RA, Brady MF, Bookman MA, et al. Abstract Book of the 35th ESMO Congress. 2010;21 suppl 8:viii307 (978PD). Burger RA, Brady MF, Fleming GF, et al. Phase III trial of bevacizumab in the primary treatment of advanced ovarian, primary peritoneal or fallopian tube cancer: a GOG study. Int J Gynecol Cancer. 2010;20 suppl 2. Accessible at: http://journals.lww.com/ijgc/Docume...Prague.pdf. Perren T, Swart AM, Pfisterer J, et al. Abstract Book of the 35th ESMO Congress. 2010;21 suppl 8:viii2 (LBA4). Pfisterer J, Perren T, Swart AM, et al. ICON7: A randomised controlled trial of bevacizumab in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer. Int J Gynecol Cancer. 2010;20 suppl 2. Accessible at: http://journals.lww.com/ijgc/Docume...Prague.pdf. McGuire WP, Hoskins WJ, Brady MF, et al. N Engl J Med. 1996;334:1-6. Brady M. Personal communication with the author. 2010. Armstrong DK, Bundy B, Wenzel L, et al. N Engl J Med. 2006;354:34-43. Katsumata N, Yasuda M, Takahashi F, et al. Lancet. 2009;374:1331-8. Thigpen T, Stuart G, du Bois A, et al. Ann Oncol. 2005;16 suppl 8:viii13-viii19. Ovarian Cancer (Including Fallopian Tube Cancer and Primary Peritoneal Cancer), Version 2.2011. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Accessible at: http://www.nccn.org/professionals/p...varian.pdf. Bevacizumab: The Correct Question Is Not “If,” But “When” Maurie Markman, MD Cancer Treatment Centers of America, Eastern Regional Medical Center Two well-designed and conducted phase II clinical trials have rather convincingly revealed that single-agent bevacizumab possesses considerable biological activity in recurrent and platinum-resistant ovarian cancer.1,2 Further, one of these second-line studies demonstrated that, compared to a large and quite rationally selected “historical control population,” use of this agent provides at least as great an opportunity for an individual patient to experience a prolonged time to subsequent disease progression as associated with other drugs which might be employed in this specific setting.1 Additional reported phase II experiences support the overall conclusion that bevacizumab possesses an impressive degree of activity in the second-line management of epithelial ovarian cancer.3,4 While the issue of defining clinical benefit was unfortunately not directly addressed in these studies (nor is such a critically relevant assessment a common practice in ovarian cancer clinical trials), it is clear that many women entered into the trials who exhibited a measurable tumor response also achieved a meaningful degree of improvement in cancer-related symptoms and quality-of-life. Thus, in the opinion of this commentator, the most appropriate question to be addressed in this current debate is not whether bevacizumab should be used as one potential standard-of-care option in the treatment of advanced ovarian cancer, but rather, when is the most rational time in the course of the malignancy to employ the agent in routine practice, with the very specific aim to favorably impact the individual woman’s clinical course and outcome (survival and cancer-related symptoms)? Accepting the standard as being the specific treatment paradigm reported in the GOG trial would essentially require that all patients with advanced ovarian cancer receive 22 cycles of bevacizumab (assuming the absence of documented disease progression or unacceptable toxicity) to achieve a median improvement in progression-free survival of 3.8 months (with, to date, no statistically significant impact on median overall survival).5 Further, as these data actually relate to a population of individuals, the multiple cycles of this not-inexpensive and not-non-toxic drug will be delivered without any evidence that the particular patient is achieving any clinical benefit beyond that associated with the carboplatin plus paclitaxel (or a comparable platinum/taxane regimen) she is also receiving as a routine component of her treatment regimen. However, if administered in the second-line (or later) setting as a single agent (or possibly as part of a regimen that includes a cytotoxic drug, assuming future evidence-based data support such a conclusion), formal assessment of the clinical utility of the approach (e.g., decrease in measurable tumor masses, reduction in pain or ascites, or a substantial reduction in the serum CA-125 level, etc.) can be undertaken after a limited number of bevacizumab cycles to determine if continuation of the agent (with its associated cost and toxicity) is medically warranted. Patients failing to achieve evidence of a meaningful objective or subjective (or both) measure of clinical benefit would have treatment with this agent stopped, while the demonstration of a favorable impact would certainly result in continuation of, and payment for, the drug. It is reasonable to strongly argue that under this alternative scenario it would be far easier to justify the cost (and potential side effects) of this very important anti-neoplastic agent in the management of an individual patient with ovarian cancer, since after the initial one to three cycles only women exhibiting at least a modest documented degree of actual clinical benefit will be continuing to receive the drug. References  Burger RA, Sill MW, Monk BJ, et al. J Clin Oncol. 2007;25:5165-71. Cannistra SA, Matulonis UA, Penson RT, et al. J Clin Oncol. 2007;25:5180-6. Garcia AA, Hirte H, Fleming G, et al. J Clin Oncol. 2008;26:76-82. Wright JD, Hagemann A, Rader JS, et al. Cancer. 2006;107:83-9. Burger RA, Brady MF, Bookman MA, et al. J Clin Oncol. 2010;28:18s (suppl; abstr LBA1). Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. CurrentControversies@asco.org Tue, 04 Jan 2011 19:05:18 GMT f1397696-738c-4295-afcd-943feb885714:2770 http://connection.asco.org/Magazine/Article/ID/2683/Treatment-Strategies-for-Localized-Central-Nervous-System-Germinoma.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=2683 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=2683&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/2683/Treatment-Strategies-for-Localized-Central-Nervous-System-Germinoma.aspx Combined chemotherapy and radiation versus radiation alone: Two opposing views Amar Gajjar, MD St. Jude Children’s Research Hospital   October 2010 Issue: Primary intracranial germ cell tumors represent 3% of all intracranial tumors in children in Europe and the United States, with a higher prevalence in Japan and Asia. The peak incidence is in the second decade of life. Germinomas account for approximately twothirds of intracranial germ cell tumors. Progression-free survival in pure germinomas is excellent, with five-year overall survival (OS) rates exceeding 90% in many retrospective and prospective series. Historically, craniospinal irradiation (CSI) followed by a boost to the primary tumor area has been regarded as the standard treatment for intracranial germinoma. However, the role of CSI in the treatment of localized germinoma has been called into question due to its late effects and the low incidence of spinal relapses in series that have omitted spinal irradiation. Excellent responses have been achieved with whole brain radiation therapy and whole-ventricle irradiation followed by a boost to the primary tumor(s). Systemic chemotherapy followed by involved field irradiation has been tested as a means of reducing radiation doses and/or volume while maintaining high cure rates. Current prospective protocols are seeking to maintain the high cure rates for this tumor while developing therapy with the fewest short- and long-term toxicities. The following represents two independent points of view: the merits of combined modality therapy, presented by Eric Bouffet, MD, compared with the benefits of treatment with CSI therapy, presented by Rolf Kortmann, MD. Important areas of discussion include contemporary staging of newly diagnosed patients with central nervous system (CNS) germinoma, cure rates with different treatment modalities alone and in combination, dose and volume of irradiation, and toxicities and late effects of each treatment approach. Reference Finlay J, da Silva NS, Lavey R, et al. Pediatr Blood Cancer. 2008;51:313-6. Combined Chemotherapy and Limited-field Radiation Therapy Eric Bouffet, MD, FRCP(C) The Hospital for Sick Children Toronto, Canada   The relative contributions of radiation therapy and chemotherapy remain a topic of debate in the treatment of highly curable CNS germinomas. The efficacy of chemotherapy in patients with intracranial germ cell tumors has been recognized since the mid-1980s,1 and cyclophosphamide, cisplatin, carboplatin, and etoposide have demonstrated activity in patients with newly diagnosed and recurrent tumors. In a pilot study of pre-radiation carboplatin for patients with intracranial germinoma, seven complete and three partial responses were observed in 10 evaluable patients.2 In another study of neoadjuvant (pre-radiation therapy) chemotherapy, the response rate to cyclophosphamide was excellent, with seven complete responses out of eight patients with germinoma.3 Although all of these drugs appear to be highly effective, the combination of carboplatin and etoposide appears to be the gold standard in the management of germinoma, as chemotherapeutic agents that require hyperhydration can be associated with significant side effects in patients with diabetes insipidus.4,5 Minimizing adverse effects The efficacy of chemotherapy observed in pilot studies has contributed to introducing pre-irradiation chemotherapy to treat patients with germinoma in order to allow a reduction in irradiation treatment volume and doses. The main objective of this combined treatment approach is to minimize potential long-term effects of large-volume, high-dose radiation—such as neurocognitive deficits, vascular complications, and endocrine deficits—particularly among patients with nonmetastatic germinoma. However, there currently is no consensus on an optimal treatment strategy, and the absence of large prospective studies with long-term follow-up precludes any definitive conclusion. Studies confirming the combined approach The feasibility and the efficacy of combining chemotherapy with limited-field radiation have been confirmed in several studies. Using a combination of carboplatin, etoposide, and ifosfamide as initial therapy, followed by a radiation treatment to the initial tumor bed with a 1-cm to 2-cm margin at a dose of 4,000 cGy, a study reported a 93.3% event-free survival and 100% OS at 32 months in a group of 29 patients.6 These results were confirmed in a follow-up report of 57 patients by the same investigators.7 Others have reported outcomes of newly diagnosed patients receiving lower doses of irradiation. Seventeen patients were treated with four cycles of either etoposide and cisplatin or ifosfamide/etoposide/cisplatin (ICE) followed by 2,400 cGy focal irradiation in 12 fractions.8 Three patients with dissemination received CSI. At a median follow-up of 24 months, 16 of 17 patients were alive without recurrence. Following these early studies, the Japanese Germ Cell Tumor (GCT) Study Group conducted a cooperative study (1995-2003) using a combination of carboplatin (450 mg/m2 on day 1) and etoposide (450 mg/m2 on days 1-3) for three courses followed by focal radiation at a dose of 24 Gy for patients with nonmetastatic germinomas. One hundred and twenty-three patients with germinoma were enrolled, and the five-year OS was 98%. However, three cooperative groups (Japanese, French, and the Societé Internationale Oncologie Pédiatrique [SIOP]) achieved similar conclusions when they reviewed the pattern of relapse among patients treated with focal irradiation and chemotherapy9-11 and reported a 10% to 15% relapse rate using this approach. Importantly, a significant number of relapses occurred in the vicinity of the primary tumor, particularly within the ventricular region. All groups concluded that focal radiation was associated with an increased risk of ventricular failure and that whole ventricular field irradiation should be the “standard” approach for patients with nonmetastatic germinoma. Ongoing studies in the SIOP group and in Japan are aimed at confirming the safety and relevance of this approach. This combined strategy only concerns patients with nonmetastatic germinoma, and the benefit of pre-radiation chemotherapy for patients with evidence of dissemination who receive craniospinal radiation is still unproven. However, this combined approach seems to be applicable to patients with bifocal tumors, and excellent outcomes have been reported with chemotherapy followed by limited-field radiation in this subgroup, which accounts for 15% to 25% of all germinomas.12,13 Unanswered questions and future studies Overall, the introduction of chemotherapy in the management of intracranial germinoma has contributed to a significant reduction in both dose and volume of radiation. Pilot studies have shown that a dose of 24 Gy and a limited field are sufficient when pre-radiation chemotherapy is used. There is currently no evidence that more intensive chemotherapy will allow further volume or dose reduction of radiation. Although current outcomes are excellent, there are still unanswered questions. Future studies should try to better identify the risk of ventricular spread of pineal and/or suprasellar germinoma in order to tailor radiation fields and volumes accordingly. References Allen JC, Bosl G, Walker R. J Neurooncol. 1985;3:147-52. Allen JC, DaRosso RC, Donahue B, et al. Cancer. 1994;74:940-4. Allen JC, Kim JH, Packer RJ. J Neurosurg. 1987;67:65-70. Afzal S, Wherrett D, Bartels U, et al. J Neurooncol. 2010;97:393-9. Kellie SJ, Boyce H, Dunkel IJ, et al. Pediatr Blood Cancer. 2004;43:126-33. Baranzelli MC, Patte C, Bouffet E, et al. Cancer. 1997;80:1792-7. Bouffet E, Baranzelli MC, Patte C, et al. Br J Cancer. 1999;79:1199-204. Sawamura Y, Shirato H, Ikeda J, et al. J Neurosurg. 1998;88:66-72. Alapetite C, Ricardi U, Saran F, et al. Med Pediatr Oncol. 2002;39:248. Calaminus G, Nicholson JC, Alapetite C, et al. Med Pediatr Oncol. 2002;39:227. Matsutani M, ed. Treatment of intracranial germ cell tumors: the second phase II study of Japanese GCT group . Abstracts from the Thirteenth International Symposium of Pediatric Neuro-oncology, Chicago: Neuro-oncology. 2008;10:420. Lafay-Cousin L, Millar BA, Mabbott D, et al. Int J Radiat Oncol Biol Phys. 2006;65:486-92. Lee L, Saran F, Hargrave D, et al. Childs Nerv Syst. 2006;22:1513-8. 18 I Craniospinal Irradiation Alone in Pure Germinoma Rolf D. Kortmann, MD University of Leipzig Leipzig, Germany   Radiation therapy in pure germinoma is indispensable in providing a cure. Chemotherapy alone cannot replace radiation therapy as sole treatment and can only be performed in a combined setting.1-3 Additionally, a reliable and complete staging—including histologic verification, assessment of tumor markers, cerebrospinal fluid cytology, and brain and spinal magnetic resonance imaging to exclude non-seminomatous germ cell tumors and metastatic spread—is mandatory. The current recommended dose to treat subclinical disease is 20 Gy to 24 Gy and 40 Gy to macroscopic tumor, independent of the addition of chemotherapy.4 Radiation therapy alone in localized disease The literature is replete with retrospective studies reporting on radiation therapy alone in pure intracranial germinoma using different treatment volumes. When reviewing the data, it becomes clear that any reduction in treatment volumes is notoriously associated with increased relapse rates, especially if staging is incomplete. Presently, the most important issue in radiation therapy is whether a reduction of treatment volumes can be afforded without the supplemental use of chemotherapy. Craniospinal irradiation CSI alone is a consequent treatment and has long been considered the gold standard, providing cure in more than 95% of patients. Rogers and colleagues reviewed published data on 343 patients who received craniospinal radiation therapy as sole primary treatment.5 Local control was achieved in all but one patient, and four (1.2%) had isolated spinal relapses. Overall there were 13 relapses (3.8%), and more than half of the reported relapses occurred outside the craniospinal axis. However, adverse late effects have been suggested, particularly in younger patients, raising the question of whether reduced treatment volumes could be applied without jeopardizing the high cure rates and whether additional chemotherapy could be avoided, as the combination of both treatment modalities may cause increased toxicities to the CNS and lead to an increased rate of secondary malignancies as suggested in a large-scale SEER analysis.6 Whole brain/whole ventricular system irradiation In modern studies that have applied various volumes to intracranial germinomas, authors tend to conclude that if staging is complete and localized disease is confirmed, spinal radiation therapy may be safely omitted. Studies with no prophylactic irradiation of the spine (in which complete staging was not obtained for all patients) reported rates of relapse to the spine have been low: 0% to 10%.7-14 In one study, the incidence of spinal relapses was 4% (two of 56) for patients treated with spinal irradiation and 3% (two of 70) for those without spinal irradiation.14 In a retrospective study, local field and/or whole brain irradiation was performed in 114 patients and CSI in 66 patients. Eight-year overall and event-free survival rates were 91% and 89%, respectively. The eight-year recurrence rates at the primary site, intracranial space, and the spinal space were 1%, 6%, and 6%, respectively, regardless of target volume.15 In 278 patients receiving either whole brain or whole ventricular irradiation, local control was achieved in 97.5%.5 The frequency of isolated spinal relapses (eight patients) did not differ significantly from that for CSI (2.9% vs. 1.2%). When whole ventricular irradiation has been used, extra-ventricular intracranial relapses have rarely been reported, suggesting that whole brain radiation therapy would not be necessary. One study showed that no isolated spinal cord relapses occurred in 41 patients with localized germinoma. Six patients received CSI and 35 did not. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. None of the 18 patients with ventricular radiation relapsed.13 Another study similarly reported three outfield relapses in 39 patients (7%) with exclusive postoperative radiation therapy to the whole supratentorial ventricles.16 Focal radiation therapy alone In studies that have delivered primarily radiation therapy alone with volumes tailored to the gross disease, focal irradiation limited to the tumor bed is associated with reduced relapse-free survival rates.11,12,16-19 In an analysis of 133 patients receiving focal radiation therapy alone, the local recurrence rate was 6.8%, and the spinal relapse rate was nearly four times higher than for whole brain or whole ventricular radiation (15 patients; 11.3%).5 The total relapse rate was 23.3%. The addition of chemotherapy cannot meaningfully reduce the recurrence rates. The relapse rate is still between 11% and 66% (median, 16%). Relapses were observed within the ventricles, mainly localized at margin or out of the radiation therapy field.2,20-23 Investigators observed six relapses in 18 patients who received local radiation therapy with a margin of 1.5 cm to the initial gross tumor volume and no relapse in nine patients after ventricular irradiation.24 It should be noted that relapsing disease requires intensive salvage treatments, including CSI and chemotherapy, bearing a high risk for acute complications and severe late effects. Chemotherapy is unable to control subclinical disease within the ventricular system and as a consequence radiation therapy in a combined setting has to include the whole ventricular system. Chemotherapy is, therefore, only causing additional toxicities without a gain in tumor control and survival. Craniospinal irradiation alone in metastatic disease Approximately 30% of patients with germinoma have metastatic disease at diagnosis, but reports on disease management are scarce and contain heterogeneous treatment concepts. In an analysis of 129 patients, 51 had multifocal or disseminated disease. Twenty-two received CSI and some received additional chemotherapy. Event-free survival for multifocal or disseminated tumors was inferior to patients with solitary tumors.15 Details, however, were not given. In the German Maligne Keimzelltumoren (MAKEI) study, 18 of 60 patients had metastatic disease. All received CSI alone without experiencing a treatment failure.25 The data published so far, however, are based on small patient numbers and therefore do not permit a reliable conclusion on optimal treatments. A reduction of treatment volumes even when combined with chemotherapy is most likely associated with an increased relapse rate. Considering the fact that chemotherapy is unable to control intracranial leptomeningeal disease within the ventricular system in localized germinoma, correspondingly subclinical leptomeningeal spread to the entire intracranial and spinal leptomeningeal space in metastatic disease would also be insufficiently treated by chemotherapy. Thus, CSI is necessary and chemotherapy would only add toxicity. Even modern imaging technologies that can detect subtle lesions would not open up the possibility to perform an individualized approach sparing as much normal tissue as possible. Potential areas at risk are, by definition, normal on imaging. Conclusion CSI in localized intracranial pure germinoma is the most robust treatment, providing cure in almost all patients. Relapses consisted of initially unrecognized teratoma, initially undetected secreting germ cell tumor, or metachronous tumor within or outside the CNS.25 In completely staged cases target volumes can apparently be safely restricted to whole ventricular radiation therapy plus boost. A prospective randomized trial to show an advantage of whole ventricular irradiation over CSI is biometrically difficult to conduct as this study would require a very large patient number. As with the current philosophy to manage intracranial ependymoma, a straightforward approach to apply this concept in a prospective controlled fashion could be favored. References Bouffet E, Baranzelli MC, Patte C, et al. Br J Cancer. 1999;79:1199-204. Alapetite C, Ricardi U, Saran F, et al. Med Pediatr Oncol. 2002;39:248. Kellie SJ, Boyce H, Dunkel IJ, et al. Pediatr Blood Cancer. 2004;43:126-33. Kortmann RD, Calaminus G, Becker G, et al. Int J Radiat Oncol Biol Phys. 2000;48(Supp 1):204. Rogers SJ, Mosleh-Shirazi MA, Saran FH. Lancet Oncol. 2005;6:509-19. Inskip PD, Curtis RE. Int J Cancer. 2007;121:2233-40. Linstadt D, Wara WM, Edwards MS, et al. Int J Radiat Oncol Biol Phys. 1988;15:291-7. Shibamoto Y, Abe M, Yamashita J, et al. Int J Radiat Oncol Biol Phys. 1988;15:285-90. Brada M, Rajan B. Br J Cancer. 1990;61:339-40. Dattoli MJ, Newall J. Int J Radiat Oncol Biol Phys. 1990;19:429-33. Wolden SL, Wara WM, Larson DA, et al. Int J Radiat Oncol Biol Phys. 1995;32:943-9. Shirato H, Nishio M, Sawamura Y, et al. Int J Radiat Oncol Biol Phys. 1997;37:511-5. Haas-Kogan DA, Missett BT, Wara WM, et al. Int J Radiat Oncol Biol Phys. 2003;56:511-8. Ogawa K, Shikama N, Toita T, et al. Int J Radiat Oncol Biol Phys. 2004;58:705-13. Shikama N, Ogawa K, Tanaka S, et al. Cancer. 2005;104:126-34. Matsutani M, Sano K, Takakura K, et al. J Neurosurg. 1997;86:446-55. Haddock MG, Schild SE, Scheithauer BW, et al. Int J Radiat Oncol Biol Phys. 1997;38:915-23. Aoyama H, Shirato H, Yoshida H, et al. Radiother Oncol. 1998;49:55-9. Shibamoto Y, Sasai K, Oya N, et al. Radiology. 2001;218:452-6. Cefalo G, Gianni MC, Lombardi F, et al. Med Pediatr Oncol. 1995;25:303. Allen JC, DaRosso R, Donahue B, et al. Cancer. 1994;74:940-4. Buckner JC, Peethambaram PP, Smithson WA, et al. J Clin Oncol. 1999;17:933-40. Nguyen QN, Chang EL, Allen PK, et al. Cancer. 2006;107:2228-36. Shirato H, Aoyama H, Ikeda J, et al. Int J Radiat Oncol Biol Phys. 2004;60:214-7. Bamberg M, Kortmann RD, Calaminus G, et al. J Clin Oncol. 1999;17:2585-92. Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. CurrentControversies@asco.org Wed, 22 Sep 2010 17:05:54 GMT f1397696-738c-4295-afcd-943feb885714:2683 http://connection.asco.org/Magazine/Article/ID/2573/Aspirin-Intake-and-Survival-after-Breast-Cancer.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=2573 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=2573&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/2573/Aspirin-Intake-and-Survival-after-Breast-Cancer.aspx An exciting study sparks questions, including the critical one: What will we tell our patients? Further Investigation Needed July 2010 Issue: Current treatment options for breast cancer are, although effective, in general very expensive, and as the global population continues to age, a steady increase in breast cancer cases can be expected, along with growing health care costs. There are currently more than 2.5 million breast cancer survivors in the United States alone,1 and the risk of recurrence and of dying of the disease remains a significant and longstanding concern for these women. The potential for an effective and low-cost medication that can be added to the arsenal of adjuvant agents to further prolong survival is exciting. The recent prospective observational study in the Nurses’ Health Study by Holmes et al. (2010) provides support for the use of aspirin after a diagnosis of breast cancer.2 The study population consisted of 4,164 female registered nurses between ages 30-55 at baseline in 1976, who were subsequently diagnosed with stage I-III breast cancer and survived at least one year. Information on aspirin use was assessed by questionnaire every two years following breast cancer diagnosis and included questions on never, past, or current regular-use, and days per week of use. Aspirin assessment was missing for 2,910 women. The primary outcomes were breast cancer mortality (assessed by family report or U.S. Postal Service, National Death Index, and death certificates) and breast cancer recurrence. Aspirin use of six to seven days per week compared with never-users was associated with a 74% reduction in risk of breast cancer death (relative risk = 0.36, 95% CI 0.24 - 0.54). A similar result was seen when comparing aspirin use of two to five days per week to never-use. This association did not change by stage, body mass index, menopausal status, or estrogen receptor status. Results for distant recurrence showed a 43% risk reduction for six to seven days per week of aspirin use versus never-use (relative risk = 0.57, 95% CI 0.39 - 0.82) and a 60% reduction in risk for two to five days per week. These findings are consistent with two previous studies3,4 that found an association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer recurrence or survival. Biologic plausibility for the associations seen in this study is supported by preclinical models. Breast cancer cells have been shown to produce greater amounts of prostaglandins than normal breast cells in vitro.5 Aspirin, among other NSAIDs, inhibits prostaglandin and COX-2 production. COX-2 knockout mice show decreased tumor growth when given NSAIDs in a variety of cancers.6 Questions of dose and duration Despite these strong results, in evaluating this study we also need to consider some of its limitations. The first issue is dosage and the question of whether there is a dose effect. Although the authors included questions on indications for aspirin use that might imply dosage (e.g., cardiovascular disease prevention, headache, etc.), actual dosages used were not ascertained. This is important information for assessing potential toxicity, particularly when considering long-term use of such agents. In addition, there was minimal information on toxicity of aspirin treatment. Further clarification of the role of both timing and duration of aspirin use following diagnosis would also be helpful, particularly since in the present study, past users (defined as those who had used aspirin after breast cancer diagnosis but had subsequently stopped) did not show a reduced risk of breast cancer death or recurrence compared to never users. This suggests that current aspirin use compared with prior use may be most important in order to obtain benefit. This also could be clarified by further mechanistic studies. Although studies of aspirin use and breast cancer incidence have been mixed,7-11 information on aspirin use prior to breast cancer diagnosis in the current study might have significance and should also be investigated. In addition, five-year duration of use (combining past and current users) was associated with only a 5% reduction in risk of breast cancer death. It would also be valuable to learn if the effects of aspirin use on breast cancer mortality differ by breast cancer subtype. In summary, we have good data from epidemiologic studies that support a role for aspirin use in preventing breast cancer recurrence and mortality. What is now needed is a study in a cohort with more detailed information, such as a prescription database, to help clarify issues and confirm findings. A randomized trial would also help answer some of these questions.However, the feasibility of such a study, particularly in the United States where aspirin intake is not uncommon, would have to be assessed first. In terms of translating these findings to clinical practice, at present we feel that the data provide reassurance to women with breast cancer—who are already taking aspirin for another purpose—that aspirin may also have an effect on their mortality. Given aspirin is not without toxicity, we currently would not recommend that women should begin using aspirin long-term for reducing their risk of breast cancer recurrence or mortality. We would await clarification on issues such as duration and dose to be obtained from more detailed trials, which will hopefully be undertaken in a timely fashion given these exciting results. References    American Cancer Society. Breast Cancer Facts & Figures 2007-2008. Atlanta: American Cancer Society, Inc. Holmes MD, Chen WY, Li L, et al. J Clin Oncol. 2010;28:1467-1472. Kwan ML, Habel LA, Slattery ML, et al. Cancer Causes Control. 2007;18:613-620. Blair CK, Sweeney C, Anderson KE. et al. Breast Cancer Res Treat. 2007;101:191-197. Bennett A, Charlier EM, McDonald AM, et al. Lancet. 1977;2:624-626. Williams CS, Tsujii M, Reese J, et al. J Clin Invest. 2000;105:1589-1594. Cook NR, Lee IM, Gaziano, et al. JAMA. 2005;294:47-55. Takkouche B, Regueira-Méndez C, Etminan M. J Natl Cancer Inst. 2008;100:1439-1447. Mangiapane S, Blettner M, Schlattmann P. Pharmacoepidemiol Drug Saf. 2008;17:115-124. Khuder SA, Mutgi AB. Br J Cancer. 2001;84:1188-1192. Bosetti C, Gallus S, La Vecchia C. Cancer Causes Control. 2006;17:871-888. Commentary by: Amy Gross, MHS, PhD candidate, Johns Hopkins Bloomberg School of Public Health; Kala Visvanathan, MB, BS, FRACP, MHS, Johns Hopkins Bloomberg School of Public Health and Sidney Kimmel Comprehensive Cancer Center Weighing the Risks vs. Benefits In 1998, tamoxifen was approved by the U.S. Food and Drug Administration (FDA) for breast cancer (BC) prevention, after being approved for reducing recurrences in patients with early-stage BC. It is therefore not surprising that a drug that appears efficacious for primary prevention of BC, such as aspirin, may also offer benefit as adjuvant treatment. Over 300 papers have been published evaluating the association between aspirin and other nonsteroidal anti-inflammatory drug (NSAID) medications and cancer prevention. While the results are conflicting, a meta-analysis of 38 studies evaluating more than two million patients found a reduced BC risk with aspirin use (relative risk = 0.87).1 Through prostaglandin reduction, these agents, along with COX-2 inhibitors, inhibit cell growth and decrease cell invasiveness in preclinical models.2 It has been shown that prostaglandin increases aromatase gene expression and, subsequently, estrogen production.3 Thus, inhibitors of prostaglandin synthesis may particularly benefit the treatment and prevention of hormone-sensitive cancer.4 Based on the preventive benefits for BC and other cancers, such as colon cancer, a prospective randomized trial was initiated evaluating the role of aromatase inhibition with or without celecoxib for the adjuvant treatment of hormone-sensitive BC in post-menopausal women (MA.27). This study was terminated early when the cardiovascular toxicities of COX-2 inhibitors were reported. Given the widespread use of aspirin and other NSAIDs for multiple medical indications, it is unclear if a prospective randomized trial evaluating the efficacy of these drugs for adjuvant BC therapy is feasible. To help us delineate the potential benefit of these medications, we can turn to the observational data from the Nurses’ Health Study. Holmes et al. evaluated the risk of BC mortality in 4,164 women diagnosed with stage I-III BC who never used, previously used, and currently used aspirin.5 Past use was defined as use prior to the diagnosis of BC. In a multivariate model, controlling for confounding factors such as stage, estrogen receptor status, menopausal status, body mass index, use of oral contraceptive pills/hormone replacement therapy, and treatments received (radiation therapy, chemotherapy, and anti-estrogen treatment), women using aspirin two to five days per week had a 71% lower risk of dying from BC as compared to nonusers, and women using aspirin six days or more per week had a 64% lower risk. Similar associations were found with BC recurrence. Causation or correlation? As with all observational data, we are left with uncertainty with regard to causality. Is aspirin use associated with better health behavior and possibly superior compliance? Are the indications for aspirin use related to BC outcome leaving the drug as an innocent bystander? While these data are subject to bias, the study has strengths that may lead us to conclude the results are likely valid. The data was collected prospectively, the quality of data has been well validated, and the follow-up time was long. The findings are biologically plausible and are in accordance with recent findings in colon cancer, in which aspirin use during and after adjuvant chemotherapy has been shown to decrease cancer-specific mortality.6,7 However, in the study, the number of deaths was low, there was insufficient data collected to evaluate for a dose response, and no predictive biomarkers were assessed, including COX-2 expression on the primary tumor. Patients using aspirin may also be using other medications that have been implicated as beneficial in BC treatment and prevention, such as metformin and statins. In future studies with more power, it would be useful to perform stratified analyses to determine if similar effects are observed in hormone-sensitive compared with insensitive tumors. What will we tell our patients? Since it is unlikely that there will be a prospective randomized trial, we depend on large observational data-sets to further characterize this promising association. Until then, it remains appropriate to discuss this medical uncertainty with patients, weighing the known risks with the potential benefits. References Takkouche B, Regueira-Mendez C, Etminan M. J Natl Cancer Inst. 2008;100:1439-47. Sheng H, Shao J, Kirkland SC, et al. J Clin Invest. 1997;99:2254-9. Zhao Y, Agarwal VR, Mendelson CR, et al. Endocrinology. 1996;137:5739-42. Terry MB, Gammon MD, Zhang FF, et al. JAMA. 2004;291:2433-40. Holmes MD, Chen WY, Li L, et al. J Clin Oncol. 2010;28:1467-72. Chan AT, Ogino S, Fuchs CS. JAMA. 2009;302:649-58. Fuchs C, Meyerhardt JA, Heseltine DL, et al. Proc Am Soc Clin Oncol. 2005;23(16s). Abstract 3530. Commentary by: Kevin Kalinsky, MD, and Dawn L. Hershman, MD, MS, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. CurrentControversies@asco.org Mon, 28 Jun 2010 14:43:29 GMT f1397696-738c-4295-afcd-943feb885714:2573 http://connection.asco.org/Magazine/Article/ID/2533/Ethical-Considerations-for-Phase-1-Clinical-Trials.aspx#Comments 1 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=2533 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=2533&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/2533/Ethical-Considerations-for-Phase-1-Clinical-Trials.aspx April 2010 Issue: Patients with metastatic cancer are often faced with an ultimately fatal disease. This often causes patients to consider any therapy that may be construed as providing any chance for improved survival. The stress of their situation may also make patients less able to evaluate data. Patients with metastatic cancer are looking for positive news, and may interpret their physician’s suggestion for palliative care as their physician “giving up on them.” The physician often does not like to give bad news and may be less direct when explaining to patients the expected results of a recommended treatment. If a patient wants treatment and their physician thinks that standard therapy is not likely to be helpful, a phase I trial examining a new therapy is a reasonable option. On average, however, phase I trials are unlikely to help the patient. Phase I trials are more likely to advance the science of oncology than to improve the survival of an individual. Before targeted therapies, the likelihood that a patient would respond to a phase I trial was approximately 3%. Since the advent of phase I trials based on the biology of the tumor and the pharmacology of the drug being tested, the response rate has increased, but only to approximately 7%. Phase I trials are testing new drugs and there is almost no data to present to the patient about expected results. Their purpose is centered on the drug—toxicity and starting dose—rather than the patient. This is uncomfortable for the patient and the oncologist. It is difficult to explain to the patient why he or she should be on a trial where the focus of attention is on the drug and not on improving the individual disease. As oncologists we are trained to represent the best interest of our patients. We are also schooled in the benefit and the necessity of clinical trials. When considering phase I trials for a patient, are these two goals mutually exclusive? This is the basis of the question, “Are phase I trials ethical?”, which is posed to our two discussants. Anthony W. Tolcher, MD, is an internationally respected phase I trialist who is director of the South Texas Accelerated Research Therapeutics (START) Phase I group. Robert L. Fine, MD, is an internist who is nationally and internationally known for his work in medical ethics and palliative care. Introduction by: Robert G. Mennel, MD; Texas Oncology PA Applying Ethical Principles to Phase I Trials Commentary by: Robert L. Fine, MD, FACP; Director, Office of Clinical Ethics and Palliative Care Baylor Health Care System Medical practice without ethical reflection reduces the physician to mere technician and robs us of our professionalism. In posing the question, “Are phase I trials ethical?”, Dr. Mennel challenges not only Dr. Tolcher and me, but every reader, for the discipline of medical ethics belongs to every medical professional willing to take responsibility for it, not just those recognized as “experts.” When confronted with a question of medical ethics, it is prudent to first clarify its meaning and reflect on how we arrive at answers to ethical questions. Only after that should we face the particular question of the moment. At the most basic level, medical ethics is about what we believe to be good or bad, right or wrong about the goals of medicine and the means used to pursue those goals. Medical ethics is not the same as medical jurisprudence, psychology, spirituality, or religion (though each may be useful in the practice of clinical ethics). Medical ethics is a philosophical discipline that informs us of what we should do, thus complementing the medical science that informs us of what we can do. So how do we decide if something is good or bad? How do we answer questions like, “Is this ethical?” Throughout history, ethicists have proposed various theories of ethical reasoning and have offered various justifications for those theories by appeal to intuition, reason, religious faith, social norms, and more. For example, duty-based ethics (Deontology) suggests that an action is right or wrong based upon particular duties, irrespective of the consequences of carrying out a particular duty. If one has a duty to advance the cause of science, then phase I trials are ethical, even though the vast majority of research subjects will not benefit personally. Consequentialist ethics (Utilitarianism) suggests that it is the outcome of an action that determines if the action was ethical. The consequentialist might argue that phase I trials are ethical, noting that the patient will die with or without enrolling in the trial, but with enrollment the good consequence of advancing science will be enhanced. One common analytic method for determining what is ethically right or wrong within the medical endeavor involves applying a set of ethical principles or virtues to the ethical question at hand. Principles of medical ethics such as beneficence or non-maleficence may guide our actions through the storm of our patient’s terminal illness as a navigation beacon guides a pilot through turbulent skies, while ethical virtues such as patience, honesty, or equanimity (William Osler’s favorite virtue) may refine our character and enhance our bedside behavior when our patients are in the greatest need. The thoughtful reader will quickly recognize that one may use the discipline of medical ethics to justify all sorts of actions. Interestingly, modern neuroscience suggests that humans, moral mammals that we are, formulate ethical judgments of right and wrong at a subconscious level, before the notions of good or bad reach our conscious awareness. I believe we then apply some ethical reasoning to the determination our subconscious mind has already reached as we consciously decide to either accept or reject our inner judgment of right or wrong. So what is your ethical judgment about phase I trials? Are they ethical? Yes… no… it depends? I prefer an affirmative answer as long as those involved in the research endeavor of phase I trials strive to honor three important concepts: fidelity, autonomy, and communitarian values. Fidelity (faithfulness). Fidelity to the patient must take priority over faithfulness to the research endeavor. Our faithfulness to the patient must always be more important than the needs of the research institution, company, colleagues, or our own career. Patients give all physicians our professional raison d’etre—our reason for being physicians. Without patients we cannot practice our profession. When we ignore the principle of fidelity, we undermine the very reason for being physicians in the first place: to serve patients. Autonomy (self-governance). Autonomy is the ethical principle at the heart of informed consent. If there is no belief in the principle of autonomy, there is no need for informed consent. True respect for autonomy, however, is more than simply allowing a patient to make a choice. Unfortunately, sometimes we allow patients to make bad decisions out of a shallow respect for autonomy, failing to recognize that the patient’s ability to make a truly informed decision is impaired. The psychological stresses of facing a terminal illness may so impair a patient’s ability to be selfgoverning that the virtuous physician must give extra time and attention to the consent process. Within that process, the researcher’s interest in protecting the patient’s autonomy must take priority over the researcher’s interest in obtaining another trial patient (see “fidelity”). Both fidelity and true respect for patient autonomy may lead the ethical physician away from enrolling a particular patient in a phase I trial. Communitarian values. It is difficult to argue that phase I trials benefit the patients involved, and as such they can be seen as violating traditional notions of beneficence. (“Whatever houses I may visit, I will come for the benefit of the sick,” notes the Hippocratic Oath.) The phase I trial participant is extremely unlikely to achieve the benefit of response, let alone cure. Within the discipline of ethics, we strive to avoid abandoning a prima facie ethical good unless it is counterbalanced by some other essential ethical good. In the case of the phase I trial, the patient is unlikely to have the benefit of response, but they may reap the emotional and social benefit of knowing they contributed to the greater good of the community. I believe physicians, beleaguered though we often feel in this political climate, must also devote ourselves to the greater good of the community through tireless efforts to enhance health care for the entire community— not just those with insurance or financial means. We must not be in the position of allowing the desperately ill patient to make the sacrifice to benefit others, including perhaps our own research career, if we are not prepared to make sacrifices to benefit others as well. Additional Reading Gazzaniga, Michael S. The Ethical Brain: The Science of Our Moral Dilemmas. New York: Dana Press; 2005. Damasio, Antonio. Looking for Spinoza: Joy, Sorrow, and the Feeling Brain. Orlando: Harcourt, Inc.; 2003. An Option When Current Therapy Fails Commentary by: Anthony W. Tolcher, MD, FRCP; Director of Clinical Research, South Texas Accelerated Research Therapeutics (START) Far too many of our patients face the prospect of non-curative therapies for metastatic disease. Despite conventional frontline treatment, disease recurrence, ever-evolving resistance to therapy, and accompanying symptoms of progressive disease is the natural history for most of our patients with advanced malignancies. This results in the clinical dilemma of whether a patient should continue on approved but marginal therapies in the third- or fourth-line setting, be considered for hospice care, or if well enough, be referred for clinical studies that will accommodate the patient. Since phase I studies accommodate patients with extensive prior therapy and diverse malignancies, many find this the only outlet for participation in a clinical trial. Although viewed by many as non-therapeutic and dose-finding, it is important to differentiate phase I clinical studies in oncology from those of other therapeutic areas. In standard phase I studies performed in normal healthy volunteers, single-dose exposure with detailed pharmacokinetics is considered the custom as no therapeutic effect is needed. In contrast, phase I studies in oncology frequently incorporate the detection of antitumor activity as a secondary objective, permit patients to receive repetitive doses of the investigational therapy to maximize the potential for benefit, and permit patients to continue on in the absence of progressive disease or doselimiting toxicity. Furthermore, in most circumstances, even those patients who experience toxicity are not automatically withdrawn from treatment but can continue on study at reduced doses to ensure that the “all pain, no gain” quandary does not occur. In an ideal world, dose escalation would be unnecessary as allometric scaling from preclinical models would predict both therapeutic and safe dose levels. Unfortunately, as in all things, we do not live in an ideal world. Dose escalation, from the conservative beginning dose levels to those that induce toxicity, creates the uncertainty that patients and doctors alike feel when considering participation in a phase I study. Is the dose too low for therapeutic benefit or is it going to give side effects that are severe? Most phase I clinicians address these uncertainties up front and directly with the patients, and it is critical for not only patient participation but also the informed consent process. Remarkably, and in contrast to widely held perception, patients generally recognize and accept the inability for anyone to predict benefit, the low likelihood of response, and the risk for toxicity. Patients frequently state reasons for their participation with phrases such as, “If it doesn’t benefit me, maybe it will benefit someone else,” or, “I am not ready to give up.” The widely reported low response rate notwithstanding, benefit is increasingly observed in phase I targeted therapies from prolonged and durable stable disease, and of course the occasional impressive response. Phase I studies frequently identify activity in tumor types that eventually lead to future approvals. Examples of activity and durable static disease (SD) in phase I studies include gefitinib and erlotinib in non-small cell lung cancer, temsirolimus and everolimus in clear cell carcinoma of the kidney and hepatocellular carcinomas, bevacizumab in breast carcinoma, sunitinib in renal cell carcinoma, and more recently IG FR1 therapies in Ewing sarcoma. Furthermore, despite the perception that these low response rates encountered in phase I studies indicate little benefit, we have seen a forward migration of the same low objective response rates (1-11 In conclusion, the consideration of a patient’s participation in a phase I study for someone with advancing metastatic disease is one of a number of options that physicians and their patients encounter during the natural history of their disease. Realistic expectations, altruistic characteristics of individual patients, and frank and open discussion of risk and benefit make phase I studies reasonable options for our patients. References Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res. 2006;12:6049-6055. Jackman DM, Yeap BY , Lindeman NI , et al. Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol. 2007;25:760-766. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132. Atkins MB , Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281. Amato RJ, Jac J, Giessinger S, et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RA D001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer. 2009;115:2438-2446. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505-2512. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293-4300. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the editor or of the American Society of Clinical Oncology. amy.fries Fri, 14 May 2010 19:46:57 GMT f1397696-738c-4295-afcd-943feb885714:2533 http://connection.asco.org/Magazine/Article/ID/2532/CA125-to-Monitor-for-Relapse-in-Epithelial-Ovarian-Cancer.aspx#Comments 0 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/RssComments.aspx?TabID=141&ModuleID=498&ArticleID=2532 http://connection.asco.org/DesktopModules/DnnForge%20-%20NewsArticles/Tracking/Trackback.aspx?ArticleID=2532&PortalID=0&TabID=141 http://connection.asco.org/Magazine/Article/ID/2532/CA125-to-Monitor-for-Relapse-in-Epithelial-Ovarian-Cancer.aspx January 2010 Issue: CA125 measurements are very useful blood tests for monitoring response to the initial therapy for the majority of patients with epithelial ovarian cancer. However, the value of CA125 levels to follow patients who are in clinical remission after first-line chemotherapy recently has been challenged in a study conducted by Gordon J. S. Rustin, MD, MBBS, and colleagues presented at the 2009 ASCO Annual Meeting. It is well known that in most patients the CA125 levels tends on average to rise several months earlier than the recognition of physical or radiologic signs of recurrence, but the effect on survival of the timing of re-initiation of chemotherapy has been unclear. In Dr. Rustin's trial, patients were randomly selected to have CA125 levels monitored for biochemical relapse versus using other clinical signs of recurrence, and each of these signs were then used to initiate second-line chemotherapy. On average, the CA125 levels rose 5 to 6 months prior to other signs of disease recurrence. The authors reported that the overall survival of patients was not improved by initiating earlier second-line chemotherapy based only on the rising CA125 levels. They recommended that the routine practice of monitoring of CA125 levels in these women with ovarian cancer in clinical remission could be modified—a controversial approach. It is unclear how this study will be applied clinically, and Stanley B. Kaye, MD, and Martin E. Gore, MD, PhD, discuss the issues that affect these important therapeutic decisions in ovarian cancer. Introduction by: Jonathan S. Berek, MD, MMS; Professor and Chair, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Director, Women's Cancer Program, Division of Gynecologic Oncology, Stanford Cancer Center Should Routine CA125 Screening Be Discontinued? Commentary by: Stanley B. Kaye, MD, FRCP, FRCR; Head of the Section of Medicine, The Institute of Cancer Research, Royal Marsden Hospital; London, United Kingdom The Medical Research Council (MRC)/European Organisation for the Research and Treatment of Cancer (EORTC) OVO5/5595 study was a well-conducted randomized trial that provided a clear conclusion to the question addressed: does early re-treatment of asymptomatic recurrent ovarian cancer based on CA125 measurement carry any survival advantage? The answer is clearly no, and many clinicians, particularly in Europe, will have concluded that their practice in delaying treatment has been justified. This study may well have a significant impact in those units where early treatment has been the norm, but should the data presented also lead to discontinuation of routine CA125 measurement? There, many clinicians may hesitate to change practice. The argument against discontinuation is that this excellent clinical trial took place during a 10-year period (1996-2006) when the options for treatment were relatively limited. Although the main planks of chemotherapy remain unchanged (taxanes and platinum compounds), the treatment of ovarian cancer is beginning to move forward in increasingly exciting ways. The era of targeted therapy has arrived; novel agents, such as those targeting angiogenesis, or those focusing on homologous recombination (HR) deficient cells, are beginning to have an effect.1 While randomized trial data are still awaited, our hope is that the paradigms for ovarian cancer treatment will change. With that change, it is quite possible that earlier recognition of disease relapse will become increasingly important. For that reason, a “tablets of stone” policy of discontinuing CA125 measurement routinely may be a mistake. Of course, a policy of continuation of CA125 monitoring invites the major problem of patient “addiction” to CA125 results.2 The anxiety that surrounds clinic visits, and the obsessive recording of CA125 data, is well known to clinicians. This has to be weighed against the potential benefits, and this trial clearly has to be considered in that equation. Some clinicians will say that another reason that early detection of relapse is important is to allow a surgically resectable recurrence to be detected and removed. This trial does not directly address that issue and, while ongoing trials are addressing the role of surgery for disease relapse in a randomized fashion, many clinicians will continue to adopt this approach, encouraged by the experience of clinical benefit in their own practices. Finally, there may be merit in looking in more detail at the rate of rise of CA125 in patients with asymptomatic first recurrence of ovarian cancer. Data from our unit indicate that patients with a CA125 doubling-time of less than 3 weeks have a median survival of 9.5 months, compared to those with a doubling-time of more than 11 weeks, who have a median survival of 34.5 months.3 As new treatments evolve, this information may well be one important factor in decision-making regarding the optimal time to begin relapse therapy. To conclude, Dr. Rustin and all the trialists are to be congratulated for a thought-provoking and potentially practice-changing trial. As the treatment of ovarian cancer enters its most exciting phase for many years, the trial provides an important framework for clinicians to use, for the benefit of all their patients with ovarian cancer. Dr. Rustin and colleagues advocate that patients are offered an informed choice regarding CA125 monitoring, and clearly an individualized approach has merit.4 However, at this particular time, routine CA125 monitoring of patients following initial treatment continues to be a justified procedure. References Yap T, Carden CP, Kaye SB. Nat Rev Cancer. 2009;9:167-181. Tummala MK, McGuire WP. J Clin Oncol. 2007;25:3570-3571. Karavasilis V, Thomas K, Harrison M, et al. J Clin Oncol. 2008;26 (May 20 suppl, abstr 5544). Hopkins ML, Coyle D, Le T, et al. Curr Oncol. 2007;14:167-172. The Timing of Treatment for Relapsed Disease Commentary by: Martin E. Gore, MD, PhD, FRCP; Professor of Cancer Medicine, Royal Marsden Hospital, Institute of Cancer Research; London, United Kingdom The MRC and EORTC are to be congratulated for performing the OV05/5955 study, which is a landmark trial in challenging some firmly held views on how best to treat patients with advanced ovarian cancer that has relapsed following first-line chemotherapy. We all have genuine admiration for the dogged determination that was required to complete this work. Many groups in Europe, and perhaps especially in the United Kingdom, have for some time questioned the practice of starting chemotherapy for relapse on the basis of a rising CA125 alone.1 OV05/5955 demonstrates that there is no survival advantage to treating patients on a rising CA125 compared to waiting until the patient develops symptoms. OV05/5955 does not inform us as to the optimum time to commence treatment for relapse because some unaddressed questions remain. There is evidence to show that one can leave a patient too long before treating a relapse, i.e., waiting until the disease gets bulky can reduce the chance of a response.2 In addition, many patients who develop symptoms at relapse have evidence of sub-acute obstruction. There are conflicting data on the significance of intestinal obstruction on the chemo-responsiveness of relapsed disease3,4 but most feel that patients with conventionally defined resistant relapse are unlikely to benefit from chemotherapy. Leaving patients to become obstructed before commencing chemotherapy may reduce their chance of a response and therefore possibly impact survival. It would be important to know the number of patients with disease above 5 cm and/or in any degree of obstruction at the time of the commencement of second-line therapy and how these two parameters relate to patients’ platinum-free interval. There is now firm evidence that the choice of treatment at relapse can have an effect on overall survival and we need to be aware of the advances that have been made in this area since the commencement of this study.5-7 In OV05/5955 the median time to second-line therapy for the patients who were treated “early” was 0.8 months, whereas it was 5.6 months for those whose treatment was delayed—yet the treatments in the two arms appear to be identical. Oncologists would usually tailor treatment at relapse according to whether or not the patient had “sensitive” or “insensitive” disease, based on the platinum-free interval and the recognised cusp for presumed continued platinum sensitivity is 6 months.8,9 One might expect patients in the early-treatment group to have a lower rate of platinum-based therapy than those whose treatment was delayed. Furthermore, from data that has emerged in the last few years, we know there is an advantage to using combination platinum-based therapy over single agent platinum for patients who relapse with a platinum-free interval of over 6 months.10,11 The fact the two randomized groups in this trial are well-balanced for the second-line therapies received is a worry, not a comfort. Finally, there are emerging data on the role of surgery in patients who experience disease recurrence after first-line chemotherapy for ovarian cancer12 and, as with the questions set out above, the data from OV05/5955 cannot be taken in isolation. We need to place them into the context of our knowledge of the natural history and biology of relapsed ovarian cancer and the predictors of benefit from both surgical and medical interventions. The stress of follow-up on our patients and the development of CA125 “addiction” is an issue of huge importance.13 The MRC/EORTC OV05/5955 study rightly re-focuses our attention on this phenomenon. Particular congratulations are due to Dr. Rustin, who has driven forward a number of concepts involving the utility of serum CA125 measurements, including this latest important study. References Gore ME. Controversies in Surveillance Options for Patients after Initial Treatment for Ovarian Cancer. 2006 ASCO Educational Book. Eisenhauer EA, Vermorken JB, van Glabbeke M. Ann Oncol. 1997;8:963-968. Bryan DN, Radbod R, Berek JS. Int J Gynecol Cancer. 2006;16:125-134. Abu-Rustum NR, Barakat RR, Venkatraman E, et al. Gynecol Oncol. 1997;64:493-495. Gore M, Oza A, Rustin G, et al. Eur J Cancer. 2002;38:57-63. Parmar MK, Ledermann JA, Colombo N, et al. Lancet. 2003;361:2099-2106. Meier W, du Bois A, Reuss A, et al. Gynecol Oncol. 2009;114:199-205. Gore ME, Fryatt I, Wiltshaw E, et al. Gynecol Oncol. 1990;36:207-211. Markman M, Rothman R, Hakes T, et al. J Clin Oncol. 1991;9:389-393. Pfisterer J, Plante M, Vergote I, et al. J Clin Oncol. 2006;24:4699-4707. Alberts DS, Liu PY, Wilczynski SP, et al. Gynecol Oncol. 2008;108:90-94. Harter P, du Bois A, Hahmann M, et al. Ann Surg Oncol. 2006;13:1702-1710. Harries M, Gore M. Lancet Oncol. 2002;3:537-545. Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology. host Fri, 23 Apr 2010 20:14:08 GMT f1397696-738c-4295-afcd-943feb885714:2532