GU Clinical Corners: A Question-and-Answer Session with Genitourinary Oncology Experts

Apr 25, 2015

Chemoradiation for local and locally advanced bladder cancer

Response provided by Matthew D. Galsky, MD, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of Genitourinary Medical Oncology at Tisch Cancer Institute.

Q: When do you use chemoradiation for local or locally advanced bladder cancer? Do you use 5-fluorouracil (5-FU)/mitomycin-C or cisplatin with radiotherapy?

Dr. Galsky: Radical cystectomy is a standard and potentially curative treatment for muscle-invasive bladder cancer. Although often considered the preferred management approach in the United States, population-based studies suggest that radical cystectomy is used in only a small subset of patients with the disease.1 This disconnect is related, at least in part, to the fact that bladder cancer is largely a disease of the elderly, and patients often have age- and smoking-related comorbidities precluding surgery.

Outside of the United States, definitive radiation, with or without chemotherapy, is embraced as a treatment standard for muscle-invasive bladder cancer. Despite important sequential clinical trials from the Radiation Therapy Oncology Group (RTOG), Massachusetts General Hospital, and other groups over a couple of decades, bladder-sparing surgery, with maximal transurethral resection of the bladder tumor followed by concurrent chemoradiation, is still endorsed as only a Category 2B recommendation in the National Comprehensive Cancer Network (NCCN) guidelines. However, chemoradiation does seem to be gaining more traction as an attractive approach within the United States.

Attitudes toward the use of chemoradiation for muscle-invasive bladder cancer and uncertainties regarding optimal patient selection have been fueled by a lack of randomized trials, the use of heterogeneous treatment regimens and schedules, preconceived notions or biases regarding treatment, patient referral patterns, and importantly, the existence of two very distinct patient populations that could potentially benefit from such treatment. That is, the majority of clinical trials exploring chemoradiation for muscle-invasive bladder cancer have enrolled patients who are both candidates for cystectomy (but interested in organ preservation) and eligible to receive cisplatin-based chemotherapy.

Although this work has been critically important, and bladder preservation is a highly laudable endpoint, a huge unmet need remains in the development of a standard treatment approach for the large proportion of patients with muscle-invasive bladder cancer for whom the risk of cystectomy (and cisplatin-based chemotherapy) is felt to outweigh the potential benefit. This is one of the reasons that the trial reported by Nicholas D. James, MD, PhD, and colleagues, which randomly selected patients with muscle-invasive bladder cancer to treatment with radiation alone versus radiation plus 5-FU plus mitomycin-C, represents a substantial step forward.2 Although not powered to detect an overall survival benefit with chemoradiation, this practical trial enrolled patients with a glomerular filtration rate of more than 25 mL/min/1.73 m2, Eastern Cooperative Oncology Group Performance Status of up to grade 2, and median age of 72, and demonstrated a five-year overall survival of 48% in patients treated with chemoradiation, an outcome comparable to that achieved in large cystectomy series.

Although I try to discuss concurrent chemoradiation as an option with all of my patients with muscle-invasive bladder cancer, if I were to look at my own practice patterns closely, I would likely find that the patients who come to me intent on a bladder-sparing approach or those who are already deemed to be ineligible for cystectomy are most likely to receive such treatment. For the former patients, I favor cisplatin-based therapy, given the impressive long-term outcomes reported from the pooled analysis of RTOG trials.3 For the latter patients, I tend to use either twice-weekly gemcitabine4 or 5-FU plus mitomycin-C. My comfort level with 5-FU plus mitomycin-C is gradually increasing. Molecular markers of chemoradiation sensitivity and uniform definitions of cystectomy ineligibility are needed to further refine the use of bladder-sparing treatment for patients who are eligible for cystectomy and to establish uniform treatment standards for those patients who are not.

References
1. Gore JL, Litwin MS, Lai J, et al. J Natl Cancer Inst. 2010;102:802-11.
2. James ND, Hussain SA, Hall E, et al. N Engl J Med. 2012;366:1477-88.
3. Mak RH, Hunt D, Shipley WU, et al. Int J Radiat Oncol. 2012;84:S121.
4. Oh KS, Soto DE, Smith DC, et al. Int J Radiat Oncol Biol Phys. 2009;74:511-17.


Examining the Preferred Treatment of Visceral Prostate Cancer

Responses provided by Christophe Massard, MD, PhD; Yohann Loriot, MD, PhD; and Karim Fizazi, MD, PhD, all of the Gustave Roussy Institute (pictured left to right).

Q: What is the preferred treatment of visceral prostate cancer?

Death from prostate cancer is invariably because of metastatic dissemination and resistance to androgen deprivation therapy (ADT). This is the definition of castration-resistant prostate cancer (CRPC), which is currently incurable. In 2015, the molecular alterations leading to tumor progression and resistance to ADT remain poorly understood, and many medical oncologists choose anticancer therapies based on clinical factors such as the type of progression (e.g., clinical progression or radiologic progression) and the presence of visceral metastases.

ADT is the main treatment for patients initially diagnosed with metastatic prostate cancer.1 Two recent phase III trials (GETUG-AFU 15 and CHAARTED) established an improvement in progression- free survival in patients with metastatic hormone-naive prostate cancer—specifically those with visceral metastases—though the effect on survival is controversial.2-3 Based on these two trials, it is recommended that patients with visceral metastases be informed about the pros and cons of frontline docetaxel combined with castration, as well as monitored tumor response based on prostate-specific antigen (PSA) and imaging.

After an initial response, most patients will ultimately relapse despite a low serum testosterone level under ADT, leading to CRPC. Several options could then be discussed with patients: docetaxel-based chemotherapy, next-generation androgen receptor axis–targeted drugs (abiraterone and enzalutamide), bone-targeted agents, immunotherapy, and clinical trials. Currently, patients with visceral metastases and rapidly progressive metastatic CRPC (mCRPC) and/or clinical progression are not usually treated with secondary endocrine therapies, probably because physicians suspect that cancer progression is not or no longer androgen receptor (AR)-driven. Consequently, these patients are mostly offered chemotherapy as the first option.

However, a recent retrospective analysis showed that patients with CRPC with visceral metastases or rapid disease progression could also benefit from next-generation endocrine therapies. The COU-AA-301 and AFFIRM trials both showed a positive effect of abiraterone acetate and prednisone on overall survival in patients with visceral disease. Moreover, patients with visceral metastases who were enrolled in the PREVAIL trial also yielded a clear clinical benefit. Whatever the chosen therapeutic option (taxanes or next-generation androgen receptor axis–targeted agents), patients need to be followed up very carefully by CT scan and physical evaluation to detect progression early, before clinical deterioration.

Last but not least, there is an urgent need to implement precision medicine in the treatment of patients with mCRPC.4 Greater knowledge of the biology of prostate cancer has led to the identification of a number of molecular alterations, some of which are promising potential targets (e.g., the fusion of the TMPRSS2 and ETS genes, various molecular abnormalities in the AR pathway, PI3K/mTOR pathway activation, and BET domain activation). Genomic profiling of mCRPC, based on molecular characterization of fresh tumor biopsies and circulating tumor cells in patients with mCRPC, is likely going to be a critical step in the selection of rationally targeted therapies in the era of precision medicine. Enrolling patients in ongoing precision medicine programs is highly recommended. Preliminary results from the PETRUS and MOSCATO programs led at the Gustave Roussy Institute demonstrate the operational feasibility of biopsies of metastatic tumors; the programs garnered high interest from patients, yielded a significant amount of tumor biopsy specimens and ad hoc molecular analyses, and provided the opportunity to enroll patients in molecularly oriented phase I/II trials.5

References

1. Horwich A, Hugosson J, de Reijke T, et al. Ann Oncol. 2013;24:1141-62.
2. Gravis G, Fizazi K, Joly F, et al. Lancet Oncol. 2013;14:149-58.
3. Sweeney C, Chen Y, Carducci MA, et al. J Clin Oncol. 2014;32:5s (suppl; abstr LBA2).
4. Loriot Y, Massard C, Fizazi K. Eur Urol. 2014; 66:653-54.
5. Hollebecque A, Massard C, De Baere T, et al. J Clin Oncol. 2013;31 (suppl; abstr 2512).


Optimal Treatment of High-Risk Localized Prostate Cancer

Response provided by Ana Molina, MD, Assistant Professor of Medicine at Weill Cornell Medical College and Assistant Attending Physician at New York-Presbyterian Hospital.

Q: A 45-year-old male is diagnosed with localized prostate cancer by biopsy with a high Gleason score. He declined surgery or radiation therapy, so he has been prescribed high doses of estrogen. He is responding with clear MRIs of the pelvis, and his PSA level is steadily declining. Is this treatment ethical? What should be next for him?

Dr. Molina: Prostate cancer is a major cause of morbidity and mortality in men. Men with localized prostate cancer (T3a), primary Gleason score of 8 to 10, or a PSA greater than 20 ng/ mL are categorized by the NCCN into a high-risk group. The standard of care for this risk group is local control with either surgery or radiation therapy in conjunction with ADT.

Patients with high-risk prostate cancer are candidates for primary external beam radiation therapy (EBRT). Large multicenter, randomized trials have demonstrated that early endocrine treatment of high-risk localized prostate cancer after definitive therapy can substantially delay disease progression and improve overall survival. Additionally, pelvic lymph node irradiation and the addition of neoadjuvant, concomitant, and adjuvant ADT for a total of two to three years is recommended. The addition of neoadjuvant and adjuvant ADT in patients with high-risk localized disease is considered the standard of care for men treated with definitive radiotherapy.

The European Organisation for Research and Treatment of Cancer evaluated the benefit of the addition of long-term ADT to EBRT in patients with prostate cancer with high metastatic risk.1 This study randomly assigned 415 patients to treatment with EBRT alone or EBRT plus three years of ADT. Longterm data demonstrated an improved 10-year overall survival (39.8% with EBRT alone vs. 58.1% with adjuvant ADT; p = 0.004).1 Similarly, other studies have demonstrated improved disease- specific and overall survival with the combination of radiotherapy plus ADT versus radiotherapy alone.2-3

Prospective clinical trials and retrospective studies have assessed the efficacy of primary ADT. In a randomized, phase III study of 875 men, Widmark et al. assessed the efficacy of endocrine therapy with and without local radiotherapy.4 The addition of local radiotherapy to endocrine treatment halved the 10-year prostate cancer–specific mortality (23.9% with ADT alone vs. 11.9% with combination) and substantially decreased overall mortality. A retrospective cohort study of 15,170 patients reported on the efficacy of primary ADT in patients not treated with curative intent.5 In the high-risk localized prostate cancer setting, the study showed that there may be some positive benefit; however, the authors concluded that primary ADT did not seem to be an effective strategy as an alternative to no therapy among men diagnosed with clinically localized prostate cancer who are not receiving curative-intent therapy.5

For this patient with localized high-risk prostate cancer, I would strongly encourage him to consider a local therapy based on the data available to date. Additional local therapies that could be considered include cryotherapy or high-intensity focused ultrasound in the setting of a clinical trial. In general, ADT is associated with adverse events that include bone loss or fractures, coronary heart disease, insulin insensitivity, diabetes, loss of muscle strength, anemia, and impaired cognitive function. No current guidelines recommend ADT monotherapy as primary treatment for patients with localized prostate cancer.

References

1. Bolla M, Van Tienhovan G, Warde P, et al. Lancet Oncol. 2010;11:1066-73.
2. Pilepick, MV, Winter K, Lawton CA, et al. Int J Radiat Oncol Biol Phys. 2005;61:1285-90.
3. Warde P, Mason M, Ding K, el al. Lancet. 2011;378:2104-11.
4. Widmark A, Klepp O, Solberg A, et al. Lancet. 2009;373:301-8.
5. Potsosky AL, Haque R, Cassidy-Bushrow AE, et al. J Clin Oncol. 2014;52:5782.


Chronic Fever, Soft Tissue Pain Following Sipuleucel-T

Response provided by James E. Ward, MD, a genitourinary oncologist with the University of California, Irvine.

Q: I have a 68-year-old male who is now eight months out from sipuleucel-T. He has had a recurrent fever of 102 to 103 degrees with soft tissue pain every two to three weeks (lasting two to four days at a time). There is no infectious source, and no similar experience has been reported from the drug manufacturer. It still seems like it must be related to treatment. What do you recommend?

Dr. Ward: Sipuleucel-T is an active cellular immunotherapy. Following leukapheresis, antigen-presenting cells are exposed ex vivo to a fusion protein containing human granulocytemacrophage colony-stimulating factor (GM-CSF) and prostatic acid phosphatase. Infusion of sipuleucel-T has been shown to provoke an immune response in recipients as measured by increased T-cell proliferation and development of antibodies to the fusion protein.1 It is approved for use in men with minimally symptomatic metastatic castrationresistant prostate cancer. Its efficacy was demonstrated in three separate phase III trials, including the definitive IMPACT trial, which resulted in a 22% reduction in the risk of death in men who received the therapy.2

Fever was among the most common adverse events in the IMPACT trial, occurring in 29.3% of patients in the sipuleucel-T arm. Arthralgia (20.7%), limb pain (14.5%), musculoskeletal pain (13.0%), pain (13.0%), and myalgia (9.8%) were also common. However, these symptoms generally occurred within one day of sipuleucel-T infusion and resolved within one to two days. These types of infusion reactions can be a result of an immunoglobulin E (IgE)-mediated allergic response (type 1 hypersensitivity reactions) or an anaphylactoid allergic reaction (non- IgE mediated), caused by the cytokine release and T-cell response as they occur in treatment with sipuleucel-T.3

Chronic fever and myalgia are not known to be adverse effects of sipuleucel-T. In a query of the drug manufacturer’s database of spontaneously reported adverse events, there was only one report of such an event in greater than 10,000 patients James E. Ward, MD treated with sipuleucel-T. It is certainly possible that this could be related to sipuleucel-T, and the symptoms should be reported to the drug manufacturer to follow up. However, I would recommend a full evaluation for other causes of fever and soft tissue pain. Your patient’s symptoms seem to fit the criteria of fever of unknown origin (FUO) in that he has experienced persistent fevers with no known source for more than three weeks despite appropriate investigation. The American Academy of Family Physicians has published an evidence-based approach to the evaluation of FUO.4 Although less common in adults, an inherited periodic fever syndrome is also possible. If no apparent cause is found after FUO evaluation, referral to an appropriate subspecialist for further investigation into a periodic fever syndrome may be warranted.

References

1. Burch PA, Breen JK, Buckner JC, et al. Clin Cancer Res. 2000;6: 2175-82.
2. Kantoff PW, Higano CS, Shore ND, et al. N Engl J Med. 2010;363:411-22.
3. Vogel WH. Clin J Oncol Nurs. 2010;14: E10-21.
4. Roth AR, Basello GM. Am Fam Physician. 2003;68:2223-8.


The following questions and answers were featured in the 2015 Genitourinary Cancers Symposium Daily News. The questions were posed by attendees of various 2014 ASCO-sponsored or co-sponsored meetings, and they are answered here by experts in the field.

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