Evidence Suggests Indications for Medical and Radiation Oncology Evaluations Pre- and Post-Surgery

Erik P. Castle, MD

Introduction

By Erik P. Castle, MD 
Mayo Clinic Arizona

The incorporation of neoadjuvant chemotherapy in the treatment of muscle-invasive bladder cancer is a complex and often controversial issue. Despite the available level 1 evidence supporting neoadjuvant chemotherapy, its use is still surprisingly low.^1,2 Reports on perioperative chemotherapy range between 11% and 17%, with the majority in the adjuvant setting.^3,4 Although in some cases there are reasons to avoid neoadjuvant chemotherapy (such as pre-operative renal dysfunction, performance status, and symptomatic disease), a significant number of patients would in fact be eligible. Other factors include surgical bias, as well as the attitude that adjuvant treatment is always an option. Unfortunately, many adjuvant trials have been plagued with the inability to adequately accrue participants, which likely reflects actual clinical practice. As many providers know, patients and physicians will often adopt a “wait and see” approach after surgery based on the quoted 5% to 10% survival advantage of chemotherapy and the recovery issues following radical cystectomy. The reality is that many patients in need of systemic therapy will not receive it after surgery in the adjuvant setting.

Unfortunately, the urologic oncology community has yet to identify barriers to the use of neoadjuvant chemotherapy that can be overcome in a widespread fashion. In some centers such as ours, we have adopted the practice of referring all patients with T2 or higher tumors for oncology consultation to discuss neoadjuvant therapy. This is certainly much easier in an integrated multispecialty practice and may be more difficult in other models of care. With increasing research into genomics and proteomics, we may be able to identify parameters beyond the standard clinicopathologic characteristics to identify patients that may benefit most from systemic therapy. Whatever the answer might be, the bottom line is that we all (surgeons, medical oncologists, and radiation oncologists) need to find a way to increase our use of perioperative systemic therapy to improve survival in the setting of invasive urothelial cell carcinoma.

Dr. Castle is an Associate Professor of Urology at Mayo Clinic Arizona. His professional interests include robotic/laparoscopic surgery and prostate and bladder cancer research.

References

1. Grossman HB, Natale RB, Tangen CM, et al. New Engl J Med. 2003;349:859-66. PMID: 12944571.
2. International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, et al. J Clin Oncol. 2011;29:2171-7. PMID: 21502557.
3. Raj GV, Karavadia S, Schlomer B, et al. Cancer. 2011;117:276-82. PMID: 20830767.
4. Fedeli U, Fedewa SA, Ward EM. J Urol. 2011;185:72-8. PMID: 21074192.

David L. Graham, MD

Achieving Optimal Multidisciplinary Treatment in Advanced Genitourinary Cancer: An Increasingly Complex Timeline

By David L. Graham, MD
Carle Physicians Group

The previous timeline of curative cancer care was significantly more straightforward. Labs or imaging would suggest a diagnosis. Biopsies would confirm a diagnosis, usually followed by a primary therapy, either surgical or radiotherapeutic. The question then was whether there was a role for chemotherapy or hormone interventions to be given in an adjuvant fashion.

The timeline has now become a bit more complex for many malignancies. Chemotherapy is being used neoadjuvantly, and newer patterns of surgery and radiotherapy used in conjunction are recommended. As a result, multispecialty communication and a willingness to make cross-specialty referrals are more vital than ever. There are certain areas, however, where this is more problematic. One of the main areas is in genitourinary oncology.

The role of chemotherapy in curative interventions for high-grade, muscle-invasive urothelial cancer was difficult to define for many years. Studies had only investigated the adjuvant use of therapy and found no survival advantage. The use of neoadjuvant chemotherapy, however, has shown a clear survival advantage. In a randomized trial, Grossman et al. demonstrated that three cycles of methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) improved median survival by 67% (77 vs. 46 months).¹ No increase in treatment-related mortality was seen. In a meta-analysis of 11 trials involving 3,005 patients, both overall and disease-free survivals were improved by the use of neoadjuvant chemotherapy precystectomy.² These and other findings led the National Comprehensive Cancer Network to state that cisplatin-based combination chemotherapy should be strongly considered in the neoadjuvant setting for cT2-4a bladder cancer. This is listed as a Category 1 recommendation.

This inserts a new branch into the bladder cancer timeline. When a patient is diagnosed with invasive bladder cancer, the urologist should refer him or her to a medical oncologist pre-operatively. Unfortunately, this does not seem to be a common occurrence. Although a number of individual comments have raised the question of compliance to this recommendation, published data are somewhat scanty. Dr. S. Machele Donat reviewed data from the National Cancer Data Base pertaining to perioperative use of chemotherapy in bladder cancer and found that only 11.6% of patients received any perioperative chemotherapy, and most of that was given postoperatively.³

A similar situation exists with prostate cancer. Several studies have examined radiotherapy following prostatectomy for selected men with locally advanced prostate cancer. SWOG 8794 was a randomized trial looking at post-prostatectomy radiation in men with extracapsular extension, seminal vesicle invasion, or positive margins. The most recent report, with a median follow-up of 12.6 years, demonstrates a tripling of biochemical failure-free survival (36% vs. 12%).⁴ A trial by the European Organisation for Research and Treatment of Cancer looked at men with extraprostatic extension or positive margins found at the time of prostatectomy and randomly assigned them to radiotherapy or observation. Five-year biochemical progression-free survival was found to increase by 59% with the addition of radiation (78% vs. 49%).⁵ Data regarding acceptance and integration of these findings into routine practice are not published, but anecdotal experience suggests a level of resistance for urologists to make these referrals.

In asking how to improve this integration, the initial question to be clarified must be the patterns in differing types of practices. In other words, do urologists act on these data differently depending on if they practice in an academic setting, a multispecialty group, or a single-specialty group? Intuitively, it would seem to be more likely that cross-dissemination of information and ideas would occur in academic or multispecialty practices, as these settings are more likely to have multispecialty tumor boards and conferences, as well as more opportunities for interactions between the specialties. This potentially raises a disturbing scenario of whether smaller practices appropriately integrate new treatment paradigms that require multispecialty interactions and care.

A strategy to define the issue

Unfortunately, intuition has not always been supported by data. With that in mind, I would propose a strategy to define the issue. ASCO, in conjunction with the American Urological Association, could send members a short online survey. Members could be asked to self-define their practices as single-specialty, multispecialty, or academic. Two different scenarios could then be advanced:

• The case of a reasonably healthy patient with cT3 bladder cancer would be described. Urologists would then be asked whether they would refer for neoadjuvant chemotherapy or take the patient directly to surgery. Medical oncologists would be asked for a general description of how often those patients are referred to them.
• The second case to be described would be the case of a patient found on prostatectomy to have either positive margins or seminal vesicle/capsular invasion. Urologists would be asked their likelihood of referring that patient for postoperative radiotherapy.

Once the picture is clarified with this reported data, the two organizations could look together at how to provide the best care to their shared patients.

This multidisciplinary integration is a national issue. Single-specialty practices exist in all sizes of communities, not just smaller towns or rural areas. Thousands of patients across the nation are not getting the best care we know to give, and they deserve our best efforts to rectify this problem.

Dr. Graham is the Medical Director for Multispecialty Clinical Research Services at Carle Physicians Group in Urbana, Illinois. He is the 2013-2014 Chair of the Society’s Integrated Media and Technology Committee, contributes regular commentary to ASCOconnection.org, and is active on Twitter (@davidgrahammd).

References

1. Grossman HB, Natale RB, Tangen CM, et al. N Engl J Med. 2003;349:859-66. PMID: 12944571.
2. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol. 2005;48:202-5. PMID: 15939524.
3. Donat SM. J Natl Compr Canc Netw. 2009;7:40-7. PMID: 19176204.
4. Thompson IM, Tangan CM, Paradelo J, et al. J Urol. 2009;181:956-62. PMID: 19167731.
5. Van der Kwast TH, Bolla M, Van Poppel H, et al. J Clin Oncol. 2007;25:4178-86. PMID: 17878474.