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Originally published as JCO Early Release 10.1200/JCO.2008.21.1524 on March 23 2009 © 2009 American Society of Clinical Oncology.
Vox Populi: Using Community-Based Studies to Determine Best Management of Early-Stage NonseminomaProvidence Cancer Center, Earle A. Chiles Research Institute, Portland, Oregon
British Columbia Cancer Agency-Vancouver Cancer Centre, University of British Columbia, Vancouver, British Columbia, Canada In this issue of Journal of Clinical Oncology, there is a quiet shot across the bow of traditional surgical management of early-stage nonseminomatous germ cell tumor. The report by Tandstad et al1 entitled "Risk-Adapted Treatment in Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer: The SWENOTECA Management Program" serves two important purposes. First, it amply (12 years, two countries, 26 centers) demonstrates the stunning success of nonsurgical management of clinical stage I testicular nonseminoma. In this community-based study of risk-adapted approaches, which minimized treatment for most patients, no deaths from progressive testicular cancer were seen in 745 patients with clinical stage I testicular nonseminoma. Additionally, the study demonstrated very low relapse rates in all categories of patients and a cause-specific survival of nearly 100%. Second, it is an elegant and clear-cut example of one of the important emerging clinical research paradigms: widely implement thoughtful straightforward guidelines, coordinate these activities as part of medical care delivery, and then carefully measure and report the outcomes from a large population.2,3 This method of conducting research has enormous implications as it measures activity and outcomes right at the level that matters most: in the community in which the vast majority of patients receive care. Swedish and Norwegian Testicular Cancer Project (SWENOTECA) data were derived by the physicians providing care for patients with average testicular cancer using available technologies and medical teams possessing somewhat varied experience. This study is not a product of what we often see, which are data emerging from studies using only selected, fit, motivated patients who are optimally imaged and treated with high-end technologies and by experienced providers. The SWENOTECA study is one study for which we should have every confidence that the results can be duplicated in the community setting. So, does the SWENOTECA study put an end to time-honored surgical approaches to management of clinical stage I testicular nonseminoma? Simply put—particularly when coupled with the recent report by Albers et al4—yes. The study by Albers et al, which included medical oncologists and urologists, reported an ambitious, well-conducted and community-based study comparing patients with clinical stage I nonseminoma randomly assigned to either traditional management with primary retroperitoneal lymph node dissection (RPLND) or to a single cycle of standard cisplatin, etoposide, and bleomycin (BEP) chemotherapy. Two clear themes emerged from the Albers et al study. First, adequacy of the RPLND was less than expected in this broad-based, multicenter study with a high number of abdominal recurrences in the patients assigned to receive primary RPLND. This finding strongly suggested that it is difficult to duplicate the surgical experience from specialized centers in the community as a whole. Second, the relapse rate with a single cycle of BEP in this setting was exceedingly low (two patients of the 191 patients in an intent-to-treat analysis: the hazard ratio for relapse surgery v chemotherapy was 7.94). The SWENOTECA study suggests a similar low relapse rate among a much larger number of patients treated with a single cycle of BEP (seven of 312 treated patients, or 2%). In both studies, the rare patients relapsing after a single cycle of BEP were successfully treated with subsequent salvage standard therapy, with no deaths from progressive testicular cancer associated with any treatment approach in either of these large community-based studies. Most of the arguments for retaining a surgery-based approach rather than either active surveillance or adjuvant chemotherapy are based on two largely theoretic concerns. The most frequently cited concern is that an active therapeutic approach is necessary because there is a significant risk of noncompliance leading to late recurrences with incurable large volume disease. Both the Albers et al4 study and the much larger SWENOTECA study clearly addressed this issue.1 Neither of these studies depended on those motivated patients who self-select by traveling to centers of experience for their care. Both studies are population-based trials. Both of these studies were conducted over a large and sometimes daunting geography. Despite broad-based populations of unselected patients, compliance was sufficient to insure that cause-specific survival was 100% and that the relapsing patient was reliably identified in a time frame that lead to straightforward management and cure. That compliance in broad-based studies is sufficient is also confirmed by a US study of surveillance in clinical stage I nonseminoma in unselected patients that reported nearly all patients relapsing with good-risk disease and no testicular cancer deaths.5 The second common argument used to reinforce the primary surgical approach is that the virgin, undissected retroperitoneum is a source for untoward downstream consequences such as late recurring unresectable teratoma or late relapsing chemotherapy-resistant viable cancer. In neither of these studies were these hypothetical fears realized. All 745 patients in the SWENOTECA study were managed without primary RPLND.1 Only 37 patients (5%) ever had any surgical management of the retroperitoneum. The majority of these RPLNDs were for postchemotherapy residual radiographic abnormalities in relapsing patients; the findings were primarily necrosis followed by teratoma, and only three patients had persistent cancer. In the single-course BEP arm of the Albers et al4 study, one patient of 191 required retroperitoneal dissection for a mature teratoma. In the SWENOTECA study, there were five (< 1%) of 745 patients recurring beyond 2 years; in the Albers et al study, only one of 388 patients experienced late relapse. All six patients in these two series were identified appropriately and were successfully managed with subsequent treatments. Median follow-up for both studies is approaching 5 years. Simply put, the world's largest combined experiences of primary nonsurgical management of clinical stage I testicular nonseminoma resulted in exposing fewer than 5% of the total population to retroperitoneal dissection without a high incidence of late relapses or unmanageable teratoma or, at the risk of being repetitive, any cancer-related deaths. The SWENOTECA study provides further support for both the European and Canadian consensus conferences for the management of germ cell tumors.1 Both of these conferences included a diverse group of testicular cancer thought leaders in urology, radiation therapy, medical oncology, and others discipline debating and defining recommendations for their countries. Both of these large, diverse, and experienced groups firmly advocated nonsurgical management of both high- and low-risk clinical stage I nonseminoma. Indeed, primary RPLND was a distant third, trailing after active surveillance or a risk-adapted combined chemotherapy/surveillance approach. There is no longer any reason to seriously consider primary surgical management as a comprehensive management strategy for clinical stage I nonseminoma. Surveillance or risk-adapted strategies can be safely delivered in the community setting. Clinging to recommend primary RPLND with a plea for all testicular cancer care to be delivered in a few referral centers does not fulfill our responsibilities to develop treatment approaches that can be used across diverse medical care delivery geographies. Primary RPLND is doomed as a broad-based approach because it represents massive overtreatment to the population as a whole without a global survival benefit. However, the same can be said of the chemotherapy-for-all approach or even a risk-adapted strategy. Here the SWENOTECA recommendations for a single cycle of BEP for high-risk and perhaps even low-risk patients require additional thought and investigation.1 The goal of the SWENOTECA study was simply to minimize the risk of relapse. Had the goal been to avoid overtreatment and maintain 100% survival, global surveillance would have been the clear winner (Table 1). The authors argue that one cycle of BEP is relatively trivial and that the goal of such a strategy is to minimize the number of patients ultimately receiving three or more cycles of therapy. They speculate from prior studies utilizing high-dose BEP (usually four or more courses) that the risks of long-term adverse effects, such as renal insufficiency, metabolic syndrome, hearing impairment, second malignancies, and infertility, are strictly proportional to the number of cycles received. This approach is similar to a "vaccine" mentality: that it is better to burden everyone with mild toxicity to decrease potential complications for a few. There are yet no data from this study or other studies to support the inference that this is an overall healthier approach for the population. We can hope that long-term data regarding the subtle long-term effects of even a single cycle of BEP are forthcoming. We already know every patient receiving even one cycle of BEP experienced hair loss; a significant disruption from work, school, and life; exposure to significant neutropenia with the rare risk of fatal complications; risk of vascular complications; rare acute chemotherapy reactions; at least temporary effect on fertility; and the anxiety and fears that all patients receiving chemotherapy face. In the SWENOTECA study, the patients receiving a single cycle of BEP were not completed spared the fear of relapse or the inconvenience of ongoing imaging. It is clearly not "one and done" for some patients with clinical stage I testicular nonseminoma.
One of the greatest strengths of the SWENOTECA study was its standardized approach to staging, risk assignment, treatment, and follow-up.1 It is said that if cooking is an art, baking is a science. Management of testicular cancer is like baking. Do it consistently and precisely, and the results are remarkably predictable. If one tries to be creative, add a dash of this or delete that, unmitigated disasters will ensue. Management of clinical stage I testicular nonseminoma must be done absolutely by the books, as was exemplified by the SWENOTECA study. Investigators were patient and precise in establishing the initial stage by formally restaging patients at the 6-week mark to eliminate patients in early evolution to regional or distant disease. They utilized a powerful, simple, broadly available, and reproducible prognostic discriminator to assign risk (presence or absence of lymphovascular invasion). They carefully stipulated treatment algorithms and follow-up templates, and they systematically collected and reported their data. Their results and safety profile were both predictable and excellent. So where do we go from here? This report offers a number of questions and opportunities for ongoing refinements of nonsurgical approaches to early-stage germ cell tumors. The primary translational question that remains is whether we can develop molecular or other predictors of recurrence that would enable us to better define risk groups with an extremely low or extremely high chance of recurrence. These groups could receive surveillance at a reduced level of scrutiny or adjuvant chemotherapy, respectively. The primary clinical question remaining is whether all patients should receive surveillance, as recommended in the Canadian consensus,6 or making recommendations by risk (low = surveillance; high = chemotherapy with two cycles of BEP), as in the European consensus.7 Will these and other large data sets help us determine optimal imaging strategies, the effect of adjuvant BEP on second primary testicular tumors, or predict the incidence of long-term adverse effects with even a single cycle of chemotherapy? Is patient autonomy in treatment decisions a good thing, or does it just shift the burden of the wrong choice to the patient with associated remorse and guilt? What was the yield of contralateral biopsy in this patient population? Why was compliance with this recommendation so low? Did patients demonstrating testicular interepithelial neoplasia all receive radiation? How do we optimally deliver nonsurgical treatment guidelines into the hands of our community partners, and how do we gauge implementation and outcomes across the population? We have irrevocably entered an era of nonsurgical management for the most common presentation of testicular nonseminoma. The new treatment paradigm optimizes care and quality survivorship for this population of patients. It can and should be delivered in the community setting and should represent the standard of care in the United States and around the world. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Craig R. Nichols, Christian Kollmannsberger Data analysis and interpretation: Craig R. Nichols, Christian Kollmannsberger Manuscript writing: Craig R. Nichols, Christian Kollmannsberger Final approval of manuscript: Craig R. Nichols, Christian Kollmannsberger REFERENCES 1. Tandstad T, Dahl O, Cohn-Cedermark G, et al: Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: The SWENOTECA management program. J Clin Oncol 13:2122–2128, 2009. 2. Conners JM: Do we need radiotherapy in early Hodgkin's lymphoma? Ann Oncol 19:82; 2008 (suppl 4. 3. Sehn LH, Donaldson J, Chhanabhai M, et al: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027–5033, 2005. 4. Albers P, Siener R, Krege S, et al: Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol 26:2966–2972, 2008. 5. Moore C, Hayes-Lattin B, Daneshmand S, et al: Characteristics of relapse in patients with clinical stage I testicular cancer. J Clin Oncol 26:674s; 2008 (suppl) abstr 16040.[CrossRef] 6. Canadian Testis Cancer Consensus Conference, King City, Ontario, Canada, October 19-20, 2007. 7. Krege S, Beyer J, Souchon R, et al: European consensus conference on diagnosis and treatment of germ cell cancer: A report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG), part II. Eur Urol 53:497–513, 2008.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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