In Germ Cell Cancer, Are We at the End of the Chemotherapy Era? Maybe-and We Are Certainly at the End of the RCT Era

Cisplatin-based chemotherapy has transformed the prognosis of testicular germ cell cancer (GCT). It has converted the chief mortal malignancy in younger men into a model for the curability of cancer. With contemporary management of metastatic disease, few patients die from GCT; the exceptions are a modest proportion of those with poor- or intermediate-risk disease, the uncommon case of nonteratomatous late relapse, and those who (in retrospect) had suboptimal management. Despite substantial research investment over the last 2 decades, progress has been slow in improving the outcomes in those patient populations still at risk for mortality from GCT.

My esteemed counterpart has a first-hand understanding of the challenges involved in making headway in effective treatment of relapsed GCT.[1] Surveillance, Epidemiology and End Results (SEER) analyses show that the survival rates of patients with distant disease in the 1995–2000 and 2002–2008 time periods were 72% and 73%, respectively.[2,3] With fewer than 400 annual testis cancer deaths estimated in the United States for the last few decades, the cumulative improvement in survival has amounted to around a handful of patients per year. The historic reports of 30% to 50% death rates in patients with intermediate- or poor-risk disease are higher than rates that can be achieved with the same regimens but superior care pathways.[4-6] If patients receive proper management, death from seminoma is an exceedingly rare event.[7]

To briefly summarize what we’ve learned from randomized controlled trials (RCTs) in the last decade: classic bleomycin, etoposide, and cisplatin (PEB) still reigns; some aspects of the use of high-dose chemotherapy have been clarified; and we now know that single-agent carboplatin can be used for stage I seminoma. As for the future, there are many ongoing trials involving combinations of gemcitabine, oxaliplatin, paclitaxel, and docetaxel-and single-agents palifosfamide, everolimus, brentuximab vedotin, and pazopanib. These are virtually all analogs of known effective chemotherapeutic agents or available targeted agents; they are being used in early-phase studies in which they take advantage of small windows of opportunity. While the standard site-based approach to chemotherapy research may still make some advances in the treatment of patients with GCT, the improvements will be incremental and proportionally miniscule in terms of lives saved. More promise lies with the general improvement in our understanding of cancer biology and the application of personalized medicine in the most desperate cases.

We have approached the limits of curability with current technology, but are there changes to our processes that can improve the care of GCT patients? Some of our treatment guidelines seem narrowly restricted. For instance, why isn’t retroperitoneal lymphadenectomy (RPLND) an option for the seminoma patient with a 2-cm retroperitoneal lymph node? Some clinicians have abandoned the use of retroperitoneal radiation treatments in the management of low-stage seminoma because of concerns about serious long-term issues in an eminently curable disease.[8] Three or four cycles of multi-agent chemotherapy, which would be required if neither RPNLD nor radiation were used, seems like a lot of treatment for a patient with low-stage seminoma and one involved node. Small studies have shown RPLND to be effective in patients with a low-stage tumor and spread to a single lymph node, and I would posit that it is less morbid and costly than chemotherapy (at least when an uncomplicated procedure is possible and this is well performed).[9] With surveillance expanding as the primary management option in stage I seminoma, the scenario in which spread to a lymph node is discovered in a patient with low-stage seminoma who is being watched will inevitably be more common. The large volume of existing observational data for low-stage seminoma might be used to reinforce a prospective single-arm study of RPLND in this setting, with the reliable backstop of multi-agent chemotherapy for those in whom this approach fails.

Many meaningful questions remain, but the approach of shotgun randomized controlled trialism that characterized the last two decades cannot be relied on to answer them. We applaud Dr. Raghavan and all his colleagues for many useful clinical trials. While the chemotherapy era may not be over, the unfocused RCT era has lingered too long.[10] Although adaptive clinical trials require much forethought, they hold much promise.[11] Certain bits of the basic biology of GCT elude us. A better understanding would allow for more focused identification of promising agents and the nimble, worthwhile clinical trials that our patients require.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Beer TM, Tangen CM, Nichols CR, et al. Southwest Oncology Group Phase II study of arsenic trioxide in patients with refractory germ cell malignancies. Cancer. 2006;106:2624-9.

2. American Cancer Society. Cancer facts and figures 2005. Atlanta: American Cancer Society; 2005.

3. American Cancer Society. Cancer facts and figures 2013. Atlanta: American Cancer Society; 2013.

4. Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA. 2008;299:672-84.

5. Kollmannsberger C, Daneshmand S, So A, et al. Management of disseminated nonseminomatous germ cell tumors with risk-based chemotherapy followed by response-guided postchemotherapy surgery. J Clin Oncol. 2010;28:537-42.

6. Ehrlich Y, Brames MJ, Beck SDW, et al. Long-term follow-up of cisplatin combination chemotherapy in patients with disseminated nonseminomatous germ cell tumors: Is a postchemotherapy retroperitoneal lymph node dissection needed after complete remission? J Clin Oncol. 2010:28:531-6.

7. Kollmannsberger C, Tyldesley S, Moore C, et al. Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies. Ann Oncol. 2011;22:808-14.

8. Travis LB, Fosså SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005;97:1354-65.

9. Mezvrishvili Z, Managadze L. Retroperitoneal lymph node dissection for high-risk stage I and stage IIA seminoma. Int Urol Nephrol. 2006;38:615-9.

10. Nichols CR, Roth B, Kollmannsberger C. Classical clinical trial design in testicular cancer: time to move on. J Clin Oncol. 2012;30:769-71.

11. Berry DA. Adaptive clinical trials in oncology. Nat Rev Clin Oncol. 2011;9:199-207.