In Germ Cell Cancer, Are We at the End of the Chemotherapy Era? No-Targeted Therapies Have Not Heralded Its Demise

Germ cell tumors (GCT) are an exemplar of the successful use of chemotherapy and of the successful interplay of phase II and phase III trials. The biggest contributor to cure in metastatic GCT is cisplatin-based chemotherapy, unchallenged after more than 30 years. There is no level 1 evidence yet to support new and targeted therapies for routine use in GCT.

Young oncologists[1] perhaps do not fully appreciate the extraordinary changes that have occurred in the management of GCT in the past 40 years. Before the 1980s, a very disappointing aspect of oncology practice was the death of young men with metastatic GCT. More than 75% of men with metastatic nonseminomatous GCT died of their disease, usually within 1 to 2 years of presentation! With the introduction of cisplatin-containing regimens,[2,3] cure rates in excess of 75% were routinely documented in this devastating disease. We also developed tumor markers for staging and evaluation of response to treatment[4,5] and identified prognostic factors in early-stage disease that connoted success with minimal therapy or the need for more aggressive use of retroperitoneal node dissection or chemotherapy.[6,7] Outcome criteria for advanced disease were developed, allowing the tailoring of chemotherapy to level of risk.[8,9]

The 1980s were characterized by efforts to reduce toxicity, but most randomized trials that tested such innovations (omission of bleomycin, replacement of cisplatin by carboplatin, or reduction of dose intensity) actually produced inferior results,[10-12] a chastening lesson that led to more cautious approaches to improving treatment. That said, the toxic effects of treatment were significant,[13] and the oncology community continued to try to improve quality of life without loss of treatment efficacy.

Several important points have become clear in recent years:

• Inadequate initial treatment is associated with increased death rates from GCT; for example, 3 doses of standard bleomycin, etoposide, and cisplatin (PEB) chemotherapy is often inadequate to achieve cure for patients with intermediate-risk metastatic disease.[14]

• Incomplete surgical resection of residual disease is also a risk factor for relapse and death.

• Poor-risk metastatic disease[9] is cured in only 50% of cases or less by standard regimens and remains an important focus for developmental therapeutics.

Fortunately, few patients present with poor-risk disease, although this has contributed to a lack of patients for inclusion in developmental programs focused on this cohort (a difficulty that has been exacerbated by the reluctance of government agencies to fund relevant studies and of clinicians to enter patients into randomized clinical trials). The British have developed the POMB/ACE rapid cycling, multi-agent regimen (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide), which may improve outcomes for poor-risk human chorionic gonadotropin (hCG)-producing tumors in particular,[15] although randomized trials have not proven this. High-dose therapy and bone marrow support also may cure patients with poor-risk or relapsed GCT, although randomized trials have been equivocal[16,17] and routine application to all cases is not appropriate.[18] If investigators were to collaborate and enter their poor-risk patients into collaborative trials, we could potentially resolve this vexed issue.[18] Newer agents, such as paclitaxel, gemcitabine, and oxaliplatin, also have modest response rates in relapsed patients, and are being explored in combination regimens, again producing durable responses in resistant disease. Nonrandomized trials are usually not sufficiently powered to allow changes in treatment to become “routine,” as they often miss case selection and salvage therapy bias-and often delude the enthusiast into misinterpreting random variation as progress.[1] That said, we didn’t need a randomized trial to confirm the utility of cisplatin against GCT because of the magnitude of its effect.

Should we view the lack of recent progress in the development of chemotherapy for GCT as a metaphor for the end of the chemotherapy era? Absolutely not! To insinuate that this is a reality ignores the extraordinary impact of chemotherapy on this disease, and also reflects the frequent North American affection for anything new and unproven in preference to anything old and established (particularly worrying in the absence of level 1 evidence). Chemotherapy remains the hallmark of cure for advanced GCT, and results will potentially be improved by more accurate treatment selection and application of prognostic factors. In addition, if we understand why chemotherapy is so effective against GCT, we may find more effective ways of applying this tool in other cancers.

We must also educate young men about earlier presentation, because delay is harmful.[19] What a missed opportunity when the US Preventive Services Task Force failed to take advantage of the chance to educate doctors and patients about the benefits of early diagnosis when issuing its report[20] on testis cancer screening!

Disclosures:

Dr. Raghavan sits on the President’s Advisory Board for Sanofi-Aventis and consults occasionally for Gerson Lehrman.

References:

1. Maroni P. 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. Oncology (Williston Park). 2013;27:1136,1143.

2. Einhorn LH. Testicular cancer as a model for a curable neoplasm. The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res. 1981;41:3275-80.

3. Peckham MJ, Barrett A, McElwain TJ, et al. Non-seminoma germ cell tumours (malignant teratoma) of the testis: results of treatment and an analysis of prognostic factors. Br J Urol. 1981;53:162-72.

4. Lange PH, McIntyre KR, Waldmann TA, et al. Alpha-fetoprotein and human chorionic gonadotrophin in the management of testicular tumors. J Urol. 1977;118:593-6.

5. Raghavan D, Gibbs J, Nogueira-Costa R, et al. The interpretation of marker protein assays: a critical appraisal in clinical studies and a xenograft model. Br J Cancer. 1980;41(suppl IV):191-4.

6. Raghavan D, Peckham MJ, Heyderman E, et al. Prognostic factors in clinical stage I non-seminomatous germ-cell tumours of the testis. Br J Cancer. 1982;45:167-73.

7. Raghavan D, Vogelzang NJ, Bosl GJ, et al. Tumor classification and size in germ-cell testicular cancer: influence on the occurrence of metastases. Cancer. 1982;50:1591-5.

8. Bosl GJ, Geller N, Cirrincione C, et al. Multivariate analysis of prognostic variables in patients with metastatic testicular cancer. Cancer Res. 1983;43:3403-7.

9. International Germ Cell Cancer Collaborative Group. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol. 1997;15:594-603.

10. Levi JA, Raghavan D, Harvey V, et al. The importance of bleomycin in combination chemotherapy for good prognosis germ cell carcinoma. J Clin Oncol. 1993;11:1300-5.

11. Horwich A, Sleijfer DT, Fossa SD, et al. Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a multi-institutional Medical Research Council/European Organization for Research and Treatment of Cancer trial. J Clin Oncol. 1997;15:1844-52.

12. Levi JA, Thomson D, Bishop J, et al. Dose intensity and outcome with combination chemotherapy for germ cell carcinoma. Eur J Cancer Clin Oncol. 1989;25:1073-7.

13. Boyer M, Raghavan D. Toxicity of treatment of germ cell tumors. Semin Oncol. 1992;19:128-42.

14. Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term follow up of a phase III study of three versus four cycles of bleomycin, etoposide and cisplatin in favorable-prognosis germ cell tumors. The Indiana University experience. J Clin Oncol. 1998;16:702-6.

15. Bower M, Newlands ES, Holden L, et al. Treatment of men with metastatic nn-seminomatous germ cell tumours with cyclical POMB/ACE chemotherapy. Ann Oncol. 1997;8:477-83.

16. Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol. 2007;25:247-56.

17. Pico JL, Rosti G, Kamar A, et al. A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol. 2005;16:1152-9.

18. Raghavan D. Salvage or savage chemotherapy for poor-risk or relapsed testis cancer-20 years later, not much has changed. Ann Oncol. 2012;23:813-4.

19. Bosl GJ, Vogelzang NJ, Goldman A, et al. Impact of delay in diagnosis on clinical stage of testicular cancer. Lancet. 1981;318:970-3.

20. US Preventive Services Task Force: Screening for testicular cancer. US Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2011;154:483-6.