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Originally published as JCO Early Release 10.1200/JCO.2003.07.967 on October 14 2003 © 2003 American Society for Clinical Oncology
New Prognostic Factors for Stage I Testicular Cancer: But Will They Make It to Broadway?Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA THE MANAGEMENT of stage I testicular cancer has changed dramatically in the last 20 years, predicated on major improvements in imaging technology1 and surgical technique2 and the evolution of effective chemotherapy.3 Visionary studies from the United Kingdom4,5 led to the introduction of close surveillance alone after orchidectomy as an approach for patients with stage I nonseminomatous germ cell tumors (NSGCT) and, subsequently, for seminoma. It appears that, after inguinal orchidectomy, outcomes with surveillance alone and salvage chemotherapy when required—in expert hands—are approximately equivalent to those obtained from retroperitoneal lymph node dissection (RPLND; for NSGCT) or from adjuvant radiotherapy (in the case of stage I seminomas), sometimes with the addition of chemotherapy for subsequent recurrent or metastatic disease.6 In recent times, attempts have been made to avoid RPLND for patients with stage I testicular cancer, because of the extent of perceived complications of such surgery and because of high cure rates with orchidectomy alone. Most of these studies have addressed the concept of risk-adapted adjuvant chemotherapy.7–9 This has involved the use of truncated schedules of adjuvant chemotherapy, although long-term follow-up from randomized trials has not yet been reported. One important concern regarding the routine use of this approach has been the concern about the late effects of cytotoxic chemotherapy, which can include a series of metabolic effects and second malignancies.10 To mitigate unnecessary toxicity, a series of recent studies has addressed specific prognostication for individual patients with stage I disease, with the intent of restricting the use of adjuvant therapies only to those patients at highest risk for metastasis. This issue is not new. A quarter of a century ago, Tom Sandeman identified vascular invasion as an adverse prognostic factor11 and subsequently proposed the use of adjuvant chemotherapy for those patients with stage I testicular cancer and with adverse risk factors.12 Soon afterward, in series of patients from the UK and from Minnesota, we demonstrated that embryonal carcinoma histology, slow tumor marker decline from the circulation after orchidectomy, and advanced T stage were adverse prognostic factors for stage I NSGCT;13,14 others have confirmed and extended these data.15–19 The current consensus is that the key adverse prognostic factors are persistent circulating tumor markers postorchidectomy, vascular invasion, and extent of local tumor involvement.20 More recent studies, including new data reported in this issue of the Journal of Clinical Oncology, suggest that the expression of oncogenes or proliferation markers, or mutations of suppressor genes may sometimes be independently prognostic factors for stage I disease.21–24 The study by Vergouwe et al24 represents an extension of their more traditional approach to histologic prognostication reported earlier this year,19 with the current study moving into the realm of molecular and cytokinetic prognostication. Although this is an elegant study, it is limited somewhat by the lack of histologic confirmation from a single center, and thus its listing of a case experience of 2,500 patients is a little misleading, given that the series represents an accumulation of several reported case series without any central pathology review. A key issue is whether any additional prognostic factors are really needed for the management of stage I testis cancer and whether they will facilitate improved treatment. It is clearly important to identify patients at increased risk of relapse regarding the use of RPLND, adjuvant chemotherapy, and surveillance. In this context, our study of surveillance showed that many patients, even with adverse risk factors, did not experience disease relapse after many years,25 and thus adjuvant therapy is clearly not essential in all such cases—an observation confirmed in many similar studies. Furthermore, we have reported a case in which a patient who experienced disease relapse after surveillance and was then treated for good-risk metastatic disease with only three cycles of cisplatin, etoposide, and bleomycin developed leukemia,26 a well-established complication of more prolonged regimens of chemotherapy. It is thus my belief that adjuvant chemotherapy should not be introduced lightly into the treatment of patients with a disease that is highly curable by more conventional means, such as retroperitoneal lymph node dissection or active surveillance, with three cycles of chemotherapy for documented relapse. I am thus not sure that these additional molecular prognosticators for stage I testis cancer will be all that helpful in the absence of more case-specific data, accompanied by central histologic review and much longer follow-up. We are at a juncture at which we need to take careful stock of progress in the management of germ cell malignancies. The average patient with stage I disease should expect cure at the first instance, and a small proportion may need salvage treatment, again with the expectation of cure. It is not clear that the introduction of two cycles of adjuvant cytotoxic treatment, with such well-defined early and late toxic effects (some of which may be lethal) is optimal management for a population of patients with a better than 90% ultimate cure rate, given that the long-term safety and efficacy have not been validated in mature randomized trials. Analogous to the work of the International Germ Cell Tumor Consensus Committee in defining risk categories for metastatic disease, the results of the North American Intergroup study, under the chairmanship of Richard Foster, will likely facilitate more accurate prognosis and optimize management of stage I testicular cancer. This registration study will categorize a large series of patients with stage I germ cell tumors, treated by a common approach, with central pathology review, and will allow a serious attempt at conventional and molecular prognostication. However, after completion of this very important trial, it may not be the best use of further scientific research funds to find additional prognostic variables that relate to the early stages of a disease with such an excellent prognosis. Such funds could be better spent in the search for a cure for many other malignancies, for a better understanding of the biology and basis of cure in germ cell malignancy, or perhaps even for our understanding of the late effects of treatment of curable cancers. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES 1. Husband JES, Koh S-M, Cook GJR: Radiologic investigation, in Raghavan D (ed), American Cancer Society Atlas of Clinical Oncology: Germ Cell Tumors, Hamilton, Canada, BC Decker Inc, 2003, pp 58–73 2. Foster RS, Birhle R, Donohue JP: Surgery of the retroperitoneum, in Raghavan D (ed), American Cancer Society Atlas of Clinical Oncology: Germ Cell Tumors, Hamilton, Canada, BC Decker Inc, 2003, pp 98–108
3. Einhorn LH: Testicular cancer: An oncological success story. Clin Cancer Res 3:2630–2632, 1997 4. Peckham MJ, Barrett A, Husband JE, et al: Orchidectomy alone in testicular stage I non-seminomatous germ cell tumours. Lancet 2:678–680, 1982[CrossRef][Medline] 5. Francis R, Bower M, Brunstrom G, et al: Surveillance for stage I testicular germ cell tumours: Results and cost benefit analysis of management options. Eur J Cancer 36:1925–1932, 2000[CrossRef][Medline] 6. Raghavan D: Active surveillance for stage I testis cancer: Attaining maturity at 21 years. Eur J Cancer 36:1891–1894, 2000[Medline] 7. Ekman EP, Edsmyr F: Chemotherapy in non-seminomatous testicular tumours stage I. Brit J Urol, 53:184–187, 1981[Medline]
8. Cullen MH, Stenning SP, Parkinson MC, et al: Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: A Medical Research Council report. J Clin Oncol 14:1106–1113, 1996
9. Pont J, Albrecht W, Postner G, et al: Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: Long-term results of a prospective trial. J Clin Oncol 14:441–448, 1996 10. Sweeney CJ, Raghavan D: Late toxicity of chemotherapy, in Raghavan D (ed), American Cancer Society Atlas of Clinical Oncology: Germ Cell Tumors, London, UK, BC Decker Inc, 2003, pp 349–362 11. Sandeman TF, Matthew JP: The staging of testicular tumors. Cancer 43:2514–2524, 1979[CrossRef][Medline] 12. Sandeman TF, Yang C: Results of adjuvant chemotherapy for low-stage nonseminomatous germ cell tumors of the testis with vascular invasion. Cancer 62:1471–1475, 1988[CrossRef][Medline] 13. 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 45:167–173, 1982[Medline] 14. Raghavan D, Vogelzang NJ, Bosl GJ, et al: Tumor classification and size in germ-cell testicular cancer: Influence on the occurrence of metastases. Cancer 50:1591–1595, 1982[CrossRef][Medline] 15. Vaeth M, Schultz HP, von der Maase H, et al: Prognostic factors in testicular germ cell tumours. Acta Radiol Oncol, 23:271–285, 1984[Medline] 16. Moriyama N, Daly JJ, Keating MA, et al: Vascular invasion as a prognosticator of metastatic disease in non-seminomatous germ-cell tumors of the testis. Cancer 56:2492–2498, 1985[CrossRef][Medline] 17. Freedman LS, Parkinson MC, Jones WG, et al: Histopathology in the prediction of relapse of patients with stage I testicular teratoma treated by orchidectomy alone. Lancet 2:294–298, 1987[CrossRef][Medline] 18. Klepp O, Olsson AM, Henrikson H, et al: Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: Multivariate analysis of a prospective multicenter study. J Clin Oncol 8:509–518, 1990[Abstract]
19. Albers P, Siener R, Kliesch S, et al: Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: Results of the German Testicular Cancer Study Group Trial. J Clin Oncol 21:1505–1512, 2003 20. American Joint Committee on Cancer: Testis—AJCC Cancer Staging Manual, New York, NY, Springer, 2002, pp 317–322 21. Ulbright TM, Orazi A, de Riese W, et al: The correlation of P53 protein expression with proliferative activity and occult metastases in clinical stage I non-seminomatous germ cell tumors of the testis. Mod Path 7:64–68, 1994[Medline] 22. Fukuda S, Shirahama T, Imazono Y, et al: Expression of vascular endothelial growth factor in patients with testicular germ cell tumors as an indicator of metastatic disease. Cancer 85:1323–1330, 1999[CrossRef][Medline] 23. Spermon JR, de Wilde PC, Hanselaar AG, et al: Alpha-catenin expression pattern and DNA image-analysis cytometry have no additional value over primary histology in clinical stage I nonseminomatous testicular cancer. B J U Int 89:278–284, 2002
24. Vergouwe Y, Steyerberg EW, Eijkemans MJC, et al: Predictors of occult metastasis in clinical stage I nonseminoma: A systematic review of 2,500 patients. J Clin Oncol 21:4092–4099, 2003 25. Raghavan D, Colls B, Levi J, et al: Surveillance for stage I non-seminomatous germ cell tumours of the testis: The optimal protocol has not yet been defined. Br J Cancer 61:522–526, 1988 26. Segelov E, Raghavan D, Coates AS, et al: Acute leukemia following chemotherapy including etoposide for testicular carcinoma. Aust N Z J Med, 23:718–719, 1993[Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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