|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.03.0361 on October 31 2005 © 2005 American Society of Clinical Oncology.
Carboplatin for Stage I Seminoma and the Sword of Damocles1 Indiana University Cancer Center, Indiana University, Indianapolis, IN
2 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY Damocles lived on the island of Sicily approximately 400 BC and served in the court of Dionysius II of Syracuse. As told by Cicero in the Tusculan disputations,1 Damocles was extremely effusive of the tyrant Dionysius and continuously told him how fortunate he was to have great power and riches. Growing weary of these comments, Dionysius one day asked Damocles if he would like to sample his lifestyle. Damocles happily agreed and was subsequently treated to a bountiful banquet that included the finest foods, wines, flowers, and music. At the end of the meal he glanced up and saw a sharp sword dangling by a single horsehair above his head. Damocles quickly left the banquet, suddenly quite content with his former life. "The Sword of Damocles" has grown to describe the feeling of impending doom.2 In this issue of the Journal of Clinical Oncology, Aparicio et al3 have used this metaphor for the stress of the long follow-up experienced by patients during surveillance for clinical stage I seminoma. In their article, the authors report their well-conducted phase II study of a so-called risk-adapted strategy in which patients with clinical stage I (a tumor that is apparently confined to the testicle, with normal serum levels of beta-human chorionic gonadotropin and alpha-fetoprotein and normal computed tomography of the chest, abdomen, and pelvis) seminoma were assigned to either surveillance or chemotherapy with carboplatin. Recently, the management of clinical stage I seminoma has become controversial. Is the stress of long follow-up and good compliance eliminated by this approach? In our opinion, the answer is no, as relapses still occur at a rate that may be worse than that observed with standard radiation therapy (RT) and at sites that are different. RT has been the standard primary treatment for clinical stage I seminoma for several decades. After approximately 20 to 25 Gy administered to the retroperitoneal and ipsilateral pelvic lymph nodes (the so-called dog-leg port), the overall recurrence rate is approximately 3% to 5%, and virtually all relapses occur outside the RT portal. The 5-year overall survival rate for patients with stage I seminoma after RT is nearly 100%.4-8 Late complications from RT, such as nontesticular second malignancies and cardiovascular disease, have been well described.9-11 In the past two decades, surveillance alone has been studied as an alternative approach to the management of patients with clinical stage I seminoma.4 The relapse rate after orchiectomy alone is approximately 15% to 20%. Investigators at the Princess Margaret Hospital (Toronto, Canada) led the efforts. In a series of 471 patients seen between 1981 and 1994, relapses occurred in 37 patients (16%) on surveillance and in 14 patients (5.7%) treated with RT, with a 5-year actuarial survival rate of 97% and a cause-specific survival rate of 99.8% for those managed with RT (n = 245) or surveillance (n = 226), respectively. Because most patients on surveillance experienced relapse in the retroperitoneum and received therapeutic RT, only 13 patients (5.7%) on surveillance and 10 patients receiving prophylactic RT required subsequent chemotherapy.11 Hence all of the patients who experienced relapse were cured with either subsequent RT or chemotherapy. With the success of chemotherapy in patients with disseminated germ cell tumors (GCTs), the role of systemic chemotherapy has been studied in seminomas. Noting that seminoma may be more chemotherapy sensitive than its nonseminomatous counterpart, some investigators have advocated single-agent carboplatin over combination therapy. The report by Aparicio et al3 from the Spanish Germ Cell Cancer Cooperative Group is one such study. An interesting feature of this article is the investigation of not only the assignment of two cycles of carboplatin as adjuvant therapy for a high-risk and surveillance for a low-risk group of patients with clinical stage I seminoma, but also the prospective use of a risk algorithm to assign high-risk or low-risk status to this patient population. These risk factors included primary tumors greater than 4 cm, and/or rete testis involvement, based on published retrospective reviews.4,12 With a median follow-up of 34 months, the 5-year disease-free survival rate was 93.4% for patients on surveillance (low risk) and 96.2% for those treated with adjuvant carboplatin chemotherapy. The estimated 5-year survival rate was 100%.3 Although this study is a noble attempt to test a risk-adapted strategy for stage I seminoma, it is difficult to embrace this concept for several reasons. CARBOPLATIN IS INFERIOR TO CISPLATIN IN DISSEMINATED GCT Carboplatin has been evaluated in GCT both as a single agent and in combination chemotherapy. Several phase II trials demonstrated single-agent activity for carboplatin, with response rates seemingly comparable to combination therapy. However, a prospective randomized trial conducted by Memorial Sloan-Kettering Cancer Center (New York, NY) and the Southwest Oncology Group found that a regimen of four cycles of carboplatin plus etoposide was inferior to a regimen of four cycles of cisplatin plus etoposide in patients with good-risk GCT.13 A trial of the Medical Research Council and European Organisation for Research and Treatment of Cancer showed that four cycles of carboplatin plus etoposide plus bleomycin was inferior to cisplatin plus etoposide plus bleomycin.14 A third trial compared single-agent carboplatin with cisplatin combination chemotherapy in patients with metastatic seminoma; both progression-free and overall survival were inferior to the combination chemotherapy, though these did not reach statistical significance.15 The authors concluded that "standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations... ." Clemm et al16 observed a 21% lower progression-free survival rate in patients who received carboplatin compared with cisplatin combination chemotherapy (cisplatin, etoposide, and ifosfamide). Bokemeyer et17 al published a pooled analysis of these two trials and reported an inferior progression-free survival rate (72% v 92%; P < .0001) and 5-year survival rate (89% v 94%; P = .09), with the nonsignificant trend for overall survival likely a consequence of salvage therapy with combination therapy. Although salvage chemotherapy may narrow or eliminate an overall survival disadvantage resulting from a higher relapse rate (as also occurred in the Memorial Sloan-Kettering Cancer Center/Southwest Oncology Group trial), the patients who receive inferior therapy and experienced relapse will necessarily suffer the consequences of a higher burden of therapy. No a priori reason exists to assume that micrometastatic disease will be more sensitive to carboplatin than overtly metastatic disease. Therefore, it is highly likely that a number of patients will experience relapse because they received an inferior drug. THE RATE AND SITES OF RELAPSE AFTER SINGLE-AGENT CARBOPLATIN ARE NOT SATISFACTORY As mentioned in the study by Bokemeyer et al, 17 the relapse rate for patients treated with single-agent carboplatin was higher (28%) than that for patients who received combination chemotherapy (8%). Aparicio et al3 report a 3% relapse rate in patients treated with carboplatin and 9% for those with rete testis invasion. Hence two cycles of carboplatin do not eliminate the risk of recurrence, and the relapse rate is higher than that expected after RT for those with rete testis invasion. Further, this relapse rate in clinical stage I seminoma is higher than the relapse rate after two cycles of adjuvant cisplatin-based chemotherapy for pathologic stage II nonseminomatous GCT, therapy which virtually eliminates the chance of developing recurrent disease.18-20 Indeed, in patients who achieve a complete remission after cisplatin plus etoposide-based combination chemotherapy for disseminated disease, the relapse rate is approximately 5% to 8%.6 Moreover, all the relapses after carboplatin for clinical stage I seminoma are reported to have occurred in the retroperitoneum, a site in which relapse rarely occurs after standard RT. THE RISK-ADAPTIVE MODEL TO PREDICT RELAPSE FOR SEMINOMA HAS NOT BEEN VALIDATED One can find little fault in the concept of therapy for a targeted high-risk population, but this study does not demonstrate that relapse of stage I seminoma can be predicted by rete testis invasion and/or size of primary tumor. Neither factor is included in the American Joint Committee on Cancer staging algorithm. More than two thirds of patients on this trial were considered high risk. Although the numbers are small, this study does suggest that lymphovascular invasion, the most common factor that predicts relapse among clinical stage I nonseminomatous GCT, is not a predictive factor in clinical stage I seminoma. In a pooled analysis of 638 patients managed by surveillance reported by Warde et al, 4 the predicted relapse rate in the presence of both factors was 68.5%, but only 15% of tumors had both characteristics. The relapse rate was 17% for primary tumors greater than 4 cm without rete testis invasion, 12% for primary tumor less than 4 cm and no rete testis invasion, and 14% for rete testis invasion and a primary tumor less than 4 cm. Hence the risk model does not seem to adequately select a truly high-risk group of patients. FOLLOW-UP IS TOO SHORT TO PRECLUDE LATE RELAPSE AFTER CARBOPLATIN At the time of the analysis, the median follow-up was 34 months. Short follow-up does not permit an insight into late relapse or toxicity, because approximately one third of relapses in patients with seminoma followed by surveillance occur after 2 years, and between 5% and 10% occur 5 years and beyond.4,5,21 Thus the relapse rate in this series is likely to increase with longer follow-up. Moreover, the recurrences are predominantly retroperitoneal. One of the advantages of prophylactic RT for clinical stage I seminoma is the near elimination of retroperitoneal recurrence and the need for radiographic follow-up, unless the patient develops symptoms. The authors recommend no difference in follow-up patterns between those patients with high-risk and low-risk disease; both patients treated with single-agent carboplatin and those on surveillance still require follow-up with computed tomography scans as well as chest x-ray and markers. These recommendations raise doubt regarding whether the stress of follow-up is actually reduced in these patients. THE LATE CONSEQUENCES OF THIS THERAPY ARE UNKNOWN The role of single-agent carboplatin therapy is justified by the authors in that overall survival is not altered (because of subsequent salvage combination chemotherapy). This justification accepts that patients experiencing relapse may therefore receive a total of up to six cycles of cisplatin-based therapy. Meinardi et al22 have observed that patients who received bleomycin, etoposide, and cisplatin therapy had an increased risk of cardiovascular disease such as myocardial infarction or ischemia (observed/expected [O/E] = 7.1) from 9 to 16 years after treatment, not including Raynaud's phenomenon and a much higher incidence of hypertension and hypercholesterolemia. Aparicio et al3 correctly state that the long-term side effects of RT include second malignancy and cardiovascular complications. Zagars et al9 reported that O/E = 1.74 for excess cancer mortality without mediastinal RT and O/E = 1.45 for cardiac events, Bachaud et al10 reported O/E = 0.62 for second neoplasm when only infradiaphragmatic RT was administered, and Travis23 reported that the O/E = 1.42 for second neoplasm in patients with seminoma. Each of these O/E risk ratios is lower for standard infradiaphragmatic RT than the late cardiovascular risk after GCT chemotherapy. In addition, the data on late toxicity after RT are obtained from series with follow-up of several decades or more, and RT techniques continue to change and dose continues to be reduced.24 Myocardial infarction, hypertension, and hypercholesterolemia resulting from GCT chemotherapy are clearly more frequent than and are (in the case of myocardial infarction) as potentially deadly as any second neoplasm. Hence one should be cautious when recommending chemotherapy for a large population of GCT patients for whom chemotherapy is not indicated and may never be necessary. In our opinion, adjuvant carboplatin chemotherapy for clinical stage I seminoma is as yet an unproven treatment alternative to standard RT, and the risk-adaptive model remains an unproven method for assessing the risk of relapse among these patients. The possibility that carboplatin is not inferior in this setting is difficult to ascertain, given the absence of randomized comparisons that take into account the likely small number of events. Uncertain frequency of late relapse, long-term toxicity, and the persistent need for surveillance are important related issues. The concept of risk-adapted therapy for patients with clinical stage I seminoma and nonseminomatous testicular GCT is an appropriate area of investigation. However, to date, the definition of a truly high-risk group of patients with clinical stage I seminoma remains elusive. The ability to recognize high-risk seminoma will likely come from the identification of more specific molecular signatures. Therefore, we continue to recommend standard RT or surveillance for clinical stage I seminoma. Perhaps the metaphor of the Sword of Damocles for clinical stage I seminoma is truly appropriate. The exuberance for a simple solution is so high and the ease of administration of two cycles of carboplatin for patients with stage I seminoma is so compelling that some physicians would rather treat with carboplatin than recommend standard RT or observation. Indeed, they may even tell their patients "how lucky they are" to have such a good-risk disease. Unfortunately, it is simply not possible to accept this approach as a standard recommendation in the absence of a formal randomized comparison. Numerous examples of randomized trials in GCTs that were performed to minimize therapy (eg, cisplatin 75 mg/m2 v cisplatin 120 mg/m2; carboplatin v cisplatin; etoposide 360 mg/m2 v 500 mg/m2; bleomycin, etoposide, and cisplatin v etoposide and cisplatin x three cycles; dog-leg v para-aortic port) unfortunately demonstrated higher relapse rates and sometimes worse survival.13-15,25-28 Perhaps we physicians should glance above our heads as we attempt to design trials for highly curable diseases or accept recommendations based on phase II trials, no matter how well performed. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Cicero: Tusculan Disputations V. 2. Gill NS: The Sword of Damocles. Ancient History Guide. http://About.com
3. Aparicio J, Germa JR, del Muro XG et al: Risk-adapted management for patients with clinical stage I seminoma: The second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 23: 8717-8723, 2005
4. Warde P, Specht L, Horwich A, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance: A pooled analysis. J Clin Oncol 20: 4448-4452, 2002 5. Chung P, Parker C, Panzarella T, et al: Surveillance in stage I testicular seminoma: Risk of late relapse. Can J Urol 9: 1637-1640, 2002[Medline] 6. Bosl GJ, Bajorin DF, Sheinfeld, et al: Cancer of the testis, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 7). Philadelphia PA, Lippincott Williams & Wilkins, 2005, pp 1269-1293 7. Garcia-Serra AM, Zlotecki RA, Morris CG, et al: Long-term results of radiotherapy for early-stage testicular seminoma. Am J Clin Oncol 28: 119-124, 2005[Medline] 8. Gurkaynak M, Akyol F, Zorlu F, et al: Stage I testicular seminoma: Para-aortic and iliac irradiation with reduced dose after orchiectomy. Urol Int 71: 385-388, 2003[Medline]
9. Zagars GK, Ballo MT, Lee AK, et al: Mortality after cure of testicular seminoma. J Clin Oncol 22: 640-647, 2004 10. Bachaud JM, Berthier F, Soulie M, et al: Second non-germ cell malignancies in patients treated for stage I-II testicular seminoma. Radiother Oncol 50: 191-197, 1999[CrossRef][Medline] 11. Warde P, Gospodarowicz MK, Panzarella T, et al: Long term outcome and cost in the management of stage I testicular seminoma. Can J Urol 7: 967-972, 2000[Medline]
12. Aparicio J, Garcia del Muro X, Maroto P, et al: Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol 14: 867-872, 2003 13. Bajorin DF, Sarosdy MF, Pfister DG, et al: Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: A multi-institutional study. J Clin Oncol 11: 598-606, 1993[Abstract]
14. Horwich A, Sleijfer D, Fossa S, 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 15: 1844-1852, 1997 15. Horwich A, Oliver RT, Wilkinson PM, et al: A Medical Research Council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma. MRC Testicular Tumour Working Party. Br J Cancer 83: 1623-1629, 2000[CrossRef][Medline] 16. Clemm C, Bokemeyer C, Gerl A, et al: Randomized trial comparing cisplatin/etoposide/ifosfamide with carboplatin monochemotherapy in patients with advanced metastatic seminoma. Proc Am Soc Clin Oncol 19: 328, 2000 (abstr 1283) 17. Bokemeyer C, Kollmannsberger C, Stenning S, et al: Metastatic seminoma treated with either single agent carboplatin or cisplatin-based combination chemotherapy: A pooled analysis of two randomized trials. Br J Cancer 91: 683-687, 2004[Medline] 18. Behnia M, Foster R, Einhorn LH, et al: Adjuvant bleomycin and cisplatin in pathological stage II nonseminomatous testicular cancer: The Indiana Unviersity experience. Eur J Cancer 36: 472-475, 2000
19. Kondagunta V, Sheinfeld J, Mazumdar M, et al: Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. J Clin Oncol 22: 464-467, 2004 20. Williams SD, Stablein DM, Einhorn LH, et al: Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med 317: 1433-1438, 1987[Abstract] 21. Choo R, Thomas G, Woo T, et al: Long-term outcome of postorchiectomy surveillance for stage I testicular seminoma. Int J Radiat Oncol Biol Phys 61: 736-740, 2005[CrossRef][Medline]
22. Meinardi MT, Gietma JA, van der Graaf WTA, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18: 1725, 2000
23. Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 89: 1429-1439, 1997
24. Jones WG, Fossa SD, Mead GM, et al: Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: A report on Medical Research Council Trial TE18, European Organisation for Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 23: 1200-1208, 2005 25. Samson MK, Rivkin SE, Jones SE, et al: Dose-response and dose-survival advantage for high versus low-dose cisplatin combined with vinblastine and bleomycin in disseminated testicular cancer: A Southwest Oncology Group study. Cancer 53: 1029-1035, 1984[CrossRef][Medline] 26. Toner GC, Stockler MR, Boyer MJ, et al: Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: A randomised trial—Australian and New Zealand Germ Cell Trial Group. Lancet 357: 739-745, 2001[CrossRef][Medline]
27. Fossa SD, Horwich A, Russell JM, et al: Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. J Clin Oncol 17: 1146-1154, 1999
28. Loehrer PJ, Johnson D, Elson P, et al: The importance of bleomycin in favorable-prognosis disseminated germ cell tumors: An Eastern Cooperative Group Trial. J Clin Oncol 13: 470-476, 1995
Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
