Stage III Seminoma
Stage III Nonseminoma
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage III seminoma is usually curable.

Standard treatment options:

• Radical inguinal orchiectomy followed by multidrug chemotherapy.[1] In seminoma patients, the residual masses after chemotherapy are often fibrotic, though persistent, discrete (large) masses (≥3 cm), which may contain residual seminoma that would require additional therapy.[2] The size of the residual mass reportedly does not correlate well with active residual disease; most residual masses do not grow, and frequent marker and computed tomographic (CT) scan evaluation is a viable option even when the residual mass is 3 cm or larger.[3] In some patients, fertility has returned following the use of bleomycin, etoposide, and cisplatin (BEP).[4] In a randomized trial, treatment with four courses of etoposide plus cisplatin (EP) has shown equal efficacy and less toxic effects than vinblastine, dactinomycin, bleomycin, cyclophosphamide, and cisplatin (VAB VI) in the treatment of good-risk patients.[5]

  Chemotherapy combinations include:

  • BEP: bleomycin plus etoposide plus cisplatin.[6,7] A modified regimen has been used in children.[8]
  • EP: etoposide plus cisplatin for four courses in good-prognosis patients.[5]

  Other regimens that appear to produce similar survival outcomes but are in less common use include:

  • PVB: cisplatin plus vinblastine plus bleomycin.[9,10]
  • VIP: etoposide plus ifosfamide plus cisplatin.

A randomized study comparing four courses of BEP to four courses of VIP showed similar overall survival and time-to-treatment failure for the two regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy.[11][Level of evidence: 1iiA] Hematologic toxic effects were substantially worse with the VIP regimen.

Residual radiologic abnormalities are common at the completion of chemotherapy. Many abnormalities gradually regress over a period of months. Some clinicians advocate empiric radiation of residual persistent abnormalities or attempts to resect residual masses 3 cm or larger. Either approach is controversial. In a combined retrospective consecutive series of 174 seminoma patients with postchemotherapy residual disease seen at ten treatment centers, empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[12][Level of evidence: 3iiDiii] In some series, surgical resection of specific masses has yielded a significant number of patients with residual seminoma that require additional therapy.[2] Nevertheless, other reports indicate that size of the residual mass does not correlate well with active residual disease, most residual masses do not grow, and frequent marker and CT scan evaluation is a viable option even when the residual mass is 3 cm or larger.[3]

Treatment options under clinical evaluation:

• Patients are usually eligible for the same chemotherapy clinical trials as those patients with nonseminomatous germ cell tumors.

Stage III nonseminoma is usually curable (70%) with standard chemotherapy. In some patients fertility has returned following the use of chemotherapy. The 30% of patients who are not cured with standard chemotherapy usually have widespread visceral metastases, high tumor markers, or mediastinal primary tumors at presentation. In most patients, an orchiectomy is performed prior to starting chemotherapy. If the diagnosis has been made by biopsy of a metastatic site and chemotherapy has been initiated, subsequent orchiectomy is generally performed because chemotherapy may not eradicate the primary cancer. Case reports illustrate that viable tumor was found on postchemotherapy orchiectomy despite complete response of metastatic lesions.[13]

Some retrospective data suggest that the experience of the treating institution may impact the outcome of patients with stage III nonseminoma. Data from 380 patients treated from 1990 to 1994 on the same study protocol at 49 institutions in the European Organization for Research and Treatment of Cancer and the Medical Research Council were analyzed.[14] Overall 2-year survival for the 55 patients treated at institutions that entered fewer than 5 patients onto the protocol was 62% (95% confidence interval [CI], 48%–75%) versus 77% (95% CI, 72%–81%) in the institutions that entered 5 or more patients onto the protocol. As in any nonrandomized study design, patient selection factors and factors leading patients to choose treatment at one center over another can make interpretation of results difficult.

The results of a large cooperative group randomized study of PVB versus BEP have been reported.[6] The BEP regimen produced less neuromuscular toxic effects and was more effective in patients with advanced disease, which makes it the preferable regimen of these two combinations. In addition, three courses of BEP have been shown to be equivalent to four courses in patients with minimal or moderate extent of disseminated germ cell tumors.[7] A randomized study has shown that bleomycin is an essential component of the BEP regimen when only three courses are administered.[15] Although another randomized study in good-prognosis patients treated with four courses of cisplatin plus vinblastine with or without bleomycin (PV with or without B) has shown better tumor-specific survival with PVB, this was offset by more toxic deaths. OS rates were not significantly different between four courses of PV versus PVB.[16]

In patients with poor-risk germ cell tumors, the standard-dose cisplatin regimen has been shown to be the equivalent of high-dose cisplatin in terms of complete response, cure rates, and survival; moreover, patients in the high-dose cisplatin regimen experienced significantly more toxic effects.[17]

Many patients with poor-risk nonseminomatous testicular germ cell tumors who have a serum beta human chorionic gonadotropin (βhCG) level higher than 50,000 IU/mL at the initiation of cisplatin-based therapy (BEP or PVB) will still have an elevated βhCG level at the completion of therapy, showing an initial rapid decrease in βhCG followed by a plateau.[18] In the absence of other signs of progressing disease, monthly evaluation with initiation of salvage therapy if and when there is serologic progression may be appropriate. Many patients, however, will remain disease-free without further therapy.[18][Level of evidence: 3iiDiv]

Patients who present with brain metastases should be treated with chemotherapy and simultaneous whole brain radiation therapy (50 Gy/25 fractions).[19]

Standard treatment options:

1. Chemotherapy:
   • BEP: bleomycin plus etoposide plus cisplatin.[6,7] A modified regimen has been used in children.[8]
   • EP: etoposide plus cisplatin for four courses in good-prognosis patients.[5]

   Other regimens that appear to produce similar survival outcomes but have been studied less extensively or are in less common use include:

   • PVB: cisplatin plus vinblastine plus bleomycin.[20]
   • POMB/ACE: platinum plus vincristine plus methotrexate plus bleomycin plus dactinomycin plus cyclophosphamide plus etoposide.[21]
   • VIP: etoposide plus ifosfamide plus cisplatin.

   A randomized study comparing four courses of BEP to four courses of VIP showed similar OS and time-to-treatment failure for the two regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy.[11][Level of evidence: 1iiA] Hematologic toxic effects were substantially worse with the VIP regimen.




2. In selected cases surgery should be used after chemotherapy to remove residual masses to determine if viable tumor cells remain, since such a finding is an indication for further chemotherapy. Surgical removal of residual masses is also necessary to prevent regrowth of teratomas and growth of nongerm cell elements present in some of these masses.[22,23]

A study has reported that regardless of initial histology, a significant risk exists of teratoma or carcinoma in residual masses after chemotherapy. Neither size of the initial tumor nor degree of shrinkage during therapy appears to accurately identify patients with residual teratoma or carcinoma. This has led some to recommend surgery with resection of all residual masses apparent on scans in patients who have normal markers after responding to chemotherapy.[24]

Some patients may have discordant pathologic findings (e.g., fibrosis/necrosis, teratoma, or carcinoma) in residual masses in the abdomen versus the chest. Some medical centers perform simultaneous retroperitoneal and thoracic operations to remove residual masses [3,25] but most do not. Although the agreement among the histologies of residual masses found after chemotherapy above versus below the diaphragm is only moderate (kappa statistic = 0.42), some evidence exists that if retroperitoneal resection is performed first, results can be used to guide decisions about whether to perform a thoracotomy.[26] In a multi-institutional case series of surgery to remove postchemotherapy residual masses in 159 patients, necrosis only was found at thoracotomy in about 90% of patients who had necrosis only in their retroperitoneal masses. The figure was about 95% if the original testicular primary tumor had contained no teratomatous elements. Conversely, the histology of residual masses at thoracotomy did not predict nearly as well the histology of retroperitoneal masses.[26]

Even patients who have initial masses of 3 cm or larger on CT scan and who, after chemotherapy have normal CT scan and markers, may have residual teratoma or carcinoma. This approach remains controversial, and no evidence exists that such an approach improves survival. The presence of persistent malignant elements in the resected specimen is an indication for additional chemotherapy.[27] In some cases, chemotherapy is initiated prior to orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation or completion of chemotherapy is advisable to remove the primary tumor. A physiologic blood-testis barrier seems to appear, and there is a higher incidence (approximately 50%) of residual cancer in the testicle than in remaining radiographically detectable retroperitoneal masses after platinum-based chemotherapy.[28] Some investigators have suggested that in children, 90% of whom have yolk sac tumors, radiation therapy should be given to residual masses after chemotherapy rather than surgery.[8]

Patients who relapse with brain metastases after a complete initial response to chemotherapy require further chemotherapy, with simultaneous whole-brain radiation therapy, and consideration of surgical excision of solitary lesions.[19]

Treatment options under clinical evaluation:

1. Clinical trials.
2. High-dose chemotherapy with autologous bone marrow transplantation in selected patients with bulky disease such as in the MSKCC-94076 trial.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Ball D, Barrett A, Peckham MJ: The management of metastatic seminoma testis. Cancer 50 (11): 2289-94, 1982.  [PUBMED Abstract]
   
   
2. Herr HW, Sheinfeld J, Puc HS, et al.: Surgery for a post-chemotherapy residual mass in seminoma. J Urol 157 (3): 860-2, 1997.  [PUBMED Abstract]
   
   
3. Schultz SM, Einhorn LH, Conces DJ Jr, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 7 (10): 1497-503, 1989.  [PUBMED Abstract]
   
   
4. Drasga RE, Einhorn LH, Williams SD, et al.: Fertility after chemotherapy for testicular cancer. J Clin Oncol 1 (3): 179-83, 1983.  [PUBMED Abstract]
   
   
5. Bajorin DF, Geller NL, Weisen SF, et al.: Two-drug therapy in patients with metastatic germ cell tumors. Cancer 67 (1): 28-32, 1991.  [PUBMED Abstract]
   
   
6. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.  [PUBMED Abstract]
   
   
7. Einhorn LH, Williams SD, Loehrer PJ, et al.: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 7 (3): 387-91, 1989.  [PUBMED Abstract]
   
   
8. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.  [PUBMED Abstract]
   
   
9. Einhorn LH, Williams SD: Chemotherapy of disseminated seminoma. Cancer Clin Trials 3 (4): 307-13, 1980.  [PUBMED Abstract]
   
   
10. Loehrer PJ Sr, Birch R, Williams SD, et al.: Chemotherapy of metastatic seminoma: the Southeastern Cancer Study Group experience. J Clin Oncol 5 (8): 1212-20, 1987.  [PUBMED Abstract]
    
    
11. Hinton S, Catalano PJ, Einhorn LH, et al.: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 97 (8): 1869-75, 2003.  [PUBMED Abstract]
    
    
12. Duchesne GM, Stenning SP, Aass N, et al.: Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 33 (6): 829-35, 1997.  [PUBMED Abstract]
    
    
13. Leibovitch I, Baniel J, Rowland RG, et al.: Malignant testicular neoplasms in immunosuppressed patients. J Urol 155 (6): 1938-42, 1996.  [PUBMED Abstract]
    
    
14. Collette L, Sylvester RJ, Stenning SP, et al.: Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 91 (10): 839-46, 1999.  [PUBMED Abstract]
    
    
15. Loehrer PJ Sr, Johnson D, Elson P, et al.: Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 13 (2): 470-6, 1995.  [PUBMED Abstract]
    
    
16. Levi JA, Raghavan D, Harvey V, et al.: The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group. J Clin Oncol 11 (7): 1300-5, 1993.  [PUBMED Abstract]
    
    
17. Nichols CR, Williams SD, Loehrer PJ, et al.: Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9 (7): 1163-72, 1991.  [PUBMED Abstract]
    
    
18. Zon RT, Nichols C, Einhorn LH: Management strategies and outcomes of germ cell tumor patients with very high human chorionic gonadotropin levels. J Clin Oncol 16 (4): 1294-7, 1998.  [PUBMED Abstract]
    
    
19. Spears WT, Morphis JG 2nd, Lester SG, et al.: Brain metastases and testicular tumors: long-term survival. Int J Radiat Oncol Biol Phys 22 (1): 17-22, 1992.  [PUBMED Abstract]
    
    
20. Einhorn LH, Williams SD: Chemotherapy of disseminated testicular cancer. A random prospective study. Cancer 46 (6): 1339-44, 1980.  [PUBMED Abstract]
    
    
21. Newlands ES, Bagshawe KD, Begent RH, et al.: Current optimum management of anaplastic germ cell tumours of the testis and other sites. Br J Urol 58 (3): 307-14, 1986.  [PUBMED Abstract]
    
    
22. Einhorn LH, Williams SD, Mandelbaum I, et al.: Surgical resection in disseminated testicular cancer following chemotherapeutic cytoreduction. Cancer 48 (4): 904-8, 1981.  [PUBMED Abstract]
    
    
23. Loehrer PJ Sr, Hui S, Clark S, et al.: Teratoma following cisplatin-based combination chemotherapy for nonseminomatous germ cell tumors: a clinicopathological correlation. J Urol 135 (6): 1183-9, 1986.  [PUBMED Abstract]
    
    
24. Toner GC, Panicek DM, Heelan RT, et al.: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 8 (10): 1683-94, 1990.  [PUBMED Abstract]
    
    
25. Brenner PC, Herr HW, Morse MJ, et al.: Simultaneous retroperitoneal, thoracic, and cervical resection of postchemotherapy residual masses in patients with metastatic nonseminomatous germ cell tumors of the testis. J Clin Oncol 14 (6): 1765-9, 1996.  [PUBMED Abstract]
    
    
26. Steyerberg EW, Donohue JP, Gerl A, et al.: Residual masses after chemotherapy for metastatic testicular cancer: the clinical implications of the association between retroperitoneal and pulmonary histology. Re-analysis of Histology in Testicular Cancer (ReHiT) Study Group. J Urol 158 (2): 474-8, 1997.  [PUBMED Abstract]
    
    
27. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol 11 (7): 1294-9, 1993.  [PUBMED Abstract]
    
    
28. Leibovitch I, Little JS Jr, Foster RS, et al.: Delayed orchiectomy after chemotherapy for metastatic nonseminomatous germ cell tumors. J Urol 155 (3): 952-4, 1996.  [PUBMED Abstract]
    
    

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