Stage II Seminoma
Stage II 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 II seminoma is divided into bulky and nonbulky disease for treatment planning and expression of prognosis. Bulky disease is generally defined as tumors larger than 5 cm on a computed tomographic (CT) scan.

Nonbulky stage II disease has a cure rate of more than 90% with radiation alone at doses of 30 Gy to 36 Gy.[1] While earlier studies reported that bulky stage II seminoma had a cure rate of 70% with radiation alone, studies using improved treatment planning and equipment as well as careful selection of patients (including the use of tumor markers) have reported an improvement in the results of radiation therapy in the treatment of patients with bulky stage II seminoma.[2,3] Combination chemotherapy with cisplatin is also effective therapy in patients with bulky stage II seminomas. 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 10 treatment centers, empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[4][Level of evidence: 3iiDiii] In some series, surgical resection of specific masses has yielded a significant number with residual seminoma that require additional therapy.[5] Nevertheless, other reports indicate that the 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.[6]

Standard treatment options:

For patients with nonbulky tumors

• Radical inguinal orchiectomy followed by radiation therapy to the retroperitoneal and ipsilateral pelvic lymph nodes. Evidence favors the omission of prophylactic radiation therapy to the mediastinum and neck.[7,8] Radiation therapy to inguinal nodes is not standard unless there has been some damage to the scrotum to put inguinal lymph nodes at risk.

For patients with bulky tumors

• Radical inguinal orchiectomy followed by combination chemotherapy (with a cisplatin-based regimen) or by radiation therapy to the abdominal and pelvic lymph nodes.[2,3,9-11] Recurrence rate is higher after radiation therapy for bulky stage II tumors than radiation therapy for nonbulky tumors, leading some authors to recommend primary chemotherapy for patients with bulky disease (≥5–10 cm).[12] Controversy exists over whether any residual masses present at the completion of chemotherapy should be empirically irradiated, or whether masses larger than 3 cm should be resected.[5,6]

Stage II nonseminoma is highly curable (>95%). If preservation of fertility is an important consideration, surgical techniques for sparing sympathetic ganglia and chains without compromising the total removal of all involved nodes are available, though this technique may not be feasible in many patients. This technique is associated with postoperative preservation of ejaculation in a large number of patients.[13-15] 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, since chemotherapy may not eradicate the primary cancer. Case reports illustrate that viable tumor was found on postchemotherapy orchiectomy despite the complete response of metastatic lesions.[16]

Standard treatment options:

1. Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes with or without fertility-preserving retroperitoneal lymph node dissection (RPLND) followed by monthly checkups, which include physical examination, chest x-ray, and serum marker tests (e.g., alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase). This option of surgery and careful follow-up, reserving chemotherapy for relapse, is particularly attractive for patients who have fewer than six positive nodes at retroperitoneal lymph node dissection, none of which are larger than 2 cm in diameter and with no extracapsular lymph node invasion. Such patients appear to have a relapse rate of about 20% to 30% if followed without chemotherapy, and most are curable with standard chemotherapy if they do relapse.[17] Patients whose markers do not return to normal following the removal of retroperitoneal lymph nodes should be treated with chemotherapy.[13,18] Presence of lymphatic or venous invasion also helps to predict which patients may relapse. In a large Testicular Cancer Intergroup Study, the relapse rate after RPLND was 64% in those who had microscopic evidence of vascular invasion in the primary tumor versus 24% in those who did not.[19] In children, surgical resection of retroperitoneal nodes is generally not performed. Patients with clinical stage II disease are given chemotherapy.[20]



2. Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes followed by chemotherapy and then monthly checkups. The results of a large study comparing the first treatment option with the second treatment option were published. Two courses of cisplatin-based chemotherapy (either cisplatin, vinblastine, bleomycin [PVB] or vinblastine, dactinomycin, bleomycin, cyclophosphamide, cisplatin [VAB VI]) prevented a relapse in more than 95% of patients. A 49% relapse rate was seen in patients assigned to observation; however, the majority of these patients could be effectively treated. The study concluded that adjuvant therapy will most often prevent relapse in patients treated with optimal surgery, follow-up, and chemotherapy; however, observation with chemotherapy only for relapse will lead to an equivalent cure rate.[21,22]



3. Radical inguinal orchiectomy followed by chemotherapy with delayed surgery for removal of residual masses (if present) followed by monthly checkups. This option is considered for patients in whom clinical examination, lymphangiogram, or CT scan show retroperitoneal masses that are large enough to cause concern about resectability.

   Chemotherapy regimens include:

   • BEP: bleomycin plus etoposide plus cisplatin for three courses.[23] A modified regimen has been used in children.[20]
   • EP: etoposide plus cisplatin for four courses in good-prognosis patients.[11]

   A randomized study has shown that bleomycin is an essential component of the BEP regimen when only three courses are administered.[24]

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

   • PVB: cisplatin plus vinblastine plus bleomycin.
   • VAB VI: vinblastine plus dactinomycin plus bleomycin plus cyclophosphamide plus cisplatin.[21]
   • VPV: vinblastine plus cisplatin plus etoposide.[25]

In a randomized comparison of PVB versus BEP, equivalent anticancer activity was seen but with less toxic effects with the use of BEP.[23,26]

If these patients do not achieve a complete response on chemotherapy, surgical removal of residual masses should be performed. The timing of such surgery requires clinical judgment but would occur most often after three or four cycles of combination chemotherapy and normalization of serum markers. The probability of finding residual teratoma or carcinoma after chemotherapy may be dependent on the histology of the primary tumor. Patients whose primary tumor contained teratomatous elements have a higher probability of having residual teratoma or carcinoma in the retroperitoneal nodes than do patients whose primary tumor contains only embryonal cancer. One study has reported that irrespective of initial histology, there is a significant risk of residual teratoma or carcinoma in residual masses after chemotherapy. Some investigators think that neither size of the initial tumor nor the 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. Some investigators recommend surgery for patients who have initial masses of 3 cm or larger [27] on a CT scan and after chemotherapy have a normal CT scan. This approach remains controversial, and no evidence is available that such an approach improves survival. The presence of persistent nonseminomatous germ cell malignant elements in the resected specimen is an indication for additional chemotherapy.[28] 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. There is a higher incidence (approximately 50%) of residual cancer in the testicle than in remaining radiographically detectable retroperitoneal masses after platinum-based chemotherapy.[29]

Treatment options under clinical evaluation:

• In some clinical trials, primary chemotherapy has been administered to patients with small volume retroperitoneal disease in an effort to avoid retroperitoneal node dissections. Although a randomized comparison has not been performed, it appears that primary chemotherapy, when compared with primary retroperitoneal node dissection, may produce similar survival in clinical stage II testicular cancer patients.[30,31]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II 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. Classen J, Souchon R, Hehr T, et al.: Radiotherapy for early stages testicular seminoma: patterns of care study in Germany. Radiother Oncol 63 (2): 179-86, 2002.  [PUBMED Abstract]
   
   
2. Smalley SR, Evans RG, Richardson RL, et al.: Radiotherapy as initial treatment for bulky stage II testicular seminomas. J Clin Oncol 3 (10): 1333-8, 1985.  [PUBMED Abstract]
   
   
3. Friedman EL, Garnick MB, Stomper PC, et al.: Therapeutic guidelines and results in advanced seminoma. J Clin Oncol 3 (10): 1325-32, 1985.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. Stutzman RE, McLeod DG: Radiation therapy: a primary treatment modality for seminoma. Urol Clin North Am 7 (3): 757-64, 1980.  [PUBMED Abstract]
   
   
8. Classen J, Schmidberger H, Meisner C, et al.: Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol 21 (6): 1101-6, 2003.  [PUBMED Abstract]
   
   
9. Ball D, Barrett A, Peckham MJ: The management of metastatic seminoma testis. Cancer 50 (11): 2289-94, 1982.  [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. 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]
    
    
12. Mason BR, Kearsley JH: Radiotherapy for stage 2 testicular seminoma: the prognostic influence of tumor bulk. J Clin Oncol 6 (12): 1856-62, 1988.  [PUBMED Abstract]
    
    
13. Lange PH, Narayan P, Fraley EE: Fertility issues following therapy for testicular cancer. Semin Urol 2 (4): 264-74, 1984.  [PUBMED Abstract]
    
    
14. Jewett MA, Kong YS, Goldberg SD, et al.: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. J Urol 139 (6): 1220-4, 1988.  [PUBMED Abstract]
    
    
15. Donohue JP, Foster RS, Rowland RG, et al.: Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 144 (2 Pt 1): 287-91; discussion 291-2, 1990.  [PUBMED Abstract]
    
    
16. Leibovitch I, Baniel J, Rowland RG, et al.: Malignant testicular neoplasms in immunosuppressed patients. J Urol 155 (6): 1938-42, 1996.  [PUBMED Abstract]
    
    
17. Richie JP, Kantoff PW: Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer? J Clin Oncol 9 (8): 1393-6, 1991.  [PUBMED Abstract]
    
    
18. Donohue JP, Einhorn LH, Williams SD: Is adjuvant chemotherapy following retroperitoneal lymph node dissection for nonseminomatous testis cancer necessary? Urol Clin North Am 7 (3): 747-56, 1980.  [PUBMED Abstract]
    
    
19. Sesterhenn IA, Weiss RB, Mostofi FK, et al.: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study. J Clin Oncol 10 (1): 69-78, 1992.  [PUBMED Abstract]
    
    
20. 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]
    
    
21. Bosl GJ, Gluckman R, Geller NL, et al.: VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors. J Clin Oncol 4 (10): 1493-9, 1986.  [PUBMED Abstract]
    
    
22. 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 (23): 1433-8, 1987.  [PUBMED Abstract]
    
    
23. 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]
    
    
24. 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]
    
    
25. Wozniak AJ, Samson MK, Shah NT, et al.: A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study. J Clin Oncol 9 (1): 70-6, 1991.  [PUBMED Abstract]
    
    
26. Stoter G, Koopman A, Vendrik CP, et al.: Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin. J Clin Oncol 7 (8): 1099-104, 1989.  [PUBMED Abstract]
    
    
27. 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]
    
    
28. 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]
    
    
29. 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]
    
    
30. Logothetis CJ, Swanson DA, Dexeus F, et al.: Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: a follow-up of 50 patients. J Clin Oncol 5 (6): 906-11, 1987.  [PUBMED Abstract]
    
    
31. Socinski MA, Garnick MB, Stomper PC, et al.: Stage II nonseminomatous germ cell tumors of the testis: an analysis of treatment options in patients with low volume retroperitoneal disease. J Urol 140 (6): 1437-41, 1988.  [PUBMED Abstract]
    
    

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