Testicular Cancer Treatment (Professional) (cont.)
Stage II Testicular Cancer
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
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 (i.e., stage IIC disease). Nonbulky disease can be further subdivided into stage IIA, meaning no lymph node mass larger than 2 cm, and stage IIB, meaning a lymph node mass between 2 cm and 5 cm.
Nonbulky stage II disease has a cure rate of about 90% to 95% with radiation alone at doses of 30 Gy to 36 Gy, [1,2,3,4] and most relapsing patients can be cured with chemotherapy. Cure rates are slightly higher for patients with stage IIA disease than for those with IIB disease, but the figures are within the range given above. Risk factors for relapse include multiple enlarged nodes.
Results for patients with stage IIC disease have been less favorable. For example, one institution reported that 9 of 16 (56%) stage IIC patients relapsed following radiation therapy, while relapse occurred in only 1 of 23 (4%) IIC patients treated with chemotherapy. A pooled analysis of earlier studies reported a 65% relapse-free survival for men receiving radiation therapy for bulky stage II seminoma. Unfortunately, there are only sparse contemporary data on the use of radiation therapy to treat bulky stage II seminomas, and there are no randomized trials comparing radiation therapy with chemotherapy in this population. Combination chemotherapy with cisplatin is effective therapy in patients with bulky stage II seminomas and has become the most widely accepted treatment option.[6,7]
Residual radiologic abnormalities are common at the completion of chemotherapy. Many abnormalities gradually regress over a period of months. Some clinicians advocate empiric attempts to resect residual masses 3 cm or larger, while others advocate close surveillance, with intervention only if the residual mass increases in size. Postchemotherapy radiation therapy has fallen out of favor, in part because of a retrospective study of a consecutive series of 174 seminoma patients with postchemotherapy residual disease seen at ten treatment centers that reported that empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[Level of evidence: 3iiDiii]
In some series, surgical resection of specific masses has yielded a significant number of patients with residual seminoma who require additional therapy. 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.
A more recent approach has been to obtain an 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan following chemotherapy. A study of 56 patients reported that positron emission tomography (PET) scans correctly identified eight of ten patients with residual seminoma with no false positives among the 46 patients with benign masses. In this study, PET scans were 100% accurate in patients with residual masses greater than 3 cm in greatest diameter whereas residual malignant masses less than 3 cm were only detected in one of three men. This study provides support for observing men with residual FDG-PET-negative masses greater than 3 cm and for performing a biopsy or resection of any FDG-PET-positive mass.
Standard treatment options for patients with nonbulky tumors:
- Radical inguinal orchiectomy followed by radiation therapy to the retroperitoneal and ipsilateral pelvic lymph nodes. Prophylactic radiation therapy to the mediastinum is contraindicated because of cardiovascular toxicity, and prophylactic radiation to the supraclavicular fossa is not standard. Radiation therapy to inguinal nodes is not standard unless there has been some damage to the scrotum to put inguinal lymph nodes at risk.
- Systemic chemotherapy using three cycles of BEP or four cycles of etoposide and cisplatin. This approach is generally reserved for stage IIA and IIB patients who have multiple areas of adenopathy in the retroperitoneum or a contraindication to radiation therapy such as a horseshoe or pelvic kidney, or inflammatory bowel disease.[7,9,10,11]
- Retroperitoneal lymph node dissection (RPLND) may be performed in those rare men who have contraindications to radiation therapy and chemotherapy.
Standard treatment options for patients with bulky tumors:
- Radical inguinal orchiectomy followed by combination chemotherapy (with a cisplatin-based regimen) using three cycles of BEP or four cycles of etoposide and cisplatin.[7,9,10,11]
- Radical inguinal orchiectomy followed by radiation therapy to the abdominal and pelvic lymph nodes. The recurrence rate is higher after radiation therapy for men with bulky stage II tumors than radiation therapy for nonbulky tumors, leading some authors to recommend primary chemotherapy for patients with bulky disease (=5 cm–10 cm).[3,12]
Stage II Nonseminoma
Stage II nonseminoma is highly curable (>95%). Men with stage II disease and persistently elevated serum tumor markers are generally treated as having stage III disease and receive chemotherapy. For men with normal markers after orchiectomy, nonseminomas are divided into stages IIA, IIB, and IIC for treatment purposes. In general, stage IIA patients undergo RPLND to confirm the staging. As many as 40% of clinical stage IIA patients will have benign findings at RPLND and will be restaged as having pathological stage I disease. RPLND can thus prevent a significant number of clinical stage IIA patients from receiving unnecessary chemotherapy.
In contrast, stage IIB and IIC patients are usually treated with systemic chemotherapy for disseminated disease because these patients have a higher relapse rate after RPLND. One study reported that by limiting RPLND to patients with earlier stage II disease and normal serum tumor markers, 5-year relapse-free survival (RFS) increased from 78% to 100% after RPLND, while RFS did not change significantly among stage II patients receiving chemotherapy (100% vs. 98%). However, the question of whether to treat patients with stage II nonseminomas germ cell tumors with RPLND or chemotherapy has never been subjected to a randomized trial.
Standard treatment options:
- For patients with clinical stage II disease and normal postorchiectomy serum tumor markers, radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes with or without fertility-preserving 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 pathological stage I or IIA disease (fewer than six positive nodes at RPLND, none of which are larger than 2 cm in diameter). Such patients appear to have a relapse rate of about 10% if followed without chemotherapy, and most are curable with standard chemotherapy if they do relapse.[13,15] Presence of lymphatic or venous invasion and the proportion of the primary tumor that is embryonal carcinoma also help to predict which patients may relapse.[16,17,18] In one study, the relapse rate in men with pathological stage I disease was 3% in men with nonembryonal carcinoma-predominant tumors, 21% in men with embryonal carcinoma-predominant tumors, and 31% in those with embryonal carcinoma-predominant tumors and lymphovascular invasion.[17,18] In children, surgical resection of retroperitoneal nodes is generally not performed. Patients with clinical stage II disease are given chemotherapy.
- For patients with clinical and pathological stage II disease and normal postorchiectomy serum tumor markers, radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes followed by two cycles of chemotherapy (i.e., etoposide and cisplatin either with or without bleomycin) and then monthly checkups.
This option of RPLND plus adjuvant chemotherapy applies to patients who have pathologically confirmed lymph node metastases as a result of RPLND and is most attractive for patients with pathological stage IIB or IIC disease. 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, and no significant differences were found in overall survival. 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 a similar cure rate.
- Radical inguinal orchiectomy followed by chemotherapy with delayed surgery for removal of residual masses (if present) followed by monthly checkups.
This option is most attractive for patients with elevated serum tumor markers and/or clinical stage IIB or IIC disease. The combination of chemotherapy plus resection of residual masses in these patients results in cure in more than 95% of patients.[14,21]
Chemotherapy regimens include:
- BEP: bleomycin plus etoposide plus cisplatin for three courses.[22,23] A modified regimen has been used in children.
- EP: etoposide plus cisplatin for four courses in good-prognosis patients.
A randomized study has shown that bleomycin is an essential component of the BEP regimen when only three courses are administered.
Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:
- PVB: cisplatin plus vinblastine plus bleomycin.
- VAB VI: vinblastine plus dactinomycin plus bleomycin plus cyclophosphamide plus cisplatin.
- VPV: vinblastine plus cisplatin plus etoposide.
In a randomized comparison of PVB versus BEP, equivalent anticancer activity was seen but with less toxic effects with the use of BEP.[20,28]
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 or stabilization of serum markers. The presence of persistently elevated markers is not a contraindication to resection of residual masses, but patients with rising markers at the end of chemotherapy are generally treated with salvage chemotherapy. Despite numerous studies, no sufficiently accurate predictors of the histology of residual masses have been validated. Therefore, the standard of care is to resect all residual masses apparent on scans in patients who have normal or stable markers after responding to chemotherapy. The presence of persistent nonseminomatous germ-cell malignant elements in the resected specimen is a poor prognostic sign and is often a trigger for additional chemotherapy. However, men with only microscopic residual cancer have a much more favorable prognosis than men with more substantial residual disease.[29,30] Identifying which patients benefit from additional chemotherapy is not possible from existing data.
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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
- Bamberg M, Schmidberger H, Meisner C, et al.: Radiotherapy for stages I and IIA/B testicular seminoma. Int J Cancer 83 (6): 823-7, 1999.
- Bauman GS, Venkatesan VM, Ago CT, et al.: Postoperative radiotherapy for Stage I/II seminoma: results for 212 patients. Int J Radiat Oncol Biol Phys 42 (2): 313-7, 1998.
- Chung PW, Gospodarowicz MK, Panzarella T, et al.: Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol 45 (6): 754-59; discussion 759-60, 2004.
- 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.
- Thomas GM: Over 20 Years of Progress in Radiation Oncology: Seminoma. Semin Radiat Oncol 7 (2): 135-145, 1997.
- Krege S, Beyer J, Souchon R, et al.: European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II. Eur Urol 53 (3): 497-513, 2008.
- Warde P, Gospodarowicz M, Panzarella T, et al.: Management of stage II seminoma. J Clin Oncol 16 (1): 290-4, 1998.
- De Santis M, Becherer A, Bokemeyer C, et al.: 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol 22 (6): 1034-9, 2004.
- Mencel PJ, Motzer RJ, Mazumdar M, et al.: Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 12 (1): 120-6, 1994.
- Gholam D, Fizazi K, Terrier-Lacombe MJ, et al.: Advanced seminoma--treatment results and prognostic factors for survival after first-line, cisplatin-based chemotherapy and for patients with recurrent disease: a single-institution experience in 145 patients. Cancer 98 (4): 745-52, 2003.
- Culine S, Abs L, Terrier-Lacombe MJ, et al.: Cisplatin-based chemotherapy in advanced seminoma: the Institut Gustave Roussy experience. Eur J Cancer 34 (3): 353-8, 1998.
- Zagars GK, Pollack A: Radiotherapy for stage II testicular seminoma. Int J Radiat Oncol Biol Phys 51 (3): 643-9, 2001.
- Stephenson AJ, Bosl GJ, Motzer RJ, et al.: Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 23 (12): 2781-8, 2005.
- Stephenson AJ, Bosl GJ, Motzer RJ, et al.: Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol 25 (35): 5597-602, 2007.
- Richie JP, Kantoff PW: Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer? J Clin Oncol 9 (8): 1393-6, 1991.
- Heidenreich A, Sesterhenn IA, Mostofi FK, et al.: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer 83 (5): 1002-11, 1998.
- Hermans BP, Sweeney CJ, Foster RS, et al.: Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 163 (6): 1721-4, 2000.
- Sweeney CJ, Hermans BP, Heilman DK, et al.: Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma--predominant testis cancer. J Clin Oncol 18 (2): 358-62, 2000.
- 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.
- 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.
- Horwich A, Norman A, Fisher C, et al.: Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis. J Urol 151 (1): 72-7; discussion 77-8, 1994.
- de Wit R, Roberts JT, Wilkinson PM, et al.: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19 (6): 1629-40, 2001.
- 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.
- Xiao H, Mazumdar M, Bajorin DF, et al.: Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol 15 (7): 2553-8, 1997.
- 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.
- 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.
- 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.
- 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.
- Fizazi K, Oldenburg J, Dunant A, et al.: Assessing prognosis and optimizing treatment in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT): results of the sCR2 international study. Ann Oncol 19 (2): 259-64, 2008.
- Spiess PE, Tannir NM, Tu SM, et al.: Viable germ cell tumor at postchemotherapy retroperitoneal lymph node dissection: can we predict patients at risk of disease progression? Cancer 110 (12): 2700-8, 2007.
- 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.
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