Stage II Testicular Cancer
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,[1-4] 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 (RFS) for men receiving radiation therapy for bulky stage II seminoma. Unfortunately, only sparse contemporary data are available 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 is no longer favored, 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 toxic effects, 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.[7,9-11]
- 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.[7,9-11]
- 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 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.[16-18] 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 subsequent surgery to remove any 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:
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:
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 the patients who 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.
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- 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. [PUBMED Abstract]
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- 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. [PUBMED Abstract]
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- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
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