Stage II Nonseminoma · Testicular Cancer

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.[13] RPLND can thus prevent a significant number of patients with clinical stage IIA disease from receiving unnecessary chemotherapy.

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In contrast, patients with stage IIB and IIC nonseminoma 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 rates increased from 78% to 100% after RPLND, while RFS did not change significantly among stage II patients receiving chemotherapy (100% vs. 98%).[14] However, the question of whether to treat patients with stage II nonseminoma germ cell tumors with RPLND or chemotherapy has never been subjected to a randomized trial.

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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 their disease relapses.[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 have disease 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.[19]

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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.[20] 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, most 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.

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Radical inguinal orchiectomy followed by chemotherapy with subsequent surgery to remove any residual masses (if present) followed by monthly checkups.[13] This option is useful 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.[25] Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:

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Radical inguinal orchiectomy followed by chemotherapy with subsequent surgery to remove any residual masses (if present) followed by monthly checkups.[13] This option is useful 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.[25] Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:

BEP: Bleomycin plus etoposide plus cisplatin for three courses.[22,23] A modified regimen has been used in children.[19]

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Radical inguinal orchiectomy followed by chemotherapy with subsequent surgery to remove any residual masses (if present) followed by monthly checkups.[13] This option is useful 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.[25] Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:

EP: Etoposide plus cisplatin for four courses in patients with a good prognosis.[24]

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Radical inguinal orchiectomy followed by chemotherapy with subsequent surgery to remove any residual masses (if present) followed by monthly checkups.[13] This option is useful 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.[25] Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:

PVB: Cisplatin plus vinblastine plus bleomycin.

Radical inguinal orchiectomy followed by chemotherapy with subsequent surgery to remove any residual masses (if present) followed by monthly checkups.[13] This option is useful 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.[25] Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:

VAB VI: Vinblastine plus dactinomycin plus bleomycin plus cyclophosphamide plus cisplatin.[26]

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Radical inguinal orchiectomy followed by chemotherapy with subsequent surgery to remove any residual masses (if present) followed by monthly checkups.[13] This option is useful 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.[25] Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:

VPV: Vinblastine plus cisplatin plus etoposide.[27]

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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]

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If these patients do not achieve a complete response with 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.

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In some cases, chemotherapy is initiated before 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.[31]

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Publication references