224225 Nonseminomatous Germ Cell Tumors: Early Stage, Late Stage
Compared with seminomas, nonseminomas are more likely to present with distant disease, are more radioresistant, and are more likely to be associated with elevated tumor markers, specifically alpha fetoprotein (AFP). Men with pure seminomas never have elevations in AFP, and a histologically defined seminoma in the context of an elevated AFP is considered a mixed germ cell tumor and should be treated as a nonseminoma.
The management of nonseminomatous germ cell tumors (NSGCTs) is dependent upon stage and tumor marker elevation. Stages I and IIA or IIB NSGCTs without significant tumor marker elevation are characterized as early stage disease, whereas late stage, or advanced disease, is defined as stage IIC, stage III, or any stage disease with significant postorchiectomy tumor marker elevation. Staging and risk classification (for advanced disease) is determined based on guidelines from the American Joint Committee on Cancer (AJCC) and International Germ Cell Cancer Consensus Group (IGCCCG) (1, 2).
EARLY STAGE DISEASE
Initial management, as in almost all testicular germ cell tumors, includes radical inguinal orchiectomy. Postorchiectomy tumor marker evaluation, chest radiograph, and abdominal and pelvic CT scan are also necessary to exclude more advanced disease.
226• Stage I NSGCT
If stage I disease is confirmed, management options following orchiectomy include active surveillance, nerve-sparing retroperitoneal lymph node dissection (RPLND), or adjuvant chemotherapy. Approximately 75% of patients with clinical stage I disease are cured with initial orchiectomy (3). Thus, adjuvant treatment (RPLND or chemotherapy) represents overtreatment in the majority of patients. Unfortunately, it is difficult to determine which patients are at the highest risk of relapse and have the most to gain from adjuvant treatment. Several risk factors for recurrence have emerged including lymphovascular invasion (LVI), predominance of an embryonal carcinoma component in the primary tumor, and pathologic T3 or T4 tumors. Men with LVI-positive tumors have relapse rates of approximately 50%, whereas men with LVI-negative tumors have relapse rates closer to 15% (4). The optimal approach to management is controversial but depends on an assessment of the likelihood of relapse, patient preference, potential for treatment toxicity, and the ability of a patient to adhere to surveillance. For men who are interested in fertility preservation, sperm banking should be performed prior to treatment with RPLND or chemotherapy.
• Stage IA NSGCT
Recommended management options include active surveillance and nerve-sparing RPLND (5). While the overall survival of patients exceeds 95% for either option, strict adherence to surveillance guidelines is crucial, as numerous studies have shown that 20% to 30% of patients who choose active surveillance experience relapse and ultimately require chemotherapy (3). Access to a urologist with extensive experience performing RPLNDs is crucial for patients who wish to proceed with this option.
Following nerve-sparing RPLND, the decision to give adjuvant chemotherapy is based on the extent of nodal involvement. Surveillance is preferred for patients with pN0 or pN1 disease (which would correlate with stage IA disease), while chemotherapy is preferred for patients with more extensive nodal involvement (pN2 or pN3). Two cycles of etoposide/cisplatin (EP) or bleomycin/etoposide/cisplatin 227(BEP) are sufficient for most patients with pN2 disease, while four cycles of EP or three cycles of BEP are recommended for patients with pN3 disease (5).
• Stage IB NSGCT
Chemotherapy or nerve-sparing RPLND is recommended by the National Comprehensive Cancer Network (NCCN) after initial orchiectomy. Several studies support the efficacy of two cycles of adjuvant BEP, although benefit from one cycle of BEP has also been established for patients unable to tolerate the toxicity of multiple cycles of chemotherapy (6). If nerve-sparing RPLND is performed, determination of the need for adjuvant chemotherapy is based on nodal involvement, similar to patients with stage IA disease.
• Stage II NSGCT
Stage II disease refers to cancers that have spread to the retroperitoneal lymph nodes. Stage II disease can be defined clinically (based on imaging alone) or pathologically (based on lymph node involvement at the time of RPLND). Of note, pelvic or inguinal lymph node involvement is considered distant disease and is indicative of advanced, stage III disease.
• Stage IIA NSGCT
Treatment depends upon the postorchiectomy tumor markers. Adjuvant chemotherapy (four cycles of EP or three cycles of BEP) or primary nerve-sparing RPLND are both reasonable options for patients with normal postorchiectomy tumor markers. However, chemotherapy is preferred in patients with elevated tumor markers. In patients who undergo primary chemotherapy, subsequent management depends upon repeat CT scan to evaluate lymph node response to treatment. Bilateral nerve-sparing RPLND is often performed for residual lesions greater than 1 cm, whereas surveillance is most often preferred for patients with residual lesions less than 1 cm or normal tumor markers. In patients who undergo primary RPLND, the decision to proceed with adjuvant chemotherapy depends on the extent of nodal involvement. As noted earlier, no chemotherapy is recommended for pN0 or pN1 disease.
228• Stage IIB NSGCT
Proper management depends on postorchiectomy tumor markers and radiographic findings. In the absence of tumor marker elevation, CT findings are used to direct treatment. If nodal involvement is confined to the retroperitoneal lymphatic drainage sites, options are to perform nerve-sparing RPLND followed by chemotherapy based on the degree of nodal involvement, as previously described, or to proceed directly with chemotherapy (four cycles of EP or three cycles of BEP) followed by RPLND or surveillance. Primary chemotherapy versus primary RPLND have comparable outcomes (relapse-free survival close to 98%) but with different side effects and toxicity (7). For patients with lymph node metastases outside the primary lymphatic drainage site, chemotherapy (four cycles of EP or three cycles of BEP) is recommended followed by nerve-sparing RPLND or surveillance (5).
• Stage I and II NSGCT With Persistent Postorchiectomy Tumor Marker Elevation
These patients should be treated as having advanced stage disease. It is very important, however, to confirm the elevated AFP and beta-human chorionic gonadotropin (HCG) levels and also ensure there is not another reason for the elevation. Liver disease, marijuana use, and hypogonadism are all known causes of tumor marker elevation.
ADVANCED STAGE DISEASE
Advanced stage NSGCT includes all patients with persistent postorchiectomy tumor marker elevation. In addition to patients with stage IIC or stage III disease, advanced-stage disease also includes patients with an extragonadal primary (mediastinal or retroperitoneal). These patients all require induction chemotherapy. The primary choice of chemotherapy depends upon the IGCCCG risk classification.
• Good-Risk NSGCT
This group includes patients with stage IS, IIA and IIB with persistent tumor marker elevation, IIC, or IIIA disease. Recommended chemotherapy includes four cycles of EP 229or three cycles of BEP. Randomized trials have shown both regimens to be generally well tolerated, with about 90% cure rate (8).
• Intermediate-Risk NSGCT (Stage IIIB)
An additional cycle of BEP (four cycles) is considered standard of care. The expected cure rate is approximately 70% with this regimen (9).
• Poor-Risk NSGCT (Stage IIIC)
Standard chemotherapy remains four cycles of BEP. However, the failure rate is high, so clinical trials are preferred if available. Etoposide/ifosfamide/cisplatin (VIP) has been compared to BEP and was found to be more toxic but equally effective (10). That being said, VIP remains a good option for patients who cannot tolerate bleomycin.
Following induction chemotherapy, repeat CT scans in addition to serum tumor markers are required. If there is a complete response with normalization of the tumor markers, the patient is managed based on the original stage of the disease (surveillance vs. RPLND). If there is a partial response or a residual mass is present, the remaining site(s) of disease should be resected. Further treatment depends upon the histology of the resected lesions. If teratoma or necrosis is seen, no chemotherapy is needed, but if residual embryonal, yolk sac, choriocarcinoma, or seminoma element is identified, two cycles of chemotherapy (EP, VIP, vinblastine/ifosfamide/cisplatin [VeIP], or paclitaxel/ifosfamide/cisplatin [TIP]) are recommended (5).
Patients with brain metastases at initial diagnosis have a poorer prognosis. Treatment of systemic disease is usually a priority in these patients, so cisplatin-based chemotherapy is usually given first. Residual disease can then be treated with radiation therapy (XRT) or surgery (5).
In patients who fail to respond to initial treatment or experience relapse, participation in clinical trials is encouraged (Table 30.1). Standard options include conventional dose chemotherapy (VeIP or TIP) or high-dose chemotherapy 230(carboplatin/etoposide [CE] or paclitaxel/ifosfamide/carboplatin/etoposide [TI-CE]) followed by autologous stem cell transplant. The TIGER trial is an ongoing phase 3 clinical trial that will hopefully answer which one of these options is clinically superior (Table 30.1).
231Several prognostic factors in patients with relapsed or refractory disease have been identified (11). Complete response to first-line therapy, low postorchiectomy serum tumor markers, and low-volume disease are considered relatively good prognostic factors. VeIP or TIP is a standard chemotherapy option in this situation, although high-dose chemotherapy with stem cell transplant is also an accepted option (5).
Poor prognostic factors include incomplete response to or progression during initial therapy, high postorchiectomy serum tumor markers, high-volume disease, or an extragonadal primary. These patients should be referred for clinical trials if available, but high-dose chemotherapy followed by autologous stem cell transplant or standard-dose salvage chemotherapy (TIP or VeIP) are both acceptable. Palliative chemotherapy or salvage surgery is also an option in carefully selected patients (5).
Palliative chemotherapy or radiation should be considered for patients with persistent or recurrent disease. Palliative chemotherapy options include combinations of gemcitabine, paclitaxel, and oxaliplatin, or oral etoposide (5).
Surveillance following successful treatment of NSGCT is vital to detect early recurrence and initiate treatment. Typical surveillance includes regular history and physicals, serum tumor markers, CT abdomen/pelvis, and chest radiographs. 232The NCCN provides detailed interval recommendations for these tests depending on the clinical or pathologic stage of the disease (5).