Careful monitoring of the serum tumor markers AFP and hCG is essential in the management of patients with GCT, as these markers are important for diagnosis, as prognostic indicators, in monitoring treatment response, and in the detection of early relapse. Approximately 70% of patients presenting with disseminated nonseminomatous GCT have increased serum concentrations of AFP and/or hCG. Although hCG concentrations may be increased in patients with either nonseminoma or seminoma histology, the AFP concentration is increased only in patients with nonseminoma. The presence of an increased AFP level in a patient whose tumor shows only seminoma indicates that an occult nonseminomatous component exists, and the patient should be treated for nonseminomatous GCT. LDH levels are not as specific as AFP or hCG but are increased in 50–60% patients with metastatic nonseminoma and in up to 80% of patients with advanced seminoma.
AFP, hCG, and LDH levels should be determined before and after orchiectomy. Increased serum AFP and hCG concentrations decay according to first-order kinetics; the half-life is 24–36 h for hCG and 5–7 days for AFP. AFP and hCG should be assayed serially during and after treatment. The reappearance of hCG and/or AFP or the failure of these markers to decline according to the predicted half-life is an indicator of persistent or recurrent tumor.
Treatment: Testicular Cancer
If, after an orchiectomy (for clinical stage I disease), radiographs and physical examination show no evidence of disease and serum AFP and hCG concentrations are either normal or declining to normal according to the known half-life, patients may be managed by either a nerve-sparing retroperitoneal lymph node dissection (RPLND) or surveillance. The retroperitoneal lymph nodes are involved by GCT (pathologic stage II) in 20–50% of these patients. The choice of surveillance or RPLND is based on the pathology of the primary tumor. If the primary tumor shows no evidence for lymphatic or vascular invasion and is limited to the testis (T1), then either option is reasonable. If lymphatic or vascular invasion is present or the tumor extends into the tunica, spermatic cord, or scrotum (T2 through T4), then surveillance should not be offered. Either approach should cure >95% of patients.
RPLND is the standard operation for removal of the regional lymph nodes of the testis (retroperitoneal nodes). The operation removes the lymph nodes draining the primary site and the nodal groups adjacent to the primary landing zone. The standard (modified bilateral) RPLND removes all node-bearing tissue down to the bifurcation of the great vessels, including the ipsilateral iliac nodes. The major long-term effect of this operation is retrograde ejaculation and infertility. Nerve-sparing RPLND, usually accomplished by identification and dissection of individual nerve fibers, may avoid injury to the sympathetic nerves responsible for ejaculation. Normal ejaculation is preserved in ∼90% of patients. Patients with pathologic stage I disease are observed, and only the <10% who relapse require additional therapy. If retroperitoneal nodes are found to be involved at RPLND, then a decision regarding adjuvant chemotherapy is made on the basis of the extent of retroperitoneal disease (see below).
Surveillance is an option in the management of clinical stage I disease when no vascular/lymphatic invasion is found (T1). Only 20–30% of patients have pathologic stage II disease, implying that most RPLNDs in this situation are not therapeutic. Surveillance and RPLND lead to equivalent long-term survival rates. Patient compliance is essential if surveillance is to be successful. Patients must be carefully followed with periodic chest radiography, physical examination, CT scan of the abdomen, and serum tumor marker determinations. The median time to relapse is approximately 7 months, and late relapses (>2 years) are rare. The 70–80% of patients who do not relapse require no intervention after orchiectomy; treatment is reserved for those who do relapse. When the primary tumor is classified as T2 through T4 (extension beyond testis and epididymis or lymphatic/vascular invasion is identified), nerve-sparing RPLND is preferred. Approximately 50% of these patients have pathologic stage II disease and are destined to relapse without the RPLND.
Patients with limited, ipsilateral retroperitoneal adenopathy (nodes usually ≤3 cm in largest diameter) and normal levels of AFP and hCG generally undergo a modified bilateral RPLND as primary management. Increased levels of either AFP or hCG or both imply metastatic disease outside the retroperitoneum; chemotherapy is used in this setting. The local recurrence rate after a properly performed RPLND is very low. Depending on the extent of disease, the postoperative management options include either surveillance or two cycles of adjuvant chemotherapy. Surveillance is the preferred approach for patients with resected "low-volume" metastases (tumor nodes ≤2 cm in diameter and <6 nodes involved) because the probability of relapse is one-third or less. For those who relapse, risk-directed chemotherapy is indicated (see below). Because relapse occurs in ≥50% of patients with "high-volume" metastases (>6 nodes involved, or any involved node >2 cm in largest diameter, or extranodal tumor extension), two cycles of adjuvant chemotherapy should be considered, as it results in a cure in ≥98% of patients. Regimens consisting of etoposide (100 mg/m2 daily on days 1–5) plus cisplatin (20 mg/m2 daily on days 1–5) with or without bleomycin (30 units per day on days 2, 9, and 16) given at 3-week intervals are effective and well tolerated.
Inguinal orchiectomy followed by retroperitoneal radiation therapy or surveillance cures nearly 100% of patients with stage I seminoma. Historically, radiation was the mainstay of treatment, But the reported association between radiation and secondary malignancies and the absence of a survival advantage of radiation over surveillance has led many to favor surveillance for patients committed to long-term follow-up. Studies have shown that approximately 15% of patients relapse, and rete testis involvement and size >4 cm have been associated with a higher relapse rate. The relapse is usually treated with chemotherapy. Long-term followup is essential, because approximately 30% of relapses occur after 2 years and 5% after 5 years. A single dose of carboplatin has also been investigated as an alternative to radiation therapy; the outcome was similar, but long-term safety data are lacking, and the retroperitoneum remained the most frequent site of relapse.
Nonbulky retroperitoneal disease (stage IIA and most IIB) is treated with retroperitoneal radiation therapy. Approximately 90% of patients achieve relapse-free survival with retroperitoneal masses <5 cm in diameter. Because at least one-third of patients with bulkier disease relapse, initial chemotherapy is preferred for all stage IIC and some stage IIB with bulkier or multifocal disease.
Chemotherapy for Advanced GCT
Regardless of histology, patients with stage IIC and stage III GCT are treated with chemotherapy. Combination chemotherapy programs based on cisplatin at doses of 100 mg/m2 plus etoposide at doses of 500 mg/m2 per cycle cure 70–80% of such patients, with or without bleomycin, depending on risk stratification (see below). A complete response (the complete disappearance of all clinical evidence of tumor on physical examination and radiography plus normal serum levels of AFP and hCG for ≥1 month) occurs after chemotherapy alone in ∼60% of patients, and another 10–20% become disease-free with surgical resection of residual masses containing viable GCT. Lower doses of cisplatin result in inferior survival rates.
The toxicity of four cycles of the bleomycin, etoposide, and cisplatin (BEP) regimen is substantial. Nausea, vomiting, and hair loss occur in most patients, although nausea and vomiting have been markedly ameliorated by modern antiemetic regimens. Myelosuppression is frequent, and symptomatic bleomycin pulmonary toxicity occurs in ∼5% of patients. Treatment-induced mortality due to neutropenia with septicemia or bleomycin-induced pulmonary failure occurs in 1–3% of patients. Dose reductions for myelosuppression are rarely indicated. Long-term permanent toxicities include nephrotoxicity (reduced glomerular filtration and persistent magnesium wasting), ototoxicity, and peripheral neuropathy. When bleomycin is administered by weekly bolus injection, Raynaud's phenomenon appears in 5–10% of patients. Other evidence of small blood vessel damage is seen less often, including transient ischemic attacks and myocardial infarction.
Because not all patients are cured and treatment may cause significant toxicities, patients are stratified into "good-risk" and "poor-risk" groups according to pretreatment clinical features. For good-risk patients, the goal is to achieve maximum efficacy with minimal toxicity. For poor-risk patients, the goal is to identify more effective therapy with tolerable toxicity.
The International Germ Cell Cancer Consensus Group developed criteria to assign patients to three risk groups (good, intermediate, poor) (Table 96–1). The marker cut offs have been incorporated into the revised TNM (primary tumor, regional nodes, metastasis) staging of GCT. Hence, TNM stage groupings are now based on both anatomy (site and extent of disease) and biology (marker status and histology). Seminoma is either good or intermediate risk, based on the absence or presence of nonpulmonary visceral metastases. No poor-risk category exists for seminoma. Marker levels play no role in defining risk for seminoma. Nonseminomas have good-, intermediate-, and poor-risk categories based on the site of the primary tumor, the presence or absence of nonpulmonary visceral metastases, and marker levels.
Table 96–1 IGCCCG Risk Classification for Advanced Germ Cell Tumors |Favorite Table|Download (.pdf)
Table 96–1 IGCCCG Risk Classification for Advanced Germ Cell Tumors
|Good||Gonadal or retroperitoneal primary site||Any primary site|
Absent nonpulmonary visceral metastases
AFP <1000 ng/mL
Beta-hCG <5000 mIU/mL
LDH <1.5 × upper limit or normal (ULN)
Absent nonpulmonary visceral metastases
Any LDH, hCG
|Intermediate||Gonadal or retroperitoneal primary site||Any primary site|
Absent nonpulmonary visceral metastases
AFP 1000–10,000 ng/mL
Beta-hCG 5000–50,000 mIU/mL
LDH 1.5–10 × ULN
Presence of nonpulmonary visceral metastases
Any LDH, hCG
Mediastinal primary site
Presence of nonpulmonary visceral metastases
AFP ≥10,000 ng/mL
LDH > 10 × ULN
|No patients classified as poor prognosis|
For ∼90% of patients with good-risk GCTs, four cycles of etoposide plus cisplatin (EP) or three cycles of BEP produce durable complete responses, with minimal acute and chronic toxicity. Pulmonary toxicity is absent when bleomycin is not used and is rare when therapy is limited to 9 weeks; myelosuppression with neutropenic fever is less frequent; and the treatment mortality rate is negligible. Approximately 75% of intermediate-risk patients and 45% of poor-risk patients achieve durable complete remission with four cycles of BEP, and no regimen has proved superior. More effective therapy is needed.
Resection of residual metastases after the completion of chemotherapy is an integral part of therapy. If the initial histology is nonseminoma and the marker values have normalized, all sites of residual disease should be resected. In general, residual retroperitoneal disease requires a modified bilateral RPLND. Thoracotomy (unilateral or bilateral) and neck dissection are less frequently required to remove residual mediastinal, pulmonary parenchymal, or cervical nodal disease. Viable tumor (seminoma, embryonal carcinoma, yolk sac tumor, or choriocarcinoma) will be present in 15%, mature teratoma in 40%, and necrotic debris and fibrosis in 45% of resected specimens. The frequency of teratoma or viable disease is highest in residual mediastinal tumors. If necrotic debris or mature teratoma is present, no further chemotherapy is necessary. If viable tumor is present but is completely excised, two additional cycles of chemotherapy are given.
If the initial histology is pure seminoma, mature teratoma is rarely present, and the most frequent finding is necrotic debris. For residual retroperitoneal disease, a complete RPLND is technically difficult owing to extensive postchemotherapy fibrosis. Observation is recommended when no radiographic abnormality exists on CT scan. Positive findings on a positron emission tomography (PET) scan correlate with viable seminoma in residua, and mandate surgical excision or biopsy.
Of patients with advanced GCT, 20–30% fail to achieve a durable complete response to first-line chemotherapy. A combination of vinblastine, ifosfamide, and cisplatin (VeIP) will cure approximately 25% of patients as a second-line therapy. Substitution of paclitaxel for vinblastine may be more effective in this setting. Patients are more likely to achieve a durable complete response if they had a testicular primary tumor and relapsed from a prior complete remission to first-line cisplatin-containing chemotherapy. In contrast, if the patient failed to achieve a complete response or has a primary mediastinal nonseminoma, then standard-dose salvage therapy is rarely beneficial. Treatment options for such patients include dose-intensive treatment, experimental therapies, and surgical resection.
Chemotherapy consisting of dose-intensive, high-dose carboplatin (≥1500 mg/m2) plus etoposide (≥1200 mg/m2), with or without cyclophosphamide, with peripheral blood stem cell support, induces a complete response in 25–40% of patients who have progressed after ifosfamide-containing salvage chemotherapy. Approximately one-half of the complete responses will be durable. High-dose therapy is standard of care for this patient population and has been suggested as treatment of choice for all patients with relapsed or refractory disease. Paclitaxel is also active in previously treated patients and shows promise in high-dose combination programs. Cure is still possible in some relapsed patients.