Treatment of Stage III Disease
Chemotherapy is the treatment of choice for patients with stage III seminomas (see Table 5) using either BEP for three cycles or EP for four cycles. The management of patients with bulky disease after chemotherapy (residual mass > 3 cm) is somewhat controversial. Investigators at MSKCC suggested that such patients require consolidation with radiotherapy or surgical removal of radiographically evident disease. Data from the Royal Marsden Hospital and the Centre Léon Bérard reported a relapse rate of 10% to 15% in patients with residual masses with or without postchemotherapy surgery or radiotherapy, supporting the practice of observation in patients with residual masses following chemotherapy. FDG-PET may be helpful in the decision to treat residual masses larger than 3 cm but should be performed 4 to 6 weeks after the last course of chemotherapy. Thus, resection is recommended for patients with residual masses larger than 3 cm and an abnormal PET scan.
As mentioned previously, patients with NSGCTs being treated with chemotherapy can be classified as having good-, intermediate-, or poor-risk disease (see Table 3). Approximately 60% of patients presenting with disseminated disease are categorized as good risk, 26% are intermediate risk, and 14% are poor risk.
Good-risk disease. Three cycles of BEP given every 3 weeks or, alternatively, four cycles of EP at the same dosages appear to yield equivalent results. More than 90% of good-risk patients should be cured with these therapies.
Two prospective randomized trials comparing cisplatin(Drug information on cisplatin) with carboplatin(Drug information on carboplatin) in good-risk patients with disseminated germ cell tumors have demonstrated inferior results for carboplatin-containing regimens.
• Postchemotherapy resection—Patients who have persistent radiographic disease with normal serum markers 4 to 6 weeks following chemotherapy for an NSGCT should undergo surgical resection of the residual mass and bilateral template RLND when possible. Histologic examination of residual disease will reveal necrotic fibrous tissue in approximately 45% of such cases, benign teratoma in about 45%, and persistent carcinoma in about 10% to 15%.
• Postresection chemotherapy—If persistent carcinoma is detected in the resected specimen, two additional cycles of EP should be administered. For patients with complete resection of mature and immature teratoma or necrosis, no additional therapy is needed.
Intermediate-risk disease. The optimal management of patients with intermediate-risk disease is not well defined. Most patients with intermediate-risk disease receive the same treatment as those with poor-risk disease (BEP for four cycles or VIP [VP-16, ifosfamide(Drug information on ifosfamide), cisplatin] for four cycles). Intermediate-risk disease, however, encompasses a heterogeneous group of patients, including those with very elevated levels of β-hCG (>5,000 but <50,000) and AFP (>1,000 but <10,000) or patients with seminoma who have non-pulmonary visceral metastses (including bone, brain, or liver). DeWit et al reported results of a phase III trial of intermediate-risk patients randomized to receive standard BEP for four cycles or Taxol plus BEP (T-BEP) for four cycles. There was no statistical difference in progression-free survival on an intent-to-treat basis, although there was a numerical advantage in progression-free survival favoring T-BEP when considering only the eligible patients (82.7% vs 70.1%). There was no difference in overall survival, however.
Poor-risk disease. A cohort of patients with disseminated germ cell tumors presents with advanced or poor-risk disease. "Poor risk" has been variously defined (see Table 3) but represents a patient population with a cure rate of 50% or less with standard cisplatin-based combination chemotherapy. Irradiation is useful in the treatment of metastatic NSGCTs to the brain.
• Chemotherapy—During the past few years, several trials have evaluated a variety of combination regimens in patients with poor-risk disease (Table 5). The regimen VIP for four cycles appears to be therapeutically equivalent to BEP for four cycles; however, for most patients with advanced disease, BEP is the preferred regimen because it produces less myelosuppression. In patients with underlying pulmonary dysfunction or primary mediastinal non-seminomatous germ cell tumor, VIP is preferred.
• High-dose chemotherapy with stem cell transplant (SCT) up-front—A North American intergroup trial randomized 219 previously untreated patients with intermediate- or poor-risk testicular germ cell tumors (TGCTs) to four cycles of BEP or two cycles of BEP followed by two tandem courses of high-dose chemotherapy plus SCT. No difference in the outcome between the two arms was seen, but greater toxicity was seen in the high-dose arm. Recently, a European trial randomized 137 patients with poor-risk disease to four cycles of BEP or one cycle of VIP followed by three cycles of high-dose VIP with SCT. The 2-year failure-free survival rates were 44.8% and 58.2% in the standard and high-dose arms, respectively. The difference was not statistically significant. Overall survival did not differ and toxicity was higher in the high-dose arm. Thus, four cycles of BEP remain the standard of care for poor-risk patients.
• Postchemotherapy resection—The ultimate goal of combination chemotherapy in these patients is the resolution of all radiographically visible disease and the normalization of tumor markers. If residual radiographic abnormalities persist in the lungs and/or abdomen, surgical resection of residual disease is indicated. Postchemotherapy RLND must clear the region of residual disease. In general, postchemotherapy resections are extremely difficult, and incomplete resections are unacceptable. After the retroperitoneum is cleared of persistent radiographic disease, persistent pulmonary lesions are resected. In cases with residual disease in the retroperitoneum and thorax, RLND should be performed first. If necrosis is found, the disease within the chest can be observed. If teratoma or cancer is noted, the supradiaphragmatic disease should be resected.
Complicating factors associated with postchemotherapy resection include the risk of oxygen toxicity secondary to bleomycin(Drug information on bleomycin) as well as intense fibrosis and adherence of residual disease to the aorta and other vital retroperitoneal organs. Inspired oxygen levels must remain below 35% to prevent bleomycin-related acute respiratory distress syndrome, which has a fatality rate of 50% or more.
After successful resection, the only visible structures remaining should include the back muscles, nerves, anterior spinous ligament, aorta, IVC, renal vessels, kidneys, and ureters. Up to 20% of patients with advanced abdominal disease may require resection of a kidney or even the IVC. Operative mortality in centers with experience performing resection of these advanced-stage tumors should be less than 2%. Although intraoperative, postoperative, and late complication rates were higher between groups receiving open primary or postchemotherapeutic RLND, they were not significantly different when the procedure was performed by fellowship-trained urologists. A more thorough RLND increases the 2-year relapse-free probability from 90% (10 nodes removed) to 97% (50 nodes removed).
• Post–complete remission RLND—patients who achieve complete remission (normal tumor markers and no residual radiographic abnormalities > 1 cm) with first-line cisplatin-based combination chemotherapy can be monitored safely without additional treatment (RLND). This was demonstrated in a retrospective review of 141 patients in complete remission. Median follow-up was 15.5 years. Six patients (4%) relapsed and two died as a result of disease progression. Five patients had late relapse and all were rendered disease-free with subsequent treatment. The 15-year disease-specific survival was 97%.
• Postresection chemotherapy—As mentioned, two additional cycles of chemotherapy are indicated for patients with persistent viable carcinoma in the resected specimen. For patients with resected teratoma of nonviable necrotic tissue, no additional chemotherapy is warranted.
Approximately 20% to 30% of patients with disseminated germ cell tumors do not attain complete remission with induction chemotherapy or relapse after such therapy. Occasional patients may be erroneously classified as having recurrent disease on the basis of false-positive markers or abnormal radiographic findings. Some of these false-positive results may be due to a growing teratoma; pseudonodules from bleomycin-induced pulmonary disease; or elevated markers from other causes, such as an elevated β-hCG level from marijuana use, cross-reactivity with luteinizing hormone, or an elevated AFP level associated with hepatitis or liver dysfunction. Another cause of persistently elevated markers is a tumor sanctuary site (eg, in the testes or brain). Assuming that false disease progression has been ruled out, several approaches to salvage therapy can be used.
The International Prognostic Factors Study Group collected data on 1,594 patients from 38 centers worldwide who progressed after first-line cisplatin-based chemotherapy. Histology, primary tumor location, response, and progression-free interval after first-line treatment, as well as levels of AFP, β-hCG, and the presence of liver, bone, or brain metastases at salvage were identified as independent prognostic variables. The patients were divided into five prognostic categories with a 2-year progression-free survival ranging between 75% and 6%.
Some patients with recurrent disease appear to have localized or minimally metastatic disease. In such cases, salvage surgery may achieve a durable complete remission. A 25% cure rate was seen in a select group of patients with elevated serum markers who underwent such surgery at Indiana University. These patients had completely resected viable carcinoma without chemotherapy following surgery.
Ifosfamide is one of a few drugs (including etoposide, gemcitabine(Drug information on gemcitabine) [Gemzar], and paclitaxel(Drug information on paclitaxel)) that have clinical activity in patients with cisplatin-refractory disease. As second-line therapy, VeIP (vinblastine, 0.11 mg/kg on days 1 and 2 [total dose = 0.22 mg/kg]; plus ifosfamide, 1.2 g/m2 [plus mesna(Drug information on mesna) (Mesnex)]; plus Platinol, 20 mg/m2, both on days 1 to 5) produces durable complete remissions in approximately 30% of NSGCT patients and 50% of seminoma patients previously treated with BEP chemotherapy (Table 5). Toxicity, which is primarily hematologic, can be minimized with the use of a colony-stimulating growth factor. TIP (taxol, 175 mg/m2 on day 1; plus ifosfamide, 1.2 g/m2 [plus mesna (Mesnex)]; plus Platinol, 20 mg/m2—both on days 1 to 5) is another salvage regimen that has been used in patients with good-risk relapsed TGCT (gonadal origin, response to cisplatin-based first-line chemotherapy and a progression-free interval of at least 6 months) with a 63% durable complete remission rate.
Seminoma. Patients with recurrent seminoma appear to be more sensitive to salvage therapy. In a study by Miller et al (J Clin Oncol 1997), 24 patients with seminoma were treated with VeIP as second-line therapy (following relapse after cisplatin-etoposide combination therapy). Of the 24 patients, 20 patients (83%) achieved a complete response, and 13 patients (54%) are long-term survivors, including 4 of 6 with extragonadal primary sites. As previously stated, patients with seminoma tend to be older than those with nonseminoma. As a result, some patients with relapsed seminoma may be older than 50 or 60 years and may have more comorbidities than their younger counterparts. For these patients, treatment with VeIP for four cycles should be considered. Other patients with relapsed seminoma should be considered for high-dose chemotherapy with stem cell rescue (see below).
High-dose chemotherapy with stem cell rescue. High-dose chemotherapy with tandem courses of carboplatin and etoposide(Drug information on etoposide) plus autologous stem cell rescue produces durable complete remission in patients with relapsed germ cell tumors. When this approach is used in patients with recurrent, but not cisplatin-refractory, disease, improved response rates are observed; more than 60% of all patients with recurrence of testicular cancer (excluding extragonadal recurrence) will be cured. Approximately 70% of patients treated with second-line therapy are curable with this approach.
A retrospective review by Einhorn et al evaluated 184 patients who had progressed on initial platinum-based therapy. They were treated with two consecutive courses of high-dose chemotherapy with carboplatin and etoposide followed by infusion of autologous peripheral-blood hematopoietic stem cells. Of the 135 patients who received this treatment as second-line therapy, 94 were disease-free; 22 of 49 patients who received this treatment as third-line therapy or later were disease-free; and 18 of 40 platinum-refractory patients were disease-free. With respect to relapsed seminoma, 74% are continuously with no evidence of disease with high-dose therapy, including 14 of 15 patients with seminoma in whom high-dose therapy was given in the second line. Investigators at MSKCC have also reported on their experience with the TICE regimen. TICE consists of one cycle of taxol plus ifosfamide followed by three cycles of high-dose carboplatin plus etoposide with stem cell rescue. One hundred seven patients were treated between 1993 and 2006. The 5-year disease-free survival was reported to be 47%, with an overall 5-year survival rate of 52%. Of special note, 5 of 21 patients with primary mediastinal NSGCT are reported to have no evidence of recurrent disease.
A retrospective review of 1,594 patients in 38 centers worldwide treated with either high-dose or conventional-dose chemotherapy as first salvage treatment showed better progression-free and overall survival with high-dose chemotherapy.The number of high-dose treatments is controversial. Indirect comparison reveals better outcomes with tandem transplants as opposed to a single transplant. In addition, the only randomized trial in patients with relapsed germ cell tumors after first-line cisplatin-based chemotherapy showed that four cycles of ifosfamide-based salvage chemotherapy was equivalent to three cycles of ifosfamide-based salvage chemotherapy plus one cycle of high-dose chemotherapy. Lorch et al initiated a randomized trial to compare a single cycle with three sequential cycles of high-dose chemotherapy in patients with relapsed germ cell tumors. That study was stopped early because of excess mortality in the sequential arm. Patients with relapsed mediastinal germ cell tumors have a poor prognosis with a 2-year disease-free rate of 0% to 11% after high-dose chemotherapy.
Other agents. Few drugs besides etoposide and ifosfamide have activity in patients with cisplatin-refractory disease. Oral etoposide given according to a long-term schedule (50 mg/m/d for 21 days) has produced objective responses in approximately 20% of patients who were previously treated with intravenous etoposide. Paclitaxel has a similar response rate in minimally pretreated patients (fewer than six cycles). Gemcitabine produces a response rate of approximately 15% in patients with cisplatin-refractory disease.
The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of gemcitabine (1,000 mg/m2) plus paclitaxel (110 mg/m2) given on days 1, 8, and 15 of a 4-week cycle for a maximum of six cycles in patients with recurrent germ cell tumors not thought to be curable with standard chemotherapy or surgery. (All were previously treated with high-dose chemotherapy.) Of 28 evaluable patients, six responded, including three who had complete responses (two of whom were free of disease at 15+ and 25+ months).
In a group of patients not considered to be curable with standard salvage chemotherapy, cisplatin plus epirubicin(Drug information on epirubicin) produced durable complete remissions in seven of 30 patients.
Sidebar: Long-term results of paclitaxel plus gemcitabine were presented at the 2011 ASCO annual meeting. The investigators reported that 10 of 32 patients (31%) had an objective response. A total of four (12.5%) are without evidence of disease at 64 to 103 months (Mulherin BP et al: J Clin Oncol 29(s):abstract 4562, 2011).