George J. Bosl

Phase III Randomized Trial of Conventional-Dose Chemotherapy With or Without High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Rescue As First-Line Treatment for Patients With Poor-Prognosis Metastatic Germ Cell Tumors

PURPOSE To investigate the role of high-dose chemotherapy (HDCT) as first-line treatment in patients with metastatic germ cell tumor (GCT) and poor-prognostic clinical features. Serum tumor marker decline during chemotherapy was assessed prospectively as a predictor of treatment outcome. PATIENTS AND METHODS In this randomized phase III trial, previously untreated patients with intermediate- or poor-risk GCT received either four cycles of standard bleomycin, etoposide, and cisplatin (BEP alone), or two cycles of BEP followed by two cycles of HDCT containing carboplatin and then by hematopoietic stem-cell rescue (BEP + HDCT). Serum tumor markers alpha-fetoprotein and human chorionic gonadotrophin were correlated with treatment outcome as a secondary end point. RESULTS Two hundred nineteen patients were randomly assigned: 108 to BEP + HDCT and 111 to BEP alone. The 1-year durable complete response rate was 52% after BEP + HDCT and 48% after BEP alone (P = .53). Patients with slow serum tumor marker decline (alpha-fetoprotein and/or human chorionic gonadotrophin) during the first two cycles of chemotherapy had a shorter progression-free survival and overall survival compared with patients with satisfactory marker decline (P = .02 and P = .03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-year durable complete response proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone (P = .03). CONCLUSION The routine inclusion of HDCT in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve treatment outcome. Frequent serum marker determinations to estimate marker decline during the first two cycles of BEP chemotherapy provide a clinically useful estimate of outcome.

Combination of Paclitaxel, Ifosfamide, and Cisplatin Is an Effective Second-Line Therapy for Patients With Relapsed Testicular Germ Cell Tumors

PURPOSE The efficacy of paclitaxel was evaluated in combination with ifosfamide and cisplatin as second-line chemotherapy for patients with relapsed testicular germ cell tumors (GCTs). PATIENTS AND METHODS Forty-six patients with progressive metastatic GCTs were treated with paclitaxel and ifosfamide plus cisplatin (TIP) as second-line therapy. Eligibility required that patients have both a testis primary tumor site and a prior complete response (CR) to a first-line chemotherapy program, which had been identified previously as favorable prognostic factors to conventional-dose salvage chemotherapy. RESULTS Thirty-two (70%) of 46 patients achieved a CR to treatment. Three patients (7%) who achieved a CR relapsed after TIP chemotherapy. Twenty-nine patients are continuously disease free at a median follow-up time of 69 months, resulting in a 63% durable CR rate and a 2-year progression-free survival rate of 65% (95% CI, 51% to 79%). CONCLUSION Four cycles of TIP as second-line therapy achieved a durable CR rate in a high proportion of patients with relapsed testicular GCT. The high CR rate emphasizes the importance of patient selection according to prognostic factors to achieve a favorable outcome to conventional-dose salvage therapy.

Medical Treatment of Advanced Testicular Cancer

CONTEXT The medical treatment of advanced testicular germ cell tumors has changed over the past 30 years, with long-term survival now achieved in the majority of patients. Clinicians need to be familiar with the available treatment regimens for testicular cancer and their associated toxic effects. OBJECTIVE To review the treatments used for advanced testicular germ cell tumors and their associated short-term and long-term complications. EVIDENCE ACQUISITION A search was performed of all English-language literature (1966 to October 2007) within the MEDLINE database using the terms neoplasms, germ cell, or embryonal or testicular neoplasms restricted to humans, drug therapy, complications, and mortality. The Cochrane Register of Controlled Trials Databases (through October 2007) was also searched using the terms testicular cancer or germ cell tumors. Bibliographies were reviewed to extract other relevant articles. One hundred eighty-six articles were selected based on pertinence to advanced testicular cancer treatment, associated complications, and late relapses with an emphasis on randomized controlled trials. DATA SYNTHESIS The treatment of advanced testicular germ cell tumors with cisplatin combination chemotherapy is based on risk stratification (good, intermediate, or poor prognosis) according to pretreatment clinical features of prognostic value. Clinical trials have demonstrated that approximately 90% of patients classified as having a good prognosis achieve a durable complete remission to either 4 cycles of etoposide and cisplatin or 3 cycles of cisplatin, etoposide, and bleomycin. Complete responses are achieved less frequently for patients with intermediate- and poor-risk germ cell tumors, in whom 4 cycles of bleomycin, etoposide, and cisplatin remains the standard of care. Second- and third-line programs, including high-dose chemotherapy, also have curative potential. Chronic toxicities associated with therapy include cardiovascular disease, infertility, and secondary malignancies. Late relapses may also occur. CONCLUSIONS Clinical trials have led to evidence-based treatment recommendations for advanced testicular cancer based on risk stratification. Clinicians should be familiar with the potential complications of these therapies.

Raynaud's Phenomenon: A Common Toxicity After Combination Chemotherapy for Testicular Cancer

Raynauds phenomenon occurred in 22 of 60 men (37%) treated with vinblastine and bleomycin with or without cisplatin for germ cell testicular cancer. An additional six patients (10%) had symptoms suggestive of Raynauds phenomenon. Patients with and without Raynauds phenomenon did not differ with respect to median age; tumor histology; total doses of vinblastine, bleomycin, and cisplatin; or the frequency of vinblastine-induced neuropathy and bleomycin-induced cutaneous toxicity. Digital ischemia occurred in 21% of patients treated with only vinblastine and bleomycin, and in 41% of patients treated also with cisplatin. Cigarette smoking was commoner in patients with than in those without Raynauds phenomenon. Hand arteriograms showed diffuse arterial narrowing and abrupt vascular cutoffs. Except for one patient with a very low titer of cold agglutinins, no patient had detectable antinuclear antibody, rheumatoid factor, cryoglobulins, or cold agglutinins. Raynauds phenomenon is a common delayed toxicity after chemotherapy with vinblastine, bleomycin, and cisplatin in patients with germ cell neoplasms.

A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors.

Standard chemotherapy for disseminated germ cell tumors (GCT) cures most patients but causes considerable acute toxicity, including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis. In addition, chronic and delayed toxicities, particularly Raynauds phenomenon, have been reported in 6% to 37% of treated patients. In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin, a randomized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin (VAB-6) and etoposide + cisplatin (EP) was conducted on 164 eligible patients with good-prognosis GCT. Seventy-nine of 82 (96%) patients receiving VAB-6 and 76/82 (93%) receiving EP achieved a complete remission (CR) with or without adjunctive surgery. Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma. With a median follow-up of 24.4 months in the VAB-6 arm and 25.9 months in the EP arm, the total, relapse-free, and event-free survival distributions were similar in the two arms. Patients receiving EP experienced less emesis (P = .05), higher nadir WBC (P = .06) and platelet counts (P = .01), less magnesium wasting (P = .0001), less mucositis (P = .09), and no pulmonary toxicity. No treatment-related mortality was observed. EP is an efficacious and less toxic regimen and is recommended for good-prognosis patients with disseminated GCT.

Paclitaxel, Ifosfamide, and Cisplatin Second-Line Therapy for Patients With Relapsed Testicular Germ Cell Cancer

PURPOSE To evaluate the dose, toxicity, and efficacy of paclitaxel in combination with ifosfamide and cisplatin as salvage therapy for patients with relapsed testicular germ cell tumors (GCTs). PATIENTS AND METHODS Thirty patients with previously treated GCTs were treated with paclitaxel and ifosfamide plus cisplatin (TIP) as second-line therapy. All had favorable prognostic features for response (testis primary tumor site and prior complete response to first-line chemotherapy program). Four cycles of paclitaxel, ifosfamide 5 g/m(2), and cisplatin 100 mg/m(2) were given 21 days apart with granulocyte colony-stimulating factor support, followed by resection of radiographic residua. The dose of paclitaxel was increased among cohorts with dose levels of 175, 215, and 250 mg/m(2); the largest dose was selected for the phase II part of the trial. RESULTS Twenty-three (77%) of 30 patients achieved a complete response to chemotherapy alone, and one patient achieved a durable partial response with normal tumor markers. Therefore, 24 (80%) achieved a favorable response. Eleven patients with normalized markers after chemotherapy underwent resection of residual tissue, with only necrosis found in 10 and mature teratoma in one. Two patients relapsed, and 22 (73%) of the favorable responses remain durable at a median follow-up duration of 33 months. Myelosuppression was the major toxicity, and two patients had grade 3 neurotoxicity. CONCLUSION Four cycles of TIP was associated with a high proportion of patients who achieved a complete response, a lack of relapse, and relative tolerability as an ifosfamide-containing salvage regimen for testicular GCTs. The high durable complete response proportion emphasizes the importance of patient selection according to prognostic factors for a favorable outcome to conventional-dose salvage therapy.

Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors.

PURPOSE A trial of paclitaxel was conducted in patients with previously treated germ cell tumors (GCT). As the identification of new agents in GCT may be compromised by restricting entry criteria to heavily pretreated patients, an alternative trial design was used in which eligibility was restricted to patients with limited prior therapy. PATIENTS AND METHODS Patients were eligible if their prior therapy was limited to one cisplatin-based regimen or < or = six cycles of prior cisplatin-based therapy. Paclitaxel 250 mg/m2 was administered by continuous infusion over 24 hours every 21 days. The dose of paclitaxel was modified for each patient based on toxicity. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg/d was administered during nadir periods. RESULTS Thirty-one patients were treated; eight patients (26%) achieved a partial (n = 5) or a complete (n = 3) response. Responses were achieved in patients who had failed to respond to treatment with cisplatin, ifosfamide, and etoposide, and in patients with poor prognostic features, ie, mediastinal primary tumor site and patients with a best prior response of an incomplete response to cisplatin therapy. One complete responder remains continuously free of disease at 13+ months and one of the five patients who achieved a partial response remains progression-free at 14+ months. CONCLUSION Paclitaxel has antitumor activity in GCT and warrants continued study in combination chemotherapy. Phase I/II trials will address its role in combination with cisplatin and ifosfamide and as a part of dose-intensive therapy. Furthermore, the study showed that a trial design in which eligibility criteria limits prior therapy was feasible, resulted in the identification of antitumor activity in a new agent, and may be considered in future trials for other promising new agents in GCT.

VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors.

One hundred sixty-six patients with germ-cell tumors (GCT) of the testis, retroperitoneum, and mediastinum were treated with cyclophosphamide, vinblastine, bleomycin, dactinomycin, and cisplatin (VAB-6), with and without maintenance chemotherapy. The overall complete response (CR) rate was 78%, 67% to chemotherapy alone, and 11% after chemotherapy and resection of viable residual cancer. The CR rate in all patients with seminoma was uniformly high, while the CR rate of patients with testicular nonseminomatous germ-cell tumors (79%) was superior to that of similar tumors of extragonadal origin (60%). The overall relapse rate was 12%, and was greater in tumors of extragonadal origin (21%) than in those of testicular origin (11%). Three relapses occurred after 2 years. Maintenance chemotherapy did not prolong either relapse-free or total survival. Toxicity was tolerable, and there were no treatment deaths. No Raynauds phenomena have occurred, with a minimum duration since start of therapy of 36 months. VAB-6 is an effective chemotherapy regimen in patients with GCT with no treatment-related deaths and a majority of patients requiring only 3 months of treatment.

Teratoma with malignant transformation in germ cell tumors in men

Pathology reports of over 580 male patients with germ cell tumors treated between 1972 and 1982 were screened for teratomas in which malignant transformation was apparent. The diagnosis was established in 17 cases. The median age was 28 years (range, 14–52). For patients with disease limited to the testis, the median survival has not been reached, with all five patients surviving disease‐free at 22+ to 120+ months. Among the 12 patients with metastatic disease, the median survival was 30.5 months (range, 12–69). All 12 patients were treated with cisplatin‐containing regimens. Six had complete respones either to chemotherapy alone or to chemotherapy plus resection of residual disease. Four of the six complete responders relapsed, and three died of progressive disease. One patient with sarcomatous differentiation was treated with a doxorubicin‐based regimen and had a partial remission, which lasted 8 months. Teratoma with malignant transformation, when found in metastatic sites, appeared to be a poor prognostic pathologic variant in male patients with germ cell tumors.

Sequential Dose-Intensive Paclitaxel, Ifosfamide, Carboplatin, and Etoposide Salvage Therapy for Germ Cell Tumor Patients

PURPOSE To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood-derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] x minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison. PATIENTS AND METHODS Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m(2) plus ifosfamide 6 g/m(2) were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1, 200 mg/m(2), and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) x min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC. RESULTS Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula. CONCLUSION Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.