Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

Prospective study of fluorodeoxyglucose-positron emission tomography imaging of lymph node basins in melanoma patients undergoing sentinel node biopsy.

PURPOSE: To prospectively compare positron emission tomography (PET) imaging of regional lymph node basins to sentinel node biopsy (SNB) in patients with American Joint Committee on Cancer (AJCC) stage I, II, and III melanoma localized to the skin. METHODS: Patients with cutaneous melanoma with Breslow's depth greater than 1 mm (AJCC T2-4N0M0) or localized regional cutaneous recurrence (TxN2bM0) underwent whole-body imaging of glucose metabolism with fluorodeoxyglucose (FDG) PET followed by SNB. PET scans were interpreted in a blinded fashion and compared with histologic analyses of SNB specimens and clinical follow-up examination. Nodal tumor volumes were estimated. RESULTS: Eighty-nine lymph node basins were evaluated by FDG-PET and SNB in 70 assessable patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDG-PET imaging: 17 proved by SNB (24.3%) and one by follow-up examination (1.4%). Median tumor volume in positive sentinel node basins was 4.3 mm3 (range, 0.07 to 523 mm3). Sensitivity of SNB for detection of occult regional lymph node metastases was 94.4%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 98.6%. Sensitivity of FDG-PET was 16.7%, specificity was 95.8%, PPV was 50%, and NPV was 81.9%. At a median follow-up duration of 16.6 months, seven patients (10%) developed recurrent disease. PET predicted one recurrence (14.3%) in a node basin missed by SNB. CONCLUSION: FDG-PET is an insensitive indicator of occult regional lymph node metastases in patients with melanoma because of the minute tumor volumes in this population. FDG-PET does not have a primary role for staging regional nodes in patients with clinically localized melanoma.

Oral etoposide in germ cell tumours.

Patients with germ cell tumours who relapse or fail to achieve disease-free status after first-line chemotherapy have a poor prognosis. When administered orally, etoposide produces responses in approximately 25% of patients whose disease is refractory to therapy and is a reasonable choice for palliative treatment in patients who are otherwise incurable. Oral etoposide has also been studied as maintenance therapy in patients who have been treated with salvage chemotherapy or surgery, with results that compare favourably with historical data. We recommend 3 months of maintenance oral etoposide for patients who achieve a complete response to any type of salvage therapy.

A phase II trial of vinorelbine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.

Forty patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated weekly with vinorelbine 30 mg/m2. Thirty-five patients received prior surgery, 20 prior chemotherapy, and 38 prior radiation therapy. Five patients were not evaluable for response and were assumed to be nonresponders. There were three confirmed responders (one complete response, two partial responses) for a response rate of 7.5% (95% confidence interval, 1.6%-20.4%). The median survival time for all patients was 5 months (range, 0.5-50 months), the median progression-free survival time was 2 months (range, 1-49 months). The most common toxicity was myelosuppression, with 60% of patients experiencing grade 3 or higher leukopenia. There was one treatment-related death resulting from sepsis. Vinorelbine has minimal activity in patients with SCCHN that does not exceed that of other currently used agents.

Detection of germ cell tumor cells in apheresis products using polymerase chain reaction.

The contamination of apheresis products with tumor cells was evaluated in patients undergoing autologous peripheral blood stem cell transplantation for germ cell tumors. A blinded, retrospective analysis was performed on 63 apheresis products from 28 patients using the PCR and primers for beta human chorionic gonadotropin (beta-HCG). Of the 20 patients with beta-HCG-secreting tumors, 8 apheresis products from 7 patients were PCR positive. PCR was negative in the 8 patients whose tumors did not secrete beta-HCG. Twenty-two apheresis products from patients with lymphoma and breast cancer were negative for beta-HCG expression. Evaluating the 20 patients with beta-HCG-secreting tumors, 100% of PCR-positive patients had elevated serum beta-HCG at the time of apheresis compared to 46.2% of PCR-negative patients (P = 0.04). A positive PCR was also associated with a higher serum beta-HCG at diagnosis (P = 0.03). Patients receiving a PCR-positive product had a higher relapse rate (85.7 versus 61.5%) and were more likely to have visceral metastasis (100 versus 61.5%), although the numbers did not reach statistical significance (P = 0.35 and 0.11, respectively). The finding of beta-HCG mRNA in apheresis products strongly suggests the presence of circulating tumor cells in a significant number of germ cell patients undergoing autologous transplantation. This assay may be useful in monitoring attempts at tumor cell depletion and in developing improved prognostic models for assessing risk of relapse after transplantation.

Ifosfamide in the treatment of advanced or recurrent squamous cell carcinoma of the head and neck: a phase II Hoosier Oncology Group trial.

The Hoosier Oncology Group conducted a trial evaluating ifosfamide in patients who had recurrent or metastatic squamous cell carcinoma of the head and neck. Patients must have received no prior chemotherapy for metastatic disease. If prior adjuvant chemotherapy was given, the last cycle must have been at least six months from time of recurrence. All patients were required to have a Karnofsky performance status of > or = 50. Twenty-four patients received treatment consisting of ifosfamide, 1.5 g/m2/day for 5 days, with cycles repeated every 3 weeks. Mesna, 300 mg/m2, was administered intravenously 15 minutes before ifosfamide and 4 and 8 hours after ifosfamide on days 1 through 5. Toxicity was predominantly hematologic, with grade 3--4 neutropenia seen in 13 patients resulting in 4 episodes of neutropenic fever. One partial response was seen in 23 evaluable patients for an overall response rate of 4.3% (95% confidence interval, 0, 12.7%). In conclusion, ifosfamide would appear to have limited single-agent activity in squamous cell carcinoma of the head and neck.

Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience.

PURPOSE: In a previously reported randomized Southeastern Cancer Study Group (SECSG) trial, three cycles of chemotherapy were found to be equivalent to four cycles in patients with favorable-prognosis germ-cell cancer. We have conducted a follow-up analysis of patients treated at Indiana University (Indianapolis, IN) to compare long-term survival between the two groups and to examine factors associated with survival. PATIENTS AND METHODS: Sixty-nine patients with minimal-stage and 49 patients with moderate-stage disseminated germ-cell tumors were randomized to either three or four courses of bleomycin, etoposide, and cisplatin (BEP) administered every 3 weeks. Median follow-up time is 10.1 years (range, 7 months to 12.6 years). Ninety-two percent of patients have an actual follow-up time of > 5 years, and 97.5% of patients have an actual follow-up time of > 3 years. RESULTS: Survival analysis shows no significant difference between the two treatment groups in terms of overall (P = .80) or disease-free (P = .93) survival. Several clinical variables were examined by univariate analysis; only serum human chorionic gonadotropin (HCG) had an impact on survival. There were two disease-related deaths in 104 patients with HCG < or = 1,000 mIU/mL and five disease-related deaths in 14 patients with HCG greater than 1,000 mIU/mL (P < .001). Ninety-eight percent (95% CI, 95.2 to 100) of patients with favorable prognosis germ-cell tumor with an initial HCG of < or = 1,000 mIU/mL are alive without evidence of disease at 5+ years. CONCLUSION: With long-term follow-up, there is no statistically significant difference in survival between three or four cycles of BEP chemotherapy in patients with favorable prognosis germ-cell carcinoma. Serum HCG elevation of greater than 1,000 mIU/mL is a significant predictor of poor outcome in patients with otherwise good-risk disease.

Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.

PURPOSE: A previously reported randomized intergroup trial demonstrated that combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was superior to single-agent cisplatin in patients with advanced urothelial carcinoma. We conducted a long-term analysis of patients included in the intergroup trial to examine factors associated with long-term survival. PATIENTS AND METHODS: Two-hundred fifty-five assessable patients with urothelial carcinoma were randomized to receive either single-agent cisplatin (70 mg/m2 on day 1) or combination chemotherapy with methotrexate (30 mg/m2 on days 1, 15, and 22), vinblastine (3 mg/m2 on days 2, 15, and 22), doxorubicin (30 mg/m2 on day 2), and cisplatin (70 mg/m2 on day 2). Courses were repeated every 28 days. The association between patient characteristics and survival was assessed using Cox proportional hazards models. RESULTS: With long-term follow-up evaluation, survival in the M-VAC arm continues to be superior to cisplatin (P = .00015, log-rank test). Predictors of survival include performance status, histology, and the presence of liver or bone metastasis. Only 3.7% of the patients randomized to M-VAC are alive and continuously disease-free at 6 years. CONCLUSION: Long-term follow-up evaluation of the intergroup trial confirms that M-VAC is superior to single-agent cisplatin in patients with advanced urothelial carcinoma; however, durable progression-free survival is rare. Patients with non-transitional-cell histology, poor performance status, and/or bone or visceral involvement fare poorly and are unlikely to benefit significantly from M-VAC chemotherapy.

Pulmonary toxicity in patients with advanced-stage germ cell tumors receiving bleomycin with and without granulocyte colony stimulating factor.

STUDY OBJECTIVES: The purpose of this study is to determine whether co-administration of granulocyte colony stimulating factor (G-CSF) and bleomycin results in enhanced pulmonary toxicity compared with bleomycin alone. DESIGN: A retrospective analysis comparing two groups of patients with advanced germ cell tumors receiving combination chemotherapy that includes bleomycin with or without G-CSF. SETTING: Indiana University Medical Center. PATIENTS: Group A consisted of 29 patients with advanced-stage germ cell tumors who were treated with combination chemotherapy that included bleomycin. All patients received concurrent prophylactic G-CSF. Group B consisted of 57 patients with advanced-stage germ cell tumors who were treated on a phase 3 study comparing standard BEP (bleomycin, etoposide, cisplatin) to BEP with twice the cisplatin dose. None of these patients received growth factor. RESULTS: Of the 29 patients who received concurrent chemotherapy and G-CSF, ten (34%; 95% confidence interval [CI], 17.9 to 54.3%) were believed to have clinically significant bleomycin toxicity. Of the 57 patients who did not receive growth factor, 19 (33%; 95% CI, 21.4 to 47.1%) had bleomycin-related toxicity. There was no difference in the incidence of pulmonary toxicity between the groups (p = 1.00 by Fisher's Exact Test). CONCLUSIONS: There is no increase in pulmonary toxicity with co-administration of G-CSF and bleomycin compared to bleomycin alone in patients with advanced germ cell tumors.

The management of patients with clinical stage I nonseminomatous testicular tumors and persistently elevated serologic markers.

PURPOSE: We reviewed our experience with patients who had nonseminomatous germ cell tumors clinically limited to the testis and persistently elevated serum human chorionic gonadotropin (HCG) or alpha-fetoprotein (AFP) levels after orchiectomy. MATERIALS AND METHODS: All patients had clinical stage I disease with persistently elevated tumor markers that were not decreasing in accordance with the expected metabolic decay rate at retroperitoneal lymph node dissection. RESULTS: Of 30 patients identified 3 had elevated AFP, 24 had elevated HCG and 3 had elevation of both markers. Of the 6 patients with elevated AFP with or without concurrent HCG elevation 5 (83%) had relapse and required chemotherapy, as did 6 of 24 (25%) with HCG elevation. CONCLUSIONS: Patients with persistently elevated AFP after orchiectomy should be treated initially with chemotherapy. Although the majority of patients with elevated serum HCG were disease-free after surgery alone, a fourth of these patients still had relapse and required chemotherapy.

Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: the Indiana University experience.

PURPOSE: Patients with relapsed extragonadal germ cell tumors (EGCT) are usually treated in an identical fashion as patients with recurrent testicular cancer. However, little is known about the long-term outcome in these patients and whether they have comparable results to patients with a testicular primary tumor. The purpose of this study was to evaluate the effect of salvage chemotherapy on long-term survival in patients with EGCT. MATERIALS AND METHODS: We conducted a retrospective review of 73 patients with relapsed extragonadal nonseminomatous germ cell tumors (GCTs) treated at Indiana University between 1976 and 1993. All patients received cisplatin-containing regimens as primary chemotherapy. RESULTS: Only five of 73 patients (7%) were long-term disease-free survivors after salvage chemotherapy. The remaining 68 patients are either dead of disease or toxicity (n = 63), or alive with progressive disease (PD) (n = 5). Twenty-eight patients received high-dose chemotherapy with autologous bone marrow transplant (ABMT) at some point during their disease, and none of these patients are continuously disease-free. CONCLUSION: Although similar salvage chemotherapy strategies will cure approximately 30% of patients with recurrent testicular cancer, new approaches are needed for EGCT.

Phase III trial of cyclophosphamide versus cyclophosphamide, doxorubicin, and methotrexate in hormone-refractory prostatic cancer. A Hoosier Oncology Group study.

BACKGROUND: Between August 1984 and November 1989, the Hoosier Oncology Group conducted a Phase III study comparing cyclophosphamide (CTX) with cyclophosphamide, doxorubicin, and methotrexate (CAM) in patients with hormone-refractory metastatic prostatic cancer to determine whether the addition of doxorubicin and methotrexate to the cyclophosphamide regimen conferred any survival advantage. METHODS: One hundred three patients were registered and randomized, 99 were evaluable for response, and all were evaluable for survival results. All had histologically confirmed metastatic prostatic cancer and had not responded to hormonal therapy. Fifty-three patients received CTX alone, and 50 received CAM. Seventy-one patients (69%) had evaluable disease, and 32 (31%) had measurable disease. RESULTS: There were no complete responses and only four (13%) partial responses in the patients with measurable disease. There was no difference in overall survival time between the two treatment arms in either patients with a Karnofsky performance status (KPS) of 80-100 (median survival, 9.0 versus 9.5 months; P = 0.93) or in those with a KPS of 50-70 (median survival, 5.0 versus 6.0 months; P = 0.51). There was no difference in overall time to progression between the two treatment arms (median time to progression; 4.4 versus 6.2 months; P = 0.07). Toxicity was tolerable in both regimens. CONCLUSIONS: It was concluded that there was no survival advantage to CAM over CTX alone. New chemotherapeutic agents with greater activity against prostatic cancer must be identified.

Salvage therapy in recurrent testicular cancer.

Patients with testicular cancer who relapse after primary chemotherapy are still curable and should be treated aggressively with this goal in mind. These patients should receive a cisplatin-based regimen, usually including ifosfamide and either vinblastine or etoposide (depending upon prior exposure to drugs). As with first-line therapy, chemotherapy should not be delayed because of blood counts alone. Because this patient population has a higher incidence of significant myelosuppression, the use of hematopoietic growth factors may be of value and is currently being investigated. Patients who achieve a CR after salvage chemotherapy can be followed as usual with monthly serum markers and chest x-rays. For those patients who have a marker-negative partial remission, resection of all residual disease (if possible) is appropriate. If the surgical specimen contains only necrotic material or teratoma, then they should also be followed without further therapy. The appropriate approach for patients with residual carcinoma at the time of surgical resection is uncertain. The standard approach at Indiana University has been to give two more cycles of chemotherapy post-operatively, however most of these patients will eventually relapse and require further treatment. Patients are currently being treated with oral etoposide for 3 months after surgery in an attempt to improve long-term survival. Whether this approach will be of benefit remains to be seen. Patients who fail second-line chemotherapy should be considered for high-dose chemotherapy with autologous bone marrow rescue. Patients who do not normalize their serologic markers with first-line chemotherapy or who relapse within 1 month after chemotherapy are truly platinum refractory and do poorly with standard-dose second line cisplatin-based chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)