Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study

PURPOSE: To compare standard therapy with bleomycin, etoposide, and cisplatin (BEP) to experimental therapy with etoposide, ifosfamide, and cisplatin (VIP) as primary treatment of men with advanced, disseminated germ cell tumors. PATIENTS AND METHODS: A total of 304 men with advanced disseminated germ cell tumors were randomly allocated to receive four courses of BEP or VIP. Two hundred ninety-nine patients were assessable for toxicity and 286 were assessable for response. Complete response rates, favorable response (complete remission, surgical free of disease, continuous partial remission for 2+ years), time to treatment failure, and overall survival were assessed. RESULTS: Overall complete remission rate (VIP, 37%; BEP, 31%), favorable response rate (VIP, 63%; BEP, 60%), failure-free at 2 years (VIP, 64%; BEP, 60%), and 2-year overall survival (VIP, 74%; BEP, 71%) were not significantly different between the two treatments. Grade 3 or worse toxicity, particularly hematologic and genitourinary toxicity, was significantly more common in patients who received VIP. CONCLUSION: BEP and VIP produce comparable favorable response rate and survival in patients with poor-risk germ cell tumors. The substitution of ifosfamide for bleomycin, however, was associated with significantly greater toxicity. Four courses of BEP remain the standard treatment for advanced disseminated germ cell tumors.     

Evaluation of long-term results of a modified VAB-6 chemotherapy regimen in a cohort of good-risk metastatic non seminomatous germ-cell tumors

From 1984 to 1988, we conducted at Institut Gustave-Roussy a phase II trial with a modified VAB-6 (mVAB-6) chemotherapy regimen in 50 patients with good prognosis metastatic non seminomatous germ-cell tumors, including 27 patients (54%) with retroperitoneal lymph nodes only. The mVAB-6 combination consisted of vinblastine 4 mg/m2/day at d1, of actinomycin D1 mg/m2/day at d1, of cyclophosphamide 600 mg/m2/day at d1, of cisplatin 120 mg/m2/day at d1 and of bleomycin 20 mg/day from d1 to d3. Four cycles of mVAB-6 were delivered every 4 weeks. A complete response was observed in 46 patients (92%). The other 4 patients achieved a partial response with normal serum tumor markers. Forty-two patients (84%) remain continuously free of disease. Eight relapses subsequently occurred 3 to 60 months after the end of treatment. Overall 45 patients (90%) remain free of disease after a median follow-up of 8 years. The long-term clinical toxicity was minimal. Three patients developed secondary tumors: 2 contralateral non seminomatous germ-cell tumors and 1 pancreatic adenocarcinoma. We conclude that the mVAB-6 regimen yielded excellent results and minimal long-term toxicity in this group of patients with very good-risk metastatic tumors.     

Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma

PURPOSE: To evaluate the antitumor activity and toxicity of concurrent biochemotherapy that uses cisplatin, vinblastine, and docarbazine (DTIC) (CVD) in combination with interferon alfa-2a (IFN-alpha) and interleukin-2 (IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS: Between October 1992 and October 1993, 53 patients with a documented diagnosis of metastatic melanoma with measurable lesions and an Eastern Oncology Cooperative Group (ECOG) performance status of 2 or less were enrolled onto this study. Patients were required to have no clinically significant cardiac dysfunction and to be free from symptomatic brain metastases. The treatment consisted of cisplatin 20 mg/m2 daily for 4 days; vinblastine 1.6 mg/m2 daily for 4 days; and DTIC 800 mg/m2 intravenously (i.v.) day 1 with IL-2 9 x 10(6) IU/m2 i.v. by continuous infusion daily for 4 days and IFN-alpha 5 x 10(6) U/m2 subcutaneously daily for 5 days, repeated at 21-day intervals. Response was assessed after two cycles and patients who responded were continued on treatment for a total of six cycles. RESULTS: Among 53 assessable patients, 11 patients (21%) achieved a complete response (CR) and 23 patients (43%) achieved a partial response (PR), for an overall objective response rate of 64%. The median time to disease progression for all patients was 5 months. The median survival of all patients entered onto the trial was 11.8 months. Among the 11 patients who achieved a CR, five patients (9%) have remained in continuous CR for 50+ to 61+ months. The toxicity of biochemotherapy consisted of severe myelosuppression, significant nausea and vomiting, and moderately severe hypotension that required inpatient hospital care for each 5-day cycle of treatment. There were no treatment-related deaths. CONCLUSION: Concurrent biochemotherapy for patients with advanced melanoma is capable of producing high CR and overall response rates and resulted in durable complete remissions in a small fraction of patients. Toxicity, although severe, was manageable in a routine inpatient hospital environment.     

Chemotherapy of germ-cell tumors of poor prognosis and role of intensification with hematological support

Poor-risk germ-cell tumors are defined by the presence of high serum tumor marker and large tumor burden. The standard treatment of this group of patients is four cycles of a combination of bleomycin, etoposide and cisplatin followed by the surgical exeresis of residual disease. Neither cisplatin dose-intensification nor alternating chemotherapy protocols, high-dose induction protocols and high-dose consolidation regimens have demonstrated better results than the standard chemotherapy regimen. The salvage treatment of germ-cell tumors is a combination of vinblastine, ifosfamide and cisplatin followed by the surgical exeresis of residual disease. The role of high-dose consolidation chemotherapy is studied in an international randomized trial. However high-dose chemotherapy is inactive in refractory disease patients. Innovative trials are developed in this group of patients.     

Final report of a phase II study of chemotherapy with bleomycin, epirubicin, and cisplatin for locally advanced and metastatic/recurrent undifferentiated carcinoma of the nasopharyngeal type

PURPOSE: This article presents an assessment of the combination of bleomycin, epirubicin, and cisplatin as induction chemotherapy before radiotherapy in the treatment of undifferentiated carcinoma of the nasopharyngeal type in patients with recurrent/metastatic disease (group A), and in previously untreated patients with locoregionally advanced disease (UICC-AJCC 87, N2-3, M0) (group B) in terms of toxicity, antitumoral activity, and therapeutic efficacy. PATIENTS AND METHODS: From January 1987 to September 1990, 111 consecutive patients with histologically proven UCNT were treated with six cycles of intravenous cisplatin (100 mg/m2 day 1) epirubicin (80 mg/m2 day 1), and bleomycin (15 mg bolus day 1), followed by 16 mg/m2/day continuous infusion for 5 days, repeated every 21 days for three cycles. Three further cycles without bleomycin were given to 44 patients in group A. In group B (67 patients), only three cycles of the same protocol were given, with a slightly lower dose of epirubicin (70 mg/m2), followed by conventional radiotherapy (70 Gy/7 weeks). RESULTS: Of 44 patients entered in group A, 38 were evaluable for response. We observed 9 (20%) complete responses and 11 (25%) partial responses, for a 45% overall response rate. In 12 patients not previously given chemotherapy, there were 4 complete responses, compared to 5 complete responses in 32 patients previously treated with chemotherapy. Four patients are alive with no evidence of disease after 53+, 60+, 61+, and 72+ months. In group B the overall response rate to chemotherapy was 98% with 42 complete (62%) and 24 partial responses (36%). Three months after the end of radiotherapy, the overall complete response rate was 94% (63 patients). After a median follow-up time of 77 months (range, 53-94), the 4-year overall survival and disease-free survival rates for this group are 66% and 60%, respectively. The median disease-free survival has not been reached at 90 months. CONCLUSION: The results of the BEC combination trial are very encouraging in metastatic and recurrrent UCNT, with durable remissions in this poor-prognosis population. The results in patients with locally advanced disease have motivated prospective phase III testing of the neoadjuvant chemotherapy approach to evaluate its impact on locoregionally advanced disease (> or =N2MO UICC-AJCC 87).     

Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: a phase II trial

PURPOSE: A phase II trial of ifosfamide, paclitaxel, and cisplatin (ITP) was conducted in previously untreated patients with advanced transitional-cell carcinoma (TCC) to assess its efficacy and toxicity. PATIENTS AND METHODS: Thirty patients with metastatic or unresectable TCC were treated with ifosfamide 1.5 g/m2/d for 3 days with paclitaxel 200 mg/m2 over 3 hours and cisplatin 70 mg/m2 on day 1 of each 28-day treatment cycle. Therapy was continued for a maximum of six cycles. Prophylactic hematopoietic growth factor (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was given on days 6 to 17 of each cycle. RESULTS: Twenty-three of 29 assessable patients (79%; 95% confidence interval [CI], 60% to 92%) demonstrated a major response (six complete [CR] and 17 partial [PR]) with response durations that ranged from 5 to 24+ months. Five patients with T4 bladder primary tumors had a major response, two with pathologic CR. At a median follow-up duration of 17.9 months, nine (31%) patients remain disease-free (range, 10+ to 24+). Hematologic toxicity included anemia, thrombocytopenia, and neutropenia; febrile neutropenia was observed in 17% of patients and 4% of cycles. No grade 4 nonhematologic toxicity was observed. Grade 3 nonhematologic toxicity included alopecia, allergy (3%), renal insufficiency (13%), and neuropathy (10%). Dose reductions or drug omissions were necessary for adverse events in seven (23%) patients. CONCLUSION: ITP is an active, well-tolerated regimen in previously untreated patients with TCC of the urothelial tract. Further study of this regimen in patients with both TCC and non-transitional-cell urothelial tumors is ongoing.     

Hemodynamic response to oxygen administration in chronic heart failure: role of chemoreflexes

OBJECTIVE: To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis. RESULTS: Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%. CONCLUSION: Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.     

Oviposition and incubation environmental effects on embryonic diapause in a ground cricket

PURPOSE: Recent studies document the value of early combined modality therapy of small cell lung cancer, but also indicate that early thoracic radiation adds to myelosuppression and can complicate further chemotherapy. Other studies indicate that simultaneous use of growth factors with thoracic radiation may be deleterious. However, temporal separation of growth factor use from cytotoxic therapy may allow dose intensity to be maintained/enhanced during combined modality treatment. We sought to integrate filgrastim into a novel chemoradiation regimen for patients with limited small cell lung cancer using an approach that separated growth factor administration from both chemotherapy and thoracic radiation. METHODS AND MATERIALS: Twenty-seven patients with limited disease small cell lung cancer were enrolled in a Phase I trial of cisplatin, ifosfamide/mesna, oral etoposide, and thoracic radiation (1.5 Gy b.i.d. x 30 fractions days 1-19 cycle 1) +/- filgrastim (5 microg/kg/day). Filgrastim was given on days 20-25 of cycle 1 after completion of radiation and following completion of oral etoposide in subsequent cycles. The primary end point was determination of maximum tolerated dose (MTD) of chemotherapy. Serial cohorts were treated with and without filgrastim. RESULTS: Because of dose-limiting thrombocytopenia, primarily, and nonhematologic toxicity, the MTDs with and without filgrastim were identical (cisplatin 20 mg/m2 i.v. and ifosfamide 1200 mg/m2 i.v., both given days 1-3, and etoposide 40 mg/m2 p.o. days 1-14). Filgrastim use shortened the duration of neutropenia at the MTD (median 4 vs. 7 days), but was not associated with a reduction in febrile neutropenia. Although growth factor administration did not allow dose escalation of this regimen, it did allow chemotherapy doses to be maintained at the MTD more frequently through four cycles of therapy. In the 24 evaluable patients, the overall response rate was 100% (71% partial and 29% complete). CONCLUSIONS: Despite careful attention to the timing of growth factor with chemoradiation, the administration of filgrastim with this regimen did not allow dose escalation. As in many other recent studies of hematopoietic growth factors given prophylactically with chemotherapy, the duration of neutropenia at the MTD was shortened and the need for dose reduction throughout treatment was reduced in patients receiving filgrastim at the MTD.     

Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma

PURPOSE: To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS: Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS: Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION: TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.     

Chemotherapy with methotrexate, vinblastine, epirubicin and carboplatin (Carbo-MVE) in transitional cell urothelial cancer. A Hellenic Co-Operative Oncology Group study

OBJECTIVES: We conducted a phase II study in order to assess the efficacy and toxicity of Carbo-MVE (carboplatin 250 mg/m2 i.v. day 1, methotrexate 25 mg/m2 i.v. days 1, 15 and 22, vinblastine 2.5 mg/m2 i.v. days 1, 15 and 22 and epirubicin 25 mg/m2 day 1). The regimen ws to be repeated every 28 days. METHODS: Forty-six patients with transitional cell carcinoma of the bladder entered the study. Patients with metastatic disease were treated for 6 cycles, while patients with locally advanced or locoregional disease had 4 cycles of induction chemotherapy followed by cystectomy or radiotherapy. RESULTS: Toxicity was generally mild and treatment well tolerated. The overall response rate was 54.4%, with 26% complete and 28.3% partial response rates. The median survival was 17.5 months with the complete responders to live significantly longer (64.82 months) than those who had a partial response (20.5 months), stable disease (15 months) or progressive disease (8.5 months). Survival was also significantly longer in patients with good performance status as well as in patients with locally advanced or locoregional disease. Finally, patients who had cystectomy as definitive treatment survived significantly longer (32 months) than those who had been irradiated (16 months). CONCLUSIONS: The Carbo-MVE regimen appears to be an effective and well-tolerated treatment in patients with transitional cell carcinoma of the bladder.     

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.     

Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer

PURPOSE: The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. PATIENTS AND METHODS: Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. RESULTS: This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. CONCLUSION: This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.     

Ifosfamide and etoposide in previously treated patients with advanced breast cancer

AIMS AND BACKGROUND: Ifosfamide is an active alkylating agent in the treatment of breast cancer, as a first-line therapy and in advanced disease. Since the combination of etoposide with an alkylating agent produces a synergistic and tolerable activity in various malignancies, in the present study, ifosfamide and etoposide were administered to patients with advanced breast cancer to evaluate the response characteristics and the toxicity profile. STUDY DESIGN: The combination of ifosfamide, mesna and etoposide was prospectively administered to 41 previously treated patients with stage IV breast carcinoma. The treatment schedule consisted of ifosfamide, 1500 mg/m2, infused over 24 hrs with 1500 mg/m2 mesna on days 1 to 5 and 120 mg/m2 etoposide, infused over 1 hr on days 1 to 3, to be repeated every 4th week. RESULTS: After a median follow-up of 10 months, an objective response rate of 23% (overall 2.5% complete remission and 20.5% partial remission) and a median response duration of 5.3 months were obtained in 39 assessable patients. The non-responder group consisted of 28.3% stable disease and 48.7% progressive disease. The prior status of chemotherapy was the only significant prognostic factor with an impact on the response rate. The overall toxicity was generally mild, with grade 3 myelotoxicity encountered in 25.7% of patients. CONCLUSIONS: The tolerable side effect profile of the ifosfamide and etoposide combination might be advantageous as regards the quality of life. To improve the rate and/or the duration of response and to clarify the precise role of the ifosfamide-etoposide combination in previously treated advanced breast cancer, further trials are warranted.     

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a "protector" haplotype

The authors evaluate the combination of three drugs, vinorelbine, ifosfamide, and cisplatin, which have been shown to produce good response rates and a significant gain in survival when any two of them are given together. Seventy-seven untreated patients with inoperable stage III-IV non-small-cell lung cancer from three centers were included. The combination consisted of cisplatin 30 mg/m2 daily, ifosfamide 1,500 mg/m2 daily, mesna 1,500 mg/m2 daily on days 1-3, and vinorelbine 25 mg/m2 daily on days 1 and 8. Four cycles were administered every 4 weeks for a total of 267 cycles, before an assessment for toxicity, effective dose intensity, response rate, and survival was made. Toxicity was mainly hematologic (grade 3-4 neutropenia (15.7%), anemia (8.2%), and thrombopenia (2.6%)) but did not require granulocyte colony-stimulating factors. Objective response rate was 41.1% (95% confidence interval, 29.5-52.9%) in 68 patients suitable for assessment. The mean time to progression and median survival were 7.7 +/- 1.3 months and 11.6 months, respectively. One-year survival was 47.1%. The effective dose intensity of cisplatin and ifosfamide correlated strongly with survival, whereas stage and performance status did not. This study confirms previously reported favorable results for response and survival rates obtained in stage III-IV non-small-cell lung cancer with the vinorelbine, ifosfamide, and cisplatin combination. Respect of a scheduled dose intensity has a clear-cut influence on survival and should be evaluated routinely in future polychemotherapy trials.     

Graves'' ophthalmopathy and tobacco smoking

BACKGROUND: Despite standard treatment, surgery and/or radiotherapy, most patients with muscle invasive bladder carcinoma die early of distant metastasis. CMV chemotherapy has demonstrated a high response rate with moderate toxicity in advanced bladder carcinoma. In an attempt to eradicate undetectable metastatic disease and to avoid cystectomies, 36 patients were given up-front CMV. MATERIALS AND METHODS: The patients were 34 males and 2 females with a median age of 62 years (45-75); performance status 0-1 (WHO) in 34 patients; histology: 34 transitional carcinomas and 2 anaplastic carcinomas (grade II: 8, grade III: 28). Clinical staging was T2-3a: 19 patients, T3b: 14 patients and T4: 3 patients. Nineteen patients had complete trans-urethral resections (TUR) at diagnosis. The multimodal protocol started with 3 CMV courses (cisplatin 100 mg/m2 i.v. d 1, methotrexate 30 mg/m2 i.v. d 1, 8 and vinblastine 4 mg/m2 i.v. d 1, 8 every 3 weeks). Patients who yielded clinical complete responses (cCR) by cystoscopy, TUR biopsies and imaging techniques were given 3 additional courses. Cystectomy was performed in non-cCR patients and as salvage treatment. RESULTS: Following 3 CMV cycles, 29 patients (81%) responded (20 cCR and 9 cPR) and 7 (19%) did not (NR). Currently, with a median follow-up of 23.5 months (13-59), 13 have died and 23 are alive, 12 of whom retain their bladders. The projected overall survival is 51% at 4.5 years. Grade 3-4 hematological toxicity was presented in 8% of the cycles. No toxic deaths were observed. CONCLUSION: The CMV regimen, after TUR, produces a high response rate with tolerable toxicity. Bladders could be preserved in half of the CR patients.     

Combined irradiation and chemotherapy using ifosfamide, cisplatin, and etoposide for children with medulloblastoma/posterior fossa primitive neuroectodermal tumor--results of a pilot study

Ten children with newly diagnosed medulloblastoma/primitive neuroectodermal tumor of the posterior fossa were treated with total surgical resection, radiation therapy, and ICE chemotherapy regimen with ifosfamide (900 mg/m2, days 1-5), cisplatin (20 mg/m2, days 1-5), and etoposide (60 mg/m2, days 1-5) every 4 weeks for eight cycles. Four children under 2 years old were at first treated with eight cycles of ICE chemotherapy, and then irradiated. The ICE regimen was well tolerated by all children, with no irreversible adverse effects. However, dose reductions during the eight cycles were inevitable mainly due to myelosuppression. Complete remissions were achieved in eight of 10 patients at 1 month after completion of the treatment. One child showed recurrence 21 months after complete remission. The disease-free survival rate was 70% with a mean observation period of 24 months after surgery. The ICE regimen is a useful treatment modality for children with medulloblastoma. Further study is warranted to clarify long-term outcome in a number of patients.     

Escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced urothelial carcinoma: an Eastern Cooperative Oncology Group trial

PURPOSE: This multicenter cooperative group phase I/II trial evaluated the toxicity and efficacy of escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: From November 1990 through October 1991, 35 patients with advanced urothelial cancer previously untreated with chemotherapy were treated with escalated dosages of M-VAC (M-VACII). In patients with prior pelvic radiotherapy, standard M-VAC (M-VACI) was administered plus rhG-CSF. For other patients, M-VACII dosages were methotrexate 40 mg/m2 (days 1, 15, and 22), vinblastine 4 mg/m2 (days 2, 15, and 22), doxorubicin 40 mg/m2 (day 2), and cisplatin 100 mg/m2 (day 2). In addition, rhG-CSF was administered at a dosage of 300 micrograms subcutaneously on days 4 to 11. Cycles were repeated every 4 weeks. For patients who tolerated the first course of therapy, subsequent escalation by 25% of all drugs was performed. RESULTS: Six complete responses and 15 partial responses were observed (60%; 95% confidence interval, 42% to 76%). The median duration of response was 4.6 months, and the median survival time was 9.4 months (range, 0.5 to 23.5+). Twenty-eight of 35 patients experienced grade 3 or 4 leukopenia, including 14 patients who developed fever associated with neutropenia. Eight (23%) early deaths were observed. CONCLUSION: This regimen (M-VACII) with escalated dosages of M-VAC was associated with significant toxicity and had no apparent benefit over M-VACI therapy with regard to complete response rate or survival. Further evaluation of the dose-intensity of the components of this regimen in this disease is likely to be of limited benefit to patients.     

Combined radiation therapy and cisplatin for locally advanced carcinoma of the urinary bladder

BACKGROUND: This study evaluates feasibility and results of combined treatment of cisplatin and radiation therapy for patients with inoperable invasive bladder carcinoma. METHODS: From January 1988 to October 1991, 69 patients received radiation therapy and concomitant cisplatin. Median age was 71 years. Most tumors were locally advanced and high grade. A macroscopically complete transurethral resection was performed initially in 18 patients. Dose of pelvic radiation ranged from 40 Gy to 45 Gy, and total dose to the bladder ranged from 55 Gy to 60 Gy. Concomitant continuous cisplatin infusion at a dose of 20-25 mg/m2/day for 5 days was delivered during the 2nd and 5th weeks of radiation. RESULTS: As of April 1993, the median follow-up time was 36.4 months (range, 18-70 months). Ninety-one percent of the patients completed radiation therapy as planned, and 78.3% completed two courses of chemotherapy. Despite one treatment-related death due to renal failure, toxicity was generally mild and acceptable. Sixty-three patients were evaluable for response. Forty-eight patients (76.2%) achieved a complete response. Actuarial overall 3-year survival rate was 37.1% for all patients. Among the patients who experienced complete response, the 3-year actuarial local control and disease-free survival rates were 65.4% and 56.3%, respectively. Twenty-six patients (37.7%) are alive and disease-free with bladder preservation. One patient is alive and disease-free after salvage cystectomy. CONCLUSIONS: Concomitant cisplatin and radiation therapy offers high probability of complete response and local control in patients with invasive bladder cancer unsuitable for surgery. These results provide a basis for randomized studies comparing this approach with conventional therapy for patients with operable carcinoma.     

Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.     

Combination chemotherapy with cisplatin-vinblastine in malignant mesothelioma

From June 1985 to March 1993, 20 consecutive patients with histologically proven malignant mesothelioma were treated with cisplatin 100 mg/m2 i.v. infusion on day 1 and vinblastine 6 mg/m2 i.v. on day 1 and 8. Treatment was repeated every 4 weeks until progression. All patients were evaluated clinically and by CT-scan and were staged (Stage IV), according to Butchard's criteria, on entry to the study. None had prior surgical excision. Eighty-one chemotherapy cycles were administered to 20 patients. One complete response, four partial responses, nine stable diseases and six progressions were noted. One partial responder entered complete response following an operation. Toxicity was acceptable and no treatment-related deaths occurred. The median survival for responders was 19.3 months; for patients with stable disease 15.7 months and for non-responders, 5.2 months. The mean duration of response was 13 months. We conclude that for this small group of patients, the combination cisplatin-vinblastine is effective, with acceptable toxicity in malignant mesothelioma. Further study with a larger number of patients is necessary.