Clinical and pathological evaluations of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) chemotherapy for advanced urothelial cancers

Fifteen patients with advanced transitional cell carcinoma of the urothelial tract were treated with methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy. Eleven patients were treated to metastatic lesions after surgical resection of primary cancers. One out of 15 patients died of chemotherapy. Of the remaining 14 patients, CR was achieved in one and PR was achieved in seven, clinically. The response rate was 57.1% and the median response duration was 12.6 months. In the patients who had been resected their primary lesions, the response rate was 70% and the duration was 14.1 months. Six patients, including five PRs and one NC, underwent surgical resection and re-staging of the residual tumors after chemotherapy. Clinical response coincided with pathological one in all 6 cases. Three patients were observed the decrease of the lung metastasis, which rate was more than 90%. Two out of 3 who did not show any invasion into the lymph channels in the resected residual tumors, have been free of a recurrence through-out the course of at 47 or at 42 months. However, another patient with lymph channel invasion died of metastasis of the mediastinal and paraaortic lymph nodes. Regarding the frequency of side effects, it seemed to be no significant difference between full and 80% doses administration. In the effectual cases, the residual tumors should be resected surgically and re-staged pathologically.     

Responses to chemotherapy or chemohormonal therapy in advanced breast cancer patients treated previously with adjuvant chemotherapy. A subset analysis of CALGB Study 8081

The Cancer and Leukemia Group B (CALGB) evaluated the response to subsequent chemotherapy or chemohormonal therapy in 46 patients with advanced breast cancer treated previously with adjuvant chemotherapy that had been completed 6 months or more before protocol entry. The results were compared with 379 patients in the same study who had not received prior adjuvant chemotherapy. The patients were treated with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF), with or without tamoxifen. There was no difference in response rate, response duration, time to treatment failure, or survival between patients who had received prior adjuvant chemotherapy and those who had not. The addition of tamoxifen to CAF failed to enhance response rates or response durations in all subgroups. Women who relapsed 6 months or more after completion of adjuvant chemotherapy did not have inherently drug-resistant tumors. They responded to standard CAF chemotherapy with the same response rate and survival as patients untreated previously with chemotherapy.     

Evaluation of systemic chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin for advanced bladder cancer

In a cooperative study of the Japanese Urological Cancer Research Group for Adriamycin, the usefulness of chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC therapy) in treating advanced or recurrent bladder cancer was examined. Evaluation of the clinical responses obtained in 86 evaluable patients revealed 13 complete responses, 29 partial responses, 4 minor responses, 19 cases of no change, and 21 cases of progressive disease. The overall response rate was 48.8% (42/86). The rate of response to M-VAC therapy at each disease site was as low as 21.4% (3/14) in bone lesions but exceeded 40% in the primary lesion, the lymph nodes, the lung, the liver, and other lesions. The clinical response to M-VAC therapy was not significantly influenced by the performance status of the patients, the dose intensity, or previous therapy. The median duration of response for the 42 responders was 22.7 weeks (range, 8.1–134.1 weeks), and the median duration of survival for the 86 evaluable patients was 9.8 months. Side effects were frequently encountered; the patients experienced anorexia, nausea, vomiting, malaise, alopecia, and leukopenia, but all of these symptoms were tolerable.Presented at the 4th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 16–17 November 1990, Osaka, Japan     

The effect of dose intensity on M-VAC therapy for advanced urothelial cancer

M-VAC therapy (methotrexate, vinblastine, Adriamycin, and cisplatin) has improved the treatment results of urothelial cancer patients. However, it is sometimes complicated by drug toxicities, including bone marrow suppression. We analyzed the relative dose intensity in each patient undergoing M-VAC chemotherapy in relation ot the chemotherapeutic effect and survival. In addition, the role of granulocyte colony-stimulating factor (G-CSF) in the dose intensity of M-VAC therapy was analyzed. Between June 1988 and March 1993, 29 patients with advanced urothelial cancer were treated with M-VAC therapy in our institution. Of 18 patients with evaluable lesions, 2 (11.1%) showed a complete response (CR) and 7 (38.9%) showed a partial response (PR), and the overall response rate was 50.0%. The median follow-up period for these 18 patients was 14.6 months and the median survival was 8.7 months, with 12 of the 18 patients being alive at the time of analysis. The relative dose intensity (RDI) for these 18 patients was 0.81 for methotrexate, 0.80 for vinblastine, 0.92 for Adriamycin, and 0.91 for cisplatin, for a mean RDI of 0.87. There was no correlation between the chemotherapeutic effect and the RDI. When we calculated the RDI for all 29 patients who underwent M-VAC therapy, G-CSF increased the RDI of Adriamycin significantly. The results of this retrospective study indicate that a dose intensity for M-VAC therapy in the range of 0.61–1.00 is unlikely to correlate with the chemotherapeutic effect, although G-CSF contributes to increasing the RDI of Adriamycin.Paper presented at the 5th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 24–25 September 1993, Hakone, Japan     

Cisplatin-based chemotherapy for the treatment of advanced transitional-cell carcinoma of the urinary tract — a preliminary report

The CMV (cisplatin, methotrexate, and vinblastine) and M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimens were used to treat 19 patients with advanced transitional-cell carcinoma (TCC) of the urothelial tract. In the CMV group, the partial response rate was 45.5% and the mean response duration was 6.3 months. No complete response was obtained in our series. The median duration of survival was 15.8 and 8.3 months in responders and nonresponders, respectively. The toxic symptoms included one case of sepsis and three cases of renal toxicity. However, nausea and vomiting were experienced by most patients and required the administration of antiemetics. In the M-VAC group, the median duration of survival for responders was longer than that of nonresponders (>10.2 vs 7.2 months), although the number of patients was too small for this difference to reach statistical significance. The toxic symptoms included one case of sepsis, two cases of renal toxicity, and nausea and vomiting in most patients. Bone metastasis in three patients did not respond to chemotherapy (CMV), a finding that is compatible with the results reported by other investigators. In summary, chemotherapy with the CMV or M-VAC regimen was effective in improving the response rate of patients. However, the duration of response was short, toxicity was severe in some cases, and the efficacy against bone lesions was poor. These problems must be solved to improve the outcome of patients with TCC following chemotherapy with the CMV or M-VAC regimens.Presented at the 4th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 16–17 November 1990, Osaka, Japan     

Chemotherapy with cisplatin, epirubicin and docetaxel in transitional cell urothelial cancer. Phase II trial

Cisplatin (CDDP), epirubicin (EPI) and docetaxel have single agent activity against urothelial transitional cell carcinoma (TCC). We evaluated the efficacy and toxicity of this combination in locally advanced or metastatic urothelial TCC. Patients with urothelial TCC who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for entry the study. Eligibility criteria were performance status 0-3, granulocyte count (AGC) > or = 1.5 (10(9)/l), platelet count > or = 100 (10(9)/l), clearance creatine > or = 60 ml/min and total bilirubin level < or = 1.5 mg/dl. Treatment consisted of EPI 40 mg/m2 intravenous push, docetaxel 75 mg/m2 in 1 h infusion with premedication and CDDP 75 mg/m2 with pre- and posthydration. Treatment was repeated every 21 days. Antiemetics with dexamethasone and 5-HT3 antagonists were used routinely. Prophylactic haematopoietic growth factors were not used. Patients were evaluated for toxicity weekly and assessed for response every two cycles of treatment. 32 patients were entered into the study and 30 patients (7 with locally advanced and 23 with metastatic disease) were assessable for response. There were 9 (30.0%) complete responses (2, 28.6% in locally advanced and 7, 30.4% in metastatic disease) and 11 (36.7%) partial responses (3, 42.9% in locally advanced and 8, 34.8% in metastatic disease) with an overall response rate (RR) of 66.7% (71.5% in locally advanced, 65.2% in metastatic disease). Overall median survival was 14.5 months (15 months for locally advanced, 12.5 months for metastatic disease). The median duration of response in patients with metastatic disease was 8.5 months. 16 (53.3%) patients required one dose reduction and 5 (16.7%) patients required two dose reductions for a nadir AGC < or = 500/mm3. Four episodes of febrile neutropenia and sepsis occurred. No patient had a dose reduction or treatment delay for any other grade 3/4 toxicity. There were no treatment delays due to myelotoxicity. Alopecia was universal. Non-haematological toxicity including mucositis, fluid retention, allergy, cutaneous toxicity, diarrhoea and neurotoxicity were mild and infrequent. The combination of EPI, docetaxel and CDDP is an active regimen for urothelial TCC. The response rate and toxicity were comparable with the M-VAC (methotrexate, vinblastine, doxorubicin, cisplastin) regimen. Phase III trials comparing this regimen with M-VAC are warranted.     

Escalated M-VAC chemotherapy and recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) in patients with advanced urothelial tract tumors

BACKGROUND:: The M-VAC regimen (methotrexate, vinblastine, adriamycin, andcisplatin) has significant antitumor activity in patients withadvanced urothelial tract cancer. Growth factors may providethe possibility of treating patients with higher doses of chemotherapy,for longer periods, with less morbidity, and improved results.A trial of an escalated dosage of M-VAC with recombinant GM-CSF(rhGMCSF) was initiated. PATIENTS AND METHODS:: 23 patients were treated with an escalated dose of M-VAC every2 weeks plus rhGM-CSF 250 micrograms/m² s.c. days 4–10.Dose level I (n = 13) was 1.65 times the dose of standard M-VAC.Adriamycin and cisplatin were given at 2.5 times the dose ofstandard M-VAC. Dose level II (n = 10) was a relative dose intensityof 1.95. Adriamycin and cisplatin were both given at 2.9 timesthe dose. CONCLUSIONS:: The response rate was 70% (95% CI 60%- 80%). Seven patients(30%) had CR, and 9 (39%) had a PR. Five (22%) patients hadstable disease and 2 (9%) had progression. Of the CR patients,3 had the CR confirmed pathologically (CRp). Response occurredin 11 patients treated at dose level I and 5 at dose level II.Toxicity was primarily hematologic. Dose level II was too toxicdue to thrombocytopenia. Non-hematologic toxicity was minimal.The value of this schedule (dose level I) compared to standardM-VAC will be further evaluated in a randomized trial to beinitiated by the Genitourinary Group of the EORTC. chemotherapy, colony stimulating factors, M-VAC, rhGM-CSF, urothelial tract tumors     

Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89.

PURPOSE: To evaluate a multimodal approach including surgery and cisplatinum chemotherapy for treatment of children with malignant sacrococcygeal germ cell tumors (GCT) and to compare adjuvant and neoadjuvant strategies in advanced tumors. PATIENTS AND METHODS: Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for nontesticular GCT Maligne Keimzelltumoren 83/86 and 89. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2) or who did not undergo tumor resection (n = 1) were excluded from this analysis. Among the 66 patients analyzed were 14 boys and 52 girls. The median age was 17.4 months (range, 7 months to 119 months). Median follow-up was 79 months (range, 4 months to 145 months). RESULTS: Fifty-two patients presented with locally advanced stage T2 tumors, and 30 patients had distant metastases at diagnosis. Patients received a median of eight cycles (range, four to nine cycles) of cisplatinum-based chemotherapy. Thirty-five patients underwent tumor resection at diagnosis and received adjuvant cisplatinum-based chemotherapy (group A). Thirty-one patients received up-front chemotherapy followed by delayed tumor resection (group B). Group B included more metastatic tumors than group A (group B, 19 of 31 patients; group A, 11 of 35 patients, P =.01). Preoperative chemotherapy facilitated complete tumor resections (group B, 20 of 31 patients; group A, five of 35 patients, P <.001) and avoided second-look surgery. Metastases at diagnosis and completeness of the first attempt of tumor resection were significant prognostic predictors; however, metastases were not predictive for patients treated with up-front chemotherapy. At 5 years follow-up, event-free survival was 0.76 +/- 0.05 (50 of 66 patients), and overall survival was 0.81 +/- 0.05 (54 of 66 patients). Four patients died as a result of therapy-related complications, and eight patients died of their tumors. Patients with locally advanced and metastatic tumors (T2b M1) fared better with neoadjuvant treatment [overall survival: 0.83 +/- 0.09 (16 of 19 patients) versus 0.45 +/- 0.15 (five of 11 patients), P =.01]. CONCLUSION: Even locally advanced and metastatic sacrococcygeal GCT can be successfully treated with up-front cisplatinum-based chemotherapy followed by delayed but complete tumor resection.     

Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse

Of 133 patients with advanced urothelial tract cancer given methotrexate (MTX), vinblastine (VBL), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (DDP) (M-VAC regimen), significant tumor regression occurred in 72% +/- 8% of 121 with transitional cell carcinoma (TCC) evaluable for response. Complete remission (CR) was achieved in 36% +/- 9% of patients, of whom 11% required the addition of surgical resection of residual disease. Although 68% of CR patients have relapsed, CR median survival will exceed 38 months compared with 11 months for partial (36%) and minor (6%) responders, and 8 months for nonresponders: 2-year and 3-year survivals were 68% and 55%, respectively, versus 0% to 7% for the remaining patients. Sixteen percent of responders developed brain lesions, half of whom had no systemic relapse at the time of progression. Three patients with non-TCC histologies did not respond. In 32 patients who had pathologic restaging, the clinical (T) understaging (T less than pathologic [P] restaging) error was 35%. Although all metastatic sites showed evidence of tumor regression, CR was noted more frequently in lung, in intraabdominal lymph nodes and masses, and in bone (24% to 35%); the rate for hepatic lesions was 15%. There were 52% of 21 N3-4M0 patients who achieved CR versus 33% of 100 with N0-+M+ lesions. Toxicity was significant with 4 (3%) drug-related deaths, 25% incidence of nadir sepsis, 58% greater than or equal to 3+ myelosuppression, and 49% with mucositis. Responsiveness of metastasis in various sites, patterns of relapse, and the usefulness of the new CR response criteria are reported, as is the current status of cisplatin and methotrexate combination regimens.     

Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer.

PURPOSE: Previously, we developed a novel biochemotherapy regimen combining interferon alpha-2b with fluorouracil and cisplatin (FAP). We now report the results of a prospective randomized trial comparing FAP with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), the standard chemotherapy regimen for locally advanced and metastatic urothelial cancer. The purpose of this study was to compare the response rates and overall survival of patients with metastatic or unresectable urothelial cancer treated with these two chemotherapy regimens. PATIENTS AND METHODS: Between October 1992 and September 1999, 172 previously untreated patients were registered and randomly assigned to treatment with either FAP or M-VAC. Patients were followed until their death. RESULTS: The pretreatment clinical characteristics of the groups were similar except for sex (P <.01). Sex did not affect prognosis or survival. The objective response rate for patients assigned to FAP was 42% (35 of 83 patients), with complete response observed in eight (10%) of 83 patients. Among the patients assigned to M-VAC, 51 (59%) of 86 had an objective response, with complete response observed in 21 (24%) of 86. The Kaplan-Meier estimate of median survival was 12.5 months for both groups. Both regimens were quite toxic, with more mucocutaneous toxicity in the FAP arm and more myelosuppression in the M-VAC arm. CONCLUSION: Although overall survival was not significantly different, patients assigned to M-VAC had a much better chance of responding to front-line therapy. Thus, FAP is very likely to be inferior to M-VAC and is certainly no less toxic. FAP cannot be recommended as part of the standard armamentarium for urothelial cancer.     

A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors

To evaluate the relative efficacy of cisplatin, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (CISCA) versus methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), a prospective randomized trial was performed in patients with advanced metastatic urothelial tumors. Patients were stratified by histologic disease type and degree of tumor dissemination. Equal distribution of the clinical characteristics was achieved. One hundred ten patients with metastatic disease of the urinary tract (86 bladder, 16 renal pelvis, seven ureter, one prostatic urethra) met eligibility criteria and were enrolled on study. These represented 82% of the total patients seen during the study period in the Section of Genitourinary Oncology who met the eligibility criteria. The combined complete and partial response rate was significantly higher for patients treated with MVAC than for those treated with CISCA (65% v 46%; P less than .05). The survival duration of MVAC-treated patients was significantly longer than that of CISCA-treated patients (mean, 62.6 weeks; median, 48.3; range, 5.0+ to 162.3+ v mean, 40.4 weeks; median, 36.1; range, 7+ to 147.1+). We conclude that MVAC chemotherapy is superior to CISCA chemotherapy, achieving a higher response rate and a longer survival for equivalent patients with metastatic urothelial tumors.     

Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma.

PURPOSE: The role of postchemotherapy surgery for patients with metastatic transitional cell carcinoma (TCC) is controversial. We retrospectively analyzed our experience with patients who underwent postchemotherapy surgery after methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy to assess an impact on long-term survival. PATIENTS AND METHODS: This report is based on the retrospective analysis of 203 patients with unresectable primary tumors or metastatic TCC, previously reported in five trials of M-VAC chemotherapy. Fifty patients underwent postchemotherapy surgery for suspected or known residual disease. Characteristics of patients selected for surgery, results of surgery, and the impact of surgery on survival were assessed. RESULTS: In 17 patients, no viable tumor was found at postchemotherapy surgery, pathologically confirming a complete response to chemotherapy. Three patients had unresectable residual TCC. In 30 patients, residual, viable TCC was completely resected, which resulted in a complete response to chemotherapy plus surgery. Ten (33%) of these 30 patients remained alive at 5 years, similar to results observed for patients who attained a complete response to chemotherapy alone (41%). Analysis by baseline extent of disease suggested that patients with unresectable primary tumors or with metastases restricted to lymph node sites were most likely to survive for 5 years. CONCLUSION: Postchemotherapy surgical resection of residual cancer may result in 5-year disease-free survival in some patients who would otherwise succumb to disease. Optimal candidates include patients whose prechemotherapy sites of disease are restricted to the primary or lymph node sites and who have a major response to chemotherapy.     

Paclitaxel and carboplatin in bladder cancer: recent developments

Paclitaxel demonstrates significant single-agent activity in advanced urothelial carcinoma. Paclitaxel/carboplatin is an active and tolerable outpatient chemotherapy treatment regimen for these patients. This regimen has been studied in several phase II trials with response rates ranging from 14 to 65%. Paclitaxel/carboplatin may be considered in patients with advanced urothelial cancer and renal insufficiency, and a recent Eastern Cooperative Oncology Group (ECOG) phase II trial investigates this regimen specifically in this patient population. Ongoing ECOG trials are comparing paclitaxel/carboplatin with M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) in both the advanced disease and adjuvant settings.     

Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy.

BACKGROUND: An every-2-week regimen of gemcitabine and paclitaxel was adapted for patients with advanced transitional cell carcinoma (TCC) who had received prior cisplatin-based chemotherapy. METHODS: Forty-one patients with advanced or metastatic TCC who had received prior cisplatin-based systemic chemotherapy were treated with an outpatient regimen of gemcitabine 2500-3000 mg/m(2) and paclitaxel 150 mg/m(2) every 2 weeks. RESULTS: Forty of 41 patients had measurable disease. Response was observed in 24 patients (60%; 95% confidence interval [CI], 45-75%). Eleven (28%) achieved complete response, and 13 (33%) obtained partial response. Twenty of 25 patients (80%; 95% CI, 64-96%) who had been previously treated in the neoadjuvant or adjuvant setting responded versus 4 of 15 (27%; 95% CI, 5-49%) in patients who received prior methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) for metastatic disease. The median duration of survival for patients given gemcitabine and paclitaxel after failing neoadjuvant or adjuvant M-VAC was 12 months (range, 2-43+), as compared with only 8 months (range, 2-28) for patients who had been treated after failure of prior therapy for metastatic disease. For all patients, the median duration of response was 6.4 months (range, 2-43.3+ months), and the median survival was 14.4 months (range, 2-43+). Thirteen patients (32%) developed World Health Organization Grade 3-4 neutropenia, with febrile neutropenia in 3 (7%) patients. Granulocyte colony-stimulating factor was given to 10 (24%) patients. There was no Grade 3-4 anemia or thrombocytopenia. CONCLUSIONS: The combination of gemcitabine and taxol in previously treated patients with recurrent TCC is highly effective and produces objective durable responses. This every-2-week schedule is a well tolerated outpatient regimen with minimal toxicity.     

Fluorouracil and recombinant human interferon alfa-2a in the treatment of metastatic chemotherapy-refractory urothelial tumors

Thirty patients with advanced metastatic and chemotherapy-refractory urothelial tumors received a combination of fluorouracil (5-FU) and recombinant human interferon alfa-2a. Thirty-six sites of metastases were present in the 30 study patients, and the median Eastern Cooperative Oncology Group performance status was 3 (range, 1 to 4). All patients had failed to respond to primary combined methotrexate/cisplatin-based chemotherapy. Nine (30%; confidence interval, 15% to 47%) of the patients achieved a partial response. The mean duration of response was more than 5.2 months (median, 6 months; range, 3 to 8 months). Two patients who achieved a partial response of 5 and 7 months' duration, respectively, had control of residual disease (one with radiation and one with surgical excision) and have remained disease-free for an additional period of more than 7 and 13 months, respectively. These data suggest that the combination of 5-FU and recombinant human interferon alfa-2a is synergistic, with clinical significance for the treatment of urothelial tumors. The response rate for this combination of drugs is higher than that anticipated for either of these agents used alone. Additional confirmatory trials are needed to evaluate the significance of these findings.     

Results of adjuvant chemotherapy for invasive urothelial cancer with lymph-node metastasis

From 1980 to 1991, 59 patients with advanced urothelial cancer (pathological stage, >pT3) underwent radical operations. Of these 59 patients, 33 had nodal involvement. This study focused on those 33 patients with nodal involvement. The primary site was the urinary bladder in 20 patients and the upper urinary tract (renal pelvis and/or ureter) in 13. In all, 13 patients underwent adjuvant chemotherapy with an M-VAC or M-VEC [methotrexate (M), vinblastine, doxorubicin (ADM) or epirubicin, and cisplatin (CDDP)] regimen, and another 8 patients were treated with other insufficient chemotherapies [CDDP+ADM or CDDP+ADM_etoposide (VP-16)]. A group of 12 patients did not receive any additional treatment. Most of the patients in the M-VAC and M-VEC groups received more than 2 cycles of the regimen (median, 3.2 cycles; range, 1–9 cycles). The overall 5-year survival rate of the M-VAC and M-VEC group was 31%, whereas the rate was 0 for the other insufficient-chemotherapy groups and the no-chemotherapy group. Of the 13 patients in the M-VAC group, 4 (31%) patients were alive without disease progression and 9 (69%) were dead due to progressive disease. In the other groups, only I patient was alive without progression. Our results suggest that adjuvant M-VAC or M-VEC chemotherapy may extend the median survival of patients with advanced urothelial cancer, but it failed to reduce the rate of cancer death.Paper presented at the 5th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 24–25 September 1993, Hakone, Japan     

Advanced small cell carcinoma of the bladder. Successful treatment with combined radical cystoprostatectomy and adjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy

Undifferentiated small cell carcinoma of the bladder is a rare tumor with pathologic features similar to those of oat cell carcinoma of the lung. This neuroendocrine neoplasm of the bladder has a highly malignant biological behavior; most patients present with either locally advanced or distant metastatic disease and die despite aggressive therapy. Here the histologic, immunocytochemical, and ultrastructural features of small cell carcinoma of the bladder are reviewed in detail. In addition, two patients with advanced small cell carcinoma of the bladder who were treated successfully with radical cystoprostatectomy and adjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy (M-VAC) are presented. Both men had regional lymph node involvement and are disease free at follow-up of 1 year and 2.5 years, respectively. This is the first report of combined surgical and M-VAC chemotherapy in the treatment of undifferentiated small cell carcinoma of the bladder.     

Acute arterial thrombosis after escalated-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy with recombinant granulocyte colony-stimulating factor. A possible new recombinant granulocyte colony-stimulating factor toxicity.

Combination chemotherapy with a regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) has produced long-term survival times in a significant proportion of patients with advanced nodal and metastatic urothelial tumors. The availability of the colony-stimulating factors has spurred interest in studies evaluating escalated dosing schedules of M-VAC in an attempt to improve major response rates and overall survival. More frequent use of the colony-stimulating factors, however, in this and other settings may be associated with unrecognized side effects. The authors report a case of arterial thrombosis in a 69-year-old man receiving recombinant granulocyte colony-stimulating factor (rhG-CSF) and escalated-dose M-VAC for treatment of a transitional cell carcinoma of the bladder. Incidents of venous thrombosis have been reported previously with the use of colony-stimulating factors, but, to the knowledge of the authors, this case represents the first report of an arterial thrombosis occurring in a patient receiving rhG-CSF.     

Combination chemotherapy of advanced breast cancer. Comparison of dibromodulcitol, doxorubicin, vincristine, and fluoxymesterone to thiotepa, doxorubicin, vinblastine, and fluoxymesterone: an Eastern Cooperative Oncology Group Study

Two Adriamycin (doxorubicin)-based chemotherapy regimens were investigated in patients with carcinoma of the breast who had failed prior systemic therapy. The two chemotherapy programs, dibromodulcitol, Adriamycin, vincristine, and Halotestin (fluoxymesterone) (DAVH), and thiotepa, Adriamycin, vinblastine, and Halotestin (TAVH), were chosen for comparison on the basis of reported response rates of 40% to 50% with remission durations of 11 months in patients refractory to other cytotoxic chemotherapy. Cycles of DAVH were repeated every 4 weeks. Cycles of TAVH were repeated every 3 weeks. Of 184 patients evaluable for response, 32% of patients treated with DAVH and 38% of patients treated with TAVH had a complete response (CR) or partial response (PR). An additional 5% of patients had nonmeasurable improvement in osseous disease for an overall rate of response (CR + PR + improvement) of 40%. Patients who had previously received cytotoxic chemotherapy for metastatic disease or had early failure after adjuvant therapy had a lower response rate to DAVH, but not to TAVH than those who did not fail prior chemotherapy. Duration of response and survival were similar with the two treatments. There were seven treatment-related deaths, five among patients receiving DAVH and two among patients receiving TAVH. Patients receiving DAVH had significantly more thrombocytopenia and neurologic toxicity than those receiving TAVH. These treatments appear to be reasonable second-line regimens and are good candidates to be used in initial therapy of metastatic disease or adjuvant therapy studies that explore the use of alternating non-cross-resistant combinations with cyclophosphamide, methotrexate, and 5-fluorouracil.     

Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy

We investigated the safety and efficacy of a methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) combination regimen as second-line chemotherapy for patients with advanced or metastatic transitional cell carcinoma who failed first-line gemcitabine and cisplatin (GC) chemotherapy. Thirty patients who had progressed or relapsed after GC chemotherapy as first-line treatment were enrolled in this study. The major toxicities were neutropaenia and thrombocytopaenia. A grade 3 or 4 neutropaenia occurred in 19 (63.3%) and a grade 3 or 4 thrombocytopaenia developed in nine patients (30.0%). There were no life-threatening complications during the study. The overall response was 30%. A complete response was achieved in two patients (6.7%) and a partial response in seven (23.3%). The overall disease control rate was 50%. Seven out of 16 patients who had responded previously to GC responded to M-VAC, while 2 out of 14 who had not responded to GC responded to M-VAC. The median response duration was 3.9 months and the median progression-free survival was 5.3 months. The median overall survival was 10.9 months. M-VAC showed encouraging efficacy and reversible toxicities in patients who had progressed after GC chemotherapy and, especially, M-VAC appears to be a reasonable option as a sequential treatment regimen in patients who responded previously to GC chemotherapy.