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

Abstract

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% f 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 a t 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 < pathologic [PI 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 NS4& patients who achieved CR versus 33% of 100 with No.+M+ lesions. Toxicity was significant with 4 (3%) drug-related deaths, 25% incidence of nadir sepsis, 58% 2 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.Cancer 64:2448-2458, 1989. noma (TCC), complete remission (CR) was achieved in 37% of patients, with 55% alive from 26+ to 49+ months, and partial remission (PR) in 3 1 % of patients. The current Phase I1 study reports the experience of the first 3 years with a follow-up of a minimum of 3 years from patient entry (median follow-up is 54 months), the responsiveness of the primary tumor and metastases at different sites, the relapse patterns, and the accuracy of clinical staging. In 46 cases, serum MTX levels obtained on day 2 were within the expected range.'Patients were hospitalized for 3 to 5 days of each monthly cycle (Table 1) for diagnostic tests and hydration with D5 1/2NS with potassium supplement to assure a urinary output of >lo0 ml/h, and until the blood urea nitrogen (BUN) and creatinine (Cr) returned to pretreatment values. Generally, DDP was given with antiemetics and 12.5 g mannitol. ADR was reduced to 15 mg/m2 in patients who had irradiation equivalent to >20 Gy in 5 2448

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer

“…The median survival time for combination regimens (e.g. methotrexate þ vinblastine, or doxorubicin þ cisplatin) is approximately 8 months (Sternberg et al, 1989). It is known that pretreatment prognostic features have an impact on individual patient outcome, thus the variation in reported survival in patients treated with chemotherapy may be biased by these features (Bajorin et al, 1999;Calabro and Sternberg, 2002).…”

Gemcitabine plus epirubicin in patients with advanced urothelial carcinoma who are not eligible for platinum‐based regimens

“…4,5 However, this regimen has substantial side effects that can be life threatening: Nausea/emesis, neutropenia, neutropenic fever, mucositis, and renal insufficiency have been reported in a significant proportion of patients, with some toxic deaths reported. 3,4,6 In a recently published trial, a reduced incidence of hematologic and nonhematologic toxicities was reported with the gemcitabine-cisplatin combination compared with M-VAC, although only patients with a good PS and normal renal function were included. 18 New combination regimens have been tested in Phase II studies.…”

“…However, very few patients are long-term survivors, 6 and the toxicities are significant: Grade 3-4 nausea and emesis, 12%; Grade 3-4 neutropenia, 24 -58% (with febrile neutropenia in 10 -25% of patients); severe mucositis, 13-17%; renal failure, 7%; and toxic deaths, 3%. 3,4 New agents, including gemcitabine, [7][8][9][10] paclitaxel, 11 and docetaxel, 12 have shown activity in patients with bladder and urinary tract transitional cell carcinomas. In Phase II trials, gemcitabine has been combined successfully with cisplatin, [13][14][15] paclitaxel, 16 and paclitaxel plus carboplatin, 17 producing interesting response rates and median survivals.…”

Survival of patients with advanced urothelial cancer treated with cisplatin-based chemotherapy

“…Anti-tumour activity has been demonstrated with several single agents, but does not prolong survival. Cisplatin-based combination chemotherapy leads to response rates between 35% and 70% and is more effective than cisplatin alone (Sternberg et al, 1989;Harker et al, 1985;Foss'a et al, 1982;Loehrer et al, 1992). Typically, the response rates from single institution studies are superior to those from multicentre trials.…”

“…Typically, the response rates from single institution studies are superior to those from multicentre trials. Prolonged survival has been reported in patients who achieve complete response (CR) (Logothetis et al, 1985;Stoter et al, 1987;Sternberg et al, 1989). Systemic cisplatin-based combination chemotherapy can be toxic, particularly in elderly patients.…”