Alan Yagoda

We evaluated the ability of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to prevent chemotherapy-induced neutropenia or to accelerate recovery from this complication and thus allow patients to receive full doses of antineoplastic agents on time, according to protocol design. Twenty-seven patients with transitional-cell carcinoma of the urothelium who were undergoing treatment with methotrexate, doxorubicin, vinblastine, and cisplatin were given rhG-CSF (up to 60 micrograms per kilogram of body weight per day) before their first cycle of combination chemotherapy, during the first cycle, or at both points. Treatment with rhG-CSF before chemotherapy resulted in a dose-dependent increase in the absolute neutrophil count. Treatment with rhG-CSF after chemotherapy significantly reduced the number of days (91 percent) per patient on which the absolute neutrophil count was 1000 per microliter or less (P = 0.0039), reduced the number of days (1 vs. 35) on which antibiotics were used to treat fever and neutropenia, and significantly increased the percentage (100 vs. 29 percent) of patients qualified to receive planned chemotherapy on day 14 of the treatment cycle (P = 0.0015). In addition, the incidence of mucositis was significantly decreased (11 vs. 44 percent, P = 0.041), as was its severity. These findings demonstrate that rhG-CSF is a potent stimulus of normal neutrophil proliferation and maturation. In addition, its administration can reduce both the hematopoietic and oral toxicity of chemotherapy.

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.

The M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) regimen was used to treat 25 patients with transitional cell carcinoma of the urothelial tract. Treatment consisted of monthly cycles of 30 mg. per m.2 methotrexate, followed 24 hours later by 3 mg. per m.2 vinblastine, 30 mg. per m.2 doxorubicin and 70 mg. per m.2 cisplatin, and concluded with repeat vinblastine and methotrexate on days 15 and 22. Significant tumor regression was noted in 71 per cent of the patients. Complete clinical remission was observed in 12 of 24 patients (50 per cent, 95 per cent confidence limits 30 to 70 per cent) with bidimensionally measurable indicator lesions, 6 of whom had pathological confirmation. After surgical exploration 4 patients required downstaging to a partial remission. The median duration of response has not yet been reached at 9.5 plus months, range 4.5 plus to 16 plus. Five patients (21 per cent) had a partial clinical remission for 4 to 8 plus months, 1 had a minor response for 4 months and 1 had stable disease for 11 months. All metastatic sites responded, including bone (6 of 8 cases), liver (3 of 5), locoregional (12 of 17) and intravesical (6 of 7) disease. Toxicity included moderately severe myelosuppression that resulted in nadir sepsis in 4 patients and a drug-related death in 1, mild to moderate anorexia, vomiting, alopecia and renal dysfunction. These preliminary results suggest that treatment with methotrexate, vinblastine, doxorubicin and cisplatin is extremely effective against locoregional and disseminated urothelial tract tumors, with the expectation (95 per cent confidence limits) of inducing objective tumor regression in 53 to 89 per cent of the cases.

Of 92 patients who received methotrexate, vinblastine, doxorubicin and cisplatin complete and partial remissions were observed in 69 +/- 10 per cent of 83 adequately treated measurable and evaluable patients with advanced stages (N+M0 and N0M+) transitional cell urothelial cancer. Complete remission was achieved in 37 +/- 10 per cent of the patients clinically, pathologically and after surgical resection of residual disease. With 17 of 31 complete responders (55 per cent) surviving for 26+ to 49+ months, the estimated probability of survival at 2 and 3 years was 71 and 55 per cent, respectively. Partial remission occurred in 31 +/- 10 per cent of the patients, while 8 per cent had a minor response and 23 per cent had progression with median survivals of 11, 11 and 7 months, respectively. Whereas all metastatic sites responded, including the bone and liver, complete tumor regression was observed more frequently with nodal, pulmonary and local-regional lesions. Brain metastases occurred within 6 to 42 months in 18 per cent of the responders, half of whom never had systemic relapse. Of the remaining 9 patients 2 with nontransitional cell histological tumors did not respond, 5 (5 per cent) were inadequately treated and 2 were excluded from response data because of inevaluable disease parameters but they were free of disease at 16+ and 31+ months. Toxicity was significant, with 20 per cent of the patients experiencing nadir sepsis, 4 per cent a drug-related death, 31 per cent +1 renal toxicity and 41 per cent +1 mucositis. The applications and advantages of the newly proposed international response criteria for bladder cancer are discussed in reference to 25 patients who underwent surgical re-staging, indicating that the disease was understaged clinically in 24 per cent (T less than P), as well as in reference to attainment of true (pathological) complete remission and to other urothelial tract trials. While this therapy seems to have limited antitumor activity against nontransitional cell histological cancer, stage Tis disease and later development of de novo lesions, the regimen is efficacious in selected patients with advanced urothelial tract transitional cell carcinoma.

BACKGROUND: Advanced adenocarcinoma of the prostate after hormonal manipulation has been noted to be a relatively chemotherapeutic nonresponsive tumor. Earlier reviews have reported objective responses, that is, complete and partial remissions in 6.5% of 3184 patients, and the current review examines the efficacy of new agents. METHODS: The current review consists of 26 new drug trials culled from papers and abstracts published between 1987-1991. RESULTS: Results of these 26 drug trials found a similar trend, 8.7% (95% confidence interval, 6.4-9.0%), indicating that hormone-resistant adenocarcinoma of the prostate still fails to respond to most cytotoxic agents. The most interesting of the new therapeutic agents is the combination of vinblastine plus estramustine. Only six agents had an objective response rate greater than 10%, such as vinblastine by continuous infusion, trimetrexate, mitoguazone, and estramustine. The recent introduction of radioactive-labeled monoclonal antibodies is intriguing and these will undoubtably be used as carriers for radiotherapeutic and cytotoxic compounds. CONCLUSIONS: Although multidrug resistance may explain the marginal efficacy of cytotoxic drugs, methods to overcome such resistance and, more importantly, new classes of agents must be developed. In addition, reliable disease markers must be found for osseous and visceral metastases to avoid the prevailing confusion in evaluating more precisely the destruction of prostate cancer cells.