Alan Yagoda

Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium

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.

M-Vac (Methotrexate, Vinblastine, Doxorubicin and Cisplatin) for Advanced Transitional Cell Carcinoma of the Urothelium

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.

A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors.

Standard chemotherapy for disseminated germ cell tumors (GCT) cures most patients but causes considerable acute toxicity, including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis. In addition, chronic and delayed toxicities, particularly Raynauds phenomenon, have been reported in 6% to 37% of treated patients. In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin, a randomized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin (VAB-6) and etoposide + cisplatin (EP) was conducted on 164 eligible patients with good-prognosis GCT. Seventy-nine of 82 (96%) patients receiving VAB-6 and 76/82 (93%) receiving EP achieved a complete remission (CR) with or without adjunctive surgery. Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma. With a median follow-up of 24.4 months in the VAB-6 arm and 25.9 months in the EP arm, the total, relapse-free, and event-free survival distributions were similar in the two arms. Patients receiving EP experienced less emesis (P = .05), higher nadir WBC (P = .06) and platelet counts (P = .01), less magnesium wasting (P = .0001), less mucositis (P = .09), and no pulmonary toxicity. No treatment-related mortality was observed. EP is an efficacious and less toxic regimen and is recommended for good-prognosis patients with disseminated GCT.

Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin)effect on the primary bladder lesion

Of 50 patients with bladder cancer given 1 to 5 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin in a pilot phase I and II study 63 per cent of 41 with pure transitional cell stage T2-4 lesions responded. While significant downstaging occurred by transurethral resection of the bladder in 70 per cent and by cytology in 60 per cent of the patients, the final T response rate by all noninvasive clinical staging procedures, including sonography and computerized tomography, revealed complete remission in 24 per cent and partial remission in 39 per cent. Of 30 patients who underwent pathological staging 33 per cent achieved stage P0 and 17 per cent stage Tis disease or P less than T. Despite extensive re-evaluation by transurethral resection of the bladder and other noninvasive staging procedures, a clinical staging error (T versus P) of 38 per cent was observed. Of the other 9 patients 4 with mixed nontransitional cell histological findings at presentation never achieved complete remission, although 3 had resolution of all transitional cell elements and 5 (10 per cent) were inevaluable. The toxicity of the regimen was generally acceptable but 6 per cent of the patients required hospitalization for neutropenic fever. While this active regimen can clinically (T) and pathologically (P) induce downstaging in a significant number of patients with primary bladder tumors, this pilot study has raised serious questions concerning the design of future nonrandomized and randomized neoadjuvant studies.

Chemotherapy of malignant hemangiopericytoma.

Thirty‐nine chemotherapy trials in 16 patients with metastatic hemangiopericytoma treated at MSKCC and 33 trials from the literature are reviewed. Adriamycin, alone or in combination drug regimens, is the most effective agent, producing complete and partial remissions in 50% of cases. Other drugs which show some activity include vincristine, cyclophosphamide, actinomycin, methotrexate and DTIC. The available data indicate malignant hemangiopericytoma should be considered chemotherapeutically responsive tumors.

Chemotherapy of urothelial tract tumors

Recent data from Phase II trials in patients with advanced transitional cell carcinoma of the urothelial tract suggest combination chemotherapy regimens are inducing a higher number of complete remissions (CR), and an overall response rate between 50% and 70%. Most active combination regimens are cisplatin + methotrexate based or cisplatin + Adriamycin (doxorubicin) based. As single agents, cis‐platin has a response rate of 30% in 320 patients, methotrexate, 29% in 236 cases, and Adriamycin, 17% in 248 cases. With each drug used singly, however, complete response is uncommon. Other active single agents include vinblastine (16% in 38 cases) and mitomycin C (13% in 42 cases). New agents being evaluated which show some promise include gallium nitrate, carboplatinum, and other antifols. In a trial by the Northern California Oncology Group which evaluated a combination of cisplatin, methotrexate, and vinblastine (CMV), 28% of 50 cases achieved a CR lasting 44 weeks, and 28% a partial remission (PR) sustained for 29 weeks. A limited number of cases required surgical debulking for obtainment of CR status. At the University of Michigan, a trial of cisplatin and dichloromethotrexate induced responses in over 60% of cases. The regimen of methotrexate, vinblastine, Adriamycin, and cisplatin (M‐VAC) has been reported to induce CR in 37% of cases, and PR in an additional 31%. In the latter trial at Memorial Hospital in over 100 cases with bidimensionally measurable advanced disease, the median survival of CR has not yet been reached at 28 months, whereas those who achieve PR survive 12 months versus 6 months for nonresponders. Indirectly, the success of such combination regimens is apparent from the increasing number of central nervous system relapses, without systemic recurrence, in complete responders. Additional data indicate that cisplatin + methotrexate, without the addition of other drugs, is also an active regimen. The attainment of CR in 20% to 40% of cases given these multidrug regimens has led to adjuvant and neoadjuvant protocols. Although results of randomized prospective trials have not yet been reported, preliminary Phase II data are promising.

Chemotherapy of metastatic bladder cancer.

Recent disease‐oriented phase II clinical trials in advanced transitional cell carcinoma of the urothelial tract have defined the therapeutic efficacy of cis‐diamminedichloride platinum II, Adriamycin and methotrexate. Other agents which may have some activity include cyclophosphamide, the podophyllotoxins, hexamethylmelamine, and possibly 5‐flourouracil. While combination drug regimens have been reported to induce higher remission rates when compared to single agents, prospective randomized trials will be needed to document enhanced therapeutic benefit. The problems in selecting appropriate patients and in defining response criteria in clinical trials in urothelial tumors are discussed. Chemotherapy data in the treatment of bladder cancer is summarized, using strict response criteria.

Bone metastases: Pathogenesis, treatment, and rationale for use of resorption inhibitors

Tumors in bone are usually metastatic, with breast, prostate, and lung tumors accounting for more than 80 percent of clinically manifest lesions. Untreated, such metastases can produce the symptoms that most concern cancer patients--pain, pathologic fractures, and paralysis through epidural cord compression. Recent advances in the understanding of the metastatic cascade and the regulation of bone formation and resorption provide unique therapeutic approaches for prevention and treatment of these lesions. This article reviews the prevalence, distribution, diagnosis, and treatment of metastatic cancer in the skeleton, as well as the processes involved in the development of such metastases, the local mediators responsible for some of the destructive changes in bone, and their pathologic results. In addition to considering some of the conventional therapeutic approaches, a rationale for the use of bone resorption inhibitors, such as the diphosphonates (bisphosphonates), is presented for the prevention and amelioration of the pathologic consequences of skeletal metastases.

A critical analysis of response criteria in patients with prostatic cancer treated with CIS-diamminedichloride platinum II

Cis‐diamminedichloride platinum II (DDP), 50–70 mg/m2 iv, q 3w was administered to 25 patients with Stage D adenocarcinoma of the prostate. Since the assessment of tumor regression in a disease‐oriented phase II study demands a clear end‐point of response, case selection was restricted to patients who had objectively measurable lesions, i.e., nodes, skin, lung and liver metastasis. Partial remission occurred in 3 (12%) and stabilization of disease in 1 patient. Responders lived 53 weeks vs. 20 weeks for non‐responders. In the dosage and schedule used in this protocol, DDP was not an active agent in the treatment of prostatic cancer. Various patient characteristics are examined and correlations made between remission rates and survival in this study vs. 4 other response schemata. A critical analysis of patient selection, “lead time”—diagnosis to chemotherapy, and the definitions of the terms “measurable” lesions, “evaluable” parameters, “objective response”, stabilization of disease and response criteria employed in the 4 schemata are also discussed.

Surgical treatment of spinal cord compression in kidney cancer.

Forty-three patients with renal-cell carcinoma underwent treatment for spinal cord compression over a 7-year period. Of these, 32 patients underwent surgery, while 11 patients underwent radiation alone. Before operation, 25 patients had relapsed following prior radiation, while seven others received postoperative radiation. A more aggressive surgical approach, tailored to the site of compression within the spinal canal, was used with the majority undergoing gross total tumor resection by an anterior approach. Immediate stability of the spine was achieved with methyl-methacrylate reconstruction of the resected segments. Preoperative spinal angiography with embolization of hypervascular tumors was carried out in eight patients. Patient parameters in the surgical and irradiated groups were comparable, except that a greater proportion of the radiation alone group had more than one organ system involved (64% v 44%). The median survival of the surgically treated patients was 13 months, compared with 3 months for those treated by radiation alone. In addition, a greater proportion of the surgically treated patients were benefitted neurologically (70%) compared with those treated by radiation (45%). With the development of effective surgical treatment for spinal metastases, early consideration for surgical treatment (before radiation) should be considered in selected patients. Preoperative spinal angiography and embolization are recommended whenever feasible to minimize intraoperative blood loss.