Ronald B. Natale

Surgical Factors Influence Bladder Cancer Outcomes: A Cooperative Group Report

PURPOSEnA randomized, cooperative group trial (Southwest Oncology Group 8710, Intergroup 0080) reported that neoadjuvant chemotherapy improved the survival of patients with locally advanced bladder cancer who were treated with radical cystectomy. We evaluated whether surgical factors from patients enrolled onto the study predicted bladder cancer outcomes.nnnPATIENTS AND METHODSnSurgical and tumor factors were recorded from surgical and pathologic reports from 268 patients with muscle-invasive bladder cancer who received radical cystectomy. Cystectomies were performed by 106 surgeons in 109 institutions. Half of the patients received neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. Variables were tested in univariate and multivariate analyses for associations with postcystectomy survival (PCS) and local recurrence (LR) in all patients receiving cystectomy.nnnRESULTSnFive-year PCS and LR rates were 54% and 15%, respectively. A multivariate model adjusted for MVAC (P =.97), age (P =.03), pathologic stage (P =.0002), and node status (P =.04) showed that surgical variables associated with longer PCS were negative margins (v positive; hazard ratio [HR], 0.37; P =.0007), and > or = 10 nodes removed (v < 10; HR, 0.51; P =.0001). These associations did not differ by treatment arms (P >.21 for all tests of interactions between treatment and surgical variables). Predictors of LR in a multivariate model adjusted for MVAC (P =.16), pathologic stage (P =.02), and node status (P =.37) were positive margins (v negative; odds ratio [OR], 11.2; P =.0001) and fewer than 10 nodes removed (v > or = 10; OR, 5.1; P =.002).nnnCONCLUSIONnSurgical factors influence bladder cancer outcomes after cystectomy, after adjustment for pathologic factors and neoadjuvant chemotherapy usage.

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.

Methotrexate: An active drug in bladder cancer

Forty‐nine patients with transitional urothelial tract tumors received methotrexate: 0.5–1.0 mg/kg I.V. Q W (40 patients) or 250 mg/M2 in a 2‐hour infusion with citrovorum factor rescue 24 hours later (nine patients). Eleven (26%, 95% confidence limits 13–39%) of 42 patients with bidimensionally measurable metastases achieved partial remission. Most responses occurred within 2–3 weeks and persisted for a median duration of six months (range, 2–20). Response rates were increased to 38% (6/16 patients, 95% confidence limits 18–65%) in patients who had no prior chemotherapy, and a 90–100% performance status (50,5/10 patients, 95% confidence limits 22–78%) compared with 19% (5/26, 95% confidence limits 8–37%) in patients who had prior chemotherapy and a ≦80% performance status (19%, 6/32 cases, 95% confidence limits 9–32%). Toxicity included mucositis and myelosuppression. A review of the literature coupled with the present data suggest that methotrexate is as active as cisplatin in the treatment of patients with advanced urinary bladder cancer.

Phase II trial of vinblastine sulfate for metastatic urothelial tract tumors

Vinblastine sulfate, 0.10–0.15 mg/kg IV every week, was given to 37 patients with bidimensionally measurable, metastatic transitional cell carcinoma of the urothelial tract. Twenty‐eight patients, the majority of whom had received extensive prior chemotherapy, had an adequate trial and five (18%; 95% confidence limits, 3–33%) achieved a partial remission (>50% decrease in tumor size) of 2–5 months duration. Responding sites included lung and nodal metastases. Toxicity, primarily leukopenia, was mild to moderate. The 18% response rate obtained in heavily pretreated cases suggests that vinblastine sulfate has some efficacy in the treatment of patients with advanced urothelial tract tumors.

Phase II Trial of Sequentially Administered Cisplatin, Cyclophosphamide and Doxorubicin for Urothelial Tract Tumors

A total of 32 patients with urothelial tract tumors, 31 of whom had bidimensionally measurable disease parameters, underwent sequential intravenous administration of 70 mg./m.2 cisplatin, 250 mg./m.2 cyclophosphamide and 45 mg./m.2 doxorubicin on days 1 to 3 every 3 to 4 weeks. Of these patients 28 (88 per cent) were treated adequately, including 13 (46 per cent, 95 per cent confidence limits of 28 to 64 per cent) who achieved a complete (2) or partial (11) remission. Almost all remissions occurred within 1 to 3 weeks and persisted for a median duration of 8 months (range 4 to 16 months), with 5 patients responding for 1 or more years. Responders lived significantly longer than nonresponders, with a median of 91 versus 38 weeks, respectively (p less than 0.001). The over-all response rate with this 3-drug combination was not statistically different from that which has been observed in previously untreated, selected patients given cisplatin only. When the results of the 3-drug combination (92 responses in 202 patients) are compared to those of cisplatin alone (85 responses in 255 patients) the 3-drug regimen is statistically superior (p less than 0.002).

Combination cyclophosphamide, adriamycin, and vincristine rapidly alternating with combination cisplatin and VP-16 in treatment of small cell lung cancer

Forty-four patients with small cell lung cancer were treated with an intensive chemotherapy induction program consisting of combination cyclophosphamide, Adriamycin, and vincristine rapidly alternating with combination cisplatin and VP-16 followed by prophylactic cranial radiotherapy. After chemotherapy induction and cranial radiotherapy, patients with limited disease received multiple-field radiotherapy consolidation to the primary tumor site and mediastinum using thoracic computed tomographic scanning for field planning, and patients with extensive disease received chemotherapy maintenance. Patients with limited disease in complete remission following radiotherapy consolidation received no further treatment unless disease recurred. It was found that cyclophosphamide, Adriamycin, and vincristine could be alternated with cisplatin plus VP-16 at two-week intervals in 80 percent of patients on an outpatient basis and that two thirds of patients achieved clinical complete remission after two courses of each regimen. Locoregional radiotherapy delivered via multiple fields was effective in increasing the complete remission rate in patients with limited disease and was well tolerated. The median survival time was 18.5 months in 24 patients with limited disease and 12.2 months in 20 patients with extensive disease. Four patients with limited disease who received chemotherapy induction and radiotherapy consolidation without maintenance chemotherapy and one patient with extensive disease remain alive and disease-free at more than five years.

Treatment of small cell carcinoma of lung with combined high dose mediastinal irradiation, whole brain prophylaxis and chemotherapy☆

Abstract Survival of patients with small cell carcinoma of lung, treated on a new combined radiotherapy-chemotherapy protocol, compares favorably with other regimens in the literature and our own previous combined approaches. Radiation, given after induction chemotherapy, consisted of whole brain prophylaxis in all 44 evaluable patients. Patients with limited disease were also treated to the primary and mediastinum to a high dose (5000 rad equivalent) using multiple fields. The new chemotherapy regimen consisted of induction with cyclophosphamide, doxorubicin, and vincristine alternated with cis-platinum and VP-16 (an epipodophyllotoxin) for two cycles, followed by consolidation with low dose cyclophosphamide and vincristine concurrent with irradiation. Patients with limited disease who achieved less than complete response, and all patients with extensive disease were not continued on maintenance chemotherapy. Out of 24 evaluable patients with limited disease, there was 73 % survival at 1 year by life-table analysis, measured from treatment initiation. After induction, 16 24 of these limited disease patients were CR (complete responders): 20 24 were CR at completion of their irradiation. Out of 20 evaluable patients with extensive disease, there was 59% survival at 1 year by life-table analysis. Only 4 44 (9%) brain parenchymal relapses occurred, one at 3 months and one at 6 months after local failure and two in patients who did not become CRs, implicating a possible re-seeding mechanism. Five patients had central nervous system relapses outside of brain parenchyma (spinal epidural and leptomeningeal); in three patients this was the initial site of failure. Significant complications included leukopenia (50% ) and thrombocytopenia (24% ) primarily during induction, and chronic pulmonary fibrosis (25% ), possibly contributing to two deaths.

Combined pneumocystis carinii and nocardia asteroides pneumonitis in a patient with an ACTH‐producing carcinoid

Combined Pneumocystis carinii and Nocardia asteroides pneumonia occurred in a patient with an adrenocorticotropin (ACTH)‐producing carcinoid after effective chemotherapy decreased elevated ectopic ACTH and endogenous corticosteroid levels. Implications regarding the pathogenesis of such infections in patients with paraneoplastic tumors are discussed.

Phase II trial of neocarzinostatin in patients with bladder and prostatic cancer. Toxicity of a five‐day IV bolus schedule

Neocarzinostatin (NCZ), a new antitumor antibiotic, was administered to 19 patients with bladder cancer, 16 patients with prostatic cancer, and 3 patients with hepatoma. All patients had objectively measurable metastatic lesions including 21 with palpable nodes or subcutaneous nodules, 10 with pulmonary nodules as demonstrated by chest x‐ray, 4 with malignant hepatomegaly, and 3 with bidimensional pelvic masses as demonstrated by CT scanning. Sixty‐five courses of NCZ were administered via an intravenous bolus daily for five days with dosages ranging from 1500 to 3000 U/m2. Immediate toxicity was not dose‐limiting except for 1 episode of anaphylaxis and 1 of acute renal failure. Myelotoxicity was delayed, dose‐dependent, noncumulative, and dose‐limiting. Thrombocytopenia was prolonged or irreversible in 5 cases. The maximally tolerated dose was 2750 U/m2. One patient with NCZ‐associated pulmonary fibrosis and 1 with biopsy‐proven hepatitis are discussed in detail. Neocarzinostatin demonstrated minimal therapeutic activity (1 partial remission) in patients with bladder cancer. There was no response in patients with prostatic cancer or hepatoma.

Phase II trial of 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea in small cell cancer of the lung.

NINETEEN PATIENTS WITH A HISTOLOGICALLY CONFIRMED diagnosis of small cell carcinoma (SCCL) of the lung were entered on trial with a new nitrosourea, l-(2-chloroethyl) - 3 - (2,6 - dioxo - 3 - piperidyl) −1 - nitrosourea (PCNU). All patients had had prior chemotherapy and 42% had received a nitrosourea. No patient had a major response to treatment with PCNU and only one patient had a minor response of short duration. Myelosuppression, particularly thrombocytopenia, was the major dose-limiting side effect. PCNU did not appear to be of benefit in patients with recurrent SCCL.