Siva Murthy

Aggressive multimodality therapy for malignant pleural mesothelioma

Nineteen patients with clinical stage I malignant pleural mesothelioma were treated with aggressive multimodality therapy. Nine patients underwent pleurectomy and decortication followed by immediate intrapleural chemotherapy with cisplatin and mitomycin C. Ten patients required pleuropneumonectomy followed within 1 week to 2 weeks by intrapleural administration of cisplatin (100 mg). Four to 8 weeks after operation, 15 patients underwent postoperative adjuvant cisplatin-based systemic chemotherapy. There were three postoperative complications (16%) requiring reoperation and one postoperative death (5%). Intrapleural chemotherapy was well tolerated with no complications. Systemic chemotherapy was poorly tolerated, and there was one chemotherapy-related death. Sixteen patients (84%) experienced good to excellent palliation. Three patients are currently alive with no evidence of recurrent disease at 10, 35, and 43 months. The median overall survival was 13 months and the median disease-free survival, 11 months. Overall and disease-free 3-year survivals were 17% and 22%, respectively. Patients with epithelial malignant pleural mesothelioma had significantly better overall survival (p = 0.037) and disease-free survival (p = 0.02) than patients with sarcomatous or biphasic malignant pleural mesothelioma. We conclude that despite major toxicity, in select patients with clinical stage I malignant pleural mesothelioma, aggressive multimodality therapy offers effective palliation and occasional long-term disease-free survival.

A phase I trial of 5-fluorouracil, folinic acid, and alpha-2a-interferon in patients with metastatic colorectal carcinoma.

The mechanisms of biochemical modulation of 5‐fluorouracil (5‐FU) cytotoxicity by folinic acid (FA) have been elucidated, and the clinical use of this combination has improved response rates and survival in patients with metastatic colorectal cancer. Recently, Phase II trials also showed potential synergism between alpha‐2a‐inter‐feron (rHuIFN‐α2a) and 5‐FU. Therefore, a Phase I trial of these three agents 5‐FU, FA, and rHuIFN‐α2a was conducted in patients with metastatic colorectal cancer. The drugs were given over 5 days, with dose escalation of either rHuIFN‐α2a or 5‐FU. Fifty‐five eligible patients were treated at eight dosing levels. The maximal tolerated dose (MTD) was as follows: 5‐FU 430 mg/m2/d intravenously (IV) on days 1 to 5, FA 200 mg/m2 IV on days 1 to 5, and rHuIFN‐α2a 4.0 × 106 U/m2/d subcutaneously on days 1 to 5. The dose‐limiting toxicities were mucositis and neutropenia. Objective responses were seen at most dosing levels, and overall 15 of 55 patients (27%; 95% confidence interval, 16% to 41%) responded (median duration, 6.5 months). A Phase II trial using the MTD is ongoing. Cancer 1992; 69:889–892.

Phase I trial of recombinant granulocyte-macrophage colony-stimulating factor in patients with lung cancer: clinical and immunologic effects.

Recombinant granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) may enhance the functional activity of monocytes and macrophages in vitro and in vivo and thereby have antitumor activity. A phase I trial using rhuGM-CSF was performed; the trial included 17 patients with unresectable and/or metastatic lung cancer. rhuGM-CSF was administered as a continuous infusion for 14 days at four dose levels: 60 micrograms/m2, 125 micrograms/m2, 250 micrograms/m2, and 500 micrograms/m2. Dose-limiting toxicity was pulmonary and occurred at 500 micrograms/m2, with the maximal tolerated dose (MTD) identified as 250 micrograms/m2. The hematologic effects of rhuGM-CSF included leukocytosis with significant correlations between dose level and the numbers of neutrophils, monocytes, eosinophils, and lymphocytes. Bronchoalveolar lavage was performed for 14 patients, and no effect on alveolar macrophage numbers was detected. Tumor biopsies were obtained in two patients, and no changes in macrophage infiltrates were detected with use of immunohistochemical studies. Serum levels of GM-CSF reached a steady state during week one and decreased or were undetectable during week two. No evidence of tumor regression was seen. rhuGM-CSF when administered as a continuous infusion was well tolerated and appears to modulate monocyte numbers and function in vivo.

Phase II trial of circadian infusion floxuridine (FUDR) in hormone refractory metastatic prostate cancer

Circadian administration of chemotherapy has been reported to decrease toxicity and possibly enhance efficacy. Between March 1991 and December 1993, 18 evaluable patients with progressive, hormone-refractory metastatic prostate cancer were treated in this phase II trial of circadian infusion floxuridine (FUDR). The drug was delivered through a central venous catheter using a CADD-Plus computerized pump such that approximately 70% of the drug was administered between 3 and 9 p.m. and the rest (30%) was administered between 9 p.m. and 3 p.m. The dose of FUDR was 0.15 mg/kg/day × 14 days every 4 weeks. A total of 79 complete cycles was administered.Two of 18 evaluable patients (11.1%) had decreases in PSA lasting five and eight months. No objective responses or improvement in bone scans was noted. The major toxicity observed was diarrhea. Although circadian infusion FUDR is feasible and tolerable, it has limited activity in hormone refractory prostate cancer.

Phase I trial of continuous infusion interleukin-2 and doxorubicin in patients with refractory malignancies

A phase I trial was performed to assess the immunomodulatory activities, maximum tolerated doses, and the toxicity of recombinant interleukin-2 (rIL-2) administered in combination with doxorubicin to patients with refractory malignancies. Therapy was administered to successive cohorts of four to six patients who were treated at three different dose levels (1A, 1B, 2A). Levels 1-2 refer to doxorubicin (40 or 60 mg/m2) given as an intravenous (i.v.) bolus on day 1, and levels A-B refer to rIL-2 (1.0 or 3.0 x 10(6) U/m2) given as a continuous i.v. infusion on days 2-5, 9-12, and 16-19. Cycles were repeated every 28 days. Seventeen patients were entered in the trial. Dose limiting toxicity consisted of neutropenia, and the maximum tolerated dose (MTD) of the combination was doxorubicin 40 mg/m2 and rIL-2 3.0 x 10(6) U/m2. No objective responses were observed. Lymphocytosis related to rIL-2 occurred and flow cytometry demonstrated significant increases in the following subsets: CD3+CD25+HLADr+ and CD11b-CD16c+CD8-. Natural killer cell activity and lymphokine-activated killer (LAK) cell precursors were increased in patients treated at dose levels 1A and 1B (40 mg/m2 doxorubicin), but no consistent changes in LAK activity were noted. No clinical responses were seen and the overall toxicity of this combination was moderate to severe. Administration of doxorubicin prior to rIL-2 does not enhance the immunologic effects of rIL-2.