A phase II study of high-dose cimetidine and the combination 5-fluorouracil, interferon alpha-2A, and leucovorin in advanced renal cell adenocarcinoma.

Cimetidine is an H2-receptor antagonist used in the management of peptic ulcer disease and other hypersecretory gastrointestinal disorders. This agent has intriguing immunomodulatory characteristics. A phase II trial of cimetidine in 19 patients with advanced malignant melanoma yielded an objective response rate of 16%. Having demonstrated that cimetidine is active in malignant melanoma, the authors conducted a phase II trial of cimetidine, 800 mg twice daily by mouth, in patients with advanced renal cell cancer. Among the 31 eligible patients, only one (3.2%) achieved a regression. It was a partial regression lasting 93 days. Median time to treatment failure was 83 days. The combination of interferon alpha-2A (IFL-RA) and 5-fluorouracil (5-FU) has been shown to be synergistic against experimental cell lines in vitro. Citrovorum factor (CF) added to 5-FU has been shown to improve objective tumor response compared with single-agent 5-FU in patients with advanced colorectal cancer. Fluorinated pyrimidines have shown some activity against renal cell cancer. We conducted a phase II trial of the combination of CF at 20 mg/m2 intravenous push followed by 5-FU at 325 mg/m2 intravenously daily for 5 days every week with interferon alpha-2A 5 x 10(6) units/m2 subcutaneously on days 1, 3, 5 in patients with advanced renal cell cancer. Among the 31 eligible patients, only two (6.5%) achieved a regression. Both were partial regressions. Median time to treatment failure was 84 days. Neither regimen is recommended for further testing in patients with advanced renal cell adenocarcinoma.

Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma.

Adoptive immunotherapy (AI) with interleukin-2 (IL-2) and lymphokine-activated killer cells (LAK) is an antineoplastic modality in which immune-activated cells are administered to a host with advanced cancer in an attempt to mediate tumor regression. Levamisole (LEV), an immune stimulant, has been suggested to have therapeutic effectiveness in a variety of cancers. After a phase I trial of recombinant IL-2 plus LEV, a phase II trial of this combination was conducted in patients with advanced malignant melanoma. Nineteen patients were entered in the trial. They received IL-2 at 3 x 10(6) U/m2 subcutaneously daily x 5 plus LEV 50 mg/ m2 orally three times daily (p.o. t.i.d.) x 5. Patients were reevaluated at four-week intervals. None of the patients achieved a partial or complete regression (PR, CR). The median time to treatment failure (refusal, progression, or off study due to toxicity) was 56 days. Grade IV toxicities included vomiting (3 patients), lethargy (1 patient), and musculoskellar pain (1 patient). This regimen is not recommended for further testing in patients with advanced malignant melanoma.

Diagnosis of right atrial metastatic melanoma by transesophageal echocardiographic-guided transvenous biopsy.

Traditionally, tissue diagnosis of malignant melanoma metastatic to the heart necessitated thoracotomy or was done at autopsy. More recently, right or left ventricular endomyocardial biopsy under fluoroscopic guidance has been used to confirm metastatic involvement of the heart by various neoplasms including malignant melanoma; results have been excellent, and morbidity has been low. High-quality images of intracardiac masses with excellent anatomic details can be obtained by transesophageal echocardiography. Herein we describe a 73-year-old man with a history of malignant melanoma in whom cardiac metastatic involvement was documented by percutaneous transesophageal echocardiographic-guided transvenous biopsy of a right atrial mass; thus, the need for a more invasive approach to tissue documentation was avoided.

Prospective phase I evaluation of radiation therapy, 5-fluorouracil, and levamisole in locally advanced gastrointestinal cancer.

PURPOSE: A recent clinical trial in patients with resected node-positive colon cancer demonstrated a clear survival advantage for patients treated with adjuvant 5-fluorouracil and levamisole. This finding led to interest in development of a Phase III trial comparing 5-fluorouracil and levamisole with 5-fluorouracil, levamisole, and radiation therapy in colon cancer patients at high risk for local recurrence. A prospective evaluation of 5-fluorouracil, levamisole, and radiation therapy was undertaken with the goal of establishing a satisfactorily tolerated regimen. METHODS AND MATERIALS: Fifteen patients were studied who had locally advanced or locally recurrent upper abdominal gastrointestinal cancer (11 patients) or large bowel cancer confined to the pelvis (4 patients). The tumor and regional lymph nodes received 45 Gy in 25 fractions. Patients with pelvic tumors subsequently were treated with a radiation boost of 5.4-9 Gy in 3-5 fractions. Systemic therapy consisted of 5-fluorouracil, 450 mg/m2, given intravenously for 3 consecutive days during the first and last weeks of radiation therapy. Levamisole, 50 mg, given orally 3 times daily was used for 3 consecutive days concurrent with initiation of radiation therapy and 5-fluorouracil, at the beginning of the third week of radiation therapy, and concurrent with the final 3-day course of 5-fluorouracil. RESULTS: Therapy was generally well tolerated. In two patients, > or = grade 3 nonhematologic toxicity developed and consisted of transient small bowel obstruction in one and severe nausea and vomiting related to levamisole administration in another. One patient experienced grade 3 hematologic toxicity with a leukocyte count nadir of 1,600 cells/microL. CONCLUSIONS: These results are similar to the toxicity profile reported elsewhere for radiation therapy and 5-fluorouracil. The addition of levamisole to radiation therapy and 5-fluorouracil does not appear to increase toxicity significantly.

Granulocyte-macrophage colony-stimulating factor. Preliminary observations on the influences of dose, schedule, and route of administration in patients receiving cyclophosphamide and carboplatin.

BACKGROUND: In an attempt to learn how best to administer granulocyte-macrophage colony-stimulating factor (GMCSF), the authors performed a Phase I study of this agent. They were interested in the influences of dose, schedule, and route of administration on the effects of GMCSF in patients receiving standardized 1-day regimens of cyclophosphamide (CYCLO) and carboplatin (CBDCA). METHODS: Between June 1988 and March 1991, 57 patients with advanced cancer received GMCSF in association with CYCLO 1 g/m2 plus CBDCA 225-700 mg/m2. After the first dose escalation to 300 mg/m2 of CBDCA, patients who had previously received chemotherapy or radiation therapy were excluded. GMCSF was administered in three different doses, five different schedules, and by two different routes. Altogether, 17 different treatment groups were observed. In addition, 24-hour GMCSF serum concentration curves were charted in four patients. RESULTS: Using four sequential groups of three patients each who had received myelosuppressive treatment, treatment with CYCLO 1 g/m2 and CBDCA 225 mg/m2, the apparent superiority of daily subcutaneous injection over 30-minute daily IV infusion of GMCSF was demonstrated graphically. Subsequently, the authors observed apparent enhancement of GMCSF effects beyond those produced by the initially selected 20-day basic 10 micrograms/kg daily SC regimen beginning 2 days after chemotherapy. When administered SC every 12 hours for 14 days beginning the day after chemotherapy, GMCSF appeared to ameliorate the severity of both leukopenia and thrombocytopenia. These effects permitted escalation of the CBDCA dose to 700 mg/m2 (with 1 g/m2 of CYCLO) before cytotoxic tolerance limits were reached. Graphic small group comparisons suggest that GMCSF given SC in doses of 5 micrograms/kg twice daily may produce comparable leukocyte and platelet support after chemotherapy with lower toxicity than occurs from higher doses. Prechemotherapy priming with GMCSF twice daily for an additional 4 days (days -6 to -3) seems to ameliorate postchemotherapy cytopenias further but at the cose of some increased risk of GMCSF toxicity. Although most of the toxic effects of moderate-dose GMCSF are controlled by antihistamines and ibuprofen, oral glucocorticoids (e.g., prednisone, 10 mg twice daily during the second week of GMCSF administration) may be required in patients with serositis, pulmonary infiltrates, or severe skin eruptions. CONCLUSIONS: Our observations suggest that GMCSF should be administered SC in doses of approximately 5 micrograms/kg every 12 hours for 10-14 days beginning the day after chemotherapy. Prechemotherapy priming with these same doses for four additional days (days -6 to -3) may additionally ameliorate postchemotherapy leukopenia and thrombocytopenia, but with increased risk of toxicity.