Showing papers by "David R. Gandara published in 1991"

Serotonin Antagonists: A New Class of Antiemetic Agents

Abstract: Despite a number of significant advances over the past decade, prevention and treatment of chemotherapy-induced emesis remain formidable problems, particularly with cisplatin-containing regimens. Nearly one third of patients receiving high-dose cisplatin still experience substantial emesis despite the best available conventional antiemetics, and the toxic effects of these agents remain quite troublesome. In recent years, a new class of agents, the serotonin antagonists, has been identified. These agents hold promise for clinical utility in a wide range of areas. Selective antagonists of the serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor have proven in early clinical trials to be potent antiemetic agents in patients receiving cytotoxic chemotherapy, with efficacy comparable to or superior to that of conventional antiemetics. Toxic effects to date with the 5-HT3 receptor antagonists have been modest. The current state of knowledge with respect to these agents as antiemetics for patients receiving cytotoxic chemotherapy is summarized.

Late consolidative radiation therapy in the treatment of limited-stage small cell lung cancer.

Abstract: Two hundred twenty-three patients were enrolled on this randomized Phase III trial testing the value of late consolidative involved-field radiation therapy in the treatment of limited-stage small cell lung cancer (SCLC). Patients were treated with induction chemotherapy consisting of alternating cycles of procarbazine, vincristine, lomustine, and cyclophosphamide (POCC) and etoposide, doxorubicin, and methotrexate (VAM) for 6 to 9 months. Responding patients were then randomized at 6 or 9 months to chemotherapy alone or to involved-field radiation therapy. All partial and complete responders received prophylactic cranial irradiation. Of the 180 eligible and evaluable patients, 80 (44%) achieved a complete response and 39 (22%) achieved a partial response (overall rate of response, 66%). Actuarial median survival time was 11.6 months, with 16% of patients surviving 2 years and 11% surviving 5 years. Forty-eight patients were randomized to chemotherapy alone (24 patients) versus chemotherapy plus involved-field radiation therapy (24 patients). There were no significant differences in time to progression or survival between those patients receiving or not receiving involved-field radiation therapy. The thorax was the site of first relapse in 58% of patients randomized to chemotherapy alone versus 29% in patients randomized to chemotherapy plus involved-field radiation therapy (P equals 0.042). The major acute toxicity was reversible myelosuppression, and the major late toxicity was chronic central nervous system dysfunction. The authors conclude that the addition of late consolidative radiation therapy to induction chemotherapy in the treatment of limited-stage SCLC is well tolerated and improves local control, but does not improve time to progression or rates of survival.

Interleukin-2, cisplatin, and 5-fluorouracil for patients with non-small cell lung and head/neck carcinomas.

Abstract: The feasibility and efficacy of treating patients with locally recurrent or metastatic non-small cell lung cancer (NSCLC) or head/neck cancer with interleukin-2 (IL-2), cisplatin, and 5-fluorouracil (5-FU) was tested. Treatment was given every 28 days and consisted of cisplatin, 100 mg/m2 on days 1 and 8; 5-FU, 1,000 mg/m2 by continuous infusion on days 1-3; and IL-2, 12 million units/m2 by i.v. bolus on days 15-19. Thirty-four patients (22 NSCLC, 12 head/neck cancer) were registered in the study. The median age was 58 years; 59% had Karnofsky performance status of 70-80% and over one-half received prior therapy. All patients were evaluable for toxicity and 29 (18 NSCLC, 11 head/neck cancer) were evaluable for response. Twenty-five patients experienced at least one grade 3 or 4 toxicity, but these toxicities were transient and, in general, well tolerated. The response rate was 37% for NSCLC (0 complete response, 7 partial response) and 55% for head/neck cancer (2 complete response, 4 partial response). Two patients with head/neck cancer responded to treatment after failing prior therapy with cisplatin/5-FU alone. The combination of IL-2, cisplatin, and 5-FU is tolerable and active for treatment of NSCLC and head/neck carcinoma; the combination may not be cross-resistant with other chemotherapy combinations. Further studies of IL-2 combined with cisplatin/5-FU are warranted to determine the most effective dose and schedule.

Weekly 24-hour continuous infusion interleukin-2 for metastatic melanoma and renal cell carcinoma: a phase I study.

Abstract: Twenty-nine patients with biopsy-confirmed metastatic melanoma (17) or metastatic renal cell carcinoma (12) were treated with escalating doses or recombinant human interleukin-2 (IL-2) administered as weekly 24-h intravenous infusions. Patients received from 3 to 12 x 10(6) C.U./m2 (18-72 x 10(6) I.U./m2) weekly over a treatment period of 1 to 16 weeks, with a median of eight weekly cycles administered. Patients in all treatment groups experienced non-life-threatening systemic side effects consisting of fever, nausea, vomiting, fluid retention, and diarrhea. Grade III hypotension was seen in four of six patients (67%) at 12 x 10(6) C.U./m2, and represented the dose-limiting toxicity. Grade IV hypotension occurred in 1 of 14 patients at 6 x 10(6) C.U./m2; no other grade IV toxicities were observed. Grade III fever occurred in 3 of 11 patients (27%) treated at 3 x 10(6) C.U./m2, 3 of 14 patients (21%) at 6 x 10(6) C.U./m2, and 3 of 6 patients (50%) at 9 x 10(6) C.U./m2. An objective response was observed in 3 of 28 evaluable patients (10%): 1 complete response and 1 partial response in renal cell cancer, and 1 partial response in a melanoma patient. We conclude that for future studies, the recommended dose of IL-2 given as a weekly 24-h infusion is 9 x 10(6) C.U./m2 and that a low rate of objective tumor response can be obtained in patients with melanoma and renal cell carcinoma using this regimen.

Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in stage IIIB non-small cell lung cancer: results of a phase I/II study.

Abstract: Alternating radiotherapy and chemotherapy increases tumor cure rates in some animal models with reduced normal tissue damage compared to sequential use of these modalities. To test this concept in non-small cell lung cancer, 23 patients with predominantly Stage IIIB disease were treated on a Northern California Oncology Group pilot study of alternating radiotherapy and high dose cisplatin. Radiotherapy consisted of 6000 cGy delivered in three separate 10-day courses of 200 cGy/fraction/day during weeks 1 and 2, 5 and 6, and 9 and 10. High dose cisplatin, 100 mg/m2 in 3% saline, was administered on weeks 3 and 4, 7 and 8, 11 and 12, and 15 and 16. The response rate in 22 eligible patients is 73% ( 16 22 ) with four complete responses and 12 partial responses. Feasibility of this approach is demonstrated by 20 22 patients completing radiotherapy and a median of 2.5 courses of chemotherapy administered. Median survival time is 14.2 months (range 2–40+ months). One- and 2-year survival rates are 64% ( 14 22 ) and 41% ( 9 22 ), respectively. Hematologic, renal, and radiation-related toxicities were significant but manageable. We conclude that rapid alternation of radiotherapy and a high dose intensity cisplatin regimen is feasible in Stage IIIB non-small cell lung cancer, with a high response rate and acceptable toxicity. The long-term impact on local control and survival remains unclear, although preliminary survival data are encouraging in this poor prognosis population. Further studies of this concept are warranted.

High Dose Cisplatin: Modulation of Toxicity

Abstract: Dose escalation of cisplatin is theoretically attractive due to the steep dose-response curve for antitumor activity. However, the dose-response relationship for cisplatin toxicity appears to be equally steep. A high dose regimen of 40 mg/m2 for 5 days in 3% saline (200 mg/m2/28 day cycle) results in dose limiting peripheral neuropathy and myelosuppression, and is associated with accumulation of ultrafiltrate platinum species. A pharmacokinetically designed regimen delivering the same projected dose intensity on a divided dose schedule (100 mg/m2 on day 1 and 8) avoids ultrafiltrate accumulation. In a phase II study in non-small cell lung cancer (NSCLC), this dose schedule resulted in a reduced incidence and severity of neuropathy and absence of severe myelosuppression. At a mean cumulative cisplatin dose of 525 mg/m2/patient, mean delivered dose intensity was 94% of projected (47.2 mg/m2/week). An encouraging response rate and median survival time in NSCLC were also observed, suggesting a positive clinical impact of enhanced dose intensity. A subsequent SWOG study comparing the 5 day high dose cisplatin regimen and the day 1 and 8 regimen in metastatic melanoma confirmed reduced toxicity of the latter dose schedule. Nephrotoxicity and ototoxicity were similar in both groups, but severe myelosuppression and neurotoxicity were confined to patients on the 5 day schedule.