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53 patients with stage IIIA non-small cell carcinoma of the lung (NSCCL) were treated with multimodality therapy consisting of induction radiotherapy (55.8 Gy) and two cycles of concurrent chemotherapy with cisplatin, 25 mg/m2 for 4 days by continuous infusion and bolus etoposide, 100 mg/m2 on days 2 and 4 of each cycle followed by surgery and adjuvant chemotherapy. Of 53 evaluable patients, 47 achieved clinical responses (9 complete response, 38 partial response) after induction therapy for a response rate of 89%. 47 patients were resectable after induction therapy, but 8 patients refused surgery and 6 patients were not eligible for surgery based on poor pulmonary function (medical contraindications). 33 patients underwent thoracotomy and in 6 patients, resection was technically unfeasible. Thus complete surgical resection was accomplished in 27 patients. After all therapy, 28 patients achieved a complete response (53%) and 19 patients a partial response (36%). Toxicities were mild. At a maximum of 75 months (median, 28 months) of follow-up, the median survival of the entire group is 24 months. The median survival of resected patients has not been reached; their 6-year survival rate is 55%. Unresected patients survived for a median of 11 months. This multimodality regimen is well-tolerated, induces a high response and resectability rate and prolongs survival in resected patients.

The pharmacokinetics of stavudine (d4T; 2',3'-didehydro-3'-deoxythymidine) were studied in patients with AIDS-related complex or AIDS enrolled in a dose-ranging phase I/II study. Twenty-two patients were studied after the first oral dose of 0.67, 1.33, 2.67, or 4 mg/kg of body weight; 17 of them underwent an additional steady-state pharmacokinetic evaluation after thrice-daily dosing of the above doses. Stavudine absorption was rapid, with mean peak concentrations of 1.2-4.2 mg/L over the four dose levels studied. From 34% to 41% of an oral dose was excreted as unchanged drug in the urine. The mean values for plasma elimination half-life ranged from 1 to 1.6 h. The absolute bioavailability of a 4 mg/kg oral dose exceeded 80%. There was no change in pharmacokinetic parameters measured after the first dose and after chronic dosing. Stavudine is a new dideoxynucleoside with more complete and less variable oral absorption than existing nucleosides used for treatment of human immunodeficiency virus infection.

Twenty-nine evaluable patients with colorectal adenocarcinoma were treated in a phase I-II trial of combination chemotherapy with a 72-h continuous infusion of cisplatin (CDDP) and 5-fluorouracil (5-FU) with an infusion of VP-16 given at 24 and 48 h after the start of therapy. There were five (17 +/- 14%) partial responses lasting 2-6 months (median, 3). Three of these responses occurred among the 10 previously untreated patients. The toxicity of this regimen was pronounced. Four of eight patients with severe neutropenia required hospitalization for infections, two of which were life-threatening; one of six patients with severe thrombocytopenia had a life-threatening hemorrhagic complication; and four patients experienced severe, dose-limiting fatigue. These complications occurred principally with CDDP and VP-16 at doses above 27.5 mg/m2/day and 110 mg/m2/dose, respectively. Mucositis occurred in six patients and limited the dose of 5-FU to 1,300 mg/m2/day. Although the response rate appeared to be high in previously untreated patients, the minimal palliative benefit of treatment and the brief duration of the responses do not compensate for the toxicity observed.

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy with 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (AZT), a thymidine nucleoside analog. By itself, AZT has limited antineoplastic efficacy. However, experimental studies indicate that 5-FU enhances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into nucleic acids. A phase I study defined the maximum tolerated dose of AZT as 7 g/m2 with hypotension during the infusion being the dose-limiting toxicity. A phase II study was performed with oral leucovorin (100 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bolus 5-FU (400 mg/m2) followed 1 h later by a 2-h infusion of AZT (7 g/m2). Treatment was given weekly for 4 weeks followed by a 1-week break, which constituted a cycle of therapy. Responses were evaluated after every two cycles. Patients continued on therapy as long as they tolerated treatment and did not have progressive disease. Of 15 evaluable patients who had received no chemotherapy there was 1 complete response and 4 partial responses (a 33% response rate), whereas only 1 of 6 patients who had received prior adjuvant chemotherapy had a partial response (17%). An additional 10 patients had stable disease lasting 2–14 months. Therapy was well tolerated with the only one instance each of grade 3 nausea and vomiting, diarrhea, anemia, and hypotension. Approximately 50% of treatments were accompanied by mild hypotension, which was easily corrected by increasing the rate of normal saline infusion. There was no difficulty administering this regimen in the outpatient setting. While the overall response rate (29%) is comparable to that seen with combinations of 5-FU and leucovorin alone, in most reported series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively little 5-FU toxicity, increasing the dose of 5-FU in this regimen would appear to be feasible and might result in a higher response rate.

2',3'-didehydro-3'-deoxythymidine (d4T) is a pyrimidine analogue and inhibitor of reverse transcriptase with potent in vitro activity against human immunodeficiency virus (HIV). A phase I trial of d4T was conducted in 41 HIV-infected patients, 12 with AIDS and 29 with AIDS-related complex (ARC). Thirty-six patients were evaluatable. The maximum tolerated dose was 2 mg/kg/day. The dose-limiting toxicity was sensory peripheral neuropathy, which occurred in 20 patients (55%). Four patients (11%) developed hepatotoxicity. Five (14%) developed anemia requiring a transfusion but not discontinuation of drug. The mean +/- SE plasma elimination half-life at all dose levels was 1.2 +/- 0.09 h. Increased or stable absolute CD4 counts were seen in most patients. The majority of patients with detectable serum p24 antigen levels had a persistent decrease by 6 months. d4T is a promising drug for patients with AIDS or ARC. This clinical trial is continuing to determine the minimal effective dose.

A phase I clinical, pharmacologic, and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting, with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed, and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day, trough levels significantly increased, perhaps reflecting prolonged absorption from the gut. No responses were observed; however, a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day, confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.