Delia F. Chiuten

Esophageal complications from combined chemoradiotherapy (cyclophosphamide + adriamycin + cisplatin + xrt) in the treatment of non-small cell lung cancer

Esophageal complications from combined chemoradiotherapy (CCRT) were analyzed in 55 patients with limited non-small cell lung cancer. CCRT consisted of chemotherapy (cyclophosphamide, doxorubicin (Adriamycin), and cisplatin: CAP) and chest irradiation (5000 rad in 25 fractions/5 weeks). Forty-five patients received two courses of CAP, followed by five weekly courses of low dose CAP and irradiation followed by maintenance courses of CAP (Group 1). Ten patients received concomitant CCRT from the onset of treatment (Group 2). Esophagitis occurred in 80% of all patients. Severe esophagitis occurred in 27% of patients of Group 1 and 40% of patients of Group 2. Esophageal stricture or fistula developed in 1 of 45 (2%) patients in Group 1, and 3 of 10 (30%) patients in Group 2 (p less than 0.025). Weekly low-dose chemotherapy administered concomitantly with chest irradiation (R) at the onset of treatment significantly increases esophageal complications. A review of the literature suggests that CCRT may be used safely with split courses of R. The duration between onset of chemotherapy either before or after R should be greater than one week.

Weekly doxorubicin versus doxorubicin every 3 weeks in cyclophosphamide, doxorubicin, and cisplatin chemotherapy for non-small cell lung cancer.

A prospective randomized study was done to determine the effect of different doxorubicin (Adriamycin [ADR], Adria Laboratories, Columbus, OH) administration (schedules every week versus every 3 weeks) on the productivity of a cyclophosphamide, ADR, cisplatin (CAP) chemotherapy regimen for patients with non‐small cell lung cancer (NSCLC). Electrocardiograms, multigated cardiac scans, echocardiograms, and endomyocardial biopsies were done serially for cardiac monitoring. Of 102 patients, 47 had inoperable limited disease (LD), 47 had extensive disease (ED), and eight had no evidence of disease. In the last group chemotherapy was given adjuvantly. Fifty‐one patients were entered into each treatment arm. The groups were formed according to extent of disease and were comparable in terms of patient characteristics. In these groups, the overall response rates using both schedules in LD patients were similar: in patients without chest irradiation previously, there was a response of 35% with ADR weekly, and 31% with ADR triweekly; in LD patients with chest irradiation previously, the response was 20% with ADR weekly, and 25% with ADR triweekly; and in ED patients, 16% with ADR weekly, and 11% with ADR triweekly. There was no significant difference in survival between the two treatment groups. However, results for all responders suggested a longer duration of response with weekly than with triweekly ADR (complete plus partial response: 35.8 versus 11A weeks, P = 0.06; minor response: 34 versus 11.5 weeks, P = 0.003, respectively). Results also suggested that weekly ADR was less cardiotoxic than triweekly ADR: 29% of patients in the former group had no changes or only minor changes in endomyocardial biopsy results, whereas all patients in the latter group had at least grade 0.5 changes at a similar dosage. The median doses of weekly ADR were higher at the same endomyocardial biopsy‐defined toxicity levels. No correlation was found between toxic effects defined by endomyocardial biopsy results and those defined by noninvasive monitoring techniques, although the number of patients assessed was small. Weekly ADR produced less granulocytopenia and a lower incidence of fever (6% versus 16%, P < 0.001) than did triweekly ADR. Alopecia, nausea, vomiting, and diarrhea were significantly less for weekly ADR than triweekly Adr (P < 0.0005, < 0.0005, and < 0.005, respectively). These data suggest that weekly ADR can achieve the same therapeutic results as the standard triweekly regimen with less cardiotoxicity, myelotoxicity, alopecia, diarrhea, nausea, and vomiting in patients with NSCLC.

Combined chemoradiotherapy in limited-disease, inoperable non-small cell lung cancer

Forty-three patients with limited-disease, inoperable non-small cell lung cancer received two intravenous courses of cyclophosphamide, Adriamycin, and cisplatin (CAP) chemotherapy over a 6-week period. This was followed by 5 weeks of combined chemoradiotherapy (CCRT) consisting of low weekly doses of CAP for 5 weeks plus 50 Gy continuous X ray therapy (XRT) to the primary tumor site. Chemotherapy was continued until disease progression occurred or until the total dose of Adriamycin reached 450 mg/m2, whichever came first. CCRT improved the response rate [complete response (CR) plus partial responses (PR)] from 25% after two courses of CAP alone to 65% after CCRT. Previous response to two courses of CAP influences response subsequent to CAP plus XRT. A pretherapy weight loss of 6% or greater had a significant adverse effect on both response and survival time. The median survival time for all patients was 50 weeks; patients whose disease responded to treatment survived significantly longer than patients with nonresponding disease. The median time until disease progression was 37 weeks. Twenty-seven patients relapsed. The first sites of relapse were local in 30% of the patients, distant in 56% of them, and both local and distant in 15%. Severe esophagitis occurred in 30% of the patients and was dose-limiting. The administration of CCRT resulted in an improved response rate compared with the rates reported in previous studies of chemotherapy or radiotherapy alone. Further improvement of the CCRT program is needed to increase long-term survival time and to decrease esophageal toxicity.

Sequential administration of thymidine, 5-fluorouracil, and PALA. A phase I-II study.

TWENTY-SEVEN PATIENTS WITH COLORECTAL ADENOCAR-CINOMA, (12) non-small cell bronchogenie carcinoma, (11) gastric adenocarcinoma (3), and adenocarci-noma of unknown primary lesion (1) were treated with the combination of thymidine (TdR), 5-fluorouracil (FU), and N-phosphonacetyl-L-aspartic acid (PALA). PALA 1 g/m2 was given over 1 hour on day 1, followed on day 2 by 30 g of TdR given over 3 hours. FU, 150–300 mg/m2, was administered sequentially over 1 hour immediately following TdR infusion. There were no responses seen using this dose schedule. Gastrointestinal and central nervous system toxicities were dose-limiting. Myelosuppression was seen at all dose levels and was not dose related. Fever and infection occurred in 16% and 3% of the courses. The maximum tolerated dosages on this schedule were PALA, 1 g/m2; TdR, 30 g; and FU, 250 mg/m2. Pharmacologic studies done revealed the following half-lives: TdR, 1.6 hours; thy-mine, 5.0 hours; FU, 6.8 hours; and FUDR, 3.7 hours. The significant prolongation of the half-life of FU with this drug combination implies that the tumor tissues may be exposed longer to the anticancer action of FU.

Phase I study of thymidine (dThd) and cisplatin (DDP) given in combination

Twenty-three patients with a variety of solid tumors were given thymidine (dThd) at a single dose of 30 g/m2 along with cisplatin (DDP) at escalating doses ranging from 25 to 120 mg/m2. The dThd was administered first, and then after 50% of the total dThd dose had been infused over 1 h, the remaining 50% was given simultaneously with DDP at a separate intravenous site over the next 2 h. Treatment was repeated at 3-week intervals. Gastrointestinal toxicity was doselimiting and dose-related with increasing dosages of DDP. Central nervous system manifestations occurred in 17% of the patients. Mild myelosuppression was observed only at DDP doses of ≥75 mg/m2. Thrombocytopenia was more severe than leukopenia. The maximum tolerated doses on this schedule were 30 g/m2 of dThd and 100 mg/m2 of DDP.