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Unlabelled: A three-arm randomized trial was performed to assess the acute and late toxicity and the impact on survival of the combination high-dose, split-course radiotherapy with 30 mg/m2 cisplatin (cDDP) weekly, with 6 mg/m2 cisplatin daily compared to radiotherapy alone in patients with non-small cell lung cancer (NSCLC). The study started in May 1984 and was closed in May 1989 after 331 patients were randomised. The analysis was performed after a minimum follow-up period of 22 months. Radiotherapy (RT) consisted of 30 Gy, 10 fractions, five fractions a week; then a 3-week split followed by 25 Gy in 10 fractions. Nausea and vomiting were increased for a majority of the patients in the combined treatment arms during treatment. There was no addition of bone marrow suppression, renal dysfunction or esophagitis. Increase of late radiation damage was not observed. Local control (= absence of local progression) was improved for patients treated according to the daily cisplatin arm. This has lead to an improvement in overall survival. There was no effect in time to distant metastasis due to the combined modality. The treatment influence was confirmed in the multivariate analysis., Conclusion: local control and survival can be improved by combining radiotherapy with daily low-dose cisplatin in patients with inoperable NSCLC.

Background and Methods: Cisplatin (cis-diamminedichloroplatinum) has been reported to enhance the cell-killing effect of radiation, an effect whose intensity varies with the schedule of administration. We randomly assigned 331 patients with nonmetastatic inoperable non-small-cell lung cancer to one of three treatments: radiotherapy for two weeks (3 Gy given 10 times, in five fractions a week), followed by a three-week rest period and then radiotherapy for two more weeks (2.5 Gy given 10 times, five fractions a week); radiotherapy on the same schedule, combined with 30 mg of cisplatin per square meter of body-surface area, given on the first day of each treatment week; or radiotherapy on the same schedule, combined with 6 mg of cisplatin per square meter, given daily before radiotherapy., Results: Survival was significantly improved in the radiotherapy-daily-cisplatin group as compared with the radiotherapy group (P = 0.009): survival in the radiotherapy-daily-cisplatin group was 54 percent at one year, 26 percent at two years, and 16 percent at three years, as compared with 46 percent, 13 percent, and 2 percent, respectively, in the radiotherapy group. Survival in the radiotherapy-weekly-cisplatin group was intermediate (44 percent, 19 percent, and 13 percent) and not significantly different from survival in either of the other two groups. The survival benefit of daily combined treatment was due to improved control of local disease (P = 0.003). Survival without local recurrence was 59 percent at one year and 31 percent at two years in the radiotherapy-daily-cisplatin group; 42 percent and 30 percent, respectively, in the radiotherapy-weekly-cisplatin group; and 41 percent and 19 percent, respectively, in the radiotherapy group. Cisplatin induced nausea and vomiting in 86 percent of the patients given it weekly and in 78 percent of those given it daily; these effects were severe in 26 percent and 28 percent, respectively., Conclusions: Cisplatin, given daily in combination with the radiotherapy described here to patients with nonmetastatic but inoperable non-small-cell lung cancer, improved rates of survival and control of local disease at the price of substantial side effects.

Clinical protocols have been designed to combine platinum-based drugs and radiation in the treatment of cancer. The rationale for this approach has been developed from preclinical studies demonstrating that platinum compounds can potentiate the cytotoxic effects of radiation toward cells. In the present study multicellular spheroids derived from squamous cell carcinoma cell line HN-1 have been used to study the effects of both cisplatin and carboplatin when administered prior to, concurrently, and after irradiation treatment. To study the influence of platinum compounds on sublethal damage repair, single and split doses of radiation were applied. Growth delay and proportion cured spheroids served as endpoints. Both cisplatin and carboplatin had no potentiating effect when administered 24 hr prior to irradiation. When administered 3 hr after completion of irradiation procedures, growth delay after single and split doses were enhanced to the same extent. The drug enhancement ratio for cisplatin was larger (1.5) than for carboplatin (1.2). Both single and split doses were enhanced by the same factor, which was interpreted as no effect on sublethal damage repair. When platinum compounds were present in the target cells at the time of irradiation, especially the split dose radiation response was strongly enhanced: the drug enhancement ratio was 3.9 for cisplatin and 3.2 for carboplatin. Recovery from sublethal damage was totally repressed. This study shows that platinum compounds can potentiate radiation and that for maximum effect the sequence of the two treatment modalities is of utmost importance. Moreover, these results may in part explain the heterogeneous outcomes of trials combining platinum compounds and radiation.

We compared cis-platin (DDP) and its analogue, carboplatin (JM8, CBDCA) in their ability to inhibit spheroid growth. The activities of DDP and JM8 were also compared in an antimetabolic assay for their ability to inhibit (3H)-thymidine incorporation in multicellular tumor spheroids. The spheroids were derived from a squamous cell carcinoma cell line HN-1, originally derived from a tumor of the tongue. To produce equal levels of growth delay in spheroids, carboplatin was required at concentrations approximately 16 times that of DDP. Carboplatin also required much longer incubation periods than DDP to produce equivalent growth delay and proportions of cured spheroids. Reflecting the initial response to chemotherapy, the antimetabolic assay showed that carboplatin was required at higher concentrations and longer exposure times to produce equal inhibition of the nucleotide precursor thymidine. These findings may have implications for the clinical use of these drugs and in particular would support a role for carboplatin in the treatment of squamous cell carcinoma of the head and neck, since total free-drug exposure of patients to carboplatin may be up to 16-fold greater than with DDP, and the clinical side effects of carboplatin have been shown to be well tolerated. However, one must be cautious about applying in vitro data to clinical situations.