Non-small-cell lung cancer (NSCLC) accounts for approximately 75% of all lung cancers (Travis et al, 1995). Only a low percentage of patients present a disease susceptible to surgical resection. In fact, approximately 40% of patients with NSCLC present with locally or regionally advanced tumours that are ineffectively treated by primary surgery. Large studies have shown that a small percentage of those patients can be cured with radiotherapy and even after using the best available radiation schedules, recurrences in the radiation field are observed in a substantial percentage of the patients (Cox et al, 1990; Arriagada et al, 1991; Graham et al, 1995).
Due to the limited benefits provided by radiation therapy alone, the use of combined chemoradiotherapy in the patients has been explored. A combination of chemotherapy and radiotherapy has been shown to improve the outcome of the patients with locally advanced NSCLC, achieving a median survival of 13–14 months and 5-year survival rates of 13–20% (Dillman et al, 1990,Dillman et al, 1996; Schaake-Koning et al, 1992; Sause et al, 1995).
In the EORTC phase III study, 08844 Schaake-koning et al (1992) demonstrated that radiotherapy combined with daily administration of low-dose cisplatin resulted in improved local control and actuarial survival in patients with unresectable NSCLC. In that study, daily administration of cisplatin proved to be more effective than a weekly schedule in potentiating the local tumour control achievable with radiation alone. In addition, Jeremic et al (1996) reported that the combination of radiation therapy and low-dose daily carboplatin (CBDCA) plus etoposide improved the survival of patients with stage III NSCLC as a result of improved local control. These results suggest that concurrent low-dose daily administration of platinum compounds enhance local control by radiation therapy, resulting in better survival of stage III NSCLC.
Many agents have been reported to have a radiosensitising effect. 5-fluorouracil (5-FU) was demonstrated to be a radiosensitiser in a preclinical study (Byfield et al, 1982). A randomised study using single-agent 5-FU in conjunction with radiotherapy suggested that, in terms of local control and patient survival, it improved the effect of radiotherapy alone (Lo et al, 1976). Although inhibition of repair of radiation-induced DNA damage has been postulated to occur, the precise cellular mechanisms by which 5-FU and radiotherapy interact have not been defined (Schilsky, 1992).
In addition to the raidosensitising effect of these agents, a combination of platinum compound and 5-FU has been shown to have synergistic antitumour activity in both preclinical and clinical studies (Scanlon et al, 1986; Olver et al, 1989; Esaki et al, 1992; Saikawa et al, 1994). The mechanism of synergism of these two agents remains unclear, although there are various hypotheses concerning the modulatory effect of platinum compounds on 5-FU. It was suggested that the platinum-induced intracellular folate level potentiates the effect of 5-fluorodeoxyuridine monophosphate by forming a covalent ternary complex with thymidylate synthase, leading to enhanced 5-FU cytotoxicity (Scanlon et al, 1986).
These results prompted us to conduct a phase I–II trial of carboplatin and continuous infusion of 5-FU in combination with concurrent radiotherapy in patients with locally advanced NSCLC. The objective of the trial was to determine the maximum tolerated dose of carboplatin that could be used in combination with continuous infusion of 5-FU and concurrent radiotherapy. The efficacy and toxicity of the combination were further evaluated in the following phase II study.