Combined chemotherapy and radiation therapy have started to replace the traditional local approach of thoracic radiotherapy alone for unresectable stage III nonsmall-cell lung cancer. By itself, thoracic radiotherapy provides local control and effective palliation of symptoms, but has a minimal effect on survival.[1-3] Novel schemes of radiation such as hyperfractionated radiation and continuous hyperfractionated accelerated radiotherapy[5,6] have been developed and tested. Saunders et al demonstrated the superiority of the continuous hyperfractionated accelerated radiotherapy regimen (57.6 Gy in 36 fractions over 12 continuous days) over conventional radiotherapy in the treatment of patients with nonsmall-cell lung cancer, but at the expense of substantial esophagitis upon completion of treatment.
The addition of chemotherapy to thoracic radiotherapy sequentially[7-10] or concurrently[11-13] has shown an improvement in survival and quality of life of unresectable nonsmall-cell lung cancer stage III patients, especially those with a good performance status and < 5% weight loss,[8-10] when compared to radiation therapy alone (Table 1). The French trial not only demonstrated an improvement in survival with the addition of chemotherapy, but also showed an improvement in systemic control with a reduction in distant metastasis when compared to radiotherapy alone.
In Dillmans [8,9] study (100 mg/m² of cisplatin(Drug information on cisplatin) [Platinol] on days 1 and 29 and 5 mg/m² of vinblastine(Drug information on vinblastine) [Velban] on days 1, 8, 15, 22, and 29, followed by radiotherapy beginning on day 50 vs radiotherapy alone), the median survival of 13.7 months in the combined-modality arm was significantly better than 9.6 months observed in the radiotherapy alone arm (P = .01), and there were twice the number of survivors at 3, 4, 5, and 7 years. This study[8,9] was duplicated by the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG),[10,11] adding a third arm consisting of hyperfractionated radiation (69.6 Gy). Results showed that 1-year and median survivals in the combined-modality arm (60% and 13.8 months, respectively) were significantly improved compared with the hyperfractionated radiation alone arm (51%, 12.3 months) and the standard thoracic radiotherapy arm (46%, 11.4 months) (P = .03). The combined-modality arm continues to show improved survival at 5-year follow-up (P = .004).
Meta-analysis of randomized studies assessing the comparative efficacy of radiation therapy alone to combined chemotherapy and radiation therapy in patients with locally advanced, unresectable nonsmall-cell lung cancer showed that the relative risk for death at 1, 2, and 3 years was reduced by 12%, 13%, and 17%, respectively, in favor of combined-modality therapy. The benefit of chemotherapy appeared to increase with time reaching the maximum at 31 to 36 months from the start of treatment. The mean gain in life expectancy was approximately 2 months at the end of 3 years, with an improvement in median survival of 1.7 months. Although chemotherapy did not impair delivery of radiation therapy, serious toxic effects, particularly febrile neutropenia and gastrointestinal disturbances, were more prevalent in patients receiving cisplatin-based chemotherapy. Thus, the addition of chemotherapy to radiotherapy offers an advantage in patients with locally advanced, unresectable stage III nonsmall-cell lung cancer, but the exact sequence of combined-modality therapy, the optimal and effective agents to be used in combination with radiation, and the best schedule of radiation therapy, are all subjects of continued investigation.
Concurrent Chemotherapy and Radiation
In an attempt to decrease the toxicity of cisplatin-based chemoradiation, we conducted a pilot study using weekly carboplatin(Drug information on carboplatin) (Paraplatin), the less toxic analog of cisplatin, and concurrent thoracic radiotherapy in patients with locally advanced nonsmall-cell lung cancer. In this study, 35 previously untreated patients with stage III nonsmall-cell lung cancer were given 100 mg/m² of carboplatin weekly, with concurrent thoracic radiotherapy (total dose, 60 Gy). The response rate was 34%, and median survival was 13 months. The treatment was well tolerated, with only three patients requiring treatment prolongations of > 1 week. This regimen demonstrated efficacy and feasibility with a mild toxicity profile, and appeared suitable for combination with other chemotherapeutic agents. In a subsequent study, we added paclitaxel(Drug information on paclitaxel) (45 mg/m² given over 3 hours), followed by carboplatin (100 mg/m² over 30 minutes) with concurrent thoracic radiotherapy (60-65 Gy over 6 or 7 weeks)[14,15] (Table 2).
Paclitaxel Plus Carboplatin
The rationale for including paclitaxel was based on its known clinical activity and its radiosensitizing potential in preclinical and clinical studies.[16-18] In advanced and metastatic nonsmall-cell lung cancer, it has shown impressive activity both as a single agent[19-20] and in combination with carboplatin.[21-24] When used in combination with thoracic radiation therapy as a single agent, the recommended dose of paclitaxel is 60 mg/m² administered as a short infusion (1 or 3 h). In our study, we used a lower paclitaxel dose of 45 mg/m² to account for the toxicity related to the addition of carboplatin in this combined-modality regimen. Only nine of the 38 patients treated who had one or more weekly doses of chemotherapy interrupted treatment for more than 1 week due to grade 3 neutropenia; the incidence of severe esophagitis was 6%. The survival of patients treated with our regimen for locally advanced nonsmall-cell lung cancer at 1, 2, and 3 years was 61%, 39%, and 39%, respectively.
Choy and colleagues have also reported the results of their combined chemoradiotherapy utilizing paclitaxel and carboplatin.[26,27] Their regimen consisted of paclitaxel (50 mg/m² 1-hour infusion weekly), carboplatin weekly (with a dose targeted to achieve an area under the concentration-time curve of 2 [AUC in mg/mL · min]), and concurrent thoracic radiation therapy (total dose, 66 Gy) (Table 3). Patients then went on to receive two additional cycles of full-dose chemotherapy with the same combination of paclitaxel and carboplatin.
Among the 37 evaluable patients, the overall response rate was 75% and the 1- and 2-year survival rates were 54% and 40%, respectively. The incidence of esophagitis (National Cancer Institute Common Toxicity Criteria grades 3 and 4) observed was 49%, but was of short duration. Other rare toxicities included nausea, vomiting, neuropathy, weight loss, and pulmonary complications.
Choy et al recently presented the results of another phase II study of 43 patients with locally advanced nonsmall-cell lung cancer who received concurrent weekly low-dose paclitaxel (50 mg/m²) and carboplatin (AUC of 2) with hyperfractionated radiation (69.6 Gy administered twice daily) instead of standard fractionation utilized in the previous trial, followed by two cycles of full-dose chemotherapy with the same agents. The incidence of grades 3 and 4 esophagitis, as measured by the RTOG scale, was 26%; 16.5% of patients had grades 3 and 4 pulmonary toxicity. One-year survival was 63%, and the median survival has not been reached. If this trial utilizing hyperfractionated radiation is put into perspective with the data previously reported by Belani et al,[14,15] and combined with data from Choys group utilizing the same chemotherapeutic agents with standard daily radiotherapy, there appears to be no advantage to giving concurrent twice-daily hyperfractionated radiation.
Hyperfractionated Accelerated Radiation
Hyperfractionated accelerated radiation therapy with no treatment on weekends has also been combined with chemotherapy in a sequential fashion. Two cycles of carboplatin (AUC of 6) and paclitaxel (175 to 225 mg/m²), followed by hyperfractionated accelerated radiation therapy to the postchemotherapy tumor volume (given in three divided daily fractions to a dose of 57.6 Gy in 12 treatment days), was used by Wagner et al at the H. Lee Moffitt Cancer Center in patients with stage III nonsmall-cell lung cancer. Induction chemotherapy was well tolerated and all 21 patients completed hyperfractionated accelerated radiation therapy as scheduled. Two weeks after hyperfractionated accelerated radiation therapy, grade 3 or 4 esophagitis occurred in 11 patients, and 10 of these required hospitalization for toxicity. The median survival for all patients was 12 months; survival at 18 months was 30%. This same schedule is now being tested in a randomized setting by the ECOG (with study chairs Chandra P. Belani and Henry Wagner) to determine the effect of hyperfractionated accelerated radiation therapy compared with standard daily radiotherapy after induction with carboplatin and paclitaxel for patients with locally advanced, unresectable nonsmall-cell lung cancer (Figure 1).