The addition of radiotherapy to the thorax has improved survival for patients with limited-stage disease, with median survivals between 14 and 18 months. Meta-analyses of more than 2000 patients suggest that thoracic radiation for limited disease results in a 25% to 30% reduction in local failure and a corresponding 5% to 7% improvement in long-term, 2-year survival.

Achieving local control using conventional chemoradiotherapy remains a challenge. The basis for a high rate of local-regional relapse probably includes a larger burden of disease (10 to 10 tumor cells), with a greater probability of intrinsic drug resistance; the possible presence of non-small-cell elements resistant to chemotherapy; poor drug delivery caused by ischemia; and drug resistance associated with tumor hypoxia. Moreover, if systemic control is enhanced with high-dose chemotherapy, detection of initial failure in local-regional sites may increase. The application of chest radiotherapy strategies includes the timing of chemotherapy and radiotherapy (ie, concurrent versus sequential versus alternating therapy), timing within therapy (early versus late), volume of the radiation port (original tumor volume or shrinking field as the tumor responds), dose, and fractionation of therapy. A randomized phase III trial (by the National Cancer Institute of Canada) compared chemotherapy with radiotherapy given beginning with either cycle 2 or cycle 6. Early radiotherapy was associated with improved local and systemic control and with a survival advantage. For lesions with substantial postobstructive infiltrates, postchemotherapy ports result in adequate local control. A second randomized trial assessing early (given with cycle 1) compared with late concurrent chest radiotherapy combined with EP for patients with limited-stage disease has been conducted by the Japanese Cooperative Oncology Group. Data from the phase III study indicate that patients treated with early chest radiotherapy lived longer than the patients treated with late chest radiotherapy. This study demonstrated that concurrent chest radiotherapy was superior to sequential administration. After a lead from a phase II study by Turrisi et al, the Eastern Cooperative Oncology Group/ Radiation Therapy Oncology Group (ECOG/RTOG) treated 412 patients with concurrent chemoradiotherapy using a total dose of 45 Gy, delivered either twice a day over 3 weeks or daily over 5 weeks. The twice-daily schedule produced higher rates of esophagitis. A survival advantage was documented. Median survival was 23 versus 19 months ( = .04), and 5-year survival was 26% versus 16% in the twice-daily and once-daily radiotherapy arms, respectively. The higher biologic dose of radiotherapy was more effective. A caveat to these encouraging long-term survival results is that twice-daily fractionation is technically challenging for patients with bilateral mediastinal adenopathy. Thus, patients in this trial were selected for lower degrees of lymphadenopathy and, therefore, may have had a somewhat better prognosis. In addition, the daily fractionated therapy was not delivered at its maximum tolerated dose (MTD), so it remains unclear if fractionation is superior.

Patients selected for combined modality treatment must have an excellent PS and good baseline pulmonary function. Thus, no radiation results in local failure rates of 90%, a total dose of 50 Gy using daily fractionation results in 60% failure rates, and a total dose of 45 Gy using twice-daily fractionation results in 48% failure rates. Choi and colleagues have completed a phase I study to determine the MTD of radiation in standard daily and hyperfractionated accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage SCLC. The twice-daily radiation MTD was 45 Gy but was not reached at 70 Gy with daily fractionation. Ongoing phase II North American cooperative group trials are exploring doses of 63 to 66 Gy concurrent with chemotherapy. A randomized evaluation of radiation dose is anticipated. Another phase III trial assessed split-course twice daily RT compared with once-daily RT. No significant differences were observed between these regimens; however, the long-term survival was favorable, possibly because of the positive influences of concurrent combined modality therapy and prophylactic cranial RT. For limited-stage disease, the NCCN guidelines recommend that radiation should be delivered concurrently with chemotherapy at a dose of either 1.5 Gy twice daily to a total dose of 45 Gy, or 1.8 Gy/day to at least 50 Gy.