The Role of Radiotherapy with Chemotherapy
Two published meta-analyses compared chemotherapy plus thoracic radiotherapy with chemotherapy alone. The first meta-analysis analyzed published results from 11 trials and the second examined individual patient data from 13 trials; there was substantial overlap between the trials analyzed in the two meta-analyses. Both meta-analyses demonstrated positive benefits for thoracic radiotherapy in combination with chemotherapy versus chemotherapy alone. One meta-analysis demonstrated an overall benefit of thoracic radiotherapy on two-year survival [Odds Ratio, 1.53; 95% Confidence Interval, 1.30 to 1.76; p=0.001] and an absolute improvement in local control of 25.3% (95% Confidence Interval, 16.5 to 34.1). The second meta-analysis indicated a three-year overall survival benefit of 5.4% ± 1.4% (standard deviation) and a Relative Risk of death of 0.86 (95% Confidence Interval, 0.78 to 0.94; p=0.001) in favour of the combined modality group. One of two randomized trials that was not included in either meta-analysis accrued 97 patients and detected a survival benefit for combined modality treatment over chemotherapy alone. The other trial, which involved the use of split-course radiotherapy and a second randomization to consolidation chemotherapy, detected no significant difference in overall survival between treatments among 386 patients, although there was a significant advantage in two-year progression-free survival for irradiated patients. The reliability of the results of the latter trial is questionable since the combined treatment arm was closed early due to toxicity.
Radiotherapy Timing--Concurrent versus Sequential or Alternating Administration
Three randomized controlled trials compared concurrent chemo-radiotherapy with either sequential or alternating chemo-radiotherapy. One trial demonstrated a non-significant increase in overall survival for patients receiving thoracic radiotherapy concurrently with chemotherapy versus sequentially following chemotherapy (p=0.097 logrank). However, a regression analysis adjusted for prognostic variables detected a significant survival benefit for concurrent treatment (Hazard Ratio, 0.70; 95% Confidence Interval, 0.52 to 0.94, p=0.02). Another small trial available only in abstract form reported no survival benefit for concurrent over sequential administration of radiotherapy (p=0.33). One randomized controlled trial which compared concurrent chemo-radiotherapy with chemotherapy alternating with thoracic radiotherapy showed no significant difference between the two treatment arms (p=0.15 logrank).
Radiotherapy Timing--Early versus Late Administration
Five randomized controlled trials investigated early versus late thoracic radiotherapy delivery. Methodologists working with the Lung Cancer Disease Site Group conducted a meta-analysis of published data involving 777 patients from three of the randomized controlled trials that examined early versus late daily thoracic radiotherapy delivery. Two of these trials administered chemotherapy concurrently with the radiotherapy and one administered it sequentially. Results of the meta-analysis indicated that there was no survival benefit to administering thoracic radiotherapy early in relation to the chemotherapy administration schedule (Odds Ratio, 1.04; 95% Confidence Interval, 0.45 to 2.43; p=0.9), although the treatment effects detected in the three trials were heterogeneous. Only one of these trials obtained a significant result: the National Cancer Institute of Canada detected a survival advantage for early, concurrent administration of thoracic radiotherapy compared with late, concurrent administration (5-year survival, 20% versus 11%, respectively, p=0.008 log rank). In addition, two randomized controlled trials compared early administration of hyperfractionated thoracic radiotherapy (concurrent with the first course of chemotherapy) to late administration (given concurrently with cycle three or four of chemotherapy). In one of those trials, early administration achieved a significantly higher local control rate and an improvement in survival that was close to statistical significance. In the other trial, there were no differences between administration schedules in complete response rate or survival.
Radiotherapy Dosage
Two randomized controlled trials examining radiotherapy dosage reported no significant survival benefit of high dose over low dose thoracic radiotherapy; although in one trial, there was an improvement in local control at higher doses.
Hyperfractionated Radiotherapy
Hyperfractionated thoracic radiotherapy has been shown in one large, fully published study (417 patients) to significantly increase the long-term survival of patients with limited small cell lung cancer (5-year survival, 26% with hyperfractionated thoracic radiotherapy versus 16% with once daily radiotherapy, p=0.04 logrank). This was achieved with an increased rate of short-term grade 3 esophagitis. A second large randomized trial (262 patients) has recently been fully published and has not detected a survival advantage for hyperfractionated thoracic radiotherapy (3-year survival, 29% with hyperfractionated thoracic radiotherapy versus 34% with once daily radiotherapy, p=0.49). Grade 3 esophagitis was again significantly more frequent in the hyperfractionated arm.