The role of thoracic radiotherapy as an adjunct to standard chemotherapy in limited-stage small-cell lung cancer

Question: Is there a role for thoracic radiotherapy (TRT) as an adjunct to standard chemotherapy in limited-stage small-cell lung cancer (SCLC)? Perspective: Evidence was selected and reviewed by a radiation oncologist of the Lung Cancer Disease Site Group (Lung DSG) of Cancer Care Ontario Practice Guidelines Initiative. The present document was reviewed and approved by the Lung DSG, which comprises medical and radiation oncologists, pathologists, surgeons, a respirologist, a medical sociologist, and two community representatives. Outcomes: Survival was the primary end point of interest. Toxicity was also considered. Results: Quality of Evidence. Two published meta-analyses comparing chemotherapy plus TRT with chemotherapy alone (CT) were selected for review. The first meta-analysis was based on published results from 11 trials; the second examined individual patient data from 13 trials. Substantial overlap existed between the trials examined by the two meta-analyses. Ten randomised controlled trials (RCTS) were also selected for review; eight of these were fully published. Seven of the ten RCTS investigated the timing of TRT delivery. The Resource Group of the Cancer Care Ontario Practice Guidelines Initiative pooled the published data from four RCTS that compared early TRT delivery with late TRT delivery. One of the ten RCTS analyzed optimal dosage of TRT delivered in conjunction with CT, while two RCTS compared once-daily TRT treatment with twice-daily TRT treatment in conjunction with CT. Benefits. Two meta-analyses demonstrated a positive benefit for TRT in combination with chemotherapy. One meta-analysis demonstrated an overall benefit of TRT on two-year survival [odds ratio (OR): 1.53; 95% confidence interval (CI): 1.30-1.76; p = 0.001] and an absolute improvement in local control of 25.3% (95% CI: 16.5-34.1%). The second meta-analysis indicated a three-year overall survival benefit of 5.4% ± 1.4% [mean ± standard deviation (SD)] and a relative risk of death of 0.86 (95% CI: 0.78-0.94; p = 0.001) in favour of the combined modality group. A meta-analysis of data from four RCTS involving 927 patients demonstrated no difference between early and late TRT (OR: 1.00; 95% CI: 0.56-1.79; p = 1.00). One RCT demonstrated an increase in survival for patients receiving TRT concurrently with chemotherapy (significance not reported). One RCT showed a statistically significant survival advantage for twice-daily TRT compared with once-daily TRT [p = 0.04 (log rank)], and one RCT indicated no significant difference between the twice-daily and once-daily TRT groups [p = 0.49 (log rank)]. One RCT demonstrated a significantly higher local control rate, median survival, and five-year survival in patients treated with hyperfractionated (HFX) TRT given early rather than late during chemotherapy. One RCT examining dosage reported no significant survival benefit of high-dose over low-dose TRT; although, at higher doses, local control was improved. Harms. One meta-analysis demonstrated an increased risk of toxic death in the combined CT-TRT group (OR: 2.54; 95% CI: 1.90-3.18; p < 0.01). Grade 3 and grade 4 thrombocytopenia were increased in the early HFX TRT group compared with late HFX TRT (p = 0.062).