Eleven RCTs were included (n=2,043, concurrent n=1,019 and sequential n=1,024): six RCTs were phase III trials and five RCTs were phase II trials. The overall quality score was rated as B1 (low to moderate risk of bias) for all included studies except one study rated C (high risk of bias).
Overall survival: Concurrent compared with sequential radiotherapy-chemotherapy was associated with a significantly higher median overall survival (median ratio 1.17, 95% CI 1.09 to 1.26; n=1,939, 10 RCTs).
Progression-free survival: Concurrent radiotherapy-chemotherapy showed no clear advantage over sequential with regard to progression-free survival (progression-free-survival ratio 1.04, 95% CI 0.93 to 1.16; n=1,559, nine RCTs). A trend in favour of the concurrent arm was noted (median progression-free survival concurrent 9.8 months versus sequential 9.1 months).
Patterns of failure: Concurrent radiotherapy-chemotherapy compared with sequential was associated with significantly lower odds of overall tumour relapses (locoregional or distant) (OR 0.82, 95% CI 0.69 to 0.97, I2=0%). No evidence of publication bias was found.
Response rate: Concurrent radiotherapy-chemotherapy compared with sequential was associated with significantly higher objective response rate (random-effects OR 1.38, 95% CI 1.10 to 1.72, Cochran Q p-value=0.007, I2=62.0%; n=1,352, nine RCTs). No evidence of publication bias was found.
Toxicity: Grade III or more neutropenia was significantly more frequent with the concurrent arm (OR 2.30, 95% CI 1.71 to 3.10), as were thrombocytopenia (OR 2.41, 95% CI 1.72 to 3.40), nausea/vomiting (OR 1.49, 95% CI 1.08 to 2.06), stomatitis (OR 2.84, 95% CI 1.01 to 8.00) and esophagitis (OR 4.88, 95% CI 3.37 to 7.30). Grade III or greater anaemia was significantly more frequent with sequential arm (OR 0.12, 95% CI 0.09 to 0.15).
There was no significant difference in the number of treatment-related severe pulmonary, neurological, infection, cardiovascular, liver and renal toxicity between the two strategies.