A Systematic Review and Meta-Analysis of Studies Comparing Concurrent Chemoradiotherapy With Radiotherapy Alone in the Treatment of Stage II Nasopharyngeal Carcinoma

Purpose The role of concurrent chemoradiotherapy (CCRT) in stage II nasopharyngeal carcinoma (NPC) is still controversial. Our objective is to evaluate the value of concurrent chemotherapy in stage II NPC receiving radiotherapy (RT). Methods We searched the PubMed, Embase, and Scopus databases for studies comparing CCRT versus RT alone in stage II NPC with survival outcomes and toxicities, including locoregional recurrence-free survival (LRFS), metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and grade 3–4 acute toxicities. The hazard ratios (HRs) of survival outcomes and risk ratios (RRs) of toxicities were extracted for meta-analysis. Subgroup analysis for stage N1 patients was performed to further explore whether these populations can earn benefits from concurrent chemotherapy. Results Nine eligible studies with a total of 4,092 patients were included. CCRT was associated with a better OS (HR = 0.61, 95% CI 0.44–0.82), LRFS (HR = 0.62, 95% CI 0.50–0.78), and PFS (HR = 0.65, 95% CI 0.54–0.79), but with similar DMFS (HR = 0.81, 95% CI = 0.46–1.45) compared with two-dimensional RT (2DRT) alone. However, CCRT showed no survival benefit in terms of OS (HR = 0.84, 95% CI 0.62–1.15), LRFS (HR = 0.85, 95% CI 0.54–1.34), DMFS (HR = 0.96, 95% CI 0.60–1.54), and PFS (HR = 0.96, 95% CI 0.66–1.37) compared with intensity-modulated RT (IMRT) alone. Subgroup analyses indicated that CCRT had similar OS (HR = 1.04, 95% CI 0.37–2.96), LRFS (HR = 0.70, 95% CI 0.34–1.45), DMFS (HR = 1.03, 95% CI 0.53–2.00), and PFS (HR = 1.04, 95% CI 0.58–1.88) in the stage N1 populations. Meanwhile, compared to RT alone, CCRT significantly increased the incidence of grade 3–4 leukopenia (RR = 4.00, 95% CI 2.29–6.97), mucositis (RR = 1.43, 95% CI 1.16–1.77), and gastrointestinal reactions (RR = 8.76, 95% CI 2.63–29.12). No significant differences of grade 3–4 toxicity in thrombocytopenia (RR = 3.45, 95% CI 0.85–13.94) was found between the two groups. Conclusion For unselected patients with stage II NPC, CCRT was superior to 2DRT alone with better LRFS, PFS, and OS, while adding concurrent chemotherapy to IMRT did not significantly improve survival but exacerbated acute toxicities. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022318253.


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Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.

Synthesis methods 13a
Describe the processes used to decide which studies were eligible for each synthesis. 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used. 13e Describe any methods used to explore possible causes of heterogeneity among study results. 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.
Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).
Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. 16b Cite studies that met many but not all inclusion criteria ('near-misses') and explain why they were excluded.

Results of syntheses 20a
For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.
20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. 20c Present results of all investigations of possible causes of heterogeneity among study results. 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.

Reporting biases 21
Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.
Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.

Discussion 23a
Provide a general interpretation of the results in the context of other evidence. 23b Discuss any limitations of the evidence included in the review. 23c Discuss any limitations of the review processes used.
23d Discuss implications of the results for practice, policy, and future research.

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered.

24b
Indicate where the review protocol can be accessed, or state that a protocol was not prepared. 24c Describe and explain any amendments to information provided at registration or in the protocol.