Risk of contralateral failure following ipsilateral neck irradiation for tonsil cancer – a systematic review and meta-analysis of 1,487 patients

Purpose: Unilateral neck radiotherapy (RT) is standard for patients with well-lateralized T1-2 tonsil carcinoma with limited neck disease (N0 or single node <3 cm). For patients that do not fit these criteria, particularly those with more advanced neck disease, unilateral neck RT is controversial. The reduction in toxicity associated with unilateral RT must be balanced with the risk of contralateral neck failure (CNF). Due to a paucity of data regarding this risk, ideal candidates for ipsilateral neck irradiation remain to be elucidated.

Methodology: A systemic review of PubMed, Embase, and Web of Science was performed (PROSPERO ID #CRD42021237637). Publications between January 1980 to June 2021 were included for analysis if they contained >20 patients treated with ipsilateral definitive of post-operative radiation for tonsil cancer.  Primary outcome was the pooled crude rate of CNF. Secondary outcomes included pooled rates of CNF stratified by T/N stage and xerostomia and gastrostomy tube use. Random effect models were used to estimate the risk of CNF. In addition, meta-regression was used to identify predictive characteristics for CNF. In 4 studies that reported both ipsilateral and bilateral RT, meta-analytic log odd ratios were used to compare risk of CNF.

Results: A total of 17 studies (16 retrospective, 1 prospective) consisting of 1,487 patients were identified. Overall, the pooled crude risk of CNF was 1.9% (95% CI 1.2-2.6). The rate of CNF by T-stage was as follows: T1 (n=458), 1.3% (0.3-2.3); T2 (n=537), 3.0% (1.6-4.4); T3 (n=54), 11.3% (3.3-19.2); T4 (n=8), 16.0% (0.0-39.8). Patients with T3-T4 tumors had a significantly higher rate of CNF than those with T1-T2 tumors: 11.6% (95% CI 4.0-19.3%) and 1.8% (1.0-2.6%), respectively (p < 0.001). The rate of CNF by N stage was: N0 (n=474), 1.2% (95% CI 0.1-2.2); N1 (n=295), 4.8% (2.4-7.2); N2a (n=146), 3.11% (0.04- 5.8); N2b (n=339), 3.1% (1.2-4.9); N3 (n=32), 0% (N/A). Rates of CNF were similar for patients with N2b-N3 and N0-N2a disease: 3% (95% CI 1.2-4.7%) and 1.7% (0.6-2.8%), respectively (p=0.072). Compared to bilateral RT, ipsilateral RT was associated with increased risk of CNF (log odds ratio 1.286 [95% CI 0.086-2.485], p=0.036). Exploratory meta-regression analyses suggest that the risk of CNF increases with chemotherapy and HPV+ disease, and decreases with surgical management and smoking history. In terms of toxicity, the rates of grade 3 xerostomia (n=304) and feeding tube use (n=588) were 0.9% (95% CI 0-1.9%) and 13.3% (8.3-18.3), respectively.

Conclusions: Ipsilateral neck irradiation is associated with a higher risk of CNF compared to bilateral irradiation, though the overall rate of CNF is low. Patients with higher T-stage are at increased risk for CNF following ipsilateral neck irradiation. These findings are among the strongest available evidence to support ipsilateral RT in T1-2N0-2b lateralized tonsil cancer and may facilitate informed risk-benefit discussions with patients.

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