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K UMAR ET AL .

Predictors of survival For all patients with oropharyngeal SCC in this cohort, the following factors were found to be statistically significant predictors of survival in the univariate models (Table 2): age, surgical approach, extranodal extension, HPV status, marital status, mucosal margins, p16 status, perineural invasion, primary tumor site, race, smoking status, T classification, and low/intermediate/high-risk stratification (by HPV or p16). For HPV-negative patients, the following factors were significant predictors of survival in the univariate models: extranodal extension, perineural invasion, primary tumor site, and T classification (Table 2). In the HPV-positive cohort, the following factors were significantly associated with survival (Table 2): surgical approach and T classifi- cation. The presence of extranodal extension nearly reached significance ( p 5 .0553). In the multivariable analysis ( n 5 260), after adjust- ment for all covariates, HPV status, extranodal extension, and T classification were independent predictors of sur- vival (Table 3). Of note, aside from HPV status, several of the factors that were predictive of survival in the RTOG 0129 (smoking status and neck disease) failed to reach significance in this patient cohort after adjustment in the multivariable model. For HPV-negative patients (multivariable model n 5 108), extranodal extension (HR of 2.322 for those with extracapsular spread [ECS]; 95% CI 5 1.359–3.968; p 5 .0021) and T classification (HR of 2.029 for those with T3/T4 disease; 95% CI 5 1.054–3.906; p 5 .0342) were the only independent predictors of survival. For HPV- positive patients (multivariable model n 5 152), the sur- gical approach and mucosal margins were the only 2 fac- tors predictive of survival (Table 3). Within the HPV- positive subgroup, those with open surgical approaches had over 3 times the hazard of death than those with transoral surgical approaches (HR 5 3.09; 95% CI 5 1.293–7.385; p 5 .0111). Those with positive margins had a HR of 2.519 (95% CI 5 1.101–5.766; p 5 .0287). There were no differences in positive margin rates between the transoral and open surgical approaches ( p 5 .2868). Recursive partitioning analysis RPA of this patient cohort revealed that HPV status was the most important predictor of overall survival (see Figure 2). For HPV-positive patients, the best outcomes were achieved in those who underwent transoral surgery and had no evidence of perineural invasion at the primary site (9 deaths/104 patients; 91.3% survival). In addition, for those HPV-positive patients who were treated with an open surgical approach, the margin status was the next most important predictor of survival, with 17 deaths out of 46 patients (63.0% survival) at last follow-up with negative margins as opposed to 6 deaths out of 8 patients (25.0% survival) if the margins were positive. For HPV- negative patients, the most important predictor of survival was the presence of ECS (58.2% vs 27.5% survival). Sur- vival rates were worst for T3/T4 tumors with ECS (13.8%).

III/IV 1.025 0.498–2.111 .9461 294 1.918 0.828–4.445 .1287 117 0.739 0.175–3.114 .6799 171 T classification T1/T2 Ref Ref Ref

T3/T4 2.946 1.999–4.341 < .0001 296 2.158 1.321–3.525 .0021 117 3.192 1.643–6.201 .0006 172

10 pack-years Ref Ref Ref > 10 pack-years 2.006 1.216–3.308 .0064 283 1.707 0.778–3.745 .1819 116 1.226 0.606–2.482 .5706 160 TNM classification I/II Ref Ref Ref

No. of

patients

Variables HR 95% CI p value patients HR 95% CI p value patients HR 95% CI p value

Overall HPV negative HPV positive No. of No. of

TABLE 2. Continued

Smoking status

Abbreviations: HPV, human papillomavirus; HR, hazard ratio; 95% CI, 95% confidence interval; BOT, base of tongue.

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