We observed no significant impact for ECS on survival outcomes in our institution's routine pathologic reporting. This lack of prognostic effect was not associated with chemotherapy-intensified adjuvant treatment. In an effort to apply a more discriminating pathological analysis, we used ECS grading, which, in general, also did not correlate with survival outcomes except for the highest grade (STMgraded), which was associated significantly with reduced survival outcomes. However, STM's negative impact was not observed in patients who received adjuvant therapy, either RT or CRT. This probably explains the mechanism of benefit to survival conferred by adjuvant RT, ie, the reduced negative prognostic impact of STMgraded, notably without additional benefit from chemotherapy.
Our study demonstrated that, although the absolute number of disease-related deaths (N = 9) differed according to the presence or absence of ECS, this variable did not correlate with reduced DFS or DSS. It is critical to note that the 9 patients who died of disease harbored other independently significant, negative prognosticators (7 patients had T3/T4 primary tumors, 4 patients had positive surgical margins, 5 patients had angioinvasion, 6 patients had STMgraded, and 4 patients did not receive any adjuvant therapy). Thus, we observed that the presence of ECS, among other important negative prognostic factors, was associated significantly with a greater number of disease-related deaths. However, after controlling for these other important prognostic factors through multivariate analysis, ECS, either by report or graded, was not a statistically significant predictor of survival.
Overall, therefore, we conclude that, in patients with p16-positive OPSCC, the prognostic effect of ECS is confined to the most severe grade, STM, ie, when tumor has obliterated the lymph node with no histologic evidence of residual lymph node tissue or architecture.23, 27, 28 Its negative impact was obviated by radiotherapy. Proposals to explain the lack of prognostic effect of routinely reported or low grades of ECS on survival include the possibility that these patients already had benefited from intensified adjuvant therapy. We addressed this possibility first by controlling for adjuvant treatment type (CRT vs RT alone) in our Cox regression multivariate models. Second, the paired analysis, matched for the presence and type of adjuvant therapy, failed to demonstrate a significant reduction in survival outcomes according to the presence of ECS versus its absence (See also next section for matched CRT vs RT study, Fig. 4). These analyses further reinforce our observation of weak or no prognostic relevance of ECS in patients with p16-positive OPSCC and caution against speculation that equivalent survivorship in the presence of ECS was caused by intensified adjuvant treatment. Thus, surgery followed by adjuvant RT to the neck attenuates the negative prognostication of ECS, an observation that is supported by previous reports.29, 30
Equivalence of Adjuvant Treatment Types in p16-Positive Oropharyngeal Carcinoma With Extracapsular Spread
Despite results from a meta-analysis of nonheterogeneous trials that demonstrated no significant benefit from adjuvant chemotherapy,31 the intensification of adjuvant treatment in the presence of ECS by CRT often is advocated. This is on the basis of Radiation Therapy Oncology Group (RTOG)3 and European Organization for Research and Treatment of Cancer (EORTC)4 trials in patients with head and neck cancer that included a pooled mix of primary sites. The majority of primary sites (58%3 and 70%,4 respectively) used in those investigations were non-oropharyngeal, and HPV status was unknown. ECS also was mixed with positive margins and other negative prognosticators, for which the improved outcomes were not stratified. Therefore, the precise impact of prognosticators and their treatment implications in the oropharyngeal cancer population, specifically those associated with HPV, is currently unpublished.
In our population of patients with p16-positive OPSCC, adjuvant CRT was not associated with increased survival. This was evident both for the entire study cohort and exclusively for the ECSreport and ECSgraded patients. CRT versus RT in patients with ECSgraded lacked any difference in survival after matching for T-stage and margin status. Furthermore, the matched groups with STMgraded, the highest degree of ECS, had the same survival with the 2 different adjuvant regimens. Therefore, our results diverge from what is reported on patients with non-HPV-related head and neck cancer in the available literature, which frequently advocates the use of postoperative chemotherapy versus RT in the presence of ECS. Our results are not surprising given the unique biology of p16-positive disease, and are intuitively reasonable given the high prevalence of ECS in a precisely defined cohort of patients with excellent survival.
Patterns of recurrence in our study indicated that distant metastasis (6 of 10 recurrences) was more common than locoregional recurrence (4 of 10 recurrences). A higher incidence of distant metastasis has been associated with ECS,32, 33 but the role of adjuvant chemotherapy for systemic control in such patients remains unclear. For example, the RTOG trial3 identified no significant reduction in the incidence of distant metastasis in “high-risk” patients who received adjuvant CRT (20%) versus RT alone (23%), and in the EORTC trial, the rates were 21% versus 25%, respectively.4
Compounding these issues, the trials document a 2-fold or greater increase in the incidence of severe acute toxicity from 34% in the RT group to 77% in the CRT group in the RTOG trial3 and 21% to 41%, respectively, in the EORTC trial.4 In addition, the administration of concurrent CRT has been associated with increased odds of long-term swallowing dysfunction in both definitive34, 35 and adjuvant14 treatment settings.
Our current study does not focus on evaluating adjuvant treatment-related toxicities but strongly supports the hypothesis that, in patients with p16-positive OPSCC who undergo surgery, the mere presence of ECS is not an accurate indicator of a poor prognosis. Therefore, the automatic application of ECS as justification for an intensified adjuvant protocol comprising CRT, particularly in the background of the toxicity described above, should be questioned. Just as the negative prognostication of ECS in the past led to addition of chemotherapy, conversely, subtraction of chemotherapy should be considered in patients with p16-positive OPSCC who do not have a poor prognosis in the presence of ECS, when managed surgically as indicated by our current results.
We demonstrate here and also have confirmed from previous studies13, 14 in predominantly p16-positive OPSCC that high T-stage is the strongest prognosticator for poor outcomes. Therefore, it is more logical to consider high T-stage as well as STMgraded and positive margin status as possible indications for intensified adjuvant therapy. A second treatment-related implication from our current study introduces the more stringent pathologist's interpretation of ECS, preventing an “upgrade” of risk status that is not justified by our data. This study is unique in characterizing both the prognostic impact and the extent of ECS in exclusively p16-positive oropharyngeal cancer and its effect on survival.
There are certain limitations in our study. First, this is a single-institution study. However, our recent multicenter study,14 with a greater sample size, had similar findings regarding ECS. Second, the current study is nonrandomized. However, adequate accrual for a randomized controlled trial to achieve sufficient statistical power to detect a significant survival outcome difference would be formidable. This is because the biologically driven good prognosis and low rates of failure (97% locoregional control, 6.5% recurrence rate in our study) in surgically treated patients with p16-positive OPSCC results in too few outcome events.14-16, 19 For the purpose of planning a future study, we estimate that, to be able to detect a statistically significant 5% difference (3-year DFS in ECS-negative patients vs ECS-positive patients, 94% vs 89%) in 3-year DFS between ECS-negative and ECS-positive patients with 80% power at an alpha of .05, in total, 2058 patients would be required. To detect a statistically significant 2.7% difference (3-year DFS with RT vs CRT, 94.5% vs 91.8%) between RT and CRT in ECS-positive patients with 80% power at an alpha of .05, we would require a total of 3252 patients. Unfortunately, there are multiple reasons why the accrual of such a large sample size from 1 or even several institutions is impractical, including patient concern for chemotherapy-related toxicity.
Third, a new, nonvalidated grading system to measure ECS may lack reproducibility. However, the method is uncomplicated, teachable, and clearly more discriminating for the detection of ECS, important features when adverse outcomes are rare and the factor under study has direct treatment implications. Furthermore, STMgraded emerged as a significant independent prognosticator. Finally, other histologic criteria may exist in these tumors that are prognostic but went unobserved. Although a small minority of patients recurred or died, it would be highly desirable to discover predictors of these events.
In summary, we conclude that ECS, as a generally reported pathologic classification, did not predict a poorer prognosis in surgically treated patients with p16-positive OPSCC. This is in marked contrast to previous studies, albeit with cohorts that included heterogeneous groups of patients with head and neck cancer and risk factors that were nonspecific to HPV-related etiology. The 1 exception is graded STM, although its effect was negated by adjuvant RT. These results were obtained independent of treatment variables; any potential benefit from chemotherapy was controlled for by using different levels of analysis. Adjuvant CRT versus RT alone conferred no additional benefits to any of the study endpoints in the presence of ECS or STM, even in closely matched groups. On the basis of our data, it is reasonable to propose that, in surgically managed patients with low T-stage, adjuvant RT alone is sufficient.