Reply to B. O'Sullivan et Al.

O’Sullivan et al highlight differences in patterns of failure among patients with p16-positive and p16-negative oropharynx cancer observed in our pooled analysis of Radiation Therapy Oncology Group (RTOG) 0129 and 0522 when compared with previously published, single-institution case-series. Although retrospective and secondary, the RTOG analysis utilized uniformly and prospectively collected, multi-institutional data. Disease progression was defined as the first event of recurrence (local, regional and/or distant), given that failure at any site affects prognosis. The RTOG data demonstrated that the timing and anatomic distribution of disease progression for p16positive and p16-negative patients were similar. Prior reports had suggested that late, distant metastases were more common among p16-positive patients. Particular concern was expressed regarding our recommendation for close surveillance within the first 2 years of follow-up. Undoubtedly, surveillance should continue beyond 2 years, as risk of recurrence (albeit lower) persists and second primaries remain possible. The majority of recurrences for p16-positive and p16-negative patients occurred within the first 2 years, and thus close surveillance during this time is warranted. Thisshouldnotbemisconstruedtosuggestthatsubsequentsurveillanceis not recommended. Current data do not support varying the timing or intensity of surveillance by p16 tumor status. O’Sullivan et al are interested in distinguishing time to locoregional failure from time to distant metastases in RTOG. For both locoregional and distant recurrence, there was no difference in median time to disease progression by p16 tumor status (Table 1). Notably, median time to distant metastases was similar for p16-positive and p16-negative patients (11.9 v 12.4 months, P .45). The longest intervals to distant metastases were 74.8 and 80.0 months for p16positive and p16-negative patients, respectively. These ranges are consistent with previously described late recurrences. O’Sullivan et al raise several possible explanations for the perceived differences between RTOG data and previous reports. Firstly, RTOG analysis was limited to patients with known p16 tumor status. While this could introduce potential bias, characteristics and treatment outcomes of patients with and without available p16 tumor status were similar. Secondly, solitary lung nodules in RTOG 0522 were defined as second primaries rather than distant metastases. To address this, RTOG 0522 lung second primaries were recategorized as distant metastases. On recalculation, median time to distant metastases in RTOG 0522 and 0129 remained within the first 12 months and was similar for p16-positive and p16-negative patients. Furthermore, first type of disease progression (distant locoregional v locoregional only: P .88) and anatomic site distributionoffirstdistantmetastases(lungvother:P .81)weresimilar. The letter notes differences in the proportion of failures that were locoregional versus distant in RTOG, Princess Margaret (PM) and Washington University (WU) reports. Indeed, a significantly larger proportion of first progression events in the pooled PM and WU series was distant compared with RTOG data (P .006). This may be treatment-related. All RTOG patients received primary chemoradiotherapy (cisplatin cetuximab). In contrast, 55.2% of PM patients did not receive chemotherapy, and 57.6% of WU patients were treated with primary surgery and variable adjuvant therapy. RTOG protocols included systemic therapy and despite within-trial randomization were largely uniform. Therefore, the lower proportion of distant metastases among patients with recurrence in RTOG may be due to chemotherapy and inherent uniformity of protocol therapy. Additional methodological differences warrant attention. Surveillance in the context of clinical trials rather than clinical care may impact estimates of time to disease progression. RTOG had frequent imaging time points, while clinical follow-up may not. Nevertheless, the majority of disease progressions in p16-positive patients in single institutional series still occur within 2 years. Lastly, definitions of clinical variables can impact observed differences and interpretation. For example, RTOG analysis focused on the first event of disease progression and did not consider subsequent events. In other calculations of time to distant metastases, patients with previous disease progression (local or locoregional) were not excluded. Locoregional failure may be a harbinger of distant disease and its treatment may affect timing to future distant metastases. Therefore, determining time to distant metastatic disease without accounting for prior local or locoregional disease progression may affect estimates. In conclusion, the letter highlights important nuances in the discussion of disease progression. Although median time to disease progression was similar for p16-positive and p16-negative patients, late distant (and locoregional) failures were observed for both. However, the overall incidence of late events is relatively rare and such late events, although devastating, are not unexpected in late survivors.