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PURPOSE The ECOG-ACRIN E3311 phase II trial demonstrated outstanding disease control (90.6% 54-month progression-free survival) after transoral surgery (TOS) with de-escalated, risk-based postoperative management in resectable human papillomavirus–associated oropharyngeal cancer. The goal of de-escalation was functional preservation. The objective of this work was to evaluate clinician-graded modified barium swallow (MBS) studies from E3311 over time and across arms for (1) aspiration and high-grade pharyngeal residue rates, (2) differences in swallow safety and efficiency, and (3) accuracy of site clinicians reporting against central MBS review. METHODS Eight hundred eighty-five MBS studies were performed on 314 patients from 50 of 59 sites at baseline, post-TOS, and 6 and 24 months postradiotherapy (RT). Swallow outcomes (aspiration, high-grade residue) were recorded by site clinicians. A subset of 414 MBS studies was centrally graded using penetration-aspiration scale scores and the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. RESULTS Aspiration, residue, and dysphagia rates significantly increased from baseline to post-TOS ( P < .01) and then decreased modestly at 6 and 24 months. At 6 months, swallow outcomes favored the 50- versus 60-Gy arm, with significantly lower aspiration and high-grade dysphagia rates, but this difference was not maintained at 24 months. MBS results reported by site clinicians demonstrated substantial agreement with those assessed by the central laboratory (PABAK, 0.75-0.84; P < .01). CONCLUSION Swallowing worsened after TOS but improved by 6 and 24 months despite adjuvant therapy. De-escalated adjuvant RT at 50 Gy reduced acute aspiration. Site-reported MBS metrics strongly aligned with DIGEST, showing potential as an accessible metric in cooperative group settings.

This phase II trial of transoral surgery (TOS) with deintensified postoperative management in human papillomavirus (HPV)–associated oropharynx cancer (OPC) enrolled patients with resectable cT1-2 stage III/IV American Joint Committee on Cancer (AJCC) seventh edition p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (arm A); those with clear margins, 2-4 + LN, or ENE ≤1 mm were randomly assigned to 50 Gy (arm B) or 60 Gy (arm C); and those with involved margins, >4 + LN, or >1 mm ENE received weekly cisplatin and 60-66 Gy (arm D). Among 359 evaluable patients, the 54-month progression-free (PFS) and overall survival (OS) were 90.6% (90% CI, 87.2% to 93.1%) and 95.3% (93.0% to 96.9%), respectively. The 54-month PFS by arm was A 93.2% (79.6% to 97.8%; all four recurrences among N1 patients), B 94.9% (89.7% to 97.5%), C 90.2% (82.7% to 94.6%), and D 85.5% (77.5% to 90.8%). The 54-month OS by arm was A 97.1% (85.7% to 99.4%), B 97.9% (93.5% to 99.3%), C 95.1% (90.1% to 97.6%), and D 92.5% (86.9% to 95.7%). PFS or OS did not differ by primary site or smoking history. TOS and neck dissection with deintensified postoperative management results in outstanding 54-month PFS and OS. Among patients with favorable pathologic characteristics, those with N1 disease are at risk of late recurrence without radiation.

Salivary glands are common organs at risk in both head and neck external beam radiotherapy (EBRT) and radiopharmaceutical therapy (RPT), but incidences of xerostomia in RPT are inconsistent with the EBRT Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) limits. In EBRT, salivary glands are usually assumed to be parallel organs, with QUANTEC guidelines based on Dmean, but this is known to be a gross over-simplification of the full complexity of the underlying functional organization. The goal of this work is to combine machine learning of EBRT dose–outcome data with stylized small-scale RPT dosimetry to discover more reliable normal tissue complication probability (NTCP) models of xerostomia across both modalities. A retrospective cohort of 211 EBRT patients was analyzed using a custom-designed in-house machine learning workflow. From this, a hierarchy of three models of increasing complexity was trained, evaluated for performance and generalization, and coupled with stylized small-scale salivary gland dosimetry to assess the influence of model complexity on the predicted NTCP for plausible patterns of RPT dose nonuniformity. The three models in the hierarchy (A, B, C), in increasing order of complexity, associate xerostomia with the following: the mean dose to the whole contralateral parotid (model A), the mean dose to a ductally localized region (model B) and a serial interaction dose term between two ductal sub-compartments (model C). While the difference between the three models for EBRT p-values and AUCs is rather marginal, for physiologically driven ductal dose distributions in RPT, the predicted reduction in TD50 can be as large as a factor of 10. These results provide hints towards a plausible reconciliation of the observed inconsistency of xerostomia in RPT with EBRT dose limits.

6009 Background: E3311 is a phase II trial of TOS by credentialed surgeons with pathology-driven deintensified post-operative management in HPV+ OPC. Intermediate risk patients were randomized between standard and reduced dose radiation. We present mature outcome data, at median follow up of 52.4 months (m). Methods: Patients were eligible who had resectable cT1-2 stage III/IV AJCC7 p16+ OPC without matted neck nodes. Those with clear margins, 0-1 + nodes (LN), and no extranodal extension (ENE) were observed (Arm A, N=38); those with clear margins, 2-4 + LN, or ENE ≤1mm were randomized to 50Gy (Arm B, N=100) or 60Gy (Arm C, N=108); those with involved margins, >4 + LN, or >1mm ENE received weekly cisplatin 40 mg/m2 and 60-66Gy (Arm D, N=113). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using a log-rank test, stratified by arm for comparisons of primary site and smoking history. Results: Among 359 evaluable patients, 54-m PFS and OS were 90.6% (90% CI: 87.2%, 93.1%) and 95.3% (90% CI: 93.0%, 96.9%). 54-m PFS by arm was: A 93.2% (90% CI: 79.6%, 97.8%); B 94.9% (90% CI: 89.7%, 97.5%); C 90.2% (90% CI: 82.7%, 94.6%) and D 85.5% (90% CI: 77.5%, 90.8%). 54-m OS by arm was: A 97.1% (90% CI: 85.7%, 99.4%); B 97.9% (90% CI: 93.5%, 99.3%), C 95.1% (90% CI: 90.1%, 97.6%) and D 92.5% (90% CI: 86.9%, 95.7%). Among patients in Arm A, 11 had N0 and 27 N1 stage. Median Arm A lymph node yield (LNY) was 29 (11 to 91 LN) and did not differ for patients with/without recurrence (p=0.83). All Arm A recurrences were in N1 patients: 1 at 18 m and 3 at > 40 m. No significant difference in PFS or OS was observed by prescribed radiation dose for intermediate risk patients (Arm B vs. C). Outcome did not differ by primary site of tonsil vs. other OPC (oOPC): 54-m PFS Tonsil 89.3% (90% CI: 84.9%, 92.5%) vs. oOPC 92.9% (90% CI: 87.0%, 96.2%), p=0.28, and 54-m OS Tonsil 94.6% (90% CI: 91.5%, 96.6%) vs oOPC 96.6% (90% CI: 92.4%, 98.5%), p=0.35. Smoking history also did not impact outcome. 54-m PFS was 89.9% (90% CI: 85.9%, 92.9%) for those with ≤10 pack-years (PY) tobacco exposure and 91.7% (90% CI: 83.9%, 95.9%) for those with >10 PY. Conclusions: TOS, neck dissection with deintensified risk-based post-operative management results in outstanding 54-m PFS and OS across all subsites of T1-2 p16+ OPC, irrespective of smoking history. Late recurrence is not increased when post-operative radiation is reduced from 60 to 50Gy for intermediate risk patients. Pathologic >1mm ENE (N=87), involved margin (N=12) or >4 involved LN (N=30) accurately identify patients at increased recurrence risk and outcomes were favorable among such patients. Among patients with favorable pathologic characteristics, a subset with N1 disease are at risk for late recurrence and further characterization of these patients is warranted. Clinical trial information: NCT01898494 .

6036 Background: E3311 is a phase II randomized study of intermediate risk HPV+ OPC patients who underwent TOS by credentialed surgeons and were then treated by pathology-guided, deintensified post-operative treatment. Recent retrospective population data suggest that time to post-operative radiotherapy (PORT) > 6 weeks is associated with worse progression-free survival (PFS). Methods: We retrospectively analyzed demographics, pathologic characteristics, and oncologic outcomes in E3311 by time to initiation of PORT (short vs long, exploring both 6 and 7 weeks postop as the cutpoint). Binary and categorical variables were compared using a chi-square test (or a Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. PFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test, which was stratified by intermediate- (Arms B/C) vs high-risk (Arm D). Results: Among 321 evaluable patients, the median time to initiation of PORT was 5.1 weeks (range 0.7-15.7); 5.0 (0.7-15.7) for Arm B, 5.1 (2.4-7.0) for Arm C, 5.6 (3.6-7.9) for Arm D. No significant difference in PFS or OS was observed whether PORT commenced by 6 or 7 weeks postoperatively, compared with longer time to initiation of PORT (p = 0.62 and 0.65, p = 0.30 and p = 0.41, respectively). 3-yr PFS rates were 93.5% (95% CI: 89.4%, 96.0%) among those treated ≤6 weeks, and 91.2% (95% CI: 81.4%, 95.9%) among those treated > 6 weeks; 3-yr OS rates were 96.1% (95% CI: 92.7%, 98.0%) among those treated ≤6 weeks, and 94.1% (95% CI: 84.9%, 97.8%) among those treated > 6 weeks. No significant differences in outcomes were observed between intermediate risk treatment arms (deintensified (50Gy) or standard dose (60Gy) RT). Additional demographic and pathologic characteristics, including primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between those with short vs long time to PORT, whether 6 or 7 weeks was used as the cutpoint. There were more T2 tumors in those treated > 7 weeks postop (84% vs. 49%, p = 0.007). PS = 1 patients were more numerous among those with shorter time to PORT (10% vs 0%, with the 7 week cutpoint). Conclusions: In contrast to retrospective NCDB data, intermediate- and high-risk HPV+ OPC patients enrolled on E3311 had favorable 3-yr PFS and OS rates that were not significantly worse when adjuvant therapy was started > 6 wks or > 7wks. These results argue against a survival advantage for initiation of PORT within 6 or 7 weeks for early-stage HPV+ OPC managed with high-quality transoral resection. The optimal time window to initiate PORT in HPV+ OPC patients remains to be determined. Clinical trial information: NCT01898494 .

6077 Background: E3311 is a phase II randomized study which showed favorable outcomes among intermediate (INT) risk HPV+ OPC patients (pts) who underwent TOS followed by pathology-guided or adapted, deintensified adjuvant treatment. Among HPV+ pts treated with definitive chemoradiation, survival outcomes are worse among those who smoked > 10 pack years (pk-yrs). Methods: We retrospectively analyzed demographics, pathologic results, and efficacy outcomes from E3311 by smoking group (current (C) vs. former (F) and > 10 vs. ≤10 pk-yrs – the latter a pre-specified stratification factor for INT patients). Binary and categorical variables were compared using a chi-square test (or Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test. Results: Among 359 evaluable pts, performance status (PS) was significantly worse for pts with > 10 pk-yrs vs. ≤10 pk-yrs (15.4% vs. 7.9% with PS of 1, p = 0.034). Primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between the groups of > 10 vs. ≤10 pk-yrs. Smoking status (F vs. C) was available for 182 pts with a history of smoking. Slightly more C vs. F smokers had tonsil as primary site (79.5% vs. 65.0%, p = 0.09). Positive margins were significantly more frequent among C smokers (10.3% vs. 2.1%; p = 0.029). Overall, there were no significant differences in PFS (p = 0.55) or OS (p = 0.94), comparing those with > 10 vs. ≤10 pk-yrs, or comparing C vs. F smokers (p = 0.76, p = 0.82, respectively). Similarly, no significant differences were observed within the treatment arms. (Table 1) Conclusions: In this analysis of smoking status in E3311, INT risk HPV+ OPC pts who are C smokers or have a history of > 10 pk-yrs had favorable 3-yr PFS and OS rates that were not significantly worse than those with < 10 pk-yrs history. This data represents the first treatment approach for HPV+ OPC in which outcomes were not influenced by smoking status. Clinical trial information: NCT01898494. [Table: see text]

PURPOSE Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus–associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.

6010 Background: Definitive or postoperative chemoradiation (CRT) is highly curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a potential deintensification strategy, we studied primary transoral surgery (TOS) and, in intermediate pathologic risk patients, reduced dose postoperative RT (PORT). Methods: E3311 is a phase II trial with randomization to reduced- or standard-dose PORT for resected stage III-IVa (AJCC7) intermediate pathologic risk HPV+ OPC, stratified by smoking history. Primary endpoints have been reported; we now present updated 3-year PFS and patient-reported outcomes (PRO), including head and neck-cancer specific quality of life (FACT-H&N) and swallowing perception and performance (MDADI). Results: Of 519 enrolled patients, 495 underwent TOS. The primary oncologic endpoint was 2-year PFS for 50 Gy (Arm B) or 60Gy (Arm C). Among 360 eligible and treated patients (ETP), Arm A (observation, N = 38) enrolled 11%, Arms B (N = 100) or C (N = 109) randomized 58%, and Arm D (66Gy + weekly cisplatin, N = 113) enrolled 31%. With 35.1 months median follow-up, 3-year PFS Kaplan-Meier estimate is 96.9% (90% CI [91.9%, 100%]) for Arm A; 94.9% (90% CI [91.3%, 98.6%]) for Arm B; 93.5% (90% CI [89.4%, 97.9%]) for Arm C; and 90.7% (90% CI [86.2%, 95.4%]) for Arm D. Recurrences and death without recurrence were 4 and 1 in Arm B, and 5 and one in Arm C. Smokers ( > 10 pack-years) did not have worse 3-year PFS in Arms B or C. Treatment arm distribution and outcome for ineligible patients who started adjuvant therapy mirrored the 360 ETP. A comparison combining arms B/C versus arm D in the proportion of patients stable/improved in FACT-H&N total score, from baseline to 6 months post-treatment as a pre-specified endpoint, was 56% vs. 38% (p value = 0.011, one-sided Fisher’s exact test); however, underlying differences in treatment and risk may be confounding. An exploratory comparison between Arms B and C revealed improvement in FACT H&N (63% in Arm B vs. 49% in Arm C had a stable/improved score, p-value = 0.056). Conclusions: Primary TOS and reduced PORT retained outstanding oncologic outcome at 35 months follow up, with favorable QOL and functional outcomes, in intermediate risk HPV+ OPC. Clinical trial information: NCT 01898494.

6500 Background: ECOG-ACRIN 3311 examines reduced postoperative therapy in patients with “intermediate risk” p16+ oropharynx cancer (OPC) undergoing primary transoral surgical management. We report the primary endpoint of 2-year progression free survival (PFS) for patients randomized to 50Gy vs 60Gy without chemotherapy. Methods: Between December 2013 and July 2017, 82 credentialed surgeons performed transoral resection (TOS) for 519 OPC patients (cT1-2 stage III/IV AJCC7 without matted neck nodes); post-operative management was determined by pathologically assessed risk. Among 353 eligible and treated patients, Arm A enrolled 10% (N=37) for clear margins, 0-1 nodes, no extranodal extension (ENE)), Arms B (50Gy, N=102) or C (60Gy, N=104) randomized 58%, for clear/close margins, 2-4 + nodes, or ENE ≤1mm, while Arm D (N=110, 60-66Gy plus weekly cisplatin, 40 mg/m2, positive margin with any T stage, >4 + nodes, or >1mm ENE) enrolled 31%. Arm D assignment was based on >1mm ENE (76%), > 4 nodes (27%), and/or positive margins (11%). Intermediate-risk patients were stratified by smoking history (>10 pk-yr). Of the 80 pts (15%) deemed ineligible, 28 had scans/labs not done per protocol, however treatment arm distribution for all patients mirrored that for the 353 pts eligible and treated. Results: Median follow-up was 31.8 months. 2 yr PFS for Arms A, B and C were 93.9% (90% CI=87.3%, 100%), 95.0% (90% CI=91.4%, 98.6%) and 95.9% (90% CI=92.6%, 99.3%) respectively, while Arm D was 90.5% (90% CI=85.9%, 95.3%). The regimen of TOS + low-dose radiation is considered worthy of further study, since the primary endpoint of the upper bound of the 90% CI (in the intermediate risk group) exceeding 85% was met. Of 17 progression events, 7 were locoregional. There were 10 distant recurrences: Arm A=1, Arm B=2, Arm C=4, Arm D=3. Grade III/IV treatment-related AE rates were 15%/2% during surgery, 13%/2% for Arm B and 25%/0% for Arm C. There were 2 treatment-related deaths (one surgical and one Arm D). Conclusions: Transoral resection of p16+ OPC is safe and results in good oncologic outcome, presenting a promising deintensification approach. For patients with low-risk disease, 2-yr PFS is favorable without post-operative therapy. For those with uninvolved surgical margins, <5 involved nodes, and minimal (<1mm) ENE, reduced dose postoperative RT without chemotherapy appears sufficient. Transoral surgery plus 50Gy should be compared to optimal non-surgical therapy in a phase III trial. Clinical trial information: NCT01898494 .