PRO-ACTIVE: Results of a pragmatic phase IV randomized trial comparing the effectiveness of prophylactic swallow intervention for patients receiving radiotherapy for head and neck cancer.

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LBA12000 Background: Swallowing therapy during radiotherapy (RT) for head and neck cancer (HNC) has gained popularity as a dysphagia mitigation strategy, yet optimal timing and intensity of therapy remains uncertain. The PRO-ACTIVE trial compared the effectiveness of prophylactic and reactive swallowing therapies during RT. We hypothesized that PRO-ACTIVE therapies are more effective than RE-ACTIVE; and, that more intensive PRO-ACTIVE (EAT+EXERCISE) is superior to less intensive PRO-ACTIVE (EAT). Methods: PRO-ACTIVE was an international, multi-site pragmatic phase IV randomized clinical trial (NCT03455608). Eligible, adult patients had functional baseline swallowing and received RT ≥60-Gy for HNC with bilateral neck fields. Prior to RT, patients were randomized 1:2:2 to 1) RE-ACTIVE, 2) PRO-ACTIVE EAT, or 3) PRO-ACTIVE EAT+EXERCISE arms and followed for 1 year. RE-ACTIVE received weekly monitoring with therapy only if/when dysphagic, and PRO-ACTIVE arms received bi-weekly therapy pre- and during RT. The primary endpoint was feeding tube (FT) use in days from the end of RT to 1 year. Secondary endpoints were patient-reported and clinician-graded outcomes. Adjusted linear regression compared FT days per intention-to-treat with a gate-keeper approach to test hypotheses in hierarchical order with 80% power to detect a small effect size (≥.21 SD) with type 1 error probability of 0.5 (two-sided). Results: 952 patients from 13 institutions were randomized to RE-ACTIVE (n=196), PRO-ACTIVE-EAT (n=377) or PRO-ACTIVE-EAT+EXERCISE (n=379). 21 (2.2%) patients exited before intervention, thus, 931 were retained for analysis. The majority had stage I/II disease (552/931, 59.3%), oropharyngeal tumors (647/931, 69.5%), and p16+ and/or HPV+ disease (680/931, 73.0%). Baseline function was excellent (499/931 (53.5%) grade 0 dysphagia, mean [SD] MDADI 86 [14]). All patients received curative intent RT (median 70 Gy), 706/931 (75.8%) with chemotherapy, and 105/931 (11.3%) with primary site surgery. 364 of 931 (39.1%) required a FT with 34.4 (SD 75.9) mean days of use. Adjusted FT days at 12-months did not meaningfully differ by pro- and re-active timing (∆5.4 days, 95% CI -6.5 to 17.2, p=0.37) or EAT versus EAT+exercise intensity (∆5.9 days, 95% CI -3.8 to 17.6, p=0.21). Swallowing-related QOL, diet, weight/BMI, and dysphagia symptoms did not differ meaningfully by arm. Conclusion: FT utilization was lower than expected and secondary measures of swallowing outcomes were favorable across all arms of the PRO-ACTIVE trial reflecting relative effectiveness of EAT and exercise therapies regardless of timing or intensity of therapy delivery during RT for HNC. As a pragmatic trial, we are robustly powered to examine heterogeneous treatment effects in subgroup analyses and image-based swallowing metrics as critical next steps. Clinical trial information: NCT03455608 .

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