PURPOSE/OBJECTIVE(S): Patients with node-positive (LN+) uterine or cervical cancer often require post-operative radiation (RT) to the pelvis and para-aortic nodes. A prospective phase II study was conducted to evaluate the efficacy of proton beam RT for LN+ uterine or cervical cancer. MATERIALS/METHODS: Patients with IIIC uterine and cervical cancer post hysterectomy and lymphadenectomy were eligible. Patients received 45 Gy(RBE) in 25 fractions with proton pencil beam scanning (PBS-PT). Primary endpoints included comparing dose volume histogram (DVH) and toxicity (CTCAE v4.02) between PBS-PT and IMRT or 3DCRT. Secondary endpoints included progression free survival (PFS), overall survival (OS), patterns of recurrence, and quality of life (QOL using FACT-En/Cx V4). RESULTS: 21 patients completed RT between 10/2013 and 10/2018. Median follow-up was 60.6 months (range, 11.2 - 68.8). There were 15 uterine and 6 cervical cancer patients. Four received pelvic and 17 received extended-field-RT. DVH comparisons showed significantly less volume treated with PBS-PT compared to 3D-CRT and IMRT for bowel, bone marrow, and kidney (all p<
0.05) at all dose levels except V45 bladder and bowel. Acute and late grade 3 GI toxicity were 14 % and 4.7 %, respectively. There were no acute or late grade 3 GU toxicities. Acute and late grade 3 hematologic toxicities were 24 % and 4.7 %, respectively. There was one late grade 3 lymphedema. The 2- and 5- year PFS were 81 % (95 % CI, 56 %-92 %) and 76 % (95 % CI, 51 %-89 %). There were no in-field recurrences. The 2- and 5-year OS were 86 % (95 % CI, 62 %-95 %) and 80 % (95 % CI, 55 %-92 %). QOL increased significantly over time with average increase of 10.7 points from baseline to 5 years (95 % CI: 0.9 to 20.4, p=0.032). CONCLUSION: Compared to photon radiotherapy, PBS-PT treats significantly less normal tissue volume. PBS-PT appears effective in preventing local-regional recurrence in LN+ patients with minimal acute and late toxicity. QOL significantly improved from baseline to 5 years.