Accelerated Hypofractionated CRT Followed by SABR Boost (HyCRT-SABR) for Locally Advanced Unresectable NSCLC: A Prospective Phase II Radiation Dose-Escalation Study


      To report on a completed Phase II prospective trial of Image-guided Hypofractionated CRT followed by dose-escalated (DE - 3 cohorts) SABR boost (HyCRT-SABR) for locally advanced unresectable NSCLC. Primary endpoint was to determine the maximal tolerated dose (MTD) or deliver a total dose of 75 Gy in 15 fractions (fx) with 3 weekly infusions of carboplatin-paclitaxel.


      HyCRT-SABR was conducted at a single academic institution under local IRB/DSMB governance. All patients received an initial 10 fx of 4 Gy with CT, followed by 3 sequential cohorts of at least 7-15 patients of 5 Gy x 5, 6 Gy x 5, 7 Gy x 5 [total dose 65 gy in 15 fx – (LOW); 70 gy in 15 fx (INT); 75 Gy in 15 fx (HIGH)]. Study was designed to end if the rate of dose limiting toxicities (DLTs) within 90 days from treatment is ≥ 33%. MTD was defined as the immediately prior dose cohort. PET-CT/4DCT was performed for treatment planning with an ITV approach. In the first 40 Gy, PTV was defined as ITV + 5 mm. A repeat PET-CT/4DCT was performed at fx 8 or 9, with an adaptive re-plan for the SABR boost. In the boost, ITV was the target volume (no PTV margin). Treatment was completed in 3 weeks without unintended breaks between initial vs. adaptive SABR boost. An intention-to-treat analysis was performed. Local control (LC), overall survival (OS) and progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and survival rates compared using the log-rank test. Acute and late (≥ 90 days) toxicities were prospectively scored.


      The study did not reach DLT endpoint, and all 3 cohorts of DE were completed. From 2010 – 2018, a total of 28 patients were enrolled and treated on protocol. All patients had stage II or III NSCLC by AJCC 7th edition. Only one subject received consolidation durvalumab (end of enrollment period in 2018). Overall median f/u time was 18 months (mos), and for the 10 surviving patients it was 27 mos. Median OS for all patients was 27 mos, with 1 and 2-year OS rates of 78% and 52%. Median PFS was 12 mos, with 1 and 2 –year PFS rates of 48% and 25%. 1, 2, 3-year LC rates were 91%, 82%, 82%. No statistical differences were seen in LC, PFS, and OS by LOW, INT, and HIGH dose cohorts (p = ns). Overall cumulative incidences of non-hematological rates of acute and late ≥ grade 3 toxicities were 11% and 7%. Numerically, there were higher rates of acute and late pulmonary ≥ grade 3 toxicities in HIGH vs. LOW+INT cohorts (22% vs 0%, p=.1; 11% vs 0%, p=.3). However, there were no differences in the rates of acute and late esophageal ≥ grade 3 toxicities in HIGH vs. LOW+INT cohorts (0% vs 5%, p=1; 0 vs 5%, p=1).


      MTD was determined to be 70 Gy in 15 fx. OS of 27 mos in this study is similar to the 60 Gy arm of RTOG 0617 and CRT alone arm in PACIFIC (29 mos). HyCRT-SABR appears effective, convenient, and well-tolerated. With improvement in OS by adding durvalumab to standard CRT, this HyCRT-SABR regimen appears promising as a back-bone treatment to test and integrate immunotherapy.


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