# Multi-Institutional Comparison of Ablative 5-Fraction Magnetic Resonance-Guided Online Adaptive Versus 15/25-Fraction Computed Tomography-Guided Moderately Hypofractionated Offline Adapted Radiation Therapy for Locally Advanced Pancreatic Cancer

## TL;DR

This study compares two radiation therapy approaches for pancreatic cancer, finding that the SMART method reduces local tumor recurrence without worsening survival or toxicity.

## Contribution

The first multi-institutional comparison of SMART and HART for locally advanced pancreatic cancer, showing SMART's potential to improve local control.

## Key findings

- SMART achieved significantly lower two-year local failure (6.5%) compared to HART (32.9%).
- SMART plans showed better target volume coverage and hotspot intensities than HART.
- Late grade >3 toxicity was lower with SMART than HART.

## Abstract

We conducted the first comparison of dose-escalated 5-fraction SMART and 15/25-fraction HART for locally advanced pancreatic cancer. Despite a higher proportion of tumors treated with SMART being located in the pancreatic head and presenting with anatomically unfavorable features, target volume coverage and hotspot intensities were greater in SMART plans, potentially facilitated by the use of online adaptive radiation therapy. Two-year local failure was significantly lower with SMART compared to HART, although two-year overall survival did not differ significantly. Both dose-escalated SMART and HART achieved favorable oncologic outcomes and should be evaluated in future prospective trials.

Background: Radiation dose escalation for locally advanced pancreatic cancer (LAPC) using stereotactic magnetic resonance (MR)-guided online adaptive radiation therapy (SMART) or computed tomography (CT)-guided moderately hypofractionated ablative radiation therapy (HART) can achieve favorable outcomes although have not previously been compared. Methods: We performed a multi-center retrospective analysis of SMART (50 Gy/5 fractions) vs. HART (75 Gy/25 fractions or 67.5 Gy/15 fractions with concurrent capecitabine) for LAPC. Gray’s test and Cox proportional regression analyses were performed to identify factors associated with local failure (LF) and overall survival (OS). Results: A total of 211 patients (SMART, n = 91; HART, n = 120) were evaluated, and none had surgery. Median follow-up after SMART and HART was 27.0 and 40.0 months, respectively (p < 0.0002). SMART achieved higher gross tumor volume (GTV) coverage and greater hotspots. Two-year LF after SMART and HART was 6.5% and 32.9% (p < 0.001), while two-year OS was 31.0% vs. 35.3% (p = 0.056), respectively. LF was associated with SMART vs. HART (HR 5.389, 95% CI: 1.298–21.975; p = 0.021) and induction mFOLFIRINOX vs. non-mFOLFIRINOX (HR 2.067, 95% CI 1.038–4.052; p = 0.047), while OS was associated with CA19-9 decrease > 40% (HR 0.725, 95% CI 0.515–0.996; p = 0.046) and GTV V120% (HR 1.022, 95% CI 1.006–1.037; p = 0.015). Acute grade > 3 toxicity was similar (3.3% vs. 5.8%; p = 0.390), while late grade > 3 toxicity was less common after SMART (2.2% vs. 9.2%; p = 0.037). Conclusions: Ablative SMART and HART both achieve favorable oncologic outcomes for LAPC with minimal toxicity. We did not observe an OS difference, although technical advantages of SMART might improve target coverage and reduce LF.