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Expert Insights: Pancreatic Cancer

Trends in Proton and Carbon Ion Therapy to Assist Clinical Choices and Research Pursuits

Jim ApisarnthanaraxIntensity-Modulated Proton Therapy for Localized Pancreas Cancer: A Dosimetric Analysis and Clinical Outcomes

Smith "Jim" Apisarnthanarax, MD

University of Washington, Seattle Cancer Care Alliance

A recent study by Jethwa et al from Mayo Clinic (Rochester, MN) reported their institutional experience using pencil-beam scanning (PBS) intensity-modulated proton therapy (IMPT) for 13 localized (borderline resectable, unresectable) pancreatic cancers, and presented a matched dosimetric comparison with photon volumetric modulated arc therapy (VMAT).1  Although this study was a retrospective analysis, the authors prospectively assessed toxicities and collected patient-reported outcomes (PRO) of quality-of-life metrics before and at the end of treatment.  IMPT delivered 45 Gy to the elective nodal region and 50 Gy to the gross tumor over 25 fractions using a simultaneous integrated-boost technique combined with concurrent capecitabine or 5-FU-based chemotherapy.

No patient experienced a grade 3 or higher acute toxicity and no decline in PROs was observed from baseline. Although these results are not novel, they add to the existing literature to confirm and showcase the potential minimal acute toxicities that protons may offer in this patient population.  With such small patient numbers, however, it is unclear the incremental reduction in acute toxicity gained with protons, particularly when compared to intensity-modulated radiation therapy (IMRT) or stereotactic body radiotherapy (SBRT), for which acute toxicities are also reported to be relatively low.  Local control was modest at best (66% at 1 year), but not particularly surprising since standard doses of 50 Gy were delivered.  The optimal benefit of protons in pancreatic cancer may not be truly realized until data on dose escalation (either with conventional fractionation or hypofractionation) with protons begin to emerge.  Importantly, just as volumetric image guidance (cone-beam computed tomography [CBCT] or CT on rails) is instrumental in delivering photon-based SBRT safely, it will also be critical to integrate volumetric imaging into image guidance and verification for safe proton dose escalation in pancreatic tumors.

A few points about the dosimetric analysis is worth mentioning.  In this study, IMPT was able to statistically and meaningfully reduce the dose (up to 45 Gy) to the small bowel, duodenum, stomach, large bowel, liver, and kidneys compared to VMAT while maintaining similar clinical target volume (CTV0 coverage.  The dosimetric advantage of protons often lies in the low-moderate dose range (0-30 Gy); however, IMPT was dosimetrically superior for doses up to 45 Gy in this study, which contrasts with other studies that showed little to no dosimetric advantage to protons above 30 Gy for localized pancreatic cancers.  As the authors pointed out, this difference may be explained by the use of multi-field optimization (“true” IMPT) versus single-field optimization and small PBS spot sizes that reduce the effective beam penumbra.  It is unclear what the dose coverages were between IMPT and VMAT at the prescription dose level and higher.  Due to the range uncertainty with protons, the max point dose and above could potentially be higher with IMPT compared to VMAT, unless methods are employed to slightly underdose target volumes that are in close proximity to organs at risk.. 

1. Jethwa KR, Tryggestad EJ, Whitaker TJ, et al: Initial experience with intensity modulated proton therapy for intact, clinically localized pancreas cancer: Clinical implementation, dosimetric analysis, acute treatment-related adverse events, and patient-reported outcomes. Adv Radiat Oncol 3:314-321, 2018. 

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