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Andrew H. Ko and Christopher H. Crane

It is well established that the development of distant metastatic disease represents the dominant pattern of tumor recurrence/progression among patients with operable and locally advanced pancreatic cancer. However, the contribution of localized or locoregional tumor burden to pancreatic cancer–associated morbidity and mortality may be underappreciated, and therefore balancing competing considerations of systemic versus local disease control becomes important in therapeutic decision-making. The role of local therapies, particularly radiation therapy, has remained somewhat controversial in this disease context. Several phase II and III trials have sought to address the relative importance and role of radiation in both the localized and locally advanced settings, including the sequencing of this modality relative to systemic therapy and its optimal means of administration. However, differences and limitations in study design have produced mixed results, particularly in terms of the contribution of radiation to overall survival benefit. An emerging paradigm that makes conceptual sense and remains the subject of active investigation is to start with a defined period of systemic treatment, thus limiting radiation to the subset of patients who do not manifest with metastatic disease during initial therapy and are therefore most likely to benefit from local control.

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Quisette P. Janssen, Jacob L. van Dam, Laura R. Prakash, Deesje Doppenberg, Christopher H. Crane, Casper H.J. van Eijck, Susannah G. Ellsworth, William R. Jarnagin, Eileen M. O’Reilly, Alessandro Paniccia, Marsha Reyngold, Marc G. Besselink, Matthew H.G. Katz, Ching-Wei D. Tzeng, Amer H. Zureikat, Bas Groot Koerkamp, Alice C. Wei, and for the Trans-Atlantic Pancreatic Surgery (TAPS) Consortium

Background: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. Methods: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012–2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0–20 vs 21–40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1–4 vs 5–8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. Results: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score–matched. After matching, median OS was 26.2 months (95% CI, 24.0–38.4) with RT versus 32.8 months (95% CI, 25.3–42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). Conclusions: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.