MR-guided radiation therapy with concurrent gemcitabine / nab-paclitaxel chemotherapy in inoperable pancreatic cancer: a TITE-CRM phase I trial

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International journal of radiation oncology, biology, physics


BACKGROUND: Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. MR-guided radiation therapy (MRgRT) may safely permit radiation and chemotherapy dose escalation.

METHODS: We conducted a single-arm phase I study to determine the maximum tolerated dose (MTD) of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m(2)) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40-45 Gy / 25 fxs with chemotherapy (600-800/75 mg/m(2)) to 60-67.5 Gy / 15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m(2)). The primary endpoint was MTD of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic or G3 gastrointestinal requiring hospitalization >3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS).

RESULTS: Thirty patients enrolled (3/2015-2/2019), with 26 evaluable patients (2 progressed before radiation, 1 determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% [3.3%-24.9%] with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m(2)) and 67.5 Gy / 15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% CI, 10.9-28.2 months). The median OS for patients with ECOG 0 and CA 19-9 <90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. 2-year LPFS and DMFS were 85% (95% CI, 63-94%) and 57% (95% CI, 34-73%), respectively.

CONCLUSIONS: Full-dose gemcitabine/nab-paclitaxel with ablative MRgRT dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS.


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ePub ahead of print