New regimen allows for margin-negative resections, extends survival in pancreatic cancer
Neoadjuvant FOLFIRINOX chemotherapy with losartan followed by chemoradiotherapy appeared associated with a high rate of margin-negative resection and improved survival among patients with locally advanced pancreatic ductal adenocarcinoma, according to results of a single-arm phase 2 study published in JAMA Oncology.
“Around 40% of [patients with] pancreatic cancer have either locally advanced or borderline resectable disease, with historically poor rates of successful surgery,” Janet E. Murphy, MD, MPH, medical oncologist in the hematology/oncology division of the department of medicine at Massachusetts General Hospital, said in a press release. “To be able to successfully remove the primary tumor in 61% of patients sets a new benchmark and offers much hope. To our knowledge, this is the first [locally advanced pancreatic cancer] clinical trial that defined surgical success as its primary outcome.”
The trial by Murphy and colleagues included 49 patients (median age, 63 years; range, 42-78; 53% women) with previously untreated locally advanced unresectable pancreatic cancer with ECOG performance status of 0 (73%) or 1 (27%) and sufficient hematologic, renal and hepatic function.
Participants received eight cycles of FOLFIRINOX — composed of fluorouracil, leucovorin, oxaliplatin and irinotecan — and the angiotensin receptor blocker losartan over a 4-month period. Previous studies in animal models of breast, ovarian and pancreatic cancer have shown losartan improves delivery of chemotherapy drugs by reducing pressures in the tumor microenvironment, according to the press release.
Patients with radiographically resectable tumors after chemotherapy, determined by evaluation of CT scans, received short-course chemoradiotherapy (25 GyE in five fractions with protons or 30 Gy in 10 fractions with photons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy in 28 fractions with a vascular boost to 58.8 Gy in 28 fractions) with fluorouracil or capecitabine.
Margin-negative resection rate served as the primary outcome.
Thirty-nine patients (80%) completed the eight cycles of FOLFIRINOX and losartan. The other 10 patients received fewer cycles because of progression (n = 5), losartan intolerance (n = 3) and toxicity (n = 2).
Thirty-eight patients underwent long-course chemoradiotherapy and seven patients received short-course chemoradiotherapy.
Following chemoradiotherapy, 42 patients proceeded to surgery and 34 underwent resection (69% of study population; 95% CI, 55-82). Margin-negative resection was achieved in 30 patients (61%; 95% CI, 46-75).
With median follow up of 17.1 months (range, 5-53.7) among 27 patients alive at the completion of the study, results showed overall median PFS of 17.5 months (95% CI, 13.9-22.7) and median OS of 31.4 months (95% CI, 18.1-38.5).
Among patients who underwent resection, median PFS was 21.3 months (95% CI, 16.6-28.2), and a median OS was 33 months (95% CI, 31.4 to not reached). Three patients who underwent resection achieved pathologic complete response.
Circulating biomarker analyses showed significant associations (P < .001) between FOLFIRINOX and losartan and decreases in expression of transforming growth factor-beta (TGF-), a key feature of the angiotensin-signaling pathway, and thrombospondin-1 (TSP1).
About half of patients in the trial (51%) experienced grade 3 or higher adverse events, the most common of which were grade 3 diarrhea, thrombocytopenia and neutropenia.
A lack of randomization served as the study’s primary limitation.
“A key part of the success of our approach was our surgeons’ willingness to attempt an operation even in patients who had the appearance of cancer at or near their blood vessels,” Murphy said in the release. “We learned in a previous study — confirmed here – that CT scan results and resectability are no longer clearly correlated after chemotherapy and radiation. While we did not see total blood vessel clearance in 61% of patients, 61% achieved complete removal of their cancer.”– by John DeRosier
Disclosures: Murphy reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.