Patients with pancreatic cancer who received chemotherapy both before and after surgery experienced longer survival rates than would be expected from surgery followed by chemotherapy, according to researchers at Yale Cancer Centre (YCC) and Yale School of Medicine.
The study included patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of pancreatic cancers. An aggressive cancer with a high mortality rate, PDAC is predicted to become the second leading cause of cancer-related deaths in the US by 2030.
The findings, say the researchers, are encouraging for the 15% to 20% of pancreatic cancer patients whose tumours are operable.
The single-arm (only one treatment type or regimen) phase 2 trial evaluated a modified form of the chemotherapy treatment FOLFIRINOX (a combination treatment consisting of leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin approved in 2011 as a first-line treatment for patients with metastatic pancreatic cancer).
Patients in the trial received six cycles of the modified FOLFIRINOX before surgery, followed by an additional six cycles of the chemotherapy treatment after surgery. The modified regimen consisted of slightly lower doses of FOLFIRINOX to improve tolerability, which was previously shown in a 2016 publication not to impact outcomes negatively.
Of the 46 patients who started the modified treatment, 37 completed all six cycles of chemotherapy before surgery and 27 had successful tumour removal operations.
For all enrolled patients, the 12-month progression-free survival rate – meaning the disease did not worsen – was 67%, indicating significant progress in controlling the disease. Furthermore, 59% of all patients lived at least two years after completing the full chemotherapy treatment plan and surgery.
The study, which was published in JAMA Oncology, was the first of its kind for patients with PDAC when senior author and YCC member Dr Jill Lacy started it in 2014. The goal had been a 12-month progression-free survival rate of at least 50% of patients.
“When the study launched, even with operable pancreatic cancers, 90% of patients were still relapsing and dying from their cancer eventually,” said Dr Michael Cecchini, the first author of the study and the co-director of the colorectal programme at the Centre for Gastrointestinal Cancers at Smilow Cancer Hospital and YCC.
“We sought to move chemotherapy up in their treatment regimen and give it before surgery to see if we could improve the outcome for our patients.”
The study used advanced techniques to monitor the progress of treatment, including analysing circulating tumour DNA (ctDNA) and using the cancer biomarker keratin 17 to help predict outcomes. For example, patients with detectable ctDNA four weeks’ post-surgery had significantly worse progression-free survival than those who had no detectable ctDNA.
Cecchini said larger randomised clinical trials are needed to continue to investigate the role of FOLFIRINOX before surgery for patients with operable PDAC.
“I think even though there have been changes in standard of care for patients with this aggressive pancreatic cancer type, we have very promising data to justify a larger study,” he said.
Study details
Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Non-randomised Controlled Trial
Michael Cecchini, Ronald Salem, Jill Lacy et al.
Published in JAMA Oncology on 20 June 2024
Key Points
Question Does perioperative 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) improve survival in patients with resectable pancreatic ductal adenocarcinoma (PDAC)?
Findings In this single-arm phase 2 nonrandomised controlled trial for resectable PDAC including 46 patients, the 12-month progression-free survival (PFS) was 67%, which met the primary end point of a 12-month PFS of 50% or greater. Detectable circulating tumour DNA levels, high tumour keratin 17 expression, and mutational signature SBS15 were associated with decreased survival.
Meaning In this study, perioperative modified FOLFIRINOX was safe and effective, with a clinically meaningful improvement in survival compared with historical controls.
Abstract
Importance
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumour, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection.
Objective
To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival.
Design, Setting, and Participants
This open-label, single-arm, phase 2 nonrandomised controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from 3 April 2014, to 16 August 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analysed from January to July 2023.
Interventions
Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumour DNA (ctDNA) levels. Tumours were evaluated for treatment response and keratin 17 (K17) expression.
Main Outcomes and Measures
The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumour molecular features, and K17 tumour levels. Survival curves were summarised using Kaplan-Meier estimator.
Results
Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had non-significantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07).
Conclusions and Relevance
This nonrandomised controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomised clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies.
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