Patient-tailored FOLFIRINOX as first line treatment of patients with advanced pancreatic adenocarcinoma

Abstract

FOLFIRINOX is one of the most effective reference regimens in the 1st line treatment of locally advanced (LA) and metastatic pancreatic cancer (mPC), despite its high toxicity. We evaluated our real-life experience with "patient-tailored intent to treat FOLFIRINOX" in patients with LA or mPC compared to other reports along with the pivotal phase III trial.We analyzed data from all consecutive patients with pancreatic ductal adenocarcinoma treated with dose-modified FOLFIRINOX in 2016 at Paul Brousse University Hospital. Irinotecan was administered whenever initial serum bilirubin was <1.5 × upper limit of normal. Oxaliplatin was stopped for severe sensory neuropathy. Initial dose reductions were made according to patient profile (eg, age, comorbidities) and later due to toxicity. The treatment was continued until surgery or disease progression. Endpoints were time to progression (TTP), overall survival (OS), objective response rate (ORR), and secondary complete resection (R0R1).Thirty-seven patients with unresectable LA or mPC received patient-tailored FOLFIRINOX as 1st line chemotherapy. There were 22 male (59%) and 15 female patients (41%) aged 44 to 81 years with LA (18 patients, 49%) and mPC (19 patients, 51%). They had World Health Organization-performance status of 0 (59%) or 1 (41%). A total of 384 cycles were administered. Median dose intensities (mg/m/w) were 28.9 for oxaliplatin, 56.8 for irinotecan, and 886.2 for 5-fluorouracil. Thirty-four patients were assessed for response; ORR and disease control rates were 47% and 85%, respectively. R0R1 rate was 30%. Median TTP and OS were 9.6 and 14.6 months. LA disease was associated with significantly longer TTP and OS (P < .001).FOLFIRINOX with patient-tailored dose adaptations seems to offer better results in patients with advanced PC. This approach in the neoadjuvant setting results in a macroscopic R0R1 in 61% of patients with initially unresectable disease. It deserves prospective evaluation to further improve outcomes in the management of advanced PC.

Figure 1

Intent to treat FOLFIRINOX in real life practice. Strategy flowchart: FOLFIRINOX combining 5FU, leucovorin, irinotecan CPT11, and oxaliplatin. All these drugs were administered when the bilirubin level was less than 1.5 ULN. If not, FOLFIRINOX was started without CPT11 until it became ≤1.5.ULN. L-OHP was stopped in case of grade 2 or more sensory neuropathy. 5FU = 5-fluorouracil, CPT11 = irinotecan, LV = leucovorin, L-OHP = oxaliplatin, ULN = upper limit of normal.

Figure 2

TTP and OS according to initial disease extension. (A) Kaplan–Meier curves of TTP according to initial disease extension. Median TTP was 19.8 mo (11.9–27.8) for locally advanced tumor and 6.7 mo (3.6–10.1) for metastatic disease; P (Log Rank) <.001. (B) Kaplan–Meier curves of OS according to initial disease extension. Median OS was not reached for locally advanced tumor. It was 9.4 mo (6.2–12.6) for metastatic disease; P (Log Rank) < .001. OS = overall survival, TTP = time to progression.

Figure 3

Intent to treat TTP and OS curves according to secondary tumor resection R0R1 in patients with LA disease. (A) Kaplan–Meier curves of TTP according to R0R1 resection, Median TTP was 19.8 mo (14.2–25.5) for resected patients and 11.2 mo (4.4–18.1) for nonresected patients, P (Log Rank) = .550. (B) Kaplan–Meier curves of OS according to R0R1 resection. Median OS was not reached for both resected and nonresected patients, P (Log Rank) = .936. LA = locally advanced, OS = overall survival, TTP = time to progression.

Figure 4

Comparison of TTP and OS curves of metastatic and LA nonresected patients. (A) Kaplan–Meier curves of TTP in metastatic and LA nonresected patients. Median TTP was 11.2 mo (4.4–18.0) for LA nonresected patients and 6.9 mo (3.6–10.1) for metastatic patients, P (Log Rank) = .030. (B) Kaplan–Meier curves of OS in metastatic and LA nonresected patients. Median OS was not reached for LA nonresected patients and 9.4 mo (6.2–12.6) for metastatic patients, P (Log Rank) = .007. LA = locally advanced, OS = overall survival, TTP = time to progression.

Figure 5

Forest-plot of prognostic factors for TTP and OS after multivariate Cox-Model hazard ratio computing. The upper plot displays the prognostic factors for intent to treat TTP (A); the plot below presents the prognostic factors of OS (B). Variables in bold are those that are significantly associated with TTP or OS. OS = overall survival, TTP = time to progression.