Sequential Treatment With GEMBRAX and Then FOLFIRINOX Followed by Stereotactic MRI-guided Radiotherapy in Patients With Locally Advanced Pancreatic Cancer

Pancreatic cancer was the third cause of death by cancer worldwide in 2016, surpassing breast cancer. It is estimated that in 2030, pancreatic cancer will become the second cause of death by cancer after lung cancer. Its prognosis is very poor, with an overall survival (OS) at 5 years, all stages included, of 5.5%. According to the French cancer registry network (FRANCIM), its incidence has more than doubled in men and women between 1990 and 2018. The world standardized incidence rates for men and women were 5.2% and 2.7% in 1990 and 11% and 7% in 2018, respectively. This means a yearly annual increase of 2.7 for men and of 3.8 for women. The often late diagnosis, in 50% of cases at stage 4, and the limited treatment options explain the very low survival rate at 5 years. Currently, only surgery associated with adjuvant chemotherapy for 6 months allows doubling this survival rate. However, this situation concerns only 20% of cases. Indeed, 50% of pancreatic cancers are discovered at stage 4, and in 30% of patients cancer is detected when not resectable and non-metastatic (i.e. borderline resectable or locally advanced). To make an unresectable cancer resectable is one of the therapeutic strategies under development. However, treatment of locally advanced pancreatic cancer (LAPC) is not standardized. Chemotherapy is a used strategy, but 30% of cases will progress to metastatic disease. Therefore, the need in LAPC to control not only the local disease but also micro-metastases has led to the development of combined strategies with chemotherapy and optimal radiotherapy. For LAPC, chemotherapy is based on two drug combinations that are classically used for the first-line treatment of metastatic disease: FOLFIRINOX (FFX) (association of 5FU, Oxaliplatin and Irinotecan) and GEMBRAX (GA) (association of gemcitabine and nab-paclitaxel). Their association has been validated by phase 3 studies showing that compared with gemcitabine alone, they allow increasing the response rate by three times (30%), and almost doubling the median survival and progression-free survival, but with higher grade 3 hematologic and neurological toxicities. FFX and GA have been assessed also in LAPC. Retrospective studies confirmed the high response rate, 30 to 80% according to the study, and a median survival of 9 to 30 months. Recently, two phase 2 studies, evaluated GA alone and GA followed by FFX, respectively, for LAPC, and confirmed the efficacy, with a response rate of 30% and a secondary resection rate of 15% and 30.6%, respectively. Moreover, in patients who underwent tumour resection after treatment, survival was longer than in those not operated (27.4 vs 14.2 months; Hazard Ratio (HZ) = 0.45; p = 0.0035). Overall Survival (OS) (n= 165 patients) was 17.2 months. GABRINOX is a sequential treatment with GA and then FFX with the aim of limiting chemoresistance, decreasing toxicities and improving dose intensity. The feasibility and tolerance of this approach as first-line treatment of metastatic disease were validated in a phase 1 study, and its efficacy in a phase 2 study in which the primary objective was reached: objective response rate of 64.9%, disease control rate of 84.2%, progression-free survival (PFS) of 10.5 months, and Overall Survival (OS) of 15.1 months. Its tolerance profile is favorable with lower percentages of patients with neutropenia (34.5%), febrile neutropenia (3.5%), and neurotoxicity (5.2%). The role of chemo-radiotherapy for LAPC remains controversial. Many old studies showed the interest of this technique for the local and global control in patients with pancreatic cancer. However, a phase 3 study compared the efficacy of chemo-radiotherapy versus chemotherapy alone in patients without disease progression after chemotherapy with a regimen that is currently considered not optimal (i.e. gemcitabine with/without erlotinib). Although OS (the main endpoint) did not improve in the chemo-radiotherapy arm compared with the chemotherapy arm, PFS was significantly increased in the chemo-radiotherapy arm with a longer period without treatment (6.1 vs 3.7 months, P = 0.02) and a lower percentage of patients with locoregional progression (32% vs 46%, P =0.03). This confirms that radiotherapy is an effective treatment in pancreatic adenocarcinoma, but that the current delivery modalities do not allow significantly improving the patient prognosis. Indeed, the study used 3D conformal radiotherapy with conventional doses and classical fractioning. Retrospective and phase 1 and 2 studies that used more optimized techniques and higher doses reported better local disease control, but without an important impact on survival. Moreover, some studies suggest significant toxicity, particularly in gastrointestinal organs. Intensity-modulated radiotherapy and integrated boost radiotherapy showed promising local control and survival results. This suggests an avenue for technological improvement and dose augmentation to improve patient prognosis. Stereotactic magnetic resonance-guided adaptive radiotherapy is a new modality for dose delivery that exploits Magnetic Resonance Imaging (MRI)-guided linear accelerators to better target the treatment volume, while optimizing the protection of organs at risk. The tumour localization in the pancreas seems to be particularly suitable for the utilization of MRI-guided linear accelerators because the radiotherapy doses are limited in function of the gastrointestinal organ tolerance: duodenum, stomach, small intestine, colon. Recently, the results of a retrospective, multicentre study on irradiation of patients with LAPC using Magnetic Resonance Imaging (MRIdian® Linac™; Viewray. The study shows that survival was improved in patients who received an augmented irradiation dose. Specifically, the 2-year OS rate was 49% for patients who received a dose higher than 70 Gy and 30% for patients who received a lower equivalent dose. The study did not report significant toxicity in patients who received high-dose radiotherapy according to the optimized modalities with daily dosimetric adjustment and target monitoring at each radiotherapy session. These data suggest that dose intensification and the stereotactic magnetic resonance-guided adaptive radiotherapy technique improve radiotherapy results; however, prospective studies are needed to confirm these data. Therefore, the phase 2 study GABRINOX-ART in which an intensified chemotherapy regimen (GABRINOX i.e GA followed by FFX) is followed by optimized adjusted radiotherapy (stereotactic magnetic resonance-guided adaptive radiotherapy) seems to be an interesting strategy to evaluate in locally advanced pancreatic cancer.