Recently, New England Journal of Medicine published a heavy study.In a trial called PRODIGE 24-ACCORD, adjuvant chemotherapy with a modified version of FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) significantly improved outcomes compared with gemcitabine in patients with pancreatic cancer after surgery.
Thierry Conroy, director of the Institute of Cancer Research, Lorraine, France, stated that "the improved version of FOLFIRINOX can achieve a median survival OS of 54 in patients with pancreatic cancer after adjuvant therapy.4 months.Compared with standard treatment gemcitabine, it was extended by 20 months and the median disease-free survival DFS was extended by nearly 9 months."
1, may subvert existing clinical practice
Many medical peers stated that this research result may subvert the existing clinical practice of postoperative pancreatic cancer patients around the world.Hedy L., Professor of Medicine, University of ChicagoDr Kindler wrote a subsequent editorial in which she said the results were impressive and truly unprecedented.
In addition, Dr. Manish Shah, Director of the Gastrointestinal Oncology Program at Weill Cornell Medical College in New York, which is not related to this study, made a similar point."The data from this study is very compelling and is a landmark study. This study aimed at assessing the best adjuvant therapy for pancreatic cancer may change the clinical practice of thousands of patients worldwide."
2, median OS extended by nearly 20 months
In the phase III open-label study, the investigators selected 493 patients from patients seen at 58 centers in France and 19 centers in Canada, after which these patients were randomly assigned to treatment with modified FOLFIRINOX (n = 247) or gemcitabine (n = 246) and formed the intent-to-treat population.
Participants aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who have undergone R0 or R1 resection surgery within 3 to 12 weeks prior to randomization.
The investigators compared the efficacy and safety of the modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.
Patients in the gemcitabine group received the standard dose (1000 mg/m2) on days 1, 8, and 15 for 24 weeks (one cycle every 28 days for 6 cycles).Patients in the modified FOLFIRINOX group received oxaliplatin (85 mg/m2), leucovorin (400 mg/m2), irinotecan (180 mg/m2, reduced to 150 mg/m2 per protocol), and fluorouracil (2400 mg every two weeks) for 24 weeks (one cycle every 14 days for 12 cycles).
The results of the study show that: during the period of 33.After a median follow-up of 6 months, median DFS was significantly longer in patients treated with modified FOLFIRINOX (21.6 months vs 12.8 months).Median OS in the modified FOLFIRINOX group was 54.4 months, while the median OS in the gemcitabine group was 35 months, an extension of nearly 20 months.The hazard ratio (HR) for cancer-related events, second cancers, or death was 0.58.Patients in the modified FOLFIRINOX group had a three-year DFS of 39.7%, 21 in the gemcitabine group.4%.
"The hazard ratio is 0.58 is impressive, "Shahr said."This means that patients receiving FOLFIRINOX have a 42% chance of getting a better DFS.This will be the new standard for patients who are able to receive a three-drug combination."
The benefit of modified FOLFIRINOX (to gemcitabine) was extended to other secondary endpoints of OS (median: 54.4 months vs.35.0 months; death HR, 0.64; p =.003); metastasis-free survival (MFS; median: 30.4 vs. 17.7 months; HR of distant metastasis or death, 0.59; p <.001); and cancer-specific survival (median: not reached vs.36.4 months; HR of death due to treatment or treatment-related complications, 0.63; p =.003).
Compared to the gemcitabine group, the 3-year OS of patients in the modified FOLFIRINOX group (63.4% vs 48.6%), MFS (48.2% vs 30.9%) and cancer-specific survival (66.2% vs 51.2%) were also significantly elevated.
3. In the modified FOLFIRINOX group, the incidence of major adverse events was significantly higher
The incidence of grade 3/4 adverse events was reported to be significantly higher in patients with modified FOLFIRINOX (modified FOLFIRINOX 75.9% vs.52.9%); grade 4 events were similar in both groups (modified FOLFIRINOX of 12.2% versus 12% for gemcitabine).All toxicities were reversible except for oxaliplatin-induced peripheral neuropathy (which lasted for 3 years in two patients).
where adverse events: diarrhea (18.6% vs. 3.7%), increased γ-glutamyltransferase levels (18.3% vs. 8.4%), paresthesia (12.7% vs. 5.4%), fatigue (11.0% vs 4.6%), sensory peripheral neuropathy (9.3% vs 8.7%), nausea 5.5% vs 0.8%), vomiting (5.1% vs 1.3%), abdominal pain (3.4% vs 0.4%) and mucositis (2.5% vs 0%).
Thrombocytopenia was significantly higher with gemcitabine (4.5% vs.1.3%).
4, which patients can be treated with the modified version of FOLFIRINOX?
Is the modified FOLFIRINOX regimen used in this trial applicable to all patients undergoing surgery for pancreatic cancer?
Kindler commented that the French research team led by Conroy was experienced and able to properly manage the toxicity of the regimen.Conroy also stated that toxicity can be managed properly and that, in addition, the supplementary appendix will provide dose modifications for the management of adverse events based on published studies.
However, Kindler added that not all patients are eligible for this therapy, first, patients need to go through Whipple [surgical procedure for pancreaticoduodenectomy], and additionally CA 19-9 levels need to be less than 180 U/mL within 3 to 12 weeks after surgery to be able to withstand chemotherapy.
5. There are still many challenges in the treatment of pancreatic cancer
Pancreatic cancer is a malignant tumor of the digestive tract with a high degree of malignancy. It is difficult to diagnose and treat. About 90% of them are ductal adenocarcinomas originating from the glandular epithelium.Its morbidity and mortality have increased significantly in recent years.The 5-year survival rate is <1%, which is one of the worst malignant tumors.
Kindler states that advances in precision medicine have not yet benefited pancreatic cancer.Surgery is the only feasible treatment, but only 15% to 20% of patients can undergo surgical resection, and only 4% of patients will live more than 10 years.
Advances in targeted therapy and immunotherapy have not, for some reason, entered pancreatic cancer.There are no drugs that can block the main mutation in pancreatic cancer, KRAS, and the results of trials of immune checkpoint inhibitors for pancreatic cancer are also disappointing because microsatellite instability is quite rare.
The investigators stated that although the modified FOLFIRINOX is not applicable to all patients, it offers at least a glimmer of hope for some patients.
Original: FOLFIRINOX or gemcitabine as Adjuvant Therapy for Pancreatic Cancer
Author: Thierry Conroy, Pascal Hammel, Mohamed Hebbar, et al