Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas

Abstract

BackgroundIn patients with adenocarcinoma of the pancreas, there are no standard second-line regimens. Many pre-clinical studies have shown that metformin alone or when combined with paclitaxel has antitumour effects on this tumour. We have tested here the combination of paclitaxel and metformin for patients with gemcitabine-refractory pancreatic cancer.MethodsAn uncontrolled phase II trial was carried out based on a two–stage Simon’s design, with metformin and paclitaxel for patients with locally advanced or metastatic pancreatic cancer whose disease had progressed during first line treatment with a gemcitabine-based regimen. The primary endpoint was the disease control rate at eight weeks as per response evaluation criteria in solid tumours (RECIST) 1.1. Patients received paclitaxel 80 mg/m2 weekly for three weeks every 28 days and metformin 850 mg p.o. t.i.d. continuously until progression or intolerance state was reached.ResultsTwenty patients were enrolled from July 2011 to January 2014: N = 6 (31.6%) achieved the primary endpoint, with all presenting stable disease. Median overall survival (OS) was 128 days (range 17–697) and the median progression free survival (PFS) was 44 days (range 14–210). Eight patients (40%) presented treatment-related G3-4 toxicities with the most common one being diarrhoea.ConclusionsDespite the encouraging pre-clinical evidence of the antitumour activity of metformin in adenocarcinoma of the pancreas, the primary endpoint of the disease control rate was not met. Besides, the treatment combination was poorly tolerated and could not be studied further. This study highlights the importance of performing clinical trials to reassure preclinical or observational data.

Metformin and pancreatic cancer survival: Real effect or immortal time bias?

“…In the present study, the pooled RR from the six cohort studies not subject to immortal time bias was 0.93 (95% CI 0.82, 1.05; p = 0.22). These findings concur with data from clinical trials: three Phase II clinical trials did not found significant improvement in pancreatic cancer survival with adjuvant metformin therapy . Although the pooled RR from the other nine cohort studies showed a reduction of 24% in pancreatic cancer mortality with metformin (RR 0.76, 95% CI 0.69, 0.84; p < 0.001), these nine studies compared metformin versus non‐metformin and were subject to immortal time bias.…”

“…These findings concur with data from clinical trials: three Phase II clinical trials did not found significant improvement in pancreatic cancer survival with adjuvant metformin therapy. [24][25][26] Although the pooled RR from the other nine cohort studies showed a reduction of 24% in pancreatic cancer mortality with metformin (RR 0.76, 95% CI 0.69, 0.84; p < 0.001), these nine studies 12,15-22 compared metformin versus non-metformin and were subject to immortal time bias. Theoretically, the presence of immortal time bias in these nine cohort studies leads to smaller values for effect estimates, favoring a beneficial effect of metformin.…”

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues

“…To date, only 3 prospective randomized studies of patients with unresectable pancreatic exocrine tumors have been published. [30][31][32] However, these studies failed to show any advantage from combining metformin with standard chemotherapy treatments.…”

Combined treatment of gemcitabine with indole-3-carbinol or metformin on drug efficacy in pancreatic cancer cell lines: The role of human equilibrative nucleoside transporters

“…In a double-blind, placebo-controlled phase II clinical trial of MET in pancreatic cancer treatment with a survival endpoint, there was no advantage for the addition of MET to erlotniab and GEM [26]. The use of MET and paclitaxel as a second line treatment for advanced pancreatic cancer was found to be poorly tolerated and the primary end point (disease control rate) was not met [63]. Some of the limitations noted in these clinical studies are self-reporting from diabetic patients, misclassification of patients, incomplete medication records, time-related bias studies, and small population size [19,21,53,64,65].…”