Long-term outcomes of GemCap for pancreatic ductal adenocarcinoma

Abstract

Results reported in the ESPAC4 trial showed that adjuvant chemotherapy with gemcitabine plus capecitabine (GemCap) produced longer overall survival (OS) than gemcitabine alone for patients with pancreatic ductal adenocarcinoma (PDAC). These patients were not safe candidates for or did not wish to take modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX). The results were published in the Journal of Clinical Oncology.¹

At a median follow-up of 104 months, patients treated with GemCap had an improvement in OS in comparison with those treated with gemcitabine alone (31.6 vs. 28.4 months); this represents a 17% lower risk of death (hazard ratio [HR], 0.83; 95% CI, 0.71–0.98; p = .031).¹ In a multivariable analysis, patients treated with GemCap had a 20% lower risk of death than those treated with gemcitabine alone (HR, 0.80; 95% CI, 0.68–0.95; p = .01).

The median relapse-free survival with GemCap (21.3 months) versus gemcitabine alone (18.3 months) represents a 35% reduction in the risk of disease progression (HR, 0.85; 95% CI, 0.72–1.00; p = .053).

The phase 3, open-label, multicenter ESPAC4 trial included 732 adults (≥18 years old) randomly assigned to gemcitabine alone (n = 367) or GemCap (n = 365) after complete macroscopic resection of PDAC. Patients were stratified by resection margin status (R0 or R1) and country of participation. Prior results at 43.2 months showed similar OS outcomes with median OS times of 28 and 25.5 months for patients treated with GemCap and gemcitabine alone, respectively; this represents an 18% reduced risk of death (HR, 0.82; 95% CI, 0.68–0.98; p = .32).²

An exploratory analysis in the current study found subgroups of patients (R0 status and negative lymph nodes) for whom GemCap may be particularly beneficial in comparison to gemcitabine alone.

For R0 status, the analysis showed that patients treated with GemCap had a significant improvement in median survival in comparison with those treated with gemcitabine alone (49.9 vs. 32.2 months); this represents a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.47–0.84; p = .002). No significant difference was seen in patients with R1 status who were treated with GemCap compared to those treated with gemcitabine alone (25.9 vs. 25.5 months, p = .28).

Negative lymph nodes also were associated with significantly higher estimated 5-year survival in patients treated with GemCap compared to those treated with gemcitabine alone (59% vs. 53%); this represents a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.41–0.98; p = .04).

Researchers further explored estimated survival rates of patients treated with GemCap compared to those treated with gemcitabine alone by subgrouping the patients by eligibility status for inclusion in the PRODIGE24 trial. The PRODIGE24 trial demonstrated superior long-term survival with mFOLFIRINOX compared to gemcitabine alone but used stricter inclusion eligibility requirements than the ESPAC4 trial.³

Researchers found that GemCap was superior to gemcitabine alone in 193 patients (26.4%) in the ESPAC4 trial who would not have been eligible for inclusion in the PRODIGE24 trial. Therefore, they were not eligible to receive mFOLFIRINOX. The median survival time of 25.9 months (vs. 20.7 months) represents a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.52–0.98; p = .03).

“GemCap remains the standard adjuvant treatment for patients with PDAC after upfront resection not fit enough for or not wishing to receive mFOLFIRINOX,” said the investigators in the study, which was led by senior author John P. Neoptolemos, MD, professor of surgery at the University of Heidelberg in Germany.¹ As for the results of the exploratory analysis, they said that “although some caution should be applied because of the exploratory nature of the analysis, the results suggest that GemCap may be particularly efficacious in R0 patients and may also be more efficacious in lymph node-negative patients.”¹

Commenting on the study, Jordan Berlin, MD, director of the Division of Hematology and Oncology at Vanderbilt–Ingram Cancer Center in Nashville, Tennessee, says that it was “exciting to see that the benefits of GemCap compared to gemcitabine alone held out over the years, suggesting that GemCap is an alternative when mFOLFIRINOX is not an option.”

He says that the results would have little impact on current clinical practice, as GemCap has long been considered a safe and effective alternative for people who are not good candidates for adjuvant mFOLFIRINOX.

Although he found the subset analyses “encouraging,” he says that it does not change the fact that for these patients (i.e., those with R0 status and/or negative lymph nodes), the choice of therapy remains mFOLFIRINOX whenever possible.

As for the comparison of GemCap and gemcitabine with respect to survival outcomes for patients who are eligible for mFOLFIRINOX based on the inclusion criteria of PRODIGE24, Dr Berlin says that the “cross-trial comparison has several hazards” and has little to no effect on their knowledge or decision-making. He notes that the 193 patients found to be ineligible for mFOLFIRINOX based on the PRODIGE24 inclusion criteria had this status because of some of the inclusion restrictions, such as the amount of time after surgery or carbohydrate antigen 19-9, and not because of criteria such as advanced age or poor performance status, which are indicative of patients who should receive GemCap.

Dr Berlin emphasizes that combining gemcitabine with nab-paclitaxel is not a good alternative to mFOLFIRINOX in the adjuvant setting, despite some physicians’ use of this combination, based on negative trial results.⁴