Lancet 2017-03-11
Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.
Abstract
Background
The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.
Methods
We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.
Findings
Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group.
Interpretation
The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.
Funding
Cancer Research UK.
Related Questions
Which neoadjuvant/adjuvant chemotherapy regimen would you select in a patient with resectable stage IB pancreatic head adenocarcinoma and MDS-SF3B1 on luspatercept (baseline Hgb of 8-9 g/dL)?
Seems a bit unfair that the patient has both! First, I would consider resection upfront to ensure this key step rather than risk additional complications of chemotherapy. Perioperative or total neoadjuvant therapy is not standard for resectable disease yet (pending Alliance trial result). Second, bo...
What group of early pancreatic cancer patients, such as pT1a, can be excluded from adjuvant chemotherapy post resection?
Short answer is none - all patients who have undergone surgery for pancreatic cancer benefit from adjuvant chemotherapy, as long as they can tolerate it.But to be a bit more detailed: Both the Neoptolemos, ESPAC-4 adjuvant trial of gem+cap, and the Conroy PRODIGE 24–ACCORD adjuvant trial of FOLFIRIN...
In a patient with borderline resectable pancreatic adenocarcinoma who received neoadjuvant FOLFIRINOX followed by resection that demonstrated residual disease, how do you proceed in the adjuvant setting?
In order to answer this question completely, I would need to know more about the neoadjuvant FOLFIRINOX that was given. In a patient who received a full 6 months of neoadjuvant therapy followed by successful surgical resection (albeit with poor response), I would not recommend continuing systemic th...
How will you decide between mFOLFIRINOX vs gemcitabine+capecitabine for resected pancreatic cancer patients?
The results of the PRODIGE-24 trial are among the most significant of the last quarter century in terms of their impact on the treatment of patients with pancreatic adenocarcinoma. The administration of mFOLFIRINOX resulted in almost a doubling of 3 yr DFS (the primary endpoint) and also extended th...
How do you approach adjuvant chemotherapy in patients with resected pancreatic adenocarcinoma?
For my good performance status patients, I offer gem/cap as per the ESPAC-4 trial. Though the incremental benefit is modest, it was statistically significant and the toxicities associated with the combination are quite manageable most of the time. I look forward to the results of three other adjuvan...