Clinical trialPhase 3Pancreatic cancer

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

Lancet · 2017732 patients enrolled; 730 patients in the final analysis (364 gemcitabine + capecitabine, 366 gemcitabine)

Neoptolemos JP, Palmer DH, Ghaneh P, et al. Lancet. 2017. 389:1011-1024

Study type: Clinical trial
Study name: ESPAC-4
Phase: Phase 3
Design: Randomised, open-label, two-arm, multicentre trial at 92 hospitals (England, Scotland, Wales, Germany, France and Sweden); 1:1 randomisation by minimisation (registration: ISRCTN96397434, EudraCT 2007-004299-38)
Sample size: 732 patients enrolled; 730 patients in the final analysis (364 gemcitabine + capecitabine, 366 gemcitabine)
Source: Lancet · 2017

In plain words

This study asked whether adding capecitabine tablets to gemcitabine injections after surgery for pancreatic cancer helps patients live longer. The answer was yes: patients who had both drugs lived on average about 28 months versus 25.5 months, and their risk of death was about 18% lower. Today, for patients whose general health is not good enough for the stronger mFOLFIRINOX regimen, this combination is an important and easier-to-tolerate option.

Key results

28.0 vs 25.5 months

Median overall survival

HR 0.82 (95% CI 0.68–0.98); p=0.032; reported after 458 deaths (95% of the target of 480 deaths)

226 of 359 vs 196 of 366

Patients with grade 3 to 4 adverse events

608 grade 3–4 adverse events in the combination group vs 481 in the gemcitabine group

Drugs in this study:Capecitabine (Xeloda)Gemcitabine (Gemzar)

Dose and schedule cards

Gemcitabine + capecitabine (ESPAC-4)

Resected pancreatic adenocarcinoma (R0 or R1) in patients unfit for mFOLFIRINOX; in the trial, started within 12 weeks after surgeryCycle length: Every 28 daysOn the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Resected pancreatic adenocarcinoma (R0 or R1) in patients unfit for mFOLFIRINOX; in the trial, started within 12 weeks after surgery

Drug	Dose	Route	Schedule
Gemcitabine	1000 mg/m²	IV over 30 minutes	Days 1, 8 and 15
Capecitabine	830 mg/m² twice daily (1660 mg/m² per day)	Oral	Days 1–21

Cycle length: Every 28 days
Duration: 6 cycles

Doses from ESPAC-4 and the capecitabine FDA label (maximum of 6 cycles).

Capecitabine: reduce the dose by 25% for creatinine clearance 30 to 50 mL/min; no dose has been established below 30 mL/min; do not use in complete DPD deficiency.

On the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Gemcitabine + capecitabine

6 cycles of 4 weeks: gemcitabine 1000 mg/m² once weekly for 3 of every 4 weeks, with oral capecitabine 1660 mg/m² (per day) for 21 days followed by 7 days of rest.

2Gemcitabine alone (control group)

6 cycles: gemcitabine 1000 mg/m² once weekly for 3 of every 4 weeks (one cycle every 4 weeks).

Source of the regimen details: Abstract of the Lancet 2017 paper (doses and schedules of gemcitabine and capecitabine)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 18 years and older with pancreatic ductal adenocarcinoma.
Macroscopically complete tumour resection (R0 or R1).
Randomisation within 12 weeks of surgery.

Endpoints

Primary endpoint: overall survival (from randomisation to death from any cause) in the intention-to-treat population.

Safety assessment: toxicity in all patients who received trial treatment. Other secondary endpoints are in the full text.

Safety and side effects

In the gemcitabine + capecitabine group, 608 grade 3 to 4 adverse events were reported in 226 of 359 patients, and in the gemcitabine-alone group, 481 grade 3 to 4 adverse events in 196 of 366 patients. The type and percentage of each adverse event are reported in the full text.

Clinical significance and place in guidelines

ESPAC-4 made gemcitabine–capecitabine the standard adjuvant treatment (before PRODIGE 24 was published). Today the 2023 ESMO guideline regards this combination as an alternative for patients who are not candidates for mFOLFIRINOX, and the NCCN guideline (version 4.2026) lists gemcitabine/capecitabine alongside mFOLFIRINOX as a category 1 preferred option for adjuvant treatment of patients who did not receive neoadjuvant therapy.

Limitations

The study was open-label. The absolute gain in median survival (about 2.5 months) is modest. Patients with good performance status and adequate recovery after surgery were enrolled. The control regimen was gemcitabine alone, and there was no direct comparison with mFOLFIRINOX.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.