Adjuvant Chemotherapy Improves Survival in Pancreatic Cancer

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The findings show that patients who can undergo surgery have a fighting chance of surviving this cancer with the combination of two commonly used chemotherapies.
— John P. Neoptolemos, MA, MB, BChir, MD, FRCE

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An adjuvant chemotherapy regimen improved overall survival in early-stage pancreatic cancer patients, in the large phase III European ESPAC-4 study reported at the 2016 ASCO Annual Meeting.1

The combination of gemcitabine and capecitabine almost doubled the 5-year survival rate, compared to gemcitabine alone, in a study of 730 patients with resected pancreatic ductal adenocarcinoma, reported John P. Neoptolemos, MA, MB, BChir, MD, FRCE, Professor of Molecular and Clinical Cancer Medicine and Chair of Surgery at the University of Liverpool in the United Kingdom.

Based on a 5-year survival rate of 29% with this combination, he said, “Adjuvant gemcitabine with capecitabine is the standard of care for resected pancreatic cancer.”

“The findings show that patients who can undergo surgery have a fighting chance of surviving this cancer with the combination of two commonly used chemotherapies,” Dr. ­Neoptolemos commented.

ESPAC-4 Details

ESPAC-4, which involved 92 sites in 6 countries, randomly assigned patients within 12 weeks of surgery to gemcitabine at 1,000 mg/m2 for 24 weeks (n = 361) or gemcitabine at 1,000 mg/m2 for 6 cycles plus capecitabine at 1,660 mg/m2/d for 24 weeks (n = 361). Patients were followed every 3 months.

Median maximum tumor size was 30 mm; 60% were R1 resections, 80% had node-positive disease, and 40% of tumors were poorly differentiated.

Progress in Pancreatic Cancer

  • For resected pancreatic cancer patients, adjuvant chemotherapy with gemcitabine plus capecitabine improved median overall survival, which reached 28.0 months with the combination vs 25.5 months with gemcitabine alone (HR = 0.82; P = .032).
  • Estimated 5-year survival with the combination was 29%.
  • The combination was well tolerated; approximately 25% of each arm reported serious adverse events.
  • Gemcitabine/capecitabine may be considered a new standard of care for resected pancreatic patients.

In December 2015, the Independent Trial Steering Committee requested that the trial proceed to full analysis. A data freeze was imposed in March 2016, before the trial reached the target number of deaths, due to the favorable outcomes with the combination.

Median overall survival for patients treated with the gemcitabine/capecitabine combination was 28.0 months, compared with 25.5 months for gemcitabine alone (hazard ratio [HR] = 0.82; P = .032).

“The difference in median survival may seem modest, but the improvement in long-term survival is substantial for this cancer,” Dr. Neoptolemos pointed out.

Adverse events were similar between the arms. Serious adverse events were observed in 107 gemcitabine-treated patients and 109 patients receiving both drugs. Of the 180 patients reporting treatment-related serious adverse events, 26% were in the monotherapy arm and 24% were in the combination arm.

The similarity in toxicity, he said, “is important, given the fact that one arm received combination chemotherapy.”

Another ‘Step Change’

Dr. Neoptolemos observed that the progress in pancreatic cancer has been slow and has occurred in the form of “step changes.” One-year survival increased from 10% in 1971 to 21% in 2010 due to greater use of chemotherapy, he noted, but 5-year survival with surgery plus fluorouracil or gemcitabine is still less than 20%.

“Adjuvant gemcitabine with capecitabine is the next step change for resected pancreatic cancer,” he said at an ASCO press briefing. “Five-year survival went from 16% with surgery plus gemcitabine to 29% with surgery plus capecitabine and gemcitabine.”

In response to questions about choosing neoadjuvant or adjuvant chemotherapy now, Dr. Neoptolemos stated that the benefit of neoadjuvant chemotherapy has not been established in randomized studies.

“The use of neoadjuvant chemotherapy requires a randomized trial to determine which patients should get it and who would benefit,” he said.

New Standard of Care

Smitha Krishnamurthi, MD

Smitha Krishnamurthi, MD

Allyson Ocean, MD

Allyson Ocean, MD

Smitha Krishnamurthi, MD, a medical oncologist at UH Case Medical Center, Associate Professor of Medicine at Case Western Reserve University, and designated ASCO spokesperson at the press briefing, agreed with Dr. Neoptolemos that these are practice-changing findings. “For patients who will receive adjuvant therapy, I think this does represent the new standard of care,” she commented.

Allyson Ocean, MD, a gastrointestinal oncologist at Weill Cornell Medicine and New York-Presbyterian Hospital, also maintained that “the combination should be a new standard of care” based on the encouraging findings in a “well-done” study of a typical patient population.

In an interview with The ASCO Post, Dr. Ocean noted, “Now we have a regimen of drugs that we have been using separately or in combination in various settings, and this treatment almost doubled the 5-year survival rate. Nearly 30% of patients were alive at 5 years, and that’s remarkable in this disease. It was also well tolerated, and patients had good quality of life.”

“We can’t ignore these data,” Dr. Ocean commented. “I think that we now need to concentrate more on early detection of pancreatic cancer. Very few patients with this disease are even able to have surgery.” ■

Disclosure: Dr. Neoptolemos has had consulting or advisory roles with Boehringer Ingelheim, Novartis, and Kael-GemVax. He has received research funding from AstraZeneca, Kael-GemVax, Pharma Nord, and Taiho Pharmaceutical and support for travel, accommodations, and expenses from NuCana BioMed. Drs. Krishnamurthi and Ocean reported no potential conflicts of interest.


1. Neoptolemos JP, Palmer D, Ghaneh P, et al: ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine and capecitabine versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma. 2016 ASCO Annual Meeting. Abstract LBA4006. Presented June 6, 2016.