Combo Chemo 'New Standard of Care' in Pancreatic Cancer

Liam Davenport

January 26, 2017

A combination of gemcitabine and capecitabine chemotherapy should be the new standard of care for patients with pancreatic cancer who have undergone resection of their tumor, as indicated by a modest but significant improvement in overall survival shown in a phase 3 trial, say the investigators.

The results from the European Study Group for Pancreatic Cancer (ESPAC)-4 trial in over 700 patients demonstrated that the drug combination achieved an 18% increase in overall survival, although relapse-free survival was not improved. Median overall survival was 28.0 months with the combination of gemcitabine plus capecitabine versus 25.5 months in the gemcitabine-alone group (hazard ratio, 0.82; P = .032).

The results were published online in The Lancet on 24 January.

Preliminary results were presented last year at the 2016 American Society of Clinical Oncology Annual Meeting, as reported by Medscape Medical News. At that time, the improvement in overall survival was described as a "step change" in the care of pancreatic cancer.

Now the results have been published. Lead researcher John P. Neoptolemos, MD, professor and the Owen and Ellen Evans Chair of Surgery, University of Liverpool, United Kingdom (UK), declared in a statement: "This is one of the biggest ever breakthroughs prolonging survival for pancreatic cancer patients."

"When this combination becomes the new standard of care, it will give many patients living with the disease valuable months and even years," he added.

He added: "The difference in short term survival may seem modest, but improvement in long-term survival is substantial for this type of cancer."

Approached for comment, Dr Neoptolemos told Medscape Medical News that, crucially, he is also "100% sure" that the current findings will translate into the real-world setting.

Peter Johnson, chief clinician at the charity Cancer Research, which funded the study, underlined in the release that pancreatic cancer "is a notoriously difficult disease to treat."

While noting that "there are still big leaps to be made," he added: "Research that tells us more about how the disease grows and spreads — and trials like this one — will be key to improve survival for patients living with the disease."

In a Comment accompanying the paper, Gael Deplanque, MD, PhD, Service d'Oncologie, Hopital Riviera-Chablais, Vevey, Switzerland, and Nicolas Demartines, MD, Service de Chirurgie Viscerale, Centre Hospitalier Universitaire Vaudois CHUV, Lausanne, Switzerland, say that the results "open the field to several questions."

As well as raising the questions of whether an increase in chemotherapy can cure more patients in this traditionally chemoresistant cancer and whether the results "really represent patients cured of pancreatic cancer," the editorialists also ask how patient survival can be improved further.

Dr Deplanque and Dr Demartines suggest: "There is clearly a need for some kind of biomarker that could guide the choice of treatment or even surgery."

While they also believe that more surgery is needed, they point out that "more surgery means the possibility to offer surgery earlier in the disease evolution, and as a consequence more often."

This, they say, could be achieved by earlier diagnosis (through, for example, the screening of higher-risk individuals) or the use of novel neoadjuvant therapies to allow surgery in patients with borderline resectable or unresectable disease.

Dr Neoptolemos said that he agreed with the editorialists about the need for a biomarker and more surgery.

He and his colleagues also propose several other chemotherapy combinations that could offer further survival gains in these patients. Of these, Dr Neoptolemos would in particular like to see the FOLFIRINOX (folinic acid, 5-flouroucil, irinotecan, and oxaliplatin) regimen studied in the near future.

Study Details

The ESPAC-4 trial was conducted across 92 European hospitals and involved 730 patients who had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas. Patients were randomly assigned to receive either six cycles of gemcitabine, 1000 mg/m2 once a week for 3 of every 4 weeks, or to gemcitabine plus oral capecitabine, 1660 mg/m2 for 21 days, then 7 days' rest.

During a median follow-up period of 43.2 months, the median overall survival was 25.5 months in the gemcitabine-alone group, compared with 28.0 months in the gemcitabine plus capecitabine group, at a hazard ratio of 0.82 (P = .032).

At 12 months, the estimated overall survival was 80.5% with gemcitabine alone vs 84.1% with gemcitabine plus capecitabine. At 24 months, overall survival was 52.1% and 53.8%, respectively.

The was no significant difference in relapse-free survival between the two treatment groups, at a median of 13.1 months for gemcitabine alone and 13.9 months for gemcitabine plus capecitabine.

Independent predictive factors for overall survival on multivariate analysis were resection margin status, postoperative carbohydrate antigen 19-9 concentrations, tumor grade, lymph node status, and maximum tumor size.

Gemcitabine plus capecitabine was associated with a statistically significant treatment effect compared with gemcitabine alone, at a hazard ratio of 0.79 (P = .016).

A total of 481 grade 3/4 adverse events were reported by 196 (53.6%) of the gemcitabine-alone patients, compared with 608 grade 3/4 adverse events in 226 (63.0%) of patients receiving gemcitabine plus capecitabine.

Describing the toxicity level with gemcitabine plus capecitabine as acceptable, the team writes: "The ESPAC-4 trial has shown a further step change in overall survival with gemcitabine plus capecitabine," adding: "In patients with resected pancreatic cancer, the results…indicate that adjuvant gemcitabine plus capecitabine is the new standard of care."

This study was funded by Cancer Research UK and sponsored by the Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. Other authors are funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden and by the NIHR Biomedical Research Centre at University College London Hospital. Dr Neoptolemos reports grants from Cancer Research UK, Taiho Pharma (Japan), KAEL GemVax (Korea), AstraZeneca, Clovis Oncology and Ventana, and Pharma Nord; payment for lectures from Amgen and Mylan; paid consultancy from Boehringer Ingelheim Pharma GmbH & Co KG, Novartis Pharma AG, KAEL GemVax, and Astellas; and educational travel grants from NUCANA, all outside the submitted work. Dr Neoptolemos is an NIHR senior investigator and is part funded by the NIHR Biomedical Research Centre at the Royal Liverpool University, Liverpool. Other authors also reported potential conflicts of interest.

Lancet. Published online January 24, 2017. Study full text, Editorial

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