Chemotherapy combination superior to monotherapy in resected pancreatic cancer

The combination of gemcitabine plus capecitabine demonstrated superior survival outcomes compared with gemcitabine alone in patients with pancreatic cancer who underwent tumor resection, according to results from the ESPAC-4 trial published in The Lancet.

These results suggest that the adjuvant combination regimen should replace the standard of care for this patient population, John P. Neoptolemos, MA, MB, BChir, MD, FRCS, FMedSci, Owen and Ellen Evans chair of surgery of the Liverpool Clinical and Cancer Research UK Trials Unit at University of Liverpool, United Kingdom, and colleagues wrote.

The ESPAC-3 trial previously confirmed that adjuvant gemcitabine should be the standard of care for pancreatic cancer based on similar survival as and less toxicity than adjuvant 5-fluorouracil/folinic acid.

However, additional clinical trials have shown better survival and tumor response with the combination of gemcitabine plus capecitabine than gemcitabine alone in advanced or metastatic pancreatic cancer.

Therefore, the researchers conducted a phase 3, open-label, multicenter, randomized clinical trial to evaluate the efficacy and safety of gemcitabine plus capecitabine compared with gemcitabine monotherapy for the treatment of resected pancreatic cancer.

Within 12 weeks of surgery, 730 patients (57% men; median age, 65 years) were randomly assigned 1:1 to receive 1,000 mg/m² gemcitabine once a week for 3 of every 4 weeks for six cycles alone (n = 366) or with 1,660 mg/m² oral capecitabine administered for 21 days followed by 7 days of rest for six cycles (n = 364).

OS served as the primary endpoint.

Median follow-up was 43.2 months.

Median OS was 28 months (95% CI, 23.5–31.5) in the combination arm compared with 25.5 months (95% CI, 22.7–27.9) in the gemcitabine group (HR = 0.82; 95% CI, 0.68–0.98).

The combination arm demonstrated superior estimated OS at 12 months (84.1% vs. 80.5%) and 24 months (53.8% vs. 52.1%).

“This is one of the biggest ever breakthroughs prolonging survival for pancreatic cancer patients,” Neoptolemos said in a press release. “When this combination becomes the new standard of care, it will give many patients living with the disease valuable months and even years. The difference in short-term survival may seem modest, but improvement in long-term survival is substantial for this type of cancer.”

Univariate survival analyses showed that smoking, pre- and postoperative CA19-9 concentrations, preoperative C-reactive protein concentrations, resection margin status, tumor grade, lymph nodes status, maximum tumor size, tumor stage, venous resection, and local invasion were all associated with survival (P < .05 for all).

Median RFS did not significantly differ in the combination and monotherapy arms (13.9 months vs. 13.1 months; HR = 0.86; 95% CI, 0.73-1.02). Rates of RFS were 23.8% for the combination and 20.9% for monotherapy at 3 years, and 18.6% for the combination and 11.9% for monotherapy at 5 years.

Safety data were available from 725 patients. Grade 3 to grade 4 adverse events occurred in 226 of 359 patients in the combination group, and 196 of 366 patients in the gemcitabine group.

The researchers suggested further assessment of therapeutic predictive response markers may be helpful to select the best treatment regimens.

“Pancreatic cancer is a notoriously difficult disease to treat. Nearly 10,000 patients are diagnosed each year in the United Kingdom, so we urgently need new ways to treat and manage this disease,” Peter Johnson, MA, MD, FRCP, chief clinician for Cancer Research UK, said in a press release. “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. There are still big leaps to be made, but Cancer Research UK is investing heavily into research to take on pancreatic cancer, and we are just starting to see the results.”

At the end of analysis, 21.8% of patients treated with gemcitabine and 25.5% of patients treated with the combination regimen were alive without disease. This means that 25 patients need to be treated with the combination to save one life, Gaël Deplanque, MSc, MD, PhD, from the University Hospital of Lausanne in Switzerland, and Nicolas Demartines, MD, FACS, FRCS, chairman of the department for visceral surgery at the University Hospital CHUV in Switzerland, wrote in an accompanying editorial.

However modest, the data from the ESPAC-4 trial were “encouraging in a disease with such high mortality,” Deplanque and Demartines wrote. Additional trials are ongoing looking at adjuvant therapy, and it is likely more chemotherapy will lead to improved outcomes in patients who have undergone surgery, they added.

“More surgery is, therefore, clearly needed if we want to cure more patients, but more surgery means the possibility to offer surgery earlier in the disease evolution, and as a consequence more often,” they wrote. “An earlier diagnosis would allow surgery to be offered earlier, for example, by the appropriate screening of individuals with higher risk for pancreatic cancer, or for borderline resectable or unresectable patients, by the use of new neoadjuvant therapeutic approaches.” – by Kristie L. Kahl

Disclosure: Neoptolemos reports grants and educational travel grants from AstraZeneca, Cancer Research UK, Clovis Oncology, KAEL GemVax, NUCANA, Pharma Nord, Taiho Pharma and Ventana; and lecturer and consultant roles with Amgen, Astellas, Boehringer Ingelheim Pharma GmbH & Co KG, KAEL GemVax, Mylan and Novartis Pharma AG. Please see the full study for a list of all other researchers’ relevant financial disclosures. Deplanque reports grants, travel grants and personal fees from AB Science, Amgen, Bavarian Nordic, Bayer, Bristol-Myers Squibb, Exelixis, Genentech, Janssen-Cilag, Lilly, Menarini, Merck, PUMA, Roche, Sanofi and Sotio. Demartines reports no relevant financial disclosures.