ESPAC-4: Gemcitabine-capecitabine combo shows improved OS in pancreatic adenocarcinoma
The improvement in overall survival (OS) among individuals given a combination of gemcitabine and capecitabine as adjuvant chemotherapy after surgically resected pancreatic adenocarcinoma highlights a potential new standard of care, according to findings of the phase III, open-label, multicentre ESPAC-4* trial.
“Even if modest, these figures are encouraging in a disease with such high mortality and clearly establishes the combination of gemcitabine and capecitabine as a new standard of care in the adjuvant setting of pancreatic ductal adenocarcinoma,” said Dr Gaël Deplanque from the Hôpital Riviera-Chablais in Vevey and Professor Nicolas Demartines from the Centre Hospitalier Universitaire Vaudois CHUV in Lausanne, Switzerland, in a separate editorial. [Lancet 2017;doi:10.1016/S0140-6736(17)30126-5]
Median OS was higher in the gemcitabine-capecitabine combination group compared with the gemcitabine monotherapy group (28.0 vs 25.5 months, hazard ratio [HR], 0.82, 95 percent confidence interval [CI], 0.68–0.98; p=0.032). [Lancet 2017;doi:10.1016/S0140-6736(16)32409-6]
Median OS was also higher in the combination group compared with the monotherapy group regardless of resection margin status (23.7 vs 23 months for positive resection margins [R1] and 39.5 vs 27.9 months for negative resection margins [R0]; p=0.0001 for both comparisons).
Estimated OS at 12 months and 24 months was higher in the combination group compared with the gemcitabine monotherapy group (84.1 percent vs 80.5 percent at 12 months and 53.8 percent vs 52.1 percent at 24 months), as was estimated 5-year survival (28.8 percent vs 16.3 percent).
Incidence of relapse or death (n=557, 74 percent vs 78 percent) and tumour recurrence (n=479, 65 percent vs 66 percent) was comparable between the gemcitabine-capecitabine and gemcitabine monotherapy groups.
There were 305 treatment-related serious adverse events reported by 25 percent of 725 patients; 26 percent in the gemcitabine monotherapy group reported 151 events, while 24 percent in the combination group reported 154 events. Grade 3–4 events were reported by 226 patients in the combination group (608 events) compared with 196 patients in the gemcitabine monotherapy group (481 events).
Grade 3 or 4 neutropenia occurred more frequently in the combination group compared with the gemcitabine monotherapy group (38 percent vs 24 percent), though the overall incidence of febrile neutropenia was low in both treatment arms. There was a lower incidence of other infective complications in the combination group compared with the monotherapy one (3 percent vs 7 percent), though a higher number of grade 3–4 diarrhoea events occurred in the combination group (5 percent vs 2 percent).
Within 12 weeks of undergoing R0 or R1 resection for ductal pancreatic adenocarcinoma, 732 patients aged ≥18 years from 92 hospitals were randomized to receive intravenous gemcitabine monotherapy for six cycles (each cycle comprised 1000 mg/m2 once a week for 3 of every 4 weeks, n=366) or in addition to oral capecitabine (1660 mg/m2 per day for 21 days followed by 7 days rest [1 cycle], n=364) for six cycles (24 weeks). The patients were followed up for a median time of 43.2 months.
“We have shown that the improvements in tumour response and disease control observed with gemcitabine plus capecitabine in advanced pancreatic cancer can translate into a clear effect in the adjuvant setting,” said the researchers.
“Based on the CONKO-001 and ESPAC-3 studies, adjuvant gemcitabine is a recognized standard of care for patients with resected pancreatic adenocarcinoma, including those with resected T1N0 disease,” said Dr Zee Ying Kiat, senior consultant in medical oncology at Parkway Cancer Centre, Singapore, who was not affiliated with the study.
“Surgery alone for resectable pancreatic adenocarcinoma is associated with a 5-year OS of approximately 8 percent. Adjuvant chemotherapy with 5-fluorouracil plus folinic acid or gemcitabine improves 5-year survival to between 16 and 21 percent. The ESPAC-4 study reports a further extension of 5-year OS to nearly 30 percent with adjuvant gemcitabine-capecitabine, without significant increase in overall toxicity,” he said.
“Combination gemcitabine-capecitabine represents a new standard of care for fit patients with resected pancreatic adenocarcinoma. However, single agent adjuvant chemotherapy remains a reasonable option, particularly for patients with a borderline performance status or a co-morbidity profile that precludes intensive therapy,” said Zee.
According to Deplanque and Demartines, the study results raise more questions including if patients should be given more surgery or more chemotherapy, and if the estimated results at 5 years are actually representative of patients cured of the condition.
“The results of several other large adjuvant trials with new drugs or a combination of drugs are eagerly awaited,” they said.