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Addition of capecitabine to adjuvant chemotherapy extends survival in pancreatic cancer
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CHICAGO — The addition of capecitabine to standard adjuvant gemcitabine chemotherapy significantly extended survival of patients with resected pancreatic ductal adenocarcinoma, according to results of a randomized phase 3 trial presented at the ASCO Annual Meeting.
The combination also appeared well tolerated, researchers said.
“Adjuvant gemcitabine with capecitabine is the second step change for resected pancreas cancer,” John P. Neoptolemos, MA, MB, BChir, MD, FMedSci, chair of surgery in the department of molecular and clinical cancer medicine at University of Liverpool in the United Kingdom, said during a press conference. “[This regimen] is now the standard of care for [this patient population].”
Pancreatic cancer is the third most common cause of cancer death in the United States, and more Americans die of pancreatic cancer than breast cancer.
“Some progress is being made, however, and we are beginning to see some clear water between the number of new cases diagnosed and the number of deaths,” Neoptolemos said.
An estimated 53,070 new cases of pancreatic cancer will be diagnosed nationwide this year, and an estimated 41,780 Americans will die of the disease, according to ASCO data.
One-year survival more than doubled — from 10% to 21% — between 1971 and 2011, primarily due to increased use of chemotherapy.
Prior studies from the European Study Group for Pancreatic Cancer (ESPAC) led to the first step change for the treatment of resected pancreatic cancer, showing 5-year survival is considerably higher with surgery plus 5-FU or gemcitabine (16% to 18%) than with surgery plus chemoradiation (11%) or surgery alone (8%).
In the ESPAC-4 trial — a multicenter, international, open-label, randomized controlled trial — Neoptolemos and colleagues assessed whether the addition of capecitabine to gemcitabine extended survival in patients with resected early-stage disease.
The analysis included 722 patients (median age, 65 years; 57% men) treated at one of 92 centers in six countries. Most patients had WHO performance status of 0 (42%) or 1 (55%).
Median postoperative CA19-9 level was 19 kU/L and median maximum tumor size was 30 mm. The majority of patients underwent R1 resections (60%) and were node positive (80%). Forty percent of patients had poorly differentiated disease.
Researchers randomly assigned patients within 12 weeks of surgery to gemcitabine plus capecitabine (n = 361) or gemcitabine alone (n = 361). Each treatment was administered for six 4-week cycles. Follow-up continued every 3 months from randomization until death.
OS served as the primary endpoint. Secondary endpoints included toxicity, RFS, 2-year and 5-year survival, and quality of life.
Patients assigned the chemotherapy combination achieved longer median OS (28 months vs. 25.5 months; HR = 0.82; 95% CI, 0.68-0.98) and were more likely to survive 5 years (29% vs. 16%).
The survival benefit with capecitabine persisted regardless of the presence of unfavorable prognostic factors, such as large tumor size, locally advanced or aggressive disease, or incomplete removal of the tumor.
“The difference in median survival may seem modest, but the improvement in long-term survival is substantial for this cancer,” Neoptolemos said. “We’ve gone from a 5-year survival rate of 8% with surgery alone to nearly 30% with adjuvant therapy.”
Researchers reported no major differences between treatment groups with regard to type or severity of adverse events.
Overall, 180 patients (25%) reported a combined 305 treatment-related serious adverse events. In the combination group, 94 patients (26%) experienced 151 treatment-related serious adverse events.
In the gemcitabine monotherapy group, 86 (24%) of patients experienced 154 treatment-related serious adverse events.
“Globally, there was no difference between the two arms, and this is very important given the fact that one arm is combination chemotherapy,” Neoptolemos said.
Researchers reported slightly higher incidence of severe diarrhea (n = 14 vs. n = 5) and fatigue (n = 16 vs. n = 14) among patients assigned the combination.
Quality of life appeared similar between groups.
Future research should assess whether adding other treatments to the capecitabine–gemcitabine combination may further improve outcomes, as well as how to predict which patients could derive the most benefit from a particular adjuvant therapy, the researchers wrote. – by Mark Leiser
Reference :
Neoptolemos JE, et al. Abstract LBA4006. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Neoptolemos reports consultant/advisory roles with Boehringer Ingelheim, Kael-Gemvax and Novartis; research funding from AstraZeneca, Kael-Gemvax, Pharma Nord and Taiho; and travel, accommodations or expenses from NuCana BioMed. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Allyson J. Ocean, MD
These results are very encouraging for patients with pancreatic cancer who are able to have surgery. Even patients with poor prognostic factors — such as poorly differentiated disease, nodal involvement, locally advanced disease or incomplete resection — demonstrated a survival benefit.
It is important to remember that most patients don’t even get to surgery, so our efforts need to be concentrated on early detection and identifying which patients should have surgery. However, it is very encouraging that we have a new standard of care for those who do undergo surgery.
The median OS benefit is very modest. Is 2 months meaningful in a disease that takes your live pretty quickly? I don’t know, but I do think it is meaningful that we saw such an improvement in 5-year survival. This combination also was very safe and didn’t affect quality of life, so now it can serve as a backbone to which we can add other agents.
We also must consider where this comes into play with radiation. Previously, for patients who had surgery and then proceeded to adjuvant treatment, I chose to treat them with chemotherapy first — typically gemcitabine alone — followed by radiation if their disease was localized after a few months based on Radiation Therapy Oncology Group data. This trial changes things, as we now have a combination chemotherapy that improves OS, but it was done without any radiation. This is a key unanswered question. There are trials looking at other regimens with and without radiation that hopefully will provide some answers.
A big-picture look at these data shows us that 30% of patients are living 5 years, but 70% are not. We need to work with the clinical trialists to develop scientifically driven, patient-centric clinical trials to improve outcomes. The numbers from this trial certainly are one step forward, but they are very far away from a cure. We should applaud these data, which are important and are practice changing, but we also have to keep in mind that we have a long way to go.
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Don S. Dizon, MD, FACP
For patients with such a difficult disease like pancreatic cancer, we are going to see incremental gains. This does provide further statistically significant improvements in survival with a combination therapy that does not add more toxicity, and I think these are important results.
Perspective
Back to TopIgor A. Astsaturov, MD, PhD
This trial is certainly welcome news for patients with pancreatic cancer. With relatively nontoxic chemotherapy in selected patients who have had surgery, the survival rates are now nearing 30%! These ESPAC4 results further confirm the idea that many pancreatic cancers are sensitive to chemotherapy, and more aggressive treatment strategy is warranted, just as it was done with FOLFIRINOX in the metastatic settings.
The trial also opens the question whether treating with chemotherapy is best timed prior to the surgery as many patients are simply not fit physically to receive any adjuvant chemotherapy regimen.
Our group has been a strong proponent of neoadjuvant therapy. Ideally, such therapy should be tailored to the molecular makeup of the pancreatic cancer. For instance, genome-unstable tumors are more sensitive to platinum and radiation.
Overall, the ESPAC4 results encourage us to be more proactive in operable pancreatic cancer.
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