Patients with pancreatic cancer who were given chemoradiotherapy (CRT) before surgery showed improved survival compared with patients who went straight to surgery, according to new findings from a phase 3 trial, known as PEROPANC-1. Both groups also had chemotherapy after surgery.
The 2-year overall survival rate with neoadjuvant CRT was 42% compared with 30% for patients who had surgery first.
"The results are preliminary and we do hope that with the final results of this trial , we can show that preoperative chemoradiotherapy is better than postoperative chemotherapy," said lead author Geertjan van Tienhoven, MD, PhD, radiation oncologist at the Department of Radiation Oncology, Academic Medical Center, Amsterdam, the Netherlands.
"We do need the final results before we can draw any definitive conclusions, but these results suggest a benefit for chemoradiation prior to surgery over surgery and adjuvant chemotherapy," he said.
The new data were presented here at the American Society of Clinical Oncology (ASCO) 2018.
Improvement in All Endpoints
A total of 246 patients with borderline resectable pancreatic cancer were randomly assigned to immediate surgery (arm A) or preoperative CRT (arm B).
Both groups received chemotherapy after surgery, and the total amount of chemotherapy given was equal in both groups.
The preoperative CRT regimen consisted of 15 rounds of 2.4 Gy combined with gemcitabine, 1000 mg/m2 on days 1, 8, and 15, preceded and followed by a cycle of gemcitabine.
Resection was performed in 72% of patients in the immediate-surgery group and 62% in the CRT group (P = .065). Among the patients who underwent resection, the R0 rate was higher in a greater proportion of patients who received preoperative treatment (63% vs 31%; P < .001).
The median overall survival was 17.1 months with preoperative CRT compared with 13.7 months (P = .074) with immediate surgery. Disease-free survival was also longer with preoperative therapy (
9.9 months vs 7.9 months; hazard ratio [HR], 0.71; P = .023).
In the subset of patients in which the tumor was surgically removed successfully, the difference in median survival was even greater: 42.1 months with preoperative treatment vs 16.8 months with immediate surgery.
Secondary endpoints also favored the neoadjuvant CRT arm : For distant metastasis-free survival, the median was 10.2 vs 17.1 months (HR, 0.63; P = .012); likewise, for locoregional recurrence-free survival, the median was 11.8 months vs not reached in the surgery-first group (HR, 0.47; P < .001).
Disease progression was seen in 50% of the neoadjuvant chemoradiation group vs 80% of the surgery-first group (P = .002), and there were more deaths (65% vs 55%; P = .074).
Van Tienhoven emphasized that these were preliminary results and that 26 more events are needed before the final analysis can be completed.
Is This Practice Changing?
In a discussion of the paper, Colin D. Weekes, MD, PhD, from Massachusetts General Hospital, Boston, pointed our that patients who received neoadjuvant therapy got "better bang for the buck" because there was a doubling in the R0 resection in the chemoradiation group. "This translated into improved disease-free survival, distant metastasis–free interval, and locoregional recurrence–free interval."
However, the intent-to-treat population analysis did not meet the criteria for statistically significant improvement in overall survival. "It's important to think about that many of these patients are going to have disease progression, and this could skew the analysis more in favor of those who are receiving postoperative therapy," he said.
"So although this study did not meet its endpoint in the intent-to-treat analysis, it does suggest that neoadjuvant therapy may be important for these patients," Weekes explained. "In the postresection analysis, there is an improvement in overall survival."
He pointed out that while the authors concluded that the results demonstrate a benefit for chemoradiation over upfront surgery, "I don't think you can conclude that based on the design of the study."
The study design cannot definitively define that neoadjuvant chemoradiation is better than direct surgical resection, he commented. But the results of this trial in aggregate with other recently published prospective trials demonstrate the benefit of radiation therapy in the neoadjuvant setting, he noted.
One question is whether the use of modern combination chemotherapy will increase the magnitude of benefit of neoadjuvant/perioperative chemoradiation-based therapy. Several ongoing studies are exploring this, Weekes added.
Approached for comment, Benjamin Golas, MD, associate site chief of surgical oncology at Mount Sinai West and Mount Sinai St. Luke's Hospital and assistant professor of surgery at the Icahn School of Medicine in New York City, said, "As the outcomes for pancreatic cancer are so poor, any randomized controlled trial that shows an increase in survival is encouraging."
But as far as any immediate clinical implications from these data, he said that neoadjuvant therapy is already used in clinical practice. Most centers that treat high volumes of pancreatic disease are probably treating borderline-resectable tumors with some type of neoadjuvant therapy — whether systemic chemotherapy or chemoradiation, he said.
"I think the biology of the disease dictates that we treat it in the neoadjuvant setting, although we don't really know what that is yet," he told Medscape Medical News.
He noted that this study used gemcitabine, but FOLFIRINOX (composed of oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil) is also being investigated. "The next trial should be radiation combined with FOLFIRINOX or some variation of that upfront, and hypothetically that may have an influence on survival," he said.
Also commenting, Igor Astsaturov, MD, PhD, associate professor and co-director of the Marvin and Concetta Greenberg Pancreatic Cancer Institute at Fox Chase Cancer Center, Philadelphia, Pennsylvania, said that these new "results reinforce the idea now widely accepted in the USA that a neoadjuvant approach is beneficial to patients with resectable pancreatic cancer."
The PEROPANC-1 trial showed statistically improved survival in the preoperative treatment group (overall survival, 17 months) compared with the surgery-alone group (overall survival, 13.5 months), he summarized. This is somewhat inferior to the previously established benchmark in ESPAC-4 (28 months) or the even higher survival (54.5 months with modified FOLFIRINOX and 35 months with gemcitabine) just reported here at ASCO 2018.
"Factors contributing to such outcomes may include unresectable, metastatic cancers or positive margins, so the full presentation of these new results will be of interest to these specific points," he added.
"In our practice, we have adopted a more aggressive neoadjuvant chemotherapy and radiation approach," said Astsaturov. "With ongoing trials testing gemcitabine and Abraxane vs FOLFIRINOX, these presented results send a signal that we are on the right track of aggressive therapy for localized pancreatic cancer."
This study received funding from the Dutch Cancer Society KWF. Van Tienhoven has disclosed no relevant financial relationships. Weekes has disclosed relationships with Celgene, Lilly, Merrimack, Genentech/Roche, AbbVie, Millennium, and Bayer. Astsaturov and Golas have disclosed no relevant financial relationships.
American Society of Clinical Oncology (ASCO) 2018. Presented June 4, 2018. Abstract LBA4002
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