Potential Role for Neoadjuvant Therapy Seen in Pancreatic Cancer

Geertjan Van Tienhoven, MD, PhD

According to preliminary findings from the phase III PREOPANC-1 trial, preoperative treatment with chemotherapy and radiation improved overall survival (OS) for patients with resectable or borderline resectable pancreatic cancer compared to immediate surgery. These data, presented at the 2018 ASCO Annual Meeting, demonstrated the potential role for neoadjuvant treatment in the pancreatic cancer treatment paradigm.

Neoadjuvant chemoradiotherapy achieved a median OS of 17.1 months versus 13.7 months with immediate surgery and adjuvant chemotherapy in the intention-to-treat population (HR, 0.74;P= .074).

“I must stress that these are preliminary results. We still need 26 more events before the final analysis, according to the statistical plan, can be done, and the final results have to be awaited before we can draw definitive conclusions. But, these preliminary results of PREOPANC suggest a benefit of preoperative chemoradiotherapy over immediate surgery followed by adjuvant chemotherapy,” said lead study author Geertjan Van Tienhoven, MD, PhD, of the Department of Radiation Oncology, Academic Medical Center in Amsterdam, Netherlands.

Currently, the standard of care for patients with resectable or borderline resectable pancreatic adenocarcinoma is surgery followed by adjuvant chemotherapy. However, Van Tienhoven noted that resection is only possible in about 15% to 20% of patients, and, even after surgery, many patients experience disease recurrence.

Previous studies have suggested the potential for neoadjuvant therapy instead of adjuvant therapy in pancreatic cancer, yet most of these data were from observational studies, Van Tienhoven commented. Therefore, a randomized, controlled study was needed to prove the benefit of the neoadjuvant approach.

PREOPANC-1 is an ongoing randomized, controlled, multicenter phase III trial that has randomized 246 patients who were eligible for surgery to either immediate surgery followed by chemotherapy with gemcitabine (n = 127) or neoadjuvant chemotherapy in combination with radiation followed by surgery and chemotherapy (n = 119).

Van Tienhoven noted that the patients were almost evenly divided between resectable and borderline resectable disease. ASCO expert Andrew S. Epstein, MD, of Memorial Sloan Kettering Cancer Center, commented after the presentation that this made for a broader, more heterogenous patient population than has been seen in other studies.

In the investigational arm, patients received 15 times of 2.4 Gy radiation combined with 1000 mg/m2 of gemcitabine on days 1, 8, and 15, which the regimen was both preceded and followed by 1 cycle of gemcitabine.

The primary endpoint of the study was OS, and secondary endpoints included microscopically complete (R0) resection rate, disease-free survival (DFS), distant metastasis-free interval, locoregional recurrence-free interval, and safety.

Van Tienhoven stressed that it was important to analyze all patients randomized for treatment in the study (the intention-to-treat population), and that findings should not be compared with more specific patient populations. “This is an intention-to-treat analysis of all the patients who have had a diagnosis of resectable pancreatic cancer,” he explained.

As of data cutoff, 142 of the 176 needed events for the primary outcome had been observed.

In the immediate surgery arm, 91 patients (72%) received surgery compared with 72 (60%) in the investigational neoadjuvant arm (P= .065). The rate of R0 resection was doubled in the preoperative treatment arm compared with the standard-of-care arm (63% vs 31%, respectively;P<.001).

Van Tienhoven noted that 10% of patients died in the treatment interval between initiation of treatment and surgery, which contributed to the lower rate of resection in the investigational arm. &ldquo;[The improved R0 resection rate] does indicate that indeed the preoperative treatment does something on the tumor that improves the outcome of surgery,&rdquo; he said.

Disease progression occurred in 80% of patients who received immediate surgery compared with 50% in the neoadjuvant therapy arm (P = .002). Deaths occurred in 83 patients (65%) in the standard treatment arm compared with 66 (55%) in the neoadjuvant arm (P= .074).

Although Van Tienhoven noted that the OS rate was just not statistically significant with aPvalue of .074, he pointed to the 2-year OS rate of 42% with neoadjuvant therapy, which compared favorably with the 2-year OS rate of 30% from surgery and adjuvant chemotherapy.

The median OS difference was especially increased in a subgroup analysis of the population of patients who had received successful surgery following neoadjuvant therapy at 42.1 months compared with 16.8 months for those who had immediate surgery.

Median DFS was 9.9 months with neoadjuvant chemotherapy and radiation therapy versus 7.9 months with surgery and adjuvant therapy (P= .023).

The median distant metastasis-free interval was 18.4 months in the investigational arm versus 10.6 months in the standard treatment arm (HR, 0.71;P= .013). Additionally, the locoregional recurrence-free interval was improved with neoadjuvant therapy compared with surgery and adjuvant therapy (median, not reached vs 11.8 months; HR, 0.55;P= .002). Van Tienhoven noted that differences could potentially be attributed to the added radiation.

Epstein commented that &ldquo;looking at preoperative therapy is particularly important, and I eagerly await the final results. I think it&rsquo;s an important step in what we know about this illness, particularly [for] the role of radiation in this setting for pancreas cancer there&rsquo;s been mixed data postoperatively, so I commend the authors for doing it upfront and contributing to what we know about what may help these patients with pancreas cancer who might ultimately get surgery.&rdquo;

Reference:

Van Tienhoven G, Versteijne E, Suker M, et al; Dutch Pancreatic Cancer Group. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): A randomized, controlled, multicenter phase III trial.J Clin Oncol.2018;36(suppl; abstr LBA4002).

&ldquo;Radiation can have downsides, so my main question as a next step would be the role of chemotherapy without radiation,&rdquo; Epstein added.