Expert Point of View: Colin D. Weekes, MD, PhD and Manish A. Shah, MD, FASCO


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Colin D. Weekes, MD, PhD

Colin D. Weekes, MD, PhD

Manish A. Shah, MD, FASCO

Manish A. Shah, MD, FASCO

Two pancreatic cancer specialists commented on the PREOPANC-1 study for The ASCO Post: Colin D. Weekes, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, Boston, who had discussed the abstract at the ASCO Annual Meeting, and Manish A. Shah, MD, FASCO, Chief of the Solid Tumor Service and Director of the Gastrointestinal Oncology Program at NewYork-Presbyterian Hospital and Weill Cornell Medicine, New York. The two agreed that the results were impressive but may have been even more so with a more aggressive neoadjuvant regimen.1

Proof-of-Principle Study

Dr. Weekes said the phase III PREOPANC-1 study and other trials of neoadjuvant approaches show that giving chemotherapy and radiotherapy before surgery has a beneficial effect in patients with resectable and borderline-resectable pancreatic cancer. “But gemcitabine was used here, and we know that is not the best drug,” he pointed out. “The current study, therefore, is more of a proof-of-principle study.” These results are consistent with a Korean study in which patients with borderline-resectable pancreatic cancer were randomized to receive either neoadjuvant chemoradiation or adjuvant chemoradiation followed by adjuvant gemcitabine. That study did demonstrate improved overall survival associated with neoadjuvant chemoradiation in an intent-to-treat analysis.2

Instead, FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) is his neoadjuvant regimen of choice. This regimen is active in localized pancreatic cancer as demonstrated in the PRODIGE adjuvant trial presented at the ASCO Annual Meeting.1 A study of FOLFIRINOX plus chemoradiation as a total neoadjuvant regimen for patients with borderline-resectable disease showed a significant improvement in clinical outcomes such as disease-free survival, R0 resection rate with median overall survival not being met at the time of publication.3 This, however, was not a randomized trial, as was the PREOPANC1 study, he said.

Dr. Shah said the Dutch PREOPANC trial is “an important study that asks the question of whether preoperative chemoradiation can improve the resection rates and ultimately the survival for this very difficult-to-treat disease.”

He continued: “The study included patients who had either clearly resectable pancreatic cancer or ‘borderline-resectable’ pancreatic cancer. This idea, a ‘borderline-resectable’ cancer, is notable because it is often the case that the imaging does not tell the complete story: sometimes a surgeon will begin an operation not sure whether he or she can remove the entire tumor with negative margins. There may be blood vessel involvement or something about the anatomy that makes a complete resection challenging. The more borderline-resectable patients there are in a particular study, the more likely the resection margin will be positive, meaning the pathologist can identify tumor cells at the cut margin of the pathology specimen.”

Overall, about half the patients enrolled in this study were borderline-resectable. Additionally, the study was designed to have a large effect size and therefore required a relatively small number of patients, he noted. “Although this is a good idea in principle, it is quite ambitious and would only be a statistically positive study if the improvement in outcome with preoperative chemotherapy and radiation was substantial,” he said. “The downside to this approach is that more modest improvements are missed.” Ultimately, the study met its accrual goal by enrolling 248 patients over just over 4 years.

‘Compelling Results’

“The results of this study were compelling,” Dr. Shah concluded, pointing to the higher rate of complete resection with preoperative therapy (63% vs 31% with immediate surgery), which was highly significant (P < .001). There was also a suggestion of benefit in overall survival with preoperative chemoradiation, which yielded a median survival of 17 months vs 13.7 months with upfront surgery.

“Notably, this endpoint didn’t meet statistical significance because the sample size was on the smaller side. However, other measures of efficacy were significant, like improvements in disease-free survival, local-regional recurrence–free interval, and distant metastasis–free interval,” he explained.

“Should this change practice? I think if you have a patient with borderline-resectable disease, the use of preoperative chemotherapy and radiation is quite compelling,” Dr. Shah commented. “But I would strongly consider using more aggressive chemotherapy, like FOLFIRINOX, in this setting, especially in light of the adjuvant Unicancer GI PRODIGE study!”

The use of FOLFIRINOX in the preoperative setting for borderline-resectable pancreatic cancer is currently being examined in the Alliance cooperative group study (ClinicalTrials.gov identifier NCT02839343). ■

DISCLOSURE: Drs. Weekes and Shah reported no conflicts of interest.

REFERENCES

1. Conroy T, Hammet P, Hebbar M, et al: Unicancer GI PRODIGE 24/CCTG PA.6 trial. 2018 ASCO Annual Meeting. Abstract LBA4001. Presented June 4, 2018.

2. Jang JY, Han Y, Lee H, et al: Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer. Ann Surg. February 16, 2018 (early release online).

3. Murphy JE, Wo JY, Ryan DP, et al: Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemotherapy for borderline resectable pancreatic adenocarcinoma: A phase 2 clinical trial. JAMA Oncol. May 3, 2018 (early release online).


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