The challenge in treating patients with borderline resectable pancreatic cancer is how to render tumors resectable and how to achieve the negative surgical margins that enhance long-term survival odds. Fortunately, neoadjuvant chemotherapy is helping to achieve these important goals, according to Bassel F. El-Rayes, MD, Professor and Vice Chair of Research and Director of the Gastrointestinal Oncology Program at Winship Cancer Institute of Emory University.
At the 2020 Debates and Didactics in Hematology and Oncology Virtual Conference, sponsored by Emory University, Dr. El-Rayes described the latest data supporting neoadjuvant therapy for borderline resectable pancreatic cancer.1
Bassel F. El-Rayes, MD
What Makes a Tumor Borderline Resectable?
Borderline resectable pancreatic cancer is differentiated from locally advanced resectable disease based on the relationship between the tumor and the superior mesenteric vein, the superior mesenteric artery, and other vessels. A fat plane lies among these structures; when it is uninvaded by cancer, the disease is deemed resectable. With borderline resectable pancreatic cancer, however, there is some loss of this fat plane and encroachment of the tumor into the superior mesenteric vein or superior mesenteric artery. In locally advanced disease, the tumor completely involves the superior mesenteric vein and “more than abuts” the superior mesenteric artery, as Dr. El-Rayes described it. “The likelihood of a curative resection in these patients is usually very low, and they are treated instead with palliative intent.”
Thus, Dr. El-Rayes declared, the clinical challenges with borderline resectable pancreatic cancer are how to get these patients to a resection and how to do a complete resection. “With this in mind,” he continued, “an upfront surgical approach in many of these patients is not off the table, but the challenge is that margin-negative resection rates fall as vessels become involved, and the surgery becomes more complicated. Thus, there is hesitancy about going directly to surgery.”
Borderline resectable pancreatic cancer also conveys a high risk for systemic disease. Preclinical models have shown that metastasis arises quite early in pancreatic cancer, even before cancer is locally invasive. No doubt, this underlies the observation that the majority of patients who undergo surgical resection still relapse with systemic disease, he said.
Evidence Supports Neoadjuvant Therapy
The role of multimodality therapy is to better downstage the tumor to facilitate margin negativity (R0) and to treat micrometastatic disease to prevent systemic recurrence. This is accomplished through newer, more active neoadjuvant chemotherapy regimens and improved radiation therapy techniques. “This has been shown [to be useful] in the adjuvant setting, and we believe it will apply in borderline resectable pancreatic cancer as well,” Dr. El-Rayes said.
“The clinical challenges with borderline resectable pancreatic cancer are how to get these patients to a resection and how to do a complete resection.”— Bassel F. El-Rayes, MD
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Supporting evidence comes from ESPAC-5F, a prospective, international, randomized phase II trial of immediate surgery vs neoadjuvant chemotherapy or chemoradiotherapy.2 Patients with borderline resectable pancreatic cancer were randomly assigned to one of four arms: 1) surgery first; 2) neoadjuvant gemcitabine plus capecitabine; 3) neoadjuvant FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, fluorouracil); or 4) chemoradiotherapy (50.45 Gy in 28 daily fractions with capecitabine throughout). All groups received adjuvant therapy after surgery.
The R0/R1 resection rate, the primary endpoint, was comparable for surgery first (44%) and preoperative therapy (41%; P = .668), as was the ability to go on to adjuvant therapy. A statistically significant benefit did emerge, however, for overall survival at 1 year (a secondary outcome), with 12-month survival rates of 77% with preoperative treatment vs 42% with immediate surgery (hazard ratio [HR] = 0.28; P < .001). The highest survival rate, 84%, was seen with FOLFIRINOX, followed by 79% with gemcitabine/capecitabine, 64% with chemoradiotherapy, and 42% with immediate surgery; however, the study was not designed for this comparison. Toxicity was higher with FOLFIRINOX but “overall manageable,” noted Dr. El-Rayes.
Benefits With FOLFIRINOX
The results are in line with those from a 2019 meta-analysis coauthored by Dr. El-Rayes, which examined FOLFIRINOX for borderline resectable pancreatic cancer.3 Neoadjuvant FOLFIRINOX yielded a resection rate of 68%, of which 84% were R0 resections. The pooled data also showed promising outcomes in terms of progression-free survival (median, 18 months) and overall survival (median, 22 months).
“Again, these numbers are encouraging, showing that when you start with FOLFIRINOX, there is a high chance of R0 resections,” observed Dr. El-Rayes.
In locally advanced unresectable pancreatic cancer, FOLFIRINOX yielded similar results in another meta-analysis, resulting in a median progression-free survival of 15 months and a median overall survival of 24 months, across studies.4 In fact, in the two meta-analyses, the Kaplan-Meier curves demonstrated nearly superimposable progression-free and overall survival curves, showing the benefit of FOLFIRINOX and reflecting a similar benefit in borderline resectable and locally advanced pancreatic cancers.
“As you may expect, as we move FOLFIRINOX into earlier stages, we see a bigger impact on outcomes,” Dr. El-Rayes said. Of note, the impact of this regimen on long-term survival appears to be greater in borderline resectable pancreatic cancer, probably because it helps more patients get to surgery, he added.
More support comes from the Alliance A021101 trial of neoadjuvant modified FOLFIRINOX followed by capecitabine-based chemoradiation.5 In that study, 68% of patients ultimately underwent pancreatectomy, 93% of whom achieved microscopically negative margins. “The interesting thing about this study is that patients who responded well to neoadjuvant therapy tended to have better long-term survival than those left with residual disease, again suggesting that response to treatment in this setting may give prognostic information as well,” declared Dr. El-Rayes.
Does Chemoradiotherapy Add Value?
The international randomized phase III PREOPANC-1 trial evaluated neoadjuvant chemoradiotherapy (various regimens) vs immediate surgery in 246 patients with resectable or borderline resectable pancreatic cancer.6 The study did not meet its primary endpoint, which was an improvement in overall survival with neoadjuvant chemoradiotherapy, although a favorable trend was seen: median overall survival was 17 months vs 14 months with immediate surgery (HR = 0.74; P = .074), increasing to 42 months vs 17 months in the subset with R0/R1 resection (HR = not reached; P < .001).
Other benefits seen with preoperative chemoradiotherapy were statistically significant: a doubling in R0 resections rates (P < .001); a 29% improvement in disease-free survival (P = .023) and distant metastases-free survival (P = .013); and a 45% improvement in locoregional recurrence (P = .002).
“This study suggested there may be a benefit to preoperative chemoradiotherapy over surgery, although it did not translate into an overall survival benefit,” commented Dr. El-Rayes. Furthermore, he noted, the trial used gemcitabine-alone, which by today’s standards would be considered suboptimal.
Role of Radiation Still Controversial
The role of radiation in the setting of borderline resectable pancreatic cancer is still controversial. “We tend to use it in patients who are not responding to chemotherapy. It may allow the surgeon to improve the margin resection,” explained Dr. El-Rayes.
In his own group’s experience, induction radiotherapy led to a median overall survival of 13 months in patients with locally advanced disease, 16 months in those with borderline resectable pancreatic cancer, and 19 months in patients with resectable disease.7 As was the custom at the time of the study, few patients also received neoadjuvant chemotherapy.
“As you may expect, as we move FOLFIRINOX into earlier stages, we see a bigger impact on outcomes.”— Bassel F. El-Rayes, MD
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The 12-month survival rates were 51% for locally advanced disease, 66% for borderline resectable pancreatic cancer, and 66% for resectable tumors; the 36-month rates were 13%, 34%, and 20%, respectively. Of note, within the borderline resectable group, patients able to undergo resection had a doubling in overall survival over those with resectable disease: 46% vs 21% at 36 months. “This suggests that preoperative therapy essentially equalized their outcomes with those of resectable patients,” Dr. El-Rayes commented.
How to Approach Nonresponders to Neoadjuvant Therapy
Dr. El-Rayes shared his approach to treating borderline resectable pancreatic cancer, including those instances in which patients do not respond well to neoadjuvant treatment. After a tumor board discussion of the case, the patient should start systemic neoadjuvant therapy, usually FOLFIRINOX, and is restaged at 2 months. If the tumor is deemed resectable at that point, the patient proceeds to surgery; if the extent of resection is predicted to be substantial, the patient may be given a short course of radiation first.
If the tumor is not resectable at 2 months—but an encouraging response has been observed (such as a reduction in CA19-9 or tumor shrinkage)—2 additional months of FOLFIRINOX may be given. The patient is then restaged; if there is still no treatment response (ie, stable disease at best), chemoradiotherapy may be the next step in rendering the tumor resectable, Dr. El-Rayes said.
DISCLOSURE: Dr. El-Rayes has served as a consultant to Novartis, Exelixis, and Bayer and has received research support from Merck, Five Prime Therapeutics, Boston Biomedical, Bristol Myers Squibb, Taiho Oncology, ICON, Bayer, Hoosier Cancer Research Network, and Cleve Biosciences.
REFERENCES
2. Ghaneh P, Palmer DH, Cicconi S, et al: ESPAC-5F: Four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine or FOLFIRINOX or chemoradiotherapy in patients with borderline resectable pancreatic cancer. ASCO20 Virtual Scientific Program. Abstract 4505.
3. Janssen QP, Buettner S, Suker M, et al: Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: A systematic review and patient-level meta-analysis. J Natl Cancer Inst 111:782-794, 2019.
4. Suker M, Beumer BR, Sadot E, et al: FOLFIRINOX for locally advanced pancreatic cancer: A systematic review and patient-level meta-analysis. Lancet Oncol 17:801-810, 2016.
5. Katz MHG, Shi Q, Ahmad SA, et al: Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer: Alliance for Clinical Trials in Oncology Trial A021101. JAMA Surg 151:e161137, 2016.
7. Shaib WL, Sayegh L, Zhang C, et al: Induction therapy in localized pancreatic cancer. Pancreas 48:913-919, 2019.
