Michael A. Choti, MD

Surgical resection followed by adjuvant therapy has been the mainstay treatment for patients with resectable pancreatic cancer. However, neoadjuvant therapy has recently been established as a potential new standard in this treatment paradigm, although this remains a topic of controversy. Following a long history with minimal advances, this strategy provides hope and insights on future avenues to further explore in order to continue improving outcomes for patients with pancreatic cancer.

“The overall pancreatic cancer [prognosis] is devastating. Even if it's an operable, removable cancer, the chance of recurrence is high, and the chance of cure with just surgery is low, so there's all there's always been a strong enthusiasm of coupling surgery with effective systemic therapy to lower the risk of recurrence,” Michael A. Choti, MD, Chief of Surgery, Banner MD Anderson Cancer Center, told Targeted Oncology in an interview for World Pancreatic Cancer Day, which occurs annual on November 19 to call attention to this disease.

The addition of systemic therapy to the treatment strategy of resectable patients with pancreatic cancer has been an important advancement, but until recently, chemotherapy had minimal benefit in this space, according to Choti. With recent advances in chemotherapy in the advanced and adjuvant setting, the use of these regimens for neoadjuvant treatment is gaining attention.

Some of the regimens include fluorouracil, leucovorin, irinotecan (Onivyde) and oxaliplatin (Exolatin) -- FOLFIRINOX); gemcitabine (Gemzar) plus nab-paclitaxel (Abraxane), or gemcitabine with capecitabine. The most preferred adjuvant approach, however, is modified FOLFIRINOX (mFOLFIRINOX). Compared with single-agent gemcitabine, the use of postoperative adjuvant mFOLFIRINOX provided optimal outcomes, improving the median overall survival of 35 months to 54.4 months (HR, 0.48; 95% CI, 0.48-0.86; P =.003).¹

The benefits of adjuvant therapy in resectable patients with pancreatic cancer has been observed in clinical trials, and this is reflected in the National Comprehensive Cancer Network (NCCN) Guidelines.2 Adjuvant therapy is recommended for use in patients who adequately recovered from the surgery and should be initiated within 12 weeks if an adjuvant approach is considered to be clinically indicated. However, the growing interest as of recent years has been moving the use of systemic therapies upfront.²

“The general enthusiasm currently is toward the use of preoperative therapy and an increasing understanding that surgery is less appropriate for many patients than previously believed,” Matthew H. G. Katz, MD, associate professor, Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, told Targeted Oncology during Pancreatic Cancer Awareness Month. “There's been an increasing willingness to better select the right treatment for the right patient, as opposed to just inappropriately using surgical resection on patients who are better served with other types of therapy.”

Selecting Patients Appropriate for Surgery

The distinction between patients with pancreatic cancer who are resectable or borderline resectable is important to consider when making treatment decisions. In patients with borderline resectable pancreatic cancer, the cancer is abutting or involving some of the main arteries and veins in the vicinity that can’t be as easily removed, and so the use of neoadjuvant therapy is particularly useful in shrinking the tumor prior to surgery in order to achieve negative surgical margins.

“If it's borderline, even though they are operable, it's associated with a higher chance of a positive margin, or that those veins need to be reconstructed,” said Choti. “Therefore, it's pretty clear now, the shift away from upfront surgery for those borderline cancers has already probably occurred. Now if it's borderline on the preoperative imaging studies, then we most recommend neoadjuvant chemotherapy.”

According to the NCCN Guidelines, patients with borderline resectable disease can receive neoadjuvant therapy in an effort to improve the chances for an R0 resection, and the treatment may include chemotherapy or chemoradiation. However, the guidelines note that treatment decisions for patients with borderline resectable disease should be considered on an individualized basis in a multidisciplinary setting.²

“The treatment depends on stage to a large degree. Patients with localized cancer who have a reasonable performance status, reasonable physiologic status, and reasonable CA 19-9 level or can reasonably be considered for surgery,” Katz said.

A select group of resectable patients who are high risk can be considered for neoadjuvant therapy prior to surgery, according to the NCCN Guidelines. High-risk features include elevated CA 19-9 levels, large primary tumors, large regional lymph nodes, excessive weight loss, and extreme pain. These patients, in particular, could be considered for a neoadjuvant approach prior to surgery, but the evidence is minimal for this approach off-study. Participation in clinical trials is highly encouraged.

Despite not being considered standard yet, the preferred neoadjuvant regimens include FOLFIRINOX, mFOLFIRINOX, or gemcitabine in combination with nab-paclitaxel. For patients harboring either BRCA1/2 or PALB2 mutations, the preferred treatments included the 2 FOLFIRINOX regimens, as well as the combination of gemcitabine with cisplatin.

Neoadjuvant Chemotherapy With or Without Radiation

These neoadjuvant regimens primarily focus on the use of chemotherapy alone. However, the combination of chemotherapy combined with radiation has been an area of interest in the neoadjuvant realm, marking another area of controversy in this space.²

“Radiation therapy is usually administered in combination with radiosensitizing chemotherapy, so called chemoradiation therapy” Choti said. “My preference is that we use radiation therapy preoperatively and selectively; typically, in borderline resectable cases. What we do at Banner MD Anderson is to give neoadjuvant chemotherapy first, and then we reassess. If the tumor has not shrunk sufficiently, we then consider the addition of radiation.”

With minimal randomized data to support the use of either neoadjuvant approach, it is still unclear what the appropriate strategy to resectable and borderline resectable patients with pancreatic cancer is.

One study conducted by the Dutch Pancreatic Cancer Group explored the use of neoadjuvant gemcitabine followed by gemcitabine and radiation prior to surgery followed by adjuvant gemcitabine compared with surgery and adjuvant gemcitabine alone in both resectable and borderline resectable patients. The phase 3 PREOPANC study failed to meet its primary end point with a median overall survival of 16.0 months with neoadjuvant therapy versus 14.3 months with the adjuvant approach (HR, 0.78; 95% CI, 0.58-1.05; P =.096), but several secondary end points favored the neoadjuvant approach, including significantly better disease-free survival and locoregional failure-free interval.³

Interestingly, findings from a preplanned subset analysis in the PREOPANC study indicated that the neoadjuvant approach induced superior overall survival among those with borderline resectable disease and no significant difference in the resectable population. However, the sample size of this study was small, and the study investigators were unable to draw a conclusion on the value of this preoperative approach.

Neoadjuvant strategies are also supported by findings from single-arm and single-institution studies, as well as meta-analyses and reviews. A single-arm non-randomized phase 2 study, in particular, reviewed the role of neoadjuvant systemic therapy in patients with pancreatic cancer, in which the primary end point of 18-month overall survival was met, highlighting the need to further explore the role of this treatment approach.⁴

The study explored the use of gemcitabine in combination with oxaliplatin. The 18-month OS rate was 63% with 24 patients alive. The median OS was determined to be 27.2 months, and the median disease-specific survival was 30.6 months. However, this was again a smaller study, in which 35 of the 38 patients enrolled had completed all 4 cycles of neoadjuvant therapy. Four patients achieved a partial response as their best response, and 28 patients had stable disease.

Out of 27 patients in the study who underwent surgery, 26 received adjuvant therapy following the operation. Among these patients, the adjuvant treatment was well-tolerated and had no unexpected toxicity. The median recurrence-free survival in this group of patients was 22 months. The patients who received surgery following neoadjuvant therapy had a significantly improved OS compared with those who did not (P =.0006).

“While there's certainly been progress, everything is a challenge still,” said Katz. “Early detection is a challenge, effective therapeutics are a challenge, knowing how much and what treatments to give is a challenge. We have seen significant progress, but I would say a lot of progress still needs to be made.”

Next Steps for Neoadjuvant Therapy

The Alliance group has initiated recruitment to a phase 3 clinical trial, in which perioperative chemotherapy will be compared with the use of adjuvant chemotherapy for resectable patients. The chemotherapy regimen patients will receive is FOLFIRINOX, as this regimen has been demonstrated to stop the growth of tumor cells in pancreatic cancer.

“This trial is designed to randomize patients who have resectable pancreatic adenocarcinoma to surgery upfront surgery followed by postoperative adjuvant chemotherapy versus perioperative chemotherapy,” Choti said. “This is an important trial, to determine if this is the right approach or not.”

The target enrollment for this study is 352 patients, who will be randomized to receive neoadjuvant treatment followed by surgery and post-operative chemotherapy or surgery followed by adjuvant chemotherapy. The primary end point is OS, and some of the secondary end points include disease-free survival, time to locoregional recurrence, time to distant metastases, pathologic complete response, rate of unrespectability, and quality of life.

“There is lot of reason for optimism that in the next 5 to 10 years, we're going to be better and better,” Choti said. “We will be better at screening, better at detection, better at diagnosis, better at studying the biology of the cancer, and we'll have better drugs, targeting the therapy and then of course as a surgeon, better surgical techniques so that will hopefully improve outcomes, improve quality of life, and improve the experience of patients who are suffering with this disease.”

_References

_{1. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379, 2395-2406. doi: 10.1056/NEJMoa1809775}

_{2. NCCN Guidelines Version 1.2021 Pancreatic Adenocarcinoma. Accessed November 13, 2020. nccn.org/professionals/physician_gls/pdf/pancreatic.pdf}

_{3. Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase iii preopanc trial. Journ of Clin Oncol. 2020;38:16, 1763-1773. doi: 10.1200/JCO.19.02274}

_{4. O’Reilly EM, Perelshteyn A, Jarnagin WR, et al. A single-arm, non-randomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma. Ann Surg. 2014;260, 142-148. doi: 10.1097/SLA.0000000000000251}