Available Therapies for Borderline Resectable Pancreatic Cancer are More Defined Through Research, But Sequencing Relies on Individualized Care

Borderline resectable pancreatic cancer (BRPC) is a disease for which the neoadjuvant treatment approach has demonstrated major advantages for patients. It is customary in the field to administer chemotherapy first, and although radiation is utilized in the space, its use is controversial, said Bassel El-Rayes, MD, during a presentation at the 2020 Debates and Didactics Hematology and Oncology (DDHO 2020) meeting.¹

The advantages associated with treating BRPC in the neoadjuvant setting include initiating system therapy early to a disease that is known to be systemic in nature, downstaging disease to improve margin negative resection, and improving survival. The most promising chemotherapy regimen to help achieve these treatment goals is FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin).

In an international patient-level meta-analysis of FOLFIRINOX in BRPC, a favorable median overall survival, resection rate, and R0-resection rate was observed in patients. The resection rate was 67.8% (95% CI, 60.1%-74.6%), and the R0-resection rate was 83.9% (95% CI, 76.8%-89.1%). The patient-level median OS was 22.2 months (95% CI, 18.8-25.6), and a median progression-free survival was also reported as 18.0 months (95% CI, 14.5-21.5).²

In an interview with Targeted Oncology, El-Rayes, professor and vice chair of research, director of the Gastrointestinal Oncology Program, and associate cancer center director at the Winship Cancer Institute of Emory University, discussed the treatment options for patients with BRPC. He also discussed sequencing the available agents for BRPC and the role of circulating tumor DNA (ctDNA) in guiding individualized treatment of the disease.

TARGETED ONCOLOGY: Can you discuss the available treatment options for BRPC? Are there any novel agents coming down the pipeline?

El-Rayes: Resectable pancreatic cancer management requires multimodality care. Many patients would require surgery, class chemotherapy, and sometimes radiation as part of their care. The sequencing of those therapies depends on individual patient situations. Most of the patients would start out with the chemotherapy approach and if there's a good response, they could proceed directly to surgery. If the response is not adequate, many times, you would do radiation prior to surgery.

There are a number of novel agents that are being looked at in pancreas cancer. Of course, agents are usually tested on stage IV disease before they are tested in a borderline resectable

setting. We're waiting for more agents to prove themselves in stage IV before we bring them into the borderline resectable setting.

TARGETED ONCOLOGY: What research supports your practices for sequencing the available agents in the field?

El-Rayes: There are a number of single-institution trials that have been reported looking at preoperative therapy followed by resection. These trials were in resectable patients as well as the borderline resectable patients.

We also saw 2 randomized trials. One trial was from a group in the Netherlands that looked at more chemoradiation prior to surgery versus going directly to surgery. The second trial, which was reported by a group in England, showed patients going directly to surgery versus

either 2 different types of chemotherapy or radiation prior to surgery.

Both trials showed an advantage for preoperative therapy. The British trial showed an advantage in terms of survival and the Dutch trial showed an advantage in terms of margin of resection. The field still needs more research to definitively define the best approach. Given the single-institution series and these 2 randomized trials, the field is moving in the direction of using some sort of preoperative therapy in the majority of patients with borderline resectable pancreatic cancer.

TARGETED ONCOLOGY: What are the key clinical challenges with treating this patient population?

El-Rayes: There are 2 main challenges with treating patients with BRPC: The first is how do we downstage the tumor to enhance local control and allow for a successful surgery that has negative margins of resection? Number 2 is how do we lower the risk of the systemic recurrence of the disease where the disease recurs in another site in the body? Lowering the risk or systemic recurrence would definitely impact long-term survival.

TARGETED ONCOLOGY: What are you suggestions for addressing the clinical challenges in pancreatic cancer?

El-Rayes: I think the approach to address these challenges is number 1, to incorporate systemic therapy early. Systemic therapy can downstage tumors when they respond and lower the risk of systemic recurrence based on the trials that were done in the adjuvant setting. This is a strategy that may help to achieve both of those goals.

TARGETED ONCOLOGY: How is ctDNA utilized to guide treatment of this patient population?

El-Rayes: ctDNA assays are becoming mainstream in the management of gastrointestinal malignancies. The role of ctDNA is to do genomic profiling when tissue is not available, and it allows us to monitor response to therapy, as well as the evolution of new mutations that can confer resistance to treatment. ctDNA can also have prognostic information, especially in resected patients. It allows us to select which group of resected patients may benefit from adjuvant therapy.

TARGETED ONCOLOGY: What is the key takeaway from your presentation at the DDHO 2020 meeting?

El-Rayes: Managing patients with BRPC requires a collaboration between a multidisciplinary team of physicians who are focused on pancreas cancer care, including medical oncology, radiation oncology, and surgery. This helps to identify a personalized approach for each patient. Not every patient should get chemotherapy and not every patient should get radiation. Knowing that, how do we select what is the best for the individual patient? Answering that question requires a team effort.

TARGETED ONCOLOGY: What does a multidisciplinary team look like at your institution? How do you collaborate to offer the best solutions for your patients?

El-Rayes: In our institution, we have a tumor board meeting that happens once a week. On that tumor board, there are surgeons, medical oncologists, pathologists, radiation oncologists, and radiologists. We present BRPC cases in that tumor and review the imaging and the pathology. Then, we put forward a care plan.

If the plan starts with chemotherapy, for example, then we would come back and represent the same case at the tumor board after they've done some chemotherapy and we’ve done repeat imaging. There is a juncture in the care of those patients whose cases are presented to the tumor board so that we can try to achieve consensus between the different disciplines on the next treatment based on the outcome of the resistance.

_References:

_{1. El-Rayes B. Sequencing therapies in borderline resectable pancreatic cancer. Presented at: 2020 Debates and Didactics in Hematology and Oncology meeting; July 16-19, 2020. Virtual.}

_{2. Janssev QP, Buetner S, Suker M, et al. Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis. JNCI J Natl Cancer Inst. 2019;111(8):782-794. doi:10.1093/jnci/djz073}