Trial to assess novel surgical procedure for locally advanced pancreatic cancer


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A clinical trial at Keck Medicine of USC will investigate a new surgical approach to treating patients with locally advanced pancreatic cancer.

The PROACTIVE trial aims to assess the effectiveness of advanced reconstruction techniques — typically used in liver transplant surgeries — in completely removing cancer from patients with pancreatic cancer that has spread to important blood vessels. These patients usually would be considered ineligible for surgery due to the tumor’s involvement with major arteries.



Quote from Steven Grossman MD, PhD



Pancreatic cancer accounts for about 3% of malignancies in the United States. However, prognosis is extremely poor, with only 10% of patients surviving 5 years after diagnosis.

“The only chance of long-term survival in pancreatic cancer, as far as we know, is to resect the primary tumor,” co-lead investigator Steven Grossman, MD, PhD, medical oncologist with Keck Medicine and deputy director for cancer services at USC Norris Comprehensive Cancer Center, told Healio.

Yuri Genyk, MD

Yuri Genyk

Now, Yuri Genyk, MD — chief of the division of hepatobiliary/pancreatic and abdominal organ transplant surgery at Keck School of Medicine — and his hepatobiliary surgical team have the technical ability to resect pancreatic tumors that only a few surgeons across the country would tackle, Grossman said.

Healio spoke with Grossman about the innovative surgical approach this trial will evaluate, as well as his hopes for advancing the science to improve outcomes in this poor-prognosis disease.

Healio: Can you briefly describe the traditionally poor outcomes in locally advanced pancreatic cancer?

Grossman: “Locally advanced pancreatic cancer” (LAPC) refers to pancreatic cancer that has grown and spread to nearby tissues and organs around the pancreas, but has not yet spread to distant parts of the body. In general, patients diagnosed with LAPC have tumors that can’t be immediately removed surgically because they’re attached to nearby structures, like blood vessels and arteries. Some of these tumors might be potentially or “borderline” removable when they’re connected to local veins that can be reconstructed using standard techniques after initial chemotherapy, with outcomes that begin to approach those seen in patients who present with initially resectable tumors.

Within the LAPC category are patients who have specific involvement of the local arteries around the pancreas. These are the patients we are targeting with this trial, though some patients with pancreatic tumors that are firmly attached to crucial blood vessels or other vital structures that cannot be reconstructed may not meet the criteria for participation in the trial, as attempting complete removal could pose a risk of causing harm to the surrounding tissues.

Healio: What does the new surgical approach entail?

Grossman: The protocol’s lead surgeon is Dr. Genyk, whose background is in hepatobiliary surgery and liver transplantation. He is applying liver transplant arterial reconstruction techniques to effectively resect pancreatic tumors with arterial involvement, and only a handful of surgeons across the country are doing this.

Dr. Genyk found in his preliminary studies that if the tumor has attached itself to one of three arteries local to the pancreas — the superior mesenteric, the common hepatic or the celiac axis — he can successfully remove the tumor and reconstruct those arteries. Thus, we have focused eligibility for the PROACTIVE study on patients whose tumors involve any of these 3 arteries. The overall objective of this protocol is to determine if we can feasibly achieve an R0 resection — meaning completely removing the tumor with negative margins — in patients with LAPC and arterial involvement.

Healio: Could this approach be superior to the current standard?

Grossman: We believe that it could be. Dr. Genyk has performed arterial reconstructions along with tumor resection on about 30 patients with LAPC, and some are long-term survivors. So, we know it’s possible, although it’s not in the peer-reviewed literature yet. Our hypothesis is that combining typical chemotherapy — which we give to patients with LAPC — with resection and arterial reconstruction will result not only in R0 resection but long-term survival. The difference is, right now, these patients do not undergo an operation. There are no long-term survivors — that’s the bottom line. We’re trying to go from a tragically small 5-year survival to one that approaches results seen in borderline resectable patients who undergo resection after upfront chemotherapy.

Healio: How will the trial be conducted, and what is the timeline for results?

Grossman: We see this effort as a multistep process. The first step is this trial, which is a

pilot study with an enrollment goal of 20 patients over 2 to 3 years. Our primary goal is to establish feasibility for incorporation of arterial reconstruction into the care of LAPC and study the rate of margin-negative R0 resection in those 20 patients. That will set the stage for the next trial, in which we will evaluate how this approach might yield improved survival outcomes over current approaches. That will be a larger study in which we can apply the surgical techniques and everything we have learned in these 20 patients. That next study potentially will be randomized to rigorously study the benefit of this intervention.

Healio: What are the potential implications of the results?

Grossman: If we break down pancreatic cancer into buckets of presentations that incorporate various stages, we have resectable patients, who generally undergo resection and then get adjuvant chemotherapy. The survival statistics have improved recently due to better surgical outcomes and the advent of adjuvant chemotherapy with 44% 5 year survival. However, less than 20% of patients with pancreatic cancer present with localized disease and eligibility for upfront surgery.

On the other side, about 50% of patients are stage IV with distant spread, and their 5-year survival is only 3%. In the middle, just under a third of patients present as locally advanced, with either borderline resectable or inoperable tumors. That is where we are hoping to make an impact. If we have a statistically valid number of long-term survivors in this group, we’ll have made a huge impact.

Healio: Is there anything else you’d like to mention?

Grossman: We have publicized the trial, and we are getting lots of great feedback and referrals. If you’re a medical oncologist or surgeon who cares for patients with LAPC, and you have a patient who presents with inoperable LAPC, this is an attractive possibility. I would recommend they reach out early. It isn’t necessary to delay upfront chemotherapy because the trial itself is very flexible, as we require chemotherapy but we don’t specify the regimen. We let the treating oncologist choose the chemotherapy — FOLFIRINOX, NALIRIFOX or gemcitabine/nab-paclitaxel — and we make sure the patient receives between 2 months and 6 months of preoperative chemotherapy from their treating oncologist . At that point, we formally screen and, if eligible, register, patients for the PROACTIVE trial. We can guide the referring oncologist to ensure smooth clinical trial enrollment and participation. Clinicians interested in referring a patient for the PROACTIVE trial can contact referral specialists by phone at (323) 865-0451 or by email at clinical.trials@med.usc.edu.

Reference:

For more information:

Steven Grossman, MD, PhD, can be reached at steven.grossman@med.usc.edu.

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