Debate Continues on Optimal Neoadjuvant Regimen in Resectable Pancreatic Cancer

Michael Choti, MD

Radiation therapy is not an essential component of neoadjuvant therapy for patients with resectable pancreatic cancer, according to Michael A. Choti, MD, MBA, FACS, who added that chemotherapy is the main treatment that should be used.

“For patients with operable cancer, the standard in the past was to operate and remove the tumor or to perform surgery and then administer adjuvant therapy after the procedure,” said Choti. “However, it is becoming clear that neoadjuvant therapy is where we are headed in the management of potentially operable pancreatic cancer.”

A debate during the 5th Annual School of Gastrointestinal Oncology™ focused on the controversial topic of whether neoadjuvant therapy should consist of chemotherapy alone or chemotherapy in combination with radiation therapy.

One of the goals of neoadjuvant therapy is to remove the cancer with negative margins. Giving neoadjuvant therapy prior to surgery can sometimes shrink the tumor, making it more operable. In this regard, radiation therapy has a great advantage because it’s a local therapy, said Choti. However, radiation therapy does not treat the micrometastatic disease that may be present elsewhere—chemotherapy does, added Choti, and negative margins can be achieved with just chemotherapy alone.

“[I believe] the conclusion at the end of this debate will be a consensus that neoadjuvant chemotherapy is the mainstay and that is what we should start with,” said Choti. “However, if the cancer does not shrink or if the cancer is considered borderline [resectable], then the selective use of radiation therapy [can be considered].”

In an interview with OncLive, Choti the chief of surgery at Banner MD Anderson Cancer Center, discussed the role of radiation therapy in neoadjuvant therapy for resectable pancreatic cancer, the many benefits of neoadjuvant therapy over up-front surgery, and minimally invasive surgical procedures that are coming to the forefront in this disease.

OncLive: For patients with resectable pancreatic cancer, should neoadjuvant treatment consist of chemotherapy alone or chemoradiation?

Choti: The topic I debated with Susan Tsai, MD, of Medical College of Wisconsin, is currently a controversial area in the management of patients with pancreatic adenocarcinoma, which is the most common form of pancreatic cancer. We have made a lot of strides and advances in how we manage this disease. This debate is focused on [neoadjuvant treatment in those with] operable cancer. Unfortunately, most pancreatic cancers present as metastatic; for these tumors, surgery is not an option. In other situations, the cancer may be considered borderline [resectable], meaning it might be possible to operate, but it might not.

This debate topic is related to whether neoadjuvant therapy should consist of chemotherapy alone or chemotherapy with radiation therapy. [The pressing question has to do with whether] radiation is an essential part of the neoadjuvant regimen for patients with operable pancreatic cancer. There is quite a bit of controversy in this area. Part of that is because the role of radiation therapy, in general, is not clear in the management of patients with pancreatic cancer. We sometimes use [radiation therapy] to shrink an inoperable or borderline [resectable] cancer.

However, this debate poses the question of, “What about in the operable setting? Should we just give chemotherapy or chemoradiation therapy?” Dr. Sai took the stance that radiation is an essential part of the therapy and I am arguing that chemotherapy is the main treatment [we should be using]. We should selectively use radiation therapy, if at all, in that situation.

What is your reasoning for your stance regarding radiation therapy in pancreatic cancer?

First, the benefit of neoadjuvant therapy for pancreatic cancer is clearly a reasonable approach, even though guidelines still suggest operating first. Results from several studies [have clearly shown] that giving some neoadjuvant therapy is the better way to go [over up-front surgery], particularly with regard to the Whipple operation, where the pancreatic cancer is in the head of the pancreas. One of the reasons is that you can give more therapy if you do the Whipple operation first. Often these patients may be frail, have a longer recovery, and may never receive the chemotherapy after surgery. If you administer [chemotherapy] up front, more patients will receive it. Another reason is that [chemotherapy] treats the micrometastatic disease, which is a big problem earlier than if you wait, delay after surgery, and then those patients never receive chemotherapy until months after the surgery. Those are the main reasons to give chemotherapy first.

The other argument for neoadjuvant therapy is that we want to remove the cancer with negative margins. Giving neoadjuvant therapy prior to surgery can sometimes shrink the cancer and make it more operable; that is where the radiation therapy has potentially the greatest advantage because it is a local therapy. Radiation does not treat the micrometastatic disease that may be present elsewhere; it treats the primary disease. However, if [the tumor] looks resectable, then that is not a primary advantage of neoadjuvant therapy because, usually, we achieve negative margins with just chemotherapy. The counterargument is that the negative margins could be improved by giving prior radiation therapy. If we give chemoradiation therapy first, then we can have a better chance of clearing the margin.

Could you speak to the shift away from up-front surgery to neoadjuvant treatment? What factors do you take into consideration when making the decision to give neoadjuvant therapy?

Many cancer surgeons will still do surgery up front for a lower-risk form of cancer. Certainly, neuroendocrine cancers and other forms of pancreatic cancer are those where we still do up-front surgery. However, for pancreatic adenocarcinoma, I believe those patients should receive neoadjuvant chemotherapy. Some have argued that in [those with] lower-risk, very small tumors that are easily operable and who have no other risk factors, [up-front surgery is the optimal approach]. If the tumor marker called CA 19-9, is elevated, that [usually signals] a worse prognosis; [these patients are] more likely to have micrometastatic disease. In that high-risk situation, more surgeons and oncologists would favor neoadjuvant therapy. However, I believe that we have now reached a point where even in the lower-risk [patients, so those with] low CA 19-9 and smaller tumors, [we’re now considering neoadjuvant therapy].

The conventional argument has been to do up-front surgery and not give preoperative therapy because it may lead to more complications after surgery. The argument was that the adverse events (AEs) associated with the chemotherapy may make the patient less fit for a big operation, particularly the Whipple operation. [I believe it’s just the opposite]: Patients who are receiving chemotherapy after surgery are the ones who have trouble getting the therapy. For the frailer patients who come in, I advise that they receive chemotherapy and come back 2 to 3 months later; [this gives them time to] get into better shape, either nutritionally or via more exercise. These patients will actually come in more fit, even [having received the] chemotherapy. I believe these patients actually better outcomes, fewer complications, and a smoother recovery; they have that time to become surgically optimized prior to [surgery].

My argument is, even in the very early-stage [cancers] that are easily resectable and have a low CA 19-9, we’re still going to perform surgery; therefore we want time to have our patients optimized [for the procedure]. We also know that regardless, we’re going to give chemotherapy because there’s no subset of [patients with] pancreatic adenocarcinoma in whom we never give chemotherapy—even if the tumor is node negative, if it’s a small cancer, or if it has low CA 19-9. We might as well give some of that chemotherapy up front; it puts patients in better shape for surgery.

My personal view is that most patients should receive [neoadjuvant therapy], regardless. Some of the guidelines, from the National Comprehensive Cancer Network [and other organizations], suggest that in the lower risk, more favorable, very small cancers that are easily resectable, [patients should receive] up-front surgery. However, my guess is that we’re moving rapidly [away from that]. Several trials have [showed that] giving up-front therapy is better than doing up-front surgery in all patients. Now the question becomes, “Should that up-front therapy be chemotherapy or chemoradiation?”

You also co-authored a study comparing robotic versus laparoscopic pancreaticoduodenectomy. Could you discuss that study and its findings?

While that study is not a randomized trial, it addresses the question of, "What is the best operative technique for doing the Whipple operation?" The standard approach in the United States is [to do] an open operation, so a laparotomy. In general, there is increasing enthusiasm regarding the use of more minimally invasive approaches in cancer surgery. We are now doing more minimally invasive procedures, so either laparoscopic surgery or robot-assisted surgery.

For example, in the distal pancreatectomy cancers, those located in the body or tail of the pancreas, there are minimally invasive operations that can be safely done. When it comes to the Whipple operation, which is more complicated, the majority of these are done through open surgery, but there is still controversy regarding whether there a role for minimally invasive or robotic-assisted [approaches] exists. Laparoscopic pancreaticoduodenectomy is being used less often, although a few centers are still performing [these operations]. Most centers that are doing minimally invasive pancreaticoduodenectomies are moving toward the use of a robotic-assisted [approach]. It’s not difficult to show that robotic-assisted surgeries [are better] than open surgeries.

Technology continues to improve. I’m pretty confident that in the next few years more Whipple operations will be done using robotic-assistance. We are not quite there yet in most centers and so I would tell patients that [the technique itself] does not matter that much. What matters is that they have an experienced surgeon, a good multidisciplinary team, and that they go to a high-volume center [for their procedure].