Neoadjuvant Chemotherapy Prior to Surgery Holds Benefit in Pancreatic Cancer

Michael A. Choti, MD, MBA

Michael A. Choti, MD, MBA

Surgery following neoadjuvant chemotherapy appears to have a number of advantages compared with adjuvant chemotherapy for patients with pancreatic cancer, but there is still some resistance to move to this new strategy, explained Michael A. Choti, MD, MBA. At the 2019 International Society of Gastrointestinal Oncology (ISGIO) Annual Conference, experts discussed the different treatment strategies for patients with pancreatic cancer, 1 of the deadliest forms of cancer discussed at this meeting.

“There are some data to support adjuvant chemotherapy, but what’s really exciting is the newer strategy that I think is becoming more standard to offer prior to surgery: neoadjuvant chemotherapy,” Choti, division chief of surgery at Banner MD Anderson Cancer Center, said during the ISGIO meeting. “Now that we are using more effective combination regimens of chemotherapy and offering it prior to surgery, we think that is a better strategy for cancers that are operable and also [for] a condition called borderline removable, where it is a little more advanced.”

As therapies have evolved over the last few years, available chemotherapy treatments are becoming more effective; by providing these therapies upfront in patients, physicians may be able to shrink the tumor prior to the surgery, which would ultimately make the disease more operable. This can also help reduce the risk of metastatic recurrence in a disease where many of the patients end up recurring after surgery.

It is commonly thought that giving chemotherapy before surgery would weaken the patient, but Choti argued that this is not the case for these patients. After receiving neoadjuvant chemotherapy 3 to 4 months before their surgery, patients tend to be in better shape, while also becoming healthier both nutritionally and physically. This makes surgical operations easier.

In an interview withTargeted Oncology, Choti discussed the treatment landscape for patients with pancreatic cancer, as well as how the role of neoadjuvant chemotherapy in this space is changing. He highlights advantages of neoadjuvant strategies, and also some other treatment options for patients with pancreatic cancer.

TARGETED ONCOLOGY: What are the current treatment options for patients with pancreatic cancer?

Choti:Pancreatic cancer is 1 of the most challenging, most deadly of all the gastrointestinal cancers that we are talking about at this meeting. Treatment options vary depending on how early it is caught. If it appears contained, based on imaging, the best and only real curative option is surgical resection. The surgical operations are challenging, but this is our best shot.

The problem is that many patients are not operable or not surgical candidates at the time they present with pancreatic cancer, so they have either metastatic disease or the cancer has locally progressed to a point where it is surrounding vascular structures and other things that may make the cancer inoperable. In the case that a pancreatic cancer is potentially operable, then the mainstay of treatment is not just surgery; it’s surgery typically combined with chemotherapy. Even when surgery is done for pancreatic cancer, the chance of it recurring is still quite high, but the mainstay of pancreatic cancer is still a combination of surgery and chemotherapy.

TARGETED ONCOLOGY: Are there data to support the combination of chemotherapy and surgery?

Choti:There are data to support the combination of surgery and chemotherapy. Historically, or I would say, until more recently, the strategy for potentially operable pancreatic cancer is doing surgery first followed by post-operative chemotherapy, adjuvant chemotherapy. There are some data to support adjuvant chemotherapy, but what’s really exciting is the newer strategy that I think is becoming more standard to offer prior to surgery: neoadjuvant chemotherapy. Now that we are using more effective combination regimens of chemotherapy and offering it prior to surgery, we think that is a better strategy for cancers that are operable and also [for] a condition called borderline removable, where it is a little more advanced. The advantage of giving chemotherapy first is that we can shrink the cancer and improve the operability.

TARGETED ONCOLOGY: What are the advantages of neoadjuvant chemotherapy?

Choti:This is something we should emphasize because still around the country, for patients who do fortunately have potentially operable pancreatic cancer, the more standard recommendation is to operate first, and the feeling of most patients is they want to get the cancer out. There’s still a continued incentive to want to do the surgery first. I feel that the cutting-edge approach for patients with operable pancreatic cancer is offering these patients neoadjuvant chemotherapy prior to surgery. The question here is why is that an advantage to giving chemotherapy after surgery, but there are definitely many advantages.

One advantage is that in many of these patients, it’s really the micro-metastatic disease, even if we don’t know it’s metastasized. There’s a high probability of having micro-metastatic disease. Now that we have more effective chemotherapies, let’s get the chemotherapy in earlier to treat it rather than waiting a period of time after they’ve had surgery and recovered. That’s 1 advantage.

The other advantage is that in some cases, some patients develop metastatic disease rapidly. Rather than rushing a patient into surgery early and then developing metastatic disease postoperatively, some patients can be saved during the neoadjuvant therapy, if you will, from an operation that’s not helping because they developed metastatic disease prior.

Another reason is while we are doing the Whipple operation more safely, it’s still a big hit on patients. Often, doing the surgery upfront, these patients may not be fit or strong enough during the recovery process to get postoperative chemotherapy. We find that by giving chemotherapy prior to surgery, they are more likely to get chemotherapy and more likely to get more chemotherapy than if we just wait to get it all after surgery.

Another advantage is there’s the convention of wanting to get the cancer out right away and giving chemotherapy for several months prior to surgery is going to beat them up before surgery and make it worse, they’ll have a harder recovery. In fact, we are finding it is just the opposite. That time that patients are on chemotherapy, while it’s not easy to undergo that therapy, these patients often get in better shape and do a kind of pre-habilitation prior to a big operation. For patients treated with neoadjuvant chemotherapy who have their surgery 3 or 4 months later, they are often in better shape nutritionally, physically, and so forth, and do better after surgery when they have had time to pre-habilitate prior to surgery. That is another strength and advantage to giving preoperative chemotherapy.

The final advantage is that it can sometimes shrink the cancer and make the operation either easier or more likely to remove it with clean margins, which is much more likely to be a successful surgery.

By giving the therapy first, you can shrink the cancer and achieve a better margin. [There are] some significant advantages to giving chemotherapy upfront, and yet there is still some resistance from many teams that think we should just do the surgery first. One emphasis from this meeting is the pendulum is going toward aggressive neoadjuvant chemotherapy in potentially operable or borderline removable pancreatic cancer.

TARGETED ONCOLOGY: What are the latest therapies in development for these patients?

Choti:There’s a lot of new work going on in new drugs and new forms of therapy in patients typically with stage IV disease, who are inoperable patients. However, the strategy has been when we find effective therapies for advanced disease, we are applying them more and more during the neoadjuvant setting or in the potentially curative situation. Really, the more common regimen currently used today is not something new. It’s not something novel. It’s not immunotherapy, and it’s not targeted therapy. It’s a combination of aggressive cytotoxic chemotherapy, and that is the most common regimen we use prior to therapy in patients who are potentially operable. The regimen is FOLFIRINOX, which is a combination of multiple kinds of chemotherapy. In addition, the other regimen that is commonly used in the stage IV setting is the combination of gemcitabine and nab-paclitaxel (Abraxane), another regimen we are offering to patients in the preoperative neoadjuvant situation in patients who are either resectable or borderline resectable pancreatic cancer.

TARGETED ONCOLOGY: What are the options for the patients that recur?

Choti:We don’t have a lot of options, but of course the treatment is typically chemotherapy in most cases. If it recurs in an area that causes a symptom, for example we can do local therapy, radiation therapy, or rarely surgical therapy in a case where it recurred in order to alleviate the symptoms. The reality is for most cases, except for very uncommon cases with pancreatic cancer, when the pancreatic cancer recurs after surgery, that is a difficult and challenging problem. We typically recommend chemotherapy. Sometimes we can have some effective aspect, and those are situations in which they are difficult to salvage from a curative standpoint.

TARGETED ONCOLOGY: What challenges remain in pancreatic cancer?

Choti:The first big challenge is that most patients unfortunately, at the time they present with the disease, they are no longer candidates for surgical resection, so it’s already metastatic. More than 50% of patients already have metastatic disease or inoperable disease at the time of presentation. The big challenge is earlier detection. There’s research going on in that area to try and detect pancreatic cancer earlier.

The second problem is that even in those patients where it appears early, even with successful surgery and successful chemotherapy, many of these patients still go on to recur and not be cured, so even when caught apparently early and potentially operable, many of those patients still unfortunately [recur]. It’s an aggressive form of cancer with a high probability of recurring, so that’s a challenge.

The other challenge is the types of surgery are complicated operations, particularly in cancers that involve the head of the pancreas, which requires a complex operation called pancreaticoduodenectomy, commonly known as the Whipple operation. This is something that is becoming more and more common to do, and our outcomes are getting better and better. Even a decade ago, it was considered high risk, and patients were afraid of this operation. It’s still a complicated operation, it still can have some complications, but now we are getting better and better at doing this more safely with faster recovery for patients. Even in those cancers that were not operable in the past that were maybe a little more advanced, borderline, or had a more advanced cancer, which would require a more complicated removal, such as removing and reconstructing the vein that is in the vicinity, now we are even doing that complex operation more safely with better outcomes, achieving better margins and better recoveries.

We’re making improvements on early detection, making improvements on better systemic chemotherapy to use with surgery to improve outcomes following surgical removal, and we’ve made significant advances in the surgical [realm] so that we can do these operations more aggressively and yet more safely.

TARGETED ONCOLOGY: What do you hope oncologists take away from this meeting in regard to treating patients with pancreatic cancer?

Choti:First of all, many of the things I said suggest it’s still a problem. I think 1 important takeaway is the advances we are making. There is a sense of optimism for this disease, not only in how we currently manage patients but optimism for the future as we now continue with research to continue to improve the outcomes. So, one is a sense of optimism that patients are doing better and better and I hope continue to do so in the future.