NORPACT-1: Neoadjuvant Chemotherapy for Resectable Pancreatic Head Cancer

EP: 1.PROSPECT: Neoadjuvant Therapy for Locally Advanced Rectal Cancer

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EP: 2.NORPACT-1: Neoadjuvant Chemotherapy for Resectable Pancreatic Head Cancer

EP: 3.NAPOLI-3: Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma

EP: 4.IMbrave050: Adjuvant Therapy for High-Risk Hepatocellular Carcinoma

EP: 5.Closing Thoughts on Recent Data in GI Cancer

Rahul Gosain, MD: Now let's switch gears and focus on pancreatic cancer. Across multiple disease sites, we've seen significant roles in success with peri-op or neoadjuvant systemic treatment. We're seeing this with lung cancer, we've also adopted this in our clinic, of course for breast cancer, however, NORPACT-1 a small study, but this was a negative study in neoadjuvant settings for pancreatic cancer. Dr Beg, can you walk us through this study design?

Muhammad Shaalan Beg, MD: We're finally seeing those trials that started five, seven years ago to start reporting when it comes to the PREOPANC trial, and now here we have the results of the NORPACT trial, where they wanted to decide- to determine whether delivering neoadjuvant therapy upfront leads to better oncologic outcomes or not. So, they took people with upfront surgery and gave them adjuvant FOLFIRINOX, which is the standard optimal adjuvant chemo regimen that we give nowadays. And the other group of patients received neoadjuvant FOLFIRINOX for four cycles, followed by surgery and the rest of the chemotherapy postoperatively. So it's a very well-designed study, very clear study upfront chemo or not, and when we look at the results here, and we look at the Kaplan-Meier curves for the upfront surgery group in blue, and the neoadjuvant chemo group in red, we see that the surgery group seems to be doing better than the group that received neoadjuvant therapy. And this caused a lot of people to pause and say like, Hey, should everyone really be getting preoperative therapy? But when we really take a deeper look into the results, first of all the study only enrolled people with pancreatic head tumor, tumor in the head of the pancreas. And if you notice on the study design, the people who were going for surgery upfront may not have required tissue diagnosis prior to surgery or biliary drainage prior to surgery, while the folks who were going to get chemotherapy did require optimization of their biliary drain and some larger diagnosis, which leads to as you know, a couple of weeks sometimes delay before initiating therapy. And when you look at the drop off that happens at different levels from the people who had sent it, to the people enrolled, to the folks who received the chemotherapy, there's quite a bit of drop off and you can decide if you do intend to treat analysis and what does that really mean and what the protocol analysis really means. Those two groups of patients we're not- didn't really have the same starting position when I think about it, and some of the FOLFIRINOX people actually ended up getting gemcitabine base regimen, and how much did that impact of treatment? Why did they not get FOLFIRINOX? Was there still some unresolved biliary obstruction maybe that was preventing them from having irinotecan-based therapy, which is why they moved to gemcitabine that ended up causing sort of impact on outcomes. We're not entirely clear, but we're definitely not seeing the neoadjuvant arm kicking it out of the park and being a clear winner. So, for me, it reminds us that we need well-designed trials to address these questions. Thankfully, we have studies such as the ALLIANCE trial and the PREOPANC-3 trial, which are going to give more data with more contemporary chemo regimens and in different health systems internationally which can help guide our treatment. But the core problem in the pancreatic space is the fact that we don't have effective treatment options. How many ways can we slice and dice the same couple of chemo regimens and see how it's going to work, we need more treatments, we need new treatments, and until we see- until we start seeing more effective treatments coming out in later stage disease it's even moving to early-stage disease, we're really looking at small impact- a small impact and sometimes conflicting results from different trials.

Rohit Gosain, MD: Thank you for covering this and rather, you said it very perfectly that there are some nuances to this trial, but again, this is a very unmet need in this arena of adenocarcinoma. Now we know that's how we saw overall survival being inferior. So, this was more easily interpretable in resectable disease. However, when we are in our multidisciplinary room, where we are labeling patients have borderline resectable, we tend to utilize neoadjuvant chemotherapy at all times. Do you think this would change the paradigm where we will be shifting some of our surgeons to go for surgery, even if it's borderline, and then consider adjuvant?

Muhammad Shaalan Beg, MD: Borderline patients were not enrolled on this study. We know from multiple studies that folks that have borderline resectable cancer based on NCCN definitions of borderline disease, end up having R1 resections or worse, and that is an independent predictor of a poor survival. So, for the borderline group, we really need R0 resection. One could argue that a lot of the resectable tumors or tail tumors would have at R0 resection anyway and are we really benefiting them. But when I think about the magnitude of impact that neoadjuvant therapy can have, it's in the borderline resectable group that we can have the biggest impact. For folks that are more advanced, well, we may not be able to convert them to resection. So, the delta improvement that we can get for that group of patients is not going to be that great. Similarly, in the resectable group, maybe the Delta isn't that great, but the borderline from my understanding of the biology and the data is actually where we can have the most impact with the neoadjuvant approach. So, for folks that have some arterial involvement in their tumor, I would strongly recommend neoadjuvant therapy in that group of patients.