In an interview with Targeted Oncology, John L. Marshall, MD, provided an overview of the evolution of treatments for patients with pancreatic cancer, as well as the current therapeutic approaches for these patients and what’s next for this treatment paradigm.
The prognosis of patients with pancreatic cancer has remained fairly dismal in comparison with other cancer types, including other gastrointestinal (GI) cancers, for which patients have reaped more benefits from the use of immunotherapy and targeted therapies. However, several advances over the last few years have provided important insights into the patient outcomes from various treatment regimens and approaches.
According to John L. Marshall, MD, more emphasis has been placed on neoadjuvant chemotherapy in the setting of localized disease, even in patients with resectable pancreatic cancer. Clinical trials have been evaluating treatment with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), as well as several gemcitabine (Gemzar) combinations, such as nab-paclitaxel (Abraxane) or capecitabine (Xeloda). The use of neoadjuvant therapy prior to surgery, with use of these different combinations, has induced promising outcomes for this patient population.
Other advances in this space include developments in surgical techniques for resecting pancreatic cancer. More patients continue to appear as candidates for primary surgery, which ultimately plays a large role in outcomes. However, the science still lacks in terms of treatment in the metastatic setting, as well as understanding the biology of this disease as a whole.
During Pancreatic Cancer Awareness Month, the unmet needs that remain in this space are brought to light, as well as the need for more research to advance this field. Two major areas of research at this time include the use of precision medicine and the role of the microbiome, which is a novel area of investigation.
“Increasingly, we are recognizing that [the microbiome] is part of our health and wellness, but my guess is it will also play an important role in the development of cancers, particularly GI cancers. We're just dipping our toe into this research, but my hope is that we will discover great things about the biology and how to intervene and treat these diseases,” said Marshall, chief of the Division of Hematology/Oncology, Medstar Georgetown University Hospital, associate director for clinical care, Georgetown Lombardi Comprehensive Cancer Center, and director of The Ruesch Center for the Cure of Gastrointestinal Cancer.
In an interview with Targeted Oncology, Marshall provided an overview of the evolution of treatments for patients with pancreatic cancer, as well as the current therapeutic approaches for these patients and what’s next for this treatment paradigm.
TARGETED ONCOLOGY: How has the treatment landscape evolved over the last few years?
Marshall: The biggest story with pancreatic cancer is that, finally, we got a few new medicines that worked in the treatment of pancreas cancer. We've begun to deploy these earlier and earlier, so once someone finds a diagnosis of localized pancreas cancer, there is more of an emphasis on neoadjuvant chemotherapy, preoperative treatment. Even in the resectable patient, there has been a series of clinical trials looking at things like FOLFIRINOX, gemcitabine/nab-paclitaxel, and even gemcitabine/capecitabine, which have been showing that this preoperative approach does prove to be a better outcomeoutcomes for patients. That has been somewhat transformative in the way we practice.
The second is that surgeons have developed remarkable techniques that will enable them to resect patients that before we couldn't, whether these are vascular reconstructions or others. More and more patients are candidates for primary surgery, which we know is fundamental to our ultimate goal of curing pancreatic cancer.
I think where we have fallen short is in the management of metastatic disease. We have improved things, and more and more patients are making it past a year, some past 2 and beyond, but we have not enjoyed some of the positive [findings] that have been seen in other cancers. Immunotherapy still plays very little role, and in terms of targeted therapy. We, we do now have PARP inhibitors newly approved for patients with BRCA germline mutations, and this helps. With doing more molecular profiling, we are finding more and more opportunities for therapy, but until we crack the nut of RAS mutations, I think we'rewe’re not going to make major headway in this disease, but not for lack of trying; there continues to be a bunch of clinical trials focused on new approaches in the treatment of pancreatic cancer, some molecularly rich, some not, but we are seeing progress. It is just much slower than we want to see.
TARGETED ONCOLOGY: Do you want to elaborate more on the different neoadjuvant treatment regimens?
Marshall: It's important what value an old person brings to the table, his memory of what came before, and we have to remember that the old standard was 5-FU, and then gemcitabine makes it on the scene, comparing it against a badly administered 5-FU, almost placebo. Gemcitabine became the new standard, and we kind of forgot 5-FU. The British brought this back with a gemcitabine/capecitabine regimen in the adjuvant setting, which we have to remember is also positive. However, with the gemcitabine, we got gemcitabine-everything, and we didn'tdidn’t manage to move the bar until we got to gemcitabine/nab-paclitaxel.
Then we got frustrated. Another group of investigators said we need to go back to 5-FU. There was some evidence of oxaliplatin working, some evidence of irinotecan working, and they said we're not wasting any time. Let's give everything, and they gave FOLFIRINOX against single-agent gemcitabine, which to me is not the real fair comparative, but it won, so we then had 2 frontline therapies. When it came time to apply neoadjuvant therapies to pancreatic cancer, FOLFIRINOX seemed a logical thing to do. That was originally a sort of standard with the highest response rate, but it’s toxic. More recent studies published this year at ASCO and ESMO demonstrated that there are gemcitabine-containing regimens; gemcitabine/ nab-paclitaxel given ain the neoadjuvant setting, performed just as well as FOLFIRINOX did in terms of overall survival and resectability and all the key measures that we have, so it was counter to some of our adjuvant data with gemcitabine/nab-paclitaxel.
Finally, another study looked at gemcitabine/capecitabine in that space and wasthis also ahad positive impact. It doesn't mean everybody has to have neoadjuvant chemotherapy, but I do think you have those 3 choices. FOLFIRINOX is still probably the standard, but I think in those patients that couldn'tcan’t handle FOLFIRINOX or have other reasons not to do that, gemcitabine-based therapy is a legitimate neoadjuvant approach.
TARGETED ONCOLOGY: What are the biggest challenges that we need to overcome right now in the pancreatic space?
Marshall: It goes from start to finish. From the start, how do you find early pancreatic cancer? What is the screening technique for this? Who should be screened? Most of the patients we diagnose are symptomatic, and therefore, their disease is fairly far along, or they just happen to get a scan or some other tests for some other reason. Then, when we find a diagnosis, in some ways, those are lucky to find early pancreas cancer. However, that seems sort of unlucky at the same time, so. So better screening would be important, and a better understanding of the biology of the disease. That's really central to everything about pancreatic cancer.
Why is it so difficult to treat? What is that interaction between the host and the tumor that is clearly preventing our therapies from working? We need more and more understanding of biology, so I think that's going to come from more and more tissue acquisition and more research funding. That's what pancreas cancer awareness month is all about, to raise everyone's awareness, not just so that we wear purple socks for a month. We acknowledge that research follows the investment, so the investment that people give for pancreas cancer awareness month, whether it's getting into a 5K or just donating to your local group, it does trickle down to discovery, and it does have an impact. We all need to invest in this. We have seen progress, and there is a direct reward for what we needinvest, which is more people cured of this disease.
TARGETED ONCOLOGY: What research is looking most promising right now in this space?
Marshall: There are 2 angles to look at this. One is the world of precision medicine, broad molecular profiling, understanding the biology of these cancers, such that new targets emerge. Out of that, we are seeing more and more therapies that are showing promise in RAS-mutated tumors. The hope is we continue that line of work because 95% of pancreas cancers have a RAS mutation, so we may see some progress in that.
The other, which is an area that we personally feel very excited about, is this concept of the microbiome. How doesdo our own bacteria in our mouths affect our GI tracts? We carry this around as part of us, right? It's not some foreign invader, and we've evolved to include it on the trip through life. Increasingly, we are recognizing that this is part of our health and wellness, but my guess is it will also play an important role in the development of cancers, particularly GI cancers. We're just dipping our toe into this research, but my hope is that we will discover great things about the biology and how to intervene and treat these diseases.
TARGETED ONCOLOGY: What advice would you like to share with community oncologists to come across patients with cancer?
Marshall: The biggest piece of advice is to get rid of your therapeutic nihilism. There are a lot of oncologists, surgeons, and others who, when they see a patient with pancreatic cancer, they begin right away with a hospice discussion, thinking that there's no point in treating that patient. We know that's not true. We know that there are patients who benefit from the treatment, and it is worth the investment. Sure, there are patients that shouldn't be treated, and I'm not saying that. However, don't say that a patient with pancreatic cancer shouldn't be treated. These people are often 60, 70, or 80 years of age and have other comorbidities, so it's a challenge. You need to have specialty surgeons that work with you. You need to have a multidisciplinary team approach. You need to give your patients a try because they will respond to treatments, and they will benefit and have a survival advantage, but not unless you give it a try.
TARGETED ONCOLOGY: How do you see this treatment landscape evolving over the next coming years?
Marshall: I think we're going to see more and more precision medicine applied. We're going to see more measures of efficacy. Resistance biomarkers will become more and more important, not only to rule in therapies, but also to rule out ineffective therapies, so I think equally important. I hope we will develop better diagnostic tools,; I see thethat ctDNA technology asis going to be immediately applicable to pancreatic cancers, and the adjuvant setting, for example.
I do think we have new and better tools, but what we worry about is the flip side, where the world itself is an unstable place. Access to health care, access to innovation, while at the same time for us all being able to afford health care, there's a tension between those 2 things in our world, but [the next] generation has to worry about that that. What will yourour health care look like in 20 years? It will be different. I think it will be better, but it won't be unlimited access, so we'll have to figure all that out as we go forward. Cancer will be a primary where we have to prove that what we're doing has benefit.