Neoadjuvant Therapy Continues to Evolve for Pancreatic Cancer

Colin Weekes, MD, PhD

Neoadjuvant therapy has become increasingly plausible for patients with advanced pancreatic cancer, as the quantity and quality of approved therapies continue to increase, according to Colin Weekes, MD, PhD.

Several studies are currently assessing neoadjuvant treatment with nab-paclitaxel (Abraxane) plus gemcitabine for patients with pancreatic cancer. Additionally, studies are looking at this combination along with other novel agents, such as FG- 3019, a monoclonal antibody that binds to connective tissue growth factor. Outside of novel agents, chemoradiation has also played a traditional role for borderline resectable disease.

OncLive: What is the current state for neoadjuvant regimens in pancreatic cancer?

OncLive interviewed Weekes, associate professor, Department of Medicine and Medical Oncology, University of Colorado, to gain further insight into the current state and future directions for neoadjuvant therapy for pancreatic cancer.Weekes: The role of neoadjuvant chemotherapy and radiation for pancreatic cancer is undergoing a metamorphosis.

Over the last several years, we’ve found it feasible to give combination chemotherapy to patients with metastatic disease. What we’ve seen with that is an increase in the survival of patients associated with the combination chemotherapy, as well as an improvement in response rates. So the tumor shrinks as we give it chemotherapy.

This is now being applied in earlier stage disease where the cancer is still potentially resectable, or borderline resectable. There are a lot of different chemotherapy regimens being used in that situation, such as FOLFIRINOX or a combination of gemcitabine and nab-paclitaxel. The other component that has evolved over this course of time as well is the types of radiation therapy that we can give.

How are these advances being applied to borderline resectable disease?

Historically, radiation therapy for pancreas cancer has been a combination of chemotherapy and radiation over usually a 5-week course of therapy. Now we can give more conformal radiation, which doesn’t necessarily require us to give additional chemotherapy. This means a shorter overall time of radiation and higher individual doses. The nice thing about this is that if it’s administered well, there is minimal toxicity.Thinking about the issue in terms of getting a patient from neoadjuvant therapy to surgery, one of the critical issues in being able to accomplish that is toxicities associated with the therapy. By giving more effective chemotherapy and minimizing radiation-induced toxicity, as well as chemotherapy-induced toxicity, the odds of getting a patient to surgery, which is the only curable method that we have for pancreatic cancer, is much greater.

What potential do you think immunotherapy could have in pancreatic cancer?

So now we are trying to give this effective therapy, improve the number of patients who actually get surgery, and improve the survival of those patients who undergo surgery for this disease. Right now, there hasn’t been a definition of what the appropriate chemotherapy is, what the appropriate lengths of time to give the chemotherapy, and if radiation is really optimal in this situation. If radiation is optimal, then is it traditional chemoradiation or is it these newer techniques which are shorter course, higher-dose radiations. Those are the principles that are currently surrounding neoadjuvant therapy. If all of that is successful, then the next step would be to add biologic therapies and immunotherapies in this setting.What we are finding out is that you can modulate the pancreas microenvironment. If you look at the mass of a pancreas tumor, what you’ll see under a microscope is that there are a lot of support cells, and support proteinaceous material called the stroma or desmoplastic reaction. That stroma also has immune cells, and so that is the majority of the tumor. The cancer cells are actually the minor component of that tumor.

What’s becoming increasingly realized is that you have to treat that stroma component as well as that cancer cell. Immunotherapy is one way to approach that, and it may be that giving certain kinds of chemotherapy or biologic therapies can actually manipulate the immune system such that you can turn the immune system against the cancer. It may be that giving chemotherapy may also prime the immune system to work against the cancer.

Those are questions that are being evaluated. There are no known answers. These immunotherapies might also depend on the type of molecule that you’re using as your therapy. This means there may be a difference between the abilities of bulky antibodies versus small molecule inhibitors to get to the tumor cell, or get to the target, to affect change from a biologic standpoint.

What are some other types of chemotherapy regimens that you would be interested in seeing investigated for pancreatic cancer?

That is based on early evidence where chemotherapy can actually modulate the stroma, which allows more chemotherapy to hit the tumor. All those different components are under evaluation currently, and there’s no “definitive” approach.Once you define what the appropriate base chemotherapy regimens are, then you have a platform to start adding on things like biologic targeted agents. If you go back to this idea that the stroma is a very complex, multi-cellular, multi-proteinaceous environment, then you can pick certain components of that environment to target. As we go forward and we learn what happens to the tumor in response to that chemotherapy, I think we’ll be able to target different components better.

Looking at the field of pancreatic cancer, where would you like to see it go?

The nice thing about doing neoadjuvant therapy is that ultimately the tumor is going to come out. So you can see the effect of your drug on the tumor once it comes out. You can use that information to plan subsequent studies to understand that if you manipulate different components of the stroma, in addition to trying to target the cancer cells, you can affect change.If you look at other solid tumors, the thing that’s happening in say lung cancer, for example, is that we are molecularly phenotyping patients and giving drugs that target those specific molecular phenotypes, which ultimately improves outcome. Eventually this is going to change the outcome for all patients, but right now we are changing the outcomes for small patient populations.

That will be one component I hope we get into — to be able to molecularly phenotype pancreas patients. The complexity of that is a little bit different because you have this huge stroma component. So it is going to be a question of what the interaction is within the microenvironment with the genetics. Being able to approach that is going to be very important going forward.

Approaching the various components of the stroma, including the pancreas stem cell, as a potential target could be important as well. There are multiple targets to think about in terms of pancreas cancer.

Overall, the hope is that we are able to significantly improve survival for these patients. The nice thing about the chemotherapy that we have now, these combination chemotherapies, is they affect change and improve survival. However, the bar still has to be moved forward quite a bit.