Cancer immunotherapy has had a significant impact on cancer treatment, transforming the landscape of oncology and providing hope for patients. Unlike traditional therapies such as chemotherapy and radiation, which target cancer cells directly, immunotherapy works by stimulating or enhancing the immune response, enabling it to recognize and destroy cancer cells more effectively.

While immunotherapy has improved survival rates for various cancers, including melanoma, kidney cancer, lung cancer, colon cancer, and certain types of leukemia and lymphoma, not all patients respond to this new form of treatment. Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology at the University of Chicago, and Sean Pitroda, MD, an Associate Professor of Radiation and Cellular Oncology, recently published a study in the Journal of Clinical Oncology reviewing data on the effectiveness of immunotherapy in metastatic cancer, where the disease has spread to other sites in the body. Their analysis suggests that in some cases, traditional local treatments like radiation or surgery might work as well or delay the need for immunotherapy or other systemic therapies, and have less toxic side effects. The following is an edited conversation about their findings.

UChicago Medicine: Immunotherapy seems like such a breakthrough in cancer treatment. Are there cases where it might not be the best option?

Ralph Weichselbaum: Some years ago, Dr. Samuel Hellman and I developed this idea that patients with a few metastases could be cured with ablative radiotherapy or surgery, and more importantly, that metastasis is a spectrum of disease. Most people assume that metastases are always widespread, and that's not necessarily true. Dr. Pitroda has done some brilliant work on this in colorectal cancer, where he was able to molecularly identify which patients who initially presented with a small number of metastases were cured with surgery. What we think is that for some patients, using surgery or high-dose radiotherapy might delay the need for immunotherapy or other systemic treatment, and in some cases, actually cure patients without needing to use immunotherapy.

UCM: Which patients might benefit better from this kind of approach?

Sean Pitroda: Patients who have metastatic disease are at a very high risk for death related to their cancer. Most patients who die of their cancer do so because of metastatic disease. It's clear that immunotherapy has changed the game for many patients with metastatic cancer, but unfortunately, many patients don't respond. What we're seeing is that there is a correlation between how much cancer you have and whether you will respond to immunotherapy. Specifically, patients who have a lot of cancer, or large tumors, tend to not respond, and patients with a relatively small tumor burden tend to respond better. That's striking, because you see the same effect with radiation or surgery, where having less burden of cancer is a more favorable predictor of whether or not a patient responds to treatment.

So, we posited that for those patients who have limited disease, radiation might serve an important role even if immunotherapy could be used. But we also propose that there may be better ways to integrate immunotherapy with current treatment strategies, such as combining radiation with immunotherapy for patients who have more advanced disease.

UCM: Why would you want to avoid immunotherapy?

RW: Immunotherapy, while a major therapeutic breakthrough, is much more toxic than people realize. So, what we're saying is, as we learn more about commonality in terms of the clinical presentation, and as we uncover molecular aspects, we'll get more guidance on who might be better for what therapy. Using clinical and molecular staging together can be very informative. If a patient has just three sites of metastasis, you might consider doing radiotherapy or surgery initially and perhaps delay or even eliminate systemic therapy. As we learn to classify metastasis better, we will get clues on how to select a combination of therapies that might be most effective. So, it's a way to individualize therapy.

UCM: You often hear that cancer is not just one disease—it’s many diseases with many different treatments. Is this the same thing, more specifically with metastatic cancer?

SP: When we treat cancers that are non-metastatic, we have precise staging systems to inform clinical management. By contrast, all metastatic disease frequently gets lumped together into one entity. There are so many factors that are not utilized to stage metastasis, and ultimately patients receive a one-size-fits-all treatment without much personalization. However, there is already a lot known about common-sense information that is very highly associated with survival for these patients. So, the better we can integrate biology and clinical factors, the more precise our approaches will be for these patients.

RW: We’re exploring how to better stage patients with clinical and molecular features, and how we can use advances in stereotactic radiotherapy combined with immunotherapy, chemotherapy or targeted therapies to improve cure rates. We think that the answer is going to be combination therapies and finding the right individual treatments for patients.