Melanie Cole, MS (Host): Welcome to the podcast series from the Specialists at Penn Medicine. I'm Melanie Cole, and today, we're highlighting proton therapy. Joining me is Dr. Alexander Lin. He's the Executive Vice Chair for the Department of Radiation Oncology at Penn Medicine. Dr. Lin, thank you so much for joining us. And before we discuss the recent Lancet study that you co-authored, and that will be our focus today, can you explain the concept of deintensification therapy and individuals with HPV+ oropharyngeal cancers.

Dr. Alexander Lin: Thanks, Melanie. It's a pleasure to be here today with you. I'm happy to discuss this [00:01:00] question. So, one of the defining features of this diagnosis, HPV-positive oropharynx cancer is that they respond very well to treatment. In fact, most patients have a very high likelihood of care with today's standard approach of treatment.

The challenge though is the treatment itself can be quite toxic. Side effects do occur during treatment, but they can also persist long after, and it can affect functions such as swallowing. Patients can complain of dry mouth, taste changes, and other aspects of quality of life. And these can impact patients for years after treatment.

And so, because patients do so well from a cancer standpoint, but suffer from the intensity of therapy, there is a strong rationale to explore what we call deintensification, meaning delivering therapy that is just as effective but less toxic. And this could be achieved through advances in surgery, radiation, or chemotherapy with a shared goal of preserving excellent [00:02:00] cure rates while reducing long-term toxicity.

Host: So, deintensification of photon radiation therapy has been investigated, Dr. Lin, previously in the oropharyngeal cancer space by substituting surgery or reducing the dose given as IMRT. Tell us a little bit about the advantage that protons have over photon in this space and a little bit about comparing these two.

Dr. Alexander Lin: Sure. So, there have been efforts to deintensify photon radiation, like reducing the dose given with IMRT or substituting surgery in [00:03:00] place of chemo and radiation, and they've been studied before. But I think proton therapy is unique. It offers a different type of approach, a different kind of opportunity here.

And the potential advantages of proton therapy come from their unique physical properties. So, protons can deposit radiation very precisely, in that sense, delivering dose to the tumor and minimizing radiation to surrounding normal tissues. And this is true whether we use proton therapy instead of surgery for something called organ preservation or after surgery in a setting called the adjuvant setting after surgery. And this precision is the foundation of proton's ability to produce side effects. And this is really important for cancers such as this, that involve structures that affect swallowing and speech and can affect long-term quality of life.

Host: The Lancet study was the first ever publication of a randomized phase III trial comparing those two, proton therapy and photon therapy in patients with stage III-IVB oropharyngeal cancer receiving chemotherapy. Can you please describe the trial, its; population, and endpoints, and the processes undertaken to ensure quality assurance in this study.

Dr. Alexander Lin: So like you said, this is the first ever randomized phase III trial directly comparing photon therapy, IMRT, versus proton therapy, for patients with this diagnosis, stage III to IVB oropharynx cancer. All these patients received concurrent chemotherapy. And this study is really important because it finally gives us high quality head-to-head evidence for this critical question. The question is, can proton therapy treat cancer just as effectively as IMRT while reducing side effects?

So, what was this study? Essentially, it's a large multicenter study. There were 21 cancer centers in the US that were involved, enrolling 440 patients, and patients were randomly assigned to receive either proton therapy [00:05:00] or IMRT, IMRT noted as the standard of care.

All patients received the same dose of radiation, which was 70 gray over 33 treatments. All patients received chemotherapy as standard of care. And the main goal here was to see whether proton therapy was as effective as photon therapy in controlling cancer. So, what did the study measure? So, the primary outcome of this study was progression-free survival, i.e., how long patients lived without their cancer recurring.

And other important outcomes that were looked at were overall survival and treatment-related side effects. What did the study find? We found that proton therapy matched photon therapy in controlling cancer, but did so with less side effects long-term and better long-term outcomes.

So, at five years, what we found was that 91% of patients receiving protons were alive compared to 81% treated with photon therapy. [00:06:00] This is a 10% difference in five-year overall survival in favor of patients receiving proton therapy. How did this study ensure quality and safety? This is important because radiation therapy requires precision, and this study used strict national and multi-institutional quality assurance steps.

First, each center had to be credentialed to participate. Second, radiation treatment plans were standardized and reviewed. Centers followed established national guidelines for chemotherapy and dosing. And finally, plan accuracy and consistency were checked across all 21 participating centers. These steps ensure that the differences in outcomes that we found were purely due to the type of radiation given, proton versus IMRT, and not due to differences in other variables just as plan quality or expertise.

Host: So, Dr. Lin, if you were to look for future [00:07:00] studies and research, and as these studies continue bench to bedside, do you see other institutions adopting this as standard of care first-line, adjuvant? Where do you see this going?

Dr. Alexander Lin: This is a critical study. It's a multicenter study. It's high-level evidence in a randomized trial. I would propose that for patients who are receiving organ preservation, chemoradiation for this diagnosis, they should, if possible, seek to receive care at a center that delivers proton therapy. The data is significant. They're clear and compelling given the five-year difference in overall survival and with a significant side effect profile in favor of proton therapy.

Host: It is, as you say, compelling. And Dr. Lin, as we wrap up, what would you like other providers to take away from this Lancet study and the future of these oropharyngeal cancers? And how would someone reach [00:08:00] you and your team at the Roberts Proton Therapy Center to refer a patient?

Dr. Alexander Lin: I would say, for patients and providers, you know, if you were caring for a patient with this diagnosis, remember this patient is going to do very well from a cancer standpoint, but they're going to live a long time potentially with side effects from therapy, and it's our obligation to try to minimize these side effects.

One way to do so is to treat with proton therapy. And so, if you would like to refer a patient or learn more, you can reach us directly by phone at the following phone number (215) 316-5006. You can access and directly contact a team member that way, or online to request an appointment or more information.

Host: Thank you so much, Dr. Lin. That was really interesting. What a great discussion. Thank you again for joining us. And other ways to refer your patient, you can call our 24/7 provider-only line at 877-937-PENN, or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/refer. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole.