David Raubach: Thank you, Dr. Frank, for joining us on this episode of the Cancer Project podcast. We really appreciate the opportunity to talk to you.

Dr. Steven J. Frank: It’s great to be here, David. Thanks so much for having me.

David Raubach: Before we came on, I had asked you — of course, we’re here at ASTRO right now, and there have been different papers released and there’s a lot going on in the industry. One of the hot topics has been the TORPEDO study, or trial, that came out of the UK recently. I was curious about your thoughts on that paper and the data that got released.

Dr. Steven J. Frank: Thank you, David. The TORPEDO trial is near and dear to my heart — I’m actually an adviser on that study. They asked me to come on and give them some insights after they had developed the trial. And as a former submariner, the name “torpedo” was pretty fun to hear. The trial, at its core, demonstrated for the first time confirmatory evidence that IMPT is comparable to IMRT and is no longer investigational or experimental.

Dr. Steven J. Frank: The phase III trial we completed — a 440-patient trial across 17 proton centers and 21 institutions — demonstrated comparable outcomes. That was important because when IMPT was first developed around 2010–2011, there were real concerns that the precision of protons could also be a detriment, especially in head and neck patients who are losing weight and whose tumors are shrinking during treatment. The worry was that the precision could cause inaccuracies in dose delivery — leading to recurrences or more toxicities. We needed to prove first that we could achieve at least comparable outcomes with the standard of care, which is IMRT.

Dr. Steven J. Frank: Our trial was a non-inferiority design, and we were able to confirm with progression-free survival that IMPT is non-inferior to IMRT. That was a big point. But what was even more exciting were the de-intensification findings — because these patients are suffering through their treatment. They’re having significant mucositis, loss of taste, difficulty swallowing, and in historical data, 60% of patients were feeding-tube dependent at the end of treatment.

David Raubach: Wow. Okay.

Dr. Steven J. Frank: Our trial demonstrated a significant reduction in gastrostomy tube and feeding tube dependence — an absolute difference of 13%, from 40% down to 27%. It also showed significant reductions in dysphagia, xerostomia, and lymphopenia. And what we’re now starting to see at five years is a 10% absolute benefit in survival. Ninety-one percent of IMPT patients are alive at five years, versus about 81% in the IMRT arm. That absolute benefit of 10% is statistically significant — and frankly, an unexpected finding in our trial.

David Raubach: What do you think are some of the reasons or explanations for the overall survival benefit? Do you think the side effects played a role?

Dr. Steven J. Frank: We’ve looked at the causes of death carefully — separating acute causes, meaning those within 90 days of treatment, from chronic causes. We also separated patients who died with active head and neck cancer from those who died without recurrence. The survival curves did not separate until about three years out. In the chronic arm, we see about 18 patients in the IMRT arm who died following progression of disease. Interestingly, there was no difference in local, regional, or distant control between the arms — about 97% local control, 96% regional control, and 91% distant control in both arms.

Dr. Steven J. Frank: What we see is that IMRT patients are dying faster following progression, and more proton patients are being successfully salvaged after they progress. One hypothesis centers on T-cell exhaustion — a concept related to immune-system function, which ties back to the lymphopenia I mentioned. With the broader dose path to normal tissues in IMRT, and the chronic inflammation that comes with it, the lymphocytes are depleted over time. When those patients eventually progress, their immune systems may not be able to activate and respond as quickly or robustly as IMPT patients. This is a hypothesis we are actively investigating with follow-on grants.

Dr. Steven J. Frank: We’re also looking at two other potential mechanisms: swallowing dysfunction leading to aspiration pneumonias that may result in late deaths not related to tumor recurrence, and changes in the oral microbiome caused by IMRT dose to the anterior oral cavity — which can affect how patients eat and ultimately impact the GI tract, potentially contributing to diabetes or cardiovascular disease. We’ve extended the trial evaluation to a total of ten years to give us the data to tease these mechanisms apart.

David Raubach: So going back to the TORPEDO study for a moment — what was its endpoint and what were the conclusions?

Dr. Steven J. Frank: The TORPEDO trial used a 12-month endpoint — feeding-tube dependence and weight loss, plus the University of Washington quality-of-life health assessment. At 12 months, both the IMPT and IMRT arms had 1.7% feeding-tube rates, and the quality-of-life instrument was not significantly different. So as a study, it was negative at its primary endpoint. But critically, it was also confirmatory — it demonstrated that IMPT is comparable to IMRT and can be considered non-investigational. That is an important conclusion.

Dr. Steven J. Frank: What the study did not capture was the feeding-tube rate at the end of treatment — the point of maximum suffering. What I saw in the presentation yesterday was that quality of life was significantly worse for IMRT patients at the end of treatment and six weeks after. Talking to the principal investigator David Thompson after the presentation, he told me that over 50% of IMRT patients were feeding-tube dependent at the end of treatment. With only 53 patients in that arm, that’s a considerable toxicity burden the 12-month endpoint completely obscures.

David Raubach: Is it typical for feeding tubes to resolve over 12 to 18 months post-treatment, so that both arms converge at that one-year mark?

Dr. Steven J. Frank: Yes, and that’s exactly the issue. In our trial, we see roughly 2.8% of IMRT patients still feeding-tube dependent at one year versus 0% in the IMPT arm. The UK health system may have chosen a 12-month endpoint because that’s when things resolve — but it doesn’t tell the story of what the patient is going through over the trajectory of their treatment. Our trial didn’t push a single toxicity primary endpoint, and I think that actually gave us a less biased assessment, because the survival endpoint lets you just take care of your patient without optimizing around a specific metric.

Dr. Steven J. Frank: And the TORPEDO trial had a median follow-up of only 24 months. We didn’t see curve separation in survival until after three years, so that data simply doesn’t exist yet from TORPEDO. What we are planning is a meta-analysis combining our data with TORPEDO’s data and two other randomized trials currently accruing in Europe — a Danish study called DHANKA and a Swedish phase II study. That will give us a much richer dataset for understanding survival and long-term outcomes.

David Raubach: You mentioned cost and cost-effectiveness earlier. I know you’re involved in research on the cost difference between IMPT and IMRT, including a study with the University of Texas employee health plan. Can you talk about what you’ve seen?

Dr. Steven J. Frank: Cost-effectiveness is critical when you’re bringing a more costly treatment to patients. Building proton centers is extremely expensive, and we need to be able to justify that expense. The average age of our trial patients was under 65 — median was about 61 — so these are people at the peak of their productive lives, not retired. They want to continue to work. They have families — kids in high school, in college, in elementary school. A feeding tube is the ultimate marker of total toxicity burden — if you need a feeding tube, you simply cannot eat enough, drink enough, or control your pain to sustain yourself, and you are clearly not going to work.

Dr. Steven J. Frank: From an employer’s standpoint, that means pulling a productive employee out of the company — and sometimes these people are running their own businesses. For families, the spouse or significant other becomes the caretaker, often needing to take FMLA leave, which also impacts their employer. These are costs that don’t show up in the direct cost of care — but they are real costs to society and financial toxicity to the patient.

Dr. Steven J. Frank: In the University of Texas system study, we looked at how we could get Blue Cross Blue Shield to pay for treatment, and what it would mean to the premiums under the UT System’s self-funded health plan. We actually saw fewer hospitalizations and fewer emergency room visits in the IMPT patients — the opposite of what we expected. And we saw a negative impact on those premiums, meaning costs went down. As a result, the UT System issued a generalized approval of proton therapy across multiple disease sites for all employees and their family members. That collaboration between MD Anderson — one of 14 institutions within the University of Texas — and the UT System was a fantastic demonstration of how outcomes data can drive real policy change.

David Raubach: That’s amazing. Well, we’ve talked a lot of science and medicine. I also want to spend some time on your background and story. Tell us about Steven Frank and how you ended up where you are today — and make sure you mention baseball.

Dr. Steven J. Frank: [Laughs] I was very fortunate to have been brought up in an environment of medical care. My father, who is my hero — he just recently passed away — was an internist and cardiologist who grew up in Huntsville, Alabama. His father was a football coach, and my father played football at Alabama, where he was Bear Bryant’s first fullback in 1958. He was also Phi Beta Kappa at Alabama — and there aren’t many football players who are Phi Beta Kappa. He then went to medical school, forgoing his senior year, became a cardiologist, and built the largest internal medicine group in Atlanta. Watching him love what he did, and love taking care of patients — that imprinted on me very early.

Dr. Steven J. Frank: I went to the University of Pennsylvania on a Navy ROTC scholarship and played baseball there as a catcher for several years. Two things came out of a high school personality assessment: military and farming. So I applied to the Naval Academy, didn’t get in, but the ROTC scholarship gave me the opportunity to have the Navy pay for college and potentially medical school as well.

Dr. Steven J. Frank: Between sophomore and junior year they exposed us to every discipline — surface ships, aviation, Navy SEALs, Marines, submarines. I went out to San Diego for submarines and the SEALs, flew up to Whidbey Island to look at jets, went down to Camp Pendleton for the Marines. After getting off the submarine that summer, I said to myself, I will never go back on one of those again. The passageway is so narrow two people have to turn sideways to walk past each other. Your bunk is the height from your elbow to the top of your hand, and about that wide. So think of a very small prison cell.

David Raubach: That reminds me of Alcatraz — I visited a couple of days ago. Those cells were probably more spacious.

Dr. Steven J. Frank: Actually, probably was. [Laughs] But what attracted me to submarines ultimately was the caliber of the people. I visited the USS Pennsylvania in Kingsland, Georgia, and what I realized was that the people on submarines are probably the brightest in the military. That drew me in. So when I went to Washington DC and met with the admiral — who looked at me, a history major, and asked what I was doing there among Caltech and Naval Academy engineers — I managed to be accepted into the nuclear submarine program.

Dr. Steven J. Frank: From there it was six months of nuclear power school in Orlando — working four in the morning to ten at night — followed by six months at a nuclear prototype facility running shift work on an actual reactor, then three months of tactical warfare school in Connecticut, and finally a submarine escape system test. I published my very first paper during that time in Connecticut, working with the Naval Undersea Medical Laboratory on whether the submarine escape system was a practical means of survival.

Dr. Steven J. Frank: Then I was assigned to the USS Batfish, a fast-attack submarine out of Charleston, South Carolina. We deployed for seven months in the Mediterranean — about 80% of the time underwater, 20% in port. You work an 18-hour cycle: six hours on shift in the reactor space or on the bridge as officer of the deck, six hours of maintenance, six hours of drills, and you try to find four hours of sleep somewhere in there. We had 10 officers and about 100 enlisted — 110 people turning sideways to pass each other in the passageway. And the food, by the way, is actually fantastic. The Navy puts its best chefs on submarines for morale.

David Raubach: So the food was better than Alcatraz, at least. When did you decide that medicine was still the right path?

Dr. Steven J. Frank: After a couple of years on the sub I recognized that a career in the Navy — which required going back to Washington DC at year four to pass the nuclear engineer’s exam, equivalent to a master’s degree in nuclear engineering, and then continuing up the ladder toward commanding your own submarine — was not the life I had envisioned when I thought about medicine. So I took my MCATs while deployed at sea and applied to medical school. I finished my service and then went to Emory Medical School in Atlanta.

David Raubach: And when did you decide on radiation oncology specifically? There’s quite a connection with the physics background from the submarine.

Dr. Steven J. Frank: I was in my third year of medical school at Grady Memorial Hospital and had never even heard of radiation oncology. A friend of mine, Chad Levitt, came back from a rotation at UCLA and told me it was the most incredible field — and that it was called radiation oncology. I had always been looking to combine engineering knowledge with medicine. So I went up to the library on the hospital rooftop, pulled out a cancer medicine textbook, and looked it up. It was all physics — and I understood all of it. I walked down the street to the radiation oncology facility, introduced myself to a resident named Steuart Burr, and he said, “Welcome to the best-kept secret in medicine.”

Dr. Steven J. Frank: I did a rotation there, then went out to MD Anderson for a month, then to UCSF for a month — wanting to see the field in different academic environments. After all of that, I knew. When I told my father I wanted to go into radiation oncology, he said, “You’re not going into radiation oncology. That’s just where we send patients and we never see them again.” That was the perception in the medical world at the time. But the technology, the patient interaction, and the opportunity to be part of a definitive curative treatment — not just palliative — was what really drew me. I matched for residency at MD Anderson and arrived in 2001.

Dr. Steven J. Frank: Proton therapy came into my world when MD Anderson started building its facility in 2003, while I was a resident. Jim Cox, my chair, believed in proton therapy so strongly that he made it a flagship project for the institution. We treated our first patient in 2006, the same year I came on faculty. I was on both the head and neck service and the GU service. When I asked one of my mentors whether we should consider treating head and neck patients with protons, he said there was no role for proton therapy in head and neck. But it made sense to me intuitively, so I started developing treatment plans with our dosimetrists and physicists and exploring whether IMPT could genuinely benefit these patients.

Dr. Steven J. Frank: The true light-bulb moment came in 2010–2011 when I treated our first IMPT head and neck patients — an oropharyngeal case and a nasopharyngeal case. I could see immediately that patients were maintaining their taste, having less mucositis, less weight loss, less difficulty swallowing. And then a second, even bigger moment: a 33-year-old woman with nasopharyngeal adenoid cystic carcinoma whose tumor wrapped around her brain stem, and nobody would treat her — not even with IMRT. Colleagues didn’t want their names associated with the case because the uncertainties were so great. We sat down, looked at what an IMPT plan could do, and said let’s try it. By her first follow-up she had a complete response. It was unbelievable.

Dr. Steven J. Frank: That case made me recognize that beyond the physics advantage — no exit dose, minimal entry dose to surrounding structures — we were also dealing with a different radiobiologic drug. The proton had distinct biological properties, not just a different dose distribution. That was enough to start me on the journey of developing a randomized trial. I went to the NRG, who were less inclined at the time because most of their member institutions didn’t have protons. So I came back and built the infrastructure at MD Anderson, then brought in Rob Foote at Mayo when they got a proton center, then Paul Busse at Mass General. That consortium grew to 17 proton centers and 21 institutions — and produced the 440-patient trial that is now being reported.

David Raubach: To think that all started back in 2006 as you were looking at those first proton therapy plans, and now here we are 19 years later at the culmination of almost two decades of work. What has that growth looked like in terms of how many patients are now treated with protons for head and neck?

Dr. Steven J. Frank: In 2008, head and neck cancer was about 3% of all proton therapy cases nationally. Today it’s roughly 35% — and it is the leading indication at our center and, I believe, nationally and internationally. Part of that growth came from our commitment to publish constantly and proactively. We have a motto: no data is left behind. We put together prospective databases, published case-matched control studies, quality-of-life studies, and outcome studies in real time. Those results were then validated at Mayo, at Mass General, and at other centers. When you see repeated data from multiple institutions, it creates validation. And ultimately everyone wanted to see randomized level-one evidence — because even during our trial, about 23% of patients crossed over: some randomized to IMPT had their insurance deny them and received IMRT, and some randomized to IMRT had insurance approval and chose protons instead. We published our methodology transparently throughout, so there could be no criticism of the approach after the fact.

David Raubach: My last question: you talked about your dad being your superhero and your inspiration. His perspective on radiation oncology must have changed significantly over time, especially as he saw what you were doing at MD Anderson — and also what happened with your mother.

Dr. Steven J. Frank: Yes. My mother, unfortunately, also passed away from cancer — she had an unknown primary and was treated with proton therapy at MD Anderson by one of my colleagues. She was told she had maybe 11 months to live and ended up living two and a half years after treatment. So my father saw what radiation oncology really was — the impact on patients during their cancer journey — not only through his son, but through his own wife. He definitely came around. He came to understand the benefit, and he was a big supporter of me all along the way.

David Raubach: When I tell people I work in radiation oncology — and I’m not a doctor — the comment I usually get is, “Well, isn’t radiation bad?” What would you say to that?

Dr. Steven J. Frank: Radiation is a very unique and important tool. Surgery has its own complications, and we’ve looked for ways to eliminate radiation in many contexts — but that has not happened. I believe radiation should be the primary modality for prostate cancer: patients maintain continence, sustain erectile function better, and patient satisfaction is remarkable. We published our 3,000-patient prostate cancer series and the results with protons are fantastic. For head and neck, with the epidemic rise of oropharyngeal cancer in the United States and nasopharyngeal cancer in Asia, proton therapy is clearly showing its value. And we’re even treating more patients with metastatic disease with radiation to give them a break from systemic therapy that causes tremendous toxicity — and potentially extending their lives. Any amount of unnecessary radiation has long fibrotic and toxic effects years after treatment is over. Proton therapy’s ability to minimize that unnecessary dose is why you’re seeing its rise as a leading modality worldwide.

David Raubach: Thank you so much for all of the amazing work that you’re doing, Dr. Frank, and for sharing your personal journey — from the Navy to radiation oncology. And thank you for all the work you’re doing on behalf of patients and the proton therapy community.

Dr. Steven J. Frank: Thank you, David. And thank you for all the great work you’re doing helping educate the community about the advantages and the history of proton therapy.