This transcript has been edited for clarity.
Cheryl Lee, MD: Welcome to Medscape InDiscussion. I'm Dr Cheryl Lee. Today, we'll be talking about radiation therapy for patients with high-risk bladder cancer. How is immunotherapy used to optimize radiation treatments for bladder cancer? What's the impact of newer technology on radiation therapy — in particular, artificial intelligence? How is this advancing treatments for bladder cancer patients? For expert guidance on these questions, we've invited Dr Sophia Kamran who is an assistant professor of radiation oncology at Harvard Medical School. She's also a practicing radiation oncologist at Massachusetts General Hospital. Her research interests include computational genomic approaches to characterize tumor evolution, and mechanisms of toxicity and resistance to radiation and chemoradiation — all with the goal of enhancing personalized approaches of radiation therapy for patients with bladder cancer and other genitourinary malignancies. Welcome, Sophia.
Sophia Kamran, MD: Thank you so much. I'm very excited to be here.
Lee: Before we get started and dive into our discussion today, I'm sure our audience would be interested in learning more about your background and what motivated you to become a physician. What made you decide to go into radiation oncology, and what exactly drove you to care for patients with bladder cancer and other genitourinary malignancies?
Kamran: I originally went to the MIT [Massachusetts Institute of Technology] School of Engineering, and I majored in biological engineering. However, I did feel like my calling was more toward patient care and medicine, so I decided to go to medical school. But I never really forgot the background I came from — which was more math-, physics-, and technology-heavy — so I went into medical school with my eyes wide open. Unfortunately, early in my second year of medical school, my mother was diagnosed with cancer. We hadn't had any experience with cancer before in my family; it's obviously a very scary time. I hadn't had a lot of classes or education on cancer yet because it was very early in my medical training, so it was a very big unknown. I spent a lot of time going with my mom to her appointments and getting to know her oncologist. I felt like it was a very special relationship that we developed with the cancer team and with the oncologist, in particular. I felt like that was unique, and I knew I wanted to have something like that in the future with my patients.
When I returned to medical school and started going through my clinical rotations, I really enjoyed my general radiology rotation, which consisted of all sorts of machinery and technology, such as MRI scans, PET scans, and CT scans. But I did really miss that special relationship I had experienced from a patient/caregiver side with an oncologist. I had a lot of mentors throughout medical school, and I told them about my different interests and that I didn't know how to marry them. One of my mentors suggested I look into a field called radiation oncology. I was blown away because we don't have any experience with radiation oncology as medical students. It's not one of our typical rotations; you usually have to ask for it. So, I decided to do a rotation specifically in radiation oncology, and I felt like that was my calling. I've done a lot of research on computational genomic approaches to enhance personalized radiation oncology, and there really isn't a higher need now than in bladder cancer. That's what drove me to study patients with genitourinary malignancies — particularly, bladder cancer — and to care for these patients as well.
Lee: That's an excellent story. So much of the improvement we've made in oncology relates to personalization of care, so to have your background in computational studies, and bringing that to computational genomics is fascinating. Increasingly, there seems to be more evidence demonstrating a role for radiation therapy across the spectrum of bladder cancer management. As patients are living longer, we're thinking more about improved quality of life. We're thinking more about targeted therapy, personalized therapy, and precision therapy. So, where does radiation fit? I want to start with an area in which we're not really applying radiation therapy to a great degree, and that's in high-risk non–muscle-invasive bladder cancer — specifically high-grade T1 bladder cancer. The Europeans have been using radiation in this space for some time, so it seems weird that we're just getting started. Are we behind? Should we be thinking more about this? Who should we be considering for radiation therapy in those with T1 disease?
Kamran: I think more data are needed, but the data are coming. We just completed a phase 2 trial looking at this very question. We've made great strides in the muscle-invasive, or T2 or beyond, disease space but not so much in the T1 disease space, which is the non–muscle-invasive bladder cancer. However, there are studies from Europe and retrospective studies that show we can successfully radiate T1 disease. I think there may have been a bias against radiation for T1 disease. People thought maybe it was more radioresistant or perhaps it wouldn't respond as well; however, we've now learned that this is not the case. There was a trial called RTOG 0926. It was a phase 2 trial evaluating bladder-sparing chemoradiation for patients who had recurrent high-grade T1 bladder tumors refractory to the traditional treatment of BCG [bacille Calmette-Guérin] and for whom cystectomy is the next step. We wanted to see how these particular patients did with bladder-sparing chemoradiation. First, how did they tolerate it? Second, what were their overall outcomes? It was a small trial, but it was presented at our national meeting this fall. We found that the 3-year freedom-from-cystectomy rate was 88%, and patients tolerated the treatment very well. Obviously, we need additional studies and larger studies; we need to validate what we found. But this is now showing that we may be able to move radiation therapy into an earlier disease space and give patients another alternative to just thinking about cystectomy.
Lee: That's fascinating and very provocative. Certainly, there are many patients who are averse to radical surgery, and radical surgery is not without significant potential complications. So, having a treatment alternative in a very select group of patients may make sense.
As we think about selecting candidates for radiation therapy, I want to move into the space of muscle-invasive disease. Over time, there's been this — I won't say contention between radiation therapy and radical surgery for patients with muscle-invasive disease. But I would say we're getting better understanding of which patient is going to be the best candidate — who will respond best and be able to maintain their bladder without invasive recurrence. I'm interested in knowing how you approach the patient with muscle-invasive disease and how you determine who is a good candidate for trimodality therapy.
Kamran: There are two gold standard options for a patient who comes to us with muscle- invasive disease. One is, obviously, the radical cystectomy. The other is trimodality therapy. The reason we call it trimodality therapy is because we unite the three major disciplines for managing it, so it's a triple specialty: We have medical oncology delivering the chemotherapy; radiation oncology delivering the radiation; and then we have urology, or the surgeons, because they play a key role upfront in performing a maximal TURBT, or transurethral resection of the bladder tumor.
Having a team-based approach has allowed us to be very successful and elevate trimodality therapy to be a gold standard option. We want to make sure we maximize benefit, so there are some candidates for whom you might say, “Oh, you might be a little bit better with one vs the other.” I would say, for a trimodality therapy, we would ideally want to make sure the patient has good renal function and ideally doesn't have bilateral hydronephrosis because we want them to be able to receive chemotherapy along with the radiation therapy. Another quality we look for is current bladder function because as we always say, “We want to make sure we spare a bladder worth saving.” If a patient has poor bladder function, I can guarantee you radiation is not going to make the bladder function any better; if anything, it can make it worse. So, the patient's quality of life will not be great afterward; we're always keeping that in the back of our minds.
The other thing to think about is to make sure the patient hasn't previously received high-dose pelvic radiation for any reason — perhaps for a different cancer — because we wouldn't be able to escalate to the doses we need to eradicate their disease. Finally, some people would say if there's diffuse bladder involvement — meaning that there are tumors throughout the bladder — it can sometimes make the upfront resection of the tumor a little bit difficult. So, you're not starting off in a great place, and then we're radiating the entire bladder, and the patient might have more difficulty getting through the treatment. It's a little bit more contentious because, as you mentioned, radiation therapy is modernizing, and there have been a lot of techniques and technological improvements added. This may not be a contraindication in the future, but at this time, we want to make sure patients have good renal function, good bladder function, and didn't have prior pelvic radiation at a high dose. My final note is that when you mentioned the personalized therapy, our team is actively investigating whether there are certain genomic features in a particular patient that can help us make a treatment decision.
Lee: I want to ask you about dose in fractionation. When we talk to patients about bladder preservation, they're counseled about the timing of therapy. Having to undergo 35 treatments or more can be a challenge for patients particularly if they need to travel. Now doses are being escalated, and the timing of therapy is being shortened. What are your thoughts there? Is this something that is going to be available for most patients?
Kamran: Right now, it's basically a moving target. In the UK, they've really adapted this hypofractionation — meaning, giving higher doses per day to try to shorten the overall duration of the radiation therapy. They've done it very successfully. We've started to adopt many of these techniques because we have these advanced technologies to target the tumor and visualize the bladder on a daily basis, making sure we're not radiating normal tissue that shouldn't receive the radiation and really reducing toxicity in these individuals. However, we would caution on the use of hypofractionation especially in combination with novel therapies such as immunotherapy, which is being explored currently. There were two phase 1 trials that were stopped early because of too many toxicities when using a high dose per day — that is, hypofractionation — and trying to shorten the overall duration in combination with immunotherapy. Unfortunately, patients developed what we call dose-limiting toxicities, so these two studies had to be stopped. Right now, we know that in combination with immunotherapy specifically, we are still going slowly, and we're not quite getting to that point. But it's being actively explored, particularly with some additional artificial intelligence techniques and even more advanced techniques called adaptive therapy. But right now, that's where we are with regard to fractionation and dose.
Lee: You mentioned immunotherapy. Radiotherapy and chemotherapy are known to increase the PD-L1 expression in bladder cancer. Where do you see immunotherapy fitting into your treatment planning? Are there trials ongoing that we're waiting for? What are your thoughts on incorporating immunotherapy into your practice?
Kamran: This is a very exciting question. There's a lot of rationale for combining radiation and immunotherapy in other solid tumors — from lung cancer and from a lot of other data we have that are very exciting — showing that they actually work in conjunction to enhance each other's outcomes. We also know that immunotherapy is very successful in the metastatic bladder cancer state. So we are now exploring how we can move the immunotherapy into an earlier disease state and combine it safely with radiation therapy to improve upon outcomes even more. We have an open trial that's called the INTACT (SWOG/NRG 1806) trial. This is our phase 3, randomized trial of concurrent chemoradiation plus or minus an immunotherapy called atezolizumab in localized muscle-invasive bladder cancer. The goal of this, exactly to your point, is to explore how we can optimize radiation therapy for patients with bladder cancer and muscle-invasive disease by adding on immunotherapy and obtain the exciting results seen in other solid tumors. Hopefully, we can translate this to bladder cancer.
Lee: In so many spaces, immunotherapy has made a big difference in outcomes for patients with bladder cancer. When you were talking about trimodality therapy and advances, you mentioned adaptive bladder radiation. Can you talk a little bit more about that? What is it, and how does it relate to artificial intelligence?
Kamran: Essentially, on a daily basis, we get a patient set up for radiation therapy, but as you can imagine, a patient's anatomy is always going to be in a slightly different position. The bladder filling is going to be a little bit different. The rectum filling is going to be a little bit different. The bowel moves constantly. So, the anatomy is always going to look a little bit different on a day-to-day basis. What we're doing is capturing the current anatomy. We're essentially doing a low-dose CT scan, and then we have artificial intelligence that is working in the background and adapting based on that day's anatomy — what we see on that day. Then, based on that new anatomy, we're developing a treatment plan for that day's radiation. The physicians are checking it to make sure everything looks okay and then delivering the treatment that day. It's unique to a patient's anatomy on the day of treatment, so we can better target the tumor area and the bladder. If we're targeting lymph nodes, we can be much more accurate because we know we're treating exactly what we want to treat based on what we see on that particular day — and not some prior day.
The use of adaptive bladder radiation might be a way to get around some of the toxicity that was seen in those trials I mentioned, in which we combined immunotherapy using a high dose of radiation per day. Unfortunately, there was toxicity seen, so those trials had to be closed. Maybe with adapting — since we can be very sure about where we're targeting and really make sure we're not getting an extra dose to the normal tissue — that's a way around the toxicity that was seen in those trials. So, again, very exciting.
Lee: Speaking of excitement, I'll ask you a little bit about stereotactic body radiation therapy [SBRT] and how you're using it, particularly in the metastatic setting. Patients are living longer. We're having to rethink how we approach local disease and also low-volume metastases. How are you incorporating SBRT in your practice?
Kamran: This is another area that is being actively explored in the bladder cancer world, and it is extrapolated from the prostate cancer world. In the prostate cancer world, several trials found that if you radiated either the metastatic lesions in low-volume metastatic prostate cancer or you radiated the prostate — that is, the primary tumor itself — patients had improved long-term outcomes compared with receiving standard-of-care treatment. Because of that and because we have the technology — we know we can safely escalate and perform SBRT to these lesions or to the primary tumor with very low toxicity — we're now extrapolating this to bladder cancer. We're trying to put together different trials and start looking at these two different entities of either radiating with SBRT to the low-volume metastatic lesions or radiating the bladder itself in patients who have low-volume bladder metastatic disease. We're very hopeful because we now have the technology. We now know that it is safe, and we know that it is very well tolerated. We're excited to start offering this — hopefully soon — to patients more and more to really understand how it impacts long-term outcomes.
Lee: This has been a fantastic discussion about radiation therapy and bladder cancer. I personally have taken away a few key clinical points. One is that patient selection continues to be key, and we're getting better. We also have the benefit of novel technologies, such as adaptive radiation in combination with artificial intelligence and in combination with some novel therapies — immunotherapy being an example of one. We also have approaches such as computational genomics that are going to allow us to use radiation therapy as effectively as possible in the right patient at the right time.
I want to thank you so much for joining me today. Any last comments for our listeners?
Kamran: Thank you again for having me. This has been so enjoyable. I would say that one thing that allows this to be so successful for bladder cancer patients is emphasizing the multidisciplinary approach — the team approach. It takes a team, and I think that all patients deserve to be seen in a multidisciplinary fashion. So, if you have bladder cancer, make sure you talk to physicians in all three disciplines [medical oncology, radiation oncology, and urology] and get the full spectrum of opinions in order to know your options.
Lee: I completely agree. Thanks, everyone, for listening. I'm Cheryl Lee for Medscape InDiscussion.
NRG Oncology/RTOG 0926: Phase II Protocol for Patients With Stage T1 Bladder Cancer to Evaluate Selective Bladder Preserving Treatment by Radiation Therapy Concurrent With Radiosensitizing Chemotherapy Following a Thorough Transurethral Surgical Re-staging
ASTRO 2021: RTOG 0926: Phase II Protocol Stage T1 Bladder Cancer to Evaluate Selective Bladder Preserving Treatment by Radiation Therapy Concurrent With Radiosensitizing Chemo Following a Thorough Transurethral Surgical Re-Staging
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Cite this: Key Advances in Radiation Therapy for Bladder Cancer - Medscape - Sep 08, 2022.