Trimodality Therapy May Be Safer Than Surgery Alone in Urothelial Cancer

While bladder cancer is the most common malignancy of the urinary system, advances in novel therapies have allowed researchers to better understand toxicities and learn about the role of bladder-sparing trimodality therapy with a focus on toxicity and functional outcomes.

Trimodal therapy has been investigated in various RTOG-led trials and consists of 3 key components: transurethral resection of the bladder tumor (TURBT), radiotherapy, and chemotherapy. With the main goal of sparing the bladder, this approach has demonstrated long-term disease-specific survival similar to radical cystectomy, according to Sophia Kamran, MD.

Within her presentation at ASCO GU, Kamran highlighted data from 4 Radiation Therapy Oncology Group (RTOG) trials which showed this treatment to be non-toxic as very low rates of late pelvic toxicity were seen in patients. Good functional and quality of life outcomes were also demonstrated as patients who had trimodality therapy reported overall improved sexual function, body image, and were less concerned about their disease state.

In an interview with Targeted Oncology^TM, Sophia Kamran, MD, radiation oncologist at Massachusetts General Hospital and assistant professor of Radiation Oncology at Harvard Medical School, discussed the effectiveness of trimodality therapy as well as other novel therapeutics in patients with bladder cancer.

What are the key goals when you combine resection radiation and chemotherapy for patients with bladder cancer?

The main goal is really to spare the bladder. Another name for it is bladder preservation therapy, but we call it trimodality therapy because it really involves all of the three main disciplines. It involves surgery, medical oncology, and radiation oncology. We work together and it's really kind of like a team sport. The main goal is obviously to spare the bladder safely with low toxicity and to get rid of the cancer. Safely means we want to make sure that it is an effective treatment, and we want to make sure it's not a toxic treatment. We want to, hopefully allow patients to keep their bladder.

What does the research currently say about the efficacy and safety of trimodality therapy?

There have been a lot of different types of trials involving chemoradiation, or trimodality therapy evaluating it in the United States, Europe, and across the globe, really. From all the trials that we have, it has been shown that it is as effective as radical cystectomy in well selected patients. Now, there has never been a head-to-head randomized trial or comparison between radical cystectomy and trimodality therapy. There have been attempted trials, but they didn't accrue, unfortunately. At this time, we don't think we're going to be able to have a direct head-to-head comparison, but this is probably the best data that we will have to date, at least at this time.

From all of the data that we have now and what was recently presented at the Genitourinary Cancer Symposium, which is probably the best evidence to date and used a very large pooled database of patients that had radical cystectomy, or trimodality therapy, they did propensity score matching, and from that, it gives us more data showing that true modality is as effective as radical cystectomy in modern series. It's very reassuring and NCCN guidelines have adopted it as being an equivalent option to radical cystectomy for patients with muscle invasive bladder cancer.

With regards to safety, that has been investigated in their earlier trials. One of the big questions was late pelvic toxicity. If you're keeping the bladder in a patient, is it even worthwhile doing or do patients really struggle? That's the main question, as otherwise, we wouldn’t want to spare the bladder. From a pooled analysis of 4 RTOG trials evaluating patients that didn't maintain their bladder, they underwent trimodal therapy, and they were followed. In terms of late pelvic toxicity, it was very low. This was also very reassuring, showing us that it's a non-toxic treatment, particularly in the late part of the game.

Finally, with regards to functional outcome and quality of life outcome that was also evaluated in a study that was published a few years ago, it looked at patients that had trimodality therapy and looked at patients that had radical cystectomy. They all received six quality of life instruments or survey instruments that had been validated. From that study, it was shown that patients that had trimodality therapy had overall improved sexual function, they had improved body image, and they had less concerned about their disease state. That also shows us that trimodality therapy allows for good functional outcome and good quality of life outcomes, which are very important things to be thinking about in terms of late toxicity and functional and quality of life outcomes.

Are there any novel therapeutics other than chemotherapy that you think can fit into a trimodality treatment strategy right now?

The utility of immune checkpoint inhibitors, also known as immunotherapy, is a very exciting area of research for clinicians and for our patients. It has been shown that in other solid tumors, not necessarily bladder cancer, that the combination of immunotherapy and radiation therapy can act synergistically and can help each other work better. If we combine the 2, we can improve upon clinical outcomes in certain patients and certain populations.

We know immune checkpoint inhibitors are effective in the metastatic setting of bladder cancer. Our thought is, what happens if we move it earlier in localized disease where it's not metastatic, and then see if we can safely combine it with radiation therapy in the trimodality treatment combination. That is being explored right now. There were some phase 1 trials looking at the combination of just radiation plus immune checkpoint inhibitors upfront, just to see if it's safe and not toxic and well tolerated. It was shown that it was safe, and they weren't looking at efficacy, they just wanted to make sure that it was safe and had low associated toxicity.

From those early phase 1 trials, because it was determined to be safe, we have moved forward, and now we're designing larger trials. Some larger trials have opened and are ongoing. Probably the largest trial of bladder sparing therapy to date is currently open and ongoing. This is the NRG SWOG1806 trial [NCT03775265], which is a phase 3 randomized trial. It is randomizing patients to either standard trimodality therapy, or trimodality therapy, plus atezolizumab [Tecentriq] , which is an immune checkpoint inhibitor. You're going to be 50/50 randomized, the goal is for 475 patients, and when I gave the talk, we had almost 250 patients enrolled nationwide.

It's on its way and we're on our way. We really think that this could be the future of bladder preservation therapy in terms of improving upon outcomes. We know that outcomes are just as good as radical cystectomy in terms of long-term survival, but perhaps we can improve upon those numbers for patients and that's exciting and what we are hoping to see.

What are your key challenges with using try modality therapy in your practice?

There are many challenges, especially with an institution that isn't used to doing bladder conservation therapy, or maybe is just trying it out. I think one of the key challenges is just organization because it really is a team sport, it's multidisciplinary. The surgeons need to be on board, medical oncology, radiation oncology, and sometimes the scheduling and organizational challenges. Making sure your patient starts on time, that the chemotherapy is lined up with the radiation, ensuring that the urologist has done a very thorough TURBT before starting, and reassuring that everything is lined up, it can be more challenging, particularly if an institution used to the scheduling and organization to get it together.

I do think that that's also beneficial for the patient because the patient really does understand that it really is a team sport. They can feel that all of us are heavily invested into their treatment, and it does take all 3. You can't lose one and still have effective treatment, you really need all 3. They often feel very reassured, knowing that they're having 3 experts work on their invasive disease and so that is also great for them.

Then, the follow up consists of frequent cystoscopies, TURBT if necessary, frequent scans, seeing the radiation oncologists or medical oncologists going forward, so that can be a little bit challenging.

Another challenge that we're running into and needs to be further investigated is when we use checkpoint inhibitors because we are now incorporating that into our treatment. Whether or not we can safely hyper-fractionated treating the bladder when we use that. The reason why I bring that up is because hyper-fractionated radiation therapy, which really involves getting a larger dose of treatment per day of radiation so we can shorten the treatment duration overall by maybe a week, a couple of weeks, just depending on what regimen you use. That has been very popular, particularly in the [United Kingdom] , and it's been used in the United States as well. However, there has been some early data showing that if you use hypo-fractionated radiation therapy in combination with these immune checkpoint inhibitors, some of the data shows that there's some unacceptable toxicity risks, particularly related to gastrointestinal toxicity.

At this time, in that very large phase 3 randomized trial, SWOG NRG 1806, we do not allow for hyper-fractionation so patients get the standard fractionations. It is kind of a prolonged treatment and we like hypo-fractionated radiation because patients like it better, they do not have to come in so many times to the radiation center, it's cost effective, etc. But, at this time, there needs to be a little bit more investigation because it just appears that there's some dose limiting toxicities when you're combining the two in the hyper-fractionated setting. That's something that's being explored a little bit more.

We are also looking into various techniques and new technologies to see if we can adapt the radiation treatment on a daily basis to try to lower some of that dose to those critical organs at risk. Perhaps that's an effective way to safely escalate the dose on a daily basis along with incorporating them into therapy. Then maybe we can get around all those dose limiting toxicities. At this time, it's still being explored and that's a challenge that we are looking into.

What does the future of radiation oncology in bladder cancer look like to you?

I think that in the future we are going to see more incorporation of these novel therapeutics. Of course, we are talking right now about immune checkpoint inhibitors, but there's all sorts of different questions that still need to be answered. There is the sequencing question, there are ABCs that are being evaluated in the metastatic setting. We don't know if we can combine them, maybe it'd be better if we start combining those with radiation therapy in some way, which would be neat, so I think there's a lot of opportunity to improve upon our current outcomes with bladder sparing therapy and with radiation oncology.

I also foresee radiation oncology moving into different areas of urothelial carcinoma. Right now, we have the muscle invasive stage that we play a big role in, but I do foresee radiation oncology moving more into the metastatic role. There is a lot of exciting data on oligometastatic disease, particularly in combination with immune checkpoint inhibitor. So, I do think that's an area of great need, where we actually see patients do extremely well if you combine it just right, and it's a right amount of metastases, and things like that.

I do foresee us playing a bigger role probably in the metastatic setting. I think we're going to further improve upon muscle-invasive disease, improve on the current treatment regimen, either by incorporating more of these novel therapies, and figuring out the sequencing using hypo-fractionation. We have adaptive planning coming down the pipeline, which is where we can adapt the radiation plan on a daily basis. I think that's great for bladder cancer. Even in earlier diseases like in tier one disease, typically non muscle invasive disease, we don't really think about radiation oncology, but there was a recent small trial that was presented at the [American Society for Radiation Oncology Annual Meeting] this past year that did show good outcomes in patients that were [bacillus Calmette-Guérin] refractory. I think that was where they were going to go on to radical cystectomy, but when we did chemo radiation, the doses were a little bit different. When we did the bladder sparing therapy, patients did very well. It was a very early trial, very small trial, but I think that needs to be further investigated.

Then there are novel therapies where there are drug eluting devices that you can put into the bladder, and they can go through drugs locally. Perhaps combining that with radiation might be very effective. I think that there are a lot more roles and a lot more areas that radiation can get involved in. I think it's very exciting to be in radiation oncology, particularly in the bladder space.