Leslie Ballas: Hello, I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai in Los Angeles, and we are so incredibly lucky today to be joined by Dr. Vedang Murthy, professor of radiation oncology at Tata Memorial Hospital in India, who is here to discuss his recent plenary session at ASTRO on the BART trial, Bladder Adjuvant Radiotherapy. Dr. Murthy, thank you so much for doing this.

Vedang Murthy: Absolute pleasure, Dr. Ballas, an honor to be here. Thank you. Hello, everyone. This is the talk I delivered at ASTRO recently on the multicenter phase three randomized trial called BART. When we look at how advanced bladder cancer is treated, essentially it's a cystectomy and a urine bag. We add chemotherapy, either neoadjuvant or adjuvant. This improves survival by about five to 8% with cisplatin. In the last two or three years, it is also believed that adding immunotherapy, particularly nivolumab, improves survival by a few percentage points. After this, we follow up the patients, and in spite of all this, when we do all this that we've got, in spite of this, unfortunately this disease is not very kind, and almost 40% of the patients succumb to their disease just in 36 months, in spite of immunotherapy. Two things about patterns of failure after cystectomy.

One, most people believe, and I am also a believer, that many of the failures are distant. That is why we give all the chemotherapy and immunotherapy, but what is not very well appreciated is that a lot of recurrences can be regional, and this came into light in the last five or six years in the work from UPenn and our own work, that patients who have certain high risk factors like T3, T4, node positivity, margin positivity, lymphovascular invasion, almost a quarter to a third of them can relapse with a component in the pelvis. When these relapses happen, they can be pretty nasty. You can see here, these are real images. These patients can suffer a lot and they can be very, very difficult to treat for the oncologists, so we have to avoid these. Unfortunately, chemotherapy doesn't seem to make a difference in preventing locoregional relapses, so what we need is a locoregional treatment, and with that background, we launched this randomized trial called BART in 2016.

These were all patients who had their cystectomy, and almost all of them had some form of perioperative chemotherapy. All of them had high risk factors, as given here. They were randomized to either observation, which was standard at that time, or to adding adjuvant radiotherapy, 50.4 Gy in 28 fractions, to the pelvic nodes and cystectomy bed. The primary endpoint was two-year LRFS with a sample size of 153. We treated the bed and the pelvis using the just published at that time international consensus guideline on contouring the bed. We included the common iliac lymph nodal region. We used stoma sparing and bowel sparing, iliac conduit sparing IMRT with daily image guidance, and the dose distribution is just an example of what we could achieve.

Now, these are the results. The median age was 57 years. A lot of lymph nodes were dissected, and the margin ... That was 20. Margin positivity was under 5%, a great testament to the surgery that our team has done. Very few neobladders were made. You can see here, about three quarters of the patients had T3/T4 disease, in the red box, and a third were clinically node positive, so really advanced disease, and 90% of the patients received some form of chemotherapy, which again, is a standard of care in this disease. Of the 153 patients randomized, the primary endpoint was analyzed by intention to treat. A few patients could not receive radiation due to either complications or they defaulted due to COVID, and the secondary endpoints were analyzed per protocol. The primary endpoint, this is the main result, two-year LRFS after a median of 47 months in surviving patients was significantly higher, both clinically and statistically significant, with 11% improvement in the endpoint.

When we looked at this per protocol, the benefit was even higher, with an HR of 0.27. We looked at the impact of adjuvant radiotherapy on subgroups, especially in those where we would think that radiotherapy might not help, for example, heavy node positivity, multiple risk factors like T3 and N-plus, and those who have received neoadjuvant chemotherapy, and all of them showed a benefit with adjuvant radiotherapy. These are the three main secondary endpoints of DFS, bladder cancer specific survival, and OS, and all of them showed a 12 to 15% absolute improvement with adjuvant radiotherapy. They were obviously quite clinically meaningful and significant, but just fell short of statistical significance, in this case.

We had some very interesting patterns of recurrence data that I presented. Basically, not a single patient who received radiotherapy had an isolated failure in the pelvis, and about a third of them, 30 and 32%, had distant failure in both the arms. The locoregional relapse was reduced from 25%, which is what we were expecting, to about 8% overall, with radiation. I presented the results of this trial last year. To summarize, the severe GI side effects, which we are all worried about, actually, is quite low, under 5%. Mild to moderate grade two GI effects were higher with radiation, as expected, and the late effects were similar, about 10%, in both the groups.

This is the largest multicentric randomized trial answering this question, and as I have shown you, the surgery, chemo, and radiation was all delivered with standard of care approach of the day. One of the factors that I thought was a weakness was we probably fell short of the sample size a little bit for statistical significance on the secondary endpoint. There was no immunotherapy use, but I don't think this is actually a weakness, probably a strength in retrospect, because it shows the value of radiation when immunotherapy is either not available or not affordable or not tolerated, which actually happens quite a lot around the world. I think the biggest problem going forward may be what we fear the adjuvant radiotherapy will do, both amongst our community in radiation oncology and among surgeons, but I hope the trial allays some of these fears that it is reasonably safe to do, and we have some wonderful opportunities of an IPD meta-analysis of similar ongoing trials, and we are very excited about some combination of radiation and immunotherapy in this very setting.

Huge gratitude to my colleagues, my hospital, my department, and of course the patients and their families for making this possible. Thank you so much.

Leslie Ballas: Thank you, Dr. Murthy. Congratulations on completion of this really amazing and important trial. Tell me a little bit about the age of the patients in India, or that were at least on the trial. As we know in the US, the average age of bladder cancer is about 72, 73 years old. Is this a function of increased smoking in India? What are your thoughts on the younger population?

Vedang Murthy: I don't think this is a unique thing for bladder. I think when we look at any data in any cancer, largely related to the life expectancy, our life expectancy is at 74 and 78 right now, so 57 to 60 is what we see for cystectomy patients. For our bladder preservation group, the average age is about 64, so I think the whole thing is related to the generally younger patient in terms of shorter life expectancy. We see that in all cancers.

Leslie Ballas: Tell me a little bit about the time to radiation following cystectomy. Do you know on average how long it was before radiation began?

Vedang Murthy: We had specified in the protocol that it should happen within eight weeks of surgery. Many patients, I think not many, but about 20% of the patients actually received adjuvant chemo, also, so we had specified that after adjuvant chemo, they should start within a month of their last chemotherapy, which most people followed. The biggest challenge we face while recruiting is patients, after the neoadjuvant chemo surgery, they're frail, they're old, they're basically fed up and they just want to go home. It is not an easy treatment, bladder cancer treatment, so to motivate them to participate in the trial was a real challenge for the whole team.

Leslie Ballas: Actually, the timing issue around the adjuvant chemo is exactly what I was going to ask, which is, you had them receive adjuvant chemo and then the radiation.

Vedang Murthy: Yes, yes. We wanted to make it inclusive. I could have fought, saying that we should do the radiation first, but because that was considered the standard of care at that time, we added the radiation afterwards, so that basically it was win-win for everyone.

Leslie Ballas: Yeah, and so, I mean, the reason that I ask that is mostly because as we think about the data that's come out, as you highlighted, CheckMate 274 as well as the AMBASSADOR trial integrating immunotherapy, and if we wanted to give both treatments to a patient, the question of course being, would we give them at the same time? Would we start with radiation and then give the immunotherapy? I know that on the AMBASSADOR trial, Dr. Apolo has said that there were patients that got radiation and IO. They have not been detailed in the publication, and so we don't know sort of anything in terms of the timing or their outcomes, but obviously that's something that, as you mentioned, would be very interesting to evaluate next.

Vedang Murthy: Yes, that's right. That is something I'm also very excited about, and to add to ... Another spoke, we are starting to give neoadjuvant IO now, so there's going to be neoadjuvant IO, cystectomy, chemotherapy, adjuvant IO, and we've got to fit radiotherapy in somewhere. What they have also not mentioned in the IO trials is the patterns of failure. That is something I'm also looking forward to.

Leslie Ballas: Thank you. Additionally, I wanted to ask you about the toxicity. You had presented that the year prior, and showed that the toxicity was very small. Actually, if you look at the toxicity from some of these IO trials, granted, it's impossible to compare across trials, and we're looking at different types of toxicity, but when you look at the grade three toxicity, the radiation seems to be less toxic.

Vedang Murthy: Yes, yes. When we started the trial, I had very little experience in irradiating the cystectomy bed. Initially, we were really wondering whether to include the bed or not. We had this discussion as well in 2016, whether, based on the UPenn data, whether the bed should be excluded, but my heart wouldn't allow that. Neither did my IRB allow it, so we had to include the bed. Why would we not treat the bed? I think it turned out to be a good decision, but 50 Gy to some of the large bowel sitting there and a little bit of small bowel, I think we did all right. I was pleasantly surprised that severe toxicity was not too much, and we have seen them for so many years now. We were worried about obstruction, subacute intestinal obstruction, and some fibrosis and other things, but they're doing fine.

Leslie Ballas: That's wonderful. Final question is, how should we integrate this today, given the current landscape that you described? Where, when I go to tumor board next, should I be arguing to put adjuvant bladder radiation in these high-risk patients?

Vedang Murthy: I think so. I think so. Our estimate was a quarter to a third of the patients will get some form of regional relapse, and as I have shown, some of them are small and some of them may not matter too much, but mostly, they are quite bad. The data, some of the data that I have not shown is that once they get a relapse, the median survival was ... In the pelvis, the median survival was only nine months, so that is something we have to avoid at all costs.

Now, how do we integrate this? I think the best time would be about four to eight weeks after their cystectomy. That is a time when they have kind of settled down and their tissues have healed. That would be a good time to start the adjuvant, or think about the adjuvant radiotherapy. Now, immunotherapy has to continue for a much longer time. I think there is flexibility in either suspending it or starting it after ... Suspending it during radiation or starting it after radiation. Having said that, I don't believe they would interact in a way that we should be worried about, so although we don't have very clear data on it, and I think there are some trials that are being planned on this, but I think adjuvant radiation and adjuvant immuno can be combined safely. They have non-overlapping side effects, so I hope that is possible to do. I think that would be the best case scenario.

Leslie Ballas: Thank you so much. Again, thank you for joining us. This was a true pleasure for me. I always love seeing you, and I can't thank you enough.

Vedang Murthy: Thank you so much, Dr. Ballas. Thank you.