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A personalized strategy of dose-escalated radiotherapy (RT) for bladder cancer had a low rate of severe late toxicity and survival comparable to historical results with cystectomy, a randomized trial showed.

Only one case of grade ≥3 late toxicity occurred among 114 patients treated with two fractionation schedules of dose-escalated adaptive RT (DART). Two-year overall survival (OS) was 80% with DART and 77% for patients treated with standard whole-bladder RT (WBRT) or standard-dose adaptive RT (SART).

Thirteen of 345 (3.8%) treated with the three regimens subsequently had salvage cystectomy, Robert Huddart, MBBS, PhD, of the Royal Marsden Hospital in London, and co-authors .

The treatment protocol for DART allowed for adjustment of RT volume and dose on the basis of bladder size and position at each clinic appointment.

"An image-guided adaptive strategy enabled radiotherapy dose escalation to over 86% of patients' bladder tumors without significant increase in toxicity," the authors stated in conclusion. "Utilization of multiple adaptive plans suggests an ongoing need for adaptive therapy to optimize treatment delivery. Dose-escalated therapy achieves promising tumor control and survival rates similar to that achieved with cystectomy, with low rates of salvage cystectomy, and should be studied in future trials."

According to a statement from Cancer Research U.K., which supported the study, "It's hoped that this type of personalized radiotherapy could one day offer a kinder and more effective way to treat some cancers."

The adaptive dose-escalated RT offers one potential strategy to address the common problem of local recurrence in bladder.

"The majority of local failures in bladder cancer specifically arise in the area where the tumor was initially," said Krishnan Patel, MD, of the National Cancer Institute's Center for Cancer Research in Bethesda, Maryland, and an expert for the American Society for Radiation Oncology (ASTRO). "That's not true in all types of cancer. Since they sort of knew the tumor was coming right back to where they initially saw it, these investigators wanted to see if pushing the radiation doses and really aggressively killing the cancer would improve the efficacy.

"Underlying this is the logic that more radiation dose kills more cells and therefore improves tumor control. That's kind of the rationale that underlies the whole field of radiation therapy."

A complicating factor is that the intestines lie on top of the bladder and the rectum is behind it and both structures are more sensitive to the effects of radiation as compared with the bladder, he continued. An additional challenge is the changing volume of the bladder throughout the day. Huddart and colleagues tried to address the problem with a protocol that standardized bladder volume. Before treatment, patients emptied the bladder and then consumed a specific amount of liquid to maintain the same volume at each treatment session.

"Suffice to say, no matter how much we try to do these things to standardize bladder size, it's not standardized," said Patel. "Even if you tell a patient to do the exact same thing on a particular day, the bladder will still have different volumes, and therefore the interface between the bladder and intestines will be different on different days."

In a further effort to maintain a standard bladder volume, investigators preplanned multiple scenarios of bladder volume. On the scheduled treatment day, they image the bladder and choose the preplanned protocol that fits best with the current volume.

"Then they dose-escalated utilizing that sort of customized strategy," said Patel. "There are some technical challenges with this and also some workflow issues. A lot of people in America may not have time to do this, and it also requires some additional resources and expertise from therapists. That's a kind of downside to this."

Huddart and an international team of investigators reported findings from the phase II trial of image-guided DART. Eligible patients had T2-T4a muscle-invasive bladder cancer and were randomized 1:1:2 to standard WBRT, SART, or DART. Within each randomized group, investigators assigned patients to two fractionation schedules: 55 Gy in 20 fractions (f) or 64 Gy/32 f for WBRT and SART, and 60 Gy/20 f or 70 Gy/32 f for DART. The trial had a primary outcome of late grade ≥3 and statistical power to rule out a toxicity rate >20% with DART.

The 345 patients included in data analysis had a median age of 72-73, 78-85% had T2 tumors, 46-52% received neoadjuvant therapy, and 70-71% received radiosensitizing therapy. Median follow-up in the three treatment arms ranged from 38-42 months.

RT-related grade ≥3 toxicity in the DART group occurred in one patient (1.7%) treated with 60 Gy/20 f and no patient treated with 70 Gy/32 f. Rates of grade ≥3 RT-related toxicity were 3.2% and 4.3% with 20-f subgroups of WBRT and SBRT, respectively and 0% in the 32-f subgroups.

"This is a new approach and tested in a phase II non-randomized manner," said Trinanjan Basu, MD, of HCG Cancer Center in Borivali, India, and also an ASTRO expert. "It will require long-term follow-up, although the approach seems exciting. This is a step towards personalized radiotherapy, and future molecular types, in addition to histology, would determine who benefits from what.

"The practice is challenging and thought provoking and should be investigated and explored further. However, a strict contouring, planning, and image-guided adaptive RT protocol remains cornerstone for this approach."

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