BARCELONA-Image-guided adaptive brachytherapy (IGABT) for patients with cervical cancer did not increase risk for ureteral stricture in European research reported at the 2018 European Society for Radiotherapy & Oncology (ESTRO 37) conference.

"Our findings show that the risks for severe to life-threatening ureteral strictures are very low in all the patients with limited stage disease," said first author Lars Fokdal MD, PhD, a clinical oncologist from Aarhus University Hospital in Denmark. He discussed his group's updated population-based findings and conclusions from analysis of data from 1,772 patients treated with brachytherapy for their locally advanced cervical cancer in the retrospective RetroEMBRACE study (with 610 patients) and the prospective EMBRACE (with 1,162 patients).

Data from a large American study in 1995 found the risk for ureteral stricture in patients with cervical cancer treated with radiotherapy was low. But patients in the study had earlier stages of cervical cancer than those in the EMBRACE studies which included a wider range of subgroups (Cancer 1995;75(3):836-843).

"We looked at the whole population from the RetroEMBRACE study and also the EMBRACE study-which in total was 1,850 patients in the updated analysis. We analyzed all the ureteral strictures. And we focused on those strictures that were severe or life-threatening," Fokdal told Oncology Times. "We had a total of 32 patients that had severe or life-threatening strictures after image-guided adaptive brachytherapy. Compared to the American study, the percentage we got was similar," he said.

"We know that in this older [U.S.] study it was only limited-stage patients that were treated with brachytherapy. In our study, we had more patients with advanced stage disease.

"So we looked at the risk factors for ureteral stricture. When we analyzed for stage and baseline hydronephrosis, we found that patients in our study that had low stages also had very low risk for ureteral stricture-approximately 1 percent at 5 years. And that's exactly the same number as from the American study," Fokdal explained.

The new analysis from EMBRACE found that there were identifiable risk factors for ureteral stricture in patients with more advanced cervical cancer. Fokdal noted there was one subgroup of patients at greatest risk. "Patients that you have to take care about are those that have advanced-stage disease with baseline hydronephrosis because they [are at] higher risk for ureteral strictures."

In the study, 88 percent of patients were treated with external beam radiotherapy at total doses between 45 and 50 Gray (Gy) delivered in up to 30 fractions, plus concomitant cisplatinin. Fifty-eight percent of patients also received high-dose-rate IGABT and the remaining 42 percent had pulsed-dose-rate IGABT. Brachytherapy was delivered with the combined intracavitary and interstitial (IC/IS) technique in 36 percent of the patients. Severe to life-threatening grade 3/4 ureteral strictures were assessed and risk factors analyzed.

Fokdal said there had been worry that therapy requiring needles (combined IC/IS brachytherapy) had the potential to increase the risk for ureteral stricture, but the study found it did not. "In our analysis of risk factors, we did not find any association of the technique used for brachytherapy [and] we did not find any impact of the needles in the subsequent ureteral strictures."

But efficacy of the brachytherapy was confirmed. "We know for sure that image-guided adaptive brachytherapy is associated with improved local control, improved survival, and reduced morbidity," he noted.

New Data

At a median follow-up of 29 months, 36 patients were diagnosed with grade 3/4 ureteral stricture. The 1,370 patients with stage I/II tumors had between 1.2 percent and 1.3 percent risk for being diagnosed with a ureteral stricture at 5 years. The 272 patients with stage III/IV tumors without hydronephrosis at diagnosis had a risk of 4.8 percent at 5 years of being diagnosed with a ureteral stricture. While the 130 patients with baseline hydronephrosis had a 23.4 percent risk.

Risk Factors

A number of factors were not associated with risk for ureteral stricture, including age, laparoscopic staging, lymph node boost, high-risk clinical target volume dose, external beam RT dose, and brachytherapy dose rate. Only hydronephrosis and tumor stage at diagnosis were independent risk factors for ureteral stricture. "We found that advanced stage and baseline hydronephrosis were associated with risk for ureteral strictures," said Fokdal.

When asked if the image-guided technique was as safe for giving brachytherapy, he stated, "Yes. It is as safe as [the] traditional technique. And we also know from other studies that morbidities are reduced compared to older techniques. And what's also very important is that local control rate and survival associated with image-guided brachytherapy is improved, which means that when you look at the total outcome-not only morbidity but also survival-there is an advantage of modern image-guided adaptive brachytherapy."

Findings Reassuring

Yolande Lievens, MD, PhD, President of ESTRO and Head of the Department of Radiation Oncology at Ghent University Hospital in Belgium, welcomed the findings. "I think they are reassuring because the first thing that the EMBRACE study wanted to do was to try to get the bottom of local control-and therefore also survival-of these patients.

"We know that by raising the dose to the cervical tumor we can get much better outcomes. So what this study has done is just to evaluate that while doing so we are not having a higher risk of ureteral strictures," she told Oncology Times. "And the study nicely shows this is not the case. The risk is there. But it's also there with less advanced techniques which deliver lower dose and have less good outcome. So this is just a very reassuring study."

Lievens called out for more data from population-based studies that have been showing that brachytherapy is a valuable part of the total treatment of cervical cancer. "Indeed, if you do not use brachytherapy, patients have a worse outcome," she said. "Optimizing brachytherapy in cervical cancer is of great value to the patients. And if we can further improve the brachytherapy with better outcome and limit the risk of negative effects-as has been shown in this study-this is very reassuring."

Commenting on the study, Bradley R. Pieters, MD, PhD, Radiation Oncologist at the Academic Medical Center, University of Amsterdam in The Netherlands, noted the technique was now certainly a standard of care. "It has become clear that, [with] image-guided brachytherapy together with external beam radiotherapy and chemotherapy, the probability to get local cure and improved survival has increased dramatically."

When Pieters was asked for his assessment of the risk for ureteral stricture in the light of the new data, he said it was low. "There is [risk] for a certain category of patients [who] already had hydronephrosis before therapy-meaning there's a kind of obstruction in the urethra already. These patients are at higher risk of eventually developing these ureteral strictures. These patients need to be followed up more carefully. But for the majority of patients who don't have hydronephrosis, image-guided therapy with interstitial needles is a safe procedure."

Peter M. Goodwin is a contributing writer.