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Although the risk of severe- to life-threatening ureteral stricture is relatively rare in women treated with image-guided adaptive brachytherapy for locally advanced cervical cancer, this risk is pronounced in those with hydronephrosis and advanced disease at diagnosis, researchers found.

An analysis of 1,772 patients with locally advanced cervical cancer enrolled in the EMBRACE and retro-EMBRACE trials of combined intracavitary and interstitial (IC/IS) brachytherapy showed that the overall risk of severe ureteral stricture in 272 women with stage III/IV tumors and no hydronephrosis at baseline was relatively low: 1.8% at 3 years and 4.8% at 5 years.

In 130 patients with stage III/IV tumors and hydronephrosis at diagnosis, however, the risk of ureteral stricture was 13.6% at 3 years and 23.4% at 5 years (P≤0.001), according to Lars U. Fokdal, MD, PhD, of Aarhus University Hospital in Denmark, and colleagues.

The study was presented at the European Society for Radiotherapy & Oncology (ESTRO 37) in Barcelona.

"In general, combined IC/IS technique was not a risk factor," said Fokdal. " from the retro-EMBRACE and EMBRACE trials have also shown that IC/IS image-guided brachytherapy is associated with a better outcome for patients in terms of survival and adverse side effects. The increased, but targeted radiation dose to the tumor controls the cancer better without adversely affecting nearby organs and tissues. Taking all these results together, we have growing evidence in favour of IC/IS [image-guided brachytherapy] for treating cervical cancer."

However, Fokdal emphasized that "it cannot be excluded that individual patients with high ureter dose due to needles positioned in close proximity to ureters may be at increased risk of ureteral stricture."

Although at diagnosis was the only independent risk factor for severe ureteral stricture, the analysis also identified other risk factors for loss of renal function and potentially life-threatening urosepsis, including:

• advanced tumor stage III/IV (P=0.05)
• tumor volume (P≤0.001)
• application of needles for (P=0.02)

The following factors were not associated with increased risk: age, laparoscopic staging, lymph node boost, high-risk clinical target volume dose, external beam radiation dose, bladder dose volume effect (D_2cm3), and brachytherapy dose rate.

This analysis demonstrates that patients at higher risk of ureteral stricture can be identified, said ESTRO President Yolande Lievens, MD, PhD, of Ghent University Hospital in Belgium. This makes it possible "to monitor them more closely and maybe use a slightly different treatment approach to decrease their risk," said Lievens, in a statement.

The EMBRACE and retro-EMBRACE "clearly illustrated that using the latest technology translates into better outcomes and value for our patients," she added.

Closer observation during IC/IS image-guided adaptive brachytherapy procedures and insertion of ureteral stents prior to radiotherapy may reduce the risk of ureteral stricture in this subset of patients, Fokdal suggested.

Akila Viswanathan, MD, MPH, of Johns Hopkins Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins Kimmel Cancer Center in Baltimore, agreed.

"Patients who are diagnosed with a ureteral stricture may receive ureteral stents placed at that time," said Viswanathan, who was not affiliated with the study. "If a ureteral stent cannot be passed through the stricture, surgical resection and re-insertion of the ureter into the bladder may be indicated depending on the location and the degree of the blockage," she told MedPage Today.

In North America, brachytherapy is the standard of care for all locally advanced cervical cancer patients receiving external beam radiation. All candidates "should receive brachytherapy given the significant survival benefit imparted by brachytherapy compared to either no brachytherapy or to an external beam boost approach," Viswanathan said.

Brachytherapy is commonly administered immediately after or during external beam radiation with concurrent chemotherapy, she pointed out. More study is needed to understand how to reduce the risk of radiation-induced ureteral stricture, which can occur many years after radiation treatment.

Viswanathan said that "many questions remain" with these study results. No dose relationship was reported, possibly because of the small number of events, she noted. Knowing the percentage of patients who had ureteral stents placed at baseline, and when the stents were removed, would also be helpful.

"Longer follow-up and more information about the procedures performed and the time-course of events will help to clarify the true risk for ureteral stricture in this population of cervical cancer patients," she said.

The analysis included 610 patents with locally advanced cervical cancer treated within the retrospective retro-EMBRACE trial and 1,162 patients treated within the prospective EMBRACE trial.

Treatment included external beam radiotherapy (45-50 Gy) delivered in 25 to 30 fractions, with concomitant cisplatin in 88% of the patients. Image-guided adaptive brachytherapy was delivered with high dose-rate brachytherapy in 58% of patients, while 42% received pulsed dose-rate brachytherapy. Brachytherapy was delivered with combined IC/IS technique in 36% of the patients. Mean D_2cm3 to the bladder was 78.1 Gy.

At a median follow-up of 29 months, 36 patients were diagnosed with grade 3/4 ureteral stricture. The actuarial 3-year risk for grade 3/4 ureteral stricture was 2.0%; 5-year risk was 3.2%.

In 1,370 patients with TNM stage I/II tumors and no hydronephrosis at diagnosis, the risk of severe ureteral stricture was 0.5%/1.2% at 3 years and 1.3%/1.3% at 5 years, respectively.

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