Roxanne Nelson, BSN, RN

September 26, 2017

SAN DIEGO, California ― Tumor control in locally advanced cervical cancer is superior with higher-dose radiation therapy, according to new findings.

Local control was significantly superior for patients who received the standard of four fractions of 7-Gy high-dose-rate (HDR) brachytherapy as compared to two fractions of 9-Gy HDR brachytherapy.

However, there was no difference in overall survival in the study, which for surviving patients has a median follow-up of 48 months.

"Our trial demonstrates that combining pelvic radiation therapy with four fractions of 7-Gy HDR brachytherapy is effective for locally advanced cervical cancer," said study coauthor May Abdel-Wahab, MD, PhD, FASTRO, director of the Division of Human Health at the International Atomic Energy Agency (IAEA) in Vienna, Austria.

"In addition, it gives physicians data-supported guidance from a large, randomized study on what to expect in terms of outcomes if a regimen of two 9-Gy fractions is used in resource-constrained settings," she said. "A dose-effect relationship is implied by an 11% reduction in local failure," she noted.

"If resources are limited and two 9-Gy fractions are used, a small decrease in local failure may be expected," she emphasized.

Dr Abdel-Wahab was speaking here at a plenary session of the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. "If resources are limited and two 9-Gy fractions are used, a small decrease in local failure may be expected."

Dr Abdel-Wahab explained that the IAEA, the organization for which she is a director, is an independent intergovernmental science and technology organization within the UN family. "It serves as a global focal point for everything nuclear, which includes health, and radiotherapy and cancer are one of our biggest interests."

She also explained why this trial was so important. The majority of patients with locally advanced cervical cancer (80%) live in lower- or middle-income countries. "Radiation therapy is a major component of the management of cervical cancer," she said. "It is essential that we have data applicable to these real-world settings."

So the trial addressed the question, Can we treat people with brachytherapy in two fractions, or do we need four fractions?

Improved Local Control With 4x7 Gy

The trial compared locoregional control and toxicity of external-beam radiotherapy (EBRT) combined with HDR brachytherapy administered in two different fractionation schedules, with or without chemotherapy, in patients with locally advanced cervical cancer.

The prospective, randomized, multicenter international trial included 601 women with cervical carcinoma of stage IIB (73.2%) or IIIB (26.8%). The patients were being treated with curative intent, and they were without contraindications for EBRT, HDR brachytherapy, and chemotherapy.

The cohort included women from seven countries: India (257 patients), Peru (147), South Africa (76), Brazil (53), Pakistan (31), Morocco (19), and Macedonia (18). The average age was 49 years.

All patients in the cohort received EBRT at 46 Gy in 23 fractions to the pelvis, and they also received HDR brachytherapy in one of two dosing schedules.

In arm A, the prescribed HDR brachytherapy was four applications of 7 Gy each to point; in arm B, it was two applications of 9 Gy; arms C and D were similar to arms A and B, but patients also received cisplatin (40 mg/m2) in weeks 1 through 5.

Overall survival for the entire cohort at 5 years was 67.2% (95% confidence interval [CI] = 62%), and survival was greater among women with stage IIB disease (71%) vs stage IIIB disease (95% CI = 58%) (P = .03).

With respect to the different schedules, overall survival rates were 73.1% and 62.2%, with and without chemotherapy, for the cohort that received pelvic radiation and 4x7 Gy HDR brachytherapy.

For patients in the 2x9 Gy HDR brachytherapy group, the overall survival rate with chemotherapy was 65.1% vs 68.3% without chemotherapy; the difference was not significant. When stratified by center and stage, the authors found that there was no statistical difference in overall survival by study arm (P = .1).

In patients with stage IIB disease, there was no statistically significant difference in survival with 4x7 Gy HDR brachytherapy compared with 2x9 Gy HDR brachytherapy, and there was no difference with or without chemotherapy. However, tumor control was lower in arms B and D compared to arms A and C (P = .0007).

The 5-year tumor control rate in arm A (4x7 Gy HDR) was 88%; in arm C (4x7 Gy HDR+chemo) it was 89%. For arm B, the rate was 78% (2x9 Gy HDR), and for arm D (2x9 Gy HDR+chemo), it was 75%.

Preferred Treatment Schedule

Commenting on the study, Vishal Gupta, MD, associate professor of radiation oncology at the Icahn School of Medicine at Mount Sinai in New York City, noted that international clinical trials are extremely difficult to conduct, especially in low-resource settings, and these "efforts should give hope for future collaborations.

"Their trial showed that 7 Gy x 4 resulted in better local control than 9 Gy x 2 for HDR brachytherapy for intermediate-stage cervix cancer," Dr Gupta told Medscape Medical News. "This did not result in a survival benefit, but it may with longer follow-up.

"Prior to these data, it may have been preferable to treat with the 9 Gy x 2 regimen, since it is fewer treatments, which is more convenient, especially in low-resource settings," he added. "However, this trial demonstrates that the 7 Gy x 4 regimen improves local control by 10% and is the preferred treatment schedule."

Another expert pointed out that this study investigated how resources could be used more effectively, given that the majority of cervical cancer cases occur in women residing in low- and middle-income countries.

"Brachytherapy is an important part of the management of cervical cancer," said Sushil Beriwal, MD, deputy director of radiation services at the University of Pittsburgh Medical Center's Cancer Center, in Pennsylvania. "They wanted to see if two fractions could be as good as four fractions, and unfortunately, it was not. Local control was inferior.

"So going by the way the study is designed, four fractions must be offered to the patient," Dr Beriwal told Medscape Medical News. "That being said, if that isn't possible, due to access or cost issues, then the study helps us quantify the difference between two and four fractions. If four cannot be done, then at least do two, which is better than not doing anything ― which is the worst option."

He reiterated that patients should be informed of the difference between receiving two or four fractions, and that the two-fraction regimen is more of a "back up" if that is the only option available, given limited resources or lack of access.

Similar Toxicity, Modest Chemo Effect

Toxicity was not significantly different among the four treatment arms. For arm A, the rate of genitourinary side effects of grade 3 or higher was 7.3%; for arm B, it was 6.7%; for arm C, 5.3%; and for arm D, 7.2%.

Cisplatin had a modest effect on toxicity for the patients in 2x9 Gy, arm B (P = .066), but the use of chemotherapy did not significantly influence overall survival, cancer-specific survival, or tumor control in the cervix and surrounding region.

Dr Adbel-Wahab pointed out that there may not have been sufficient statistical power to detect an effect for chemotherapy.

"Surprisingly, this trial did not show any benefit in locoregional control or survival with the addition of chemotherapy," said Dr Gupta. He added that this finding contradicts prior studies.

"It would be interesting to know if the patients who were randomized to cisplatin actually received the prescribed dose," he noted, although there were no differences in rates of major toxicity from the different brachytherapy regimens or from chemotherapy.

Dr Abdel-Wahab is a member of the United Nations agency task force steering committee educational and expert panel and the ACR and Florida Radiological Society. The other authors and Dr Gupta have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract LBA-2, presented September 25, 2017.

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