Nick Mulcahy

September 24, 2013

ATLANTA — The world standard for the treatment of advanced cervical cancer does not improve overall survival, according to the first-ever randomized controlled trial of patients with advanced-stage disease.

However, the standard treatment — adding chemotherapy to radiotherapy (RT) — did significantly improve disease-free survival, said lead author Antonio Zuliani, MD, a radiation oncologist at Campinas State University in Brazil.

He spoke during a press briefing here at the American Society for Radiation Oncology 55th Annual Meeting.

Previous randomized trials have shown a survival benefit when chemotherapy is added to RT, but most of those studies involved women with earlier-stage cervical cancer, he noted.

It has not been clear whether this standard improves overall survival in patients with advanced disease, Dr. Zuliani explained.

To determine whether it does, he and his colleagues conducted a 10-year randomized trial comparing concomitant cisplatin plus external-beam RT and high-dose-rate brachytherapy with RT alone (external-beam RT plus brachytherapy and no chemotherapy).

The trial involved 147 women with stage IIIB squamous cell cervical cancer.

Brazil was a logical site for the study, said Dr. Zuliani, because advanced-stage cervical cancer is mostly a disease of "less developed" countries. Screening has made diagnosis at an advanced stage relatively rare in the United States and other places.

The combination of cisplatin plus the 2 RT modalities used in this study is also the standard of care for advanced disease in the United States, said press-briefing moderator Beth Erickson, MD, from the Medical College of Wisconsin in Milwaukee, who was not involved in the study.

However, in the United States, the brachytherapy can be either high or low dose, she noted, adding that low-dose brachytherapy necessitates a few days in the hospital.

In the Brazilian study, patients treated with cisplatin plus RT had significantly better disease-free survival than those treated with RT alone (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28 - 0.98; P = .04), and better overall survival, although that was not significant (HR, 0.67; 95% CI, 0.37 - 1.183; = .16).

For all patients, mean follow-up was 54.9 months.

Approximately 60% of the 2 treatment groups survived to year 5. That is in keeping with historic data on advanced disease — 40% to 60% of women with advanced disease survive that long, said Dr. Zuliani.

"Great" New Safety Information

Importantly, the results indicate that levels of toxicity are "acceptable" with chemotherapy plus RT, said Dr. Zuliani.

"This study was great in adding information on the safety of combining high-dose brachytherapy with chemotherapy and external-beam radiotherapy," said Dr. Erickson.

There has been "some concern" about toxicity with the combination of high-dose brachytherapy and chemotherapy, she explained, adding that late effects have been a particular worry.

However, toxicity levels, measured with the Cooperative Group Common Toxicity Criteria of the Radiation Therapy Oncology Group, were similar in the 2 groups.

Table. Toxic Effects in the 2 Treatment Groups

Toxic Effects Cisplatin Plus RT, % RT Alone, % P Value
Grade 1/2 acute toxicity 37.5 28.0 .29
Grade 3/4 late toxicity 9.7 3.0 .29

 

Worse Function, Worse Outcomes

The study was conducted from 2003 to 2010, with follow-up lasting until January 2013.

All of the study patients received external-beam RT of 45 Gy to the pelvic region in 25 fractions, a 14.4 Gy boost to the compromised parametrium (the connective tissue and fat adjacent to the uterus), and high-dose-rate brachytherapy in 4 weekly fractions of 7 Gy (to where the uterine artery crosses the uterine artery).

The cisplatin was administered weekly in intravenous doses of 40 mg/m² during the pelvic RT sessions.

Disease-free and overall survival were significantly worse in women who had a Karnofsky score — a measure of functionality in everyday living — below 90. The same was true for women with bilateral wall invasion and a baseline hemoglobin level below 10 mg/dL.

"We were pleased by the increase in local control and the very low toxicity rates [in this trial]. We believe that these results demonstrate that this combined treatment protocol is safe to offer patients and provides some beneficial improvements in disease-free survival and toxicity levels," said Dr. Zuliani in a press statement.

Dr. Zuliani and Dr. Erickson have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 55th Annual Meeting: Abstract 8. Presented September 22, 2013.

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