1. Carlson, Robert H.

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ATLANTA-A randomized controlled trial comparing external-beam radiotherapy and high-dose rate brachytherapy vs. chemo-radiotherapy for patients with stage IIIB squamous cell carcinoma of the cervix found a small but statistically significant survival benefit with the addition of cisplatin. Importantly, though, as reported here at the American Society for Radiation Oncology Annual Meeting (Abstract 8), the regimen was associated with acceptable toxicity.

Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

Adding chemotherapy to radiotherapy is known to improve outcomes in early-stage cervical cancer, but until now trials have not demonstrated benefit for patients with later stages, said Antonio C. Zuliani, MD, a radiation oncologist at Campinas State University in Brazil, who presented the data.


He said the best evidence for disease-free and overall survival of women with stage IIIB cervical cancer undergoing chemo-radiotherapy vs. radiotherapy has been from a meta-analysis of 18 trials (Cervical Cancer Meta-analysis Collaboration, 2010)-which showed a decrease in benefit from 10 percent for patients with stages IB-IIA disease to three percent for those with stage III-IVA.


In this new randomized, controlled trial, women with stage IIIB squamous cervical cancer received external-beam radiotherapy and high-dose rate brachytherapy with or without cisplatin. The study endpoints were disease-free and overall survival. All patients received external-beam radiation (45 Gy) to the pelvic region in 25 fractions, a 14.4 Gy boost to compromised parametria, and high-dose rate brachytherapy in four weekly fractions of 7 Gy prescribed to point A (the crossing of the uterine artery and the ureter). The chemo-radiotherapy group also received weekly cisplatin (40 mg/m2) during the pelvic brachytherapy.

ANTONIO C. ZULIANI, ... - Click to enlarge in new windowANTONIO C. ZULIANI, MD. ANTONIO C. ZULIANI, MD: "In testing the new approach of chemotherapy with traditional external-beam radiation therapy and high-dose rate brachytherapy, we were extremely cautious about possible toxicity, and we were pleased by an increase in local control and the very low toxicity rates."

Between September 2003 and July 2010, 147 patients were accrued-72 patients receiving chemo-radiotherapy and 75 radiotherapy alone. The mean follow-up was 54.9 months.


Women with a Karnofsky performance scores of less than 90 had a significantly worse disease-free survival, with a relative risk of 2.52, Zuliani reported. The same was true for women with bilateral wall invasion (relative risk of 2.93), and baseline hemoglobin under 10 mg/dL (relative risk of 2.22).


On the other hand, disease-free survival was significantly better in women assigned to chemo-radiotherapy (relative risk of 0.52). Overall survival was also negatively associated with a Karnofsky score of under 90 (relative risk of 2.75), and with baseline hemoglobin under 10 mg/dL (relative risk of 2.22).


Again, patients in the chemo-radiotherapy group had a better overall survival rate, but this was not statistically significant (relative risk of 0.67), he said.


Grade 1/2 acute toxicity was 37.5 percent for patients receiving chemo-radiotherapy, and 28 percent for those receiving radiotherapy alone. Grade 3/4 late toxicity was 9.7 percent for chemo-radiotherapy and three percent for radiotherapy.


"In testing the new approach of chemotherapy with traditional external-beam radiation therapy and high-dose rate brachytherapy, we were extremely cautious about possible toxicity, and we were pleased by an increase in local control and the very low toxicity rates," Zuliani said. "We believe these results demonstrate that this combined treatment protocol is safe to offer to patients and provides some beneficial improvements in disease-free survival and toxicity levels."


Other Patient Groups

In a news conference during the meeting, the moderator, Beth A. Erickson, MD, Professor of Radiation Oncology at Medical College of Wisconsin, said the regimen could be useful in patients with advanced cervix cancer who are at high risk for dying of disease outside of the radiation field-especially those with bulky tumors and a high risk of para-aortic lymph node involvement.


Another group who could potentially benefit are frail patients and those with comorbidities, many of whom are socioeconomically deprived, she noted. "They haven't been screened for other diseases-that's why they have stage III cervix cancer, because of delayed diagnosis-and those are other compounding factors that impact survival," she added.


Erickson mentioned an ongoing clinical trial that will address this population, the Outback Trial, using cisplatin and radiation therapy with or without carboplatin and paclitaxel to treat patients with locally advanced cervical cancer. "This is giving advanced cervical cancer patients chemotherapy after chemo-radiation to try to reduce this risk of distant metastases, and therefore also improve survival," she said.

JASON C. YE, MD. JAS... - Click to enlarge in new windowJASON C. YE, MD. JASON C. YE, MD, said that future research should include longer follow-up and examination of possible reductions in toxicity due to evolving radiotherapy technologies.

Risk of Second Breast Cancers and Cardiac Mortality

The author of another study reported at the meeting noted that while breast-conservation treatment incorporating lumpectomy and radiotherapy appears to be equivalent to mastectomy in overall survival and breast-cancer specific survival, the potential adverse late effects of radiotherapy to the chest area have been a concern. New data, however, show that those risks may not be as significant as believed-i.e., there was no measurable increase in the risk of cardiac mortality, breast cancer mortality, or secondary cancer mortality in the chest area in patients with best-prognosis breast cancer treated with external-beam radiotherapy.


Jason C. Ye, MD, a third-year resident at New York Presbyterian Hospital/Weill Cornell Medical College, described the retrospective review of SEER data, which he said supports the continued use of breast-conserving therapy in patients with early-stage breast cancer.


The study identified 5,385 women who had breast-conserving surgery or mastectomy for stage T1aN0 breast malignancy in 1990 to 1997. The incidence of mortality was compared between the radiotherapy and no-radiotherapy groups to assess overall survival, breast cancer survival, second tumor-specific survival, and cardiac cause-specific survival.


The median age of the 2,397 patients who received radiotherapy after breast cancer surgery was 55, and 59 for the 2,988 patients in the no-radiotherapy group. Median follow-up was 169 and 171 months, respectively.


Ye reported a 10-year overall survival of 91.6 percent for patients in the radiotherapy group versus 87.0 percent for those in the no-radiotherapy group; 10-year breast cancer survival was 97.0 percent for radiotherapy vs. 95.7 percent for the no-radiotherapy group; 10-year cardiac cause-specific survival was 96.7 percent vs. 92.7 percent; and lung cancer mortality was 1.9 percent vs. 1.6 percent.


"To our surprise, the cardiac cause-specific survival was better in the radiation arm," he said. "Also, in the radiotherapy group, having left-sided breast cancer did not increase the incidence of cardiac mortality compared with right sided breast cancer."


There were no statistically significant incidences in mortality due to subsequent lung, esophageal, or soft tissue cancers, lymphoma, or leukemia cancers, Ye said. The cancers causing the most common second cancer mortality were lung (2%), lymphoma (0.4%), leukemia (0.4%), soft tissue including heart (0.06%), and esophageal (0.04%.


Limitations Noted

Ye said a limitation of the study is that the results cannot be applied to younger patients when making decisions about breast conservation or radiation, since fewer than five percent of the patients in the study were under age 40. Also, the cardiac outcomes may have been influenced by selection bias if physicians treating at the time based their decision to use radiation or not on the patient's health status. In addition, the study could not control for smoking and comorbidities.


Future research, he said, should include longer follow-up and examination of possible reductions in toxicity due to evolving radiotherapy technologies such as 3D conformal radiation therapy, intensity-modulated radiation therapy, and hypofractionated radiation therapy.



The abstracts for both studies can be accessed at