Cisplatin Added to RT Ups Survival in Advanced Cervical Cancer

NEW ORLEANS—In the treatment of locoregionally advanced cervical cancer, the addition of cisplatin (Platinol)-containing chemotherapy to a radiation therapy regimen significantly improves overall and disease-free survival, according to RTOG 90-01. Patricia J. Eifel, MD, of the Department of Radiation Oncology, M.D. Anderson Cancer Center, presented the data at the American Society for Therapeutic Radiology and Oncology plenary session (abstract plenary 1).

Preliminary findings from this study in 1999 "stimulated widespread evolution in the standard treatment of patients with high-risk cervical cancer," Dr. Eifel said. The updated analysis also included information about late complications.

The study was a randomized trial comparing extended-field radiotherapy with chemoradiation in 403 women enrolled between 1990 and 1997. Patients had stage IIB-IVA cervical cancer, stage IB2-IIA disease with a tumor diameter 5 cm or larger, or positive pelvic lymph nodes. Para-aortic lymph nodes were evaluated with either lymphangiogram or lymphadenectomy.

Patients were stratified by stage (IB-IIB and III-IVA) and by method of lymph node evaluation, Dr. Eifel said. Overall, 25% had positive pelvic lymph nodes and 30% had stage III-IVA disease. For patients with stage IB-IIB disease, median tumor diameter was 6 cm. In spite of disease stage, all patients were considered to have quite bulky and locally advanced disease.

One group (n = 195 evaluable) was randomized to receive extended-field radiation therapy, with 45 Gy to the pelvis and para-aortic nodes followed by low-dose-rate intracavitary radiation (brachy-therapy). The other group (n = 195 evaluable) received chemoradiation, with 45 Gy pelvic radiation therapy, intracavitary radiation therapy, and three cycles of concomitant chemotherapy with cisplatin 75 mg/m² and fluorouracil (5-FU) 4 g/m² by continuous infusion over 96 hours.

More than two thirds of patients (68%) completed three cycles of chemotherapy, and 81% received at least two cycles. The median dose of radiation was 86 to 87 Gy, and median duration of treatment was 58 days. Median follow-up was 4.6 years altogether, and 6.6 years for surviving patients.

Study Results

The overall survival rate was 52% for patients in the radiation arm and 73% for the chemoradiation group (P < .0001). Disease-free survival rates were 43% and 67%, respectively (P < .0001), and pelvic recurrence rates were 34% and 18%, respectively (P < .0001).

Recurrence in the para-aortic lymph nodes was not significantly different between the groups (4% for radiation therapy and 7% for chemoradiation). However, other distant metastases were significantly more frequent for patients treated with radiation alone: 31% vs 18%; P = .0001).

"The highly statistically significant and impressive improvement in survival with chemoradiation has been maintained over time, with a survival rate of 73% for these patients with a highly significant P value, and a reduction in the risk of death by approximately 50%," Dr. Eifel said. "The results suggest that women with high-risk cervical cancer should receive chemotherapy in conjunction with radiation therapy. The addition of chemotherapy improves survival rates without significantly increasing late treatment-related side effects."

Improvements in Subgroups

Although the study was not powered to detect a treatment difference within the stratified subgroups, of the 272 patients with stage IB-IIB disease, those treated with chemoradiation had a significantly better overall survival at 5 years than those treated with radiation therapy alone: 79% vs 55% (P < .0001). Freedom from cause-specific failure was 82% with chemoradiation, "despite the high-risk nature of this population," with a 50% reduction in the risk of recurrence, she added.

Similarly, of the 117 patients with stage III-IVA disease, there was a trend toward better overall survival for those treated with chemoradiation. "In the initial publication, much was made about the absence of a statistically significant difference in this group. Again, this small group was underpowered for comparison, but there was a trend for improved survival and a significant difference (P = .05) in freedom from cause-specific failure (62%). This is a very good result for this group of patients," Dr. Eifel said.

Patients with stage III and IV disease receiving chemoradiation had about the same survival rate as patients with stage I and II disease who had extended-field irradiation, she noted.

Toxicity

The 5-year rates of late grade 3 or higher treatment-related toxicity were comparable for patients in each treatment arm: 12% and 13% for radiation and chemoradiation, respectively. Most of the notable complications were gastrointestinal or genitourinary, and the rate for these was 11% in each arm, she said. Most complications occurred by 2 years post-treatment.

Dr. Eifel noted that at publication of the preliminary results from RTOG 90-01, several similar trials also showed significant improvements with cisplatin-containing chemoradiation. More recently, she said, a small study from the National Cancer Institute of Canada failed to show a significant advantage for cisplatin chemotherapy.

Discussion

Discussant Kathryn Greven, MD, professor of radiation oncology, Wake Forest University School of Medicine, called RTOG 90-01 a "benchmark trial" in patients typically considered inoperable. "All groups of patients demonstrated improvement in outcome and improvement in cause-specific survival with the addition of chemotherapy to radiation," she said. Compared with other studies that have evaluated che-moradiation in this patient population, Dr. Greven said, "the strength of this trial is that the control arm was radiation therapy alone, lymph node evaluation was fairly rigid, and chemotherapy included cisplatin and fluorouracil."

In addition, she noted, two thirds of patients received a third cycle of chemotherapy during brachytherapy, and higher doses of radiation and overall short treatment time optimized radiation therapy.

"Because this is the only trial to demonstrate a decrease in local recurrence as well as distant recurrence, I believe that treatment with cisplatin and 5-FU should be considered potentially more effective than weekly cisplatin alone," Dr. Greven said. "But in spite of the fact that this is definitely a home run for the treatment of cervical cancer, there is still room for improvement. At least one third of women will still recur with distant disease, and as many as 40% of women with stage III disease will recur."