Clinical investigation: cervix
Long-term follow-up of RTOG 92-10: cervical cancer with positive para-aortic lymph nodes

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Abstract

Purpose: The purpose of this study was to evaluate the late toxicity and efficacy of twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes.

Patients and Methods: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and lumbar para-aortic lymph nodes (simultaneously) at 4–6-h intervals, 5 days per week. The total external radiation doses were 24–48 Gy to the whole pelvis, 12–36 Gy parametrial boost, and 48 Gy to the lumbar para-aortic region with an additional boost to a total dose 54–58 Gy to the positive para-aortic lymph node(s). One or two intracavitary implants were performed to deliver a minimum total dose of 85 Gy to point A. Cisplatin (75 mg/m2; Days 1, 22, and 43) and 5-fluorouracil (1,000 mg/m2/24 h × 4 consecutive days, beginning on Days 1, 22, and 43) were given for two or three cycles.

Results: Thirty patients with clinical Stages I–IV carcinoma of the cervix with biopsy-proven para-aortic lymph node metastases were enrolled in this study. Hyperfractionated external irradiation was completed in 87% (26 of 30). Brachytherapy was given in two implants to 47% (14 of 30) and in one implant to 33% (10 of 30); 13% (4 of 30) did not receive brachytherapy, 1 patient had three implants, and 1 had five high-dose-rate implants. Radiotherapy was completed per protocol in 70%. Three cycles of chemotherapy were given to 23% (7 of 30); 73% (22 of 30) received two cycles, and 1 patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Acute toxicity from radiotherapy was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. Late toxicity was Grade 1 in 10%, Grade 2 in 17%, Grade 3 in 7%, and Grade 4 in 17%. Grade 5 toxicity occurred in 1 patient during the course of therapy, but none had a late Grade 5 toxicity. The median follow-up time for the 7 patients alive at the time of last follow-up was 57 months. The overall survival estimates were 46% at 2 years and 29% at 4 years. The probability of local-regional failure was 40% at 1 year and 50% at 2 and 3 years. The probability of disease failure at any site was 46% at 1 year, 60% at 2 years, and 63% at 3 years.

Conclusion: The results suggest that twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (17%, 5 of 29) of Grade 4 late toxicity. One patient died of acute complications of therapy. The survival estimates seem no better than standard fractionation irradiation without chemotherapy.

Introduction

The survival outcome of patients with carcinoma of the cervix and positive para-aortic lymph nodes is poor. Retrospective studies of these patients have demonstrated a 5-year survival of about 30% (1). Treatment failures occur in the pelvis, the para-aortic region, and at distant metastatic sites. These failures occur because most patients present with advanced pelvic disease, bulky para-aortic disease, and unrecognized sites of distant metastatic disease at the time of diagnosis.

The rationale for the treatment method chosen for this study was threefold. Hyperfractionated radiotherapy was used to increase the radiation dose to the pelvis and para-aortic regions. Chemotherapy was used to increase the sensitivity of tumor cells in the pelvis and para-aortic regions to irradiation and to act as a cytotoxic agent for micrometastatic disease outside the irradiation portals (2).

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Patient characteristics

Conditions for eligibility for entry onto the study were squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix with biopsy-proven positive para-aortic lymph nodes. The stage of the patient’s disease could be clinical Stages I, II, III, or IVa, with no evidence of disease outside the pelvis, except to the lumbar para-aortic lymph nodes. Patients were required to be older than 17 years of age, have a Karnofsky performance status ≥60, and have no medical

Results

A total of 30 patients were entered onto the study from August 1992 to February 1995. All 30 patients were eligible and evaluable. The analysis was performed on all data received at RTOG headquarters as of February 2000. Twenty-three patients were dead, and 7 patients were alive. The median follow-up of the 7 patients alive at the time of last follow-up was 57 months.

The pretreatment characteristics of the patients are shown in Table 1. Patient age ranged from 29 to 72 years, with a median of

Discussion

The objectives of this treatment protocol were threefold. The feasibility and tolerance of hyperfractionated external irradiation to the pelvis and para-aortic region and intracavitary brachytherapy and concurrent chemotherapy were determined. The acute and late toxicity of this treatment regime was determined. The possibility of improving pelvic tumor control and distant metastasis was evaluated.

The initial results of this treatment protocol have been reported (2). These results have been

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