Clinical Investigation
Prospective Multi-Institutional Study of Definitive Radiotherapy With High-Dose-Rate Intracavitary Brachytherapy in Patients With Nonbulky (<4-cm) Stage I and II Uterine Cervical Cancer (JAROG0401/JROSG04-2)

Presented at the 12th Annual Meeting of the Japanese Group of Brachytherapy/Japanese Society for Therapeutic Radiology and Oncology (JGB/JASTRO), Tokyo, Japan, May 15-16, 2010; and at the 52nd Annual Meeting of the American Society for Radiation Oncology, San Diego, CA, Oct 31–November 4, 2010.
https://doi.org/10.1016/j.ijrobp.2011.01.022Get rights and content

Purpose

To determine the efficacy of a definitive radiotherapy protocol using high-dose-rate intracavitary brachytherapy (HDR-ICBT) with a low cumulative dose schedule in nonbulky early-stage cervical cancer patients, we conducted a prospective multi-institutional study.

Methods and Materials

Eligible patients had squamous cell carcinoma of the intact uterine cervix, Federation of Gynecologic Oncology and Obstetrics (FIGO) stages Ib1, IIa, and IIb, tumor size <40 mm in diameter (assessed by T2-weighted magnetic resonance imaging), and no pelvic/para-aortic lymphadenopathy. The treatment protocol consisted of whole-pelvis external beam radiotherapy (EBRT) of 20 Gy/10 fractions, pelvic EBRT with midline block of 30 Gy/15 fractions, and HDR-ICBT of 24 Gy/4 fractions (at point A). The cumulative biologically effective dose (BED) was 62 Gy10 (α/β = 10) at point A. The primary endpoint was the 2-year pelvic disease progression-free (PDPF) rate. All patients received a radiotherapy quality assurance review.

Results

Between September 2004 and July 2007, 60 eligible patients were enrolled. Thirty-six patients were assessed with FIGO stage Ib1; 12 patients with stage IIa; and 12 patients with stage IIb. Median tumor diameter was 28 mm (range, 6–39 mm). Median overall treatment time was 43 days. Median follow-up was 49 months (range, 7–72 months). Seven patients developed recurrences: 3 patients had pelvic recurrences (2 central, 1 nodal), and 4 patients had distant metastases. The 2-year PDPF was 96% (95% confidence interval [CI], 92%–100%). The 2-year disease-free and overall survival rates were 90% (95% CI, 82%–98%) and 95% (95% CI, 89%–100%), respectively. The 2-year late complication rates (according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer of Grade ≥1) were 18% (95% CI, 8%–28%) for large intestine/rectum, 4% (95% CI, 0%–8%) for small intestine, and 0% for bladder. No Grade ≥3 cases were observed for genitourinary/gastrointestinal late complications.

Conclusions

These results suggest that definitive radiotherapy using HDR-ICBT with a low cumulative dose schedule (BED, 62 Gy10 at point A) can provide excellent local control without severe toxicity in nonbulky (<4-cm) early-stage cervical cancer.

Introduction

Numerous retrospective studies of definitive radiotherapy (RT) have reported favorable local control with an acceptable level of toxicity for patients with early-stage cervical cancer 1, 2, 3, 4. A randomized clinical trial (RCT) performed in Italy in the 1990s revealed no significant difference in overall survival between patients treated with surgery and those treated with definitive RT (5). As a result, definitive radiotherapy has been accepted as one of the treatment options for early-stage cervical cancer (6).

Standard definitive RT for uterine cervical cancer consists of external beam RT (EBRT) to the whole pelvis and intracavitary brachytherapy (ICBT) (6). Several RCTs have demonstrated that high-dose-rate ICBT (HDR-ICBT) achieves rates of local control and late toxicity that are similar to those of low-dose-rate ICBT (LDR-ICBT) 7, 8. Therefore, HDR-ICBT will likely replace LDR-ICBT as the standard of treatment, with several advantages over the LDR-ICBT. Dosing schedules of HDR-ICBT (i.e., total dose and fractions in combination with EBRT) differ substantially among various countries, both in clinical practice 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 and in published guidelines 21, 22. Table 1 lists various schedules for definitive RT with HDR-ICBT along with pelvic control rates for stage I and II cervical cancer 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. Immediately evident is the lack of a clear dose-response relationship between biologically effective dose (BED) at point A and pelvic control, which has been previously noted (23).

We have identified two possible factors that explain the lack of a clear dose-response relationship in these retrospective studies. The first is potential bias in the doses delivered to each patient; that is, patients with a poor response to RT might have received higher total doses than good responders. Second, most of these studies did not include tumor size assessment, which was another serious limitation for comparison among the various series. Tumor size is one of the most important parameters affecting local control in radiotherapy for cervical cancer and may vary widely even within the same Federation of Gynecologic Oncology and Obstetrics (FIGO) stage (24). Therefore, a prospective study based on appropriate tumor size assessment and a fixed dose schedule would seem warranted to determine an optimum dosing schedule of HDR-ICBT.

Magnetic resonance imaging (MRI) is one of the most useful imaging modalities to evaluate tumor size objectively in cervical cancer 25, 26, 27. Toita et al. (28) retrospectively analyzed the relationship between local control and tumor diameter as assessed by MRI in a small series. In that series, in patients with American Brachytherapy Society (ABS)-defined early disease (stage I/II, <4 cm) (22), the 3-year actuarial pelvic control rate was 96%, within the dose range of 48 Gy10 to 77 Gy10 (28). Pelvic control rates by BED values were 5 out of 5 (5/5) for 48 Gy10, 7/7 for 62 Gy10 (α/β = 10), 2/2 for 68 Gy10, and 8/9 for 77 Gy10 (28). As shown in Table 1, Japanese investigators have reported favorable pelvic control rates with a total BED of 46 to 68 Gy10 despite no objective tumor size assessment. These findings suggest that a cumulative dose of 46 to 68 Gy10 may be adequate to achieve local control of nonbulky (<4-cm) early-stage cervical cancer.

Based on the above background data, the Japanese Radiation Oncology Study Group (JROSG; http://www.jrosg.jp) conducted a prospective multi-institutional study to assess the efficacy and toxicity of a definitive RT schedule with low cumulative doses in patients with nonbulky stage I and II uterine cervical cancer. We report herein the endpoint results of that prospective study.

Section snippets

Patient eligibility criteria

Eligible patients had histologically proven squamous cell carcinoma of the intact uterine cervix and FIGO stage Ib1, IIa, or IIb disease. Study patients were between 20 and 85 years of age. A complete physical examination, a pelvic examination performed without anesthesia, and a chest X-ray were required to determine the clinical stage. Patients also were required to have cervical tumors less than 40 mm in diameter, assessed by T2-weighted MRI, and negative pelvic and para-aortic lymph nodes

Patient characteristics

Between September 2004 and July 2007, 60 patients were enrolled from 13 institutions. No patient was assessed as ineligible. Therefore, 60 patients formed the patient cohort for the analysis. Pretreatment characteristics for the eligible patients are listed in Table 2.

Acute toxicity and compliance

Forty-four patients (72%) were treated on an inpatient basis. The acute toxicity profiles during and after the protocol treatment period (within 90 days) are shown in Table 3. Only one patient experienced toxicity necessitating

Discussion

To our knowledge, this is the first multi-institutional prospective study to evaluate the efficacy and toxicity of a defined radiotherapy schedule with HDR-ICBT for uterine cervical cancer. Our prospective study demonstrated good 2-year and 3-year PDPF rates of 96% (95% CI, 92%–100%) and an acceptable level of toxicity in 60 patients with nonbulky (<4-cm, assessed by MRI) stage I and II cervical cancer. These results suggest the clinical validity of previously reported results of other Japanese

Conclusions

In conclusion, the results of our study suggest that definitive radiotherapy consisting of whole-pelvis EBRT of 20 Gy/10 fractions, pelvic EBRT with an MB of 30 Gy/15 fractions, and HDR-ICBT of 24 Gy/4 fractions at point A (BED 62 Gy10) is an effective and safe treatment for stage I and II cervical cancer patients with small (<4-cm) tumor diameter. Recently, the value of dose-volume histogram parameters for predicting local control in MR image-guided BT has been investigated for treating

Acknowledgments

The authors thank Ms. Asazawa for constant assistance.

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    This study was supported by grants from Ministry of Health, Labor and Welfare (Grant-in-Aid for Cancer Research nos. 16-12 and 20-5), Ministry of Health, and the Japan Society for the Promotion of Sciences (No. 16591214, 18591387, and 21591614).

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