Clinical Investigation
Insufficiency Fractures After Pelvic Radiation Therapy for Uterine Cervical Cancer: An Analysis of Subjects in a Prospective Multi-institutional Trial, and Cooperative Study of the Japan Radiation Oncology Group (JAROG) and Japanese Radiation Oncology Study Group (JROSG)

Presented in part at the 52nd Annual Meeting of the American Society for Radiation Oncology (ASTRO) in San Diego, CA, October 31-November, 2010.
https://doi.org/10.1016/j.ijrobp.2012.03.042Get rights and content

Purpose

To investigate pelvic insufficiency fractures (IF) after definitive pelvic radiation therapy for early-stage uterine cervical cancer, by analyzing subjects of a prospective, multi-institutional study.

Materials and Methods

Between September 2004 and July 2007, 59 eligible patients were analyzed. The median age was 73 years (range, 37-84 years). The International Federation of Gynecologic Oncology and Obstetrics stages were Ib1 in 35, IIa in 12, and IIb in 12 patients. Patients were treated with the constant method, which consisted of whole-pelvic external-beam radiation therapy of 50 Gy/25 fractions and high-dose-rate intracavitary brachytherapy of 24 Gy/4 fractions without chemotherapy. After radiation therapy the patients were evaluated by both pelvic CT and pelvic MRI at 3, 6, 12, 18, and 24 months. Diagnosis of IF was made when the patients had both CT and MRI findings, neither recurrent tumor lesions nor traumatic histories. The CT findings of IF were defined as fracture lines or sclerotic linear changes in the bones, and MRI findings of IF were defined as signal intensity changes in the bones, both on T1- and T2-weighted images.

Results

The median follow-up was 24 months. The 2-year pelvic IF cumulative occurrence rate was 36.9% (21 patients). Using Common Terminology Criteria for Adverse Events version 3.0, grade 1, 2, and 3 IF were seen in 12 (21%), 6 (10%), and 3 patients (5%), respectively. Sixteen patients had multiple fractures, so IF were identified at 44 sites. The pelvic IF were frequently seen at the sacroileal joints (32 sites, 72%). Nine patients complained of pain. All patients' pains were palliated by rest or non-narcotic analgesic drugs. Higher age (>70 years) and low body weight (<50 kg) were thought to be risk factors for pelvic IF (P=.007 and P=.013, Cox hazard test).

Conclusions

Cervical cancer patients with higher age and low body weight may be at some risk for the development of pelvic IF after pelvic radiation therapy.

Introduction

Insufficiency fractures (IF) are a type of stress fracture, occurring after normal or physiologic stress on bone with decreased mineralization and elastic resistance (1). Insufficiency fractures of the pelvic bones are thought to be associated with postmenopausal or corticosteroid-induced osteoporosis 1, 2. Pelvic radiation therapy (RT) also can affect the development of pelvic IF, although the precise pathogenesis is as yet unclear 1, 2. Although some investigators 3, 4, 5 have reported that pelvic IF are an uncommon adverse event in irradiated patients with gynecologic cancer, others 6, 7, 8, 9, 10 have reported that radiation-induced pelvic IF were frequently observed in women after RT. It seems that the precise incidence of IF is unclear. The findings on conventional radiographs are usually subtle 2, 10 and may be misleading. The fractures usually show increased uptake on radionuclide bone scans. A pattern of increased uptake in the body of the sacrum and in one or both sacrum alae 1, 2, 11 is indicative of a fracture, but increased uptake may also be present in metastases and sacroiliac joint osteoarthritis (12). The importance of understanding a pelvic IF lies in the potential for its misdiagnosis as bony metastases. Computed tomography (CT) is capable of displaying fracture lines and/or sclerotic changes associated with IF 8, 9, 11, whereas magnetic resonance imaging (MRI) is highly sensitive for revealing the reactive bone marrow changes associated with IF 9, 13.

Not only for unresectable locally advanced stages, RT has played an important role in the treatment of early-stage cervical cancer. Originally, to determine the efficacy of definitive RT 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 (JAROG0401/JROSG04-2) (14). Two-year pelvic disease progression-free rate was the primary endpoint, and late complication including IF was one of the secondary endpoints in the study (14). At first, IF was evaluated by only symptomatic features. However, we noticed that some follow-up imaging features after RT had shown IF of pelvic bones in several asymptomatic patients. Therefore, we planned this additional study to assess pelvic IF by adding a minute imaging evaluation prospectively, without changing the schedule and methods of the follow-up CT and MRI in the protocol.

The purpose of this study was to investigate the incidence of radiation-induced pelvic IF using CT and MRI and to investigate the risk factors and radiation doses associated with IF, as well as the distribution of IF sites among patients with this complication. In our study, patients were treated with the constant RT method described in the protocol and followed with CT and MRI regularly. To our knowledge, this is the first multi-institutional prospective analysis on IF.

Section snippets

Patient eligibility criteria

The women enrolled in these analyses were a group of patients with cervical carcinoma who were treated with a protocol JAROG0401/JROSG04-2) (14). Eligible patients had histologically proven squamous cell carcinoma of the intact uterine cervix with International Federation of Gynecologic Oncology and Obstetrics (FIGO) stage Ib1/IIa/IIb disease and were aged 20-80 years. A complete physical examination, pelvic examination performed without anesthesia, and chest X-ray were required to determine

Patients

Between September 2004 and July 2007, 60 patients were enrolled from 13 institutions. One patient was considered ineligible, leaving 59 patients in the final patient cohort.

The median age was 73 years (range, 37-84 years). The eligible patients had squamous cell carcinoma of the uterine cervix, and the FIGO stages were Ib1 in 35, IIa in 12, and IIb in 12 patients. No patients had pelvic/paraortic lymphadenopathy. The median follow-up was 24 months.

Incidents and clinical characteristics of IF

A total of 21 patients were diagnosed with IF

Discussion

Insufficiency fractures occur most often in elderly women with postmenopausal osteoporosis (2). Other predisposing factors include rheumatoid arthritis, corticosteroid therapy, heparin use, diabetes mellitus, low body weight, current smoking, and RT (15). Fu et al (16) reported that the incidence of IF increased when the dose was above the threshold of 45 Gy. However, there have been no tolerance dose data for IF. In conventional pelvic RT, the irradiated dose of the pelvic bone is usually

Acknowledgment

The authors thank Ms. Y Asazawa and Ms. K Ayabe for their helpful assistance.

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This study was supported by Ministry of Health, Labor and Welfare (Japan) Grant-in-Aid for Cancer Research No. 16-12.

Conflict of interest: none.

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