The definitive treatment of choice for locally advanced or inoperable cervical cancer is external beam radiotherapy (ERT), concomitant chemotherapy, and brachytherapy (BRT).1,2 Brachytherapy, an essential component in the treatment of cervical carcinoma, has stimulated enthusiasm for high-dose–rate (HDR) delivery in recent years, offering outpatient treatment, easy radiation protection, low cost, and improved tumor dose distribution. In intracavitary (IC) BRT of cervical cancer, an applicator (a uterine tandem and vaginal ovoid or a ring-tandem applicator) is placed in the uterine cavity and vaginal fornices under sedation or anesthesia.
Intraoperative complications of IC BRT include vaginal lacerations and penetration of the tandem into the uterine wall causing perforation of the uterus and of other pelvic organs with the applicator. The incidence of uterine perforation during BRT application ranges from 1.75% to 13.7%,3–5 and the most common sites of perforation are the uterine fundus and posterior wall of the fundus.3,5,6 The predisposing factors for uterine perforation are advanced age (more than 60 years), anatomic distortions of the cervix, advanced diseases causing cervical stenosis, postirradiation fibrosis, and previous cone biopsy.3,7 Other predisposing factors include extremely an anteverted or a retroverted uterus.4,6
Although most cases of uterine perforation resolve spontaneously without sequelae after conservative treatment, infection, hemorrhage, or peritoneal tumor seeding may occur.5 Another important potential consequence of uterine perforation is the uncertainty in the prescribed dose distribution around the incorrectly inserted applicator, which may cause underdosage of the target volume, compromising the local control probability.8 Therefore, accurate positioning of the applicator is critical for delivering appropriate doses of irradiation to the target volume while keeping the doses to the surrounding organs at risk below their tolerance limits. To achieve appropriate application, intraoperative ultrasound (IUS) facilitates ideal tandem placement and decreases the risk of uterine perforation, thereby diminishing an underappreciated source of toxicity while optimizing disease control.9–11 However, a recent survey of BRT specialists indicates that only 56% have used IUS at some point, and those physicians using IUS rarely use it for every insertion (median, 42% of insertions).12
The main objective of the present study was to determine the incidence and characteristics of uterine perforation at our department in the era of 3-dimensional (3D) computed tomography (CT)–based BRT. We evaluated the characteristics of the patients presenting with perforation and reviewed their management and the impact of the perforation on the treatment course.
MATERIALS AND METHODS
The clinical and radiologic data of 238 patients with biopsy-proven cervical cancer were retrospectively evaluated. All patients had undergone tandem-based IC BRT as a component of definitive treatment between February 2008 and June 2013. Thirty-eight patients were excluded because of 2-dimensional–based IC. The characteristics of the 200 patients who had undergone 3D-based BRT are summarized in Table 1.
Patients without distant metastasis were treated with a combination of 3D conformal ERT with concurrent weekly dose of 40 mg/m2 cisplatin and HDR BRT, as previously described.13 A total of 50.4 Gy ERT (1.8 Gy per fraction, daily, Monday through Friday) was delivered using 18-megavolts photons. External beam radiotherapy was planned with a 4-field box technique using a treatment planning system (Eclipse; Varian Medical Systems, Palo Alto, CA). Three-dimensional BRT planning was performed using 7 Gy per fraction prescribed to the target minimum that was administered in 4 fractions. Brachytherapy was performed using a remote afterloading HDR unit with a radioactive iridium-192 source (VariSource; Varian Medical Systems). The IC BRT procedure was initiated at the end of ERT.
From 2007 to mid-2008, conventional treatment planning was performed via fluoroscopy using orthogonal images. Since mid-2008, routine CT imaging has been performed with all HDR BRT procedures for treatment planning purposes. In addition, after 2009, magnetic resonance imaging (MRI) was administered after completion of ERT and before BRT application to assess treatment response and facilitate the BRT application.
Computed tomography–compatible Fletcher-Suit applicators or ring-tandem applicators were used during IC BRT and consisted of uterine tandems with various angles (15, 30, and 45 degrees) and various lengths (2, 4, and 6 cm). In addition, a pair of ovoids with various diameters (20, 25, and 30 mm) in Fletcher-Suit applicators or a ring-tandem applicator was used. A thorough gynecologic examination was carried out by an experienced radiation oncologist (C.O.) before each insertion. The application technique and applicators were individually adapted to each patient at each insertion based on the clinical and radiologic findings. Inpatients who had undergone an MRI before BRT, the application and treatment planning were performed according to the treatment response.
The insertion was carried out with sedation and analgesia and was placed in the lithotomy position. Patients were not given specific instructions for rectal preparation, but they were encouraged to empty their bowels before a simulation procedure and before the subsequent IC BRT procedure. Appropriate anterior and posterior vaginal packing was used to fix the applicator position and to displace the bladder and rectum away from the vaginal applicators. After the IC application, the applicator was fixed with a universal applicator clamping device (Varian), which was positioned underneath the patient.
After the insertion, the patients were transported to the CT scanner. The paradigm of our BRT dose prescription and treatment planning practice is represented by the image-guided adaptive BRT of cervix cancer described elsewhere.13,14
Toxicity was graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer common toxicity criteria. Late toxicity was recorded retrospectively by a thorough review of the patient’s hospital charts.
The patient characteristics of 200 patients who underwent image-guided IC BRT are summarized in Table 1. Of the 200 patients, 17 (8.5%) had uterine perforation. A total of 626 applications had CT images for BRT planning after tandem placement. Of the 626 applications with CT images, 30 (4.8%) resulted in uterine perforation.
The median age of the entire group was 60 years (range, 21–89 years). The median age of patients with perforation was higher (68 years; range, 44–89 years) than those patients without perforation (59 years; range, 21–87 years). The mean (SD) tumor size at diagnosis was larger in patients with perforation (7.0 [1.5] cm) than in patients without perforation (5.0 [1.5] cm; Fig. 1).
The most frequent perforation site was the posterior uterine wall (8 patients), followed by the fundus (5 patients) and anterior wall (4 patients). In all these patients, anatomic distortion resulted in uncertain tandem positioning during the procedure with resultant suspected perforation. Eight patients were perforated only once, 8 patients were perforated twice, and 2 patients were perforated 3 times. Of the 7 patients with a retroverted uterus, 4 (57%) had uterine perforation during IC, whereas only 10 (5%) of the 193 patients with an anteverted uterus had uterine perforation.
In 67 patients with MRI delivered before BRT, only 3 (4%) had uterine perforation; 2 of these 3 patients with uterine perforation had a retroverted uterus (Fig. 2). However, of the 133 patients with no MRI evaluation before BRT, 14 (11%) had uterine perforation.
All perforations were detected by CT after applicator placement. After each perforation, the applicator was removed, and prophylactic antibiotics were administered in patients at high risk or with necrotic lesions. No significant clinical sequelae resulted. In all patients, the second attempt to place the IC BRT device was successfully confirmed on CT after applicator placement, and no additional perforations were noted (Fig. 3). No operative consultations with other services were required secondary to difficulty with device placement. In 2 patients with a retroverted uterus, uterine perforation occurred 3 times, and the application was corrected thereafter. These 2 patients had stage IIIB disease and residual disease completely obstructing the cervical os.
According to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late toxicity criteria, 2 patients with uterine perforation developed grade 2 chronic rectal toxicity, including diarrhea, tenesmus, nausea, and vomiting, whereas only 1 patient developed grade 2 chronic bladder and urethra toxicity (dysuria, polyuria, and incontinence). All of these patients responded to conservative management. Four patients developed grade 3 bladder toxicity with severe hematuria and frequency, and 2 patients developed grade 3 and 4 gastrointestinal system toxicity (1 patient with bowel obstruction and 1 patient with fistula formation). Among patients who developed fistula formation, only 1 patient had retroverted uterus. The incidence of vaginal lacerations was not systematically recorded. At the time of the last follow-up, there were no signs of intraperitoneal tumor cell seeding in any of the patients in whom uterine perforation occurred.
In the current study, we reviewed the data concerning BRT applications for cervical cancer and analyzed uterine perforation during IC tandem applications. We found uterine perforation occurred more frequently in patients with advanced age, larger tumors, a distorted or stenotic cervical os, and a retroverted uterus; results that were similar to literature findings. In addition, MRI delivered before BRT for assessingthe ERT response, resulted in a lower rate of uterine perforation.
A modern approach in treatment planning for cervical carcinoma is based on CT sections and 3D dose distribution. Advantages of 3D imaging in gynecologic BRT that may lead to improved patient outcome, irrespective of the dose rate, include avoidance or early detection of a uterine perforation, ensuring target coverage, and avoidance of an excessive dose to the surrounding organs. Thus, better assessment of dose distributions in the target volumes and surrounding normal tissues is achieved. In 2004, guidelines were published for proposing image-based BRT for cervical cancer, and CT-guided BRT planning is frequently used.15
Large retrospective series without either routine IUS or CT indicate that the incidence of perforation ranges from 1% to 3%.3,8,16,17 However, in the absence of routine postoperative CT imaging, these series likely underestimated the incidence of perforation. Importantly, the 2 series reported that the incidence of unrecognized perforations ranged from 10% to 13.7% of procedures as assessed by routine postoperative CT in the absence of IUS.4,10 Davidson et al10 reported a 10% incidence of uterine perforation in 21 women with 35 insertions. Barnes et al4 detected uterine perforation in 13.7% of the cases with 124 sequential tandem insertions in 114 patients. Our perforation rates were less than those in previously reported series. The reason for the lower rates of uterine perforation in our series is that we treated the patient using 4 fractions of BRT, making the applications after the first insertion easier. Second, nearly one third of our patients had preoperative MRI.
There is evidence in the literature to indicate that the use of IUS decreases the uterine perforation rate.5,7,11 Granai etal7 reported about routine IUS for 72 patients and noted noclinically evident perforations. Schaner et al11 reported a1.4% incidence of uterine perforation in 356 IUS-guided applicator placements. Segedin et al5 found uterine perforations in 13 (3.0%) of the 428 applications in 10 (4.6%) of the 219 patients. All these studies demonstrated the feasibility of IUS-guided BRT, and the authors suggested that the use of IUS diminishes the risk of perforation 5- to 10-fold. However, the use of ultrasonography (USG) requires some experience, and not all departments have the capability to perform USG-guided BRT, particularly in departments with a high patient overload. In our clinic, after 2009, we began to use MRI for evaluating ERT response, which is a significant prognostic factor, and for delineating the residual tumors to achieve better dose coverage. In addition, MRI clearly demonstrated uterine position, whether retroverted or highly anteverted. In a retroverted uterus, we tried to insert the applicator according to the position of the uterus. Unfortunately, in 2 patients with a retroverted uterus, although they had preoperative MRI, uterine perforation was observed in 3 applications. Thus, more intense care should be given in such cases. In patients with a highly anteverted uterus, we preferred to inflate the bladder with saline for better positioning of the uterus. Besides these 2 patients with a retroverted uterus, only 1 (1.5%) patient with preoperative MRI had uterine perforation; a finding that is similar to IUS-guided BRT application series. However, in patients with uterine perforation, there were not more adverse effects because these patients were treated with corrected tandem insertion resulting in appropriate dose distribution.
In the treatment of cervical cancer, the importance of optimal applicator placement in local control and toxicity is well established.18,19 However, perforation remains a frequent complication, even in cases that appear straightforward. Classic standards for assessing the adequacy of applicator placement are insufficiently sensitive to consistently detect perforation. New modalities, including laparoscopy, USG, and CT, are effective in detecting uterine perforation; however, only intraoperative USG provides cost-effective, real-time guidance and confirmation of tandem placement. However, the limitation of USG is its low-resolution capacity in detecting solid tumors compared with MRI and CT. In addition, USG has been widely used in complicated cases, but the role of routine USG is less well established.
The present study possesses limitations. The retrospective nature of our study is the largest limitation. Second, particularly in cases with difficult application, such as a retroverted uterus, IUS could be much more feasible, and appropriate tandem insertion could be performed without causing uterine perforation.20 Finally, we only reported our experience with cervical BRT; however, the clinical outcomes of uterine perforation regarding disease control and survival should also be performed in a large prospective series.
In the present study, we demonstrated that uterine perforation is a complication that could be detected during uterine tandem insertion. Older age, larger tumors, a retroverted uterus, and a stenotic cervical os were all predisposing factors for uterine perforation during BRT. Our study is also important in demonstrating that preoperative MRI, which evaluates the treatment response of ERT and demonstrates the uterus position, decreases the risk of uterine perforation during tandem insertion. Preoperative MRI is a feasible and safe method and could be used preoperatively at centers where IUS is not used in routine practice.
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