Brachytherapy 13 (2014) 542e547
Image-based three-dimensional conformal brachytherapy for medically inoperable endometrial carcinoma Beant S. Gill1, Hayeon Kim1, Chris Houser1, Adam Olsen1, Joseph Kelley2, Robert P. Edwards2, John Comerci2, Paniti Sukumvanich2, Alexander B. Olawaiye2, Marilyn Huang2, Madeleine Courtney-Brooks2, Sushil Beriwal1,* 2
1 Department of Radiation Oncology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA Department of Gynecologic Oncology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA
ABSTRACT
PURPOSE: Definitive radiotherapy is a viable option for medically inoperable patients with early stage endometrial cancer. We present our experience using image-based brachytherapy (BT). METHODS AND MATERIALS: Patients with medically inoperable clinical Stage I endometrial adenocarcinoma received definitive BT with or without external beam radiotherapy. High-dose-rate BT was delivered using MRI- or CT-based planning for each fraction. For patients with an MRI, gross tumor volume (GTV) was contoured although dose was still prescribed to the clinical treatment volume (CTV), including the entire uterus, cervix, and upper 1e2 cm of vagina. Equivalent 2 Gy doses (EQD2) were calculated. RESULTS: Thirty-eight patients were treated from 2007 to 2013, 20 receiving BT alone with a median dose of 37.5 Gy in five to six fractions. For combined therapy, median external beam and BT doses were 45 and 25 Gy in four to five fractions. With 15-month median followup, the 2-year actuarial local control and overall survival were 90.6% and 94.4%. No Grade 2e5 late toxicities were observed. Mean CTV D90 EQD2 for BT alone and combined therapy was 48.6 5.6 and 72.4 6.0 Gy, whereas mean GTV D90 EQD2 was 172.3 59.6 and 138.0 64.6 Gy. CONCLUSIONS: Image-based BT is feasible for medically inoperable early stage endometrial cancer with excellent early results. Despite low CTV doses, high doses delivered to GTV with BT likely accounts for high local control. Endometrial cancer guidelines for image-based planning are needed to define target volumes based on risk with differential dose delivery. Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Endometrial cancer; Brachytherapy; Inoperable; Radiotherapy; MRI
Introduction Endometrial cancer is the most common gynecologic malignancy in the United States with approximately 49,560 new cases in 2013 (1). For patients with localized disease, the standard treatment entails upfront surgery with total hysterectomy, bilateral salpingo-oophorectomy with or without pelvic and para-aortic lymph node dissection
Received 24 April 2014; received in revised form 27 June 2014; accepted 8 July 2014. Results presented at the American Brachytherapy Society Annual Meeting, April 4, 2014, in San Diego, CA, USA. * Corresponding author. Department of Radiation Oncology, MageeWomens Hospital, 300 Halket Street, Pittsburgh, PA 15213. Tel.: þ412641-4600; fax: +412-641-1085. E-mail address: [email protected] (S. Beriwal).
(2). Based on risk factors established from surgery, adjuvant therapy may include external beam radiotherapy (EBRT) and/or intracavitary brachytherapy (BT) to reduce the risk of locoregional failure (3e5). The increasing incidence of endometrial cancer in the United States is likely because of improved surveillance and a growing aging population. Endometrial cancer frequently presents in older patients such that 3.4e9% of patients have comorbidities that preclude surgical intervention (6, 7). Definitive radiation therapy with BT alone or combined with EBRT has emerged as an acceptable alternative for this select population (8e10). Given the increased application of three-dimensional (3D) planning for EBRT, a similar technique is being increasingly applied to BT in the form of image-guided brachytherapy (IGBT) (11). For example, in the treatment of cervical cancer, IGBT has been shown to improve local
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B.S. Gill et al. / Brachytherapy 13 (2014) 542e547
control and decrease toxicities because of more accurate delineation of the target volume and dose optimization, which helps reduce dose to adjacent rectum, sigmoid, and bladder (12e14). At present, the Groupe Europeen de Curietherapie and European Society for Therapeutic Radiation and Oncology (GEC-ESTRO) guidelines have been published to bring uniformity to target delineation and doseevolume parameters (15, 16). On the contrary, such guidelines do not yet exist for the treatment of endometrial cancer. MRI has been shown to be superior in assessing tumor volume for endometrial cancer, including depth of myometrial invasion, as compared with CT and ultrasound (17). At our institution, patients with medically inoperable endometrial cancer who are treated with BT now undergo MRI as a part of treatment planning to accurately define the disease extent, similar to the approach used in cervical cancer. In this report, we aim to establish this approach by presenting dosimetric findings and early clinical outcomes for patients treated with IGBT with either CT- or MRI-based planning. Methods and materials Between February 2007 and September 2013, patients treated at our institution for histologically proven clinical Stage I adenocarcinoma of the endometrium were retrospectively identified. All patients were deemed medically inoperable and therefore treated with radiotherapy with definitive intent. Patients were staged using clinical examination and imaging modalities including a pelvic MRI scan. BT alone was used for patients with Grade 1e2, low-volume disease, defined as less than 50% myometrial invasion and tumor size #2 cm on MRI. Alternatively, for patients with Grade 3 and/or high-volume disease, EBRT was first used and followed by intracavitary BT. EBRT was delivered with either 3D conformal or intensity-modulated radiotherapy technique. The clinical treatment volume (CTV) included the entire uterus, cervix, upper half of the vagina, and pelvic lymph nodes, including
543
the lower common iliac, external iliac, and internal iliac nodes. High-dose-rate (HDR) BT was used once or twice weekly starting in the last week of EBRT or as monotherapy. An MR-compatible Smit Sleeve (Nucletron, an Elekta company; Elekta AB, Stockholm, Sweden) was placed in the operating room before initiation of BT. It is our institutional standard for patients with a maximum uterine width of 5 cm or less based on CT or MRI to be treated with a single tandem and cylinder applicator. Tandem length was based on uterine length, which was established by a uterine sound. Cylinder diameter varied from 2.5 to 3.5 cm based on vaginal vault width, selecting the largest fitting diameter that was determined by pretreatment clinical examination. Patients with a maximum uterine width greater than 5 cm are generally treated with a Rotte ‘‘Y’’ applicator (Elekta) (10). If patients are unable to lay flat for a prolonged period as required for the ‘‘Y’’ applicator or decline this option, then they were treated with a single tandem and cylinder applicator despite uterine width limitations. Patients treated with a Rotte ‘‘Y’’ applicator are excluded from this analysis because these are not MRI-compatible applicators. CT and/or MRI were completed after each applicator placement with dose optimization and planning based on uterine size, configuration, and disease location. For patients who underwent MRI-based planning, the gross tumor volume (GTV) was contoured. The CTV for BT included the GTV, entire uterus, cervix, and upper 1e2 cm of the vagina (Fig. 1). Although the GTV was identified, the prescription dose was still delivered to the CTV. Key organs at risk (OARs) including the rectum, bladder, sigmoid, and small bowel were also contoured. Treatment plans were generated on the PLATO Brachytherapy Planning System, version 14.3 (Nucletron) or the Oncentra Brachy Planning System, version 4.3 (Elekta). Plans were manually optimized with each application, where initially standard weighting was placed at each source position and then manually adjusted to adequately cover the CTV and avoid critical structures.
Fig. 1. MRI-guided brachytherapy plan. The gross tumor volume (dark blue) and clinical treatment volume (bright red) are contoured with overlying isodose lines (yellow 150%, red 100%, and green 80%). A sagittal reconstructed view is also shown (right) with T2 hyperintense gross disease seen along the fundus within the 150% isodose line.
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The dose to 2 cc (D2cc) for OARs and dose to 90% (D90) of the target volume were recorded in addition to the dose at point W, a traditional prescription dose point defined as 2 cm below the tip of the tandem and half the maximum uterine width. Equivalent 2 Gy doses (EQD2) were recorded incorporating an a/b of 10 for tumor and three for normal tissue (18). Optimization goals were as follows: CTV D90 $100%, rectum D2cc EQD2 #70 Gy, sigmoid D2cc #70 Gy, and bladder D2cc EQD2 #85 Gy. Priority was placed on meeting critical organ constraints and thus, when needed, CTV coverage was compromised. Followup examinations consisted of a history and physical examination, including pelvic examination, cervical cytology, and MRI wherever feasible. Radiographic response was based on residual signal abnormality and defined as complete response, partial response (residual signal abnormality), or progression. Local failure was defined by imaging progression or confirmatory endometrial biopsy. The Radiation Therapy Oncology Group toxicity scale was used to retrospectively grade treatment-related toxicity. Statistical analysis was completed using SPSS, version 17.0 (SPSS, Inc., Chicago, IL). A two-tailed paired t test was conducted when comparing dosimetric parameters within the same plan. KaplaneMeier survival analyses were used to estimate local control and overall survival.
Thirty-eight consecutive patients were included in this analysis with a median age of 69 years (Table 1). All patients Table 1 Patient and treatment characteristics
Age, median Grade 1 2 3 Uterine width, median Reason for inoperability Patient preference Morbid obesity Multiple medical comorbidities Pulmonary comorbidities Cardiac comorbidities Advanced age Adhesions (surgical difficulty) Cirrhosis Stroke/risk of discontinuing anticoagulation Thrombocytopenia Technique BT alone EBRT þ BT Image-based planning modality MRI CT with pretreatment MRI CT alone
MRI utilization Nineteen (50%) patients underwent MRI-based planning where an MRI was completed after applicator placement for BT. The remaining patients had CT-based planning, 13 (34%) having an MRI before BT to identify the location of gross disease, and six (15.8%) having CT alone. The latter cohort was unable to complete an MRI either before or after applicator placement because of limitations with body habitus, claustrophobia, incompatible pacemakers, and/or uterine size, where the length of the MRcompatible tandem limited the ability to reach the fundus. Dosimetry
Results
Characteristics
had clinical International Federation of Gynecology and Obstetrics (FIGO) Stage I disease with most of them (57.9%) having Grade 1 adenocarcinoma. The most commonly identified reasons for inoperability were multiple medical comorbidities (31.6%) and cardiovascular risk (13.2%). Patients were almost evenly distributed between BT alone (52.6%) and combined EBRT and BT (47.4%). The median dose of EBRT delivered was 45 Gy (range, 45e46.8 Gy). The median dose of BT delivered as monotherapy was 37.5 Gy (range, 35e45 Gy) in five to six equal fractions; with combined therapy, the median dose of BT was 25 Gy (range, 20.8e27.5 Gy) in four to five equal fractions.
n (% or range) 69 (53e90) 22 15 1 5.6 cm 3 4 12 3 5 4 3 1 2 1
(57.9) (39.5) (2.6) (3.1e8.0 cm) (7.9) (10.5) (31.6) (7.9) (13.2) (10.5) (7.9) (2.6) (5.3) (2.6)
20 (52.6) 18 (47.4) 19 (50.0) 13 (34.2) 6 (15.8)
BT 5 brachytherapy; EBRT 5 external beam radiotherapy.
Key dosimetric findings are summarized in Table 2. For BT alone, the mean bladder, sigmoid, and rectum D2cc EQD2 values were 46.8, 41.5, and 26.3 Gy. The mean bladder, sigmoid, and rectum D2cc EQD2 values for patients treated with combined therapy were 71.7, 64.6, and 59.8 Gy. Relative to the prescription dose, the mean point W dose was 3.8% less than the CTV D90 dose with greater variability (Table 3, p 5 0.01). Based on imaging findings by MRI, the mean GTVs for BT alone and combined Table 2 Summary of dosimetric findings for image-based HDR treatment planning Characteristics
BT alone (n 5 20)
EBRT þ BT (n 5 18)
4.5 62.1
5.4 1.9 172.3 59.6
8.9 6.5 138.0 64.6
25.9 13.3
82.0 28.0 48.6 5.6
87.6 24.0 72.4 6.0
18.3
26.3 8.9
59.8 4.0
13.6
41.5 8.6
64.6 4.9
15.2
46.8 10.4
71.7 6.1
All patients (n 5 38)
GTV, mean SD Volume (cc) 6.8 D90 EQD2 (Gy) 160.0 CTV, mean SD Volume (cc) 85.7 D90 EQD2 (Gy) 59.9 Rectum D2cc EQD2 (Gy) Mean SD 42.2 Sigmoid D2cc EQD2 (Gy) Mean SD 52.4 Bladder D2cc EQD2 (Gy) Mean SD 58.6
HDR 5 high dose rate; BT 5 brachytherapy; EBRT 5 external beam radiotherapy; GTV 5 gross tumor volume; SD 5 standard deviation; D90 5 dose delivered to 90% volume; EQD2 5 equivalent dose at 2 Gy per fraction; CTV 5 clinical treatment volume; D2cc 5 dose delivered to 2 cc of the volume.
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Table 3 Comparison of Point W and CTV D90 doses from each brachytherapy plan Point/volume Point W Mean SD CTV D90 Mean SD p-Value (two-tailed t test)
Absolute dose (Gy)
Relative dose (% of prescription dose)
5.6 1.7
87.8 17.8
5.9 1.4 0.03
91.6 11.5 0.01
CTV 5 clinical treatment volume; D90 5 dose delivered to 90% volume; SD 5 standard deviation.
therapy patients at the time of BT were 5.4 1.9 and 8.9 6.5 cc. Despite relatively low CTV, D90 EQD2 values particularly for patients treated with BT alone, the mean cumulative GTV D90 EQD2 value for this subset was 172.3 59.6 Gy. Mean cumulative GTV D90 EQD2 for those with combined therapy was 138.0 64.6 Gy. No dosimetric correlation was established between those patients who had a local failure. Their respective CTV D90 EQD2 values were 46.1 Gy (monotherapy) and 75.2 Gy (combined therapy). One patient did not have an MRI completed to delineate the GTV, whereas the other had an MRI with no identifiable gross disease. Clinical outcomes One patient developed vaginal bleeding after applicator insertion requiring transfusion. No other Radiation Therapy Oncology Group Grade 3 or greater acute or late toxicities occurred. Most patients (92.1%) had cessation of vaginal bleeding after treatment. Followup MRI was completed on 21 patients (55.3%) with 13 patients (61.9%) demonstrating complete resolution of the T2 signal abnormality. The remaining patients had either residual indeterminate signal abnormality (33.3%) or progression of disease (4.8%). The patient who had progressive enlargement of intrauterine disease underwent endometrial biopsy that demonstrated cellular atypia but was nonetheless coded as a local failure. With a median followup of 15.0 months (3.0e80.9 months), only 2 patients developed local failure for a 2-year actuarial local control rate of 90.6% (Fig. 2). The second local failure occurred at 22 months in a patient with bulky Grade 1 disease who was treated with combined EBRT and BT. This patient chose not to undergo further treatment after local failure and died from comorbid conditions 4 months later. No significant factors associated with local failure were identified. There were no patients who developed regional or distant metastases, and therefore there were no cancerrelated deaths. The actuarial 2-year overall survival estimate was 94.4%, although a total of 8 patients (21.1%) have died from other medical causes (Fig. 3).
Fig. 2. Local control with an actuarial 2-year local control rate of 90.6% (95% confidence interval, 83.8e97.4).
patients who are medically unable to undergo surgery for their endometrial cancer. Although this population has a high risk of death from other medical comorbidities, lack of treatment for endometrial cancer may further not only shorten survival but also impact quality of life. A progressively growing body of literature exists regarding the use of definitive radiotherapy as an alternative treatment for inoperable patients (19e22). Although the benefits of 3D imageebased BT are being discovered among cervical cancer patients with regard to both improved cancer control and decreased toxicities, there has been little application of this approach toward endometrial cancer (12). Our series is one of the few reported with a sizable population demonstrating the efficacy of this approach with improved results compared with historical series (19e22). The largest reported series for definitive HDR BT originated from University of Vienna. With 280 patients
Discussion Increasing prevalence of endometrial cancer in an aging population has resulted in a small but substantial group of
Fig. 3. KaplaneMeier estimate of overall survival with a 2-year survival rate of 94.4% (95% confidence interval, 90.6e98.2).
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receiving two-dimensional (2D) planned intracavitary BT, the 5-year local control rates for Stage IA and IB disease were 86% and 68.8% (19). Kucera et al. (20) reported a followup series for this same patient cohort demonstrating that in the 2D era, uterine size impacted local control. Other series, including our own institutional reports, suggest local recurrence rates ranging from 12% to 29% (21e23). Limited effective salvage options remain for these patients who cannot undergo surgery. Similar to that seen in cervical cancer, the question remains whether the addition of 3D IGBT may improve local control and limit toxicities, which has ranged up to a rate of 21% in the 2D era (21). The only series for 3D imageebased planning and optimization for HDR BT in this setting was reported by Weitmann et al. (23) using a Heyman capsule and either CT or MRI. With 12 patients, all achieved a complete remission with no severe toxicities (Grade 3e4) observed. Evaluation of dosimetry suggested that covering the entire uterus was not feasible in many cases because of high doses to adjacent OARs. The mean coverage of the CTV by the prescribed dose was 68% with a median D90 of 40.8 Gy. In comparison, our series is the largest regarding the use of IGBT for inoperable endometrial cancer and similarly shows low doses to the CTV with a mean D90 EQD2 of 59.9 Gy, whereas the delineated GTV received a mean D90 EQD2 of 160.0 Gy. In comparison, radiation oncologists often recommend doses exceeding 60 Gy to gross disease in other cancer subsites. With an actuarial 2-year local control rate of 90.6% and similar dosimetric findings, these results bring into question prescribing dose to the entire uterus. The 2000 American Brachytherapy Society guidelines recommend prescribing dose to the uterine serosa, corresponding to point W, which would entail coverage of the entire uterus (24). However, Nguyen and Petereit (21) demonstrated that by prescribing to point W at 7 Gy per fraction for five fractions resulted in unacceptably high complication rates. Our dosimetric analysis highlights the value of 3D imageebased optimization with a significant difference in point W as compared with CTV D90. Although the absolute mean difference was small, the variability emphasizes the lack of reliability in prescribing to a point rather than a defined volume. Most importantly, toxicity rates were considerably low, and tumor control was not compromised with this approach, indicating the value of BT in providing a high dose to the uterine lining, which is the origin of endometrial cancer. Although other factors such as improved clinical staging and 3D BT planning may have contributed, treatment integration of MRI may have further enhanced the high rate of local control seen here by the ability to delineate gross disease. Preoperative series have shown the value of MRI over CT or ultrasound for endometrial cancer staging. Frei et al. (25) demonstrated that MRI significantly impacted the probability of deep myometrial invasion seen intraoperatively. Preoperative staging with MRI confirmed 80% sensitivity and 100% specificity in detection of deep myometrial
invasion, proving reliability of this imaging approach (26). Compared with CT or ultrasound, MRI has superior sensitivity and specificity, thus making this the optimal imaging for endometrial cancer (17). More accurate delineation of the gross disease, particularly with conformal therapy such as BT, may ultimately translate into improved outcomes such as that seen here and at McGill University, where patients who underwent MRI during the course of BT had no relapses (27). Unfortunately, implementation of this approach in radiation oncology departments has been largely limited because of challenges with MRI access. Our findings suggest the benefit of image-based BT for endometrial cancer and the need for modernized guidelines to establish this approach. Coverage of the entire uterus has been well known to be technically challenging and, in the era of MRI staging, most likely unnecessary. Despite low D90 EQD2 doses to the CTV in our patients treated with BT alone (range, 34.5e57.2 Gy), the identified GTV received on average nearly two to three times the equivalent dose (D90 EQD2 range, 100.3e295.6 Gy). Therefore, with integration of MRI, differential dosing should be incorporated such that the entire uterus, cervix, and upper vagina (CTV) receive a sufficient dose for microscopic disease between 45 and 60 Gy, whereas gross disease receives an EQD2 at least 80e90 Gy, which is feasible given the dose gradient achieved with BT. For those without a definable GTV, the entire endometrial cavity should at least receive a similar EQD2 dose of 80e90 Gy given this is the origin of disease. Our institution has recently adopted MRI-guided BT planning whenever feasible, and thus the followup of this patient cohort is limited. Because of this limitation, local control may be overestimated and morbidity may be underestimated. Nonetheless, a large proportion of the patients treated underwent followup MRI with most demonstrating a complete T2 signal response. The dosimetry in the 2 patients who had failure appeared adequate, and thus local failure may have been a consequence of radiographic underestimation of disease, particularly in the patient unable to undergo MRI. One notable limitation of our study, and other similar reports, is the nature of the analysis, which is retrospective. In our experience, patient selection for BT is critical to reach acceptable outcomes. From an anatomical perspective, delivery of intracavitary BT is challenging for patients with long uterine lengths given that much of the disease seen on MRI originates at the fundus. Currently, the largest MR-compatible tandem measures 8.0 cm, and thus uterine lengths beyond this may not be suitable for this approach. Previously we used a 5.0-cm cutoff for uterine width; however, with these results, BT may still be a feasible approach based on the location and depth of gross disease and critical organs. Last, patient selection also applies to expected survival. Many of these patients have multiple comorbidities, and therefore clinical judgment is needed to identify patients who will benefit from treatment.
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Conclusions Modernization of BT techniques with the use of imagebased planning and optimization and integration of MRI in our series has resulted in excellent local control and no severe late toxicity with the use of definitive radiotherapy. Our data suggest that full prescription dose coverage is unnecessary to the entire uterus as the tumor is often confined to the endometrium or inner myometrium, which receives a higher dose than that prescribed to the uterine serosal point. High delivered doses to the gross disease and endometrial lining likely account for high rates of tumor control. As previously done with cervical cancer BT, guidelines for image-based BT planning for endometrial cancer are needed to define target volumes at risk with differential dosing to these volumes.
[13]
[14]
[15]
[16]
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Image-based three-dimensional conformal brachytherapy for medically inoperable endometrial carcinoma Beant S. Gill1, Hayeon Kim1, Chris Houser1, Adam Olsen1, Joseph Kelley2, Robert P. Edwards2, John Comerci2, Paniti Sukumvanich2, Alexander B. Olawaiye2, Marilyn Huang2, Madeleine Courtney-Brooks2, Sushil Beriwal1,* 2
1 Department of Radiation Oncology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA Department of Gynecologic Oncology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA
ABSTRACT
PURPOSE: Definitive radiotherapy is a viable option for medically inoperable patients with early stage endometrial cancer. We present our experience using image-based brachytherapy (BT). METHODS AND MATERIALS: Patients with medically inoperable clinical Stage I endometrial adenocarcinoma received definitive BT with or without external beam radiotherapy. High-dose-rate BT was delivered using MRI- or CT-based planning for each fraction. For patients with an MRI, gross tumor volume (GTV) was contoured although dose was still prescribed to the clinical treatment volume (CTV), including the entire uterus, cervix, and upper 1e2 cm of vagina. Equivalent 2 Gy doses (EQD2) were calculated. RESULTS: Thirty-eight patients were treated from 2007 to 2013, 20 receiving BT alone with a median dose of 37.5 Gy in five to six fractions. For combined therapy, median external beam and BT doses were 45 and 25 Gy in four to five fractions. With 15-month median followup, the 2-year actuarial local control and overall survival were 90.6% and 94.4%. No Grade 2e5 late toxicities were observed. Mean CTV D90 EQD2 for BT alone and combined therapy was 48.6 5.6 and 72.4 6.0 Gy, whereas mean GTV D90 EQD2 was 172.3 59.6 and 138.0 64.6 Gy. CONCLUSIONS: Image-based BT is feasible for medically inoperable early stage endometrial cancer with excellent early results. Despite low CTV doses, high doses delivered to GTV with BT likely accounts for high local control. Endometrial cancer guidelines for image-based planning are needed to define target volumes based on risk with differential dose delivery. Ó 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Endometrial cancer; Brachytherapy; Inoperable; Radiotherapy; MRI
Introduction Endometrial cancer is the most common gynecologic malignancy in the United States with approximately 49,560 new cases in 2013 (1). For patients with localized disease, the standard treatment entails upfront surgery with total hysterectomy, bilateral salpingo-oophorectomy with or without pelvic and para-aortic lymph node dissection
Received 24 April 2014; received in revised form 27 June 2014; accepted 8 July 2014. Results presented at the American Brachytherapy Society Annual Meeting, April 4, 2014, in San Diego, CA, USA. * Corresponding author. Department of Radiation Oncology, MageeWomens Hospital, 300 Halket Street, Pittsburgh, PA 15213. Tel.: þ412641-4600; fax: +412-641-1085. E-mail address: [email protected] (S. Beriwal).
(2). Based on risk factors established from surgery, adjuvant therapy may include external beam radiotherapy (EBRT) and/or intracavitary brachytherapy (BT) to reduce the risk of locoregional failure (3e5). The increasing incidence of endometrial cancer in the United States is likely because of improved surveillance and a growing aging population. Endometrial cancer frequently presents in older patients such that 3.4e9% of patients have comorbidities that preclude surgical intervention (6, 7). Definitive radiation therapy with BT alone or combined with EBRT has emerged as an acceptable alternative for this select population (8e10). Given the increased application of three-dimensional (3D) planning for EBRT, a similar technique is being increasingly applied to BT in the form of image-guided brachytherapy (IGBT) (11). For example, in the treatment of cervical cancer, IGBT has been shown to improve local
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control and decrease toxicities because of more accurate delineation of the target volume and dose optimization, which helps reduce dose to adjacent rectum, sigmoid, and bladder (12e14). At present, the Groupe Europeen de Curietherapie and European Society for Therapeutic Radiation and Oncology (GEC-ESTRO) guidelines have been published to bring uniformity to target delineation and doseevolume parameters (15, 16). On the contrary, such guidelines do not yet exist for the treatment of endometrial cancer. MRI has been shown to be superior in assessing tumor volume for endometrial cancer, including depth of myometrial invasion, as compared with CT and ultrasound (17). At our institution, patients with medically inoperable endometrial cancer who are treated with BT now undergo MRI as a part of treatment planning to accurately define the disease extent, similar to the approach used in cervical cancer. In this report, we aim to establish this approach by presenting dosimetric findings and early clinical outcomes for patients treated with IGBT with either CT- or MRI-based planning. Methods and materials Between February 2007 and September 2013, patients treated at our institution for histologically proven clinical Stage I adenocarcinoma of the endometrium were retrospectively identified. All patients were deemed medically inoperable and therefore treated with radiotherapy with definitive intent. Patients were staged using clinical examination and imaging modalities including a pelvic MRI scan. BT alone was used for patients with Grade 1e2, low-volume disease, defined as less than 50% myometrial invasion and tumor size #2 cm on MRI. Alternatively, for patients with Grade 3 and/or high-volume disease, EBRT was first used and followed by intracavitary BT. EBRT was delivered with either 3D conformal or intensity-modulated radiotherapy technique. The clinical treatment volume (CTV) included the entire uterus, cervix, upper half of the vagina, and pelvic lymph nodes, including
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the lower common iliac, external iliac, and internal iliac nodes. High-dose-rate (HDR) BT was used once or twice weekly starting in the last week of EBRT or as monotherapy. An MR-compatible Smit Sleeve (Nucletron, an Elekta company; Elekta AB, Stockholm, Sweden) was placed in the operating room before initiation of BT. It is our institutional standard for patients with a maximum uterine width of 5 cm or less based on CT or MRI to be treated with a single tandem and cylinder applicator. Tandem length was based on uterine length, which was established by a uterine sound. Cylinder diameter varied from 2.5 to 3.5 cm based on vaginal vault width, selecting the largest fitting diameter that was determined by pretreatment clinical examination. Patients with a maximum uterine width greater than 5 cm are generally treated with a Rotte ‘‘Y’’ applicator (Elekta) (10). If patients are unable to lay flat for a prolonged period as required for the ‘‘Y’’ applicator or decline this option, then they were treated with a single tandem and cylinder applicator despite uterine width limitations. Patients treated with a Rotte ‘‘Y’’ applicator are excluded from this analysis because these are not MRI-compatible applicators. CT and/or MRI were completed after each applicator placement with dose optimization and planning based on uterine size, configuration, and disease location. For patients who underwent MRI-based planning, the gross tumor volume (GTV) was contoured. The CTV for BT included the GTV, entire uterus, cervix, and upper 1e2 cm of the vagina (Fig. 1). Although the GTV was identified, the prescription dose was still delivered to the CTV. Key organs at risk (OARs) including the rectum, bladder, sigmoid, and small bowel were also contoured. Treatment plans were generated on the PLATO Brachytherapy Planning System, version 14.3 (Nucletron) or the Oncentra Brachy Planning System, version 4.3 (Elekta). Plans were manually optimized with each application, where initially standard weighting was placed at each source position and then manually adjusted to adequately cover the CTV and avoid critical structures.
Fig. 1. MRI-guided brachytherapy plan. The gross tumor volume (dark blue) and clinical treatment volume (bright red) are contoured with overlying isodose lines (yellow 150%, red 100%, and green 80%). A sagittal reconstructed view is also shown (right) with T2 hyperintense gross disease seen along the fundus within the 150% isodose line.
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The dose to 2 cc (D2cc) for OARs and dose to 90% (D90) of the target volume were recorded in addition to the dose at point W, a traditional prescription dose point defined as 2 cm below the tip of the tandem and half the maximum uterine width. Equivalent 2 Gy doses (EQD2) were recorded incorporating an a/b of 10 for tumor and three for normal tissue (18). Optimization goals were as follows: CTV D90 $100%, rectum D2cc EQD2 #70 Gy, sigmoid D2cc #70 Gy, and bladder D2cc EQD2 #85 Gy. Priority was placed on meeting critical organ constraints and thus, when needed, CTV coverage was compromised. Followup examinations consisted of a history and physical examination, including pelvic examination, cervical cytology, and MRI wherever feasible. Radiographic response was based on residual signal abnormality and defined as complete response, partial response (residual signal abnormality), or progression. Local failure was defined by imaging progression or confirmatory endometrial biopsy. The Radiation Therapy Oncology Group toxicity scale was used to retrospectively grade treatment-related toxicity. Statistical analysis was completed using SPSS, version 17.0 (SPSS, Inc., Chicago, IL). A two-tailed paired t test was conducted when comparing dosimetric parameters within the same plan. KaplaneMeier survival analyses were used to estimate local control and overall survival.
Thirty-eight consecutive patients were included in this analysis with a median age of 69 years (Table 1). All patients Table 1 Patient and treatment characteristics
Age, median Grade 1 2 3 Uterine width, median Reason for inoperability Patient preference Morbid obesity Multiple medical comorbidities Pulmonary comorbidities Cardiac comorbidities Advanced age Adhesions (surgical difficulty) Cirrhosis Stroke/risk of discontinuing anticoagulation Thrombocytopenia Technique BT alone EBRT þ BT Image-based planning modality MRI CT with pretreatment MRI CT alone
MRI utilization Nineteen (50%) patients underwent MRI-based planning where an MRI was completed after applicator placement for BT. The remaining patients had CT-based planning, 13 (34%) having an MRI before BT to identify the location of gross disease, and six (15.8%) having CT alone. The latter cohort was unable to complete an MRI either before or after applicator placement because of limitations with body habitus, claustrophobia, incompatible pacemakers, and/or uterine size, where the length of the MRcompatible tandem limited the ability to reach the fundus. Dosimetry
Results
Characteristics
had clinical International Federation of Gynecology and Obstetrics (FIGO) Stage I disease with most of them (57.9%) having Grade 1 adenocarcinoma. The most commonly identified reasons for inoperability were multiple medical comorbidities (31.6%) and cardiovascular risk (13.2%). Patients were almost evenly distributed between BT alone (52.6%) and combined EBRT and BT (47.4%). The median dose of EBRT delivered was 45 Gy (range, 45e46.8 Gy). The median dose of BT delivered as monotherapy was 37.5 Gy (range, 35e45 Gy) in five to six equal fractions; with combined therapy, the median dose of BT was 25 Gy (range, 20.8e27.5 Gy) in four to five equal fractions.
n (% or range) 69 (53e90) 22 15 1 5.6 cm 3 4 12 3 5 4 3 1 2 1
(57.9) (39.5) (2.6) (3.1e8.0 cm) (7.9) (10.5) (31.6) (7.9) (13.2) (10.5) (7.9) (2.6) (5.3) (2.6)
20 (52.6) 18 (47.4) 19 (50.0) 13 (34.2) 6 (15.8)
BT 5 brachytherapy; EBRT 5 external beam radiotherapy.
Key dosimetric findings are summarized in Table 2. For BT alone, the mean bladder, sigmoid, and rectum D2cc EQD2 values were 46.8, 41.5, and 26.3 Gy. The mean bladder, sigmoid, and rectum D2cc EQD2 values for patients treated with combined therapy were 71.7, 64.6, and 59.8 Gy. Relative to the prescription dose, the mean point W dose was 3.8% less than the CTV D90 dose with greater variability (Table 3, p 5 0.01). Based on imaging findings by MRI, the mean GTVs for BT alone and combined Table 2 Summary of dosimetric findings for image-based HDR treatment planning Characteristics
BT alone (n 5 20)
EBRT þ BT (n 5 18)
4.5 62.1
5.4 1.9 172.3 59.6
8.9 6.5 138.0 64.6
25.9 13.3
82.0 28.0 48.6 5.6
87.6 24.0 72.4 6.0
18.3
26.3 8.9
59.8 4.0
13.6
41.5 8.6
64.6 4.9
15.2
46.8 10.4
71.7 6.1
All patients (n 5 38)
GTV, mean SD Volume (cc) 6.8 D90 EQD2 (Gy) 160.0 CTV, mean SD Volume (cc) 85.7 D90 EQD2 (Gy) 59.9 Rectum D2cc EQD2 (Gy) Mean SD 42.2 Sigmoid D2cc EQD2 (Gy) Mean SD 52.4 Bladder D2cc EQD2 (Gy) Mean SD 58.6
HDR 5 high dose rate; BT 5 brachytherapy; EBRT 5 external beam radiotherapy; GTV 5 gross tumor volume; SD 5 standard deviation; D90 5 dose delivered to 90% volume; EQD2 5 equivalent dose at 2 Gy per fraction; CTV 5 clinical treatment volume; D2cc 5 dose delivered to 2 cc of the volume.
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Table 3 Comparison of Point W and CTV D90 doses from each brachytherapy plan Point/volume Point W Mean SD CTV D90 Mean SD p-Value (two-tailed t test)
Absolute dose (Gy)
Relative dose (% of prescription dose)
5.6 1.7
87.8 17.8
5.9 1.4 0.03
91.6 11.5 0.01
CTV 5 clinical treatment volume; D90 5 dose delivered to 90% volume; SD 5 standard deviation.
therapy patients at the time of BT were 5.4 1.9 and 8.9 6.5 cc. Despite relatively low CTV, D90 EQD2 values particularly for patients treated with BT alone, the mean cumulative GTV D90 EQD2 value for this subset was 172.3 59.6 Gy. Mean cumulative GTV D90 EQD2 for those with combined therapy was 138.0 64.6 Gy. No dosimetric correlation was established between those patients who had a local failure. Their respective CTV D90 EQD2 values were 46.1 Gy (monotherapy) and 75.2 Gy (combined therapy). One patient did not have an MRI completed to delineate the GTV, whereas the other had an MRI with no identifiable gross disease. Clinical outcomes One patient developed vaginal bleeding after applicator insertion requiring transfusion. No other Radiation Therapy Oncology Group Grade 3 or greater acute or late toxicities occurred. Most patients (92.1%) had cessation of vaginal bleeding after treatment. Followup MRI was completed on 21 patients (55.3%) with 13 patients (61.9%) demonstrating complete resolution of the T2 signal abnormality. The remaining patients had either residual indeterminate signal abnormality (33.3%) or progression of disease (4.8%). The patient who had progressive enlargement of intrauterine disease underwent endometrial biopsy that demonstrated cellular atypia but was nonetheless coded as a local failure. With a median followup of 15.0 months (3.0e80.9 months), only 2 patients developed local failure for a 2-year actuarial local control rate of 90.6% (Fig. 2). The second local failure occurred at 22 months in a patient with bulky Grade 1 disease who was treated with combined EBRT and BT. This patient chose not to undergo further treatment after local failure and died from comorbid conditions 4 months later. No significant factors associated with local failure were identified. There were no patients who developed regional or distant metastases, and therefore there were no cancerrelated deaths. The actuarial 2-year overall survival estimate was 94.4%, although a total of 8 patients (21.1%) have died from other medical causes (Fig. 3).
Fig. 2. Local control with an actuarial 2-year local control rate of 90.6% (95% confidence interval, 83.8e97.4).
patients who are medically unable to undergo surgery for their endometrial cancer. Although this population has a high risk of death from other medical comorbidities, lack of treatment for endometrial cancer may further not only shorten survival but also impact quality of life. A progressively growing body of literature exists regarding the use of definitive radiotherapy as an alternative treatment for inoperable patients (19e22). Although the benefits of 3D imageebased BT are being discovered among cervical cancer patients with regard to both improved cancer control and decreased toxicities, there has been little application of this approach toward endometrial cancer (12). Our series is one of the few reported with a sizable population demonstrating the efficacy of this approach with improved results compared with historical series (19e22). The largest reported series for definitive HDR BT originated from University of Vienna. With 280 patients
Discussion Increasing prevalence of endometrial cancer in an aging population has resulted in a small but substantial group of
Fig. 3. KaplaneMeier estimate of overall survival with a 2-year survival rate of 94.4% (95% confidence interval, 90.6e98.2).
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receiving two-dimensional (2D) planned intracavitary BT, the 5-year local control rates for Stage IA and IB disease were 86% and 68.8% (19). Kucera et al. (20) reported a followup series for this same patient cohort demonstrating that in the 2D era, uterine size impacted local control. Other series, including our own institutional reports, suggest local recurrence rates ranging from 12% to 29% (21e23). Limited effective salvage options remain for these patients who cannot undergo surgery. Similar to that seen in cervical cancer, the question remains whether the addition of 3D IGBT may improve local control and limit toxicities, which has ranged up to a rate of 21% in the 2D era (21). The only series for 3D imageebased planning and optimization for HDR BT in this setting was reported by Weitmann et al. (23) using a Heyman capsule and either CT or MRI. With 12 patients, all achieved a complete remission with no severe toxicities (Grade 3e4) observed. Evaluation of dosimetry suggested that covering the entire uterus was not feasible in many cases because of high doses to adjacent OARs. The mean coverage of the CTV by the prescribed dose was 68% with a median D90 of 40.8 Gy. In comparison, our series is the largest regarding the use of IGBT for inoperable endometrial cancer and similarly shows low doses to the CTV with a mean D90 EQD2 of 59.9 Gy, whereas the delineated GTV received a mean D90 EQD2 of 160.0 Gy. In comparison, radiation oncologists often recommend doses exceeding 60 Gy to gross disease in other cancer subsites. With an actuarial 2-year local control rate of 90.6% and similar dosimetric findings, these results bring into question prescribing dose to the entire uterus. The 2000 American Brachytherapy Society guidelines recommend prescribing dose to the uterine serosa, corresponding to point W, which would entail coverage of the entire uterus (24). However, Nguyen and Petereit (21) demonstrated that by prescribing to point W at 7 Gy per fraction for five fractions resulted in unacceptably high complication rates. Our dosimetric analysis highlights the value of 3D imageebased optimization with a significant difference in point W as compared with CTV D90. Although the absolute mean difference was small, the variability emphasizes the lack of reliability in prescribing to a point rather than a defined volume. Most importantly, toxicity rates were considerably low, and tumor control was not compromised with this approach, indicating the value of BT in providing a high dose to the uterine lining, which is the origin of endometrial cancer. Although other factors such as improved clinical staging and 3D BT planning may have contributed, treatment integration of MRI may have further enhanced the high rate of local control seen here by the ability to delineate gross disease. Preoperative series have shown the value of MRI over CT or ultrasound for endometrial cancer staging. Frei et al. (25) demonstrated that MRI significantly impacted the probability of deep myometrial invasion seen intraoperatively. Preoperative staging with MRI confirmed 80% sensitivity and 100% specificity in detection of deep myometrial
invasion, proving reliability of this imaging approach (26). Compared with CT or ultrasound, MRI has superior sensitivity and specificity, thus making this the optimal imaging for endometrial cancer (17). More accurate delineation of the gross disease, particularly with conformal therapy such as BT, may ultimately translate into improved outcomes such as that seen here and at McGill University, where patients who underwent MRI during the course of BT had no relapses (27). Unfortunately, implementation of this approach in radiation oncology departments has been largely limited because of challenges with MRI access. Our findings suggest the benefit of image-based BT for endometrial cancer and the need for modernized guidelines to establish this approach. Coverage of the entire uterus has been well known to be technically challenging and, in the era of MRI staging, most likely unnecessary. Despite low D90 EQD2 doses to the CTV in our patients treated with BT alone (range, 34.5e57.2 Gy), the identified GTV received on average nearly two to three times the equivalent dose (D90 EQD2 range, 100.3e295.6 Gy). Therefore, with integration of MRI, differential dosing should be incorporated such that the entire uterus, cervix, and upper vagina (CTV) receive a sufficient dose for microscopic disease between 45 and 60 Gy, whereas gross disease receives an EQD2 at least 80e90 Gy, which is feasible given the dose gradient achieved with BT. For those without a definable GTV, the entire endometrial cavity should at least receive a similar EQD2 dose of 80e90 Gy given this is the origin of disease. Our institution has recently adopted MRI-guided BT planning whenever feasible, and thus the followup of this patient cohort is limited. Because of this limitation, local control may be overestimated and morbidity may be underestimated. Nonetheless, a large proportion of the patients treated underwent followup MRI with most demonstrating a complete T2 signal response. The dosimetry in the 2 patients who had failure appeared adequate, and thus local failure may have been a consequence of radiographic underestimation of disease, particularly in the patient unable to undergo MRI. One notable limitation of our study, and other similar reports, is the nature of the analysis, which is retrospective. In our experience, patient selection for BT is critical to reach acceptable outcomes. From an anatomical perspective, delivery of intracavitary BT is challenging for patients with long uterine lengths given that much of the disease seen on MRI originates at the fundus. Currently, the largest MR-compatible tandem measures 8.0 cm, and thus uterine lengths beyond this may not be suitable for this approach. Previously we used a 5.0-cm cutoff for uterine width; however, with these results, BT may still be a feasible approach based on the location and depth of gross disease and critical organs. Last, patient selection also applies to expected survival. Many of these patients have multiple comorbidities, and therefore clinical judgment is needed to identify patients who will benefit from treatment.
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Conclusions Modernization of BT techniques with the use of imagebased planning and optimization and integration of MRI in our series has resulted in excellent local control and no severe late toxicity with the use of definitive radiotherapy. Our data suggest that full prescription dose coverage is unnecessary to the entire uterus as the tumor is often confined to the endometrium or inner myometrium, which receives a higher dose than that prescribed to the uterine serosal point. High delivered doses to the gross disease and endometrial lining likely account for high rates of tumor control. As previously done with cervical cancer BT, guidelines for image-based BT planning for endometrial cancer are needed to define target volumes at risk with differential dosing to these volumes.
[13]
[14]
[15]
[16]
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