- Email: [email protected]
High-dose-rate interstitial brachytherapy for the treatment of high-volume locally recurrent endometrial carcinoma
Brachytherapy
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(2016)
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High-dose-rate interstitial brachytherapy for the treatment of high-volume locally recurrent endometrial carcinoma Kitty Huang1, David D’Souza1,*, Nikhilesh Patil2, Vikram Velker1, Eric Leung3, Larry Stitt1, Frances Whiston1, Akira Sugimoto1, Jacob McGee1, Michel Prefontaine1 1 Department of Oncology, London Health Sciences Centre, Western University, London, Ontario, Canada Department of Radiation Oncology, Capital District Health Authority, Dalhousie University, Nova Scotia, Canada 3 Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
2
ABSTRACT
PURPOSE: Limited therapeutic options are available for the treatment of locally recurrent endometrial carcinoma. Our objective was to report an institutional experience using interstitial brachytherapy (IBT) to treat significant recurrent endometrial carcinoma, including previously irradiated disease. METHODS AND MATERIALS: Between December 2004 and September 2012, 40 patients with high-volume locally recurrent endometrial cancer were treated by high-dose-rate IBT (external beam radiation therapy (EBRT). Sixteen patients had prior radiotherapy: EBRT alone (n 5 5), intracavitary brachytherapy alone (n 5 3), or EBRT with intracavitary brachytherapy boost (n 5 8). Actuarial outcome rates were calculated using the KaplaneMeier method and compared using the log-rank test. RESULTS: Median followup interval was 18 months. Median disease-free interval was 61 months. Actuarial local control, progression-free survival (PFS), and overall survival were 74% and 60%, 70% and 51%, and 83% and 72% at 12 and 24 months, respectively. p-Values for local control, progression-free survival, and overall survival between patient who had prior RT (n 5 16) to no prior RT (n 5 24) were p 5 0.38, 0.32, and 0.90, respectively. Acute toxicities include Grade 1e2 pain (5%), genitourinary (7%), gastrointestinal (12%), soft tissue (5%), and dermatologic (12%). Four patients observed late Grade 3e4 toxicities, including rectal bleeding/fistula and soft tissue necrosis. CONCLUSIONS: High-dose-rate IBT is an effective treatment for locally recurrent endometrial carcinoma with an acceptable toxicity profile. Outcomes are similar between previously irradiated and nonirradiated patients. In women who have received prior radiotherapy and are often considered for palliative treatment, interstitial brachytherapy is a potentially curative option. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Endometrial carcinoma; Salvage; High volume; High dose rate; Interstitial brachytherapy
Introduction Endometrial carcinoma is the most common gynecologic malignancy in North America (1, 2). The standard curative treatment for endometrial carcinoma involves a hysterectomy at the minimum, and depending on the stage Received 11 April 2016; received in revised form 16 May 2016; accepted 20 June 2016. Conflict of interest: No actual or potential conflicts of interest exist. * Corresponding author. London Regional Cancer Program, 790 Commissioners Rd E, London, Ontario, Canada. Tel.: 519-685-8500; fax: 519-685-8627. E-mail address: [email protected] (D. D’Souza).
and recurrence risk, can include adjuvant radiotherapy (RT) for improved local control (LC) or chemotherapy. Although patients with limited stage disease have a favorable prognosis, local recurrences of 13% for all patients and !5% for early stage have been reported (3). According to the PORTEC-2 study of early Stage I or IIA endometrial carcinoma patients with high-intermediate risk features, reported 5-year vaginal recurrence rates were 1.8% after vaginal brachytherapy(VBT) and 1.6% after external beam radiation therapy (EBRT); and 5-year locoregional relapse rates (vaginal and/or pelvic) were 5.1% after VBT and 2.1% after EBRT. Most local recurrences occur at the vaginal vault, which is commonly within an area of prior radiation (4, 5).
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.06.010
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K. Huang et al. / Brachytherapy
Salvage treatment options depend on site and size of recurrence and prior treatment(s). Previously, nonirradiated patients can be treated with curative intent brachytherapy and external beam radiotherapy. However, treatment of patients with locally recurrent disease following initial treatment with pelvic irradiation presents a clinical challenge. Normal tissue dose tolerances may restrict the ability to safely deliver radical doses of radiation necessary to eradicate the disease using standard techniques. As a result, such patients often receive a palliative course of radiation. Surgical salvage typically involves a pelvic exenteration, which confers a significant risk of operative mortality and morbidity in a disease that affects a predominantly older population. Intracavitary or VBT is a common salvage option for treating recurrent endometrial cancer; however, concerns about dose coverage tend to limit its use to only small nonbulky vaginal recurrences. For bulky or extensive recurrences that cannot be adequately treated by VBT alone, interstitial brachytherapy (IBT) offers a potential and flexible solution. IBT is not only able to offer better dose coverage as compared to intracavitary brachytherapy (ICB), its optimal dose fall-off to spare normal surrounding tissue is advantageous over external beam radiotherapy. Successful treatment of local vaginal recurrence of endometrial cancer and other gynecologic malignancies has previously been reported; however, the vast majority are in patients initially treated by primary surgery alone without RT or in patients salvaged mainly by vaginal vault brachytherapy. Studies on high-dose-rate (HDR) IBT for recurrent uterine cancer rather than a heterogeneous group of gynecologic cancers are few. Especially in the setting of prior pelvic irradiation with IBT used as salvage treatment, outcomes are lacking and not well reported. Our objective is to report an institutional experience using HDR IBT, either alone or in combination with EBRT to treat significant locally recurrent endometrial carcinoma (which we defined in our study as large volume, paravaginal extension, lower vaginal disease) including women requiring reirradiation.
Methods Patient population Between December 2004 and September 2012, 40 patients with locally recurrent endometrial cancer underwent HDR IBT. These patients were identified from a REB-approved institutional database. This database was compiled from both retrospective and prospective data collection of any patient treated with IBT for gynecologic malignancies, as described previously (6). Additional followup data of patients lost to oncologic followup were further abstracted by outside physician correspondence.
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Patients had a clinical diagnosis of locally recurrent endometrial carcinoma and were deemed unsuitable for ICB either alone or with EBRT on the basis of size/ thickness of disease (O10 mm thick before treatment or size O2 cm) or location (most commonly the periurethral or paravaginal/parametrial region). Locally recurrent disease was diagnosed via pelvic examination and CT or MRI followed by histologic confirmation by biopsy. When suspected, regional or distant metastatic disease was evaluated by CT/MR imaging. Patients with evidence of regional or distant metastatic disease were excluded. RT consisted of IBT either alone or in combination with EBRT. Patients previously treated by ICB or EBRT or both were categorized in the prior RT group. Prior RT dosages consisted of 4500 cGy in 25 fractions to the pelvis and prior ICB boost consisted of 2100 cGy in 3 fractions alone or 1500 cGy in 3 fractions in combination with EBRT. Salvage RT pelvic dose was 4500 cGy in 25 fractions and was only given in the setting of a previously untreated pelvis. Brachytherapy technique Details of IBT procedure, image acquisition, and treatment planning are available in published literature (6). Briefly, catheter implantation was performed using a perineal implant template with a four-channel vaginal cylinder, and placement was based on prior imaging (CT, MR) and clinical examination at time of recurrence and then subsequently. Postimplant image acquisition by CT scan was obtained, and treatment planning and optimization was performed using BrachyVision (Varian Medical Systems Inc., Palo Alto, CA) treatment planning system. Clinical target volume (ascertained from initial clinical examination, diagnostic imaging, and examination under anesthesia), organ at risks (bladder, rectum, sigmoid, and small bowel), and dwell positions were delineated, and the plan was optimized based on dose volume histogram and isodose distribution curves. IBT dosages were determined based on biologically effective dose calculation and compared to equivalent 2 Gy fractions (EQD2). In the setting of prior irradiation, dose was determined using the following considerations: (1) dose needed to achieve a reasonable chance of controlling disease, (2) time elapsed from prior radiation to the area, (3) previous radiation dose given, that is EBRT alone vs. EBRT and VBT, (4) location, that is vaginal vault and within previously radiated volume vs. lower vagina and out of the previously radiated field. Median IBT prescription doses was 700 cGy 3 fractions and ranged from 500 to 750 cGy 3 fractions with the exception of 2 patients, one treated with 850 cGy in 2 fractions and the other with 550 cGy in 5 fractions. Assuming no repair from prior treatments, median cumulative EQD2 was 71.1 Gy (63e105.8 Gy EQD2); patients treated with prior RT received a median cumulative EQD2 of 74 Gy (63e105.8 Gy), and those without prior RT received an EQD2 of 71.1 Gy (68.3e77.1 Gy).
K. Huang et al. / Brachytherapy
Statistical analysis Followup time was calculated from time of IBT to date of last followup or death. Actuarial estimates of LC and overall survival (OS) were calculated using the KaplaneMeier method. LC was determined by date of last followup with absence of clinical, radiographic, or histological evidence of disease progression. OS was calculated by the date of diagnosis of endometrial cancer recurrence until death. Toxicities were evaluated according to Common Toxicity Criteria for Adverse Events (v. 4). Results were compared by a logrank test and statistical significance set at p!0.05. Statistical analysis was performed using SAS (version 8.1).
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Table 2 Local control, progression-free survival, and overall survival for patients with recurrent endometrial cancer, with and without prior radiation, treated with HDR IBT
Outcome Local control 1 yr 2 yr Progression-free survival 1 yr 2 yr Overall survival 1 yr 2 yr
All patients (n 5 40)
Without prior RT (n 5 24)
With prior RT (n 5 16)
74% 60%
77% 64%
70% 53%
70% 51%
73% 55%
65% 44%
83% 72%
81% 76%
86% 67%
p-value 0.38
0.32
0.90
Results
HDR 5 high dose rate; IBT 5 interstitial brachytherapy; RT 5 radiotherapy.
Patient characteristics including prior treatment modalities are summarized in Table 1. Median followup interval was 18 months, and median disease-free interval was 61 months. As shown in Table 2 and Fig. 1, actuarial LC rates at 12 and 24 months were 74% and 60%, respectively. Progression-free survival (PFS) rates at 12 and 24 months were 70% and 51%, respectively, including 15 locoregional recurrences and three distant recurrences. OS rates at 12 and 24 months were 83% and 72%, respectively. Comparing patients who had prior RT (n 5 16) to no prior RT (n 5 24), LC rates were 70% and 53%, compared to 77% and 64% at 12 and 24 months, respectively ( p 5 0.38). Similarly, PFS rates were 65% and 44% (prior RT), compared to
73% and 55% (no prior RT) at 12 and 24 months ( p 5 0.32). OS at 12 and 24 months were 86% and 67% (prior RT); 81% and 76% (no prior RT), respectively ( p 5 0.90). Grade 1e2 toxicities in the acute setting, or within 6 months, include pain (5%), genitourinary (7%), gastrointestinal (12%), soft tissue (5%), and dermatologic (12%). Acute Grade 3 or higher was not observed. The rates of Grade 3 and 4 long-term toxicity were low and include rectal bleeding, rectovaginal fistula, cystitis, radiation necrosis, and secondary osteoarthritis (Table 3). Median EQD2 for patients experiencing no toxicity was 71.1 Gy (68.3e98 Gy), and any toxicity was 74 Gy (63e105.8 Gy).
Table 1 Patient characteristics
Discussion
Patient characteristic Age (yr) Median Range Median disease-free interval (mo) Initial FIGO stage I II III IV Histology Adenocarcinoma NOS Endometrioid Serous/clear cell Sarcoma Undifferentiated CA Size of recurrence (CTV) !50 cc 50e100 cc O100 cc Prior treatment Chemotherapy (carboplatin/paclitaxel) EBRT (45 Gy in 25 fractions) BT (1500e2100 cGy in 3 fractions)
n 69 38e91 61 28 8 2 2
68% 20% 5% 5%
9 25 4 1 1
22.5% 62.5% 10% 2.5% 2.5%
19 16 5
48% 40% 12%
5 13 11
12% 32% 28%
NOS 5 not otherwise specified; CA 5 carcinoma; CTV 5 clinical target volume; EBRT 5 external beam radiotherapy; BT 5 brachytherapy; FIGO 5 The International Federation of Gynecology and Obstetrics.
Limited salvage therapy options are available for the recurrence of endometrial cancer that are not small in size and contained within the upper vagina. While most women are seen regularly in followup after initial surgery radiation, our experience shows that some will present with local recurrence with a higher volume or distribution of disease at the time of recurrence. Concerns for the ability to deliver a radical dose of radiation, especially within an area of prior RT, or unacceptable rates of surgical mortality and morbidity in patients can often restrict treatment intent to palliation alone. With advances in brachytherapy including image guidance and treatment planning, HDR IBT is emerging as a potentially curative treatment option for bulky recurrenceselarge volume disease not curable by ICB alone, by allowing high doses to be delivered to gross disease with good sparing of surrounding tissues. However, IBT is not widely offered and supporting data for its safe and effective use is lacking particularly with HDR. This study reports on clinical outcomes of 40 patients with recurrent endometrial cancer salvaged with HDR IBT. Our institutional experience showed favorable outcomes in terms of LC, PFS, OS, and toxicity with a median followup interval of 18 months.
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Table 3 Acute and late toxicity for patients with recurrent endometrial cancer, treated with HDR IBT Toxicity
All patients, n (%) Prior RT
Acute toxicity Any Grade 12 (30) Grades 1e2 Dermatologic 5 (12.5) Soft tissue 2 (5) Gastrointestinal 5 (12.5) Genitourinary 3 (7.5) Pain 2 (5) Late toxicity Any grade 12 (30) Grades 1e2 Dermatologic 4 (10) Soft tissue 2 (5) Gastrointestinal 6 (15) Genitourinary d Reproductive/ Sexual 8 (20) Pain 1 (2.5) Grades 3e4 Soft tissue 1 (2.5) Gastrointestinal 2 (5) Genitourinary 1 (2.5) Musculoskeletal 1 (2.5)
Comments
No prior RT: No Grade 3 or n56 higher toxicity Prior RT: n56
No prior RT: Severe Grade 3e4 n58 toxicities, include Prior RT: rectal bleeding, n54 radiation necrosis, rectovaginal fistula, cystitis, secondary osteoarthritis No Grade 5 toxicity
HDR 5 high dose rate; IBT 5 interstitial brachytherapy; RT 5 radiotherapy.
Fig. 1. KaplaneMeier estimates of (a) local control, (b) progression-free survival, and (c) overall survival. RT 5 radiotherapy.
Previous studies on brachytherapy for recurrent endometrial carcinoma within the last decade are characterized by small or highly heterogeneous patient populations and treatments, making robust comparison and interpretation challenging (6e11). Studies often include only smaller volumes of recurrence, whereas large volume recurrences have
been suggested to be a poor prognostic indicator (11). Status of prior RT also varies among studies, which is important since outcomes in patients with gynecologic cancer recurrence after prior radiation are considered to be unfavorable, with approximate 5-year OS of 40% despite salvage pelvic exenteration (12). Indeed, patients with high-volume recurrences and patients treated with prior RT are two common exclusion criteria for either treatment or analysis in a variety of previous literature. Although our patient population is often considered palliative, salvage IBT achieved OS outcomes comparable to patients with small volume recurrences. This suggests tumor volume may not be a prognostic indicator when adequate doses of radiation can be delivered to recurrent disease and, as such, should not preclude select patients from being offered radical treatment options. In Table 4, our OS rates are comparable to other reported series involving an arguably more favorable patient population that were salvaged mainly by vaginal vault brachytherapy (7, 9). Our LC rates from IBT seem inferior (60% 2-year LC as compared to 96% 2-year LC by Lee et al.), which may be a result of selection bias as our series excluded small vaginal recurrences treatable by VBT. However, our data are congruent with recent literature on IBT salvage of gynecologic malignancies, reporting LC rates ranging from 71.5% at 1 year to 47% at 5 years (8, 10, 11). Recent studies regarding reirradiation for recurrent endometrial cancer are scarce; a comparison of the limited
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Table 4 Summary of contemporary studies on VBT or IBT salvage for recurrent endometrial cancer Study
BT salvage
Outcome
No prior RT (%)
Prior RT (%)
p
Grade $3 toxicity after salvage
Lee et al., 2013. n 5 44 (n 5 13 prior RT) Vargo et al., 2014. n 5 41 (no prior RT) Present study n 5 40 (n 5 17 prior RT)
LDR/HDR IBT (80%), VBT (20%) HDR VBT (73%)/IBT (27%) HDR IBT
2 yr LC 2 yr OS 3 yr LC 3 yr OS 2 yr LC 2 yr OS
96 80 95 67 64 76
61 55 d
0.1 0.1 d
9% (n 5 4) All IBT 3 with prior RT 5% (n 5 2)
53 67
0.38 0.90
Acute: 0% Late: 2.5% soft tissue, 5% GI, 2.5% GU, 2.5% MSK
LDR 5 low dose rate; HDR 5 high dose rate; BT 5 brachytherapy; IBT 5 interstitial brachytherapy; VBT 5 vaginal brachytherapy; RT 5 radiotherapy; LC 5 local control; OS 5 overall survival; GU 5 genitourinary; GI 5 gastrointestinal; MSK 5 musculoskeletal.
outcome data to our study is provided in Tables 4 and 5 (8, 9, 11). Our data support that reirradiation status was not found to be a significant prognostic indicator and supports the use of IBT in previously irradiated and nonirradiated patients for radical intent (9). Lee et al., reported on interstitial and intracavitary salvage brachytherapy in patients with and without prior radiation, showing a trend for less favorable outcomes in previously irradiated patients. Amsbaugh et al. reported on a group of 21 patients with recurrent gynecologic cancer, the vast majority of which (n 5 18) had prior radiation, concluding that reirradiation is both safe and effective (11). Our study found favorable survival in this group with a 2-year OS of 67% for previously radiated patients, in comparison to 52.5e55%. Our results are also in keeping with previous studies with larger and more heterogeneous patient populations,
reporting on all endometrial cancer salvage outcomes regardless of technique (VBT or IBT), or all gynecologic malignancies salvaged with IBT, as summarized in Tables 3e5 (6). Comparing our outcomes against these other studies supports the validity of our selected data set. Differences between these prior studies may be due to differences in patient populations (i.e., inclusion of patients with various gynecologic malignancies or regional recurrence), lower dose prescriptions especially in the reirradiation scenario, and older brachytherapy techniques (9, 11). In contrast to standard salvage techniques whereby curative outcomes may not be achieved without unacceptable toxicity, our data confirm the safety of IBT. No severe acute toxicity of Grade 3 or more was observed, including in the reirradiation scenario. Although toxicity risk factors such as prior RT and cumulative EQD2 were not clearly associated
Table 5 Summary of contemporary studies on HDR IBT for gynecologic CA No prior RT (%)
Prior RT (%)
All pts (%)
1 yr LRC 1 yr PFS 1 yr OS 2 yr OS 3 yr LC 3 yr DFS 3 yr OS
d
d
68 65 73
d
71.5 66.0 82.2 52.5 d
2 yr LC 2 yr DFS þ Gr $3 CFS 2 yr OS 5 yr LC 5 yr DSS
d
d 40
71.4 59.3
42.9% 28.6% vaginal 9.5% urinary 19% rectal 4% (n 5 2) acute 21% late (14 events in 10 pt; 3 recurrence cases; fistula, necrosis, fibrosis/induration, bleeding/telangiectasia, hip fracture) 20% (n 5 3) (1 Grade 5, bowel obstruction, fistula)
d
d
47 43
n/a (9% side effects and severe complications)
1 yr LC 1 yr PFS 1 yr OS 2 yr LC 2 yr PFS 2 yr OS
77 73 81 64 56 76
73 68 87 55 47 68
75 71 83 60 51 73
Acute: 0% Late: 2.5% soft tissue, 5% GI, 2.5% GU, 2.5% MSK
Study
BT salvage
Patient population
Outcome
Amsbaugh et al., 2015
LDR/HDR IBT
n 5 21 (11 endometrial, 18 prior RT)
D’Souza et al., 2014
HDR IBT
n 5 47 primary and recurrent gyne CA (13 recurrent endometrial)
Martinez-Monge et al., 2014
HDR IBT
n 5 15 recurrent gyne CA (6 endometrial)
Weitmann et al. 2006
HDR/PDR IBT
Present study
HDR IBT
n 5 23 recurrent cervical or endometrial CA (6 endometrial) n 5 40 recurrent endometrial CA (n 5 17 prior RT)
Gr $3 toxicity after salvage
LDR 5 low dose rate; HDR 5 high dose rate; IBT 5 interstitial brachytherapy; CA 5 carcinoma; RT 5 radiotherapy; BT 5 brachytherapy; LRC 5 locoregional control; LC 5 local control; DSS 5 disease-specific survival; CFS 5 complication-free survival; PFS 5 progression-free survival; OS 5 overall survival; GU 5 genitourinary; GI 5 gastrointestinal; MSK 5 musculoskeletal.
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to toxicity in our study, conclusions cannot be drawn based on our small number of observed events. Toxicity data for direct correlation to our study are not available in the literature; however, in heterogeneous data sets (some that did not offer EBRT salvage for concerns of toxicity), Grade 3 or more toxicity generally range between 4% and 42.9% (Tables 3 and 4) (6e9,11). The low rates of acute Grade 3 or greater toxicity in treating primarily larger recurrences, many with prior radiation affirms that IBT is a reasonable and safe treatment option. While this compares favorably to the literature, such differences may be due to variations in dose, implantation procedure, CT or MRI-guidance techniques, and planning priorities and parameters. Additional reporting of results will help to further optimize brachytherapy fractionation in a way that improves LC of disease with minimal significant toxicity. The strengths of our study must be weighed against its limitations. To the best of our knowledge, our study is the largest study to date focusing on the outcomes of HDR IBT for locally recurrent endometrial carcinoma, regardless of prior radiation status, providing much needed clinical outcome data in this population. However, the relatively short median followup time and limited patient population of our study may limit the detection of late outcomes and differences in patient groups. Another limitation is the generalizability of our results, since IBT is a highly specialized technique that is available in a limited number of cancer treatment facilities and outcomes are dependent on the quality of implant procedure and treatment planning. Our study is also subject to selection bias, arguably having more fit patients offered radical HDR IBT rather than pursuing a palliative approach. Of note, our practice was to treat women with small recurrences with ICB with IBT given only to those thought to benefit from it. Further research is needed to help guide clinical practices surrounding the use of IBT as a salvage therapy option for recurrent endometrial cancer. Long-term outcomes of IBT are not yet well understood, and given its favorable clinical outcomes, long-term toxicity data gain importance. Larger studies including pooling of data may help to better understand the influences of various prognostic factors such as size, histology, and time to recurrence, along with optimal brachytherapy dose and other planning variables. Alternative treatment options for salvage that are also less morbid than pelvic exenteration such as SABR and addition of systemic agents to improve our outcomes are also an area that warrants further research (13, 14). In conclusion, this study supports the safe and effective use of salvage IBT for higher volume vaginal recurrences of endometrial carcinoma in women who might otherwise be treated palliatively. Outcomes are favorable in terms of 1e2 year LC, PFS, OS, and treatment-related toxicity. Results are comparable between previously irradiated and
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nonirradiated groups, suggesting prior radiation should not be a deterrent to offering women curative intent salvage HDR IBT for recurrent endometrial cancer.
Acknowledgments The authors thank dedicated brachytherapy nurses Tamie Murray and Leanne Derrah for their expertise and support; and Elizabeth Jewlal for her assistance with data collection. References [1] Canadian Cancer Statistics. Available at: http://www.cancer.ca. Accessed July 21, 2015. [2] http://seer.cancer.gov. Accessed July 29, 2015. [3] Fung-Kee-Fung M, Dodge J, Elit L, et al. Follow-up after primary therapy for endometrial cancer: A systematic review. Gynecol Oncol 2006;101:520e529. [4] Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: Multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404e1411. [5] Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744e751. [6] D’Souza D, Wiebe E, Patil N, et al. CT-based interstitial brachytherapy in advanced gynecologic malignancies: Outcomes from a single institution experience. Brachytherapy 2014;13:225e232. [7] Vargo JA, Kim H, Houser CJ, et al. Definitive salvage for vaginal recurrence of endometrial cancer: The impact of modern intensitymodulated-radiotherapy with image-based HDR brachytherapy and the interplay of the PORTEC 1 risk stratification. Radiother Oncol 2014;113:126e131. [8] Martinez-Monge R, Cambeiro M, Rodriguez-Ruiz ME, et al. Phase II trial of image-based high-dose-rate interstitial brachytherapy for previously irradiated gynecologic cancer. Brachytherapy 2014;13: 219e224. [9] Lee LJ, Damato AL, Viswanathan AN. Clinical outcomes following 3D image-guided brachytherapy for vaginal recurrence of endometrial cancer. Gynecol Oncol 2013;131:586e592. [10] Weitmann HD, Knocke TH, Waldhausl C, et al. Ultrasound-guided interstitial brachytherapy in the treatment of advanced vaginal recurrences from cervical and endometrial carcinoma. Strahlentherapie Onkol 2006;182:86e95. [11] Amsbaugh MJ, Bhatt N, Hunter T, et al. Computed tomography planned interstitial brachytherapy for recurrent gynecologic cancer. Brachytherapy 2015;14:600e605. [12] Westin SN, Rallapalli V, Fellman B, et al. Overall survival after pelvic exenteration for gynecologic malignancy. Gynecol Oncol 2014; 134:546e551. [13] Kunos CA, Sherertz TM, Mislmani M, et al. Phase I trial of carboplatin and gemcitabine chemotherapy and stereotactic ablative radiosurgery for the palliative treatment of persistent or recurrent gynecologic cancer. Front Oncol 2015;5:126. [14] Guckenberger M, Bachmann J, Wulf J, et al. Stereotactic body radiotherapy for local boost irradiation in unfavourable locally recurrent gynaecological cancer. Radiother Oncol 2010;94:53e59.
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High-dose-rate interstitial brachytherapy for the treatment of high-volume locally recurrent endometrial carcinoma Kitty Huang1, David D’Souza1,*, Nikhilesh Patil2, Vikram Velker1, Eric Leung3, Larry Stitt1, Frances Whiston1, Akira Sugimoto1, Jacob McGee1, Michel Prefontaine1 1 Department of Oncology, London Health Sciences Centre, Western University, London, Ontario, Canada Department of Radiation Oncology, Capital District Health Authority, Dalhousie University, Nova Scotia, Canada 3 Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
2
ABSTRACT
PURPOSE: Limited therapeutic options are available for the treatment of locally recurrent endometrial carcinoma. Our objective was to report an institutional experience using interstitial brachytherapy (IBT) to treat significant recurrent endometrial carcinoma, including previously irradiated disease. METHODS AND MATERIALS: Between December 2004 and September 2012, 40 patients with high-volume locally recurrent endometrial cancer were treated by high-dose-rate IBT (external beam radiation therapy (EBRT). Sixteen patients had prior radiotherapy: EBRT alone (n 5 5), intracavitary brachytherapy alone (n 5 3), or EBRT with intracavitary brachytherapy boost (n 5 8). Actuarial outcome rates were calculated using the KaplaneMeier method and compared using the log-rank test. RESULTS: Median followup interval was 18 months. Median disease-free interval was 61 months. Actuarial local control, progression-free survival (PFS), and overall survival were 74% and 60%, 70% and 51%, and 83% and 72% at 12 and 24 months, respectively. p-Values for local control, progression-free survival, and overall survival between patient who had prior RT (n 5 16) to no prior RT (n 5 24) were p 5 0.38, 0.32, and 0.90, respectively. Acute toxicities include Grade 1e2 pain (5%), genitourinary (7%), gastrointestinal (12%), soft tissue (5%), and dermatologic (12%). Four patients observed late Grade 3e4 toxicities, including rectal bleeding/fistula and soft tissue necrosis. CONCLUSIONS: High-dose-rate IBT is an effective treatment for locally recurrent endometrial carcinoma with an acceptable toxicity profile. Outcomes are similar between previously irradiated and nonirradiated patients. In women who have received prior radiotherapy and are often considered for palliative treatment, interstitial brachytherapy is a potentially curative option. Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Endometrial carcinoma; Salvage; High volume; High dose rate; Interstitial brachytherapy
Introduction Endometrial carcinoma is the most common gynecologic malignancy in North America (1, 2). The standard curative treatment for endometrial carcinoma involves a hysterectomy at the minimum, and depending on the stage Received 11 April 2016; received in revised form 16 May 2016; accepted 20 June 2016. Conflict of interest: No actual or potential conflicts of interest exist. * Corresponding author. London Regional Cancer Program, 790 Commissioners Rd E, London, Ontario, Canada. Tel.: 519-685-8500; fax: 519-685-8627. E-mail address: [email protected] (D. D’Souza).
and recurrence risk, can include adjuvant radiotherapy (RT) for improved local control (LC) or chemotherapy. Although patients with limited stage disease have a favorable prognosis, local recurrences of 13% for all patients and !5% for early stage have been reported (3). According to the PORTEC-2 study of early Stage I or IIA endometrial carcinoma patients with high-intermediate risk features, reported 5-year vaginal recurrence rates were 1.8% after vaginal brachytherapy(VBT) and 1.6% after external beam radiation therapy (EBRT); and 5-year locoregional relapse rates (vaginal and/or pelvic) were 5.1% after VBT and 2.1% after EBRT. Most local recurrences occur at the vaginal vault, which is commonly within an area of prior radiation (4, 5).
1538-4721/$ - see front matter Ó 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.06.010
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K. Huang et al. / Brachytherapy
Salvage treatment options depend on site and size of recurrence and prior treatment(s). Previously, nonirradiated patients can be treated with curative intent brachytherapy and external beam radiotherapy. However, treatment of patients with locally recurrent disease following initial treatment with pelvic irradiation presents a clinical challenge. Normal tissue dose tolerances may restrict the ability to safely deliver radical doses of radiation necessary to eradicate the disease using standard techniques. As a result, such patients often receive a palliative course of radiation. Surgical salvage typically involves a pelvic exenteration, which confers a significant risk of operative mortality and morbidity in a disease that affects a predominantly older population. Intracavitary or VBT is a common salvage option for treating recurrent endometrial cancer; however, concerns about dose coverage tend to limit its use to only small nonbulky vaginal recurrences. For bulky or extensive recurrences that cannot be adequately treated by VBT alone, interstitial brachytherapy (IBT) offers a potential and flexible solution. IBT is not only able to offer better dose coverage as compared to intracavitary brachytherapy (ICB), its optimal dose fall-off to spare normal surrounding tissue is advantageous over external beam radiotherapy. Successful treatment of local vaginal recurrence of endometrial cancer and other gynecologic malignancies has previously been reported; however, the vast majority are in patients initially treated by primary surgery alone without RT or in patients salvaged mainly by vaginal vault brachytherapy. Studies on high-dose-rate (HDR) IBT for recurrent uterine cancer rather than a heterogeneous group of gynecologic cancers are few. Especially in the setting of prior pelvic irradiation with IBT used as salvage treatment, outcomes are lacking and not well reported. Our objective is to report an institutional experience using HDR IBT, either alone or in combination with EBRT to treat significant locally recurrent endometrial carcinoma (which we defined in our study as large volume, paravaginal extension, lower vaginal disease) including women requiring reirradiation.
Methods Patient population Between December 2004 and September 2012, 40 patients with locally recurrent endometrial cancer underwent HDR IBT. These patients were identified from a REB-approved institutional database. This database was compiled from both retrospective and prospective data collection of any patient treated with IBT for gynecologic malignancies, as described previously (6). Additional followup data of patients lost to oncologic followup were further abstracted by outside physician correspondence.
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Patients had a clinical diagnosis of locally recurrent endometrial carcinoma and were deemed unsuitable for ICB either alone or with EBRT on the basis of size/ thickness of disease (O10 mm thick before treatment or size O2 cm) or location (most commonly the periurethral or paravaginal/parametrial region). Locally recurrent disease was diagnosed via pelvic examination and CT or MRI followed by histologic confirmation by biopsy. When suspected, regional or distant metastatic disease was evaluated by CT/MR imaging. Patients with evidence of regional or distant metastatic disease were excluded. RT consisted of IBT either alone or in combination with EBRT. Patients previously treated by ICB or EBRT or both were categorized in the prior RT group. Prior RT dosages consisted of 4500 cGy in 25 fractions to the pelvis and prior ICB boost consisted of 2100 cGy in 3 fractions alone or 1500 cGy in 3 fractions in combination with EBRT. Salvage RT pelvic dose was 4500 cGy in 25 fractions and was only given in the setting of a previously untreated pelvis. Brachytherapy technique Details of IBT procedure, image acquisition, and treatment planning are available in published literature (6). Briefly, catheter implantation was performed using a perineal implant template with a four-channel vaginal cylinder, and placement was based on prior imaging (CT, MR) and clinical examination at time of recurrence and then subsequently. Postimplant image acquisition by CT scan was obtained, and treatment planning and optimization was performed using BrachyVision (Varian Medical Systems Inc., Palo Alto, CA) treatment planning system. Clinical target volume (ascertained from initial clinical examination, diagnostic imaging, and examination under anesthesia), organ at risks (bladder, rectum, sigmoid, and small bowel), and dwell positions were delineated, and the plan was optimized based on dose volume histogram and isodose distribution curves. IBT dosages were determined based on biologically effective dose calculation and compared to equivalent 2 Gy fractions (EQD2). In the setting of prior irradiation, dose was determined using the following considerations: (1) dose needed to achieve a reasonable chance of controlling disease, (2) time elapsed from prior radiation to the area, (3) previous radiation dose given, that is EBRT alone vs. EBRT and VBT, (4) location, that is vaginal vault and within previously radiated volume vs. lower vagina and out of the previously radiated field. Median IBT prescription doses was 700 cGy 3 fractions and ranged from 500 to 750 cGy 3 fractions with the exception of 2 patients, one treated with 850 cGy in 2 fractions and the other with 550 cGy in 5 fractions. Assuming no repair from prior treatments, median cumulative EQD2 was 71.1 Gy (63e105.8 Gy EQD2); patients treated with prior RT received a median cumulative EQD2 of 74 Gy (63e105.8 Gy), and those without prior RT received an EQD2 of 71.1 Gy (68.3e77.1 Gy).
K. Huang et al. / Brachytherapy
Statistical analysis Followup time was calculated from time of IBT to date of last followup or death. Actuarial estimates of LC and overall survival (OS) were calculated using the KaplaneMeier method. LC was determined by date of last followup with absence of clinical, radiographic, or histological evidence of disease progression. OS was calculated by the date of diagnosis of endometrial cancer recurrence until death. Toxicities were evaluated according to Common Toxicity Criteria for Adverse Events (v. 4). Results were compared by a logrank test and statistical significance set at p!0.05. Statistical analysis was performed using SAS (version 8.1).
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Table 2 Local control, progression-free survival, and overall survival for patients with recurrent endometrial cancer, with and without prior radiation, treated with HDR IBT
Outcome Local control 1 yr 2 yr Progression-free survival 1 yr 2 yr Overall survival 1 yr 2 yr
All patients (n 5 40)
Without prior RT (n 5 24)
With prior RT (n 5 16)
74% 60%
77% 64%
70% 53%
70% 51%
73% 55%
65% 44%
83% 72%
81% 76%
86% 67%
p-value 0.38
0.32
0.90
Results
HDR 5 high dose rate; IBT 5 interstitial brachytherapy; RT 5 radiotherapy.
Patient characteristics including prior treatment modalities are summarized in Table 1. Median followup interval was 18 months, and median disease-free interval was 61 months. As shown in Table 2 and Fig. 1, actuarial LC rates at 12 and 24 months were 74% and 60%, respectively. Progression-free survival (PFS) rates at 12 and 24 months were 70% and 51%, respectively, including 15 locoregional recurrences and three distant recurrences. OS rates at 12 and 24 months were 83% and 72%, respectively. Comparing patients who had prior RT (n 5 16) to no prior RT (n 5 24), LC rates were 70% and 53%, compared to 77% and 64% at 12 and 24 months, respectively ( p 5 0.38). Similarly, PFS rates were 65% and 44% (prior RT), compared to
73% and 55% (no prior RT) at 12 and 24 months ( p 5 0.32). OS at 12 and 24 months were 86% and 67% (prior RT); 81% and 76% (no prior RT), respectively ( p 5 0.90). Grade 1e2 toxicities in the acute setting, or within 6 months, include pain (5%), genitourinary (7%), gastrointestinal (12%), soft tissue (5%), and dermatologic (12%). Acute Grade 3 or higher was not observed. The rates of Grade 3 and 4 long-term toxicity were low and include rectal bleeding, rectovaginal fistula, cystitis, radiation necrosis, and secondary osteoarthritis (Table 3). Median EQD2 for patients experiencing no toxicity was 71.1 Gy (68.3e98 Gy), and any toxicity was 74 Gy (63e105.8 Gy).
Table 1 Patient characteristics
Discussion
Patient characteristic Age (yr) Median Range Median disease-free interval (mo) Initial FIGO stage I II III IV Histology Adenocarcinoma NOS Endometrioid Serous/clear cell Sarcoma Undifferentiated CA Size of recurrence (CTV) !50 cc 50e100 cc O100 cc Prior treatment Chemotherapy (carboplatin/paclitaxel) EBRT (45 Gy in 25 fractions) BT (1500e2100 cGy in 3 fractions)
n 69 38e91 61 28 8 2 2
68% 20% 5% 5%
9 25 4 1 1
22.5% 62.5% 10% 2.5% 2.5%
19 16 5
48% 40% 12%
5 13 11
12% 32% 28%
NOS 5 not otherwise specified; CA 5 carcinoma; CTV 5 clinical target volume; EBRT 5 external beam radiotherapy; BT 5 brachytherapy; FIGO 5 The International Federation of Gynecology and Obstetrics.
Limited salvage therapy options are available for the recurrence of endometrial cancer that are not small in size and contained within the upper vagina. While most women are seen regularly in followup after initial surgery radiation, our experience shows that some will present with local recurrence with a higher volume or distribution of disease at the time of recurrence. Concerns for the ability to deliver a radical dose of radiation, especially within an area of prior RT, or unacceptable rates of surgical mortality and morbidity in patients can often restrict treatment intent to palliation alone. With advances in brachytherapy including image guidance and treatment planning, HDR IBT is emerging as a potentially curative treatment option for bulky recurrenceselarge volume disease not curable by ICB alone, by allowing high doses to be delivered to gross disease with good sparing of surrounding tissues. However, IBT is not widely offered and supporting data for its safe and effective use is lacking particularly with HDR. This study reports on clinical outcomes of 40 patients with recurrent endometrial cancer salvaged with HDR IBT. Our institutional experience showed favorable outcomes in terms of LC, PFS, OS, and toxicity with a median followup interval of 18 months.
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Table 3 Acute and late toxicity for patients with recurrent endometrial cancer, treated with HDR IBT Toxicity
All patients, n (%) Prior RT
Acute toxicity Any Grade 12 (30) Grades 1e2 Dermatologic 5 (12.5) Soft tissue 2 (5) Gastrointestinal 5 (12.5) Genitourinary 3 (7.5) Pain 2 (5) Late toxicity Any grade 12 (30) Grades 1e2 Dermatologic 4 (10) Soft tissue 2 (5) Gastrointestinal 6 (15) Genitourinary d Reproductive/ Sexual 8 (20) Pain 1 (2.5) Grades 3e4 Soft tissue 1 (2.5) Gastrointestinal 2 (5) Genitourinary 1 (2.5) Musculoskeletal 1 (2.5)
Comments
No prior RT: No Grade 3 or n56 higher toxicity Prior RT: n56
No prior RT: Severe Grade 3e4 n58 toxicities, include Prior RT: rectal bleeding, n54 radiation necrosis, rectovaginal fistula, cystitis, secondary osteoarthritis No Grade 5 toxicity
HDR 5 high dose rate; IBT 5 interstitial brachytherapy; RT 5 radiotherapy.
Fig. 1. KaplaneMeier estimates of (a) local control, (b) progression-free survival, and (c) overall survival. RT 5 radiotherapy.
Previous studies on brachytherapy for recurrent endometrial carcinoma within the last decade are characterized by small or highly heterogeneous patient populations and treatments, making robust comparison and interpretation challenging (6e11). Studies often include only smaller volumes of recurrence, whereas large volume recurrences have
been suggested to be a poor prognostic indicator (11). Status of prior RT also varies among studies, which is important since outcomes in patients with gynecologic cancer recurrence after prior radiation are considered to be unfavorable, with approximate 5-year OS of 40% despite salvage pelvic exenteration (12). Indeed, patients with high-volume recurrences and patients treated with prior RT are two common exclusion criteria for either treatment or analysis in a variety of previous literature. Although our patient population is often considered palliative, salvage IBT achieved OS outcomes comparable to patients with small volume recurrences. This suggests tumor volume may not be a prognostic indicator when adequate doses of radiation can be delivered to recurrent disease and, as such, should not preclude select patients from being offered radical treatment options. In Table 4, our OS rates are comparable to other reported series involving an arguably more favorable patient population that were salvaged mainly by vaginal vault brachytherapy (7, 9). Our LC rates from IBT seem inferior (60% 2-year LC as compared to 96% 2-year LC by Lee et al.), which may be a result of selection bias as our series excluded small vaginal recurrences treatable by VBT. However, our data are congruent with recent literature on IBT salvage of gynecologic malignancies, reporting LC rates ranging from 71.5% at 1 year to 47% at 5 years (8, 10, 11). Recent studies regarding reirradiation for recurrent endometrial cancer are scarce; a comparison of the limited
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Table 4 Summary of contemporary studies on VBT or IBT salvage for recurrent endometrial cancer Study
BT salvage
Outcome
No prior RT (%)
Prior RT (%)
p
Grade $3 toxicity after salvage
Lee et al., 2013. n 5 44 (n 5 13 prior RT) Vargo et al., 2014. n 5 41 (no prior RT) Present study n 5 40 (n 5 17 prior RT)
LDR/HDR IBT (80%), VBT (20%) HDR VBT (73%)/IBT (27%) HDR IBT
2 yr LC 2 yr OS 3 yr LC 3 yr OS 2 yr LC 2 yr OS
96 80 95 67 64 76
61 55 d
0.1 0.1 d
9% (n 5 4) All IBT 3 with prior RT 5% (n 5 2)
53 67
0.38 0.90
Acute: 0% Late: 2.5% soft tissue, 5% GI, 2.5% GU, 2.5% MSK
LDR 5 low dose rate; HDR 5 high dose rate; BT 5 brachytherapy; IBT 5 interstitial brachytherapy; VBT 5 vaginal brachytherapy; RT 5 radiotherapy; LC 5 local control; OS 5 overall survival; GU 5 genitourinary; GI 5 gastrointestinal; MSK 5 musculoskeletal.
outcome data to our study is provided in Tables 4 and 5 (8, 9, 11). Our data support that reirradiation status was not found to be a significant prognostic indicator and supports the use of IBT in previously irradiated and nonirradiated patients for radical intent (9). Lee et al., reported on interstitial and intracavitary salvage brachytherapy in patients with and without prior radiation, showing a trend for less favorable outcomes in previously irradiated patients. Amsbaugh et al. reported on a group of 21 patients with recurrent gynecologic cancer, the vast majority of which (n 5 18) had prior radiation, concluding that reirradiation is both safe and effective (11). Our study found favorable survival in this group with a 2-year OS of 67% for previously radiated patients, in comparison to 52.5e55%. Our results are also in keeping with previous studies with larger and more heterogeneous patient populations,
reporting on all endometrial cancer salvage outcomes regardless of technique (VBT or IBT), or all gynecologic malignancies salvaged with IBT, as summarized in Tables 3e5 (6). Comparing our outcomes against these other studies supports the validity of our selected data set. Differences between these prior studies may be due to differences in patient populations (i.e., inclusion of patients with various gynecologic malignancies or regional recurrence), lower dose prescriptions especially in the reirradiation scenario, and older brachytherapy techniques (9, 11). In contrast to standard salvage techniques whereby curative outcomes may not be achieved without unacceptable toxicity, our data confirm the safety of IBT. No severe acute toxicity of Grade 3 or more was observed, including in the reirradiation scenario. Although toxicity risk factors such as prior RT and cumulative EQD2 were not clearly associated
Table 5 Summary of contemporary studies on HDR IBT for gynecologic CA No prior RT (%)
Prior RT (%)
All pts (%)
1 yr LRC 1 yr PFS 1 yr OS 2 yr OS 3 yr LC 3 yr DFS 3 yr OS
d
d
68 65 73
d
71.5 66.0 82.2 52.5 d
2 yr LC 2 yr DFS þ Gr $3 CFS 2 yr OS 5 yr LC 5 yr DSS
d
d 40
71.4 59.3
42.9% 28.6% vaginal 9.5% urinary 19% rectal 4% (n 5 2) acute 21% late (14 events in 10 pt; 3 recurrence cases; fistula, necrosis, fibrosis/induration, bleeding/telangiectasia, hip fracture) 20% (n 5 3) (1 Grade 5, bowel obstruction, fistula)
d
d
47 43
n/a (9% side effects and severe complications)
1 yr LC 1 yr PFS 1 yr OS 2 yr LC 2 yr PFS 2 yr OS
77 73 81 64 56 76
73 68 87 55 47 68
75 71 83 60 51 73
Acute: 0% Late: 2.5% soft tissue, 5% GI, 2.5% GU, 2.5% MSK
Study
BT salvage
Patient population
Outcome
Amsbaugh et al., 2015
LDR/HDR IBT
n 5 21 (11 endometrial, 18 prior RT)
D’Souza et al., 2014
HDR IBT
n 5 47 primary and recurrent gyne CA (13 recurrent endometrial)
Martinez-Monge et al., 2014
HDR IBT
n 5 15 recurrent gyne CA (6 endometrial)
Weitmann et al. 2006
HDR/PDR IBT
Present study
HDR IBT
n 5 23 recurrent cervical or endometrial CA (6 endometrial) n 5 40 recurrent endometrial CA (n 5 17 prior RT)
Gr $3 toxicity after salvage
LDR 5 low dose rate; HDR 5 high dose rate; IBT 5 interstitial brachytherapy; CA 5 carcinoma; RT 5 radiotherapy; BT 5 brachytherapy; LRC 5 locoregional control; LC 5 local control; DSS 5 disease-specific survival; CFS 5 complication-free survival; PFS 5 progression-free survival; OS 5 overall survival; GU 5 genitourinary; GI 5 gastrointestinal; MSK 5 musculoskeletal.
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to toxicity in our study, conclusions cannot be drawn based on our small number of observed events. Toxicity data for direct correlation to our study are not available in the literature; however, in heterogeneous data sets (some that did not offer EBRT salvage for concerns of toxicity), Grade 3 or more toxicity generally range between 4% and 42.9% (Tables 3 and 4) (6e9,11). The low rates of acute Grade 3 or greater toxicity in treating primarily larger recurrences, many with prior radiation affirms that IBT is a reasonable and safe treatment option. While this compares favorably to the literature, such differences may be due to variations in dose, implantation procedure, CT or MRI-guidance techniques, and planning priorities and parameters. Additional reporting of results will help to further optimize brachytherapy fractionation in a way that improves LC of disease with minimal significant toxicity. The strengths of our study must be weighed against its limitations. To the best of our knowledge, our study is the largest study to date focusing on the outcomes of HDR IBT for locally recurrent endometrial carcinoma, regardless of prior radiation status, providing much needed clinical outcome data in this population. However, the relatively short median followup time and limited patient population of our study may limit the detection of late outcomes and differences in patient groups. Another limitation is the generalizability of our results, since IBT is a highly specialized technique that is available in a limited number of cancer treatment facilities and outcomes are dependent on the quality of implant procedure and treatment planning. Our study is also subject to selection bias, arguably having more fit patients offered radical HDR IBT rather than pursuing a palliative approach. Of note, our practice was to treat women with small recurrences with ICB with IBT given only to those thought to benefit from it. Further research is needed to help guide clinical practices surrounding the use of IBT as a salvage therapy option for recurrent endometrial cancer. Long-term outcomes of IBT are not yet well understood, and given its favorable clinical outcomes, long-term toxicity data gain importance. Larger studies including pooling of data may help to better understand the influences of various prognostic factors such as size, histology, and time to recurrence, along with optimal brachytherapy dose and other planning variables. Alternative treatment options for salvage that are also less morbid than pelvic exenteration such as SABR and addition of systemic agents to improve our outcomes are also an area that warrants further research (13, 14). In conclusion, this study supports the safe and effective use of salvage IBT for higher volume vaginal recurrences of endometrial carcinoma in women who might otherwise be treated palliatively. Outcomes are favorable in terms of 1e2 year LC, PFS, OS, and treatment-related toxicity. Results are comparable between previously irradiated and
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nonirradiated groups, suggesting prior radiation should not be a deterrent to offering women curative intent salvage HDR IBT for recurrent endometrial cancer.
Acknowledgments The authors thank dedicated brachytherapy nurses Tamie Murray and Leanne Derrah for their expertise and support; and Elizabeth Jewlal for her assistance with data collection. References [1] Canadian Cancer Statistics. Available at: http://www.cancer.ca. Accessed July 21, 2015. [2] http://seer.cancer.gov. Accessed July 29, 2015. [3] Fung-Kee-Fung M, Dodge J, Elit L, et al. Follow-up after primary therapy for endometrial cancer: A systematic review. Gynecol Oncol 2006;101:520e529. [4] Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: Multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404e1411. [5] Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744e751. [6] D’Souza D, Wiebe E, Patil N, et al. CT-based interstitial brachytherapy in advanced gynecologic malignancies: Outcomes from a single institution experience. Brachytherapy 2014;13:225e232. [7] Vargo JA, Kim H, Houser CJ, et al. Definitive salvage for vaginal recurrence of endometrial cancer: The impact of modern intensitymodulated-radiotherapy with image-based HDR brachytherapy and the interplay of the PORTEC 1 risk stratification. Radiother Oncol 2014;113:126e131. [8] Martinez-Monge R, Cambeiro M, Rodriguez-Ruiz ME, et al. Phase II trial of image-based high-dose-rate interstitial brachytherapy for previously irradiated gynecologic cancer. Brachytherapy 2014;13: 219e224. [9] Lee LJ, Damato AL, Viswanathan AN. Clinical outcomes following 3D image-guided brachytherapy for vaginal recurrence of endometrial cancer. Gynecol Oncol 2013;131:586e592. [10] Weitmann HD, Knocke TH, Waldhausl C, et al. Ultrasound-guided interstitial brachytherapy in the treatment of advanced vaginal recurrences from cervical and endometrial carcinoma. Strahlentherapie Onkol 2006;182:86e95. [11] Amsbaugh MJ, Bhatt N, Hunter T, et al. Computed tomography planned interstitial brachytherapy for recurrent gynecologic cancer. Brachytherapy 2015;14:600e605. [12] Westin SN, Rallapalli V, Fellman B, et al. Overall survival after pelvic exenteration for gynecologic malignancy. Gynecol Oncol 2014; 134:546e551. [13] Kunos CA, Sherertz TM, Mislmani M, et al. Phase I trial of carboplatin and gemcitabine chemotherapy and stereotactic ablative radiosurgery for the palliative treatment of persistent or recurrent gynecologic cancer. Front Oncol 2015;5:126. [14] Guckenberger M, Bachmann J, Wulf J, et al. Stereotactic body radiotherapy for local boost irradiation in unfavourable locally recurrent gynaecological cancer. Radiother Oncol 2010;94:53e59.