Preoperative Radiotherapy for Inoperable Stage II Endometrial Cancer: Insights into Improving Treatment and Outcomes

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1 Preoperative Radiotherapy for Inoperable Stage II Endometrial Cancer: Insights into Improving Treatment and Outcomes Marette H. Lee, MD, Christina Aquino-Parsons, MD, Paul J. Hoskins, MD, Peter Lim, MD, Janice S. Kwon, MD, MPH Division of Gynaecologic Oncology, University of British Columbia and BC Cancer Agency, Vancouver BC Abstract Objective: To review recurrence patterns and survival outcomes of women receiving preoperative radiotherapy for clinical stage II endometrial cancer in British Columbia. Methods: We performed a retrospective population-based cohort study of all patients with clinical stage II endometrial cancer who were referred to the British Columbia Cancer Agency from 2000 to 2008, deemed ineligible for primary surgery, and therefore offered preoperative radiotherapy followed by surgery. Patient demographics, uterine risk factors, timing and details of treatments, and timing and sites of recurrence were obtained from patient records. Primary outcome measures were the sites and rates of recurrence and recurrence-free survival. Results: We identified 29 patients with a mean age of 61 years (range 41 to 83) and median follow-up of 3.1 years (range 0.3 to 5.3). Three-year overall survival was 79%, and median recurrence-free survival was 2.5 years. Eight patients had recurrence of disease (27.6%), with a median time to recurrence of 1.3 years, (range 0.4 to 2.7). Six of these eight women had two or more high-risk uterine factors (deep myometrial invasion, grade 3 tumour), ovarian involvement, or adverse histological type (carcinosarcoma), compared with only one of 21 patients without recurrence. Seven of eight women had recurrence outside the radiated volume of tissue. Median survival after recurrence was 1.0 years (range 0.4 to 2.2). Conclusions: Women with clinical stage II endometrial cancer had a significant risk of recurrence when treated with preoperative radiotherapy followed by surgery. They were more likely to have distant recurrences, implying the need for an alternate treatment paradigm. Key Words: Endometrial carcinoma, preoperative radiotherapy, recurrence Competing Interests: None declared. Received on September 6, 2012 Accepted on April 23, 2013 Résumé Objectif : Passer en revue les profils de récurrence et les issues en matière de survie, en ce qui concerne les femmes qui reçoivent une radiothérapie préopératoire en raison de la présence d un cancer de l endomètre de stade clinique II en Colombie-Britannique. Méthodes : Nous avons mené une étude de cohorte rétrospective en population générale qui portait sur toutes les patientes présentant un cancer de l endomètre de stade clinique II qui ont été orientées vers la British Columbia Cancer Agency entre 2000 et 2008, qui étaient estimées comme étant inadmissibles à la chirurgie primaire et qui, donc, se sont vu offrir une radiothérapie préopératoire suivie d une chirurgie. Les caractéristiques démographiques des patientes, les facteurs de risque utérins, la chronologie et les détails des traitements, et la chronologie et les sites des récurrences ont été tirés des dossiers des patientes. La survie sans récurrence et les sites et les taux de récurrence constituaient les critères d évaluation primaires. Résultats : Nous avons identifié 29 patientes dont l âge moyen était de 61 ans (plage de 41 à 83) et dont le suivi médian était de 3,1 ans (plage de 0,3 à 5,3). Le taux global de survie à trois ans était de 79 % et la survie médiane sans récurrence était de 2,5 ans. Huit patientes ont connu une récurrence de la maladie (27,6 %), le délai médian avant l apparition de la récurrence étant de 1,3 an (plage de 0,4 à 2,7). Six de ces huit femmes présentaient deux facteurs de risque utérins élevés ou plus (envahissement myométrial profond, tumeur de grade 3), un envahissement ovarien ou un type histologique indésirable (carcinosarcome), par comparaison avec seulement une des 21 patientes n ayant pas connu de récurrence. Sept des huit femmes ont connu une récurrence au-delà du volume de tissu irradié. La survie médiane à la suite de la récurrence était de 1,0 an (plage de 0,4 à 2,2). Conclusions : Les femmes présentant un cancer de l endomètre de stade clinique II étaient exposées à un risque significatif de récurrence lorsqu elles ont été traitées au moyen d une radiothérapie préopératoire suivie d une chirurgie. Elles étaient plus susceptibles de présenter des récurrences distantes, ce qui sous-entend la nécessité de formuler un autre paradigme de traitement. J Obstet Gynaecol Can 2013;35(7): JULY JOGC JUILLET

2 INTRODUCTION For women who have endometrial cancer with gross cervical involvement (clinical stage II), the National Comprehensive Cancer Network recommends either radical hysterectomy and bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy, or, if the cancer is inoperable, dual modality treatment with pelvic radiotherapy followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy with para-aortic lymphadenectomy. 1 The British Columbia Cancer Agency has had a more conservative policy for women with stage II endometrial cancer. If there is gross cervical involvement or the cervix or parametria are palpably abnormal, primary pelvic radiotherapy is recommended followed by extrafascial TAHBSO, without lymphadenectomy. 2 Preoperative radiation does not allow accurate staging or the assessment of high-risk tumour factors used to decide the need for adjuvant therapy. 3 5 Some patients may have earlier stage, lower risk disease that does not warrant radiation. Conversely, other patients may have high-risk uterine factors or even stage III disease, and they may have benefited from the addition of chemotherapy. 2,6 11 The objective of this study was to conduct a populationbased analysis of women with clinical stage II endometrial cancer treated with preoperative radiotherapy followed by TAHBSO, to characterize outcomes and potential risk factors, and in so doing to assess the efficacy of this treatment paradigm. METHODS We conducted a retrospective population-based cohort study of women in British Columbia who had received preoperative RT according to BCCA guidelines for clinical stage II endometrial cancer (external beam RT: 4500cGy to the pelvis in 25 fractions and intracavitary low-dose radiation brachytherapy: 2700cGy to point A). 2 The goal of preoperative RT was to inactivate potential disease in the cervix and parametria. Potential remaining uterine disease was removed via TAHBSO performed by a gynaecologic oncologist. Our primary outcome measures were survival outcomes and rates and patterns of recurrence. ABBREVIATIONS BCCA British Columbia Cancer Agency RT radiotherapy TAHBSO total abdominal hysterectomy and bilateral salpingo-oophorectomy Cases were identified from the BCCA population-based registry from January 1, 2000, to December 31, Potential cases were identified as patients who had a diagnosis of endometrial cancer (all histologic types except small cell), clinical involvement of the cervix on visualization or palpation (clinical stage II), negative pelvic and para-aortic lymph nodes on CT (when performed), and who were treated with radiation therapy followed by hysterectomy. Given the occasional ambiguity regarding the primary tumour site, we also searched for patients who had a diagnosis of cervical cancer (adenocarcinoma or adenosquamous carcinoma) and a hysterectomy within six months of completion of radiation treatment. Of the 58 cases identified, 29 were excluded. Reasons for exclusion involved having stage 1 disease and being medically unfit for surgery (n = 2), having stage 3 (n = 15) or stage 4 (n = 3) disease on examination or imaging, having postoperative rather than preoperative radiation (n = 7), or having a cervical primary (n = 2). Data were collected regarding patient demographics; pretreatment histopathology and staging investigations; dose and timing of radiation, surgery and chemotherapy; surgical pathology; patient outcomes including time to recurrence, recurrence location and treatment; and date of last followup or death and cause of death. Pathology reports were reviewed regarding evidence of residual disease and high risk uterine factors (including deep myometrial invasion [> 50%], cervical stromal involvement, high grade tumour and adverse histological type [serous, clear cell, carcinosarcoma]). Diseasefree survival and overall survival were calculated using Kaplan Meier curves based on the start date of radiotherapy to the date of recurrence and date of death, respectively, or censored at last follow-up. Fisher exact test was employed to analyze the relationship between disease recurrence and risk factors for recurrence. Ethics approval was obtained from University of British Columbia BCCA Research Ethics Board. RESULTS We included 29 patients from the BCCA provincial registry in this study. The mean age of diagnosis was 62 years (range 41 to 83). All patients had clinical involvement of the cervix and received preoperative radiotherapy (external beam to pelvis + intracavitary brachytherapy) followed by extrafascial hysterectomy and removal of the remaining adnexa. Only one patient had a pelvic lymphadenectomy. Descriptions of clinical involvement of the cervix at diagnosis were highly variable, ranging from a 4 cm mass replacing the cervix to a normal appearing cervix with an abnormal 636 JULY JOGC JUILLET 2013

3 Preoperative Radiotherapy for Inoperable Stage II Endometrial Cancer: Insights into Improving Treatment and Outcomes Table 1. Initial pre-radiotherapy biopsy versus post-radiotherapy histologic subtype and grade Pre-radiotherapy n (%) Post-radiotherapy n (%) Histologic subtype Endometrioid 25 (86.2) 14 (48.3) Serous 1 (3.5) 1 (3.5) Clear cell 1 (3.5) 1 (3.5) Undifferentiated 1 (3.5) 0 Carcinosarcoma 1 (3.5) 2 (6.9) CAH 0 2 (6.9) Unassigned 0 4 (13.8) Negative 0 5 (17.2) Grade 1 6 (20.7) 4 (13.8) 2 15 (51.7) 2 (6.9) 3 7 (24.1) 7 (24.1) Unassigned 1 (3.5) 11 (37.9) Negative 0 5 (17.2) CAH: complex atypical hyperplasia feeling endocervix to an otherwise normal cervix that was slightly firm on palpation. The median number of days between completion of RT and date of surgery was 63 days (range 31 to 99). Overall median follow-up time was three years (range 0.3 to 5.3). Two patients were lost to follow-up after surgery was completed. Exclusion of these two patients did not change the three-year overall survival rate of 79% and the twoyear disease-free survival rate of 75%. Only one patient in the non-relapsing group died, of unknown causes. Comparative pre-treatment biopsy and post-treatment histopathology results are shown in Table 1. After preoperative radiotherapy, five women (17.2%) had no residual tumour and two (6.9%) had only complex atypical hyperplasia. Of those with residual tumour following radiotherapy, no grade was assigned in 11/29 cases, and no histological type was specified in 4/29 cases, because of difficulties with interpretation following radiation. Eight of 29 patients had recurrence of disease (27.6%). Recurrences were diagnosed clinically on examination with or without biopsy, or by imaging as indicated by symptomatology. Treatment of recurrences was individualized for each patient. Six of these eight women had distant recurrences. Only one patient had recurrence within the radiated volume of tissue. Recurrences occurred in the vagina (n = 1), pelvis (n = 1), supraclavicular node (n = 1), abdomen (n = 2), para-aortic lymph nodes (n = 3), and lung (n = 3). Median time to recurrence was 1.3 years (range 0.1 to 2.4). At last follow-up, seven of eight patients who had recurrence had died of disease. Median survival after diagnosis of recurrence was one year (range 0.4 to 2.2). The associations between potential risk factors and recurrence are shown in Table 2. Although not statistically significant because of small numbers, there was a trend towards increased high-risk postoperative histology (P = 0.052) and grade 3 tumours (P = 0.06) in patients whose disease recurred. Of the eight who had recurrence, six still had at least two high-risk uterine factors on post-radiotherapy hysterectomy histology (a grade 3 tumour with deep myometrial invasion [n = 4], 11 ovarian involvement [n = 1], or high-risk histological type [carcinosarcoma, n = 1]), whereas only one of 21 patients who did not have recurrence had a similar risk profile (P < 0.001, Fisher exact test). Older age and the presence of residual cervical disease on preoperative MRI, endocervical curettage before surgery, or in the final hysterectomy specimen were not associated with recurrence. Of the six patients with residual disease on hysterectomy pathology who had recurrence, all had high-risk uterine factors. Only two patients with apparent high-risk disease at hysterectomy did not have recurrence; one of these had grade 1 endometrioid adenocarcinoma with deep myometrial invasion and cervical stromal involvement, and the other had high-grade serous adenocarcinoma with deep myometrial invasion and lymphovascular-space invasion. JULY JOGC JUILLET

4 Table 2. Comparison of risk factors according to recurrence Risk factor Recurrence n = 8 (%) No recurrence n = 21 (%) P Mean age, years * Evidence of cervical disease on pre-treatment MRI 2 (40) 5 (55.6) n = 5 n = 9 Residual cervical disease on preoperative endocervical curettage 2 (25.0) 6 (28.6) Residual disease in hysterectomy specimen 6 (75) 18 (85.7) High risk histologic subtype (serous, carcinosarcoma, clear cell) 3 (37.5) 1 (4.8) Grade 3 adenocarcinoma 4 (50) 3 (14.3) High risk factors on final pathology 6 (75.0) 1 (4.8) <0.001 *t test Fisher exact test, two-tailed High-risk factors included the combination of a grade 3 endometrioid tumour with deep myometrial invasion (n = 4); a high-risk histologic type, including carcinosarcoma (n = 1) and serous carcinoma (n = 1); or ovarian involvement (n = 1). DISCUSSION We found that women with clinical stage II endometrial cancer who were treated with preoperative pelvic radiotherapy followed by TAHBSO in British Columbia had a significant risk of recurrence (27.6%), and the majority of recurrences were distant. Clinical staging of endometrial cancer correlates poorly with surgical staging 3 5 and clinical outcomes The advantage of primary surgical staging is that it provides specific prognostic information and facilitates directed therapy to maximize survival and to minimize the effects of under treatment (i.e., recurrent disease or increased mortality) and the potential morbidity associated with overtreatment. 15 Disparities in five-year survival have been reported for clinical and surgical stage II disease (67.6% and 78.3%, respectively), demonstrating the phenomenon of stage migration where many clinically staged patients have more advanced occult disease. 12 In a population-based study of endometrial cancer outcomes in British Columbia from 2005 to 2009, women with cervical stromal involvement found at primary surgical staging (including lymphadenectomy) had a 37.5% risk of pelvic nodal disease. 10 In retrospective series of patients with clinical stage II endometrial cancer, diseasefree survival after primary surgery followed by adjuvant radiation was not significantly different from diseasefree survival after preoperative radiotherapy followed by surgery. 13,16 These studies all support a general approach using primary surgical staging for endometrial cancer even when the cervix is clinically involved. However, primary radiotherapy may be necessary where gynaecologic oncologists are unavailable, when the primary tumour does not seem resectable, or when the patient is medically unfit for surgery. If surgery is feasible after radiotherapy, the National Comprehensive Cancer Network recommends para-aortic lymphadenectomy along with TAH BSO, to assess for extra-uterine disease risk and inform choices about possible adjuvant chemotherapy. 1 Higgins et al. 16 reported a 7.1% rate of para-aortic lymph node involvement in 74 patients treated in this manner. In our series, three of eight patients had recurrences in the para-aortic lymph nodes, suggesting that these nodes should be assessed at surgery. However, five patients had distant recurrence, suggesting that para-aortic lymphadenectomy alone may not be sufficient and that adjuvant chemotherapy may still be warranted even in the absence of para-aortic nodal disease. When preoperative radiotherapy is used to treat stage II disease, patients are at significant risk of recurrence, particularly distant recurrence. This suggests that they may need systemic treatment. Radiotherapy is effective in decreasing local-regional recurrence, but not distant metastases or survival outcomes. 12,17 19 There is increasing evidence that chemotherapy improves survival in both early and advanced stage disease. 6 9,18,20 Response rates to primary chemotherapy in advanced endometrial cancer are high (60% to 78% for serous and non-serous histologic types, respectively 21 ), and neoadjuvant chemotherapy has been used in advanced inoperable endometrial cancer, resulting in optimal debulking rates of 80%. 22 Trimodality therapy (surgery, radiation, chemotherapy) has been used in women with advanced endometrial cancer, 6,23 25 and as there is increasing evidence that chemotherapy may be beneficial for those with early stage high-risk disease, 7,9 there may be a role for trimodality therapy in stage II endometrial cancer as well. 638 JULY JOGC JUILLET 2013

5 Preoperative Radiotherapy for Inoperable Stage II Endometrial Cancer: Insights into Improving Treatment and Outcomes CONCLUSION Women with clinical stage II endometrial cancer have a significant risk of disease recurrence. The results of this study suggest that we must continue to advocate for surgical staging whenever possible to accurately assess disease distribution and tailor treatment accordingly. However, when patients have inoperable clinical stage II endometrial cancer, consideration might be given to neoadjuvant chemotherapy (because the risk of nodal or distant metastases appears to be high), followed by completion hysterectomy. Radiation would be offered afterwards, as these patients are still at high risk for pelvic recurrence of disease. REFERENCES 1. Greer BE, Koh WJ, Abu-Rustum N, Bookman MA, Bristow RE, Campos SM, et al. Uterine neoplasms. Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2009;7(5): Endometrium. 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