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Adjuvant radiation in early stage, unfavorable histology endometrial carcinoma is associated with improved local control and survival
Gynecologic Oncology 133 (2014) 250–255
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Adjuvant radiation in early stage, unfavorable histology endometrial carcinoma is associated with improved local control and survival David Ly a, Braden D. Rowley b, Mark K. Dodson c, Pat A. Soisson c, Christopher J. Jolles d, David K. Gaffney a,⁎, William T. Sause e a
Huntsman Cancer Institute, University of Utah, Department of Radiation Oncology, Salt Lake City, UT, USA Intermountain Healthcare, Oncology Clinical Program, Salt Lake City, UT, USA Huntsman Cancer Institute, University of Utah, Division of Gynecological Oncology, Salt Lake City, UT, USA d Special Gynecology and Oncology, Riverton, UT, USA e Intermountain Medical Center, Radiation Oncology, Salt Lake City, UT, USA b c
H I G H L I G H T S • We compared the association of adjuvant radiation therapy and outcomes in patients with unfavorable histology, FIGO IA endometrial cancer. • Adjuvant radiation therapy was associated with a significant improvement in local–regional control. • Adjuvant radiation therapy was associated with a significant improvement in overall survival.
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Article history: Received 4 December 2013 Accepted 23 February 2014 Available online 28 February 2014 Keywords: Endometrial Radiation Radiotherapy Clear cell Papillary serous Unfavorable histology
a b s t r a c t Objective. Unfavorable histology endometrial carcinomas confer worse prognosis. We determined the association of adjuvant radiation on local recurrence and survival for unfavorable, early stage endometrial cancer. Methods. We retrospectively identified 125 patients who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid), endometrial carcinoma treated between 1992 and 2011. Patients were restaged according to current FIGO 2009 guidelines. Primary endpoint was local control and secondary endpoints were distant recurrence and overall survival. Results. The median age of the cohort was 67 years old with a mean follow up 152 months. Adjuvant radiation was delivered in 60 patients (48%). There were a total of 24 recurrences; 5 had local–regional recurrences, 4 local and distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. The 5-year local–regional control was 97.8% in patients who received radiation and 80.1% in patients who did not receive radiation (p = 0.018). The 5-year overall survival rate was 68.1% if patients did not receive radiation and 84.9% if they did receive radiation (p = 0.0062). On univariate analysis, only radiation (HR 0.12, 95% CI: 0.03 to 0.49, p-value = 0.018) was associated with a significant increase in local relapse free survival. Conclusions. Adjuvant radiation therapy was significantly associated with an improvement in local–regional control and overall survival in patients with unfavorable histology, early stage endometrial cancer. © 2014 Elsevier B.V. All rights reserved.
Introduction Endometrial carcinoma is the most common gynecologic malignancy in the United States with an incidence of 40,000 cases a year. Approximately 80% of endometrial carcinomas are of Type I origin (endometrioid adenocarcinomas) while the second most common histologies are of Type II origin (clear cell and papillary serous). Type I tumors are estrogen dependent tumors, and patients are more likely ⁎ Corresponding author at: University of Utah, Department of Radiation Oncology, 1950 Circle of Hope, RM 1570, Salt Lake City, UT 84112, USA. Fax: +1 801 585 2666. E-mail address: [email protected] (D.K. Gaffney).
http://dx.doi.org/10.1016/j.ygyno.2014.02.032 0090-8258/© 2014 Elsevier B.V. All rights reserved.
to be diagnosed at an earlier stage. Type II tumors are estrogen independent, more frequently harbor a p53 mutation, and are more likely to be diagnosed with metastatic disease. Grade 3 adenocarcinomas, clear cell and papillary serous endometrial cancers are thought to have poorer prognosis compared to their low or intermediate grade histologic counterparts [1,2]. A study of patients from the SEER database demonstrates poorer survival in patients with clear cell and papillary serous subtypes compared to grade 3 endometrial adenocarcinomas [3]. However, a review from the annual report of FIGO demonstrates equivalent survival for papillary serous and clear cell subtypes compared to grade 3 endometrial adenocarcinomas [4]. Grade 3 endometrioid adenocarcinomas portend a worse prognosis compared to their grade 1 and 2
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counterparts [5]. Because of poorer outcomes, adjuvant radiation therapy has been used to improve local control. Recent recommendation guidelines by the Society of Gynecologic Oncology note that vaginal brachytherapy may be considered in the management of Stage IA uterine papillary serous cancer [6]. In a subsequent review by the Society of Gynecologic Oncology, no definitive recommendations could be made for adjuvant treatment of clear cell endometrial cancer [7]. Randomized trials that have evaluated the role of radiation therapy in early stage endometrial cancer patients have not been conclusive for patients with high risk histologies [8–10]. Several retrospective studies have attempted to examine the importance of vaginal cuff brachytherapy in early stage endometrial cancer. FIGO Stage I, unfavorable histology endometrial cancers are quite rare, and constitute approximately 9–14% of all endometrial cancers [3,4,11]; FIGO IA cancers are even more rare. Barney, et al. showed that in a retrospective review of Stage I endometrial carcinoma patients with clear cell and/or papillary serous histology following surgery and vaginal brachytherapy, the 5 year estimates of vaginal recurrence were 3% [12]. Similarly, a retrospective review of 37 patients of Stage I and II clear cell or papillary serous histology who had adjuvant vaginal brachytherapy had a 2 year vaginal recurrence rate of 3.2% [13]. However, these studies did not evaluate a comparison group of women who did not receive vaginal brachytherapy. In addition, these studies did not evaluate FIGO IA patients alone. Our hypothesis is that very, early stage (FIGO IA) endometrial cancer patients with unfavorable histologies have high local recurrence rates and adjuvant radiation therapy can improve local–regional relapse. Methods We retrospectively identified 2816 patients with endometrial carcinoma at Intermountain Healthcare and the University of Utah who had a hysterectomy between 1992 and 2011. Based upon previously constructed databases, we identified patients with less than half myometrial invasion. We excluded patients with positive lymph nodes and patients with Grade 1 or Grade 2 histology. This would, therefore, lead to inclusion of patients who were staged as FIGO IIIa (FIGO 1998 staging). Pathology reports were then re-reviewed to ensure patient eligibility. Based upon these criteria, we then identified 125 patients with endometrial carcinoma who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid adenocarcinoma), endometrial carcinoma treated between 1992 and 2011. Data regarding demographics, surgical report, pathology, radiation delivery, and follow-up were obtained. Patient cohort Patients were staged according to current FIGO 2009 guidelines. This was an IRB approved study, IRB number 1024494. Exclusion criteria included uterine sarcoma histology, prior or concurrent diagnosis of other non-cutaneous malignancy, prior chemotherapy or previous pelvic radiation therapy. All patients who were enrolled on the study had less than b50% myometrial invasion (FIGO IA) and negative margins after surgery. Additionally, the precise myometrial depth of penetration were obtained in 78 patients (62.4%), lymphovascular space invasion was available in 88 patients (70.4%), largest tumor diameter was available in 94 patients (75.2%), tumor volume was available in 37 patients (29.6%), and cytology was available in 77 patients (61.6%). Univariate analysis was performed on the data that was available. Radiation Adjuvant radiotherapy was routinely offered in this patient cohort; however, patients and their physicians could refuse adjuvant treatment. Radiation therapy was delivered by external beam radiotherapy and/or
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brachytherapy. External beam radiotherapy was delivered using traditional pelvic fields utilizing either a 3 or 4 field techniques and treated using high energy photons. In more recent years, CT-based planning was utilized. Brachytherapy was administered either using a high dose rate (HDR) or low dose rate (LDR) technique. The majority of patients received HDR brachytherapy via a vaginal cylinder, which was prescribed to either the vaginal surface or 0.5 cm depth. LDR therapy was prescribed to the vaginal surface. The length of the vagina that was treated by brachytherapy included the entire vaginal length that was l–2 cm proximal from the end of the vaginal canal. Endpoints Primary endpoint is for local–regional control, which is defined as any recurrent disease in the pelvis identified by physical examination, biopsy or imaging. In addition, we further defined local–regional recurrence as vaginal recurrence or pelvic recurrence. Secondary endpoints are distant recurrence and overall survival. Statistics Demographics were evaluated using an unpaired Student's t test (two sided test) and chi-squared test for comparison of means. Kaplan–Meier method was utilized to determine time to endpoint. The endpoints were calculated from the date of surgery to the date of the outcome. Patients were censored at the last date of follow up if the above endpoints did not occur. Endpoint and survival data was obtained from the written paper or electronic medical record. The logrank test was used to compare the outcomes between groups. For univariate analysis, chi-square test examined the association with the given outcome. Because there were far too few events in our cohort, we did not complete a multivariate model. A p-value of ≤ 0.05 was considered significant. Results We identified 125 subjects who had pathologic confirmation of FIGO IA disease with unfavorable histology and had a margin negative resection; 86 subjects obtained care at Intermountain Healthcare and 39 subjects obtained care at the University of Utah. The median age of the cohort was 67 years old and median follow up of 30.4 months (range: 0.03 to 244.7 months). Adjuvant radiation therapy was delivered in 60 patients (48%) and 65 patients did not have any adjuvant radiation therapy (52%). Complete list of demographics is available in Table 1. The radiation therapy cohort was more likely to have worse prognostic features such as LVSI, and deeper myometrial invasion. The radiation therapy group was more likely to have a greater number of lymph nodes dissected. In comparison, the group that did not undergo radiotherapy had a higher frequency of papillary serous histology; however, the histologic difference was not statistically significant. The radiotherapy group was more likely to undergo pelvic lymph node dissection (87%) compared to the non-radiotherapy group (71%) (p = 0.03). The radiotherapy group was more likely to undergo chemotherapy (11.6%) compared to the non-radiotherapy group (0%) (p = .007). Of the 7 patients that had chemotherapy, 4 had HDR brachytherapy, 1 had pelvic radiotherapy alone, 1 had a combination of pelvic and HDR brachytherapy and the last patient did not have radiation records that were available. Radiation therapy Of the 60 patients who had radiation administered, 18 (30%) patients had external beam radiation therapy to the pelvis with a median dose of 4860 cGy (range: 4500 cGy to 5400 cGy) in 27 fractions (range: 25 to 30 fractions). Brachytherapy was administered in 38 (63.3%) patients. Two patients had a combination of both external
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Table 1 Demographics.
Age (years) median, (95% CI) Tumor volume (cm3) median, (95% CI) Largest tumor dimension (cm) median, (95% CI) LVSI positive Depth of myometrial invasion (mm) median, (range) Total myometrial depth (mm) median, (range) Cytology positive Pelvic lymph node dissection (%) Periaortic lymph node dissection (%) Nodes dissected, median, (95% CI) Radiation, any External beam (EBRT) Brachytherapy EBRT + brachytherapy Not specified Chemotherapy Histology Grade 3 adenocarcinoma Papillary serous adenocarcinoma Clear cell adenocarcinoma Mixed Grade 3, other
Radiation
No radiation
p-value
68 (63.8,69) 2.5 (2.0, 3.45) 2.7 (2.57, 3.48) 6 3.3 (0, 11) 16 (6, 25) 1 52 (87%) 31 (52%) 13 (12, 17)
66 (64.4, 69.8) 3.5 (2.9, 5.0) 3.5 (2.76, 4.16) 0 1.8 (0, 9) 17 (1.9, 31) 0 47 (72%) 20 (30%) 8 (7, 13)
p p p p p p
18 38 2 2 7
0
34 16 7 2 1
30 23 8 1 3
beam and brachytherapy. Two patients had unspecified radiotherapy treated in 1999 and 2004 (detailed records were not available). Of the 38 patients who had brachytherapy, high-dose rate brachytherapy was administered to 35 patients to a median dose of 1950 cGy prescribed to ½ cm in 3 fractions and low-dose rate brachytherapy was administered to 3 patients to a median dose of 6000 cGy to the vaginal surface. All patients finished their prescribed treatment. Over time, the use of radiation therapy has evolved at our institutions. Between 1992 and 2000, 12 patients had radiation, while 27 patients did not have radiation. Of the 12 who had radiation during this period, 8 had external pelvic radiotherapy, 1 had a combination of external pelvic and HDR radiotherapy, 1 had LDR brachytherapy, 1 had HDR brachytherapy and 1 had unknown radiotherapy. From 2001 through 2011, 48 patients had radiation, while 38 patients did not have radiation. Of the 48 who had radiation during this time period, 10 had external pelvic radiotherapy, 36 patients had brachytherapy, 1 had a combination of external pelvic and HDR radiotherapy and 1 had unknown radiotherapy. Local–regional recurrence The 5 year local–regional control for all patients was 89.4%. There were a total of 24 patients with either distant or local–regional recurrence; 5 had local–regional only recurrences, 4 local–regional and
A
= = = = = =
0.75 0.11 0.40 0.02 0.014 0.35
p = 0.048 p = 0.018 p = 0.04
p = 0.007 p = 0.61
distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. Of the 9 local–regional recurrences, 2 had a vaginal only recurrence, 1 had vaginal and pelvic recurrence, 2 had pelvic only recurrence and 4 had a local–regional recurrence with metastatic disease. The Venn diagram in Fig. 1A and B demonstrates improved local– regional control with the radiation treatment cohort. The median time to local recurrence for all patients was not reached. The 5-year local– regional control for patients who received radiation was 97.8%, while the 5-year local–regional control for patients who did not receive radiation was 80.1% (p = 0.018, Fig. 2). Of the 60 patients who had adjuvant radiation therapy, one had a recurrence at the vaginal apex and recurred concurrently in the pelvis, peritoneum and liver. Of the 65 patients who did not have adjuvant radiation, 8 had a local–regional recurrence which included 3 with a vaginal only recurrence, 1 vaginal and pelvic recurrence and 4 had pelvic recurrence. Of the eight individuals with a local–regional recurrence, seven received salvage external beam radiotherapy. The median salvage dose of external beam radiotherapy was 4500 cGy in 25 fractions (range 3500 cGy to 5580 cGy). In addition, two of the seven who had external beam radiotherapy also received vaginal cuff brachytherapy at 1800 cGy in three fractions and 2400 cGy in four fractions, respectively. In patients with local–regional recurrences alone, chemotherapy and surgery were not utilized. Despite our salvage therapy in seven of our patients, five of the patients died.
B
5
7 0
1
0
2
1
1
0 0
0
0
2
2
Fig. 1. A: Local and distant recurrences in the subjects that received radiation therapy. B: Local and distant recurrences in the subjects who did not receive radiation therapy.
D. Ly et al. / Gynecologic Oncology 133 (2014) 250–255
253
Free of Local Recurrence (%) 100
75
50
25
0
50
100
150
200
250
Time (months) Fig. 2. Kaplan–Meier analysis of freedom of local regional recurrence.
Distant and any recurrence The 5-year overall distant relapse free survival for the entire cohort was 79.7%. The 5-year distant relapse free survival rate was 73.3% if patients did not receive adjuvant radiation and 85.1% if they did receive adjuvant radiation (p = 0.507). The median time to any recurrence (local or distant) was not reached. The 5-year relapse free survival rate was 71.9%. The 5-year relapse free survival rate was 59.6% if patients did not receive adjuvant radiation and 83% if they did receive adjuvant radiation (p = 0.056). Overall survival The median survival time for the entire cohort was 175.9 months; at 5-years the overall survival was 76.0%. The median survival time in the
cohort that received radiation versus no radiation was not yet estimable versus 149 months, respectively. The 5-year overall survival rate was 68.1% if patients did not receive adjuvant radiation and 84.9% if they did receive adjuvant radiation (p = 0.0062, Fig. 3). Univariate analysis By univariate analysis, decreased local–regional recurrence was associated with radiation (HR 0.12, 95% CI 0.003 to 0.94, p = 0.018), but it was not associated with age, depth of myometrial invasion, LVSI, histology, tumor volume, greatest tumor length, nodes removed, whether lymph node dissection was performed or use of chemotherapy (Table 2). Overall survival was associated with age, use of radiation therapy, tumor volume and greatest tumor length (Table 3). In addition,
Time (months) Overall Survival (%) 100
75
50
25
0
50
100
150
200
250
Time (months) Fig. 3. Kaplan–Meier analysis of overall survival.
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Table 2 Univariate analysis for local recurrence.
Age Radiation, administered Chemotherapy, administered LVSI Myometrial depth, increased Tumor volume Tumor dimension Lymph node dissection Lymph nodes removed Histology Grade 3 adenocarcinoma Clear cell Papillary serous Mixed Other, grade 3
Hazard ratio (95% CI)
p-value
1.07 (1.00 to 1.16) 0.12 (0.03 to 0.49) 0.35 (0.07 to 0.71) 3.79 (0.44 to 32.9) 0.93 (0.65 to 1.31) 1.44 (0.59 to 3.53) 1.13 (0.75 to 1.70) 0.68 (0.14 to 3.35) 0.99 (0.92 to 1.05)
p p p p p p p p p
3.49 (0.69 to 17.7) 1.00 – 0.56 (0.06 to 4.83) –
p = 0.68
= = = = = = = = =
0.056 0.018 0.55 0.23 0.67 0.43 0.55 0.64 0.64
we completed analysis subgrouping patients who had clear cell or papillary serous histology into one group versus patients with other grade 3 histologies. Patients with other grade 3 histologies versus patients with clear cell or papillary serous histology had a hazard ratio for death of 0.67 (95% CI of 0.36 to 1.26) with a p-value of 0.21. Only radiation therapy was significantly associated with both an improvement in local–regional recurrence and overall survival. Chemotherapy was not associated with improvement in local–regional recurrence or distant metastatic disease (HR 0.36, 95% CI: 0.04 to 3.48, p = 0.16); however, only 7 patients received chemotherapy.
Discussion In this study of 125 patients with early stage, unfavorable histology endometrial cancer, adjuvant radiation therapy was associated with a significant improvement in local–regional control (vaginal and pelvic) at 5 years. Many randomized studies have shown improved local recurrence with external beam radiotherapy to the pelvis for early stage endometrial carcinoma [10,14–16]. Based on these trials, radiotherapy to the pelvis has been utilized at our institutions for intermediate and high risk women. PORTEC 2 demonstrated that vaginal cuff brachytherapy alone provides similar vaginal relapse rates compared to pelvic radiotherapy [8]. Because of this, routine treatment for early stage, unfavorable histology endometrial cancer at our institutions currently includes vaginal cuff brachytherapy. Our data supports the use of adjuvant radiation therapy in patients with early stage, unfavorable histology endometrial cancer. Similar rates of local recurrence were described at other institutions in which adjuvant radiation was utilized in a similar population [12,13]. We also examined the association of other predictors for local recurrence and overall survival. One of the predictors that we examined, LVSI, was not significantly associated with local recurrence or overall survival. Most data indicate LVSI as an adverse prognostic factor. In one study Table 3 Univariate analysis for overall survival.
Age Radiation, administered Chemotherapy, administered LVSI Myometrial depth, increased Tumor volume Tumor dimension Lymph node dissection Lymph nodes removed Histology Grade 3 adenocarcinoma Clear cell Papillary serous Mixed Other, grade 3
Hazard ratio (range)
p-value
1.11 (1.07 to 1.15) 0.36 (0.19 to 0.66) 1.03 (0.25 to 4.27) 1.94 (0.57 to 6.58) 1.11 (0.93 to 1.31) 1.26 (1.03 to 1.53) 1.22 (1.02 to 1.48) 0.93 (0.46 to 1.89) 0.99 (0.97 to 1.02)
p p p p p p p p p
0.668 (0.34 to 1.32) 1.00 – 1.37 (0.19 to 9.76) 1.16 (0.36 to 3.69)
p = 0.72
b .0001 = 0.003 = 0.97 = 0.32 = 0.24 = 0.03 = 0.04 = 0.85 = 0.59
of Stage I and II patients with type II endometrial carcinoma, lack of LVSI was associated with decreased local recurrence [17]. However, in a cohort from the Cleveland Clinic of 206 patients with Stage I or II papillary serous endometrial carcinoma, LVSI was not predictive for recurrence or overall survival on univariate analysis [18]. We were able to demonstrate an association with age and overall survival. In addition, there was a trend for a higher risk of local recurrence with increasing age; however, this was not statistically significant. Previous studies in unfavorable histology patients with early stage endometrial carcinoma have demonstrated a higher risk of local recurrence with age [19,20]. In our cohort, we did not identify a trend for increased local recurrence based upon the differences on histology; papillary serous and clear cell histology were not associated with worse recurrence or overall survival in our study compared to grade 3 endometrioid adenocarcinoma. Some studies have determined worse overall survival with clear cell or serous carcinoma compared to grade 3 endometrioid carcinoma [21]. However, a large cohort review of the FIGO database showed no difference in overall survival between grade 3 endometrioid carcinoma versus papillary serous or clear cell type [4]. Chemotherapy continues to be a dilemma in patients with unfavorable histology, early stage endometrial cancer. At Yale, an analysis of 74 patients with Stage I papillary serous carcinoma, revealed an association with improved disease free survival and overall survival with the addition of platinum-based chemotherapy [22]. At Mayo Clinic, a cohort of 189 patients with FIGO I or II, grade 3 endometrial carcinoma, serous or clear cell type were analyzed, and chemotherapy was not associated with improved overall survival [23]. Distant metastatic disease is a troubling issue in our patient cohort; the overall rate of distant metastatic disease was 20% at 5 years. Compared to our results, patients from Memorial Sloan Kettering Cancer Center who underwent adjuvant vaginal cuff brachytherapy and concurrent carboplatin and paclitaxel had a more favorable 5 year distant recurrence rate of 10% [24]. GOG 0249 is examining the benefit of pelvic radiation versus vaginal cuff radiation with carboplatin and paclitaxel in patients with high risk stage I or II endometrial cancer. Future studies will define the utility of chemotherapy in this cohort. At 5-years, local–regional control was significantly increased from 80.1% to 97.8% with adjuvant radiation therapy. In a previous registry study of 55 patients with high risk, early stage endometrial carcinoma who had pelvic radiotherapy, only one had a local recurrence [25]. In a retrospective analysis of 103 patients with FIGO I papillary serous or clear cell endometrial carcinoma that had surgery and vaginal cuff brachytherapy, the 5-year local regional recurrence was 7% and vaginal recurrence was 3% [12]. Our local–regional recurrence rate compares similarly when adjuvant radiation therapy is administered. In our cohort at 5 years, the overall survival rate was significantly improved with radiation therapy from 76% to 84.9% (p = 0.0062). Our data for overall survival compares favorably with data from the Mayo Clinic in which their overall survival was 84% at 5 years [12]. Based on our univariate analysis, overall survival was significantly associated with age, radiation, greatest tumor dimension and tumor volume on univariate analysis. In a smaller patient cohort at Henry Ford Hospital, no overall survival benefit with radiation therapy in Stage I or II, type II endometrial carcinomas was observed [17]. Although the rate of distant metastatic disease was not altered by radiation in our study, overall survival was improved in patients who received radiation. We hypothesize that gynecologic local recurrences are difficult to salvage and can lead to decreased overall survival; in our cohort of seven patients that were salvaged with radiation therapy, five died. Our study was limited in that it is retrospective and is therefore subject to bias. However, our radiation and no adjuvant radiation groups were similar in most regards. The radiation group tended to have worse prognostic features and was more likely to have been positive for LVSI, and have a greater depth of myometrial invasion. The
D. Ly et al. / Gynecologic Oncology 133 (2014) 250–255
radiotherapy group also had a greater number of nodes dissected and 7 patients in this group received chemotherapy. However, on univariate analysis, the aforementioned differences were not associated with a significant difference in local control or overall survival. The radiation therapy that was administered at our institutions' varied over time. Some of the patients received external pelvic radiotherapy and others have received LDR or HDR to the vaginal cuff. In more recent years, external pelvic radiotherapy has been administered less often and vaginal cuff brachytherapy has been favored after the publication of randomized trials. Therefore, the use of adjuvant radiation in recent years has increased, as there has been greater preference for shorter treatment courses. Adjuvant radiation therapy is associated with increased local– regional control in patients with early stage (FIGO IA) endometrial carcinoma who have grade 3 endometrioid adenocarcinoma, clear cell or papillary serous carcinoma. In addition, in this retrospective series radiation therapy is associated with a significant survival benefit on both univariate analysis. Further studies and prospective trials should be implemented to evaluate the benefit of various adjuvant therapies. Conflict of interest statement The above authors have no disclosures.
References [1] Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55–65. [2] Page BR, Pappas L, Cooke EW, Gaffney DK. Does the FIGO 2009 endometrial cancer staging system more accurately correlate with clinical outcome in different histologies? Revised staging, endometrial cancer, histology. Int J Gynecol Cancer 2012;22:593–8. [3] Hamilton CA, Cheung MK, Osann K, Chen L, Teng NN, Longacre TA, et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer 2006;94:642–6. [4] Creasman WT, Kohler MF, Odicino F, Maisonneuve P, Boyle P. Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium. Gynecol Oncol 2004;95:593–6. [5] Alektiar KM, McKee A, Lin O, Venkatraman E, Zelefsky MJ, McKee B, et al. Is there a difference in outcome between stage I-II endometrial cancer of papillary serous/ clear cell and endometrioid FIGO Grade 3 cancer? Int J Radiat Oncol Biol Phys 2002;54:79–85. [6] Boruta II DM, Gehrig PA, Fader AN, Olawaiye AB. Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol 2009;115:142–53. [7] Olawaiye AB, Boruta II DM. Management of women with clear cell endometrial cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol 2009; 113:277–83. [8] Nout RA, Smit VT, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet 2010;375:816–23.
255
[9] Onsrud M, Cvancarova M, Hellebust TP, Trope CG, Kristensen GB, Lindemann K. Long-term outcomes after pelvic radiation for early-stage endometrial cancer. J Clin Oncol 2013;31:3951–6. [10] Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and metaanalysis. Lancet 2009;373:137–46. [11] Kim HJ, Kim TJ, Lee YY, Choi CH, Lee JW, Bae DS, et al. A comparison of uterine papillary serous, clear cell carcinomas, and grade 3 endometrioid corpus cancers using 2009 FIGO staging system. J Gynecol Oncol 2013;24:120–7. [12] Barney BM, Petersen IA, Mariani A, Dowdy SC, Bakkum-Gamez JN, Haddock MG. The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer. Int J Radiat Oncol Biol Phys 2013;85:109–15. [13] Townamchai K, Berkowitz R, Bhagwat M, Damato AL, Friesen S, Lee LJ, et al. Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer. Gynecol Oncol 2013;129:18–21. [14] Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56:419–27. [15] Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, 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;355:1404–11. [16] Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, 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;92:744–51. [17] Yechieli R, Rasool N, Robbins JR, Cogan CM, Elshaikh MA. Adjuvant radiation therapy for patients with type II endometrial carcinoma: impact on tumor recurrence and survival. Int J Gynecol Cancer 2013;23:763–8. [18] Fader AN, Starks D, Gehrig PA, Secord AA, Frasure HE, O'Malley DM, et al. An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC). Gynecol Oncol 2009;115:244–8. [19] Alektiar KM, Venkatraman E, Abu-Rustum N, Barakat RR. Is endometrial carcinoma intrinsically more aggressive in elderly patients? Cancer 2003;98:2368–77. [20] Vance S, Yechieli R, Cogan C, Hanna R, Munkarah A, Elshaikh MA. The prognostic significance of age in surgically staged patients with Type II endometrial carcinoma. Gynecol Oncol 2012;126:16–9. [21] Cirisano Jr FD, Robboy SJ, Dodge RK, Bentley RC, Krigman HR, Synan IS, et al. The outcome of stage I-II clinically and surgically staged papillary serous and clear cell endometrial cancers when compared with endometrioid carcinoma. Gynecol Oncol 2000;77:55–65. [22] Kelly MG, O'Malley DM, Hui P, McAlpine J, Yu H, Rutherford TJ, et al. Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol 2005;98: 353–9. [23] Ayeni TA, Bakkum-Gamez JN, Mariani A, McGree ME, Weaver AL, Haddock MG, et al. Comparative outcomes assessment of uterine grade 3 endometrioid, serous, and clear cell carcinomas. Gynecol Oncol 2013;129:478–85. [24] Kiess AP, Damast S, Makker V, Kollmeier MA, Gardner GJ, Aghajanian C, et al. Fiveyear outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-II papillary serous endometrial cancer. Gynecol Oncol 2012;127:321–5. [25] Jutzi L, Hoskins P, Lim P, Aquino-Parsons C, Tinker A, Kwon JS. The importance of adjuvant chemotherapy and pelvic radiotherapy in high-risk early stage endometrial carcinoma. Gynecol Oncol 2013;131:581–5.
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Adjuvant radiation in early stage, unfavorable histology endometrial carcinoma is associated with improved local control and survival David Ly a, Braden D. Rowley b, Mark K. Dodson c, Pat A. Soisson c, Christopher J. Jolles d, David K. Gaffney a,⁎, William T. Sause e a
Huntsman Cancer Institute, University of Utah, Department of Radiation Oncology, Salt Lake City, UT, USA Intermountain Healthcare, Oncology Clinical Program, Salt Lake City, UT, USA Huntsman Cancer Institute, University of Utah, Division of Gynecological Oncology, Salt Lake City, UT, USA d Special Gynecology and Oncology, Riverton, UT, USA e Intermountain Medical Center, Radiation Oncology, Salt Lake City, UT, USA b c
H I G H L I G H T S • We compared the association of adjuvant radiation therapy and outcomes in patients with unfavorable histology, FIGO IA endometrial cancer. • Adjuvant radiation therapy was associated with a significant improvement in local–regional control. • Adjuvant radiation therapy was associated with a significant improvement in overall survival.
a r t i c l e
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Article history: Received 4 December 2013 Accepted 23 February 2014 Available online 28 February 2014 Keywords: Endometrial Radiation Radiotherapy Clear cell Papillary serous Unfavorable histology
a b s t r a c t Objective. Unfavorable histology endometrial carcinomas confer worse prognosis. We determined the association of adjuvant radiation on local recurrence and survival for unfavorable, early stage endometrial cancer. Methods. We retrospectively identified 125 patients who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid), endometrial carcinoma treated between 1992 and 2011. Patients were restaged according to current FIGO 2009 guidelines. Primary endpoint was local control and secondary endpoints were distant recurrence and overall survival. Results. The median age of the cohort was 67 years old with a mean follow up 152 months. Adjuvant radiation was delivered in 60 patients (48%). There were a total of 24 recurrences; 5 had local–regional recurrences, 4 local and distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. The 5-year local–regional control was 97.8% in patients who received radiation and 80.1% in patients who did not receive radiation (p = 0.018). The 5-year overall survival rate was 68.1% if patients did not receive radiation and 84.9% if they did receive radiation (p = 0.0062). On univariate analysis, only radiation (HR 0.12, 95% CI: 0.03 to 0.49, p-value = 0.018) was associated with a significant increase in local relapse free survival. Conclusions. Adjuvant radiation therapy was significantly associated with an improvement in local–regional control and overall survival in patients with unfavorable histology, early stage endometrial cancer. © 2014 Elsevier B.V. All rights reserved.
Introduction Endometrial carcinoma is the most common gynecologic malignancy in the United States with an incidence of 40,000 cases a year. Approximately 80% of endometrial carcinomas are of Type I origin (endometrioid adenocarcinomas) while the second most common histologies are of Type II origin (clear cell and papillary serous). Type I tumors are estrogen dependent tumors, and patients are more likely ⁎ Corresponding author at: University of Utah, Department of Radiation Oncology, 1950 Circle of Hope, RM 1570, Salt Lake City, UT 84112, USA. Fax: +1 801 585 2666. E-mail address: [email protected] (D.K. Gaffney).
http://dx.doi.org/10.1016/j.ygyno.2014.02.032 0090-8258/© 2014 Elsevier B.V. All rights reserved.
to be diagnosed at an earlier stage. Type II tumors are estrogen independent, more frequently harbor a p53 mutation, and are more likely to be diagnosed with metastatic disease. Grade 3 adenocarcinomas, clear cell and papillary serous endometrial cancers are thought to have poorer prognosis compared to their low or intermediate grade histologic counterparts [1,2]. A study of patients from the SEER database demonstrates poorer survival in patients with clear cell and papillary serous subtypes compared to grade 3 endometrial adenocarcinomas [3]. However, a review from the annual report of FIGO demonstrates equivalent survival for papillary serous and clear cell subtypes compared to grade 3 endometrial adenocarcinomas [4]. Grade 3 endometrioid adenocarcinomas portend a worse prognosis compared to their grade 1 and 2
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counterparts [5]. Because of poorer outcomes, adjuvant radiation therapy has been used to improve local control. Recent recommendation guidelines by the Society of Gynecologic Oncology note that vaginal brachytherapy may be considered in the management of Stage IA uterine papillary serous cancer [6]. In a subsequent review by the Society of Gynecologic Oncology, no definitive recommendations could be made for adjuvant treatment of clear cell endometrial cancer [7]. Randomized trials that have evaluated the role of radiation therapy in early stage endometrial cancer patients have not been conclusive for patients with high risk histologies [8–10]. Several retrospective studies have attempted to examine the importance of vaginal cuff brachytherapy in early stage endometrial cancer. FIGO Stage I, unfavorable histology endometrial cancers are quite rare, and constitute approximately 9–14% of all endometrial cancers [3,4,11]; FIGO IA cancers are even more rare. Barney, et al. showed that in a retrospective review of Stage I endometrial carcinoma patients with clear cell and/or papillary serous histology following surgery and vaginal brachytherapy, the 5 year estimates of vaginal recurrence were 3% [12]. Similarly, a retrospective review of 37 patients of Stage I and II clear cell or papillary serous histology who had adjuvant vaginal brachytherapy had a 2 year vaginal recurrence rate of 3.2% [13]. However, these studies did not evaluate a comparison group of women who did not receive vaginal brachytherapy. In addition, these studies did not evaluate FIGO IA patients alone. Our hypothesis is that very, early stage (FIGO IA) endometrial cancer patients with unfavorable histologies have high local recurrence rates and adjuvant radiation therapy can improve local–regional relapse. Methods We retrospectively identified 2816 patients with endometrial carcinoma at Intermountain Healthcare and the University of Utah who had a hysterectomy between 1992 and 2011. Based upon previously constructed databases, we identified patients with less than half myometrial invasion. We excluded patients with positive lymph nodes and patients with Grade 1 or Grade 2 histology. This would, therefore, lead to inclusion of patients who were staged as FIGO IIIa (FIGO 1998 staging). Pathology reports were then re-reviewed to ensure patient eligibility. Based upon these criteria, we then identified 125 patients with endometrial carcinoma who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid adenocarcinoma), endometrial carcinoma treated between 1992 and 2011. Data regarding demographics, surgical report, pathology, radiation delivery, and follow-up were obtained. Patient cohort Patients were staged according to current FIGO 2009 guidelines. This was an IRB approved study, IRB number 1024494. Exclusion criteria included uterine sarcoma histology, prior or concurrent diagnosis of other non-cutaneous malignancy, prior chemotherapy or previous pelvic radiation therapy. All patients who were enrolled on the study had less than b50% myometrial invasion (FIGO IA) and negative margins after surgery. Additionally, the precise myometrial depth of penetration were obtained in 78 patients (62.4%), lymphovascular space invasion was available in 88 patients (70.4%), largest tumor diameter was available in 94 patients (75.2%), tumor volume was available in 37 patients (29.6%), and cytology was available in 77 patients (61.6%). Univariate analysis was performed on the data that was available. Radiation Adjuvant radiotherapy was routinely offered in this patient cohort; however, patients and their physicians could refuse adjuvant treatment. Radiation therapy was delivered by external beam radiotherapy and/or
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brachytherapy. External beam radiotherapy was delivered using traditional pelvic fields utilizing either a 3 or 4 field techniques and treated using high energy photons. In more recent years, CT-based planning was utilized. Brachytherapy was administered either using a high dose rate (HDR) or low dose rate (LDR) technique. The majority of patients received HDR brachytherapy via a vaginal cylinder, which was prescribed to either the vaginal surface or 0.5 cm depth. LDR therapy was prescribed to the vaginal surface. The length of the vagina that was treated by brachytherapy included the entire vaginal length that was l–2 cm proximal from the end of the vaginal canal. Endpoints Primary endpoint is for local–regional control, which is defined as any recurrent disease in the pelvis identified by physical examination, biopsy or imaging. In addition, we further defined local–regional recurrence as vaginal recurrence or pelvic recurrence. Secondary endpoints are distant recurrence and overall survival. Statistics Demographics were evaluated using an unpaired Student's t test (two sided test) and chi-squared test for comparison of means. Kaplan–Meier method was utilized to determine time to endpoint. The endpoints were calculated from the date of surgery to the date of the outcome. Patients were censored at the last date of follow up if the above endpoints did not occur. Endpoint and survival data was obtained from the written paper or electronic medical record. The logrank test was used to compare the outcomes between groups. For univariate analysis, chi-square test examined the association with the given outcome. Because there were far too few events in our cohort, we did not complete a multivariate model. A p-value of ≤ 0.05 was considered significant. Results We identified 125 subjects who had pathologic confirmation of FIGO IA disease with unfavorable histology and had a margin negative resection; 86 subjects obtained care at Intermountain Healthcare and 39 subjects obtained care at the University of Utah. The median age of the cohort was 67 years old and median follow up of 30.4 months (range: 0.03 to 244.7 months). Adjuvant radiation therapy was delivered in 60 patients (48%) and 65 patients did not have any adjuvant radiation therapy (52%). Complete list of demographics is available in Table 1. The radiation therapy cohort was more likely to have worse prognostic features such as LVSI, and deeper myometrial invasion. The radiation therapy group was more likely to have a greater number of lymph nodes dissected. In comparison, the group that did not undergo radiotherapy had a higher frequency of papillary serous histology; however, the histologic difference was not statistically significant. The radiotherapy group was more likely to undergo pelvic lymph node dissection (87%) compared to the non-radiotherapy group (71%) (p = 0.03). The radiotherapy group was more likely to undergo chemotherapy (11.6%) compared to the non-radiotherapy group (0%) (p = .007). Of the 7 patients that had chemotherapy, 4 had HDR brachytherapy, 1 had pelvic radiotherapy alone, 1 had a combination of pelvic and HDR brachytherapy and the last patient did not have radiation records that were available. Radiation therapy Of the 60 patients who had radiation administered, 18 (30%) patients had external beam radiation therapy to the pelvis with a median dose of 4860 cGy (range: 4500 cGy to 5400 cGy) in 27 fractions (range: 25 to 30 fractions). Brachytherapy was administered in 38 (63.3%) patients. Two patients had a combination of both external
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Table 1 Demographics.
Age (years) median, (95% CI) Tumor volume (cm3) median, (95% CI) Largest tumor dimension (cm) median, (95% CI) LVSI positive Depth of myometrial invasion (mm) median, (range) Total myometrial depth (mm) median, (range) Cytology positive Pelvic lymph node dissection (%) Periaortic lymph node dissection (%) Nodes dissected, median, (95% CI) Radiation, any External beam (EBRT) Brachytherapy EBRT + brachytherapy Not specified Chemotherapy Histology Grade 3 adenocarcinoma Papillary serous adenocarcinoma Clear cell adenocarcinoma Mixed Grade 3, other
Radiation
No radiation
p-value
68 (63.8,69) 2.5 (2.0, 3.45) 2.7 (2.57, 3.48) 6 3.3 (0, 11) 16 (6, 25) 1 52 (87%) 31 (52%) 13 (12, 17)
66 (64.4, 69.8) 3.5 (2.9, 5.0) 3.5 (2.76, 4.16) 0 1.8 (0, 9) 17 (1.9, 31) 0 47 (72%) 20 (30%) 8 (7, 13)
p p p p p p
18 38 2 2 7
0
34 16 7 2 1
30 23 8 1 3
beam and brachytherapy. Two patients had unspecified radiotherapy treated in 1999 and 2004 (detailed records were not available). Of the 38 patients who had brachytherapy, high-dose rate brachytherapy was administered to 35 patients to a median dose of 1950 cGy prescribed to ½ cm in 3 fractions and low-dose rate brachytherapy was administered to 3 patients to a median dose of 6000 cGy to the vaginal surface. All patients finished their prescribed treatment. Over time, the use of radiation therapy has evolved at our institutions. Between 1992 and 2000, 12 patients had radiation, while 27 patients did not have radiation. Of the 12 who had radiation during this period, 8 had external pelvic radiotherapy, 1 had a combination of external pelvic and HDR radiotherapy, 1 had LDR brachytherapy, 1 had HDR brachytherapy and 1 had unknown radiotherapy. From 2001 through 2011, 48 patients had radiation, while 38 patients did not have radiation. Of the 48 who had radiation during this time period, 10 had external pelvic radiotherapy, 36 patients had brachytherapy, 1 had a combination of external pelvic and HDR radiotherapy and 1 had unknown radiotherapy. Local–regional recurrence The 5 year local–regional control for all patients was 89.4%. There were a total of 24 patients with either distant or local–regional recurrence; 5 had local–regional only recurrences, 4 local–regional and
A
= = = = = =
0.75 0.11 0.40 0.02 0.014 0.35
p = 0.048 p = 0.018 p = 0.04
p = 0.007 p = 0.61
distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. Of the 9 local–regional recurrences, 2 had a vaginal only recurrence, 1 had vaginal and pelvic recurrence, 2 had pelvic only recurrence and 4 had a local–regional recurrence with metastatic disease. The Venn diagram in Fig. 1A and B demonstrates improved local– regional control with the radiation treatment cohort. The median time to local recurrence for all patients was not reached. The 5-year local– regional control for patients who received radiation was 97.8%, while the 5-year local–regional control for patients who did not receive radiation was 80.1% (p = 0.018, Fig. 2). Of the 60 patients who had adjuvant radiation therapy, one had a recurrence at the vaginal apex and recurred concurrently in the pelvis, peritoneum and liver. Of the 65 patients who did not have adjuvant radiation, 8 had a local–regional recurrence which included 3 with a vaginal only recurrence, 1 vaginal and pelvic recurrence and 4 had pelvic recurrence. Of the eight individuals with a local–regional recurrence, seven received salvage external beam radiotherapy. The median salvage dose of external beam radiotherapy was 4500 cGy in 25 fractions (range 3500 cGy to 5580 cGy). In addition, two of the seven who had external beam radiotherapy also received vaginal cuff brachytherapy at 1800 cGy in three fractions and 2400 cGy in four fractions, respectively. In patients with local–regional recurrences alone, chemotherapy and surgery were not utilized. Despite our salvage therapy in seven of our patients, five of the patients died.
B
5
7 0
1
0
2
1
1
0 0
0
0
2
2
Fig. 1. A: Local and distant recurrences in the subjects that received radiation therapy. B: Local and distant recurrences in the subjects who did not receive radiation therapy.
D. Ly et al. / Gynecologic Oncology 133 (2014) 250–255
253
Free of Local Recurrence (%) 100
75
50
25
0
50
100
150
200
250
Time (months) Fig. 2. Kaplan–Meier analysis of freedom of local regional recurrence.
Distant and any recurrence The 5-year overall distant relapse free survival for the entire cohort was 79.7%. The 5-year distant relapse free survival rate was 73.3% if patients did not receive adjuvant radiation and 85.1% if they did receive adjuvant radiation (p = 0.507). The median time to any recurrence (local or distant) was not reached. The 5-year relapse free survival rate was 71.9%. The 5-year relapse free survival rate was 59.6% if patients did not receive adjuvant radiation and 83% if they did receive adjuvant radiation (p = 0.056). Overall survival The median survival time for the entire cohort was 175.9 months; at 5-years the overall survival was 76.0%. The median survival time in the
cohort that received radiation versus no radiation was not yet estimable versus 149 months, respectively. The 5-year overall survival rate was 68.1% if patients did not receive adjuvant radiation and 84.9% if they did receive adjuvant radiation (p = 0.0062, Fig. 3). Univariate analysis By univariate analysis, decreased local–regional recurrence was associated with radiation (HR 0.12, 95% CI 0.003 to 0.94, p = 0.018), but it was not associated with age, depth of myometrial invasion, LVSI, histology, tumor volume, greatest tumor length, nodes removed, whether lymph node dissection was performed or use of chemotherapy (Table 2). Overall survival was associated with age, use of radiation therapy, tumor volume and greatest tumor length (Table 3). In addition,
Time (months) Overall Survival (%) 100
75
50
25
0
50
100
150
200
250
Time (months) Fig. 3. Kaplan–Meier analysis of overall survival.
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Table 2 Univariate analysis for local recurrence.
Age Radiation, administered Chemotherapy, administered LVSI Myometrial depth, increased Tumor volume Tumor dimension Lymph node dissection Lymph nodes removed Histology Grade 3 adenocarcinoma Clear cell Papillary serous Mixed Other, grade 3
Hazard ratio (95% CI)
p-value
1.07 (1.00 to 1.16) 0.12 (0.03 to 0.49) 0.35 (0.07 to 0.71) 3.79 (0.44 to 32.9) 0.93 (0.65 to 1.31) 1.44 (0.59 to 3.53) 1.13 (0.75 to 1.70) 0.68 (0.14 to 3.35) 0.99 (0.92 to 1.05)
p p p p p p p p p
3.49 (0.69 to 17.7) 1.00 – 0.56 (0.06 to 4.83) –
p = 0.68
= = = = = = = = =
0.056 0.018 0.55 0.23 0.67 0.43 0.55 0.64 0.64
we completed analysis subgrouping patients who had clear cell or papillary serous histology into one group versus patients with other grade 3 histologies. Patients with other grade 3 histologies versus patients with clear cell or papillary serous histology had a hazard ratio for death of 0.67 (95% CI of 0.36 to 1.26) with a p-value of 0.21. Only radiation therapy was significantly associated with both an improvement in local–regional recurrence and overall survival. Chemotherapy was not associated with improvement in local–regional recurrence or distant metastatic disease (HR 0.36, 95% CI: 0.04 to 3.48, p = 0.16); however, only 7 patients received chemotherapy.
Discussion In this study of 125 patients with early stage, unfavorable histology endometrial cancer, adjuvant radiation therapy was associated with a significant improvement in local–regional control (vaginal and pelvic) at 5 years. Many randomized studies have shown improved local recurrence with external beam radiotherapy to the pelvis for early stage endometrial carcinoma [10,14–16]. Based on these trials, radiotherapy to the pelvis has been utilized at our institutions for intermediate and high risk women. PORTEC 2 demonstrated that vaginal cuff brachytherapy alone provides similar vaginal relapse rates compared to pelvic radiotherapy [8]. Because of this, routine treatment for early stage, unfavorable histology endometrial cancer at our institutions currently includes vaginal cuff brachytherapy. Our data supports the use of adjuvant radiation therapy in patients with early stage, unfavorable histology endometrial cancer. Similar rates of local recurrence were described at other institutions in which adjuvant radiation was utilized in a similar population [12,13]. We also examined the association of other predictors for local recurrence and overall survival. One of the predictors that we examined, LVSI, was not significantly associated with local recurrence or overall survival. Most data indicate LVSI as an adverse prognostic factor. In one study Table 3 Univariate analysis for overall survival.
Age Radiation, administered Chemotherapy, administered LVSI Myometrial depth, increased Tumor volume Tumor dimension Lymph node dissection Lymph nodes removed Histology Grade 3 adenocarcinoma Clear cell Papillary serous Mixed Other, grade 3
Hazard ratio (range)
p-value
1.11 (1.07 to 1.15) 0.36 (0.19 to 0.66) 1.03 (0.25 to 4.27) 1.94 (0.57 to 6.58) 1.11 (0.93 to 1.31) 1.26 (1.03 to 1.53) 1.22 (1.02 to 1.48) 0.93 (0.46 to 1.89) 0.99 (0.97 to 1.02)
p p p p p p p p p
0.668 (0.34 to 1.32) 1.00 – 1.37 (0.19 to 9.76) 1.16 (0.36 to 3.69)
p = 0.72
b .0001 = 0.003 = 0.97 = 0.32 = 0.24 = 0.03 = 0.04 = 0.85 = 0.59
of Stage I and II patients with type II endometrial carcinoma, lack of LVSI was associated with decreased local recurrence [17]. However, in a cohort from the Cleveland Clinic of 206 patients with Stage I or II papillary serous endometrial carcinoma, LVSI was not predictive for recurrence or overall survival on univariate analysis [18]. We were able to demonstrate an association with age and overall survival. In addition, there was a trend for a higher risk of local recurrence with increasing age; however, this was not statistically significant. Previous studies in unfavorable histology patients with early stage endometrial carcinoma have demonstrated a higher risk of local recurrence with age [19,20]. In our cohort, we did not identify a trend for increased local recurrence based upon the differences on histology; papillary serous and clear cell histology were not associated with worse recurrence or overall survival in our study compared to grade 3 endometrioid adenocarcinoma. Some studies have determined worse overall survival with clear cell or serous carcinoma compared to grade 3 endometrioid carcinoma [21]. However, a large cohort review of the FIGO database showed no difference in overall survival between grade 3 endometrioid carcinoma versus papillary serous or clear cell type [4]. Chemotherapy continues to be a dilemma in patients with unfavorable histology, early stage endometrial cancer. At Yale, an analysis of 74 patients with Stage I papillary serous carcinoma, revealed an association with improved disease free survival and overall survival with the addition of platinum-based chemotherapy [22]. At Mayo Clinic, a cohort of 189 patients with FIGO I or II, grade 3 endometrial carcinoma, serous or clear cell type were analyzed, and chemotherapy was not associated with improved overall survival [23]. Distant metastatic disease is a troubling issue in our patient cohort; the overall rate of distant metastatic disease was 20% at 5 years. Compared to our results, patients from Memorial Sloan Kettering Cancer Center who underwent adjuvant vaginal cuff brachytherapy and concurrent carboplatin and paclitaxel had a more favorable 5 year distant recurrence rate of 10% [24]. GOG 0249 is examining the benefit of pelvic radiation versus vaginal cuff radiation with carboplatin and paclitaxel in patients with high risk stage I or II endometrial cancer. Future studies will define the utility of chemotherapy in this cohort. At 5-years, local–regional control was significantly increased from 80.1% to 97.8% with adjuvant radiation therapy. In a previous registry study of 55 patients with high risk, early stage endometrial carcinoma who had pelvic radiotherapy, only one had a local recurrence [25]. In a retrospective analysis of 103 patients with FIGO I papillary serous or clear cell endometrial carcinoma that had surgery and vaginal cuff brachytherapy, the 5-year local regional recurrence was 7% and vaginal recurrence was 3% [12]. Our local–regional recurrence rate compares similarly when adjuvant radiation therapy is administered. In our cohort at 5 years, the overall survival rate was significantly improved with radiation therapy from 76% to 84.9% (p = 0.0062). Our data for overall survival compares favorably with data from the Mayo Clinic in which their overall survival was 84% at 5 years [12]. Based on our univariate analysis, overall survival was significantly associated with age, radiation, greatest tumor dimension and tumor volume on univariate analysis. In a smaller patient cohort at Henry Ford Hospital, no overall survival benefit with radiation therapy in Stage I or II, type II endometrial carcinomas was observed [17]. Although the rate of distant metastatic disease was not altered by radiation in our study, overall survival was improved in patients who received radiation. We hypothesize that gynecologic local recurrences are difficult to salvage and can lead to decreased overall survival; in our cohort of seven patients that were salvaged with radiation therapy, five died. Our study was limited in that it is retrospective and is therefore subject to bias. However, our radiation and no adjuvant radiation groups were similar in most regards. The radiation group tended to have worse prognostic features and was more likely to have been positive for LVSI, and have a greater depth of myometrial invasion. The
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radiotherapy group also had a greater number of nodes dissected and 7 patients in this group received chemotherapy. However, on univariate analysis, the aforementioned differences were not associated with a significant difference in local control or overall survival. The radiation therapy that was administered at our institutions' varied over time. Some of the patients received external pelvic radiotherapy and others have received LDR or HDR to the vaginal cuff. In more recent years, external pelvic radiotherapy has been administered less often and vaginal cuff brachytherapy has been favored after the publication of randomized trials. Therefore, the use of adjuvant radiation in recent years has increased, as there has been greater preference for shorter treatment courses. Adjuvant radiation therapy is associated with increased local– regional control in patients with early stage (FIGO IA) endometrial carcinoma who have grade 3 endometrioid adenocarcinoma, clear cell or papillary serous carcinoma. In addition, in this retrospective series radiation therapy is associated with a significant survival benefit on both univariate analysis. Further studies and prospective trials should be implemented to evaluate the benefit of various adjuvant therapies. Conflict of interest statement The above authors have no disclosures.
References [1] Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55–65. [2] Page BR, Pappas L, Cooke EW, Gaffney DK. Does the FIGO 2009 endometrial cancer staging system more accurately correlate with clinical outcome in different histologies? Revised staging, endometrial cancer, histology. Int J Gynecol Cancer 2012;22:593–8. [3] Hamilton CA, Cheung MK, Osann K, Chen L, Teng NN, Longacre TA, et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer 2006;94:642–6. [4] Creasman WT, Kohler MF, Odicino F, Maisonneuve P, Boyle P. Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium. Gynecol Oncol 2004;95:593–6. [5] Alektiar KM, McKee A, Lin O, Venkatraman E, Zelefsky MJ, McKee B, et al. Is there a difference in outcome between stage I-II endometrial cancer of papillary serous/ clear cell and endometrioid FIGO Grade 3 cancer? Int J Radiat Oncol Biol Phys 2002;54:79–85. [6] Boruta II DM, Gehrig PA, Fader AN, Olawaiye AB. Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol 2009;115:142–53. [7] Olawaiye AB, Boruta II DM. Management of women with clear cell endometrial cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol 2009; 113:277–83. [8] Nout RA, Smit VT, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet 2010;375:816–23.
255
[9] Onsrud M, Cvancarova M, Hellebust TP, Trope CG, Kristensen GB, Lindemann K. Long-term outcomes after pelvic radiation for early-stage endometrial cancer. J Clin Oncol 2013;31:3951–6. [10] Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and metaanalysis. Lancet 2009;373:137–46. [11] Kim HJ, Kim TJ, Lee YY, Choi CH, Lee JW, Bae DS, et al. A comparison of uterine papillary serous, clear cell carcinomas, and grade 3 endometrioid corpus cancers using 2009 FIGO staging system. J Gynecol Oncol 2013;24:120–7. [12] Barney BM, Petersen IA, Mariani A, Dowdy SC, Bakkum-Gamez JN, Haddock MG. The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer. Int J Radiat Oncol Biol Phys 2013;85:109–15. [13] Townamchai K, Berkowitz R, Bhagwat M, Damato AL, Friesen S, Lee LJ, et al. Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer. Gynecol Oncol 2013;129:18–21. [14] Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56:419–27. [15] Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, 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;355:1404–11. [16] Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, 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;92:744–51. [17] Yechieli R, Rasool N, Robbins JR, Cogan CM, Elshaikh MA. Adjuvant radiation therapy for patients with type II endometrial carcinoma: impact on tumor recurrence and survival. Int J Gynecol Cancer 2013;23:763–8. [18] Fader AN, Starks D, Gehrig PA, Secord AA, Frasure HE, O'Malley DM, et al. An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC). Gynecol Oncol 2009;115:244–8. [19] Alektiar KM, Venkatraman E, Abu-Rustum N, Barakat RR. Is endometrial carcinoma intrinsically more aggressive in elderly patients? Cancer 2003;98:2368–77. [20] Vance S, Yechieli R, Cogan C, Hanna R, Munkarah A, Elshaikh MA. The prognostic significance of age in surgically staged patients with Type II endometrial carcinoma. Gynecol Oncol 2012;126:16–9. [21] Cirisano Jr FD, Robboy SJ, Dodge RK, Bentley RC, Krigman HR, Synan IS, et al. The outcome of stage I-II clinically and surgically staged papillary serous and clear cell endometrial cancers when compared with endometrioid carcinoma. Gynecol Oncol 2000;77:55–65. [22] Kelly MG, O'Malley DM, Hui P, McAlpine J, Yu H, Rutherford TJ, et al. Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol 2005;98: 353–9. [23] Ayeni TA, Bakkum-Gamez JN, Mariani A, McGree ME, Weaver AL, Haddock MG, et al. Comparative outcomes assessment of uterine grade 3 endometrioid, serous, and clear cell carcinomas. Gynecol Oncol 2013;129:478–85. [24] Kiess AP, Damast S, Makker V, Kollmeier MA, Gardner GJ, Aghajanian C, et al. Fiveyear outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-II papillary serous endometrial cancer. Gynecol Oncol 2012;127:321–5. [25] Jutzi L, Hoskins P, Lim P, Aquino-Parsons C, Tinker A, Kwon JS. The importance of adjuvant chemotherapy and pelvic radiotherapy in high-risk early stage endometrial carcinoma. Gynecol Oncol 2013;131:581–5.