Correspondence: Dr AB Olawaiye, 300 Halket Street, Office 2130, Pittsburgh, PA, USA.

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1 DOI: / Gynaecological oncology Survival advantage associated with multimodal therapy in women with node-positive (stage-iiic) uterine papillary serous carcinoma: a National Cancer Database study JF Lin, a KMu~niz, b P Sukumvanich, a P Gehrig, c S Beriwal, a JL Kelley, a RP Edwards, a AB Olawaiye a a Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA b Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA c University of North Carolina School of Medicine, Chapel Hill, NC, USA Correspondence: Dr AB Olawaiye, 300 Halket Street, Office 2130, Pittsburgh, PA, USA. olawaiyea@mail.magee.edu Accepted 10 September Published Online 5 November Objective Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer. Adjuvant chemotherapy (CT) has become standard care in treatment of women with advanced-stage UPSC, but the role of consolidative radiotherapy (RT) is unclear. This study aims to evaluate survival outcomes of multimodal therapy. Design Retrospective cohort study using a National Cancer Database (NCDB). Setting United States of America. Sample A total of 1816 women diagnosed with UPSC. Methods All women diagnosed with surgically staged FIGO (International Federation of Gynecology and Obstetrics) stage-iiic UPSC were identified in the NCDB from January 1998 to December Overall survival (OS) was estimated using the Kaplan Meier method. Univariate and multivariable analyses were performed to identify and control for prognostic factors. Main outcome measure Overall survival. Results A total of cases of uterine cancer were identified, of which were UPSC. Of these women, underwent lymph-node examination, 2902 (20.6%) were found to have stage- IIIC disease, and 1816 received chemotherapy. Younger age and higher number of total lymph nodes examined were independently predictive of receiving multimodality (CT + RT) therapy, compared with CT only. Median OS was 33.6 and 42.6 months, for the CT and CT + RT groups, respectively (P < ). Exploratory univariate analyses found age, comorbidity index, tumour size, and number of dissected and positive lymph nodes to be also associated with survival. Multivariable analysis controlling for the above found the use of consolidative radiotherapy to be independently predictive of improved OS, with a hazard ratio of 0.69 (95% confidence interval, 95% CI ). Conclusions Patients with stage-iiic UPSC may benefit from multimodal treatment that includes adjuvant radiotherapy in addition to chemotherapy. Keywords Chemotherapy, radiotherapy, UPSC. Tweetable abstract In this study of 1816 women with uterine papillary serous cancer, adjuvant radiotherapy increased survival. Please cite this paper as: Lin JF, Mu~niz K, Sukumvanich P, Gehrig P, Beriwal S, Kelley JL, Edwards RP, Olawaiye AB. Survival advantage associated with multimodal therapy in women with node-positive (stage-iiic) uterine papillary serous carcinoma: a National Cancer Database study. BJOG 2016;123: Introduction Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer (type II). UPSC behaves more similarly to ovarian serous carcinoma, as compared with endometrial carcinoma, in its tendency to metastasize to the lymph nodes and peritoneal surfaces. UPSC represents about 10% of endometrial carcinomas, yet it is responsible for up to 40% of all deaths and recurrences associated with endometrial cancer. 1 Prognosis for women with UPSC is poor, with 5-year overall survival (OS) rates ranging from 18 to 27%, probably as a consequence of extrauterine spread at presentation, which is found in approximately 60 70% of women. 2 Given the rarity of UPSC and lack of evidence-based data to guide treatment, consensus opinion has been difficult to reach. Because UPSC has a tendency to spread to peritoneal surfaces early in its clinical course, much like ovarian 1846 ª 2015 Royal College of Obstetricians and Gynaecologists

2 Radiotherapy for uterine serous cancer cancer, the depth of tumour invasion is not a reliable indicator of whether UPSC has metastasized. In fact, as many as 40% of women are found to have extrauterine disease with limited or no myometrial invasion by the primary tumour. 3 Not only are recurrence rates for UPSC much higher than those for endometrioid tumours, recurrence is also more likely to be distant. 4,5 Because of histological and clinical similarities to serous epithelial ovarian carcinoma, current Society of Gynecologic Oncology (SGO) guidelines recommend comprehensive surgical staging and platinum/taxane-based adjuvant chemotherapy to be the cornerstone of the management of this disease. 4 In women with lymph node-only extrauterine spread (International Federation of Gynecology and Obstetrics, FIGO, stage IIIC), considerable controversy exists on the use of multimodal therapy with both radiotherapy and chemotherapy, as has been advocated for stage-iiic endometrioid endometrial cancer. 6,7 Using a large national cancer database, we aim to determine whether treatment of stage-iiic UPSC with consolidative radiotherapy in addition to chemotherapy (CT + RT) is associated with a survival advantage, compared with chemotherapy alone (CT). Methods Patients with UPSC diagnosed between January 1998 and December 2010 were identified from the National Cancer Database (NCDB) using ICD-O-3 histology codes 8260, 8441, 8460, and These histology codes are for pure UPSC; mixed-histology tumours were excluded. The data set was then restricted to women who underwent surgical staging with (at least) total hysterectomy, bilateral salpingo-oophorectomy, and documentation of lymph-node examination, found to be stage IIIC (IIIC1 or IIIC2), without evidence of other, distant metastatic disease. All patient, facility, disease, and treatment variables were abstracted. Exploratory univariate analyses examining the effects of patient, facility, and disease factors on whether or not the patient received multimodality therapy were performed on the following clinicopathologic variables: age, race, Hispanic ethnicity, Charlson Deyo comorbidity index, insurance status, urban status, education and income level of the patient s area of residence, distance to treating facility, facility location and academic status, year of diagnosis, lymph node yield, number of positive lymph nodes, tumour size, and surgical approach. For these analyses, we used the chi-square or log-rank test to identify which of these factors are associated with the use of multimodality therapy (CT + RT), compared with chemotherapy alone (CT). Continuous variables were grouped into quartiles to facilitate comparison, and multiplicity was controlled for by the Bonferroni Holm method. 8 Duration of survival was reported from the date of diagnosis to the date of death; surviving women were censored at the date of last contact. OS was estimated using the Kaplan Meier method, and reported in months. 9 Multivariable analyses were performed with single-step binary logistic regression, 10 and step-wise Cox proportional hazards models, constructed using the enter method. 11,12 For the Cox proportional hazards model, covariates identified from exploratory univariate analyses were entered at the first step and radiotherapy use was entered at the second step. All statistical tests were two-sided, and differences were considered significant with a threshold of P < 0.05; 95% confidence intervals (95% CIs) are also reported. All statistical testing was performed using SPSS 19.0 (IBM, Armonk, NY, USA). Results A total of cases of endometrial cancer were identified. Of these, were of the pure UPSC subtype. Of the women identified as having UPSC, underwent lymph-node examination (surgical resection as well as nodal aspiration), with a median of 12 nodes examined. The surgical route was not consistently recorded in the early years included in the data, hence the small number of data points shown in Table 1. This is mainly because most women at that time had laparotomy, and therefore the route of surgery was not considered an important data point to capture. The minimal-access approach for major staging surgery has become more popular in the last decade. A total of 2902 (20.6%) women were found to have stage-iiic disease, out of whom 1816 (62.6%) received adjuvant chemotherapy. All analyses were performed on this subgroup of women. The median age of the group is 67 years. Patients were divided into those who received adjuvant chemotherapy only (CT group; n = 881; 49%) and those who received multimodal therapy, with both adjuvant chemotherapy and radiotherapy (CT + RT group; n = 926; 51%). Radiation treatment information was unavailable for nine women. Of those receiving CT + RT, 366 (40.8%) received brachytherapy as part of radiation treatment, but there were 41 cases with unknown brachytherapy information. NCDB does not have information on the extent of radiation field. The median follow-up time was 25.8 months (with a range of months). The results derived from exploratory univariate analyses are shown in Table 1. Of the factors included, younger age (P = 0.003) and higher number of total lymph nodes examined (P = 0.005) were associated with receiving ª 2015 Royal College of Obstetricians and Gynaecologists 1847

3 Lin et al. Table 1. Factors associated with multimodality therapy Table 1. (Continued) n (% within subgroup) CT + RT v 2 OR n (% within subgroup) CT + RT v 2 OR Age (years) < (55.8) (54.5) (48.8) (44.6) Ethnicity White 698 (52.3) African-American 186 (47.7) Native American/ 3 (100) Alaskan Asian/Pacific Islander 19 (45.3) ( ) per year Hispanic ethnicity Non-Hispanic 810 (51.7) Hispanic 39 (51.3) Charlson Deyo comorbidity index (53.4) (46.2) 2 24 (46.2) Insurance status Uninsured 28 (48.3) Insured 873 (51.1) Urban status Rural 15 (41.7) Urban 123 (51.9) Metropolitan 743 (51.2) Percentage of high school graduates in patient zip code (50.0) (51.0) (48.4) > (54.2) Income of patient zip code <$ (45.9) 0.11 $ (51.1) $ (50.4) $ (54.5) Distance from patient zip code to treating facility <4 miles 240 (54.3) miles 222 (51.2) miles 230 (52.3) >29 miles 206 (47.4) Facility location Northeast 287 (53.2) South 221 (49.0) Midwest 282 (50.4) West 136 (52.7) Facility academic status Community cancer 72 (54.5) centre Comprehensive community cancer centre 402 (52.0) Academic/research 440 (49.7) centre Year of diagnosis (50.1) (53.7) (49.7) (52.1) Number of total lymph nodes (47.4) (49.7) (50.5) (59.0) Number of positive lymph nodes (55.0) (54.1) (50.9) (44.9) Tumour size (cm) (50.3) (50.6) (47.2) > (51.7) Surgical approach Robot-assisted 10 (41.7) Laparoscopic 7 (77.8) Open 35 (49.3) ( ) per lymph node adjuvant CT + RT, as opposed to CT alone. On binary logistic regression, younger age (odds ratio, OR 0.98; 95% CI ) and higher number of lymph nodes examined (OR 1.01; 95% CI ) remained independently predictive of receiving CT + RT (Table 1). The median OS for CT and CT + RT groups were 33.6 months (95% CI months) and 42.6 months (95% CI months), respectively (P < ; Figure 1; Table 2). Exploratory univariate analyses, performed on the same clinicopathologic variables above, as well as two additional treatment variables (administration of immunotherapy and hormonal therapy) found age, comorbidity index, tumour size, and number of total and positive lymph nodes to be significantly associated with survival (all P < ; Table 2), along with multimodality therapy. Multivariable analysis, controlling for the above factors, found radiotherapy to be independently predictive of improved OS, with a hazard ratio of death of 0.69 (95% CI ). The adjusted survival for multimodality therapy is plotted and shown in Figure 2, with an adjusted median survival advantage of >13 months ª 2015 Royal College of Obstetricians and Gynaecologists

4 Radiotherapy for uterine serous cancer Proportion surviving Discussion Overall survival Therapy Months from diagnosis Chemotherap only Multmodalit 200 Figure 1. Overall survival. Unadjusted overall survival according to type of therapy received. Patients who received radiotherapy in addition to chemotherapy (red) had a significantly longer survival than those who received chemotherapy only (yellow). Main findings Uterine papillary serous carcinoma (UPSC) displays aggressive clinical behaviour, with a strong tendency to metastasize and recur along both nodal and peritoneal sites. Adjuvant chemotherapy has led to an improvement in survival, whereas the role of consolidative radiotherapy has remained unclear. According to our analysis, the addition of adjuvant radiotherapy to chemotherapy in the treatment of women with stage-iiic UPSC is associated with a significant improvement in OS. This is clinically important, as the use of adjuvant radiation in this patient population varies in practice (as evidenced by the fact that only 51% of women in this large national database were treated with CT + RT because of the perception that outcome is unlikely to be affected by the addition of adjuvant radiation). Strengths The strengths of this study include the large number of women, the inclusion of many key details, and representative data collection. The number of women analysed, 1816, is larger than most previously reported studies for this disease. The inclusion of chemotherapy as well as comorbidity data, which are absent in the Surveillance, Epidemiology, and End Results (SEER) database, 13 is key for the study of this disease. The representative data collection, of 70% of Table 2. Factors associated with survival Median OS (months) Log-rank test HR death Age (years) < ( ) < ( ) ( ) ( ) per year ( ) Race White ( ) African-American ( ) Native American/ 66 (NA) Alaskan Asian/Pacific ( ) Islander Hispanic ethnicity Non-Hispanic 36.9 ( ) Hispanic ( ) Charlson Deyo comorbidity index ( ) < Referent ( ) 1.43 ( ) ( ) 1.55 ( ) Insurance status Uninsured ( ) Insured ( ) Urban status Rural ( ) Urban ( ) Metropolitan ( ) Percentage of high school graduates in patient zip code ( ) ( ) ( ) > ( ) Income of patient zip code <$ ( ) $ ( ) $ ( ) $ ( ) Distance from patient zip code to treating facility (miles) < ( ) ( ) ( ) > ( ) Facility location Northeast ( ) South 36.9 ( ) Midwest ( ) West ( ) Facility academic status Community ( ) cancer centre Comprehensive ( ) community cancer centre Academic/ ( ) research centre Year of diagnosis ( ) ( ) ª 2015 Royal College of Obstetricians and Gynaecologists 1849

5 Lin et al. Table 2. (Continued) Median OS (months) Log-rank test HR death ( ) ( ) Number of total lymph nodes ( ) < ( ) ( ) ( ) per lymph ( ) node Number of positive lymph nodes ( ) < ( ) ( ) ( ) per lymph ( ) node Tumour size (cm) ( ) < ( ) ( ) > ( ) Hormonal therapy Not administered 36.9 ( ) Administered 32.3 ( ) Therapy Chemotherapy only Proportion surviving Chemotherapy and radiotherapy 100% 80% 60% 40% 20% 0% 0 ( ) per cm ( ) < Referent ( ) 0.69 ( ) Adjusted survival Therapy Chemotherap only Multimodali Months from diagnosis 100 Figure 2. Adjusted survival. Adjusted for age, Charlson Deyo comorbidity score, tumour size, and number of total and positive lymph nodes. When survival was adjusted for multimodal therapy, the addition of radiotherapy (red) led to a 13-month increase in adjusted median overall survival, compared with chemotherapy alone (yellow). all newly diagnosed cancer cases in the USA, from all regions, and from facilities of varying academic status, allows insight into the current state of practice in the management of this disease, which we found to be split nearly on whether or not to give multimodality therapy or only chemotherapy in very similar populations, by all characteristics, except age and nodal parameters. We believe that this current NCDB analysis is the largest retrospective series to date of stage-iiic UPSC women undergoing multimodal therapy to explore the survival outcomes. Limitations The limitations of the present study include its retrospective nature, lack of standardisation or details on chemoand radiotherapy prescriptions, and data on management of recurrent disease. Retrospective studies are inherently subject to selection and reporting bias, although NCDB has a 70% capture rate of newly diagnosed malignancies in the USA, with quality-assurance mechanisms in place to ensure accurate data capture, 14,15 which mitigates some concerns of bias. Although we have more chemotherapy (including when it was given with respect to surgery and the number of chemotherapeutic agents administered) and radiotherapy (including dose/modality of regional and boost treatments, and their timing with respect to surgery) data here than in prior US national database studies, certain key factors, notably the exact chemotherapy agents (e.g. platinum/taxane-containing or not), location of radiation field (pelvic or extended), and sequence with respect to each other (e.g. sandwiched or sequential) are not available. Finally, no information on disease recurrence or disease status at time of last contact or death is available. Interpretation Undoubtedly there is a need for both local and systemic control in advanced-stage UPSC, and the use of multimodal therapy in these women addresses the fact that most relapses after adjuvant radiation occur outside of the radiated area. Several authors have reported the utility of administering platinum-based chemotherapy regimens in combination with radiation in women with UPSC A phase-ii pilot study of radiation sandwiched between platinum/taxane-based chemotherapy in women with all stages of UPSC demonstrated this regimen as being well tolerated and efficacious for women with completely resected UPSC. 19 Secord et al. 7 reported improved survival in women with advanced-stage endometrial cancer using a regimen of chemotherapy followed by radiation and additional chemotherapy, compared with other sequential modalities. Collectively, these prior data, along with data from the present study, suggest that combined multimodal therapy, involving adjuvant chemotherapy and radiation, 1850 ª 2015 Royal College of Obstetricians and Gynaecologists

6 Radiotherapy for uterine serous cancer may improve survival in women with advanced-stage disease compared with either modality alone. The benefit of multimodal therapy in early-stage UPSC has been reported in the Nordic Society of Gynecologic Oncology/European Organization for the Research and Treatment of Cancer (NSOG/EORTC) trial, where the combination of radiation therapy and chemotherapy was superior to radiation therapy alone. 20 That study showed that the sequential addition of CT to RT was associated with a significant 36% reduction in the risk of relapse or death, and was associated with a significant 49% reduction in the risk of death from endometrial cancer. After conducting a randomised trial comparing RT with CT, Maggi et al. 21 suggested that the two modalities might be complementary, as RT seemed to achieve better locoregional control, whereas CT seemed to better control the distant spread. In terms of management for advanced-stage UPSC, the role of adjuvant chemotherapy was established in Gynecologic Oncology Group Protocol 122 (GOG 122). 22 In the GOG 122 study, women with surgically staged endometrial cancer at FIGO stages III and IV were randomised to either whole abdominal radiation or doxorubicin/cisplatin chemotherapy. UPSC represented approximately 21% of women in each arm, and there was no subgroup analysis for UPSC. The hazard ratio for progression and death favoured the chemotherapy arm, with an HR of 0.71 (95% CI ; P = 0.007) and 0.68 (95% CI ; P = 0.004), respectively. The results of this study added to the data collected from other retrospective studies describing poor outcomes in women with advanced-stage or recurrent UPSC treated with radiation only, leading to the adoption of systemic therapy as the primary treatment modality in the management of this disease. The GOG 122 study raised the question of the appropriateness of combining radiation therapy and chemotherapy for women with FIGO stage-iii or -IV endometrial carcinoma of any histology. 2 There are only limited data from small retrospective studies that show combined modality treatment improves outcomes, compared with chemotherapy alone, 6,23 although a continuing GOG protocol (GOG 258) aims to address this question for all endometrial cancer subtypes. Conclusion The optimal management of women with advanced-stage UPSC is yet to be defined, and there is imperative clinical need to develop postoperative adjuvant treatment regimens that improve survival with acceptable toxicity. Our study adds to the growing body of evidence demonstrating that there is a survival benefit of combining both postoperative chemotherapy and radiation therapy for women with advanced UPSC. Our findings, although intriguing, need to be evaluated in a prospective setting. Disclosure of interests None declared. Completed disclosure of interests form available to view online as supporting information. Contribution to authorship ABO: conceived the research idea; requested data from NCDB; manuscript development. JFL: data collation; statistical analysis; manuscript development. KM: data collation; manuscript development. PS: helped with the data request; manuscript development. PG: concept advice; manuscript development; editing. SB: statistical analysis; manuscript development. JLK: manuscript development and editing. RPE: manuscript development and editing. Details of ethic approval Approval from the Institutional Review Board (IRB) or any other ethics committee was not required for this study because it used a publicly available database. Funding No funding was required for this study. & References 1 Fader AN, Boruta D, Olawaiye AB, Gehrig PA. Uterine papillary serous carcinoma: epidemiology, pathogenesis and management. Curr Opin Obstet Gynecol 2010;22: del Carmen MG, Birrer M, Schorge JO. 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