Prognostic Factors for Survival in Patients with Carcinoma Endometrium

Article published online: 2023-02-06 THIEME Original Article Genitourinary/Gynecologic Cancer Prognostic Factors for Survival in Patients with Carcinoma Endometrium Aparna Mullangath Prakasan1 Minolin Dhas1 Krishnapillai M. Jagathnathkrishna2 1 1 Susan Mathews John Joseph Suchetha Sambasivan3 Francis V. James1 1 Department of Radiation Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India 2 Department of Biostatistics and Epidemiology, Regional Cancer Centre, Thiruvananthapuram, India 3 Division of Gynecological Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India Aswin Kumar1 Address for correspondence Francis. V. James, MD, Gynaec Oncology Clinic, Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India (e-mail: fvjames9@gmail.com). South Asian J Cancer 2022;11(4):309–314. Abstract Aparna Mullangath Prakasan Keywords ► ► ► ► ► prognosis radiotherapy surgery survival uterine neoplasms Objective The study aimed to see the clinical outcome and to identify prognostic factors for survival in patients with carcinoma endometrium. Methods Patients registered at Regional Cancer Centre, Thiruvananthapuram, Kerala, India, with carcinoma endometrium from January 2009 to December 2013 were identified from hospital registry. Data regarding patient demographics, tumor characteristics, treatment schedules, and follow-up were collected using a structured proforma. Survival estimates were generated using the Kaplan–Meier method. Univariate analysis was done using chi-square and Fisher’s exact tests. Multivariate analysis using the Cox regression model was performed to determine the impact of prognostic factors on outcome. The statistical analysis was done using SPSS software version 11. Results The median follow-up of the 686 patients was 95 months (range 3–178 months).There were 432 stage 1 (63%), 100 stage II (14.6%), 108 stage III (15.7%), and 46 stage IV patients (6.7%). The 5-year overall survival was 89.2%. Prognostic factors for survival on univariate analysis were age 60 years or older, nonendometrioid histology, high-grade tumor, cervical stromal involvement, para-aortic node involvement, negative progesterone receptor expression, deep myometrial invasion advanced stage, surgery versus no surgery, serosal involvement, and ovarian and fallopian tube involvement. However, on multivariate analysis, age over 60 years, higher histological grade, advanced stage, and deep myometrial and parametrial invasion were associated with significantly poorer survival. Conclusion We found that age over 60 years at presentation, higher grade, advanced stage, deep myometrial invasion, and parametrial invasion were associated with poorer survival. DOI https://doi.org/10.1055/s-0041-1735563 ISSN 2278-330X © 2022. MedIntel Services Pvt Ltd. All rights reserved. This is an open access article published by Thieme under the terms of the How to cite this article: Prakasan AM, Dhas M, Jagathnathkrishna KM, et al. Prognostic Factors for Survival in Patients with Carcinoma Endometrium. South Asian J Cancer 2022;11(4):309–314. Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/ 4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd., A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 309 310 Prognostic Factors for Survival in Carcinoma Endometrium Introduction Incidence of endometrial cancer is on the rise in India.1 The publications of the outcome of patients and the prognostic factors of endometrial cancer are few from India. Dietary and hormonal factors are probably the cause for the increasing incidence.1 The study aimed to see the clinical outcome and to identify prognostic factors for survival. Materials and Methods Following approval from the institutional review board, case files of all patients with endometrial carcinoma registered at Regional Cancer Centre (RCC), Thiruvananthapuram, Kerala, India, from January 2009 to December 2013 were retrieved from the hospital database. During this period, a total of 757 endometrial cancer patients were registered at the center. Patients who were registered for a second opinion, for brachytherapy alone, and who presented with recurrence were excluded from the study. After these exclusions, 686 patients were available for analysis. Each of these patients’ records were reviewed and data on patient characteristics, disease characteristics, staging evaluation, and treatment factors were recorded. The outcome of treatment, recurrence, morbidity data, and last follow-up updates were documented and entered into a structured proforma. Survival estimates were generated using the Kaplan–Meier method. Univariate and multivariate analyses were done using the Cox regression model to determine the impact of prognostic factors on outcome. Overall survival (OS) was defined as the period from the date of diagnosis until the date of death. Various patient, tumor, and treatment-related factors were correlated with OS. Results The mean age of the 686 patients was 57 years (range 25–85 years). The majority of the patients (60.5%) were less than 60 years old. Comorbid illnesses were present in many; 20.7% had both diabetes and hypertension. The majority of the patients were postmenopausal (80%) at presentation. Most of the patients were multiparous (93.1%). Only 3.2% of the patients had a family history of malignancy. The pathological type was endometrioid in 78% and nonendometrioid in the rest (12%), which included papillary serous carcinoma, mucinous carcinoma, malignant mixed Mullerian tumor, adenosquamous carcinoma, and poorly differentiated carcinoma. The majority of the patients had total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) 66.9%, and 22.3% of patients had TAH with BSO and bilateral pelvic lymph node dissection and 3% had omentectomy along with lymph node dissection. The histological grade was 3 in 35.4% and the rest were grades 1 and 2. ►Table 1 shows patient characteristics. After surgery, intermediate-risk patients were treated with vaginal brachytherapy; high-risk patients were treated with pelvic radiotherapy with or without chemotherapy. Patients with grade 3 onwards received chemotherapy with or without radiotherapy. The 5-year OS probability for the South Asian Journal of Cancer Vol. 11 No. 4/2022 Aparna et al. entire group was 89.2%. At a median follow-up of 95 months, 126 patients (18.3%) relapsed. In these relapsed patients, 44 were locoregional failures (central pelvis and pelvic nodes) and 82 were distant failures (outside pelvis). Among the distant relapses, common sites affected were the lung followed by peritoneum, nonregional lymph nodes, liver, bone, and brain. Prognostic factors for survival on univariate analysis were age over 60 years; nonendometrioid histological type; high grade of the tumor; cervical stromal involvement; para-aortic node involvement; deep myometrial invasion (>50%); adnexal, parametrial, and serosal involvement; peritoneal deposits; advanced stage; inoperability; and pelvic and para-aortic nodal metastasis. However, on multivariate analysis patients with age over 60 years, histological grade 3, higher stages of 3 and 4 and myometrial invasion more than 50%, and parametrial invasion had significantly poorer survival. ►Table 2 shows the univariate analysis and ►Table 3 shows the multivariate analysis. Old age was associated with poor survival. Discussion After the Gynecologic Oncology Group (GOG) 33 study, various prognostic factors were identified and risk grouping was done.2 The study showed that deep myometrial invasion and grade 3 disease was associated with higher chances of lymph nodal metastasis. In other studies age, tumor grade, lymphovascular space invasion, depth of infiltration, and progesterone receptor status were found important.3–5 GOG 99 and Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) trials defined risk groups for women to predict who may benefit from adjuvant therapy. PORTEC group defines high intermediate risk (HIR) as those with two of the following: age older than 60 years, grade 3 diseases, or 50% myometrial invasion.6 GOG defines HIR based on age and the number of risk factors (grade 2–3, the presence of LVSI (lymphovascular space invasion), or outer one-third myometrial invasion). Patients aged more than 70 years must have one risk factor, those aged 50 to 70 years must have two risk factors, and those younger than 50 years must have all three risk factors.7 Analysis of pooled data from PORTEC 1 and PORTEC 2 showed patient age, tumor grade, and LVSI were highly predictive of locoregional relapse, distant relapse, and OS.3 Age has been identified as a predictor of recurrence and survival in many studies.8,9 Many trials have used age cutoff around 60 years.9 In an analysis based on the Surveillance, Epidemiology, and End Results database, it was reported that cancer-specific mortality is higher in older women, even after adjusting for treatment differences.9 In a few studies, age was not a significant factor for mortality.10 The ESMO ESTRO ESGO (European Society of Medical Oncology - European Society for Radiotherapy & Oncology - European Society of Gynecological Oncology) consensus guidelines have not considered age as a risk factor for prognostic grouping.11 We have grouped patients into two groups as in the PORTEC study group as we had only a few patients older © 2022. MedIntel Services Pvt Ltd. All rights reserved. Prognostic Factors for Survival in Carcinoma Endometrium Aparna et al. Table 1 Patient characteristics Parameters Age Menopausal status Parity Histology Grade of endometrioid cancer Myometrial invasion Frequency Percentage <60 years 415 60.5 60 years 271 39.5 Premenopausal 137 20 Postmenopausal 549 79.9 Nulliparous 46 6.3 Multiparous 640 93.7 Endometrioid 535 78 Nonendometrioid 151 12 1 86 12.5 2 357 52 3 243 35.4 No 29 4.2 <50% 314 45.8 50% 343 50 Pelvic lymph node–positive 64 9.3 Para-aortic node–positive 42 6.1 Positive 98 14.3 Negative 83 12.1 Positive 144 21 Negative 41 6 Estrogen receptor Progesterone receptor CEA Stage of disease Type of surgery Positive 91 13.3 Negative 61 8.9 1A 289 42.1 1B 142 21 2 100 14.6 3 107 15.8 4 46 6.8 TAH þ BSO 459 66.9 TAH þ BSO þ PLND  PALN sampling 153 22 TAH þ BSO þ PLND þ omentectomy 22 3 Other surgeries 52 7 No surgery 30 4.3 Abbreviations: CEA, carcinoembryonic antigen; PALN, para-aortic lymph node; PLND, pelvic lymph node dissection; TAH þ BSO, total abdominal hysterectomy with salpingo-oophorectomy. than 70 years. Older women had higher-grade tumors (p < 0.002) and more advanced-stage disease (p < 0.001). They are less likely to undergo pelvic lymph node dissection along with hysterectomy and adjuvant treatment because of comorbidities. A significant association between age and survival could be identified in our study and age above 60 years carried poorer survival. Regarding other risk factors which were associated with poor outcome in our study, one was the histological grade of endometrial carcinoma. Grade 3 was associated with an 81.3% OS probability at 5 years compared to 94% in grade 2 tumors. The histological grade is the most established factor for recurrence in most reports.3,4 The grade was not a significant factor in a few studies.8 Depth of myometrial infiltration was a significant factor for relapse and survival in many studies.10 In our study, myometrial invasion of more than half was associated with 82.6% 5-year survival probability compared to 95.4% for those with less myometrial invasion. Depth of infiltration could be related to worse histological grade also. The advanced stage is associated with poor outcome. The 5-year survival for stage I disease is approximately 80 to 90%, stage II is 80%, stage III is 50 to 70%, and stage IV is 20% according to the literature considering the prognostic value South Asian Journal of Cancer Vol. 11 No. 4/2022 © 2022. MedIntel Services Pvt Ltd. All rights reserved. 311 312 Prognostic Factors for Survival in Carcinoma Endometrium Aparna et al. Table 2 Univariate analysis of overall survival Factors p-Value Hazard ratio (HR) 95.0% Confidence interval (CI) for HR Lower Upper Age (>60 years vs. 60 years) 0.006 1.863 1.194 2.907 Parity (multiparous vs. nulliparous) 0.350 1.616 0.591 4.422 Menopausal status (post vs. pre) 0.154 1.565 0.846 2.895 Comorbid conditions (no illness) 0.137 Comorbid conditions (diabetes vs. no illness) 0.412 1.348 0.661 2.749 Comorbid conditions (hypertension vs. no illness) 0.164 1.536 0.84 2.808 Comorbid conditions (diabetes þ hypertension vs. no illness) 0.023 1.902 1.093 3.310 Surgery (not done vs. done) 0.001 5.878 2.684 12.871 Nonendometriod vs. endometriod 0.001 2.617 1.652 4.144 Grade (1) 0.001 Grade (2 vs. 1) 0.816 0.906 0.394 2.080 Grade (3 vs. 1) 0.019 2.593 1.168 5.757 Stage (1) 0.001 Stage (2 vs. 1) 0.632 1.211 0.552 2.658 Stage (3 vs. 1) 0.001 4.741 2.82 7.97 Stage (4 vs. 1) 0.001 9.557 4.938 18.499 Myometrial invasion (>50% vs. <50%) 0.001 5.137 2.924 9.026 Ovarian/fallopian tube invasion (yes vs. no) 0.001 3.010 1.659 5.462 Serosal invasion (yes vs. no) 0.001 3.506 1.686 7.292 Endocervix extension (yes vs. no) 0.243 1.399 0.797 2.457 Cervical stroma invasion (yes vs. no) 0.001 2.374 1.427 3.95 Parametrial invasion (yes vs. no) 0.001 6.035 3.008 12.107 Peritonial deposits (yes vs. no) 0.001 5.336 2.743 10.38 Lymphovascular invasion (yes vs. no) 0.009 3.352 1.353 8.306 Para-aortic lymph node metastasis (yes vs. no) 0.001 4.500 2.478 8.173 Pelvic node metastasis (yes vs. no) 0.001 3.256 1.901 5.576 Lung metastasis (yes vs. no) 0.021 3.900 1.229 12.374 ER (negative vs. positive) 0.470 1.344 0.603 2.999 PR (negative vs. positive) 0.022 2.703 1.156 6.322 Carcinoembryonic antigen (CEA) (negative vs. positive) 0.988 0.993 0.385 2.561 Adjuvant treatment (no vs. yes) 0.068 1.545 0.969 2.464 Abbreviations: ER, estrogen receptor; PR, progesterone receptor. of stage for 2009 International Federation of Gynecology and Obstetrics (FIGO) classification.12 In our study also advanced stage was associated with poor outcome. Parametrial invasion in endometrial cancer is not always a continuation of cervical stromal invasion. Other factors that are associated with parametrial invasion are more than half of myometrial invasion, lymph node metastasis, ovarian metastasis, and lymphovascular space invasion. It reflects the advanced stage of the disease and is associated with poor outcome.13 The parametrial invasion was a bad factor affecting survival in multivariate analysis in our study. The 5-year OS for patients who had no serosal involvement was 83.5% South Asian Journal of Cancer Vol. 11 No. 4/2022 versus 75% for those who had serosal involvement. We could find serosal involvement significant for poor survival on univariate analysis only. Creasman et al showed adnexal involvement was associated with a higher risk for lymph node involvement.2 Fortynine patients had ovary or fallopian tube involvement in the present study. The patients who had either ovarian or fallopian tube involvement had an inferior 5 years OS of 73.6% compared to 90.4% of patients who did not have adnexal involvement. These patients are staged as stage 3A indicating grave prognosis in FIGO and Union for International Cancer Control (UICC) staging. © 2022. MedIntel Services Pvt Ltd. All rights reserved. Prognostic Factors for Survival in Carcinoma Endometrium Aparna et al. Table 3 Multivariate analysis of overall survival Factors Hazard ratio (HR) p-Value 95.0% Confidence interval (CI) for HR Lower Upper 1.845 1.175 2.897 Age (>60 years vs. 60 years) 0.008 Grade (1) 0.024 Grade (2 vs. 1) 0.184 0.560 0.238 1.317 Grade (3 vs. 1) 0.826 1.099 0.474 2.551 Stage (1) 0.001 Stage (2 vs. 1) 0.846 0.923 0.412 2.071 Stage (3 vs. 1) 0.003 2.535 1.38 4.654 Stage (4 vs. 1) 0.001 5.413 2.661 11.012 Myometrial invasion (>50% vs. <50%) 0.001 3.031 1.632 5.629 Parametrial invasion (yes vs. no) 0.041 2.247 1.035 4.879 The 5-year OS of patients with pelvic node involvement was 74.5% compared to 90.7% for patients without pelvic node involvement, and OS of patients with para-aortic nodal involvement was only 65%. Nonendometrioid histology was associated with poorer survival in most studies affecting survival.4,14 This was significant in univariate analysis for us but not in multivariate analysis. Most of our patients with nonendometrioid histology presented with the advanced-stage disease may be the reason it was not significant in the multivariate analysis. Progesterone receptor (PR)–negative tumors have been examined by other authors previously and found to be an adverse feature.5 We could test estrogen receptors (ER) in 181 patients, 83 were negative and 98 were positive. Progesterone receptors were tested in 185 patients, out of which 41 were negative. There was no significant difference in the survival probability in our patients based on hormone receptor status. Surgery is the primary curative modality for endometrial cancer. Inoperable patients had a very poor outcome. For the patients who had undergone total hysterectomy with or without pelvic lymph node dissection, the 5-year survival was 90.1%. Our analysis did not show any significant difference between TAH and BSO and TAH and BSO with pelvic lymph node dissection. Recently there is a lot of enthusiasm in the search for molecular factors that are useful to predict chances of recurrence in endometrial carcinoma. Abnormal p53, mismatch repair deficiency, presence of POLE mutation, and no specific molecular profile have been described for risk grouping of patients after surgical treatment.15 The PORTEC 4 trial is examining the value of the approach. and adjuvant treatment was delivered based on slide review report and post op imaging. Conclusion Patients older than 60 years diagnosed with endometrial cancer had poorer survival. Other well-established factors like a deep myometrial invasion, grade 3 tumors, advanced stage, and parametrial invasion also had a poorer outcome. Adjuvant treatment recommendations for this cancer need further refinement. Newer molecular typing is required for better stratification of patients for the selection of adjuvant treatment. Disclaimers None. IRB Approval Approved by the scientific committee, institutional review board, Regional Cancer Center, Thiruvananthapuram, Kerala, India. IRB number: 09/2018/08 Conflict of Interest None declared. Acknowledgments We would like to thank Dr Rema P for sharing clinical data. We are thankful to the medical records officer and staff for their support. References 1 Murthy NS, Shalini S, Sastry NB, Suman G, Sreekantaiah P, Mathew Limitations of the Study Being retrospective analysis, data on toxicities associated with treatment were not properly documented. Data on patients who were lost to follow-up were updated using telephonic conversations and personal letters. Many of the patients had primary surgery outside the center (TAH þ BSO) A. Increase in incidence of cancer of corpus uteri: estimation of time trends—an Indian scenario. Eur J Cancer Prev 2011;20(01): 25–32 2 Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A gynecologic oncology group study. Cancer 1987;60(8, Suppl):2035–2041 South Asian Journal of Cancer Vol. 11 No. 4/2022 © 2022. MedIntel Services Pvt Ltd. All rights reserved. 313 314 Prognostic Factors for Survival in Carcinoma Endometrium Aparna et al. 3 Creutzberg CL, van Stiphout RG, Nout RA, et al. Nomograms for 4 5 6 7 8 prediction of outcome with or without adjuvant radiation therapy for patients with endometrial cancer: a pooled analysis of PORTEC-1 and PORTEC-2 trials. Int J Radiat Oncol Biol Phys 2015;91 (03):530–539 Kim M, Kwon BS, Chang HK, et al. Survival outcomes of adjuvant radiotherapy and chemotherapy in women with stage I serous papillary and clear cell carcinoma of the endometrium: a Korean multicenter study. J Gynecol Oncol 2019;30(03): e44 van der Putten LJM, Visser NCM, van de Vijver K, et al. 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Obstet Gynecol 2010;116(05):1141–1149 Disaia PJ. Predicting parametrial involvement in endometrial cancer: is this the end for radical hysterectomies in stage II endometrial cancers? Obstet Gynecol 2010;116(05):1016–1017 Altman AD, Ferguson SE, Atenafu EG, et al. Canadian high risk endometrial cancer (CHREC) consortium: analyzing the clinical behavior of high risk endometrial cancers. Gynecol Oncol 2015; 139(02):268–274 Bosse T, Nout RA, McAlpine JN, et al. Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups. Am J Surg Pathol 2018;42(05):561–568 Erratum: The article has been corrected as per Erratum. DOI of the Erratum is 10.1055/s-0043-1764147. South Asian Journal of Cancer Vol. 11 No. 4/2022 © 2022. MedIntel Services Pvt Ltd. All rights reserved.