Clinical Outcomes of Uterine Body Cancers Treated in a Tertiary Cancer Center

Introduction

Endometrial cancer is one of the commonly prevalent malignancies worldwide. The higher incidence is probably due to the increased prevalence of high-risk factors such as obesity, diabetes, hypertension, and exogenous or endogenous hyperestrogenism in developed nations. The outcomes are better in endometrial cancer due to its earlier stage of presentation.1 As per the estimates of GLOBOCAN 2020, cancers of corpus uteri is the sixth most common malignancy among females worldwide (417,367 new cases, 4.5%).2 About 75 to 80% of histology are of endometrioid adenocarcinoma which is the most common, which carries good prognosis.3 Overall survival (OS) is approximately 96% which drops to 67% in lymph node positive disease.4 Serous and clear cell histology make up about 10 and 4%, respectively, both have worse prognosis due to the nature of advanced stage at presentation.5 Uterine sarcomas are a rare group that constitute 3 to 9% of malignant uterine body tumors and less than 1% of all gynecological malignancies.6 Aggressive biology and propensity to local recurrence and distant dissemination characterized by less favorable outcomes with 2-year actuarial survival of 36%. The majority of endometrial cancers are being diagnosed as early-stage disease with a good prognosis after surgery alone. Identifying the patients with early-stage disease with highest risk for recurrence who needs adjuvant therapy and also avoiding overtreatment considering the risk of toxicities for low-risk group is challenging. Postoperative adjuvant therapy is based on the presence of adverse prognostic factors from the surgical staging. The decision on adjuvant therapy has been defined according to various risk stratifications based on international trials to assess the overall benefit of such treatment. Data on survival outcomes in Indian population is less. We had proposed to study the clinical outcomes of uterine body cancers treated in a tertiary cancer care center in South India.

Materials and Methods

Our study was a retrospective record-based study. The records of all patients diagnosed as malignancy in uterus and treated with surgery alone or with adjuvant treatment in the departments of Obstetrics and Gynaecology and Radiation Oncology, JIPMER from January 2013 to December 2017 were retrieved. Institutional ethical committee permission was obtained prior to the start of the study. The details such as age, comorbidities, parity (nulliparous/multiparous), menopausal status, surgery details, and postoperative histopathological report from which histology type, grade of tumor, myometrial invasion, lymphovascular space invasion, pathological stage, and nodal staging were collected. The details of adjuvant treatment received, type of radiation, duration and dose, brachytherapy and chemotherapy details, type of recurrences, metastases, status at last follow-up, and treatment received for recurrences were recorded. Revised International Federation of Gynecology and Obstetrics (FIGO) 2018 staging system was applied to the group. Patients were stratified into various risk groups based on risk stratification by European Society of Medical Oncology/European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology (ESMO-ESGO-ESTRO), depending on histopathological details. Further analysis and factors affecting outcome were analyzed according to risk grouping. OS and disease-free survival (DFS) were calculated as the time between completion of treatment and date of occurrence of the event. An event in OS analysis was taken as death of the patient due to any cause or date of last follow-up. An event in DFS analysis was taken as disease recurrence at local or distal or both sites or death due to disease or date of last follow-up. Data entry and analysis were done using SPSS version 21. For the survival analysis, Kaplan–Meier survival estimator was used. Cox regression was used to test the significance of association of factors with outcomes in terms of hazard ratio (HR).

Results

A total of 198 patient records diagnosed with uterine body tumors between January 2013 and December 2017 were identified from the departments of Obstetrics and Gynaecology and Radiation Oncology, JIPMER. Of these, 20 records were found to be either simple or complex endometrial hyperplasia on postoperative histologic examination and so were excluded from the study. Fig. 1 shows the flow of details retrieved from records.

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Fig. 1: Flowchart showing details retrieved from records.

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Overall Survival

The mean OS of all patients is 68 months (n = 178), median was not reached. Five-year OS is 79%. The mean OS for carcinoma/carcinosarcoma is 68 months (n = 172 patients), for which median was not reached and the 5-year OS is 78%. Among the 6 patients with sarcoma, 2 patients were lost to follow-up, 4 were alive at the time of last follow-up date among which 3 are free of disease and 1 had distant recurrence. Median survival is not reached for stage I. Forty months for stage II, 71 months for stage III, and 8 months for stage IV. Fig. 2 shows Kaplan–Meier survival curve for OS.

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Fig. 2: Kaplan–Meir survival curve—overall survival.

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Disease-Free Survival

DFS was calculated only for patients who had undergone upfront surgery. Accordingly, out of 141 patients of carcinomas/carcinosarcoma analyzed, 10 recurrences were found in which 6 had vault recurrence, 3 were distant, and 1 at both sites. No recurrences were identified in patients who had received adjuvant radiation. The mean DFS was 65 months, median not reached. The 5-year DFS was 76%. There was no significant difference in DFS among the different risk groups (p 0.517). All the 6 vault recurrences were planned for further treatment with radical radiation, 4 of them completed treatment. Two patients are alive with no evidence of disease at the last follow-up. Fig. 3 shows Kaplan–Meier DFS.

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Fig. 3: Kaplan–Meir survival curve—disease-free survival.

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Discussion

This is a retrospective study performed in a tertiary cancer care center to evaluate the outcomes of uterine body cancers treated over a 5-year span. Initially, we intended to analyze the outcomes of both carcinomas and sarcomas, but subsequent analysis was done only on carcinomas due to poor numbers in the latter. The majority of our study population were in stage I (50%) comparing the proportion reported from Tata Memorial Hospital (TMH), Mumbai (68%), which was studied on only early-stage disease.7 In terms of complete surgical staging including lymph node dissection, approximately 51% (55 of 107 patients) of stage I and II underwent either sampling or pelvic with or without para-aortic nodal dissection. Mahantshetty et al reported 47% of complete surgical staging which was defined as TAH + BSO and bilateral PLND and was 51% in Kumar et al study.78 Among the patients who did not receive any adjuvant treatment, in the low-risk group 6% presented with recurrence (1 in 15 patients), 8% (1 in 12 patients) in the intermediate-risk group, 33% (1 in 3 patients) in the high-intermediate group, and 6% (1 in 17 patients) in the high-risk group.

Besides, there were six more local recurrences where information on risk category was not available. All these six cases did not receive adjuvant radiotherapy (RT). All patients with recurrence were planned for further treatment with radical radiation, four of whom had completed the intended treatment. Two patients were still alive and disease free till the time of last follow-up. The recurrence rate was higher in the high-intermediate risk group which did not receive adjuvant radiation, explaining the need of adjuvant RT in this setting. Recurrence rates were low in the high-risk group which might be explained by the adjuvant treatment received by majority of the patients. The overall incidence of locoregional recurrence rates in the low-, intermediate-, and high-risk groups was reported as 5, 12, and 14% in the PORTEC-2 trial, 10, 7, and14% by Mahantshetty et al, 10, 8, and 6% by Kumar et al, respectively.789 In our study, as the risk category of all patients with local recurrences were not available, the overall recurrence rates (local/distant/both) for both treated and untreated cases observed is reported as 5, 3.5, 16, and 2% in the low, intermediate, high-intermediate, and high-risk groups.

The 5-year OS and 5-year DFS of high-intermediate cases in PORTEC-2 as defined by “age > 60 years and stage 1C grade 1 or 2 disease, or stage 1B grade 3 disease; and stage 2A disease, any age,” were reported as 84 and 82%, respectively, in the vaginal brachytherapy arm, and 79 and 78%, respectively, in the external beam RT arm.9 Our study had defined high-intermediate risk as per the ESMO-ESTRO-ESGO risk stratification,1 and survival rates were found to be 75% (5-year OS) and 80% (5-year DFS). Our 5-year OS rates observed in low, intermediate, high-intermediate, and high-risk were 91, 88, 75, and 81.5%, respectively. Mahantshetty et al found 5-year OS of 97, 98, and 85% in low-, intermediate-, and high-risk, respectively, whereas Kumar et al reported them as 96, 82 and 68%, respectively.78 Similarly, the 5-year DFS rates observed in our study were 82, 95, 80, and 81.5% for low, intermediate, high-intermediate, and high-risk, respectively, while in the other study, the rates were 84, 85 and 60%, respectively.7

As per PORTEC-1, with age ≥ 60, the HR for relapse was 3.2 and HR for death was 3.1 (p = 0.003 and p = 0.02). In our study it was 1.07 (p = 0.5) and 1.33 (p = 0.8) for relapse and death, respectively. In the same PORTEC-1 study, grade 3 disease had HR for death of 4.9 (p = 0.0008), but it is not significant in our study with HR of 1.5 (p = 0.6) for death. The patients who did not receive RT had high HR for relapse 3.9, p < 0.0001, in the PORTEC-1 group. Similarly, in our study, patients who had received RT had less HR for relapse 0.35, p = 0.04, which was significant. Other factors like myometrial invasion > 50% and grade 1 were not found to be significant in both PORTEC-1 and our study.1011

In univariate and multivariate analysis in the study from TMH, Mumbai,7 tumor grade and type of radiation had significant impact in OS and grade and invasion of myometrium impacted DFS. Lymphadenectomy was not found to have significant impact on OS and progression-free survival in our study population. There was even no significant impact in early-stage endometrioid cancers in the study from TMH, Mumbai.7

The retrospective nature of our study is a major limitation since the outcomes depended profoundly on the availability of patient data. We were able to retrieve as much information from the records as possible from both the departments of Obstetrics and Gynaecology and Radiation Oncology. We had limited information on risk categorization, disease recurrence, and chemotherapy treatment. Data regarding radiation toxicities in bowel/bladder/vagina was very scarce to generate any meaningful information.

Conclusion

The survival outcomes in terms of DFS and OS were comparable with the literature. Higher risk of death in node positive patients and high risk of recurrence in patients not receiving adjuvant treatment was found.