|Ahead of print publication
Endometrial cancer risk factors, treatment, and survival outcomes as per the European Society for Medical Oncology (ESMO) - European Society of Gynaecological Oncology (ESGO) - European Society for Radiotherapy and Oncology (ESTRO) risk groups and International Federation of Gynecology and Obstetrics (FIGO) staging: An experience from developing world
Nidhi Gupta1, Awadhesh Pandey1, Kislay Dimri1, Alka Sehgal2, Ranjeev Bhagat3, Suraj1, Gurbir Gill1
1 Department of Radiation Oncology, Government Medical College and Hospital, Chandigarh, India
2 Department of Obstetrics and Gynaecology, Government Medical College and Hospital, Chandigarh, India
3 Department of Pathology, Government Medical College and Hospital, Chandigarh, India
|Date of Submission||19-Jul-2021|
|Date of Decision||13-Aug-2021|
|Date of Acceptance||24-Aug-2021|
|Date of Web Publication||11-Nov-2022|
Department of Radiation Oncology, Government Medical College and Hospital, Chandigarh
Source of Support: None, Conflict of Interest: None
Introduction: There is limited data on endometrial cancer from developing countries. The risk groups as defined by the ESMO-ESGO-ESTRO and their recommendations for adjuvant treatment have redefined the management protocols. In this retrospective analysis, the outcomes are assessed in the light of the new risk groups and FIGO staging.
Material Methods: One hundred and two patients of endometrial cancer reporting to the Department of Radiation Oncology from 2015 to 2019 were analysed retrospectively. Patients were stratified as per the ESMO-ESGO-ESTRO risk groups and FIGO staging. Patients were analysed for demographic profile, histopathology details, FIGO stage, treatment modalities received as per the ESMO-ESGO-ESTRO risk groups and the outcomes in terms of disease free survival and overall survival.
Results: A total of 102 patients were analysed. The mean age at presentation was 57.7 years. Seventy four percent (74.41%) were stage I patients, 14.7 % were stage II, 8.8% were stage III and remaining 2% were stage IV. The mean disease free survival for the patients in FIGO stage I, II, III and IV were found to be 63.5 (59.9 – 67) months, 60.5 (54.2 – 66.9) months, 30.9 (21.5 – 40.2) months and 15.4 (7.8 – 23.0) months respectively. The 5-year overall survival of patients in Stage I was 90.3%. The 3-year mortality of Stage III patients was 58.3%. While there was no mortality observed among Stage II patients, none of the Stage IV patient survived beyond 20 months. The 5-year disease-free survival for patients in Low Risk (LR) group, Intermediate Risk (IR) group and High Risk (HR) group was found to be 91.3%, 90% and 87% respectively. None of the patient in High Intermediate Risk (HIR) group experienced progression of disease and 33.3% patients in advanced group were disease free at 2 years follow-up. The multivariate analysis showed that lymph node involvement is significantly associated with disease-free (p=0.03) and overall survival (p=0.04).
Conclusion: Even in the developing world, majority of patients present in early stage with survival outcomes comparable to the West. FIGO stage and lymph node involvement continue to be the most important prognostic markers for disease outcomes.
Keywords: Cancer, endometrial, European Society for Medical Oncology-European Society of Gynaecological Oncology-European Society for Radiotherapy and Oncology, International Federation of Gynecology and Obstetrics, management, survival
|How to cite this URL:|
Gupta N, Pandey A, Dimri K, Sehgal A, Bhagat R, Suraj, Gill G. Endometrial cancer risk factors, treatment, and survival outcomes as per the European Society for Medical Oncology (ESMO) - European Society of Gynaecological Oncology (ESGO) - European Society for Radiotherapy and Oncology (ESTRO) risk groups and International Federation of Gynecology and Obstetrics (FIGO) staging: An experience from developing world. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=361019
| > Introduction|| |
Endometrial cancer is the most common gynecological cancer in the developed countries but when it comes to developing countries like India, it has a low incidence. According to the GLOBOCAN 2018 cancer statistics, there are an estimated 382,069 new cases and 89,929 deaths attributed to endometrial cancer worldwide. The age-standardized rates for endometrial cancer in the world are 8.7/100,000 women. According to the International Agency for Research on Cancer, the incidence rate of endometrial cancer is increasing rapidly compared with 2018 and is estimated to increase by more than 50% worldwide by 2040. Endometrial cancer accounts for 1.7% of cancer cases in females in India as compared to breast cancer (16.8%) and cervical cancer (10.8%). The age-standardized rates for endometrial cancer in India are 2.4/100,000 women.
Due to the low incidence, country-specific data on the outcomes for endometrial cancer are very sparse. The International Federation of Gynecology and Obstetrics (FIGO) staging for endometrial cancers continues to be the single most important prognostic factor. This FIGO staging is a surgicopathological staging that involves surgical removal of uterus and adnexa, with or without pelvic and para-aortic lymphadenectomy. Surgery is the primary modality of treatment in all endometrial cancers. Adjuvant treatment is dependent on postoperative surgical stage and may include vaginal brachytherapy, external beam radiation, chemotherapy, or a combination of the above. Majority of endometrial cancers are present in Stage I, however, there is vast heterogeneity within this Stage I associated with depth of myometrial invasion (MI), grade, lymphovascular invasion (LVI), and adequacy of surgery. Addressal of the lymph nodes in early stages remains a controversial topic. To bring more clarity in the adjuvant management of endometrial cancers, risk grouping is helpful. The categorization of endometrial cancer as per the risk groups has been an evolving subject with recent updates including molecular markers.
There is limited data on the outcomes of endometrial cancer from our country. Some of the literature reports the outcomes as per the PORTEC risk groups while some describe about the lymph node involvement incidence, without the outcomes. None of the studies report the outcomes as per the most acceptable recent European Society for Medical Oncology-European Society of Gynaecological Oncology-European Society for Radiotherapy and Oncology (ESMO-ESGO-ESTRO) risk groups. There is not much consensus on the issue of lymph node dissection (LND) in endometrial cancer with respect to which lymph node groups to be dissected, prognostic impact, and therapeutic benefit of LND, specifically in early-stage patients, which form the majority. We report here a retrospective analysis of 102 endometrial cancer patients presenting to a tertiary care center which is also a graduate and postgraduate teaching institute in North India. The aim of the analysis was to share our experience in treating this rare site as per the FIGO stage and the most commonly utilized risk groups of the ESMO-ESGO-ESTRO guidelines. We analyzed the outcomes of treatment with respect to stage, histology, grade, depth of involvement, LND, LVI, and lymph node involvement. We report the 5-year outcomes of these endometrial cancer patients in terms of disease free survival (DFS) and overall survival (OS).
| > Materials and Methods|| |
We undertook a retrospective analysis of endometrial cancer patients presenting to the Department of Radiation Oncology during the years 2015–2019 in a large Tertiary Cancer Care Centre in North India. All patients had a confirmed histopathological diagnosis of endometrial cancer. Majority of the patients had undergone surgery at our institute and few were operated outside the institute. Those with histopathology from outside the institute had their histopathology reviewed by the institution histopathology department. The patients were analyzed according to the FIGO 2009 staging system and also subclassified according to the most commonly used risk groups of the ESMO-ESGO-ESTRO consensus statement. Patients were analyzed for their demographic profile, risk factors that included obesity, hypertension diabetes and parity; type of surgery whether LND was done or not. Histopathology details including histology of tumor, grade (G), depth of myometrial invasion, LVI, and lymph node involvement were assessed. The type of adjuvant treatment received including external beam radiation, brachytherapy, chemotherapy, or a combination of these was analyzed. Details of external radiation dose, brachytherapy dose, type and number of chemotherapy cycles received were also assessed. Outcomes were reported in terms of DFS and OS as per the FIGO stage and the risk groups. The patients with recurrence were analyzed in detail regarding the type of recurrence and the associated risk factors. Risk groups used for classification as per the standard ESMO-ESGO-ESTRO guidelines were defined as:
- Low Risk (Risk factor (RF) 1): Stage I, Endometrioid, G1G2, <50% MI, lymphovascular space invasion (LVSI) negative
- Intermediate Risk (RF 2): Stage I, Endometrioid, G1G2, >50% MI, LVSI negative
- High Intermediate risk (RF 3): (i) Stage I, Endometrioid, G3, <50% MI; (ii) Stage I, Endometrioid, G1G2, LVSI positive
- High risk (RF 4): (i) Stage I, Endometrioid, G3, >50% MI; (ii) Stage II; (iii) Stage III, endometrioid, no residual disease; (iv) nonendometrioid (serous/clear cell/undifferentiated/carcinosarcoma)
- Advanced/Metastatic (RF 5): (i) Stage III residual disease; (ii) Stage IVA, IVB.
External beam radiation therapy (EBRT) was delivered by cobalt 60 teletherapy unit, using a conventional 2D X-ray-based planning using the bony landmarks. Patients with anterio-posterior separation of more than 18 cm were treated by 4 fields box technique, the rest were treated by an anterior posterior field. Brachytherapy was delivered by Iridium 192 HDR, prescribed at 0.5 cm from the vaginal surface using vaginal cylinders (Sorbo). As per the institutional protocol, 4 cm length of the vagina was treated.
Statistical analysis was done using Statistical Package for Social Sciences version 17 (Chicago, IL, USA). Descriptive statistics were performed for clinical and demographic parameters. The mean DFS and OS were computed, stratified by the FIGO stage of disease and ESMO-ESGO-ESTRO risk groups. Cox-regression survival analysis was used to assess the factors influencing OS and DFS. Age of patient (>60 or <60), LVI, grade of tumor, depth of tumor infiltration, and lymph node involvement were included as covariates. Bootstrapping over 1000 simulations was done to estimate the coefficient and 95% confidence intervals.
| > Results|| |
A total of 102 patients were analyzed. Majority (98%) were the classical endometrioid (Type I) carcinoma and 2% were nonendometrioid (Type II) histology. The mean age at presentation was 57.7 years. Demographic characters are as shown in [Table 1]. Eighty-four percentage of the patients were postmenopausal. The comorbidities present included diabetes (14%), hypertension (24.5%), both diabetes and hypertension co-existent (20%), and obesity (42.8%). Only 2% of the patients were nulliparous. The mean follow-up period in the study group was 33.3 months.
Histopathology and staging
Surgery is the primary modality of treatment and all but two of the 102 patients did not undergo resection at presentation. Majority of the patients (74.5%) were operated in our institute and majority (71.6%) underwent LND. One of the patients with serous cell histology was Stage IV at presentation and was not operated. Another patient was unresectable at presentation and progressed on neoadjuvant chemotherapy and hence did not have a surgical staging. One of the patients underwent a complete surgery but intraoperative omental biopsy from a suspicious lesion was positive for metastasis, and hence, the patient was upstaged to Stage IV. Of the patients who underwent LND, pelvic lymphadenectomy was done in majority and only two patients underwent para-aortic LND. Seventy-four percent (74.41%) were Stage I patients, 14.7% were Stage II, 8.8% were Stage III, and remaining 2% were Stage IV. Histopathology details with staging are shown in [Table 2]. Most common grade on histology was Grade 2 (60.8%) followed by Grade 1 (26.5%) and Grade 3 (12.7%). Majority of the patients (54.9%) had <50% myometrial invasion with 2% of patients showing invasion through the full serosal thickness. Lymph node positivity was seen in 6.9% of patients while 18.6% of patients were positive for LVI.
|Table 2: Pathology details and International Federation of Gynecology and Obstetrics staging|
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Adjuvant treatment received by the patients as per the risk groups is summarized in [Table 3]. Majority 30 (73.2%) of LR patients were kept on observation followed by vaginal brachytherapy 9 (22%) only. In the IR category, 9 (42.9%) patients received vaginal brachytherapy while 12 (57.1%) patients received EBRT. Of the nine patients in the HIR group, one patient refused for adjuvant treatment and of the remaining 4 (50%) underwent EBRT and 4 (50%) were treated by vaginal brachytherapy alone. In the HR group, 19 (76%) patients were treated by EBRT with 11 (44%) also receiving brachytherapy along with EBRT. Three (12%) patients also received chemotherapy with EBRT, one patient received adjuvant chemotherapy only while three patients did not give consent for adjuvant treatment. In the advanced risk group, two patients had Stage IV disease while one patient was unresectable with progressive disease on chemotherapy. Of the remaining three patients with residual disease postoperatively, received both EBRT and chemotherapy.
The various EBRT and vaginal brachytherapy dose schedules used were as described in [Table 1]. The most commonly used EBRT schedule was 50 Gray in 25 fractions. The most commonly used vaginal brachytherapy dose schedule was 21 gray in 3 fractions prescribed at 0.5 cm from vaginal surface. The chemotherapy used in first line consisted of injection paclitaxel 175 mg/m2 with injection carboplatin area under curve 5, the chemotherapy used in the second line consisted of injection adriamycin 60 mg/m2 and injection cisplatin 50 mg/m2. The median number of cycles given was 6 (range 4–9).
Three patients (IAG2) in the low-risk category who had undergone pelvic LND, recurred locally in the vault, had not received any adjuvant treatment postoperatively, did not have any apparent risk factors and two of these could be successfully salvaged at recurrence by EBRT and brachytherapy while one progressed after treatment. One patient (IBG 1) in the IR group who recurred both in the lymph nodes and distantly had not undergo LND during initial surgery although the patient had received postoperative EBRT and brachytherapy. In the high-risk group, two of the patients (IAG3, IIBG2) who recurred had refused adjuvant treatment. The third patient (IIIC1G2) in the HR group developed pelvic deposits on follow-up.
The mean DFS [Figure 1] for the patients in FIGO Stages I, II, III, and IV was found to be 63.5 (59.9–67) months, 60.5 (54.2–66.9), 30.9 (21.5–40.2) months, and 15.4 (7.8–23.0) months, respectively. The stage-wise trend in DFS was found to be statistically significant (P < 0.001). The 5-year OS [Figure 2] of patients in Stage I was 90.3%. The 3-year mortality of Stage III patients was 58.3%. While there was no mortality observed among Stage II patients, none of the Stage IV patient survived beyond 20 months.
|Figure 1: Disease-free survival as per the International Federation of Gynecology and Obstetrics (FIGO) stage|
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|Figure 2: Overall survival as per International Federation of Gynecology and Obstetrics (FIGO) stage|
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The 5-year DFS for patients in LR group, IR group, and HR group was found to be 91.3%, 90%, and 87%, respectively. None of the patient in HIR group experienced progression of disease, and 33.3% patients in advanced group were disease free at 2-year follow-up. The 5-year OS for patients in LR group, IR group, and HR group was found to be 96.6%, 83.3%, and 90.6%, respectively. None of the patient in HIR group experienced mortality and only 33.3% patients in advanced risk group survived at 2-year follow-up.
Overall, the multivariate analysis showed that lymph node involvement is significantly associated with DFS (P = 0.03) and OS (P = 0.04).
| > Discussion|| |
Endometrial cancer most commonly arises in postmenopausal women and 84% of the patients in our study were postmenopausal with the mean age of presentation being 57.7 years, this is almost a decade younger than the mean age at presentation in the west. Multiple risk factors are involved in the development of endometrial cancer including obesity, hypertension, diabetes, and nulliparity. In our study, 58.5% patients were either suffering from diabetes, hypertension, or both. Besides 42.8% of patients were obese, increasing the incidence of obesity in the developing world may explain the rising incidence of endometrial cancer. LND in Stage I patients remains controversial, yet 73.7% (56/76) of the Stage I patients had undergone LND. There is vast heterogeneity in Stage I patients, and hence, risk categorization as per the ESMO-ESGO-ESTRO guidelines helps to further plan adjuvant treatment.
Various studies,,, have shown that low-risk patients have 95% relapse-free survival after surgery alone. Addition of vaginal brachytherapy in this risk group does not show any advantage as the risk of local recurrence in this group is <5%. In our study, 73% of patients in the LR group were kept on observation while 22% received brachytherapy. In our study, the 5-year DFS and OS in LR group were 91.3% and 96.6%, respectively. In a previous study from India, the corresponding DFS and OS for LR group (as per the PORTEC risk groups) were 84% and 95%. Stage I patients in the low-risk category who recurred on observation had no risk factor, signifying that further research is required to identify the risk factors at molecular level which may identify these patients in LR category who need adjuvant treatment. However, in these patients if recurrence is local and diagnosed timely, these patients can be salvaged with radiation and brachytherapy, and hence, these patients need to be kept on informed surveillance for longer periods. Further radiation instead of being used as an adjuvant treatment may be reserved for salvage in patients with recurrence. Various studies, have shown that LND can be omitted in the low-risk group patients, and in our study also, no additional recurrence was seen in patients not undergoing LND. Further adjuvant treatment may be tailored independent of the LND, rather than adding EBRT to compensate for missed LND.
In the IR group, adjuvant treatment can be vaginal brachytherapy or patients <60 years can be kept on observation. PORTEC1, GOG 99, Norwegian and Astec studies, and meta-analysis by Kong et al. showed that EBRT reduced the risk of pelvic recurrence from 14% to 4% in IR group patients at the cost of increased toxicity and did not change the OS. In our study in the IR category, 42.9% patients received vaginal brachytherapy while 57.1% patients received EBRT. The 5-year DFS and OS in the IR group in our study were 90% and 83.3%, respectively. The 5-year survival in various trials with adjuvant treatment (EBRT) for IR group varies from 81%, 92%, and 84%. EBRT in our study was preferred in the IR category, particularly for patients who did not undergo LND, to compensate for the inadequate surgery. Recent literature, however, shows that routine LND is not recommended for IR group.,
PORTEC 2 and the Swedish trial showed no difference in vaginal recurrence or OS when brachytherapy is compared with EBRT in HIR patients, however, toxicity and quality of life were worse with EBRT., If the LND has been done and all LNs are negative, patients can be offered vaginal brachytherapy alone, if LND has not been done, LVI is positive or histology shows Grade 3 tumor, then EBRT should be preferred as these are risk factors for increased incidence of LN recurrence and distant metastasis. Patients with extensive LVI as compared to focal LVI, irrespective of the lymph node status may be considered for EBRT. Addition of EBRT is associated with added toxicity. GOG 249 has shown no benefit of adjuvant chemotherapy in this group. In our study of the 9 patients in the HIR group, 8 had undergone LND and 50% of patients received EBRT and 50% were treated by vaginal brachytherapy alone. The LVI was positive in 6 of these 8 patients. As there was no recurrence or mortality in this group with small number of patients in our study, it is difficult to compare the effect of adjuvant treatment on DFS or OS.
In the high-risk group, external-beam pelvic radiation is the standard treatment to prevent pelvic relapse. Chemotherapy should be added to prevent systemic relapses for subgroups with (i) Stage I (IBG3), endometrioid, Grade 3, ≥50% myometrial invasion, without LND (ii) Stage II, Grade 3 or LVSI positive without LND, (iii) Stage III endometrial cancer without residual disease. When considering chemotherapy, giving radiation and chemotherapy in combination are preferable than giving the two modalities sequentially., In our study in the HR group, 19 (76%) patients were treated by EBRT with 11 (44%) also receiving brachytherapy along with EBRT. Three (12%) patients also received chemotherapy with EBRT, one patient received adjuvant chemotherapy only. Majority of patients in our study in HR risk group comprised of Stage II patients (IIBG2–8, IIAG2–4, IIAG1–2, IIBG3–1) which explains the use of EBRT and brachytherapy in majority of this risk group with less use of chemotherapy. As reported in the literature, in our study also, Stage II tumors were associated with deep myometrial invasion. The 5-year DFS and OS for HR group in our study were 87% and 90.6%, respectively. This is higher than expected and can be explained on the basis that majority of patients in our study were Stage II.
The nonendometrioid histology within the high-risk group included two patients, one with serous cell carcinoma was Stage IV at presentation signifying that serous cell endometrial cancer is an aggressive histology with presentation in advanced stages. The other patient of clear cell carcinoma, though Stage IA at presentation, refused for any adjuvant treatment and recurred in the vault.
In the advanced group, surgery is recommended if an optimal cytoreduction can be achieved. For unresectable cases or medically inoperable cases, EBRT may be considered. Systemic treatment with hormone therapy may be considered for hormone receptor-positive tumors else chemotherapy with paclitaxel and carboplatin remains the regimen of choice. In our study, majority of advanced cases were treated with palliative intent, chemotherapy being the predominant treatment. Fifty percent of the patients (3/6) had residual disease postcytoreduction and hence received adjuvant external beam radiation as well. Only 33.3% of patients in advanced risk group survived at 2-year follow-up.
Lymph node involvement remains the single most adverse prognostic factor for carcinoma endometrium,, and our multivariate analysis showed that lymph node involvement is statistically significantly associated with DFS (P = 0.03) and OS (P = 0.04). LVSI positivity remains an important predictor for lymph node involvement and guides decision-making for adjuvant treatment. In our study, 5 of the 7 patients with LN-positive disease also had an LVSI positive. However, on multivariate analysis, the LVSI involvement was not statistically associated with DFS or OS.
Regardless of tumor type, the estimated 5-year OS according to the 26th FIGO annual report is 85%–90% for Stage I, 75%–85% for Stage II, 50%–65% for Stage III, and 20%–25% for Stage IV. The 5-year OS [Figure 2] of patients in our study was 90.3% for Stage I. The 3-year mortality of Stage III patients was 58.3%, while there was no mortality observed among Stage II patients. None of the Stage IV patients survived beyond 20 months.
The strength of our study is that it analyses the same set of patients with respect to the FIGO staging and the commonly used risk groups. In the scenario of so much conflicting adjuvant treatment guidelines, with a global learning curve, which has evolved over years, our study analysis shows the result in the light of the currently recommended treatment guidelines, taking into consideration, the risk groups, the LVSI, histology, and LND status.
Drawbacks of the study are the retrospective nature of the analysis and the small patient number. Another limitation of the study is that data on toxicities arising from the treatment were not clearly available due to the retrospective nature of the data.
With the upcoming molecular classification of the endometrial tumors, the adjuvant treatment guidelines are likely to witness further evolution and recommendations that will affect the practice in the clinics.
| > Conclusion|| |
The present study confirms the important prognostic factors FIGO stage, histology, higher grade, myometrial invasion, LN involvement, and LVI. It again emphasizes that LND may be omitted in the low-risk endometrial cancer, which forms the majority of the patients. Patients in the LR group can be kept on observation postoperatively with radiation being reserved as salvage treatment option. Patients in the IR should be treated by adjuvant vaginal brachytherapy. For the HIR, if LND has not been done or LVSI is positive, patients should receive EBRT else vaginal brachytherapy constitutes to be a sufficient treatment. In the HR group, EBRT remains the standard adjuvant treatment, chemotherapy is integrated with radiation in selected cases. Molecular classification and its clinical application remain an upcoming area of interest for endometrial cancers.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]