|Ahead of print
Long-term survival outcome of advanced epithelial ovarian cancer: A single institutional study
Patel Viral1, Anupama Rajanbabu1, Keechilat Pavithran2, K Chithrathara3, Indu R Nair4, Renjitha Bhaskaran5, Paleth Gangadharan6, DK Vijaykumar1
1 Department of Gynecological Oncology, Amrita Institute of Medical Science, Kochi, Kerala, India
2 Department of Medical Oncology, Amrita Institute of Medical Science, Kochi, Kerala, India
3 Department of Gynecological Oncology, VPS Lakeshore hospital, Kochi, Kerala, India
4 Department of Pathology, Amrita Institute of Medical Science, Kochi, Kerala, India
5 Department of Biostatistics, Amrita Institute of Medical Science, Kochi, Kerala, India
6 Department of Cancer Registry, Amrita Institute of Medical Science, Kochi, Kerala, India
|Date of Submission||21-Feb-2019|
|Date of Decision||20-Oct-2019|
|Date of Acceptance||24-Oct-2019|
Department of Gynecological Oncology, Amrita Institute of Medical Science, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
Background: A number of patients with advanced-stage epithelial ovarian cancer do survive beyond 5 years. The long-term follow-up data are limited, especially for the Indian setting. We evaluated the 10-year survival outcome and influencing clinicopathological factors.
Methods: A retrospective analysis of advanced-stage epithelial ovarian cancer patients who underwent primary cytoreductive surgery (PCS) or interval cytoreductive surgery (ICS) from 2005 to 2008 was conducted. Survival analysis was performed with the Kaplan–Meier method, and the Cox proportional hazards model was used for prognostic clinicopathological factors analysis.
Results: Ninety-four patients with a median age of 54.5 (18–79) years were evaluated. The median follow-up period was 11.2 years. The overall survival (OS) rates at 5, 7, and 10 years were 37%, 23%, and 18%, respectively. The median OS (MOS) was 46 (95% confidence interval [CI], 36–55.8) months and progression-free survival (PFS) was 19.5 (15.3–23.6) months. Long-term survival was significantly predicted by R0 resection (complete cytoreduction with no macroscopic residual disease) and PFS >20 months while prolonged PFS was influenced by age ≤55 years and R0 resection. For the R0 resection group, patients who underwent PCS had better overall survival in comparison with ICS [72.1(25.2-119) months vs 47.4 (34.9–59.9)months] on 10 years follow-up but was not significant statistically.
Conclusion: Patients with age ≤55 years, R0 resection, PFS >20 months have a better 10-year survival outcome. Among R0 resection, patients undergoing PCS have clinically a better outcome on 10-year follow-up.
Keywords: 10 years survival, epithelial ovarian cancer, India, ovarian carcinoma
Key Message: Young age, complete cytoreduction and prolonged progression-free survival are associated with better long term overall survival in advanced epithelial ovarian cancer patients. Primary cytoreductive surgery with complete cytoreduction has better oncological outcome on long term (10 years) follow-up in comparison with interval cytoreductive surgery. A progression-free survival of more than 20 months is predictive of long term survival.
|How to cite this URL:|
Viral P, Rajanbabu A, Pavithran K, Chithrathara K, Nair IR, Bhaskaran R, Gangadharan P, Vijaykumar D K. Long-term survival outcome of advanced epithelial ovarian cancer: A single institutional study. Indian J Cancer [Epub ahead of print] [cited 2021 Jan 25]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297015
| » Introduction|| |
Ovarian cancer is one of the most common cancers among women in India after breast and cervical cancer, with an annual occurrence of 36170 new cases and 24015 deaths. Worldwide, annually, approximately 295,414 new cases of ovarian cancer and around 184,799 deaths are reported because of this lethal malignancy. The peak incidence of epithelial ovarian malignancy occurs in postmenopausal women at 60–64 years of age. At the time of diagnosis, around 70% of the women have the advanced-stage disease as it is asymptomatic till late stage and a 5-year survival rate for advanced-stage ovarian carcinoma is around 35%.,
In India, the Indian Council of Medical Research (ICMR) data show variation in the age-adjusted incidence rate of ovarian cancer ranging from 1.7 to 15.2 per 100,000 among different population-based cancer registries during a period of 2012–2014.
Epithelial ovarian cancer is one of the most lethal malignancies. However, with advancements in surgery and chemotherapy, the survival of patients has improved. The Society of Gynecologic Oncology (SGO) recommends follow-up every 3 months for the first 2 years and every 6 months for next 3 years. After 5 years of primary treatment, yearly follow-up is recommended for a lifetime. After 5 years, many patients are lost to follow-up. This may limit the understanding of late recurrences and long-term oncological outcomes in epithelial ovarian cancer patients. Few studies have revealed continued recurrence beyond 5 years among patients with optimal cytoreduction, and provided survival data of up to 7 years.,
Available data for 10 years follow-up of epithelial ovarian cancer are limited. Ten years survival rate provides a better understanding of prognosis and its influencing factors for long-term survival among ovarian cancer patients. This study is intended to identify different clinicopathological characteristics of epithelial ovarian cancer influencing recurrence and 10-year survival.
| » Materials and Method|| |
This is a retrospective cohort analysis of advanced-stage epithelial ovarian cancer patients treated with curative intent from a single cancer center in India. Approval from Institutional Ethics Committee (IRB-AIMS-2018-263) was taken for the study. We were able to retrieve and collect clinicopathological parameters and survival details of all patients from the hospital-based electronic medical record system. Inadequate details of follow-up and survival were completed with the help of a hospital-based cancer registry by postal or telephonic follow-up.
Patient with advanced-stage disease (International Federation of Gynecology and Obstetrics [FIGO] Stage III and IV ovarian, Fallopian tube More Details or primary peritoneal carcinoma) who underwent primary cytoreductive surgery (PCS) or interval cytoreductive surgery (ICS) from 2005 to 2008 at this cancer center with minimum 10 years follow-up details were included. Patients with a nonepithelial ovarian tumor, Stage I and II (FIGO) disease, and those who did not undergo PCS or ICS surgery at our institution were excluded. Twenty-seven patients with <10 years follow-up details were not included in the survival analysis (even though we had their details). The flow diagram [Figure 1] describes the selection process of the study population.
Patients were divided into two study groups (R0 vs R1 and R2) according to residual disease after cytoreductive surgery. Residual disease postsurgery was reported as R0, R1, or R2. R0 was defined as no macroscopic residual disease after surgery. R1 and R2 were defined as macroscopic residual disease postsurgery with a maximum diameter of <1 cm and >1 cm, respectively. PCS and ICS was based on patient age, patient performance status to determine fitness for surgery, and assessment of resectability as assessed by surgeon based on computed tomography (CT) scan findings. Patients with bulky upper abdomen disease (multiple mesenteric disease and involvement of porta hepatis) with or without ascites were considered for neoadjuvant chemotherapy (NACT) followed by ICS.
Details collected included clinicopathological and intraoperative characteristics, details of adjuvant treatment, and recurrence and present status.
Overall survival (OS) was considered as the length of time from either the date of diagnosis/surgery or the start of treatment for cancer to date of last follow-up or death. Progression-free survival (PFS) was defined as the length of time during and after the treatment of cancer until the date of recurrence or progression.
We compared baseline patient characteristics of R0 resection vs R1 and R2 resection using Pearson's chi-square test to examine relationships between categorical variables and student t-test for continuous variables.
To test the statistical significance of the difference in the survival probability for parameters like tumor characteristics, age, pathological, and surgical details, the Kaplan–Meier analysis was used and comparison was done using a two-sided logrank test. Survival analyses were done on time to event outcomes. The primary endpoint was 10 years OS and PFS for advanced-stage epithelial ovarian cancer patients undergoing surgery. The secondary endpoint was to find out clinicopathological parameters for predicting long-term survival. The Cox proportional hazards regression model was used in both univariate and multivariate analysis. All statistical analyses were performed using IBM Statistical Package for the Social Sciences (SPSS) software for Windows (version 20.0).
| » Results|| |
Three hundred and sixty-nine ovarian cancer patients were identified from the hospital-based cancer registry database. Out of these, 121 patients were operated at our institute and after considering the exclusion criteria, 94 advanced-stage epithelial ovarian cancer patients were included in the study for final analysis. Overall, the median follow-up period was 11.2 years. At the end of 10 years follow-up, 77 (82%) patients had died and 17 (18%) patients were alive. The median age of study population was 54.5 (18–79) years. Out of the 94 patients, 51 (54%) patients were aged ≤55 years and 84 (89%) patients had serous histology.
From the study group, 24 (25.5%) patients underwent PCS and out of them 20 (83%) were R0 resection. Remaining 70 (74.5%) patients underwent ICS and from that 52 (74%) were R0 resection. Out of the total 94 patients, 72 (77%) had R0 resection and 22 (23%) had R1/R2 resection.
Around 82 (87%) patients had stage III disease and the remaining 12 (13%) patients had stage IV disease. We were unable to collect data regarding histopathological grading in 19 (20%) patients. Histopathological data analysis of remaining patients showed that 14 (15%) patients had low-grade ovarian cancer and 61 (65%) had high-grade ovarian cancer. Eighty-four (89%) patients had serous epithelial ovarian cancer.
R0 vs R1 and R2 resection groups were comparable [Table 1]. In the entire study population, the median OS (MOS) was 46 (95% confidence interval [CI], 36–55.8) months and PFS was 19.5 (15.3–23.6) months. The MOS and PFS for R0 resection were 49 (32.8–65.2) months and 23 (16.5–29.4) months, respectively. Patients with R1/R2 resection experienced an OS of 27.5 (8.4–46.6) months and PFS of 12 (8.3–15.6) months. On statistical analysis, R0 resection had significantly superior OS (P < 0.001) and PFS (P < 0.001) in comparison with R1/R2 resection.
Among patients with R0 resection, patients who underwent PCS experienced a trend toward better OS on long-term follow-up in comparison with ICS, but it was statistically nonsignificant [Figure 2]. The PCS and ICS patients with R0 resection had MOS of 72.1 (95% CI, 25.2–119) months and 47.4 (34.9–59.9) months, respectively. Recurrence was noted in 59 patients of the R0 resection group and for all R1/R2 patients. The median time to first recurrence was 18.6 months for the whole study group.
|Figure 2: Comparison of 10 years OS between PCS vs ICS patients with R0 resection. PCS = Primary cytoreductive surgery, ICS = Interval cytoreductive surgery, N = Number, HR = Hazard ratio, CI = Confidence interval, OS = Overall survival|
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On subgroup analysis, higher OS was found among patients with age ≤55 years and PFS >20 months [Figure 3] and [Figure 4]. Patients with PFS ≤20 months vs PFS >20 months experienced MOS of 24.7 (95% CI, 16.6–32.8) months and 70.7 (56.4–85) months, respectively. Platinum sensitivity (with the cutoff for 6 months) had no impact for prolonging survival but PFS >20 months had better oncologic outcomes. The MOS of patients aged ≤55 years and >55 years was 48.8 (95% CI, 26.8–70.8) months and 38.5 (24.6–52.4) months, respectively. When the whole study population was divided into groups of age ≤55 and >55 years, the groups were found comparable in terms of type of cytoreductive surgery (PCS vs ICS, P = 0.64); extent of surgical resection (R0 vs R1/R2, P = 0.31); chemotherapy cycle taken (neoadjuvant or adjuvant, P = 0.89); and tumor grade (low grade vs high grade, P = 0.55). Details for chemotherapy were available for 92 patients and all of them received six cycles of chemotherapy. Of the 70 patients who underwent ICS, 63 (90%) had received three or four cycles of NACT and remaining 7 (10%) patients had received six cycles of NACT. Two of the seventy-two (3%) patients with R0 cytoreduction relapsed within 6 months of last chemotherapy.
|Figure 3:Comparison of 10 years OS between age group ≤55 vs >55 years. N = Number, HR = Hazard ratio, CI = Confidence interval, OS = Overall survival|
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|Figure 4: Comparison of 10 years OS among patients with PFS ≤20 vs >20 months. N = Number, PFS: Progression-free survival, HR = Hazard ratio, CI = Confidence interval|
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The OS at 5, 7, and 10 years for the entire study population was 37%, 23%, and 18%, respectively. Among R0 resection group, the OS at 5, 7, and 10 years was 46%, 30.5%, and 22%, respectively. For the R1/R2 resection group, OS at 5 years interval was 9% and no patients survived beyond 7 years.
Among the 27 patients who were excluded from the analysis because of lack of follow-up, 11 patients had PCS and the remaining 16 had ICS. R0 was achieved in 21 while the remaining 6 had R1/R2—many of them were lost to follow-up as they had left their place of residence without forwarding addresses or contact numbers.
[Table 2] presents the hazard ratio by univariate and multivariate analysis for OS and PFS. Upon univariate analysis, age ≤55 years, R0 resection, PFS >20 months, and PCS with R0 resection were associated with long-term survival. Multivariate analysis with the Cox regression model concluded that R0 resection and >20 months PFS were significant indicators for 10 years survival while R0 resection and age ≤55 years were predictors for better PFS.
| » Discussion|| |
In this case series, age ≤55 years, R0 resection, and PFS >20 months were significant predictors for 10-year survival. In the R0 resection group, PCS is suggestive of better long-term survival, but the results were not statistically significant. The serum CA 125 value, stage of the disease, and tumor grade (low grade vs high grade) and type (serous vs non-serous) did not have any association with 10 years survival in advanced-stage epithelial ovarian cancer in our series.
The OS and PFS for patients who underwent R0 resection were superior compared with the R1/R2 resection group. This finding is consistent with the existing literature.,
For PCS and ICS groups, patients with R0 resection had similar survival curves until 6 years of follow-up. They diverged beyond that period showing a better outcome among the PCS group, which was not significant statistically. Adequate sample size and long-term follow-up may show a significantly better outcome for PCS with R0 resection. This result is similar to a few published studies.,
The median age in our study was 55 years, which is a decade less than that from reported Western literature. However, our result is comparable with other published Indian data., Studies have shown that age has no association with long-term survival, but in our study, age did show significance. Our analysis showed that younger age has a significantly better outcome for long-term survival; this result might be because of a difference in the median age of our population or geographical variation. Data for received chemotherapy and histology grade were only available for 51 and 75 patients, respectively; hence, the comparability of both age groups (≤55 and >55 years) without bias is questionable.
R0 resection and PFS >20 months are significant factors that can strongly predict 10-year survival for advanced-stage ovarian cancer. In our analysis, R0 resection and age ≤55 years were important factors that predicted prolonged PFS, which corresponded with the result published by Klar et al. Upon univariate analysis, younger age was found to have a significant association with 10 year OS, but no statistical significance was identified for long-term OS using the multivariate model. This might be because of the small sample size or geographical variation among study population.
Recently published Solo-1 trial showed a superior PFS among newly diagnosed advanced-stage epithelial ovarian cancer patients with BRCA mutation who received olaparib. As the cost of BRCA mutation testing and olaparib treatment (poly adenosine diphosphate ribose polymerase inhibitor [PARP]) are high, it is not a feasible and affordable option at present in the Indian scenario. For interval cytoreduction and recurrent disease, recently hyperthermic intraperitoneal chemotherapy (HIPEC) was found to have better outcomes. The role of HIPEC in PCS is still debatable. Identifying parameters having association with long-term survival are of utmost importance and would provide important information in Indian population as we can decide on which factors we can focus based on the limited resources available.
Here, we tried to identify which factors can predict 10-year OS. As per our analysis, we can predict and categorize patients who may have increased probability for 10-year OS. Younger patients with R0 resection at PCS and longer PFS (>20 months) have long-term survival. We should strongly consider secondary cytoreductive surgery (SCS) among this group of patients for recurrence, provided there is a good performance status, as they may have better outcomes when compared with others having R1/R2 resection, older age group, and shorter PFS.
Predicting which patients are likely to have 10-year survival would help in categorizing patients into high risk for relapse of disease. This type of stratification may be a guide to tailor clinical trials and novel therapies for the optimal benefit of patients.
Limitations of our study are its retrospective nature, small sample size, lack of follow-up details for 22% of the total target population, insufficient data for chemotherapy and histology grade in some, and nonavailability of patient performance status information. Reliable 10-year follow-up details because of hospital-based cancer registry and electronic medical record system is a strong point of our research.
Our research found a younger median age of the Indian population for ovarian cancer and showed a long-term survival among younger age groups, which are different in comparison with published Western literature. Hence, large multicentric trials for Indian population should be considered as available data are limited.
| » Conclusion|| |
The survival rate on 10 years follow-up for advanced epithelial ovarian carcinoma is around 18% and factors like R0 resection at initial cytoreductive surgery, younger age, and long PFS are strongly associated with 10 years of survival. PCS, provided R0 resection is obtained, can have a better outcome on long-term follow-up.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Berek JS, Kehoe ST, Kumar L, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2018;143:59-78.
Ahmad SZ, Rajanbabu A, Vijaykumar DK, Haji AG, Pavithran K. A prospective comparison of perioperative morbidity in advanced epithelial ovarian cancer: Primary versus interval cytoreduction - experience from India. South Asian J Cancer 2015;4:107-10.
] [Full text]
Rauh-Hain JA, Alejandro Rauh-Hain J, Melamed A, Wright A, Gockley A, Clemmer JT, et al.
Overall survival following neoadjuvant chemotherapy vs primary cytoreductive surgery in women with epithelial ovarian cancer. JAMA Oncology 2017;3:76.
National centre for disease informatics and research, National cancer registry programme. Three-year report of population based cancer registries 2012-2014. Indian Council of Medical Research; 2016. p. 58. Available from: http://www.ncdirindia.org/ncrp/annual_reports.aspx
. [Last accessed on 2019 Nov 07].
Wu J, Sun H, Yang L, Deng Y, Yan Y, Wang S, et al.
Improved survival in ovarian cancer, with widening survival gaps of races and socioeconomic status: A period analysis, 1983-2012. J Cancer 2018;9:3548-56.
Salani R, Backes FJ, Fung MF, Holschneider CH, Parker LP, Bristow RE, et al.
Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol 2011;204:466-78.
Rodriguez N, Miller A, Richard S, Rungruang B, Hamilton C, Bookman M, et al.
Upper abdominal procedures in advanced stage ovarian or primary peritoneal carcinoma patients with minimal or no gross residual disease: An analysis of GOG 182. Gynecol Oncol 2012;125:S23-4.
Horowitz NS, Miller A, Rungruang B, Richard SD, Rodriguez N, Bookman MA, et al.
Does aggressive surgery improve outcomes? Interaction between preoperative disease burden and complex surgery in patients with advanced-stage ovarian cancer. Obstet Gynecol Surv 2015;70:390-2.
Melamed A, Manning-Geist B, Bregar AJ, Diver EJ, Goodman A, Del Carmen MG, et al.
Associations between residual disease and survival in epithelial ovarian cancer by histologic type. Gynecol Oncol 2017;147:250-6.
Fagö-Olsen CL, Ottesen B, Kehlet H, Antonsen SL, Christensen IJ, Markauskas A, et al.
Does neoadjuvant chemotherapy impair long-term survival for ovarian cancer patients? A nationwide Danish study. Gynecol Oncol 2014;132:292-8.
Javellana M, Hoppenot C, Lengyel E. The road to long-term survival: Surgical approach and longitudinal treatments of long-term survivors of advanced-stage serous ovarian cancer. Gynecol Oncol 2019;152:228-34.
Rosen B, Laframboise S, Ferguson S, Dodge J, Bernardini M, Murphy J, et al.
The impacts of neoadjuvant chemotherapy and of debulking surgery on survival from advanced ovarian cancer. Gynecol Oncol 2014;134:462-7.
Maheshwari A, Kumar N, Gupta S, Rekhi B, Shylasree TS, Dusane R, et al.
Outcomes of advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy. Indian J Cancer 2018;55:50-4.
] [Full text]
Ramachandran A, Rajanbabu A, Bagul KG, Pavithran K, Vijaykumar DK. Correlation of pattern of spread and outcomes in advanced epithelial ovarian cancers. Indian J Surg Oncol 2017;9:126-32.
Hamilton CA, Miller A, Casablanca Y, Horowitz NS, Rungruang B, Krivak TC, et al.
Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: An NRG Oncology/Gynecologic Oncology Group ancillary data study. Gynecol Oncol 2018;148:275-80.
Klar M, Hasenburg A, Hasanov M, Hilpert F, Meier W, Pfisterer J, et al.
Prognostic factors in young ovarian cancer patients: An analysis of four prospective phase III intergroup trials of the AGO Study Group, GINECO and NSGO. Eur J Cancer 2016;66:114-24.
Shimokawa M, Kogawa T, Shimada T, Saito T, Kumagai H, Ohki M, et al.
Overall survival and post-progression survival are potent endpoint in phase III trials of second/third-line chemotherapy for advanced or recurrent epithelial ovarian cancer. J Cancer 2018;9:872-9.
Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al.
Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N
Engl J Med 2018;379:2495-505.
Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N
Engl J Med 2018;378:1362-4.
Du Bois A, Vergote I, Ferron G, Reuss A, Meier W, Greggi S, et al.
Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20. J Clin Oncol 2017;35:5501-5501. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.5501
[Last accessed on 2020 Sep 02].
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]