|Ahead of print publication
First-line chemotherapy analysis on survival in carcinoma ovary patients: Data from a Northern Indian cancer center
Atika Dogra1, Vineet Talwar2, Varun Goel2, Rupinder Sekhon3, Sudhir Kumar Rawal3
1 Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
3 Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
|Date of Submission||10-Jul-2020|
|Date of Decision||29-Aug-2020|
|Date of Acceptance||07-Oct-2020|
|Date of Web Publication||05-Aug-2021|
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, Delhi - 110 085
Source of Support: None, Conflict of Interest: None
Aims: This study aims to assess the survival and identify the prognostic factors in ovarian cancer patients treated with surgery and carboplatin/paclitaxel based first-line chemotherapy (CT).
Settings and Design: The electronic medical records of all ovarian cancer patients registered during January 2009 and December 2017 were screened retrospectively.
Subjects and Methods: A total of 440 cases were included in accordance with the inclusion/exclusion criteria of study. The comprehensive data regarding demography, treatment, chemotoxicities, recurrence, and others were collated and analyzed.
Statistical Analysis Used: Cox regression analysis was used for univariate and multivariate analyses of prognostic factors.
Results: The median age at diagnosis was 50.6 years. All cases had got CT-related morbidity but no associated mortality. The median recurrence-free survival (RFS) and mean overall survival (OS) were 30 (95% confidence interval [CI]: 24.65–35.38) months and 40.4 months, respectively. A significant difference was observed among the RFS (P < 0.001); and OS (P = 0.036) in relation to the stage of disease. Furthermore, patients who relapsed post first-line CT had 36%, 9%, 3% recurrence in second-, third-, and fourth-line CT regimens, respectively. Multivariate analysis proved the histology, low-grade serous, to be the favorable prognostic factor for RFS (hazard ratio = 0.18; 95% CI: 0.04–0.82).
Conclusions: Surgery and first-line CT with carboplatin/paclitaxel lead-to-moderate long-term survival in ovarian cancer. The likelihood of relapse is fairly high as stage advances. Low-grade serous histology is an independent prognostic factor for RFS.
Keywords: Ovarian cancer, overall survival, prognostic factor, recurrence-free survival, toxicity profile
|How to cite this URL:|
Dogra A, Talwar V, Goel V, Sekhon R, Rawal SK. First-line chemotherapy analysis on survival in carcinoma ovary patients: Data from a Northern Indian cancer center. J Can Res Ther [Epub ahead of print] [cited 2022 Jun 25]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=323175
| > Introduction|| |
Ovarian cancer has the worst prognosis and the highest mortality rate among gynecologic cancers. Surgery and first-line systemic chemotherapy (CT) collectively induce a complete and partial response in about 80% cases, with a pathologic complete remission rate of approximately 25%. Lamentably, around 70% of cases relapse and many go through a series of recurrences after primary treatment. This study is aimed at assessing the survival details and identifying the prognostic factors in ovarian cancer cohort treated with a combination of surgery and carboplatin/paclitaxel-based first-line CT.
| > Subjects and Methods|| |
The study was granted a waiver by the Institutional Review Board since this was a retrospective study and the patients' data had been anonymized. The selection of cases was done considering the inclusion and exclusion criteria as mentioned in [Figure 1].
A total of 440 cases befit the inclusion/exclusion criteria of the study. The diagnosis of disease was based upon the cytopathological evaluation of pleural/ascitic fluid or histopathological confirmation from representative lesions, where needed. In addition to serum CA-125 and radiological investigations, other blood tests such as complete blood count, lipid profile, and kidney function test along with clinical examination including general physical check-up and gynecological examination were done in all cases. The radiological investigations included contrast enhanced computed tomography for abdomen, CA-125, Two-dimensional echocardiography, electrocardiography, and posteroanterior chest X-ray. As the confirmation of diagnosis was done by microscopic examination, the possibility of primary tumor in gastrointestinal (GI) region was ruled out by imaging and immunohistochemistry, wherever required.
The detailed information related to age, presenting symptoms, co-morbidities, personal history of previous cancer (s)/gynecologic disorders, family history of cancer, social habits, marital status, were assembled from the original electronic medical records of patients. The co-morbidities were subdivided in to two categories; cardiac related and noncardiac related. The first group includes hypertension, coronary artery disease, dilated cardiomyopathy deep vein thrombosis and rheumatoid heart disease. Noncardiac-related comorbidities include respiratory, endocrine, metabolic, nutritional, renal, hematopoietic, neurological as well as musculoskeletal conditions. Further, the data on clinical characteristics, FIGO staging, treatment details, toxicities, recurrence, follow-up, and others were collated. The entire set of patients was followed-up until June 2019. Thirty-one percent cases could not be contacted telephonically even after multiple attempts and were considered lost to follow-up. The primary endpoint of the study was recurrence-free survival (RFS). Other study endpoints included overall survival (OS), chemo-toxicities and prognostic factors.
The patients were treated with paclitaxel/carboplatin based neoadjuvant/adjuvant first-line CT and surgery as primary cancer directed treatment. The forms of operative surgery were optimal, sub-optimal and fertility-preserving surgery. The doses of paclitaxel were calculated in accordance with patients' body surface area and carboplatin doses were calculated as per area under curve-5. Parenteral paclitaxel and carboplatin based first-line CT was administered on day I and II at every 21 days. The protocol was modified only in 6 subjects in accordance with their fitness. The assessment of response was done after 3 cycles and each patient was given a total of 6 cycles except for a few. Eighteen subjects had received lesser and 7 cases were given more than 6 cycles of CT.
The identification of CT related toxicity was done according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0, DCTD, NCI, NIH, DHHS, Bethesda, Maryland). The information regarding the grade of chemo-toxicities was missing in 274 (62.3%) patients' records; hence, this feature could not be studied comprehensively.
Response to chemotherapy
The assessment of treatment response was done after 3 cycles/6 cycles by comparing the radiological scans with the baseline scans. The complete response, partial response and progressive disease were determined according to Response Evaluation Criteria in Solid Tumors (RECIST), 1.1. In addition, the levels of serum CA-125 were also compared.
The initial diagnosis of recurrence was based on the developing symptoms and clinical examination with the detection of a rising CA-125 value. It was further confirmed with computed tomography/positron emitting tomography and histopathological evaluation, where needed. Except for a few who were lost to follow-up, majority of cases were treated with second-line CT, third-line CT and so on, as per the standard guidelines. The second-line CT regimens included liposomal doxorubicin, platinum and bevacizumab (bevacizumab given depending upon finances). The third-line CT options comprised gemcitabine, platinum, topotecan, and etoposide. The A moderate number of patients underwent secondary cytoreductive surgery (CRS) along with CT. A very few were treated only with CRS and the patients with distant metastasis were given radiotherapy as indicated, in combination with CT.
The data were analyzed using IBM SPSS software (Version 23, SPSS Inc., Chicago, IL, USA). The quantitative data were presented by mean (standard deviation [SD]) or median (range) and qualitative data were presented in frequencies/proportions. The patients with missing data were omitted from the analysis. Cox regression analysis was used for univariate and multivariate analyses of prognostic factors. The survival curves were evaluated with the Kaplan-Meier method and the differences were assessed by stratified log-rank test. The RFS was calculated from the date of surgery until the date of relapse or progression of disease/date of death or last contact, whichever occurred first. The OS was calculated as the duration between date of diagnosis and date of death or last contact.
| > Results|| |
The mean and median ages at diagnosis were 50.6 (SD, 10.51) and 50 (range, 20–79) years respectively. The median level of serum CA-125 was 539 (range, 4-17,326) μg/ml. [Table 1] represents a brief overview of the clinical data of studied cohort. The majority of symptoms were related to GI such as abdominal pain, abdominal distension, loss of appetite, and altered bowel habits. Some of the others included genitourinary related symptoms such as abnormal vaginal bleeding and urinary problems, however; the rest comprise of dyspnea, fever, fatigue, and so forth. Of the total 440, 333 (75.7%) cases had bilateral disease at diagnosis. The history of ovarian cysts was present in 30 (6.8%), absent in 407 (92.5%), and missing in 3 (0.7%) cases. The history of hysterectomy was present and absent in 30 (6.8%) and 410 (93.2%) subjects, respectively. The personal history of prior cancer was present in 3 (0.7%) cases; 2 had the cancer of breast and 1 had endometrial carcinoma. The family history of cancer was positive in 59 (13.4%), negative in 378 (85.9%) and missing in 3 (0.7%) cases. Majority of subjects had no comorbidity. The cardiac related co-morbidity included dilated cardiomyopathy, deep vein thrombosis, and rheumatoid heart disease. Noncardiac-related comorbidities include respiratory, endocrine, metabolic, nutritional, renal, hematopoietic, neurological as well as musculoskeletal conditions.
All patients included in the study had received cancer directed treatment at our institute, though some had received part of treatment elsewhere too. The CRS was done in 423 (96.1%) cases and 430 (97.7%) cases had received first line CT in our institute. Majority of the subjects were given adjuvant CT, however; 48 (10.9%) cases were given neo-adjuvant CT before interval debulking surgery. The median time interval from surgery to start of adjuvant CT was 24 (range, 10–90) days. The median number of cycles of CT given was 6 (range, 3–12). All patients had experienced complications during CT in one or other form(s) as mentioned in [Table 2]. The evaluation of sub-group of cases (166; 37.7%) with available information on grades of toxicities revealed that 162 patients (97.6%) had experienced Grade I/II toxicities and were managed actively. Only 2 patients had got peripheral neuropathy (central nervous system related toxicity) with Grade III and IV each, however; 1 had experienced Grade III GI related chemotoxic effects and another patient had got grade IV neutropenia.
Six patients had shown the progression of disease during initial therapy and hence, those were excluded from analyses of recurrence. More than half of the patients (235, 54.1%) had developed the recurrence at least once until last follow-up/date of contact. Many patients had experienced multiple recurrences also. Of 235 subjects, 122 (51.9%) had got recurrence once, however; 84 (35.7%), 21 (9.1%), and 8 (3.3) experienced the recurrences twice, thrice, and four times respectively.
At a median follow-up of 33.5 months, the median RFS was 30 months (95% confidence interval: 24.65–35.38). The 5-year and 8-year RFS rates for complete set of patients were found to be 33% and 28%, respectively [Figure 2]a. The 5-year RFS rates for early-Stage (I and II), Stage III, and Stage IV were 66%, 25%, and 30%, respectively. The 8-year RFS rates were found to be 61%, 19%, and 30% for early-stage, stage III, and stage IV correspondingly. A significant difference was observed between the RFS of different disease stages [Figure 2]b. Similarly, the difference between RFS of different forms of histology was found to be significant [Figure 2]c. The clear-cell carcinoma (73%) had the highest RFS followed by low-grade serous (67%), endometrioid type (64%), mucinous tumors (46%), and high-grade serous type (26.2%) at 5-years.
|Figure 2: Kaplan-Meier survival curves. (a) General recurrence-free survival. (b) Recurrence-free survival corresponding to staging. (c) Recurrencefree survival corresponding to tumor histology|
Click here to view
The mean OS was 40.4 months. The 5-year and 8-year OS rates for all patients were found to be 75% and 57% respectively [Figure 3]a. The 5-year OS rates for cases with early-Stage (I-II), Stage III, and Stage IV groups were 92%, 76%, and 78%, respectively. The 8-year OS rates for early-stage, Stage III, and stage IV were 53%, 59%, and 77% correspondingly. A significant difference was observed between the OS of different stage groups [Figure 3]b. Contrary to RFS, the difference between OS of different histology subtypes was not significant [Figure 3]c. Clear-cell tumors type had the highest 5-year OS rates (87%) followed by other forms such as slow-grade serous (80%), endometrioid (79%), high-grade serous (75%), and mucinous tumor (66%).
|Figure 3: Kaplan-Meier survival curves. (a) General overall survival. (b) Overall survival corresponding to staging. (c) Overall survival corresponding to tumor histology|
Click here to view
Predictors of recurrence-free survival and overall survival
The demographic and clinicopathological variables such as age, serum CA-125 level, symptoms' duration, family history of cancer, comorbidities, menopausal status, stage of the disease, and histology of tumor were analyzed to find out the prognostic factors. The univariate analysis revealed the age, CA-125 level, family history of cancer, stage, noncardiac-related comorbidity and tumor histology (low-grade serous tumors, mucinous tumors, and undifferentiated tumors) to be the prognostic factors for RFS [Table 3]. However, multivariate analysis proved only low-grade serous tumor type of histology to be the favorable prognostic factor for RFS. For OS, the univariate analysis revealed all studied factors to be the prognostic factors [Table 4]. However, the multivariate analysis confirmed cardiac related comorbidity to be the favorable prognostic factor for OS.
|Table 3: Cox proportional hazards model analysis of prognostic variables for recurrence-free survival|
Click here to view
|Table 4: Cox proportional hazards model analysis of prognostic variables for overall survival|
Click here to view
| > Discussion|| |
To our knowledge, this is the first study in India to assess the survival outcomes in a large group treated with the combination of surgery and mentioned regime of CT. In the present study, we studied the RFS, OS and prognostic factors of 440 ovarian cancer subjects treated with surgery and paclitaxel/carboplatin based first-line CT. We have found the CT regimen to be safe and effective in the management of ovarian cancer. Our findings suggest that OS was higher than the RFS in our studied cohort.
The most common symptoms were related to GI and make it the challenging to differentiate the symptoms of this malignancy from those of other conditions, such as irritable bowel syndrome or other GI disease. The median age at diagnosis was 50 years which implies that in 50% of total cases disease occurred by the age of 50 years. This is comparable with an Indian study, but differs from the western data which revealed the median ages at diagnosis as 63 and 64 years., Our finding is supported by a study by Fuh et al. which observed that Asians are more likely to present at a younger age compared to Caucasians. Despite being the studied population young, a majority of cases had achieved postmenopausal status. It reflects that the women included in this study had faced early menopause. This is in congruence with the existing literature which mentions that the average age of menopause among Indian women is much less than their Western counterparts.,
Ten percent of cases had a positive family history for breast and/or ovarian cancer. The majority of cases had FIGO stage III cancer at diagnosis which is comparable with the existing literature.,, It indicates that early-stage ovarian cancer is typically asymptomatic and the disease gets detected at advanced stage. The proportion of patients (91%) who underwent optimal debulking in our study was comparable with another study by Kim et al. The predominant type of histopathology was high-grade serous in our study; which is considered as aggressive and generally gets diagnosed at an advanced stage.
The median time interval of 24 days from surgery to start of adjuvant CT is comparable with another study. An extended time interval between surgery and start of adjuvant CT has been related with earlier disease recurrence and shorter survival., Since no death was reported due to the toxicity of carboplatin and paclitaxel, the regime was moderately tolerated by all patients. The less toxicity, fair tolerance, and simple administration make this regime a preferred treatment in advanced cancers of ovary. More than half (54%) of all patients had got the recurrence once or more frequently. This may be due to the large number of cases being at an advanced stage and/or with high-grade serous pathology. The median RFS and overall 5-year RFS rate in our study are 30 months and 33%, respectively, and are comparable with another study. The 5-year RFS rates among early stage and advanced stage groups were in congruence with that reported by Fuh et al. The significant difference between the RFS relating to the disease stage is consistent with that stated by a study. The type of histopathology affects the extent of disease and consequently, the different rates of recurrence in ovarian cancer. The lowest RFS has been depicted by high-grade serous histology; with a significant difference amongst studied histology types. The high-grade ovarian serous tumors are more aggressive and have inferior outcomes than other types.,
Five-year OS rates in early-stage and regional stage disease are 92% and 76%, respectively, this is in line with OS rates in our study. While, our general OS combined for all stages is in agreement with the literature, it varies from other studies which reported lower OS.,, The probable cause may be the noninclusion of all metastatic cases, except a few which had only pleural effusion. Another possible reason may be the younger age group in our studied cohort. A significant difference between OS with respect to stage corroborates with survival data from Tang et al. Our study demonstrates that low-grade serous histology is an independent prognostic factor for RFS., The limitation of our study is that some patients were lost to follow-up. They could not be contacted due to either outdated contact information or 4 being cases of other nations.
| > Conclusion|| |
The combination of surgery with carboplatin/paclitaxel based CT leads to moderate long-term survival in ovarian cancer. Low-grade serous histology is an independent prognostic factor for RFS. The likelihood of relapse is fairly high, consequently the RFS is short. Hence, there is an unmet need to identify the molecules which drive the recurrence. The identification of newer targets and the development of molecular-targeted therapies would be worth further investigation.
We acknowledge Ms Poonam Thakur and Mr. Navneet Singh for their assistance in data extraction.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Momenimovahed Z, Tiznobaik A, Taheri S, Salehiniya H. Ovarian cancer in the world: Epidemiology and risk factors. Int J Womens Health 2019;11:287-99.
Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al
. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 2000;92:699-708.
Marchetti C, Muzii L, Romito A, Benedetti Panici P. First-line treatment of women with advanced ovarian cancer: Focus on bevacizumab. Onco Targets Ther 2019;12:1095-103.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al
. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
Gajjar K, Ogden G, Mujahid MI, Razvi K. Symptoms and risk factors of ovarian cancer: A survey in primary care. ISRN Obstet Gynecol 2012;2012:754197.
Prasad AE, Nandennava M, Ganesh MS, Karpurmath SV, Hatti J. Demographic and clinicopathologic profile of malignant epithelial ovarian tumors: An experience from a tertiary cancer care centre in Bangalore, South India. Int J Reprod Contracept Obstet Gynecol 2017;6:856-60.
Akeson M, Zetterqvist BM, Dahllöf K, Brännström M, Horvath G. Effect of adjuvant paclitaxel and carboplatin for advanced stage epithelial ovarian cancer: A population-based cohort study of all patients in western Sweden with long-term follow-up. Acta Obstet Gynecol Scand 2008;87:1343-52.
Fuh KC, Shin JY, Kapp DS, Brooks RA, Ueda S, Urban RR, et al
. Survival differences of Asian and caucasian epithelial ovarian cancer patients in the United States. Gynecol Oncol 2015;136:491-7.
Dogra A, Mehta A, Doval DC. Are basal-like and non-basal-like triple-negative breast cancers really different? J Oncol 2020;2020:4061063.
Ahuja M. Age of menopause and determinants of menopause age: A PAN India survey by IMS. J Midlife Health 2016;7:126-31.
Parazzini F, La Vecchia C, Negri E, Franceschi S, Tozzi L. Family history of breast, ovarian and endometrial cancer and risk of breast cancer. Int J Epidemiol 1993;22:614-8.
Kim M, Suh DH, Choi JY, Bu J, Kang YT, Kim K, et al
. Post-debulking circulating tumor cell as a poor prognostic marker in advanced stage ovarian cancer: A prospective observational study. Medicine (Baltimore) 2019;98:e15354.
Gadducci A, Guarneri V, Peccatori FA, Ronzino G, Scandurra G, Zamagni C, et al
. Current strategies for the targeted treatment of high-grade serous epithelial ovarian cancer and relevance of BRCA mutational status. J Ovarian Res 2019;12:9.
Flynn PM, Paul J, Cruickshank DJ, Scottish Gynaecological Cancer Trials Group. Does the interval from primary surgery to chemotherapy influence progression-free survival in ovarian cancer? Gynecol Oncol 2002;86:354-7.
Hofstetter G, Concin N, Braicu I, Chekerov R, Sehouli J, Cadron I, et al
. The time interval from surgery to start of chemotherapy significantly impacts prognosis in patients with advanced serous ovarian carcinoma-analysis of patient data in the prospective OVCAD study. Gynecol Oncol 2013;131:15-20.
Tewari KS, Java JJ, Eskander RN, Monk BJ, Burger RA. Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study. Ann Oncol 2016;27:114-21.
Dessai SB, Chakraborty S, Babu T, Nayanar S, Bhattacharjee A, Jones J, et al
. Tolerance of weekly paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin. Indian J Cancer 2016;53:280-3.
] [Full text]
Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al
. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-200.
Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J Obstet Gynecol 2008;198:459.e1-8.
Le Saux O, Decullier E, Freyer G, Glehen O, Bakrin N. Long-term survival in patients with epithelial ovarian cancer following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Int J Hyperthermia 2018;35:652-7.
Tang H, Liu Y, Wang X, Guan L, Chen W, Jiang H, et al
. Clear cell carcinoma of the ovary: Clinicopathologic features and outcomes in a Chinese cohort. Medicine (Baltimore) 2018;97:e10881.
Manchana T, Kobwitaya K. Survival outcomes for different subtypes of epithelial ovarian cancer. Clin Res Obstet Gynecol 2018;1:1-7.
Wentzensen N, Poole EM, Trabert B, White E, Arslan AA, Patel AV, et al
. Ovarian cancer risk factors by histologic subtype: An analysis from the ovarian cancer cohort consortium. J Clin Oncol 2016;34:2888-98.
Miyoshi A, Kanao S, Naoi H, Otsuka H, Yokoi T. Ovarian cancer: Post-relapse survival and prognostic factors. J Clin Gynaecol Obstet 2018;7:31-6.
Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, et al
. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: Two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003;95:105-12.
Ezzati M, Abdullah A, Shariftabrizi A, Hou J, Kopf M, Stedman JK, et al
. Recent advancements in prognostic factors of epithelial ovarian carcinoma. Int Sch Res Notices 2014;2014:953509.
Hannibal CG, Vang R, Junge J, Kjaerbye-Thygesen A, Kurman RJ, Kjaer SK. A binary histologic grading system for ovarian serous carcinoma is an independent prognostic factor: A population-based study of 4317 women diagnosed in Denmark 1978-2006. Gynecol Oncol 2012;125:655-60.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]