|Year : 2018 | Volume
| Issue : 1 | Page : 50-54
Outcomes of advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy
Amita Maheshwari1, Neha Kumar1, Sudeep Gupta2, Bharat Rekhi3, TS Shylasree1, Rohit Dusane4, Jyoti Bajpai2, Jaya Ghosh2, Seema Gulia2, Kedar Deodhar3, Santosh Menon3, Palak Popat5, Nilesh Sable5, Meenakshi Thakur5, Rajendra Kerkar1
1 Department of Gynecologic Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Biostatistics, Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||23-Aug-2018|
Department of Gynecologic Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Ovarian cancer is the fourth most common cancer in Indian women. Majority of these are epithelial ovarian cancers (EOCs), most of which present in advanced stage. Women with poor performance status and/or those unlikely to achieve optimal debulking at upfront surgery, benefit from neoadjuvant chemotherapy (NACT) followed by interval cytoreduction, with lesser surgical morbidity and equal survival rates as compared to primary cytoreduction. Methodology: This was a retrospective analysis of patients with advanced ovarian cancer, treated with NACT followed by interval debulking surgery at Tata Memorial Hospital from January 2014 to December 2014. Results: Epithelial cancers constituted 84.4% (n = 406) of all cases of ovarian malignancies. Of these, overwhelming majority (84.3%, n = 342) were in the advanced stage. Sixty percent of all EOC patients received NACT. The mean baseline serum CA-125 level in women treated with NACT was 4294.7 U/ml (range, 11–151,200 U/ml). The median number of NACT cycles (paclitaxel + carboplatin) was 3. Optimal cytoreduction was achieved in 81.5% cases. The rates of Grade 3 or 4 intraoperative and postoperative complications were 4% each. The median postoperative stay was 5 days and the median time between surgery and adjuvant chemotherapy was 20 days. The median progression-free survival (PFS) was 15.15 months (95% confidence interval [CI]: 12.95–17.34), and the median overall survival (OS) was 34.73 months. Multivariate analysis revealed that optimal cytoreduction (hazard ratio [HR] = 2.04 [95% CI: 1.15–3.62]; P = 0.015) and number of NACT cycles (3 vs. >3; HR = 1.51 [95% CI: 1.06–2.16]; P = 0.022) were significantly associated with PFS, and optimal cytoreduction (HR = 3.21 [95% CI: 1.53–6.73]; P = 0.002) and ECOG status (0–1 vs. ≥2; HR = 2.64 [95% CI: 1.25–5.55]; P = 0.011) with OS. Conclusions: High rates of optimal cytoreduction were achieved at interval cytoreductive surgery after NACT, with acceptable surgical morbidity, early start of adjuvant chemotherapy, and survival outcomes comparable to international standards.
Keywords: Advanced ovarian cancer, neoadjuvant chemotherapy
|How to cite this article:|
Maheshwari A, Kumar N, Gupta S, Rekhi B, Shylasree T S, Dusane R, Bajpai J, Ghosh J, Gulia S, Deodhar K, Menon S, Popat P, Sable N, Thakur M, Kerkar R. Outcomes of advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy. Indian J Cancer 2018;55:50-4
|How to cite this URL:|
Maheshwari A, Kumar N, Gupta S, Rekhi B, Shylasree T S, Dusane R, Bajpai J, Ghosh J, Gulia S, Deodhar K, Menon S, Popat P, Sable N, Thakur M, Kerkar R. Outcomes of advanced epithelial ovarian cancer treated with neoadjuvant chemotherapy. Indian J Cancer [serial online] 2018 [cited 2018 Dec 10];55:50-4. Available from: http://www.indianjcancer.com/text.asp?2018/55/1/50/239594
| » Introduction|| |
Ovarian cancer is the fourth most common cancer in Indian women with an incidence of 4.9 cases per 100,000 (GLOBOCAN 2012). Ninety percent of ovarian cancers are derived from coelomic epithelium. Germ cell tumors account for 5% of ovarian cancers and sex cord-stromal tumors approximately 7%. The common epithelial ovarian cancers (EOCs) include high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (<5%). They all have different epidemiology, molecular profiles, clinical presentations, patterns of spread, response to chemotherapy, and hence different prognosis. About 70% of patients with EOC present with advanced disease, as a result of the lack of any satisfactory screening test and specific symptoms.
Complete resection during cytoreductive surgery is the most important independent prognostic factor in advanced EOC. Survival is inversely related to the residual disease after surgery. In a meta-analysis of 6885 patients with Stage III or IV ovarian carcinoma, Bristow et al. found that each 10% increase in maximal cytoreduction rates was associated with a 5.5% increase in median survival time. A review of 11,999 patients with advanced ovarian cancer reported that the median overall survival (OS) for patients with no residual disease was 70 months, compared to 53 months for patients with 1–5 mm, 40 months for patients with 1–10 mm, and 30 months for patients with >10 mm (P < 0.001). The authors concluded that although the aim of cytoreductive surgery should be leaving no gross residual disease, there is still a significant benefit in trying to achieve “optimal” residual disease status (i.e., <1 cm), because such patients have a 10 months longer median OS, compared to patients with suboptimal residual disease.
However, patients with advanced ovarian cancer who do not achieve optimal debulking at the end of primary cytoreductive surgery do not benefit from this procedure and are likely to experience morbidity associated with extensive surgery. Neoadjuvant chemotherapy (NACT) before cytoreductive surgery has been extensively studied in patients who are unlikely to attain optimal cytoreduction or are poor surgical candidates. Two randomized controlled trials, conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the Medical Research Council (MRC) Clinical Trials Unit, have shown no significant differences in progression-free (PFS) and OS between the group with primary cytoreduction and the one with NACT followed by interval cytoreduction., The median PFS was 12 months for both the groups in the EORTC trial and the OS was 29 months and 30 months, respectively. Optimal cytoreduction, defined as largest residual tumor <1 cm, was achieved in 41.6% of patients after primary cytoreduction and 80.6% of the patient after interval cytoreduction. Postoperative death (within 28 days of surgery) and surgical morbidity were lesser in the interval cytoreduction surgery group.
The decision whether a patient with advanced ovarian carcinoma (Stage IIIC or IV) is a better candidate for primary or interval cytoreduction depends on many factors including the patient's performance status, surgeon's experience, and computed tomography (CT) imaging, which provides information about the extent of the disease and whether optimal cytoreduction is likely. The American Society of Clinical Oncology (ASCO) and the Society of Gynecologic Oncology (SGO) recommend that for women with a high likelihood of achieving optimal cytoreduction, primary cytoreductive surgery (PCS) is recommended over NACT. However, for women who have a high perioperative risk profile or women who are fit for PCS but are deemed unlikely to have cytoreduction to <1 cm (ideally to no visible disease) by a gynecologic oncologist, NACT is recommended over PCS. NACT is associated with less peri- and post-operative morbidity and mortality and shorter hospitalizations. Interval cytoreductive surgery should be performed after ≤4 cycles of NACT for women with a response to chemotherapy or stable disease.
Being a tertiary cancer care center, majority of ovarian cancer patients presenting to Tata Memorial Centre have advanced disease and/or are in poor performance status and therefore unsuitable for upfront surgery. The aim of this study was to review the outcomes of advanced EOC patients treated with NACT protocol at out center.
| » Methodology|| |
This was a retrospective analysis of advanced ovarian cancer patients who were treated with NACT at Tata Memorial Hospital, Mumbai, over a period of 1 year, i.e., from January 2014 to December 2014. All patients had serum CA-125 levels and a contrast-enhanced CT scan of the abdomen and pelvis before treatment. The diagnosis of ovarian cancer was made on the basis of cytopathological evaluation of ascitic or pleural fluid or histopathological confirmation of biopsies from representative lesions, where necessary.
All new cases with advanced EOC were jointly assessed by the gynecologic and medical oncologists. Patients who had a good performance status and/or were likely to be optimally cytoreduced underwent primary cytoreduction followed by six cycles of adjuvant platinum-based chemotherapy (Paclitaxel and Carboplatin). Patients who were in poor general condition and/or not likely to be debulked optimally were offered NACT (Paclitaxel and Carboplatin) followed by interval cytoreduction and then adjuvant chemotherapy. Optimal cytoreduction was defined as no evidence of macroscopically visible residual disease or residual disease ≤1 cm. After the completion of primary treatment, patients were followed up 3–4 monthly for the first 2 years and 6 monthly thereafter. At each follow-up visit, a complete physical examination and serum CA-125 level was done. Imaging was advised in case patient presented with symptoms, or a rise in serum CA-125 levels (serological relapse).
Demographic data including age and education were obtained from the medical records. Clinical data included the extent and type of surgery, intra- and post-operative complications, and neoadjuvant and adjuvant chemotherapy protocols. The records were reviewed for follow-up details including recurrence, if any, date of recurrence and treatment of recurrent disease. PFS was calculated in months from the date of completion of treatment to the date of first recurrence or progression or death, whichever occurred earlier. OS was calculated in months from the date of completion of treatment to the date of death, either due to disease or any other cause.
SPSS Version 20 was used for the statistical analysis (Armonk, NY: IBM Corp). Demographic-, clinical-, and disease-related variables are presented as frequency (percentage), mean (standard deviation [SD]), and median, as appropriate. Frequency distributions were compared using Chi-square and Fisher's exact tests, and mean and median values in the groups were compared using the Student's t-test and the Mann–Whitney U-test. P <0.05 was considered statistically significant. Survival curves and rates were calculated using the Kaplan–Meier method. Differences in survival were assessed using the log-rank test for categorical factors and Cox's proportional hazards model for continuous factors in univariate analysis. A multivariate analysis was done using Cox's proportional hazards model to determine the risk factors after adjustment for known prognostic variables.
| » Results|| |
In the year 2014, 3,321 new patients were registered under Gynecologic Oncology Disease Management Group, out of which 994 (30%) presented with either diagnosed or suspected ovarian cancer. Finally, the diagnosis of ovarian malignancy was confirmed in 510 patients, while others had either benign pathology or nonovarian malignancy. The sociodemographic profile of patients revealed that 44% came from rural areas and 56% from urban regions. Forty-four percent patients were from Maharashtra while 56% were from other states. Nineteen percent of women were illiterate, 24% had received primary education, 33% secondary education, and 24% were graduates or above. Out of all patients (n = 510), 49% received treatment at our center, 7% were unfit for curative treatment and received palliative care only, 15% had treatment planned by us and received it outside, and 29% patients came for second opinion only.
Histopathologic analysis showed that 84.4% (n = 406) of the ovarian malignancies were epithelial cancers, 7.9% germ cell tumors (n = 38), 3.5% sex cord-stromal tumors (n = 17), and 4.2% borderline tumors (n = 20). The median age of women presenting with EOCs was 52 years (19–88), germ cell tumors 25.5 years (18–61), sex cord-stromal tumors 44 years (20–68), and borderline ovarian tumors 32.5 years (22–73). The 3-year OS in cases of EOCs was 56.3%, in cases of germ cell tumors was 94.4%, in sex cord-stromal tumors was 91.7%, and in cases of borderline ovarian tumors was 100% [Figure 1]. [Table 1] shows the clinicopathological characteristics of women with EOCs (n = 406), of which 15.7% (n = 64) were in early (I and II) stage and 84.3% (n = 342) in the advanced stage. The OS in early and advanced stages of EOCs is depicted in [Figure 2].
|Figure 1: Overall Survival of epithelial, germ cell, sex cord-stromal, and borderline ovarian cancers|
Click here to view
|Table 1: Clinicopathological characteristics of women with epithelial ovarian cancers|
Click here to view
|Figure 2: Overall survival of early and advanced stage epithelial ovarian cancers|
Click here to view
Of the 342 patients with advanced disease, 244 (71.3%) received NACT and 232 women (67.8%) underwent interval cytoreduction. Follow-up data were available for 208 patients treated with NACT protocol, and these were included in survival analysis. The median age of these women was 55 years (range, 21–84). Twenty-two percent presented with ECOG status 0, 63% ECOG 1, and 15% ECOG 2–3. The mean baseline serum CA-125 level was 4294.7 U/ml (range 11–151,200 U/ml). The median number of NACT cycles (paclitaxel + carboplatin) received before surgery was 3 (SD ± 0.775). While majority of women responded to paclitaxel and carboplatin, 5.3% of women (n = 13) treated with NACT were switched to second-line chemotherapy due to suboptimal response. The median time interval between last chemotherapy and surgery was 39 days (SD ± 22.16).
Optimal cytoreduction to no gross residual disease was achieved in 81.5% cases. The rate of Grade 3 or 4 intraoperative complications including hemorrhage (blood loss >1000 ml) and bowel injury was 4%. The median postoperative stay was 5 days (SD ± 2.6). Postoperative complications including febrile illness and reexploration occurred in 4% patients. The median time between surgery and adjuvant chemotherapy was 20 days (SD ± 9.85).
The median duration of follow-up was 22.7 months (SD ± 8.63). The 3-year PFS was 22.6% and 3-year OS was 59.4%. The median PFS was 15.15 months (95% confidence interval [CI]: 12.95–17.34) and the median OS was 34.73 months. In patients who had an optimal cytoreduction, median PFS was 15.2 months (95% CI: 12.9–17.6) compared to 6.7 months (95% CI: 4.5–9) in those with suboptimal cytoreduction (P = 0.001). The median OS was 34.7 months in the group that underwent optimal cytoreduction, while it was 22.6 months (95% CI: 21.3–23.8) in cases with suboptimal cytoreduction (P = 0.000). Survival curves in women with R0 (no gross residual disease), R1 (residual disease ≤1 cm), and R2 (residual disease >1 cm) cytoreduction are shown in [Figure 3] and [Figure 4].
|Figure 3: Progression-free survival in women with R0, R1, and R2 resection|
Click here to view
Optimal cytoreduction and number of chemotherapy cycles (3 vs. >3) before interval cytoreduction were the factors significantly associated with PFS, on univariate as well as multivariate analysis. Both univariate and multivariate analyses for OS showed that optimal cytoreduction and ECOG status were significant factors [Table 2].
|Table 2: Univariate and multivariate analysis – factors affecting progression-free survival and overall survival in epithelial ovarian cancers|
Click here to view
| » Discussion|| |
Majority of women presenting to our center were from outside Maharashtra, indicating the referral practices of the country and the dire need for more regional cancer centers, to optimize cancer care. The ovarian cancer cases were not just concentrated in the urban population; in fact, 44% of the women came from rural areas. The median age of women with EOC was 52 years. This is a decade younger than the median age reported in the Western literature. The exact reason for this age difference is not known; however, this could be a reflection of the overall demographic profile of Indian population with a relatively younger population than the west or due to referral bias.
The median number of NACT cycles before interval cytoreduction was 3 (SD ± 0.775). The number of chemotherapy cycles (3 vs. >3) was also significantly associated with PFS, on univariate (P = 0.032) and multivariate (P = 0.022) analysis. Bristow and Chi, in a meta-analysis of 835 patients undergoing interval cytoreduction, had reported that within the rate of 3–6 cycles, each incremental chemotherapy cycle was associated with a decrease in 4.1 months in median survival (P = 0.046).
Optimal cytoreduction was achieved in 81.5% cases. In the EORTC trial, on comparing primary and interval cytoreduction, optimal cytoreduction (largest residual tumour ≤1 cm) was achieved in 80.6% patients after interval debulking. The rates of Grade 3 and 4 intraoperative and postoperative complications in the present study were less, and similar to those reported in the EORTC trial. There was no perioperative mortality in the present series.
The median hospital stay after interval cytoreduction was short (5 days) and the median time between surgery and adjuvant chemotherapy was 20 days. Hence, most patients were able to start adjuvant chemotherapy by 3 weeks postsurgery. Although, in our study, time intervals between NACT, debulking surgery, and adjuvant chemotherapy were not significantly associated with survival, they have been shown to affect survival in some studies. Timing of cytotoxic treatment (≤28 days vs. >28 days; hazard ratio [HR]: 1.73 (95% CI: 1.08–2.78), P = 0.022) was found to be a significant prognostic factor for OS by Hofstetter et al., in 191 patients with advanced serous (FIGO III–IV) ovarian cancer from the prospective multicenter study OVCAD (Ovarian CAncer Diagnosis). Time interval from surgery to initiation of chemotherapy was significantly correlated with OS in patients with postoperative residual disease (HR: 2.24 [95% CI: 1.08–4.66],
P = 0.031).
In our study, the 3-year OS for advanced stage cancers receiving NACT was 59.4%. As per reported literature, 5-year survival rate in cases of advanced ovarian cancers is 30%–55%. In the present study, the median PFS was 15.15 months and median OS was 34.73 months. These rates are comparable to those reported in EORTC and MRC-CHORUS trials, which compared primary and interval cytoreduction in advanced EOCs.,
Although limited by its retrospective design and relatively short period of follow-up, this study provided valuable information about the distribution of different histological subtypes of ovarian cancers presenting at our center. It also gave insight into the operative and survival outcomes of women with advanced EOC treated with NACT-interval cytoreduction.
| » Conclusion|| |
This study shows that we achieved high rates of optimal cytoreduction with no gross residual disease, in cases of advanced stage EOCs, undergoing interval cytoreduction. This was associated with very less surgical morbidity, short hospital stay, and early start of adjuvant chemotherapy. The survival rates in these women were comparable to those reported in the literature.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al
. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer (IARC); 2013.
Quirk JT, Natarajan N. Ovarian cancer incidence in the United States, 1992-1999. Gynecol Oncol 2005;97:519-23.
Ziebarth AJ, Landen CN Jr., Alvarez RD. Molecular/genetic therapies in ovarian cancer: Future opportunities and challenges. Clin Obstet Gynecol 2012;55:156-72.
Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 2002;20:1248-59.
Chiva LM, Castellanos T, Alonso S, Gonzalez-Martin A. Minimal macroscopic residual disease (0.1-1 cm). Is it still a surgical goal in advanced ovarian cancer? Int J Gynecol Cancer 2016;26:906-11.
Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al
. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943-53.
Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, et al.
Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): An open-label, randomised, controlled, non-inferiority trial. Lancet 2015;386:249-57.
Wright AA, Bohlke K, Armstrong DK, Bookman MA, Cliby WA, Coleman RL, et al
. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016;34:3460-73.
Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: A meta-analysis. Gynecol Oncol 2006;103:1070-6.
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.
Romanidis K, Nagorni EA, Halkia E, Pitiakoudis M. The role of cytoreductive surgery in advanced ovarian cancer: The general surgeon's perspective. J BUON 2014;19:598-604.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]