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Table of Contents
EDITORIAL
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 217-220

Patterns of care for ovarian cancer


1 Department of Gynecological Oncology, Dharamshila Narayana Super Specialty Hospital, New Delhi, India
2 Department of Medical Oncology, Narayana Super Specialty Hospital, Gurugram, Haryana, India

Date of Web Publication20-Dec-2019

Correspondence Address:
Satinder Kaur
Department of Gynecological Oncology, Dharamshila Narayana Super Specialty Hospital, Vasundhara Enclave: New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_84_19

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How to cite this article:
Kaur S, Singh R. Patterns of care for ovarian cancer. Cancer Res Stat Treat 2019;2:217-20

How to cite this URL:
Kaur S, Singh R. Patterns of care for ovarian cancer. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Feb 28];2:217-20. Available from: http://www.crstonline.com/text.asp?2019/2/2/217/273700



Ovarian cancer is the second most common gynecological malignancy in Indian females.[1] The treatment of women with epithelial ovarian cancer (EOC) has evolved in the last decade both with respect to surgical principles from redefining the role of lymphadenectomy, interval debulking surgery to hyperthermic intraperitoneal chemotherapy (HIPEC) and chemotherapy regimens such as the use of angiogenesis and/or poly-ADP ribose polymerase (PARP) inhibitors. Along with the evolution of these principles, it is only natural to have diverse practice patterns for the treatment of this cancer in various countries or across a large country such as India because of varying resources as well as training facilities.

There are various reports in the literature regarding the changing pattern of care in ovarian cancer from India and the South Asian Association for Regional Cooperation (SAARC) countries, but these have compared the trends in a single institute over the preceding couple of years or a decade. The survey published in this issue of the journal by Sapkota et al.[2] is unique in that the questionnaire compiles the experience sharing of medical, gynecological, and radiation oncologists from different institutes across India and Nepal. As we discuss the results, we must recognize the fact that only 29.1% (n = 75/258) of the physicians responded, and the majority of them were medical oncologists. Responders being from the major academic centers, the median of four patients per month seen by each participant in the survey seems low.

It was encouraging to see that majority of the participants were in favor of fertility preservation in Stage I, but it is to be kept in mind that only Stage IA low-grade serous, Grade 1 endometrioid and mucinous carcinomas are safe for fertility preservation surgery.[3] Fertility preservation surgery is acceptable for Stage 1C1 as per some guidelines though with an increase in recurrence risk. This is because most of the recurrences occur in the opposite conserved ovary and are salvageable.[4] We have to remember that the controversy of lymphadenectomy is for advanced and not early ovarian cancer. For early cancers, node status is important to decide whether or not to give chemotherapy, the number of cycles, and also for determining the exact clinicopathological stage for prognosis. Considering the above facts, it is surprising to see that 20% of the participants are not addressing the lymph nodes for early ovarian cancer. For advanced ovarian cancer, the Lymphadenectomy in Ovarian Neoplasms (LION) trial demonstrated that in patients with clinically negative lymph nodes, systematic pelvic and paraaortic lymphadenectomy was not associated with better outcomes than no lymphadenectomy and was associated with a higher incidence of postoperative complications.[5] As per the survey results, there is a difference of response pertaining to the extent of lymphadenectomy, with more surgeons doing pelvic compared to paraaortic lymph node dissection. It is recommended that we must systematically remove any abnormally enlarged nodes in advanced ovarian cancer and sample/remove both pelvic and paraaortic non-enlarged lymph nodes for early ovarian cancer, and this defines the indications and extent or location of lymphadenectomy.[6]

The majority of the respondents in the survey were not in favor of adjuvant chemotherapy for early ovarian cancer, and if they opted for chemotherapy, the median number of cycles given was 4 (3 vs. 6). As per the recent European Society for Medical Oncology (ESMO)-European Society for Gynecological Oncology (ESGO) guidelines, Stage IA ovarian cancer of low-grade serous, Grade 1 and 2 endometroid type, and mucinous expansile carcinoma should not be offered adjuvant chemotherapy.[4] Bell et al. conducted a randomized trial of three versus six cycles of chemotherapy for early ovarian cancer (Stage IA Grade 3 [or clear cell], Stage IB Grade 3 [or clear cell], Stage IC, or Stage II disease). This Gynecological Oncology Group (GOG) trial found that longer treatment was not associated with significant reduction in recurrence risk and resulted in additional toxicity.[7] A subsequent exploratory analysis of this GOG study revealed that shorter course of adjuvant therapy was associated with a significant reduction in the recurrence risk for non-serous tumors but not for serous tumors.

Complete resection of all macroscopic disease (optimal cytoreduction) is the single most important independent prognostic factor in advanced early ovarian cancer (EOC). Neoadjuvant chemotherapy followed by interval debulking surgery has been proposed in the management of advanced ovarian cancer in order to increase the rate of complete optimal cytoreduction and reduced surgical morbidity. For Stage III and IV ovarian cancers, almost 2/3rd of the participants have the experience of complete cytoreduction after neoadjuvant chemotherapy. On the contrary, 42/75 physicians felt that they could achieve optimal primary cytoreduction in only half of their patients. Two randomized controlled trials, conducted by the European Organization for Research and Treatment of Cancer (EORTC) and the Medical Research Council (MRC) Clinical Trials Unit, have shown that the use of neoadjuvant chemotherapy reduced perioperative morbidity and the extent of surgical resection and increased the chances of optimal cytoreduction with primary cytoreduction as compared to interval cytoreduction. Despite the above fact, no significant differences in progression-free survival (PFS) and overall survival (OS) could be elucidated between the group with and without neoadjuvant chemotherapy.[8],[9]

Maheshwari et al. conducted a retrospective analysis of 342 patients with advanced ovarian cancer at Tata Memorial Hospital, Mumbai, treated with neoadjuvant chemotherapy followed by interval debulking surgery. Two hundred and forty-four (71.3%) patients received neoadjuvant chemotherapy and 232 (67.8%) underwent interval cytoreduction.[10] Patients received a median of three cycles of paclitaxel and carboplatin prior to surgery. Optimal cytoreduction to no gross residual disease was achieved in 81.5% of cases. Rajanbabu et al. in a surgical audit of their gynecological oncology unit from 2004 to 2010 at Amrita Institute, Kochi, analyzed their data of 198 patients.[11] Optimal debulking rate of 81% was achieved with 70% for primary surgery and 88% following neoadjuvant chemotherapy. The optimal cytoreduction rate improved from 55% in 2004 to 97% in 2010 and in the neoadjuvant chemotherapy group, the optimal cytoreduction rate increased from 60% to 100% by 2010. The above two examples from two tertiary gynecological oncology units in India achieving a very high rate of optimal cytoreduction as compared to the survey results clearly underscore the significance of having a dedicated surgeon trained in gynecologic oncology surgery and also the importance of multidisciplinary meetings to choose wisely between neoadjuvant chemotherapy and primary cytoreduction.

With the growing evidence and experience with intraperitoneal chemotherapy, the dilemma to find the best scenario for normothermic/heated chemotherapy is highly debatable. Nearly 50%–60% of the physicians in the survey recommended intraperitoneal (IP) or HIPEC for advanced ovarian cancer. GOG 172 was a landmark trial which revealed a statistically significant improvement in OS in the arm with IP chemotherapy, thus prompting a National Cancer Institute alert that all women with optimally resected early ovarian cancer should be counseled regarding and considered for IP therapy with cisplatin at 100 mg/m2.[12] Despite Level 1 evidence, the GOG 172 protocol was not adopted widely due to the associated myelosuppression, neuropathy, and gastrointestinal adverse events and thus poor tolerability and compliance to IP chemotherapy.

HIPEC has the advantage of a single infusion administered intraoperatively at the time of surgery. It is hypothesized that heated chemotherapy between 40°C and 42°C at the time of primary or interval cytoreductive surgery is the most efficient way of controlling microscopic or subcentimetric residual peritoneal disease volume. Only two randomized trials till date have explored the role of HIPEC in newly diagnosed ovarian cancer. Lim et al. randomized 184 patients who had undergone R0/R1 resection to HIPEC cisplatin 75 mg/m2 over 90 min or no HIPEC and found no difference in either the 2-year PFS or 5-year OS between the HIPEC and control groups.[13] Hyperthermic intraperitoneal chemotherapy in ovarian cancer (OV HIPEC) was the second study to randomize 245 patients in a Phase III manner, who had received three cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin and had at least stable disease with R0/R1 interval cytoreductive surgery, followed by either HIPEC cisplatin 100 mg/m2 over 90 min or no HIPEC.[14] The intention-to-treat analysis showed an improvement in the primary end point of PFS, favoring the HIPEC arm that also translated into an OS benefit. Based on these data, although some centers have adopted HIPEC as a new standard of care, it is not ready for prime time and we need more convincing and uniform results from the ongoing Phase III trials (OV HIPEC2 and HIPECOVA). In addition, as discussed below, equal progress in systemic therapy such as the use of bevacizumab and/or olaparib maintenance in first-line advanced ovarian cancer have set new benchmarks for trials exploring HIPEC.

There have been numerous experiments regarding the different schedule of taxanes and platinum in adjuvant therapy for advanced ovarian cancer, such as the dose-dense protocol, weekly versus 3-weekly, cisplatin versus carboplatin, docetaxel versus paclitaxel, and doublet versus triplet regimen. As of today, 3-weekly paclitaxel at 175 mg/m2 and carboplatin dosed at area under the curve 5–6 is accepted uniformly across the globe as the most common chemotherapy schedule. Angiogenesis is one of the key drivers, and bevacizumab has been tested with or following adjuvant chemotherapy as maintenance therapy to delay progression in advanced early ovarian cancer. GOG 218 compared paclitaxel and carboplatin every 3 weeks to paclitaxel and carboplatin with concomitant bevacizumab (15 mg/kg) with or without maintenance for a total of 15 months in patients with postsurgical residual Stage III and IV early ovarian cancer. The arm that included maintenance bevacizumab demonstrated a significant improvement in PFS compared with placebo (12.0 vs. 18.2 months; hazard ratio [HR], 0.62 [0.52–0.75]) and later led to approval by the Food and Drug Administration (FDA) of this triplet.[15]

The newest class of agents approved by the FDA to treat newly diagnosed advanced ovarian cancer are the PARP inhibitors. Recently, the results of the SOLO1 trial showed the importance of the use of PARP inhibition in patients whose disease was controlled after first-line chemotherapy in BRCA-mutated patients. This Phase III trial of 388 patients at a median follow-up of 41 months demonstrated a 70% risk reduction of disease progression or death (Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; HR, 0.30; 95% confidence interval [CI], 0.23–0.41; P = 0.001) with olaparib maintenance therapy after complete or partial response on first-line standard, platinum-based chemotherapy.[16] Moving forward, the results of PAOLA-1/ENGOT-ov25 were presented at ESMO, September 2019, in which patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) Stage III–IV, high-grade serous or endometrioid ovarian cancer with or without BRCA mutation, in clinical complete or partial response following platinum-based chemotherapy plus bevacizumab, were randomized 2:1 to receive oral olaparib at 300 mg twice daily for up to 24 months or placebo plus bevacizumab at 15 mg/kg on day 1 every 3 weeks for 15 months. The primary end point of median PFS in the combination arm of bevacizumab and olaparib was 22.1 months compared to 16.6 months with placebo (HR, 0.59; 95% CI, 0.49–0.72; P < 0.0001). Maximum benefit was seen among patients whose tumors were BRCA mutated and homologous recombination deficiency positive.[17]

To summarize, management of newly diagnosed advanced ovarian cancer is a challenge and with a growing number of patients in our country, the oncologist is bound to face this difficult question more often. There have been tremendous advances in India, such as development of dedicated gynecologic oncology units and training courses across the country, which partially achieve the quest of optimal and more radical cytoreductions. Similarly, there have been advances in systemic therapy such as usage of bevacizumab and olaparib, which are now available in generic form, but still cost is a limiting factor to use these drugs for the masses.[18] It is prime time to have India-specific guidelines, and an attempt under the National Cancer Grid (resource-stratified guidelines) is underway to bring uniformity of the basic principles of care of ovarian cancer.



 
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Bell J, Brady MF, Young RC, Lage J, Walker JL, Look KY, et al. Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2006;102:432-9.  Back to cited text no. 7
    
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11.
Rajanbabu A, Kuriakose S, Ahmad SZ, Khadakban T, Khadakban D, Venkatesan R, et al. Evolution of surgery in advanced epithelial ovarian cancer in a dedicated gynaecologic oncology unit-seven year audit from a tertiary care centre in a developing country. Ecancermedicalscience 2014;8:422.  Back to cited text no. 11
    
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van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HWR, Hermans RHM, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med 2018;378:230-40.  Back to cited text no. 14
    
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Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-83.  Back to cited text no. 15
    
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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.  Back to cited text no. 16
    
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Ray-Coquard IL. Breakthrough from PAOLA1 GINECO/ENgOT-ov25 trial: Adding Olaparib to Bevacizumab Maintenance Demonstrates Substantial Clinical Benefit in Newly Diagnosed Advanced Ovarian Cancer. Available from: https://www.esmo.org'Oncology-News. [Last accessed on 2019 Oct 04].  Back to cited text no. 17
    
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