| [Download PDF]
|Year : 2009 | Volume
| Issue : 1 | Page : 28--33
Study of 'patterns of care' of ovarian cancer patients in a specialized cancer institute in Kolkata, eastern India
P Basu1, P De1, S Mandal2, K Ray3, J Biswas3,
1 Department of Gynecologic Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India
2 Department of Medical Records, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India
3 Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India
Department of Gynecologic Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata
Background Ovarian cancer is one of the leading cancers in Indian women. The current standard of care is a combination of surgical staging, maximal surgical effort to achieve cytoreduction, and judicious use of chemotherapy. Multimodality therapy can reduce mortality, but the practice and uptake of such therapy in Indian Institutions are not up to the desired level. Objectives To study the protocol adherence for ovarian cancer management along with patient compliance and evaluate their effects on survival. Materials and Methods: The retrospective study obtained and analyzed data from records of patients operated for ovarian cancer at a Regional Cancer Center in eastern India between January 2002 and December 2006. Results: The records of 202 patients were evaluable. None of the patients who had primary surgery outside the institute had staging information. A substantial number of patients operated at the institute had incomplete surgical staging, inadequate information on residual disease after surgery, and incomplete histology report. Only 20.3% patients could have optimal cytoreduction after surgery. Compliance to chemotherapy was poor. The median overall survival time and disease-free survival time were 24 months and 5 months, respectively. The residual disease after surgery significantly affected the overall survival, but not the disease-free survival. Incomplete chemotherapy was found to adversely affect survival after adjusting for advanced stage and bulky residual disease. Conclusion: Management of ovarian cancer is suboptimal even in the specialized cancer institute. Poor patient compliance to chemotherapy is one of the major factors adversely affecting survival from advanced ovarian cancer.
|How to cite this article:|
Basu P, De P, Mandal S, Ray K, Biswas J. Study of 'patterns of care' of ovarian cancer patients in a specialized cancer institute in Kolkata, eastern India.Indian J Cancer 2009;46:28-33
|How to cite this URL:|
Basu P, De P, Mandal S, Ray K, Biswas J. Study of 'patterns of care' of ovarian cancer patients in a specialized cancer institute in Kolkata, eastern India. Indian J Cancer [serial online] 2009 [cited 2020 Oct 24 ];46:28-33
Available from: https://www.indianjcancer.com/text.asp?2009/46/1/28/48592
Ovarian cancer is the sixth most common cancer (age standardized incidence rate: 6.6/100,000) and the seventh leading cause of cancer deaths (age standardized mortality rate: 4.0/100,000) among women worldwide.  In most of the population-based cancer registries in India, ovarian cancer is the third leading site of cancer among women, trailing behind cervix and breast cancer. The age-adjusted incidence rates of ovarian cancer vary between 5.4 and 8.0 per 100,000 population in different parts of the country. 
Ovarian cancer has the worst prognosis among all gynecological malignancies. The overall 5-year survival is approximately 45%, primarily due to the late stage at diagnosis of the disease.  India with its one billion population has a huge burden of the disease. In comparison, the number of comprehensive cancer centers that can offer appropriate multidisciplinary care is quite meager. Most of the ovarian cancers are initially operated by general gynecologists since trained gynecological oncologists are very few in the country. Many of the patients receive suboptimal management due to logistics and socioeconomic constraints. A large number of the patients belong to rural areas and have poor access to specialized healthcare. The prohibitive cost of antineoplastic drugs is a major deterrent for many of the patients to continue with the treatment. Advanced stage of disease at diagnosis, inappropriate management, and poor compliance to therapy all together are responsible for the dismal survival rates. There is a need to objectively assess these factors in the context of ovarian cancer management in Indian scenario.
Keeping that objective in view, the present study was conducted at a Regional Cancer Institute, a public-funded comprehensive cancer center situated in eastern India. The institute caters mostly to the patients belonging to the lower socioeconomic strata of the society. On an average, 100 new ovarian cancer patients are registered in the Department of Gynecological Oncology of the institute every year. A retrospective analysis of the records of the ovarian cancer patients operated at the institute was done to evaluate the contemporary management, adherence to standard of care, compliance of the patients, and different factors influencing the survival.
Materials and Methods
The medical records of all invasive ovarian cancer patients registered at the cancer institute between January 2002 and December 2006 were reviewed. A total of 218 ovarian cancer patients were operated at the institute during that period. Of them, the records of 202 patients were considered evaluable as the diagnosis of ovarian cancer was confirmed by histology and the disease status of the patients at last contact was recorded.
Data available as on 31 October 2007 were used for this analysis. If a patient did not attend the institute during the preceding three months and if she was known to be alive at last contact, a telephone call was made to her telephone number, if available, to find out if she was still alive. The date of death was enquired from the patient's relatives if she had passed away.
Descriptive method was used to summarize patient characteristics, type, and extent of tumor and treatment data. The date of surgery at the cancer institute was the initial event from which survival analysis was done. Overall survival was defined as the time from the date of surgery until the date of death from any cause. Disease-free survival was defined as the time from the date of surgery till the date when presence of disease (residual/recurrent) was first recorded. The Kaplan-Meier method was used to estimate the survival and log-rank test was used to assess the statistically significant differences between the survival curves. Multivariate analysis was performed using the Cox proportional hazard model to test the significance of various factors with regard to survival.
The information about age distribution, tumor stage, and treatment are summarized in [Table 1]. The mean age of the patients with epithelial tumors was 48.8 + 11.2 years and that of the patients with germ cell tumors was 26.0 + 12.9 years.
More than 80.0% of the patients were in stage-III or -IV at the time of registration. None of the patients who had primary surgery outside ( n = 38, 18.8%) had adequately completed operative notes to ascertain the stage of the disease. Nearly half of these patients were operated using transverse incisions. Staging was not done appropriately or information was inadequate in 29 patients (17.7%) operated at the cancer institute.
The most common histological types were serous adenocarcinoma among the epithelial malignancies and dysgerminoma among the germ cell tumors [Table 2]. The type of adenocarcinoma was not specified in 26 (12.9%) patients. Tumor grade was mentioned in 84 (41.6%) histology reports.
The primary surgery was done outside the cancer institute in 38 patients of whom nine received adjuvant chemotherapy before registering at the institute. All these patients were reoperated at the institute due to bulky residual disease or due to recurrence. None of these patients were given chemotherapy at the institute before second surgery. Of the 164 patients who had their primary surgery at the cancer institute, only nine (5.5%) were administered neoadjuvant chemotherapy.
In spite of the patients being operated at the cancer institute by trained gynecological oncologists, optimal debulking (residual disease n = 20; 9.9%).
There were 10 patients (4.9%) who died within 30 days of surgery and were considered postsurgery mortalities. Among them, seven had stage-IIIC disease, two had stage-IV disease, and one had recurrent disease. The most common cause of postoperative death was hemorrhagic shock.
According to the institutional protocol, postoperative chemotherapy was advised to all patients of ovarian carcinoma, except those who had stage-IA/IB disease with grade I/II tumor. Patients with stage-IV disease having multiple metastases and/or poor performance score were not offered chemotherapy. Apart from nine patients in stage-I, five patients in stage-IV, and ten patients who expired within one month of surgery, all 178 patients were advised to undergo adjuvant chemotherapy. Out of them, only 81 patients received chemotherapy at the institute [Table 3]. As documented in our hospital records, the compliance to chemotherapy was extremely poor (45.5%).
It is possible that few of the noncompliant patients attended other hospitals for chemotherapy. By and large the patients dropped out either because they could not afford to buy the chemotherapy drugs or because hospital beds were not available to accommodate them.
The chemotherapy regimens administered postoperatively are listed in [Table 4]. The most frequently administered chemotherapy for epithelial malignancies was a combination of cisplatinum and cyclophosphamide. The bleomycin, etoposide, and cisplatin combination was used for treatment of germ cell tumors. Paclitaxel with carboplatin or cisplatin was administered to 25 patients (30.8%).
The cycles of chemotherapy could be completed as per initial plan in only 39 (48.1%) patients. The reasons for the high drop-out rate could be unacceptable toxicities, inability to buy the cytotoxic drugs, inability to travel repeatedly to the institute from far-off villages, or lack of familial support. Even among those patients who completed the prescribed number of cycles of chemotherapy, the total treatment duration was inordinately prolonged (more than 150 days) in 25 patients (64.0%). No patient received intraperitoneal chemotherapy.
The median overall survival time calculated by Kaplan-Meyer survival curve for the 202 patients was 24 months. The median disease-free survival was only five months [Figure 1].
Several studies have clearly demonstrated that there is an inverse correlation between the amount of residual tumor after surgery and survival. We observed that patients who had P = 0.006) [Figure 2]. However, the observed overall survival of 100% for the first group is clearly an overestimate. This can be explained by the facts that the number of patients in this group was small ( n = 41) and that most of them dropped out early (noncompliant to follow up).
However, the difference in disease-free survival between the two groups was not that significant (log-rank statistics 0.29; P = 0.058) [Figure 3].
The improved disease-free survival that could be achieved by optimal debulking was negated by the fact that a large number of patients with advanced disease did not receive adjuvant chemotherapy at all or received inadequately.
On multivariate analysis, incomplete chemotherapy was found to be a significant factor adversely influencing overall survival after adjusting for advanced stage and residual tumor at operation (Hazard ratio 6.6; CI 3.1-13.8; P = 0.00).
The standard of care for ovarian cancer is thorough surgical staging with optimal cytoreduction followed by a platinum-based chemotherapy, if there is a significant risk of recurrence. A vertical incision is mandatory to gain adequate access to the upper abdomen. Peritoneal fluid or peritoneal wash should be sent for cytology and the entire abdomen should be explored to look for the extent of disease including metastases. Debulking of all visible tumors (including total abdominal hysterectomy and bilateral salpingo-oophorectomy), omentectomy, pelvic and para-aortic node dissection, and representative biopsies from different parts of the abdominal cavity should be done. A thorough staging procedure can upstage up to 30% of the clinically 'early' stage ovarian cancers and save them from inadequate treatment.  We observed that all patients operated outside the cancer institute were not staged appropriately. In many developed countries, all known or suspected ovarian cancer patients are referred to trained gynecological oncologists for surgery. There is ample evidence that patients with advanced ovarian malignancies have significant survival advantage when a gynecologic oncologist is involved in their care.  In India, trained gynecological oncologists are handful in number. The general gynecologists need to be trained and oriented. The present study reveals that even in a specialized cancer institute, nearly one-fifth of the patients were not staged appropriately.
Nearly 80% of all the malignant ovarian tumors in our study were epithelial in origin, a pattern consistent with other studies. The histologic grades of the tumors were missing in substantial number of patients though grade is an important independent prognostic factor in patients with epithelial ovarian cancers. 
The aim of surgical effort in advanced ovarian cancer should be to reduce the burden of residual tumor to a point at which the adjuvant therapy will be optimally effective. Griffiths et al. used a multiple linear regression equation with survival as the dependent variable to control simultaneously for the multiple factors that contribute to the ultimate outcome in the individual patient.  The most important therapeutic factor proven to be the size of the largest residual mass after primary surgery. The present case series had a very poor survival rate, primarily because of the fact that nearly 70% of the patients was left with large residual disease even after completion of surgery at the cancer institute. Many of these patients already had a suboptimal primary attempt of debulking outside. Chemotherapy administered for 2-3 cycles prior to the second surgery would have improved the resectability of disease. A European Organization for Research and Treatment of Cancer (EORTC) study showed that interval debulking surgery after few cycles of chemotherapy improved survival in patients who had suboptimal primary debulking surgery.  Contradictory results were obtained by Gynecological Oncology Group (GOG) in a similar study.  They did not observe any significant benefit in overall or progression-free survival of the suboptimally debulked patients who had interval surgery compared to those who continued to have chemotherapy. Such contradiction can be explained by the fact that in the GOG study primary surgery was done only by trained gynecological cancer surgeons who did maximal surgical effort for cytoreduction. This was not necessarily a requisite for the EORTC trial. The EORTC group also used suboptimal chemotherapy.
In our case series, none of the patients were given chemotherapy before secondary debulking. Only 5.5% of the patients who had primary surgery at the cancer institute received neoadjuvant chemotherapy. Considering the large proportion of advanced stage disease the number should have been higher.
The modern era of combination chemotherapy started in the eighth decade of last millennium, when the high efficacy of cisplatin in epithelial ovarian cancer was reported. Cyclophosphamide-cisplatin combination became the standard protocol for the management of advanced epithelial ovarian cancer. The same protocol was introduced at Chittaranjan National Cancer Institute also. The results of the GOG 111 trial published in 1996 convincingly established the superiority of paclitaxel and cisplatin combination over the cyclophosphamide-cisplatin combination in the treatment of stage-III and -IV disease.  The overall response rate as well as the clinical complete response rate were significantly better in the paclitaxel arm. The risk of death was 39% lower among those treated with paclitaxel regimen. Subsequently, carboplatin replaced cisplatin as the analog with fewer marked side effects. At our institute the preferred protocol for treating advanced epithelial ovarian cancer is a combination of paclitaxel (175 mg/m 2 for 3 hours) with carboplatin (AUC of 6.0). Due to the prohibitively high cost of the medicines, most of our patients cannot afford the treatment of first choice and settle for the cisplatin-cyclophosphamide combination. Even though this combination is much more economical, many patients find it hard to bear the expenses.
As most of our patients come from far-off places chemotherapy cannot be administered on day-care basis. Due to inadequate number of beds in the hospital the cycles of chemotherapy cannot be maintained properly for most of the patients. Many patients drop out as they find it difficult to visit the hospital repeatedly. A randomized trial by International Collaborative Ovarian Neoplasm (ICON 3) reported that carboplatin alone has same overall survival as that of palcitaxel-carboplatin combination with more favorable toxicity profile in treatment of stage I-IV ovarian cancer.  Though the ICON3 results were not replicated by other studies, from logistics point of view, carboplatin alone may be more suitable for our kind of setup.  The total administration time is less. So, the patient can be discharged early leaving adequate time for her to go back home on the same day. The fewer toxicities will help to improve compliance and the total treatment cost will be within reach of many of our patients.
The major limitation of our study is that it is a retrospective one and was solely dependent on the data extracted from the medical records. Incomplete or missing records have the potential to introduce bias in the study and affect the outcome.
As observed by the present study, the modifiable factors that can improve the survival from advanced ovarian cancer are the bulk of disease left behind after primary surgery and the compliance of patients to chemotherapy. The specialized cancer institutes in the country need more trained gynecologic oncologists and have to improve their infrastructure to accommodate more patients with advanced disease. The high cost of anticancer medicines will still remain as a stumbling block. The standard-of-care protocols need to be tailored to the local situations and needs.
|1||Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108|
|2||Consolidated Report of Population Based Cancer Registries 2001-2004. National Cancer Registry Program. Indian Council of Medical Research. Bangalore: 2006. |
|3||Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al . Cancer statistics, 2006. CA Cancer J Clin 2006;56:106-30.|
|4||Young RC, Decker DG, Wharton JT, Piver MS, Sindelar WF, Edwards BK, et al . Staging laparotomy in early ovarian cancer. JAMA 1983;250:3072-6.|
|5||Carney ME, Lancaster JM, Ford C, Tsodikov A, Wiggins C. A population-based study of patterns of care for ovarian cancer: Who is seen by a gynecologic oncologist and who is not? Gynecol Oncol 2002;84:36-42.|
|6||DiSaia PJ, Creasman WT. Epithlial Ovarian Cancer. In: DiSaia PJ, Creasman WT, editors. Clinical gynecologic oncology. 6 th ed. St. Louise: Mosby Inc; 2005. p. 289-346.|
|7||Griffiths CT, Parker LM, Fuller AF Jr. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Treat Rep 1979:63:235-40.|
|8||van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, et al . The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Eng J Med 1995;332:629-34.|
|9||Rose PG, Nerenstone S, Brady MF; Gynecologic Oncology Group. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351:2489-97.|
|10||McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al . Cyclophosphamide and cisplatic compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6.|
|11||International Collaborative Ovarian Neoplasm (ICON) Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single agent carboplatin or cyclophosphamide, doxorubicin and cisplatin in women with ovarian cancer: the ICON 3 randomized trial. Lancet 2002;360:505-15.|
|12||Aletti GD, Gallenberg MM, Cliby WA, Jatoi A, Hartmann LC. Current Management Strategies for Ovarian Cancer. Mayo Clin Proc 2007;82:751-70.|