Tumor type and substage predict survival in stage I and II ovarian carcinoma: Insights and implications
Introduction
Young et al. reported in 1990 that women diagnosed with well-differentiated (grade 1) or moderately-differentiated (grade 2) ovarian carcinomas confined to the ovaries (stage Ia and Ib) had a similar 5-year overall survival rate (94% versus 98%) [1]. A much larger study of 1545 patients with stage I ovarian carcinoma reported grade as the most powerful prognostic indicator of disease-specific survival (grade 2 versus grade 1 hazard ratio 3.13 [95% confidence interval 1.68–5.85]) [2]. This resulted in a widely adopted treatment recommendation that women diagnosed with ovarian carcinoma, stage Ia and grade 1, should not receive adjuvant therapy [3]. Many centers include stage Ib, grade 1 in this low-risk category; some authors have suggested that the diploid subgroup of grade 2 tumors also does not need adjuvant therapy when diagnosed at stage Ia [4], [5]. A significant problem with these recommendations, however, is that grade assignment lacks reproducibility (k = 0.27–0.40, depending on the grading system used) [6], [7], [8], suggesting that grade is not a sufficiently reliable basis for individual treatment recommendations. It would be desirable to base practice on more robust variables.
Driven by better understanding of the molecular characteristics of tumor types, there have been recent changes in histopathological tumor type assignment [9], [10], [11]. Using contemporary histopathological criteria, type diagnosis is much more reproducible (kappa (k) = 0.77) than it was previously [6]. Tumor type is now appreciated to reflect different diseases, with type-specific risk factors, precursor lesions, molecular events during oncogenesis, biomarker expression, clinical behavior and response to chemotherapy [12], [13]. Tumor type-specific management has been suggested for ovarian carcinomas [14], as has been introduced for breast carcinomas [15]. Five tumor types account for 98% of ovarian carcinomas: high-grade serous, endometrioid, clear cell, mucinous and low-grade serous; the latter is a molecularly and clinically distinct ovarian carcinoma type, and not part of a continuum of disease with the more common high-grade serous carcinoma [16].
We hypothesized that tumor type could be used to identify patients with a low risk of death due to recurrent ovarian carcinoma (defined for the purpose of this study as a disease-specific survival at 10 years (DSS10y) ≥ 95%).
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Study population
The British Columbia Cancer Agency (BCCA) provides cancer care for British Columbia's population, now approximately 4.1 million. Between the years 1984 and 2003 a total of 2947 women were referred to the BCCA for ovarian cancer management of which 1326 were stage I–II carcinomas. All cases were requested and 652 cases (49%) were available for full slide review. Two expert gynecological pathologists (C.B.G. and M.K.) reviewed all slides blinded to patient outcome data. Tumor type and grade (
Results
The clinicopathological features of the cases studied are presented in Table 1. Mean patient age was 57.2 years (range 26.4–89.6 years). Follow-up time ranged from 26 months to 23.6 years, with a mean follow-up time for censored patients of 7.2 years. Two hundred sixteen patients died during follow-up and 139 of the 216 deaths were due to ovarian carcinoma. The Kaplan–Meier survival analyses showed a relapse-free survival (RFS) at 5 and 10 years of 72.4% and 66.6%, respectively, and DSS5y and
Discussion
We defined the study endpoint of excellent outcome as ≥ 95% DSS10y. Establishing risk thresholds above which no meaningful benefit from adjuvant therapy can be expected is controversial. In the early 1990s a risk of 20% seemed acceptable for avoiding adjuvant therapy [1], [20]. With the development of more tolerable therapy this threshold is now often set between 5 and 10%. In addition to results based upon our strict definition of excellent outcome [DSS10y ≥ 95%], we present results in a way
Disclosure statement
The authors declare no potential conflicts of interest.
Acknowledgments
M.K. has received fellowship support from Eli Lilly Canada. C.B.G. was supported by the National Cancer Institute of Canada (#017051) and an unrestricted educational grant from sanofi aventis. This work was supported by a unit grant to OvCaRe from the Michael Smith Foundation for Health Research (#INRUA005045). We thank Nhu Le, Anna Tinker and Paul Hoskins for critical review of the manuscript.
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Present address: Department of Pathology and Laboratory Services, University of Calgary, Calgary, Alberta, Canada.