Although ovarian cancer is the eighth most common malignancy in American women (12.8 per 100,000 women), it ranks as the fifth leading cancer mortality cause (8.6 per 100,000 women).1 In 2010, 21,880 new cases of ovarian cancer and 13,850 deaths were estimated.2 Ovarian cancer epidemiologic studies provide essential information for directing treatment. Accurate survival statistics offer patients an understanding of the disease nature and course and guide oncologists in counseling and management. Investigating survival over time also may identify trends and disease characteristics that have broad population-based implications. Therefore, identifying the best tools for measuring and evaluating ovarian cancer survival is paramount.
With advancements in ovarian cancer surgery and chemotherapy, the median survival of optimally cytoreduced patients is 62 months, providing evidence that many patients are alive beyond 5 years.3 These patients likely are living with disease recurrence rather than living cancer-free, and some oncologists consider ovarian cancer a chronic disease.4 Thus, 10-year survival estimates may provide prognostic information and may be a more appropriate endpoint for ovarian cancer.
There are several outcomes that describe survival. Disease-specific survival and overall survival, defined as the time elapsed from surgery or diagnosis to death from disease or from any cause, respectively, as survival parameters for ovarian cancer population-based research are problematic.5 Disease-specific survival is difficult to calculate because information on cause-of-death is often unreliable or unavailable.6 Overall survival approximates true survival and is consistent with relative survival in young populations because of lack of competing causes of death; however, in older populations such as those with ovarian cancer, the separation of cancer mortality from other causes becomes challenging.5 However, relative survival is a measure of excessive mortality and is defined by the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) group as “the ratio of proportion of observed survivors in a cohort of cancer patients to the proportion of expected survivors in a comparable set of cancer free individuals.”7 Unlike overall survival and disease-specific survival, relative survival accounts for death from intercurrent illness and adjusts for the general survival rate of the United States population (life expectancy) for the age, sex, race, and date at which the age was coded.7 Given the lack of data on 10-year ovarian cancer survival, the potential benefit of using the relative survival statistic compared with overall survival or disease-specific survival, and the importance of this information to patients and oncologists, we sought to estimate relative survival on population-based level.
MATERIALS AND METHODS
The SEER database from 1995 to 2007 was utilized for this analysis. Surveillance, Epidemiology, and End Results, a premier source for population-based cancer statistics in the United States, is a national cancer surveillance program within the National Cancer Institute that collects incidence, prevalence, and survival information from 17 SEER registries covering 28% of the United States population. Institutional Review Board exemption was obtained from the University of Kentucky Institutional Review Board before proceeding with the study. For this analysis, all epithelial ovarian cancer patients with diagnoses between 1995 and 2007 with primary invasive epithelial ovarian cancer who were actively followed-up and age 20 years or older were included. Death certificate or autopsy-only cases (1.5%) and alive cases with no follow-up information (0.9%) were excluded.
Tumors were staged using the third and sixth editions of the American Joint Committee on Cancer's Manual for Staging of Cancer for years 1995–2003 and 2004–2007, respectively.8,9 Major histology types were defined using the International Classification of Diseases O-3 codes (SEER Site Recode C569): serous (8050, 8260, 8441, 8442, 8450, 8460, 8461, 8462, 8463); endometrioid (8380, 8382, 8383); mucinous (8144, 8384, 8470, 8471, 8472, 8480, 8481, 8482); clear cell (8005, 8310, 8443); epithelial not otherwise specified (8140, 8255, 8323, 8440, 8452); and other epithelial including mixed histology (8010, 8020, 8052, 8070, 8071, 8072, 8074, 8084, 8120, 8122, 8130, 8490, 8560, 8570). Carcinosarcomas were excluded. The first course treatment was based on two variables: for years 1995–1997, codes for site-specific surgery with values 10–90 were categorized as surgery and 0–7 were categorized as no surgery; for year 1998–2007, codes for surgery at primary site surgery with values 25–90 were categorized as surgery and 0–17 were categorized as no surgery. Residence in urban or rural areas at the county level was categorized using 2003 Rural-Urban Continuum Codes as values 1–3 (metropolitan), which are considered urban, and 4–9 (nonmetropolitan), which are considered rural.
Relative survival is a ratio of the survival in cancer patients and the survival in a comparable set of cancer-free individuals. Relative survival was calculated using the Ederer I method by dividing the observed survival of cancer patients with the expected survival in a matched general United States female population of corresponding age, race, and calendar period.10 The actuarial life table method with monthly intervals was used to calculate annual relative survival over 10 years. Relative survival was estimated with stratification for clinical factors such as stage, type of first treatment (surgery compared with no surgery), and demographic factors such as age, race, and classification of residence (rural compared with urban) to identify factors associated with survival. Publicly available software SEER*Stat 6.5.23 was used to generate all statistics.
There were 40,692 patients who met inclusion criteria. The median age at diagnosis was 62 years, and the majority of patients were Caucasian (85%) and from urban communities (90%) (Table 1).
Forty-eight percent of patients were noted to have serous adenocarcinoma, and most patients had high-grade (36%) and advanced-stage disease (stage III, 39%; stage IV, 27%) (Table 2). Seventy-eight percent of patients were able to undergo primary surgery.
The relative survival rates across all stages for 2, 5, and 10 years were 65%, 44%, and 36%, respectively (Table 3). Thus, at 10 years from diagnosis, 36% of the patients in the entire cohort are still alive. Although less than 5-year survival, 10-year values reflect a reduced slope of decline in survival in years 5–10 as compared with years 1–5. The population was stratified by age, race, residence, and surgery as primary therapy. For all cases combined, advanced age and African American race were associated with decreased relative survival, whereas relative survival was comparable for those living in rural compared with urban areas. Across all stages, relative survival rates at 5 and 10 years were 53% and 42% for those who had surgery and 8% and 6% for those who did not. Note that for stage III disease, patients who were not able to undergo surgery as primary treatment have a 4.1% 10-year survival rate compared with 25% for those undergoing primary cytoreduction. Additionally, patients older than 75 years of age with stage III disease have 5-year and 10-year survival rates at least 5%–10% lower than their younger counterparts.
In an attempt to elucidate the effect of age, race, residence, and surgery as primary therapy, the analysis also was further stratified by stage (Table 4 and Fig. 1). Relative survival rates at 5 years were 89%, 70%, 36%, and 17% for stages I, II, III, and IV, respectively. The relative survival rates at 10 years were 84%, 59%, 23%, and 8% for stages I, II, III, and IV, respectively. Similar to the entire cohort, the reduced slope of decline in relative survival in years 5–10 as compared with years 1–5 also holds true when further stratified by stage. For example, although relative survival is poor at 5 years for stage III disease (decreasing from 100% at year 0 to 36% at year 5, a change of 64%), survival is only reduced another 13% at 10 years (from 36% to 23%). Similarly, for stage IV, a lower decline was noted between years 5 and 10 compared with years 1 and 5.
Survival in advanced ovarian cancer is poor and the majority of patients have advanced disease diagnosed. Although 75% of patients with advanced ovarian cancer will achieve clinical remission, the majority will experience relapse, progress, and die of disease, with 5-year survival approximately 30%.11 Limited information is available concerning relative survival in ovarian cancer at 10 years or otherwise. Recently, with advancements in treatment, ovarian cancer relapse for platinum-sensitive disease may be considered as a chronic disease with the potential for multiple remissions and relapses.4 Thus, 10-year relative survival in epithelial ovarian cancer provides significant prognostic information for patients who may be alive with disease at 5 years from diagnosis.
Evaluating 10-year survival using relative survival as the primary measure is advantageous compared with disease-specific survival or overall survival because it accounts for competing causes of death by adjusting for the general survival rate for that same age, race, and date of diagnosis. Markman et al12 described that the median overall survival for patients younger than 65 years exceeded 4 years, whereas those older than 65 had a median survival of 24 months. Given the median age of ovarian cancer diagnosis (63 years) and the competing risk of death from comorbidities, relative survival may be a better measure of survival;5,13 however, limited literature is available for 10-year survival rates in ovarian cancer as demonstrated by a complete MEDLINE search from 1948 to May 3, 2012, using the search terms “10-year, ” “ten-year,” “relative survival,” “survival,” “epithelial ovarian cancer,” and “ovarian cancer.” A Swedish study published in 2009 of 682 patients with epithelial ovarian cancer found a 10-year relative survival rate of 38.4%.14 Larger population-based analyses of 10-year relative survival in epithelial ovarian cancer have not been published in the English language or in United States populations.
One of the key findings in this report is the notable reduction in the slope of decline in survival during years 5–10 after diagnosis, as compared with years 1–5. For example, relative survival for stage III disease was poor at 5 years at 36%; however, the 10-year relative survival of 23% for stage III disease is higher than expected. This may be related to a number of factors, including more aggressive primary surgery,15,16 better therapy for primary3,17–20 and recurrent disease,21–23 and the appropriate use of secondary cytoreductive surgery at recurrence with two current ongoing clinical trials addressing this question (GOG-0213 and DESTOP III). Additionally, the data suggest that more patients than previously reported, although still a low number, may be salvaged after recurrence.23
The relative survival reduced slope of decline in years 5–10 after ovarian cancer diagnosis confirms 5-year survival as an important clinical endpoint. Whereas epithelial ovarian cancer has an overall poor prognosis, with marked decline in survival at 5 years for advanced-stage disease, those who survive past 5 years have reason to be more optimistic concerning their survival rates for the subsequent 5 years. The knowledge of improved relative survival after the 5-year point can provide important prognostic information for patients facing survivorship.24
In this study, patients undergoing primary cytoreductive surgery had drastically improved survival compared with those patients undergoing an alternative primary therapy. Across all stages, relative survival rates at 5 and 10 years were 53% and 42% for those who had surgery and 8% and 6% for those who did not. Given that this is a nonrandomized population-based study with uncontrollable SEER data limitations with confounding variables, we are cautious in interpreting these population-based results. It is possible the patients from the SEER database not undergoing primary debulking, the standard of care in this country during the years of study, reflect a high-risk population because of medical comorbidities, disease burden, or other factors related to poorer survival. Thus, we are unable to make further conclusions regarding the effectiveness of surgical compared with neoadjuvant treatment using these data. Recent prospective and randomized trials, including EORTC 55971, attempted to address this question. Although EORTC 55971 demonstrated that patients with extensive disease have similar survival (progression-free survival 12 months and overall survival 29–30 months), when administered neoadjuvant chemotherapy as compared with primary surgery25 the survival was similar to that of those with upfront suboptimal cytoreduction (progression-free survival 13–18 months and overall survival 24–38 months)18 and substantially worse than that of those with optimal debulking (progression-free survival 18–24 months and overall survival 50–66 months).3 It is difficult and statistically invalid to make comparisons between these trials with different study populations. Hence, the definitive best primary therapy, upfront cytoreduction or neoadjuvant chemotherapy, is still a central topic of much debate.
African American race was associated with a decreased relative survival at all stages in our research. Previous SEER studies also have identified a decreased overall survival and a 40% increased risk of not undergoing site-specific surgery for African American women with primary ovarian cancer as compared with Caucasians.26 In 2011, Bristow et al27 examined ovarian cancer patterns of care and race in women with stage IIIC epithelial ovarian cancer. This study was conducted at a tertiary care center and found that African American patients were as likely as Caucasian patients to undergo appropriate treatment with cytoreductive surgery and chemotherapy and suggested that equal access to high-level gynecologic oncology care at multidisciplinary tertiary care center can mitigate the survival difference between races.27 The SEER database alone cannot account for these factors and additional research is necessary to evaluate the relationship of race and ovarian cancer survival.
As in all SEER studies, our research strengths include the large population size and the ability to stratify based on age, race, stage, classification of residence, and surgery as primary therapy. Likewise, our study is limited by the inherent restrictions of a population-based database. Although all borderline tumors and all nonmalignant cases were excluded, the lack of pathologic validation in SEER could have led to misclassification of tumors. Disease stage in a large database such as SEER is dependent on the data present and could introduce bias because various participating institutions may not perform complete surgical staging. Additionally, because the study cut-off date is at the end of year 2007, only patients with diagnoses in years 1995–1997 were actively followed-up for more than 10 years. Whereas the survival rates at year 10 are less stable than the survival rates at year 5, adding data before 1995 could potentially significantly alter the outcome because this is approximately the same time that paclitaxel was integrated into ovarian cancer management.
We believe improved survival in our study reflects advances in both surgical and adjuvant therapy; however, population-based database research such as SEER does not allow testing of this hypothesis. It is possible that 10-year survivors also may represent a much different subset of patients regarding the natural history of disease. Future research comparing factors associated with 10-year survivors compared with less than 5-year survivors may provide some insight.
In summary, we demonstrate relative survival rates at 5 years (36%) are improved over historic reports of 5-year overall survival of 30%. We believe that the 10-year relative survival for stage III is higher than expected, providing patients and oncologists valuable prognostic information. Despite the potential costs, the inclusion of a 10-year endpoint in the future may be warranted to confirm or refute these findings.
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© 2012 The American College of Obstetricians and Gynecologists
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