Abstract
Background:
Relatively little is known about factors associated with long-term survival (LTS) following a diagnosis of ovarian cancer.
Methods:
We conducted a retrospective study of high-grade serous ovarian cancer (HGSOC) to explore predictors of LTS (defined as ≥ 7 years of survival) using electronic medical record data from a network of integrated health care systems. Multivariable logistic regression with forward-selection was used to compare characteristics of women who survived ≥7 years after diagnosis (n=148) to those who died within 7 years of diagnosis (n=494).
Results:
Our final model included study site, age, stage at diagnosis, CA-125, comorbidity score, receipt of chemotherapy, BMI, and four separate comorbid conditions: weight loss, depression, hypothyroidism and liver disease. Of these, only younger age, lower stage, and depression were statistically significantly associated with LTS.
Conclusions:
We did not identify any new characteristics associated with HGSOC survival.
Impact:
Prognosis of ovarian cancer generally remains poor. Large, pooled studies of ovarian cancer are needed to identify characteristics that may improve survival.
Introduction
Despite intense study, relatively little is known about factors associated with long term survival (LTS) from ovarian cancer1. Ovarian cancer is rare and survival is poor (47% 5-year survival).2 These characteristics make it difficult to study in a single institution or cohort. We conducted a retrospective observational study of high-grade serous ovarian cancer (HGSOC) to explore predictors of LTS, using data from five integrated health systems in the Cancer Research Network (CRN, https://crn.cancer.gov).3
Materials and Methods
All data for this analysis were derived from the Virtual Data Warehouse (VDW), a common data model which includes standardized, individual-level data extracted from the electronic medical record from the participating sites.4 We identified all incident cases of ovarian cancer diagnosed between 2000–2008 at five integrated health systems affiliated with the CRN: Health Partners (Minnesota), and four Kaiser Permanente regions: Colorado, Northern California, Northwest, and Washington state. This study received Institutional Review Board approval and a waiver of informed consent.
We limited this analysis to cases of incident high-grade (grade 3 or 4) serous (morphology codes between 8440 and 8490) ovarian cancer, stages I-IV. We defined LTS as survival ≥ 7 years and used the VDW to follow patients through December 31, 2015 for death, disenrollment, or end of follow-up. Cases were included if they were age 18 years or older at diagnosis and enrolled continuously with a drug coverage in their health care plan for at least 1 year prior to diagnosis. Cases were excluded if they were known to be alive but disenrolled before 7 years of follow-up.
Logistic regression was employed to model associations between covariates and the outcome of LTS. All covariates were assessed in the year prior to diagnosis. We used forward-selection to build the model and retained all variables with a p-value < 0.3. We decided a priori that age, stage, and CA-125 level at diagnosis would be in the final model as these factors have been previously reported to be associated with survival among ovarian cancer cases.5,6 We computed the Elixhauser comorbidity score7 for each case and included individual components of the score in the model-building process if at least 20 patients had the condition. All analyses were conducted using SAS/STAT software, Version 9.4 (SAS Institute Inc., Cary, NC, USA). We conducted a post-hoc power calculation for our study. We had 80% power, using a two-sided test with an α = 0.05, to detect an OR >1.6 with one primary predictor. Power calculations were performed in PASS.
Results
We identified 2,388 incident stage I-IV ovarian cancers. Of these, we excluded 298 patients who were not enrolled at least 1 year prior to diagnosis with a drug coverage benefit, and 160 who did not have a record of death and were not continuously enrolled at least 7 years post diagnosis. There were an additional 1,288 cancers that were not high-grade serous tumors, of those, 62% (n=578) were missing information to classify the tumor grade. This left a total of 642 high-grade serous ovarian cancers for analysis.
Table 1 shows the characteristics that were considered for inclusion in the logistic regression model. The median survival time was 38 months (95% confidence interval (CI): 35 – 42 months); 148 (23%) survived at least 7 years and were considered long-term survivors, while the remainder (N=494, 77%) survived fewer than 7 years. Our final logistic regression model included study site, age, stage at diagnosis, CA-125 (categorized as <35 or ≥35 units/ml), comorbidity score (categorized as 0, 1, 2 or ≥3), receipt of chemotherapy, body mass index (BMI, in categories), and four separate comorbid conditions: weight loss, depression, hypothyroidism and liver disease (see Figure 1 for odd ratios (OR) and 95% confidence intervals (CI)). Information on BMI and smoking status were missing on approximately half of the population. Patients diagnosed at an earlier stage had statistically significantly higher odds of LTS than patients diagnosed at a later stage (p<0.0001). Younger patients were statistically more likely to survive than older patients (p=0.009), and a diagnosis of depression within the year prior to a cancer diagnosis was inversely associated with LTS (p=0.011). Our final model had a c-statistic of 0.806 suggesting a strong model fit.
Table 1.
Characteristics of ovarian cancer cases at five Cancer Research Network sites stratified by survival time.
| Characteristic | All (n=642) |
Survived < 7 years (n=494) |
Survived ≥7 years (n= 148) |
p- value1 |
|---|---|---|---|---|
| CRN Site | ||||
| Site 1 | 7 (1.1%) | 5 (1%) | 2 (1.4%) | 0.070 |
| Site 2 | 54 (8.4%) | 48 (9.7%) | 6 (4.1%) | |
| Site 3 | 68 (10.6%) | 47 (9.5%) | 21 (14.2%) | |
| Site 4 | 442 (68.8%) | 335 (67.8%) | 107 (72.3%) | |
| Site 5 | 71 (11.1%) | 59 (11.9%) | 12 (8.1%) | |
| Race/Ethnicity | ||||
| Non-Hispanic white | 504 (78.5%) | 391 (81.1%) | 113 (76.9%) | 0.392 |
| Hispanic | 62 (9.7%) | 46 (9.5%) | 16 (10.9%) | |
| Non-Hispanic Asian | 36 (5.6%) | 27 (5.6%) | 9 (6.1%) | |
| Non-Hispanic black | 24 (3.7%) | 15 (3.1%) | 9 (6.1%) | |
| Other/multi, non-Hispanic | 3 (0.5%) | 3 (0.6%) | 0 (0%) | |
| Missing2 | 13 (2%) | |||
| Age at diagnosis (years) | ||||
| 18–49 | 73 (11.4%) | 48 (9.7%) | 25 (16.9%) | <0.001 |
| 50–59 | 182 (28.3%) | 129 (26.1%) | 53 (35.8%) | |
| 60–69 | 190 (29.6%) | 145 (29.4%) | 45 (30.4%) | |
| ≥70 | 197 (30.7%) | 172 (34.8%) | 25 (16.9%) | |
| Smoking Status | ||||
| Current | 44 (6.9%) | 33 (16%) | 11 (15.5%) | 0.410 |
| Former | 66 (10.3%) | 53 (25.7%) | 13 (18.3%) | |
| Never/Passive | 167 (26%) | 120 (58.3%) | 47 (66.2%) | |
| Missing2 | 365 (56.9%) | |||
| BMI Group (kg/m2) | ||||
| Underweight/Normal (BMI=13.0–24.9) | 129 (20.1%) | 93 (38.9%) | 36 (47.4%) | 0.289 |
| Overweight (BMI=25.0–29.9) | 91 (14.2%) | 74 (31%) | 17 (22.4%) | |
| Obese (BMI≥30.0) | 95 (14.8%) | 72 (30.1%) | 23 (30.3%) | |
| Missing2 | 327 (50.9%) | |||
| AJCC Stage at diagnosis | ||||
| Stage I | 45 (7.0%) | 15 (3.0%) | 30 (20.3%) | <0.001 |
| Stage II | 38 (5.9%) | 20 (4.0%) | 18 (12.2%) | |
| Stage III | 363 (56.5%) | 276 (55.9%) | 87 (58.8%) | |
| Stage IV | 196 (30.5%) | 183 (37%) | 13 (8.8%) | |
| Grade | ||||
| 3 | 516 (80.4%) | 402 (81.4%) | 114 (77%) | 0.243 |
| 4 | 126 (19.6%) | 92 (18.6%) | 34 (23%) | |
| Received chemotherapy treatment | ||||
| Yes | 573 (89.3%) | 434 (89.1%) | 139 (93.9%) | |
| No | 62 (9.7%) | 53 (10.9%) | 9 (6.1%) | 0.085 |
| Missing2 | 7 (1.1%) | |||
| CA-125 Prior to Treatment | ||||
| CA 125 < 35 (U/mL) | 58 (9%) | 34 (8.1%) | 24 (17.8%) | 0.001 |
| CA 125 ≥ 35 (U/mL) | 499 (77.7%) | 388 (91.9%) | 111 (82.2%) | |
| Missing2 | 85 (13.2%) | |||
| Estrogen use | ||||
| ≥2 pharmacy fills for systemic Estrogen in year prior to diagnosis | 173 (26.9%) | 135 (27.3%) | 38 (25.7%) | 0.691 |
| ≥2 pharmacy fills for non-systemic vaginal estrogen in year prior to diagnosis | 27 (4.2%) | 22 (4.5%) | 5 (3.4%) | 0.568 |
| Private pay insurance plan | ||||
| Yes | 166 (25.9%) | 136 (27.8%) | 30 (20.5%) | |
| No | 469 (73.1%) | 353 (72.2%) | 116 (79.5%) | 0.080 |
| Missing2 | 7 (1.1%) | |||
| Commercial insurance plan | ||||
| Yes | 550 (85.7%) | 415 (84.3%) | 135 (91.8%) | |
| No | 89 (13.9%) | 77 (15.7%) | 12 (8.2%) | 0.021 |
| Missing2 | 3 (0.5%) | |||
| Elixhauser score in the year prior to diagnosis | ||||
| 0 | 150 (23.4%) | 113 (22.9%) | 37 (25%) | 0.054 |
| 1 | 175 (27.3%) | 125 (25.3%) | 50 (33.8%) | |
| 2 | 130 (20.2%) | 100 (20.2%) | 30 (20.3%) | |
| ≥ 3 | 187 (29.1%) | 156 (31.6%) | 31 (20.9%) | |
| Individual Elixhauser-scored conditions where n≥20 | ||||
| Arrhythmia | 55 (8.6%) | 47 (9.5%) | 8 (5.4%) | 0.117 |
| Congestive Heart Failure | 24 (3.7%) | 22 (4.5%) | 2 (1.4%) | 0.081 |
| Chronic Pulmonary Disease | 109 (17%) | 84 (17%) | 25 (16.9%) | 0.975 |
| Depression | 91 (14.2%) | 76 (15.4%) | 15 (10.1%) | 0.108 |
| Diabetes | 72 (11.2%) | 61 (12.3%) | 11 (7.4%) | 0.096 |
| Drug abuse | 25 (3.9%) | 19 (3.8%) | 6 (4.1%) | 0.909 |
| Fluid and Electrolyte Disorders | 57 (8.9%) | 50 (10.1%) | 7 (4.7%) | 0.043 |
| Hypertension | 265 (41.3%) | 207 (41.9%) | 58 (39.2%) | 0.556 |
| Hypothyroidism | 96 (15%) | 83 (16.8%) | 13 (8.8%) | 0.016 |
| Liver disease | 22 (3.4%) | 21 (4.3%) | 1 (0.7%) | 0.036 |
| Weight loss | 39 (6.1%) | 36 (7.3%) | 3 (2.0%) | 0.019 |
Chi-square p-value
Missing values not included in statistical calculations of chi-square tests. All categories include missing for “all” group only.
Figure 1.
Adjusted odds ratios contains multivariable adjusted odds ratios and 95% confidence intervals for factors associated with long term survival of incident high-grade serous ovarian cancer.
Discussion
In this exploratory analysis using electronic medical record data, we did not identify any new medical conditions or characteristics that may be associated with LTS of HGSOC. Others8 have reported on comorbidities associated with ovarian cancer survival with mixed results. The strengths of this study include a rich data resource of an insured population that allows for detailed capture of comorbidities, treatment and follow-up. However, we lacked information on BMI and smoking status on a large proportion of the study population. We had no data on family history or genetic susceptibility which would have strengthened our analysis.
Grant Support:
This work was conducted in the Cancer Research Network(CRN) funded by the NCI (U24CA171524).
M.M. Epstein received additional support by a grant from The University of Massachusetts Center for Clinical and Translational Science (KL2TR01455).
C.L. Pearce received grant funding from the NCI (P30 CA046592).
Abbreviations:
- BMI
body mass index
- CI
confidence interval
- CRN
Cancer Research Network
- HGSOC
high-grade serous ovarian cancer
- LTS
long term survival
- OR
odds ratio
- VDW
virtual data warehouse
Footnotes
Conflict of Interest Statement: The authors declare no potential conflicts of interest.
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