Cervical cancer remains the most common cause of death related to gynecologic malignancies in reproductive-aged women in the United States.1 Early-stage disease generally has a favorable prognosis and cure is possible with either surgery or radiation.2 The standard surgical approach for early-stage cervical cancer is simple or radical hysterectomy with additional pelvic lymphadenectomy based on the tumor's stage.3,4
Generally, the risk of occult ovarian metastasis is low in early-stage cervical cancer.5–7 The National Comprehensive Cancer Network guideline, removal of the ovaries at hysterectomy for early-stage cervical cancer is considered “optional” after weighing risks and benefits, and evidence-based guidelines to define the criteria for ovarian conservation for women with early-stage cervical cancer are currently lacking.4 Adenocarcinoma histology increases the risk of ovarian metastasis8 and when present may deter the surgeon from conserving the ovaries. Although some argue that ovarian conservation is not recommended for adenocarcinomas, even among those with early-stage tumors, it has also been suggested that ovarian conservation is safe in women with adenocarcinomas.5–7
The benefits of ovarian conservation for young women with early-stage cervical cancer include both short-term and long-term aspects.9–12 In the long term, bilateral oophorectomy increases the risk for the development of osteoporosis and cardiovascular disease.9 The objectives of the study were to 1) examine characteristics of women who had ovarian conservation during hysterectomy for early-stage cervical cancer and 2) to examine survival among young women with early-stage cervical cancer who had ovarian conservation.
MATERIALS AND METHODS
The Surveillance, Epidemiology, and End Results Program is a population-based database launched in 1973 that is supported and managed by the National Cancer Institute in the United States.13 The registry data are abstracted and coded by cancer registrars who are trained by the National Cancer Registrars Association. Data quality is assured by the program through rigorous quality control studies and data assessments.13 This database covers approximately 27.8% of the U.S. population from 11 states and seven areas and is publicly available and deidentified. The University of Southern California institutional review board exempted this study from review because it uses deidentified publicly available data. SEER*Stat 8.2.1 was used to extract the data set (1983–2012).
Within the extracted data set, patients with stage I cervical cancer with known oophorectomy status were included in the study. Cervical sarcomas, metastatic tumors to the uterine cervix, and patients who received preoperative radiotherapy were excluded. Variables ascertained from the database were patient demographics, tumor information, treatment patterns, and survival outcomes. The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) publication guideline for observational studies was followed.14
Patient demographics included age and year at diagnosis, ethnicity, marital status, and registration area. Tumor information included cancer stage, histologic subtype, tumor grade, tumor size, and lymph node status. Recorded cancer stage was reclassified into American Joint Committee on Cancer 7th staging classification schema. The International Classification of Diseases for Oncology, 3rd Edition site/histology validation list and World Health Organization histologic classification were used for grouping histologic subtypes as shown in Appendix 1, available online at http://links.lww.com/AOG/A890. Treatment patterns included type of hysterectomy performed and postoperative radiotherapy.
Women with a surgical code for oophorectomy were classified as having undergone oophorectomy; those without a code for oophorectomy were considered to have had ovarian conservation. If the surgical codes did not specify oophorectomy status, these cases were considered as unknown oophorectomy status. Survival data, including cause-specific survival and all-cause mortality (overall survival), are collected through linkages with state mortality records and the National Death Index.13 Cervical cancer–specific survival was defined as the time interval between the initial cervical cancer diagnosis and the date of death resulting from cervical cancer. Overall survival was defined as the time interval between the initial cervical cancer diagnosis and date of death from any reason. Among women who died, causes of death were examined (cervical cancer, other malignancy, cardiovascular disease, and other chronic disease) and grouped as previously described.15,16
The primary objective of the analysis was to examine characteristics and trends in ovarian conservation for stage I cervical cancer. The secondary objective was to examine survival among women younger than 50 years of age with stage I cervical cancer who underwent ovarian conservation and received no radiotherapy. This age cutoff was chosen based on the mean age of spontaneous menopause in the North American population.17 Women who had ovarian conservation were compared with those who underwent oophorectomy.
The statistical significance of age at diagnosis was assessed by Student t test. Ordinal and categorical variables were examined with χ2 tests. Binary logistic regression models were used for multivariable analysis to determine independent factors associated with ovarian conservation, and the magnitude of statistical significance was expressed with odds ratio (OR) and 95% confidence interval (CI). Patient demographics, tumor factors, and treatment patterns were entered in the final model.
Joinpoint Regression Program 22.214.171.124 was obtained from the National Cancer Institute and used to evaluate temporal and age-related trends in use of ovarian conservation.18 Frequencies of ovarian conservation modeled as a function of calendar year and patient age using a piecewise linear regression after log transformation. The presence of inflection points, which was interpreted as a change in trend, was determined using the permutation test.19
The Kaplan-Meier method was used to construct survival and cumulative risk curves, and statistical significance between the curves was compared with log-rank tests. Survival was also examined using Cox proportional hazard regression models, and the magnitude of statistical significance was expressed with hazard ratio (HR) and 95% CI. Covariates entered in the final model were patient demographics, tumor factors, and treatment patterns.
Because mortality rates in young women with early-stage cervical cancer are generally low, there is a potential chance that the event numbers may be small and multivariable models may not adequately adjust the baseline difference resulting in overfitting. To overcome this limitation, we additionally performed a propensity score matching as the alternative corroboration to examine the association of ovarian conservation and survival.
Propensity score for ovarian conservation was computed for each case determined by multivariable logistic regression analysis. Patient demographics, tumor characteristics, and treatment pattern were entered in the propensity score model. One-to-one propensity score matching between the ovarian conservation group and the oophorectomy group was performed through an automated algorithm with the propensity score difference cutoff being 1%.
The variance inflation factor was determined among covariates in multivariable analysis, and a value of 2.0 or greater was interpreted as multicollinearity. A P<.05 was considered statistical significant (two-tailed). SPSS 22.0 was used for the analysis.
The patient selection criteria are shown in Fig. 1. Among 16,511 women with stage I cervical cancer who underwent hysterectomy, 5,014 (30.4%) had ovarian conservation and 11,497 (69.6%) underwent oophorectomy. The characteristics associated with ovarian conservation are shown in Tables 1 and 2.
Younger women were more likely to have ovarian conservation (age younger than 40 years 50.5%, 40–49 years 26.3%, and 50 years or older 9.5%, P<.001). When a trend analysis was performed (Fig. 2A), the frequency of ovarian conservation declined significantly with each additional year of age (percentage change per year 12.7, 95% CI 10.3–15.0, P<.001) between age 39 and 53 years. The age-dependent decline in the frequency of ovarian conservation reached a nadir at age 53 years. Over this age interval, the frequency of ovarian conservation declined from 43.3% (95% CI 40.2–46.4) at age 39 years to 6.0% (95% CI 4.5–7.5) at age 53 years (risk difference 37.3%, 95% CI 35.7–38.9).
The frequency of ovarian conservation slightly increased between 1983 and 2012 among women younger than 50 years of age with stage IA disease (annual percent change 0.6, 95% CI 0.14–1.09, P=.013; Fig. 2B), reaching 57.2% (95% CI 54.1–60.3) in 2012. For stage IB disease in women younger than 50 years of age, the frequency of ovarian conservation significantly increased between 1983 and 1998 (annual percent change 14.6, 95% CI 10.5–18.9, P<.001) and reached a plateau after 1998 (P=.11). An increasing frequency of ovarian conservation was also seen among women younger than 50 years of age with stage I adenocarcinoma histology between 1985 and 1999 (annual percent change 10.0, 95% CI 6.2–13.9, P<.001) that was higher than that for women with squamous histology between 1983 and 1999 (annual percent change 4.4, 95% CI 2.6–6.3, P<.001; Fig. 3).
In a multivariable analysis of factors associated with ovarian conservation, women 40–49 years of age (adjusted OR 3.79, 95% CI 3.37–4.27, P<.001) and younger than 40 years of age (adjusted OR 16.8, 95% CI 14.0–18.9, P<.001) were more likely to have ovarian conservation compared with women older than 50 years of age (Table 2). Those with stage IA disease were more likely to have ovarian conservation (adjusted OR 1.39, 95% CI 1.24–1.56, P<.001) compared with stage IB disease. Among the histologic subtypes, those with squamous histology were most likely to have ovarian conservation (adjusted OR 1.41, 95% CI 1.26–1.58, P<.001) compared with adenocarcinoma type. Among women younger than 50 years of age, the patients with stage IB disease were more likely to have adenocarcinoma or adenosquamous histology and undergo radical hysterectomy when compared with patients with stage IA disease (both, P<.001; Appendix 2, available online at http://links.lww.com/AOG/A890).
In a subgroup of 9,419 women younger than 50 years of age with stage IA–B cervical cancer who underwent hysterectomy without radiotherapy, 3,908 (41.5%) women had ovarian conservation (Fig. 1). Among 5,526 women younger than 50 years of age with stage IA disease who underwent hysterectomy without radiotherapy, ovarian conservation was used in 2,936 (53.1%, 95% CI 51.8–54.4) patients. In this subgroup, the median follow-up was 10.3 years for the patients undergoing ovarian conservation and 11.7 years for those undergoing oophorectomy. There were 1,068 (19.3%) women who had a follow-up longer than 10 years. Patient ages at cervical cancer diagnosis among women who had long-term follow-up in the two groups are shown in Appendix 3, available online at http://links.lww.com/AOG/A890. Patient demographics were compared between patients undergoing ovarian conservation and those undergoing oophorectomy (Table 3).
Women who underwent ovarian conservation were more often younger, Hispanic, single, residents of the western United States, had stage IA1 disease, had squamous histology, and were less likely to undergo radical hysterectomy (all, P<.01). On univariable analysis, ovarian conservation was not associated with cervical cancer–specific survival compared with oophorectomy (20-year survival rates 98.8% compared with 97.8%, P=.12; Fig. 4A). In contrast, ovarian conservation was significantly associated with improved overall survival (93.5% compared with 86.8%, HR 0.54, 95% CI 0.43–0.68, P<.001; Fig. 4B). On multivariable analysis (Table 4), ovarian conservation remained an independent prognostic factor for improved overall survival among women younger than 50 years of age with stage IA cervical cancer who underwent hysterectomy. (adjusted HR 0.63, 95% CI 0.49–0.82, P=.001).
Patterns of death were examined in women younger than 50 years of age with stage IA disease who underwent hysterectomy (Appendix 4, available online at http://links.lww.com/AOG/A890). There were a total of 346 (6.3%) deaths noted. Death resulting from cervical cancer, cardiovascular disease, and other chronic disease was reported in 61, 64, and 26 patients, respectively. Ovarian conservation was significantly associated with a decreased cumulative risk of death resulting from cardiovascular disease (20-year rates 1.2% compared with 3.3%, HR 0.38, 95% CI 0.22–0.65, P<.001; Fig. 4C) and death attributable to other chronic disease (0.5% compared with 1.4%, HR 0.29, 95% CI 0.12–0.73, P=.005; Fig. 4D). On multivariable analysis controlling for patient demographics, tumor factors, and treatment patterns (Table 4), ovarian conservation remained an independent predictor for decreased risk of death from cardiovascular disease (adjusted HR 0.47, 95% CI 0.26–0.86, P=.014) and death from another chronic disease (adjusted HR 0.24, 95% CI 0.09–0.65, P=.005) among women younger than 50 years of age with stage IA cervical cancer.
Patient demographics were compared between patients undergoing ovarian conservation and those undergoing oophorectomy among women younger than 50 years of age with stage IB cervical cancer (n=3,893; Appendix 5, available online at http://links.lww.com/AOG/A890). Median follow-up was 8.0 years for the ovarian conservation group and 15.8 years for the oophorectomy group. There were 985 (25.3%) women who had a follow-up longer than 10 years. There were 455 (11.7%) deaths recorded in this group. On univariable analysis, ovarian conservation was not associated with cervical cancer–specific survival (20-year rate 93.1% compared with 92.0%, P=.37; Fig. 4E), overall survival (86.7% compared with 84.6%, P=.12; Fig. 4F) or cumulative risk of cardiovascular death (0.7% compared with 1.1%, P=.32).
Prognostic factors for cervical cancer–specific survival were examined for 765 women younger than 50 years of age with stage I cervical cancer with adenocarcinoma histology who underwent ovarian conservation at hysterectomy without postoperative radiotherapy compared with 2,950 patients with squamous histology (Appendices 6 and 7, available online at http://links.lww.com/AOG/A890). Women with adenocarcinoma histology were more likely to have stage IB disease and lower grade tumors (both, P<.001). On multivariable analysis, adenocarcinoma histology was not associated with increased cervical cancer–specific mortality compared with squamous type (P=.55). Among patients with stage IB disease, there was no difference in cervical cancer–specific survival rates between adenocarcinoma and squamous types (P=.55). In this subgroup, women with high substage (stage IB, adjusted HR 4.05, 95% CI 2.27–7.24, P<.001) and grade 3 tumors (adjusted HR 3.12, 95% CI 1.21–8.01, P=.02) remained at increased risks for decreased cervical cancer–specific survival.
Results of the propensity score matching for women younger than 50 years of age with stage IA disease who received no radiotherapy after surgery between the ovarian conservation group and the oophorectomy group are shown in Appendix 8, available online at http://links.lww.com/AOG/A890 (n=3,072). Postmatching patient demographics, tumor characteristics, and treatment patterns were similar between the two groups (all, P>.05).
After matching, the ovarian conservation group had significantly higher 20-year overall survival rates (91.3% compared with 85.7%, HR 0.66, 95% CI 0.49–0.88, P=.005) but had similar cervical cancer–specific survival rates (98.5% compared with 97.5%, HR 0.76, 95% CI 0.39–1.48, P=.42) compared with the oophorectomy group (Appendix 9, panels A–B, available online at http://links.lww.com/AOG/A890). Similarly, 20-year cumulative death rates from cardiovascular disease (2.0% compared with 4.1%, HR 0.53, 95% CI 0.28–0.99, P=.043) and from other chronic diseases (0.7% compared with 1.9%, HR 0.30, 95% CI 0.10–0.91, P=.024) were significantly lower in the ovarian conservation group compared with the oophorectomy group (Appendix 9, panels C–D, available online at http://links.lww.com/AOG/A890).
After propensity score matching, overall survival and cumulative risks of death from cardiovascular disease or another chronic disease were similar between the ovarian conservation group and the oophorectomy group in women younger than 50 years of age with stage IB disease (data not shown).
Key findings of this study are that ovarian conservation was associated with improved long-term overall survival and decreased mortality from cardiovascular and other chronic diseases without increasing mortality from cervical cancer among young women with stage IA tumors.
Unlike young women with early-stage endometrial cancer for whom the frequency of ovarian conservation at surgical treatment remains low,20,21 young women with early-stage cervical cancer had a high frequency of ovarian conservation that has increased steadily over the past decade, reaching nearly 60% for stage IA disease. This is likely based on the rationale that cervical cancer is generally ovarian hormone-insensitive and the rate of ovarian metastasis from cervical cancer is low.7,22
Our study supports recent population-based studies demonstrating the association of early oophorectomy and increased mortality.23,24 As has also been suggested in prior works, surgical menopause in young women is associated with increased risk of cardiovascular disease.9,25 This theory is supported by a study that demonstrated an increased risk of postoperative nonalcoholic fatty liver disease that was associated with postoperative development of metabolic syndrome after early surgical menopause.10 Metabolic syndrome leads to subclinical atherosclerotic vascular changes resulting in increased risk of clinical cardiovascular disease in the long term.26
Our study also demonstrated that ovarian conservation in young women with early-stage cervical cancer was associated with a lower risk of death from other chronic diseases. The effects of estrogen on women's health include not only cardiovascular protection, but also bone health and neuroprotection.27–29 Because this data set does not have specific information about timing of onset and incidence of other ovarian hormone-related diseases such as bone fractures and cognitive disease, additional studies to examine these complications in women with cervical cancer will be of interest.
Historically, cervical adenocarcinoma has been reported to have a higher rate of ovarian metastasis compared with squamous type.8 This is particularly concerning in young women because cervical adenocarcinoma is associated with younger age and early-stage disease in which surgical treatment plays a pivotal role in management.30 Therefore, our results are reassuring and support prior studies describing the safety of ovarian conservation even in early-stage adenocarcinoma with absence of risk factors.5,8,31
Our study showed that the association of ovarian conservation and overall survival was not seen in women with stage IB disease. It is speculated that differences in patient characteristics, tumor factors, and treatment patterns in this subgroup compared with the stage IA group might lead to differences in ovarian function after surgery. For instance, women with stage IB neoplasms were more likely to undergo radical hysterectomy that is likely to diminish ovarian function sooner after surgery compared with simple hysterectomy.32 Additionally, ovarian conservation in stage IB disease was uncommon until the late 1990s, which resulted in a short follow-up and small sample size in this group. Because cardiovascular events generally take a long period of time to develop,26 nonsignificant results for survival analysis in patients with stage IB in our study may be the result of lead time bias.
Recent studies have demonstrated that even hysterectomy can reduce ovarian function in premenopausal women.33,34 For early-stage cervical cancer, cancer-specific survival was similar between therapeutic cervical conization and total hysterectomy.35 Therefore, to maximize the effects of estrogen on long-term health and survival, cervical conization with pelvic lymphadenectomy may possibly be an attractive approach in young women with early-stage cervical cancer [Studying the physical function and quality of life before and after surgery in patients with stage I cervical cancer. ClinicalTrials.gov, NCT01649089].
We recognize several important limitations. First, we lack data on why the decision to perform oophorectomy or to offer ovarian conservation was made; thus, our findings are susceptible to selection bias. Those women who had ovarian conservation are potentially healthier and may have had a better performance status. Similarly, women who underwent ovarian conservation to retain ovarian function may be more proactive in general health aspects. Second, we cannot exclude the possibility that a small number of women had previously undergone oophorectomy and thus may have been misclassified. Third, we are unable to perform complete risk adjustment. Numerous factors such as postoperative hormone therapy, smoking status, dyslipidemia, and hypertension are associated with the development of cardiovascular disease and another chronic disease that is not captured in the data set. Fourth, this database does not have information for chemotherapy, which can alter ovarian function. Strengths of the study include large sample size and long-term follow-up with validated mortality records.
Because long-term survival is possible in young women with early-stage cervical cancer, treatment planning needs to consider long-term health issues in this population. Oncologists are recommended to discuss risks and benefits of ovarian conservation when surgical treatment is planned for young women with early-stage cervical cancer for both squamous and adenocarcinoma types. In light of the negative health effect of loss of ovarian function, it is important for the practitioner caring for a young woman with a history of hysterectomy for cervical cancer to determine whether oophorectomy was performed and whether the patient is in menopause to guide counseling in regard to hormone therapy.
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