Association of Guideline-Concordant Care With Survival, Health Care Utilization, and Costs Among Older Women With Advanced Epithelial Ovarian Cancer

ABSTRACT

Objectives: To examine guideline-concordant care (GCC) for ovarian cancer, identify its predictors, and evaluate the associations between GCC and survival, health care expenditures, and utilization.

Study Design: A retrospective cohort study using Surveillance, Epidemiology, and End Results–Medicare data.

Methods: Women aged 66 to 90 years who received a diagnosis of stage II or higher epithelial ovarian cancer during 2011-2015 were included (N = 3237). The National Comprehensive Cancer Network clinical practice guidelines were used to identify GCC. Logistic regression was conducted to identify predictors of GCC, a Cox proportional hazards model was used to examine mortality, and generalized linear models were used to examine mean monthly Medicare expenditures and health care utilization.

Results: Approximately 57% of women received GCC and 11.6% of women did not receive any cancer-specific treatment. Women who were relatively older (adjusted odds ratio [AOR], 0.272; 95% CI, 0.210-0.351), had Census tract income of $50,000 or less (AOR, 0.709; 95% CI, 0.551-0.913), had a psychiatric condition (AOR, 0.655; 95% CI, 0.464-0.923), and had adenocarcinoma histology (AOR, 0.564; 95% CI, 0.441-0.721) were significantly less likely to receive GCC. Race/ethnicity was not found to be a significant predictor of GCC. Women who received surgery only or chemotherapy only had a significant higher hazard of all-cause mortality and ovarian cancer–specific mortality compared with those who received GCC (surgery only: adjusted HR [AHR], 2.307; chemotherapy only: AHR, 1.802). Receiving chemotherapy only was associated with 45% (P < .0001) higher mean monthly expenditures compared with those who received GCC.

Conclusions: Non-GCC was associated with worsened survival, higher health care utilization, and increased expenditures. It is important to highlight that women who received GCC were associated with better survival likely due to favorable prognostic clinical factors.

Am J Manag Care. 2023;29(10):e292-e298. https://doi.org/10.37765/ajmc.2023.89443

Takeaway Points

Non–guideline-concordant care for ovarian cancer was associated with higher all-cause and cancer-specific mortality, increased health care utilization, and increased Medicare expenditures, highlighting opportunities for improving cancer care in this vulnerable group.

• Older studies show that less than half of patients with ovarian cancer received treatment as per guidelines.
• Approximately 57% of the older women with advanced epithelial cancer in our study received treatment as per the National Comprehensive Cancer Network guidelines.
• Women 75 years and older with advanced stages of cancer, adenocarcinoma histology subtype, and/or preexisting psychiatric conditions were less likely to receive guideline-concordant care.

Epithelial ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related deaths among women in the United States.¹ Approximately 57% of cases of ovarian cancer are diagnosed at an advanced stage.² Advancements in ovarian cancer treatment over the past few decades have reduced the mortality risk by 23%.³

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend a combination of surgical staging and cytoreductive surgery, with adjuvant/neoadjuvant chemotherapy for advanced epithelial ovarian cancers.⁴ Older studies show that less than half of patients with ovarian cancer received treatment per guidelines.^5-8 Furthermore, Black-White racial disparities existed in receiving guideline-concordant care (GCC).⁹ These studies, however, used data on cancer cases diagnosed before 2010, and hence do not represent the current trends in ovarian cancer treatment. One study included cases diagnosed during 2002-2011 and identified that 56% of women received GCC.¹⁰ Non-GCC is associated with decreased survival.^8,10,11 However, a dearth of recent literature examines whether GCC is associated with lower health care utilization and expenditures among women with advanced epithelial ovarian cancer.

Several studies of GCC in women with advanced epithelial ovarian cancer included covariates such as age,^5-10,12 socioeconomic characteristics,^6-8,10-12 comorbidities,^7,10-12 and cancer-related characteristics.^8-11 Importantly, none of these studies controlled for performance status (PS), which is a score that estimates patients’ ability to independently perform certain activities of daily living. PS is a critical indicator for treatment decisions in patients with advanced cancer and for predicting health outcomes.¹³ Other factors such as health care access, including availability of oncology hospitals and gynecologic oncologists in the area of a patient’s residence, were not controlled for in the prior studies. Poor access to care can adversely affect receipt of optimal cancer care and treatment outcomes, particularly for those with advanced disease.¹⁴

We examined GCC for older women who received a diagnosis of advanced epithelial ovarian cancer during 2011-2015 using Surveillance, Epidemiology, and End Results (SEER)–Medicare data. We further sought to identify predictors for GCC and to evaluate the associations between GCC and (1) survival, (2) Medicare expenditures, and (3) health care resource utilization.

MATERIALS AND METHODS

Study Design and Data Source

A longitudinal retrospective cohort study was conducted using the SEER-Medicare linked database.¹⁵ This data set was further linked with the Area Health Resource File using state- and county-level information to obtain Census tract data on income, education, number of hospitals offering oncology services, and number of gynecologists in subspecialty (eg, gynecological oncology, hospice and palliative medicine [obstetric and gynecological], reproductive endocrinology).¹⁶

Study Cohort

We included women aged 66 to 90 years who received a diagnosis of epithelial ovarian cancer as their first pathologically confirmed tumor from January 1, 2011, through December 31, 2015; were enrolled in the Medicare fee-for-service program; and had advanced-stage disease (stage II-stage IV) as classified by the American Joint Committee on Cancer AJCC Cancer Staging Manual, Seventh Edition.¹⁷ We required women to have continuous enrollment in Medicare Parts A and B 12 months prior to cancer diagnosis and at least 6 months following cancer diagnosis or until the end of the enrollment period or death, whichever came first. Women who received a diagnosis of ovarian cancer at autopsy or on a death certificate and those with missing information on cancer stage were excluded.

GCC

Guideline-concordant primary treatment for advanced epithelial ovarian cancer was determined based on NCCN guidelines.4 All versions of these guidelines for each year during 2011-2015 were used to identify the recommended primary treatment strategies for epithelial ovarian cancer. For patients with stage II to IV epithelial ovarian cancer, the NCCN guidelines recommend surgical staging, cytoreductive surgery, and multiagent chemotherapy, including a platinum agent and a taxane as primary treatment.

Women were determined to have received GCC if they were treated in accordance with both surgical and chemotherapy guidelines. Surgery and chemotherapy were identified from Medicare claims using the respective billing codes (eAppendix Table 1 [eAppendix available at ajmc.com]).

We created a dichotomous variable categorized as GCC and non-GCC as well as a multinomial variable categorized as (1) surgery and chemotherapy (GCC), (2) surgery only, (3) chemotherapy only, and (4) no treatment. In the preliminary analysis, we found that only 11.6% of the eligible study cohort received no treatment; they had a short median survival of 2.4 months and were not included in the further multivariable regression analyses to identify the predictors of GCC and to evaluate the associations of GCC with survival and utilization.

Survival

Survival was assessed as the time in days from the date of cancer diagnosis until death, end of Medicare enrollment, or end of the study period (December 31, 2016), whichever occurred first. Ovarian cancer–specific survival was defined as the time from the date of cancer diagnosis until death from ovarian cancer. Patients were censored if they were alive until the end of the study or Medicare enrollment period or if their cause of death was not ovarian cancer.

Health Care Resource Utilization

All-cause health care utilization included inpatient visits, emergency department visits, and hospice care derived from Medicare claims files. A log of follow-up years was used as an offset in regressions to control for differences in follow-up time.

Medicare Expenditures

Information on all-cause expenditures to Medicare was derived from Medicare claims files, including inpatient, hospital outpatient, carrier, and durable medical equipment records. Expenditures were summed over the follow-up period and a mean monthly expenditure for each woman was calculated. All expenditures were adjusted to 2020 US$ using the consumer price index.¹⁸

Exploratory Variables

We used the Andersen Behavioral Model of Health Services Utilization for the selection of potential factors that affect GCC.¹⁹ According to this model, use of health care services is a function of predisposing factors (age at cancer diagnosis, race/ethnicity), enabling factors (marital status, Census tract household income, and Census tract percentage of people aged ≥ 25 years with at least 4 years of college education), need-related factors (tumor grade, cancer stage, tumor size, lymph node involvement, tumor histology [serous, adenocarcinoma, endometroid/mucinous/clear cell, others], comorbidity scores derived from co-occurring chronic conditions within 12 months before ovarian cancer diagnosis,^20,21 and proxies for performance status²²), and external health care environmental factors (SEER region, location of residence [urban/rural], Census tract–level data on number of hospitals offering oncology services, and number of gynecologists in subspecialty in the area of patient’s residence).

Statistical Analysis

Chi-square tests were used to describe differences in exploratory variables among the 4 treatment groups. Multivariable logistic regression was used to identify significant predictors associated with GCC. The Kaplan-Meier method was used to estimate median survival time, and the log-rank test was used to assess the difference between survival curves by GCC. Multivariable Cox proportional hazards regressions were used to examine all-cause mortality and ovarian cancer–specific mortality by GCC.

Separate multivariable negative binomial regression was used for each component of health care resource utilization to obtain the adjusted incidence rate ratios (AIRRs) by treatment groups. A generalized linear model with log link and γ distribution was used to examine the mean monthly Medicare expenditures, adjusted for covariates. The regression estimates (β) obtained from the generalized linear model were exponentiated to provide with percent higher or lower monthly expenditures.

All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc) with the significance level set to 0.05.

RESULTS

Descriptive Characteristics

A total of 3237 patients with advanced epithelial ovarian cancer, with a median follow-up of 22.0 months, were included in the study (eAppendix Figure 1). Approximately 57.2% (n = 1852) of women received GCC per the NCCN treatment guidelines (eAppendix Table 2). The remaining 42.8% (n = 1385) did not receive GCC; 9.8% received surgery only, 21.3% received chemotherapy only, and 11.6% did not receive either surgery or chemotherapy. Women who received GCC were significantly more likely to be aged 66 to 74 years, be married/partnered, have good performance status, and have a stage III or IV tumor.

Predictors of Guideline-Concordant Primary Treatment

Women who did not receive any treatment (n = 377) were excluded from all multivariable analyses, rendering the study cohort of 2860. Women aged 70 to 74 years (adjusted odds ratio [AOR], 0.713; 95% CI, 0.553-0.920), 75 to 79 years (AOR, 0.480; 95% CI, 0.370-0.624), and 80 years and older (AOR, 0.272; 95% CI, 0.210-0.351) were significantly less likely to receive GCC compared with those aged 66 to 69 years (Table 1 [part A and part B]). Women who were single/divorced/widowed (AOR, 0.691; 95% CI, 0.579-0.825), resided in an area with a mean Census tract income of less than $50,000 (AOR, 0.709; 95% CI, 0.551-0.913), and lived in the Western region of the United States (AOR, 0.711; 95% CI, 0.557-0.910) were significantly less likely to receive GCC. Compared with women with no psychiatric comorbidities, those who had any psychiatric condition were 34.5% less likely to receive GCC (AOR, 0.655; 95% CI, 0.464-0.923). Furthermore, women with stage IV cancer (AOR, 0.735; 95% CI, 0.542-0.996) and with adenocarcinoma histology (AOR, 0.564; 95% CI, 0.441-0.721) were significantly less likely to receive GCC.

All-Cause Mortality and Ovarian Cancer–Specific Mortality

eAppendix Figures 2 and 3 present all-cause and ovarian cancer–specific mortality curves by treatment groups. Median overall survival was 44.3 months, 21.6 months, and 19.8 months for women who received both surgery and chemotherapy, surgery only, and chemotherapy only, respectively.

After controlling for covariates, women who received surgery only or chemotherapy only had greater all-cause mortality compared with those who received surgery and chemotherapy (surgery only: adjusted HR [AHR], 2.307; 95% CI, 1.966-2.707; chemotherapy only: AHR, 1.802; 95% CI, 1.572-2.066; P < .0001) (Table 2). Additionally, the hazards of dying from ovarian cancer were found to be higher among those who received surgery only (AHR, 2.332; 95% CI, 1.916-2.837) or chemotherapy only (AHR, 1.643; 95% CI, 1.386-1.947) compared with women who received GCC.

Health Care Resource Utilization and Medicare Expenditures

Compared with women who received GCC, women who received surgery only and those who received chemotherapy only had adjusted rates of inpatient visits (surgery only: AIRR, 2.530; 95% CI, 2.235-2.863; chemotherapy only: AIRR, 1.716; 95% CI, 1.526-1.928) (Table 3). Similarly, compared with women who received GCC, those who received surgery only and chemotherapy only had 81% and 63% higher rates of emergency department visits, respectively (surgery only: AIRR, 1.809; 95% CI, 1.442-2.856; chemotherapy only: AIRR, 1.633; 1.443-1.848). The number of hospice visits were found to be significantly higher among those who received surgery only (AIRR, 1.959; 95% CI, 1.527-2.513) or chemotherapy only (AIRR, 1.721; 95% CI, 1.327-2.251) compared with those who received both surgery and chemotherapy.

In a multivariable adjusted analysis, the mean monthly overall Medicare expenditures for women who received surgery only and chemotherapy only were higher by 114.4% and 45.2%, respectively, compared with those for women who received both surgery and chemotherapy (Table 3).

DISCUSSION

This study used a population-based cohort of older women with advanced epithelial ovarian cancer to investigate disparities in adherence to guideline-concordant primary treatment and its association with survival, health care expenditures, and utilization. Approximately 57% of women with advanced disease received GCC, consistent with earlier reports. Taylor et al used 2002-2011 SEER-Medicare data and found that 55.2% of women received GCC, consistent with what we found.¹⁰ However, Bristow et al found that 30% of women with ovarian cancer received treatment as per the NCCN guidelines¹¹; these lower guideline concordance rates may partly be due to inclusion of only women with diagnoses of stage IIIC to IV tumors in their study.

Consistent with earlier reports,^9,13 we found that among women who did not receive GCC, half of them received chemotherapy only as their treatment. Patients who are not good candidates for surgery—such as some with stage IV disease, significant medical comorbidities, and/or poor performance status—may receive treatment with neoadjuvant chemotherapy only. Of note, 12% of older women with advanced epithelial ovarian cancer did not receive either surgery or chemotherapy, a finding slightly lower than that reported by Taylor et al, suggesting opportunities for improvement in the delivery of cancer care in geriatric patients.¹⁰ Treatment decision-making is difficult for medically complex, older patients with cancer and involves balancing life-prolonging cancer treatments with adverse events and functional decline following treatment.²³ Several factors including the patient perspective, the physician’s clinical judgment, and health system–related factors can affect treatment decision-making. A comprehensive geriatric assessment of a patient prior to treatment decision-making helps the physician and the patient identify an appropriate treatment regimen based on the patient’s functional status and needs.²⁴

We found that women 70 years and older with advanced stages of cancer were less likely to receive GCC, which is in accordance with previous study findings.^10,11,25 Gynecologic oncologists may consider frail, relatively older women with metastatic disease and multiple comorbidities to be poor candidates for surgical treatment and may perceive chemotherapy and/or palliative care as the best treatment option. Additionally, women with preexisting psychiatric conditions were less likely to receive GCC, a finding consistent with that reported for patients with bladder cancer.²⁶ This highlights the importance of ensuring appropriate cancer treatment and support for this underserved group. Although older patients with comorbidities are less likely to receive optimal treatment, we did not find comorbidity index to be significantly associated with non-GCC after adjusting for other covariates in the model. We were unable to control for severity of comorbid conditions in this study, which could be one of the reasons for the nonsignificant association between comorbidity and receiving GCC. For cancer-specific characteristics, we found that women with adenocarcinoma histology were 44% less likely to receive GCC compared with women with serous histology. Published literature has shown an association between atypical histologic subtypes and increased likelihood of nonadherent ovarian cancer care.^5,10 The primary treatment for ovarian cancer histologic subtypes does not differ and follows the recommendations of the NCCN guidelines. Clinical treatment for all carcinomas, including large cell carcinoma and adenocarcinoma not otherwise specified, is similar to that for high-grade serous carcinomas, which are the most common subtype.²⁷ These findings emphasize the importance of receiving both surgery and chemotherapy, especially for women with certain histologic malignancies.

Other factors associated with non-GCC included marital status, lower income, and geographic region. Women living in areas with lower Census tract–level mean income and living without a partner may face greater difficulty in accessing health care, thus leading to suboptimal treatment and poor survival outcomes.^5,28,29 A meta-analysis has shown a significant reduction in the receipt of optimal treatment for those with lower socioeconomic status.²⁹ In addition, we found that compared with women living in the Northeast, those living in the West were less likely to receive GCC. Our study findings provide preliminary evidence of geographic disparities in treatment for ovarian cancer that require further investigation to ensure equitable care for all. Contradictory to previous findings, race was not found to be a significant predictor of GCC after adjusting for study covariates.^9,10 The reasons underlying these disparities are complex, as multiple health care dimensions other than socioeconomic status and insurance status need to be examined. A recent study reported associations among affordability and accessibility, components of health care dimensions, and guideline-concordant treatment of ovarian cancer in relation to racial/ethnic disparities.³⁰

Women who received GCC had significantly improved survival compared with those who received surgery only or chemotherapy only, a finding in accordance with previous literature.^6,8,9 Furthermore, those who received chemotherapy alone had a relatively lower risk of mortality compared with those who received surgery alone. In the United States, the standard of care for advanced ovarian cancer has been primary debulking surgery followed by adjuvant chemotherapy.⁴ A study found a substantial decrease in the use of primary debulking surgery while the use of platinum and taxane agents increased during the same period.⁷ Lin et al reported similar findings and suggested that chemotherapy should be offered first for women unable to receive optimal treatment, as chemotherapy alone is associated with better survival than surgery alone.⁸ Further, to assess survival differences by factors among patients who received GCC, a subgroup analysis was conducted for the GCC cohort. Within the GCC group, those who were unmarried, had at least 2 comorbidities, and had stage IV tumors had higher all-cause mortality. Patient comorbidities are one of the independent predictors associated with greater hazard of progression-free and overall survival in women with epithelial ovarian cancer.³¹

Treatment regimens not consistent with the NCCN guidelines have contributed to an increase in US cancer spending.³² Our study was one of the few to examine the association of GCC with health care utilization and Medicare expenditures among older women with advanced epithelial ovarian cancer. Health care resource utilization, in the form of inpatient hospitalizations, emergency department visits, and hospice use, was significantly more frequent among patients who received non-GCC compared with those who received GCC. Additionally, mean monthly Medicare expenditures were higher for women who did not receive GCC compared with those who received GCC. A study using SEER-Medicare data from 1995 to 2007 found that mean total costs for women with stage III/IV ovarian cancer who received non-GCC were $7564 higher than for those who received GCC.¹² Similar trends have been found in studies of other cancer types.³³

Limitations

The findings of the current study provide valuable and recent real-world evidence about GCC among women with advanced epithelial ovarian cancer. Several limitations must be considered for appropriate interpretation of our study findings. The SEER-Medicare database does not capture information on the severity of comorbidities, quality of life, patient preferences, and physician perspectives that might affect treatment selection. Furthermore, we examined all-cause expenditures and utilization and did not differentiate expenditures and utilization associated with ovarian cancer or specific comorbidities. We established associations between GCC and clinical and economic outcomes; however, this does not imply causal effect. Because of the inability to account for unmeasured confounders, there is a possibility of unmeasured confounding. Women in the GCC cohort had good prognostic factors such as younger age, being married, good performance status, and no comorbidities that might be associated with better survival. Despite adjusting for several measured prognostic variables, we cannot rule out the possibility of unmeasured and residual confounding. Although we used the most recent data available at the time of the study, our findings may not completely reflect current treatment patterns. Several targeted therapies have been approved for advanced ovarian cancer—first the PARP inhibitor olaparib (Lynparza) in late 2014 for patients with a BRCA mutation and the latest PARP inhibitor, niraparib (Zejula), in 2017; both were approved as a maintenance treatment for ovarian cancer. Lastly, the findings from this study cannot be generalized to women younger than 65 years and those enrolled in commercial insurance plans.

CONCLUSIONS

More than 40% of older women with advanced epithelial ovarian cancer did not receive guideline-recommended care. Non-GCC was associated with higher all-cause and cancer-specific mortality, increased health care utilization, and increased Medicare expenditures, highlighting opportunities for improving cancer care in this vulnerable group.

Acknowledgments

The authors wish to thank Andrew Descoteaux, MS, BSPS, for his contributions to the manuscript.

Author Affiliations: Department of Pharmacy Practice and Clinical Research, University of Rhode Island (SK, AD, BRB, AH, AV), Kingston, RI.

Source of Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Dr Vyas was partially supported by institutional development award #U54GM115677 from the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health, which funds advance clinical and translational research. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS.

Prior Presentation: Part of this work was presented at The Professional Society for Health Economics and Outcomes Research (ISPOR) 2021 Virtual Annual Conference, May 17-20, 2021.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (SK, AV); acquisition of data (AV); analysis and interpretation of data (SK, BRB, AH, AV); drafting of the manuscript (SK, BRB, AH, AV); critical revision of the manuscript for important intellectual content (SK, BRB, AH, AV); statistical analysis (SK, AV); obtaining funding (AV); administrative, technical, or logistic support (AV); and supervision (AV).

Address Correspondence to: Shweta Kamat, MS, Department of Pharmacy Practice, University of Rhode Island, 7 Greenhouse Rd, Kingston, RI 02881. Email: Shweta_Kamat@URI.edu.

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