Resource Utilization and Expenditures During the “Watchful Waiting” Period in Patients With Recurrent Ovarian Cancer

Abstract: This article aims to quantify the use of health services during the watchful waiting period after second-line platinum-based therapy among patients with ovarian cancer. Women newly diagnosed with ovarian, fallopian tube, or primary peritoneal cancer between January 1, 2010, and September 30, 2015, and subsequently treated with 2 lines of platinum-containing chemotherapy were selected from the MarketScan® claims data. Inpatient admissions, emergency room (ER) visits, and their associated diagnoses and costs were analyzed during the watchful waiting period. A total of 1176 patients were included. The median duration of watchful waiting was approximately 5.5 months. During the watchful waiting period, 41.8% had either an inpatient admission or ER visit. Approximately 30% of patients were hospitalized for a total of 585 admissions (1.7 admissions per hospitalized patient), with an average (standard deviation [SD]) cost per hospitalization of $27,802 ($36,032). Overall, 320 patients had 679 ER visits (2.1 per patient) with an average (SD) cost per patient with ER visits of $1115 ($1974). Findings suggest a substantial ongoing disease burden with frequent hospitalization and ER visits during the watchful waiting period.

It is estimated that there will be more than 22,000 new ovarian cancer cases and approximately 14,000 deaths due to ovarian cancer in the United States in 2017.¹ Most diagnoses (88%) occur at ages 45 and older and at a median age of 63.¹ Prognosis is improved for patients diagnosed at earlier stages: 5-year survival is 92.5% for women diagnosed with localized disease, 73.0% for those with regional lymph node involvement, and 28.9% for those with distant metastases.^1,2 Unfortunately, most women (80%) are diagnosed with regional or distant metastases.¹ 

National Comprehensive Cancer Network (NCCN) treatment guidelines recommend primary surgical cytoreduction or neoadjuvant chemotherapy as the primary treatment for most cases of ovarian cancer, followed by a chemotherapy regimen.³ The cornerstone of drug treatment in the first-line advanced disease setting is platinum therapy (cisplatin or carboplatin) plus a taxane (paclitaxel or docetaxel).^4,5 Following first-line treatment, 85% of patients will experience disease recurrence, at which point the cancer is considered incurable.^4,5 Recurrent disease is usually treated again with platinum-based chemotherapy as long as progression occurred more than 6 months after the last dose of chemotherapy (which suggests platinum sensitivity).^6-8 Duration of progression-free survival (PFS) decreases with each subsequent line of chemotherapy.^9,10 Risk for cumulative toxicities also increases with each line of treatment.^9,10 After response to platinum-based therapy, for patients responding to platinum treatment NCCN guidelines recommend disease monitoring, consisting of clinic visits, pelvic examinations, cancer antigen 125 monitoring, imaging, and genetic risk evaluation. Patients with recurrent disease may also be treated with poly (ADP-ribose) polymerase (PARP) inhibitor or bevacizumab maintenance therapy.³ Given the equal weighing of observation vs proven maintenance treatments by NCCN guidelines, many patients enter an observational period (“watchful waiting”) and do not receive maintenance treatment. 

There is little research on the burden of illness during watchful waiting periods. Studies usually focus on a particular period of time after initial diagnosis or surgery^11,12 or phases of care that include some active treatment.¹³ Studies conducted during watchful waiting have focused on surveillance costs¹⁴ or the cost-effectiveness of maintenance therapies.^15,16 The objective of this study was to investigate the frequency and timing of hospitalizations and emergency room (ER) visits that occur during the watchful waiting period after second-line platinum treatment and quantify the associated direct health care costs.

Methods

This retrospective cohort study conducted in the United States used administrative health care claims data from the 2009-2015 MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases (IBM Watson Health). These databases contain the complete longitudinal records of inpatient and outpatient services and prescription drug claims for an annual average of 37 million commercially insured and 3 million Medicare-eligible individuals in each of the study years, covered under a variety of commercial health plans, including dates of service, places of service, and all payments. All database records are de-identified and fully compliant with US patient confidentiality requirements set forth in Sections 164.514 (a)-(b)1ii of the Health Insurance Portability and Accountability Act (HIPAA) regarding the determination and documentation of statistically de-identified data. Because this study used only de-identified patient records and did not involve the collection, use, or transmittal of individually identifiable data, institutional review board approval to conduct this study was not necessary.

Participants

Patients were selected who had 1 or more inpatient claims or 2 or more outpatient claims ≥30 days apart with a diagnosis of ovarian, fallopian tube, or primary peritoneal cancer, identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 183.0: Malignant neoplasm of ovary; 183.2: Malignant neoplasm of fallopian tube; 158.x: Malignant neoplasm of retroperitoneum or peritoneum, between January 1, 2010, and September 30, 2015. The index date was the date of the earliest qualifying claim for ovarian cancer. Patients were required to be at least 18 years old on their index date and continuously enrolled in health insurance with both medical and pharmacy benefits for ≥12 months before and ≥1 month after their index date with no medical or pharmacy claims indicative of ovarian cancer within 12 months before the index date to ensure that they were newly diagnosed. Patients were followed up starting with the index date until the earliest of the end of continuous insurance enrollment, inpatient death, or the end of the study period (September 30, 2015). Patients were further required to have had 2 lines of platinum-based chemotherapy (ie, platinum-based chemotherapy during first-line and second-line) with no maintenance therapy during second-line treatment
(Figure 1; see Table 1 for a list of therapies). 

Age, geographic region, and primary payer type were assessed at the index date. The presence of comorbid conditions was assessed using diagnoses recorded during the baseline period of 12 months before the index date. The National Cancer Institute (NCI) modified Deyo-Charlson comorbidity index¹⁷ was computed using diagnoses during the baseline period. The presence of metastatic disease at index was assessed using diagnoses of secondary neoplasms recorded during the baseline period, specifically ICD-9-CM 197.xx: Secondary malignant neoplasms of respiratory and digestive system and 198.xx: Secondary malignant neoplasms of other specified sites (excludes lymph nodes).

Study Design

Therapy lines were defined using the dates on health care claims. The first line of therapy started on the date of the first claim for a chemotherapy agent on or after the index date. Its regimen comprised all chemotherapeutic agents prescribed within 28 days of start. A 28-day window was selected because the NCCN guidelines for ovarian cancer recommend that first-line intravenous chemotherapy regimens restart every 3 weeks.³ To allow for delays in infusion due to scheduling conflicts and other minor delays in the treatment regimen schedule, all agents added within 28 days were considered part of the first-line regimen. Patients were considered to be on their first line of therapy until the earliest of initiation of a second line of therapy (defined as the addition of a chemotherapeutic agent that was not part of the first-line regimen >28 days after the start of the first line of therapy), discontinuation of therapy (based on a gap of >60 days following the last administration of chemotherapy), inpatient death, end of continuous enrollment, or end of study period. Second-line therapy started on the date of the second claim for a chemotherapy that was not part of the earlier therapy regimen >28 days after the line of therapy start date. Therapy-ending events for the second line of therapy were the same as those for the first line of therapy. 

The second therapy line was segmented into up to 3 distinct periods: active treatment, maintenance treatment, and watchful waiting. The active treatment period began at the start of the second therapy line and ended with the discontinuation of therapy or the initiation of third-line or maintenance therapy. Bevacizumab was considered to be an active therapy if it followed a period of nontreatment, but if it was initiated with other treatment or within 60 days following the end of another active treatment, it was classified as maintenance treatment. The watchful waiting period began at the end of second-line active therapy and ended with the initiation of a subsequent active treatment or the end of the patient’s available follow-up. Patients who had maintenance treatment after second-line therapy and prior to the watchful waiting period were excluded. A patient could not be on any active or maintenance therapy during the watchful waiting period. 

Inpatient admissions and ER visits were analyzed during the watchful waiting period. These included the number of inpatient admissions and ER visits, the inpatient length of stay, the principal diagnosis on inpatient claims, and the diagnosis in the first position on ER claims. ER visits that resulted in an inpatient admission were counted as inpatient admissions, not as separate ER visits. The time from the beginning of the watchful waiting period to the first inpatient admission and ER visit were examined using Kaplan-Meier curves. Expenditures for inpatient admissions and ER visits were the total reimbursed amount including insurer payments and patient copayments, deductibles, and co-insurance. Expenditures for inpatient admissions included the amount paid to hospitals as well as to other health care service providers, such as physicians, who provided services during the hospitalization. Expenditures for services provided under capitated arrangements were estimated using payment proxies based on MarketScan data for paid claims at the procedure level. US dollar estimates were adjusted to 2015 levels using the Consumer Price Index for Medical Care. 

Results

There were 1176 patients with recurrent ovarian cancer who had an observed watchful waiting period after 2 lines of platinum-based chemotherapy (Figure 1). The malignant neoplasms diagnosed at index were 978 (83.2%) ovary, 115 (9.8%) retroperitoneum or peritoneum, 23 (2.0%) fallopian tube, and 60 (5.1%) with more than one malignant neoplasm location diagnosed on the index date. Average age at diagnosis was 61.5 years. Average NCI modified Deyo-Charlson comorbidity index computed during the 12-month baseline period was 0.3, and 10.2% of patients had diagnostic evidence of metastatic disease at index (Table 2). 

The median duration of the watchful waiting period was 165.5 days (5.5 months). During the watchful waiting period, 491 patients (41.8%) had either an inpatient admission or ER visit. A total of 353 patients (30.0%) had an inpatient admission. Overall, there were 585 inpatient admissions, an average of 1.7 admissions per patient with at least one hospitalization. The average length of hospital stay was 10.4 days (standard deviation [SD] 13.3, median 5). Total hospitalization costs for all hospitalizations during the watchful waiting period averaged $27,802 (SD $36,032, median $15,952; Table 3). 

Patients who were hospitalized had prescriptions for more types of drugs in the baseline period. The hospitalized group also had a higher proportion with diabetes and a higher average Deyo-Charlson comorbidity index, although these differences were not statistically significant (Table 2). 

The most common principal inpatient diagnoses at the 4-digit ICD-9-CM level were 183.0: Malignant neoplasm of ovary (8.9%); 560.9: Unspecified intestinal obstruction (6.3%); 560.8: Other specified intestinal obstruction (6.0%); and 197.6: Secondary malignant neoplasm of retroperitoneum and peritoneum (3.4%) (Table 4). A total of 63.4% of hospitalized patients had no surgical procedure during the inpatient admission. Among those with a surgical procedure, the most common ICD-9-CM procedure codes were 45.62: Other partial resection of small intestine (2.2%), 54.59: Other lysis of peritoneal adhesions (1.9%), and 38.7: Interruption of the vena cava (1.7%) for primary procedures (Table 5). The median time from the beginning of the watchful waiting period to inpatient admission was 61 days (Figure 2). 

During the watchful waiting period, 320 patients (27.2%) had a total of 679 ER visits, which is an average of 2.1 visits per patient among those who visited the ER. Total ER costs for all ER visits during the period averaged $1115 (SD $1974, median $481; Table 3). Patients with ER visits were older and likely to have had dysrhythmias and diabetes and had significantly higher Deyo-Charlson comorbidity indices and prescriptions for more types of drugs during the baseline period (Table 2). The most common 4-digit ICD-9-CM diagnoses in the first position of the ER insurance claims were 789.0: Abdominal pain (15.5%); 786.5: Chest pain (5.6%); 183.0: Malignant neoplasm of ovary (5.4%); and 560.9: Unspecified intestinal obstruction (4.1%) (Table 6). The median time from the beginning of the watchful waiting period to the patient’s first ER visit was 68.5 days (Figure 3).

Discussion 

This study found that a large proportion of patients were hospitalized (30.0%) or had ER visits (27.2%) during the watchful waiting period. Furthermore, the average length of stay in the hospital was quite long (10.4 days, median of 5 days), and many patients had more than one ER visit during the period. Of those hospitalized, they had, on average, 1.7 hospitalizations per patient; of those with ER visits, they averaged 2.1 visits per patient. These proportions of patients hospitalized or with ER visits are higher than were found in a study of patients during an active-treatment period using the same claims data source.¹⁸ Wright and colleagues selected patients with ovarian cancer who were treated with surgery followed by chemotherapy, focusing on the first 6 months after surgery, and found 23.8% overall had a hospitalization and 19.8% had an ER visit.¹⁸

We also found that hospitalizations were costly, with a per-event average of $27,802 (median $15,952) during the watchful waiting period. Although most studies do not report inpatient costs separately, a context for our results can be found in a study by Urban and colleagues of the first year of treatment of patients aged ≥65 years with stage III/IV ovarian cancer. Patients with NCCN guideline-consistent surgery and chemotherapy had average inpatient costs (in 2009 dollars) of $36,644 ($18,050 surgery and $18,594 other inpatient).¹²

These results show that the watchful waiting period does not constitute a “treatment holiday” for a significant portion of patients. Also, consistent with what has been observed in clinical trials, these patients progress quickly, with a median treatment-free period of 5.5 months. During this period, a significant portion of patients (41.8%) are hospitalized or visit the ER, and the visits are mostly for cancer-related issues. Thus, the patient disease burden during this period is significant. 

Other research has shown that the PFS period is shorter after each new treatment and subsequent relapse. In a study of 2074 patients with at least one relapse treatment after the first line of therapy, median times after the first, second, third, fourth, and fifth relapse were 10.2, 6.4, 5.6, 4.4, and 4.1 months, respectively.^9,10 Better treatment options are needed to extend the treatment-free period and reduce patient burden. Maintenance treatment has been shown to increase the PFS period after chemotherapy¹⁹ and has the potential to help alleviate patient burden during this period. The use of maintenance treatment to extend the time to progression (to greater than 6 months) may increase the number of patients who are eligible for further platinum-based chemotherapy.²⁰

Clinical trial research suggests that maintenance treatment may extend PFS while still preserving quality of life (QoL). In a trial that evaluated patient-reported outcomes in women who received niraparib for maintenance treatment, common grade 3/4 toxicities with niraparib were mainly hematologic in nature and had no significant impairment on QoL compared with patients receiving placebo.²¹ QoL was also explored in the phase 3 SOLO2 trial of maintenance therapy with olaparib among patients with relapsed ovarian cancer and 2 or more lines of chemotherapy. QoL outcomes were defined as a change in the trial outcome index over 12 months and as time without symptoms or toxicity. Compared with patients receiving placebo, there was no significant difference in healthcare-related QoL but a significantly longer time without symptoms or toxicity.^22,23 

With the increase in PFS and stable patient QoL with maintenance therapy suggesting a more prominent role in care for women with recurrent disease, additional studies will be necessary to determine whether treatment can decrease hospitalizations and ER visits. Although there are cost-effectiveness studies of maintenance therapies for ovarian cancer,^15,23 these studies mainly compare different therapies. None have assessed health care resource use during the maintenance therapy period. These studies should take care to address the selection bias regarding who receives maintenance treatment.

To our knowledge, this is the first study to identify and examine the watchful waiting period in ovarian cancer using real-world claims-based data. The recent adoption of maintenance therapies following clinical trial results²⁴ has led to an increased focus on real-world utilization of patients initiating watchful waiting vs maintenance treatment. Both the watchful waiting period and maintenance treatment can be difficult to define outside of a clinical trial setting due to several factors, such as the delay between medical claims data in the real world, the complicated nature of treatment, and lines of therapy among women with recurrent ovarian cancer. We expect that additional research will be conducted using real-world data to examine the increasing number of maintenance therapies. 

This study is not without limitations. This study was conducted using insurance claims data and may not be generalizable to patients without insurance or those with Medicare but no supplemental insurance. In addition, because these data are not linked to cancer registry data, information on cancer stage, race/ethnicity, or tumor characteristics was not available. Furthermore, we relied on insurance claims to determine the date of diagnosis and all received treatments and recognize that some misclassifications are inherent in claims-based analyses. However, our requirements of one inpatient ovarian cancer diagnosis and the requirement of at least 2 lines of platinum-based chemotherapy help to ensure that the patients selected were indeed treated for recurrent ovarian cancer. Finally, the health care resource use reported in this study could have included those associated with end-of-life care. Because claims data do not capture deaths that occurred outside hospitals, it was not feasible to distinguish end-of-life care from standard care during the watchful waiting period. In addition, patients who did not respond to second-line therapy and opted to receive palliative care might have been included in the study population, and their relative size is unknown due to the lack of clinical response data. Strengths of the insurance data are that expenditures are accurately captured, all types of health care providers (eg, hospitals, laboratories, pharmacies) are included, the sample size is substantial, and patients of all ages are available for study.

Conclusion

Many patients with recurrent ovarian cancer are observed without further treatment after their second-line platinum treatment (often referred to as watchful waiting). Data regarding health care resource use during the watchful waiting period have not been previously available. This study found that, during the watchful waiting period after second-line platinum-based therapy when patients with recurrent ovarian cancer were not undergoing active or maintenance therapies, hospitalizations and ER visits were frequent and costly. It is hoped that improved therapies will reduce this burden on patients with ovarian cancer. In addition, in light of rising health care costs and a shift toward personalized, value-based care, clinical pathways in oncology are an avenue to drive optimal, patient-centered, cost-effective care. 

References 

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