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Introduction
In the United States (US), it is estimated that a total of 22,220 cases of gastric cancer will be diagnosed in 2014, representing 1.3% of all new cancer cases, and 10,990 deaths will occur as a result.1 Gastric cancer predominantly affects older individuals. In the US, the annual incidence of this malignancy in people younger than 65 years is 2.9 per 100,000 people, compared with 39.4 per 100,000 people among those aged 65 years or older.2 Patients with early-stage gastric cancer are often asymptomatic or have non-specific symptoms. Consequently, in the US, only 25% of patients have localized disease at the time of diagnosis. Conversely, 30% have regional spread at the time of diagnosis, and 34% have distant metastases. The remaining 11% of patients are unstaged.2
In countries with a relatively low incidence of gastric cancer, such as the US, population-based screening is costly and unwarranted. However, people with high-risk conditions (e.g., older individuals with chronic gastric atrophy, pernicious anemia, gastric polyps, or familial cancer syndromes) may benefit from early detection efforts.3 Although patients diagnosed with localized gastric cancer in the US have a reasonable possibility of being cured (estimated 5-year relative survival [5YS] of 63.2%), those diagnosed with regional spread have an estimated 5YS of only 28.4%, and those diagnosed with distant metastases have a 5YS of only 3.9%.2
Among patients diagnosed with advanced gastric cancer (locally advanced/unresectable or metastatic disease), chemotherapy is typically used to palliate symptoms and prolong survival. Current (2014) National Comprehensive Cancer Network (NCCN) guidelines recommend the use of a combination of platinum- and fluoropyrimidine-based cytotoxic agents as the first-line chemotherapy regimen for this population.4 Research suggests that patients with metastatic gastric cancer receiving first-line chemotherapy have improved survival (8~12 months) compared with patients receiving best supportive care only (3~5 months).5 For patients who fail first-line therapy, NCCN guidelines suggest single-agent chemotherapy as second-line therapy.4
As 62% of patients diagnosed with gastric cancer are 65 years old or older at diagnosis,2 the current economic impact of gastric cancer on the Medicare system, which serves as the primary insurance provider for the elderly in the US, has not been widely evaluated. The objective of this study was to assess real-world treatment patterns, health care utilization and associated costs, and survival among Medicare-enrolled patients diagnosed with locally advanced/unresectable or metastatic gastric cancer who received NCCN-recommended first-line treatment with fluoropyrimidine- and/or platinum-based chemotherapy.
Materials and Methods
1. Study design and data source
The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was analyzed from 2000 through 2009 in this retrospective longitudinal cohort study. The SEER-Medicare database, its contents, and methods of collection are described in detail elsewhere.67891011 At the time of this study, data for elderly SEER patients with an incident cancer diagnosis between 1991 and 2007 were available together with their linked Medicare claims through 2009 (for services covered under Medicare Parts A and B). However, data on outpatient prescription drug claims covered under Medicare Part D were only available for 2007 through 2009, as the Medicare Part D prescription drug plan did not take effect until 2006.
2. Patient selection
Patients were initially eligible for this study if they had a diagnosis of gastric cancer (International Classification of Diseases for Oncology, Third Edition [ICD-O-3] codes: C16.0 to C16.9), which includes cancer of the gastroesophageal junction (GEJ), during the period from July 1, 2000 through December 31, 2007. The patient sample was further restricted to those for whom gastric cancer was either the first diagnosed malignancy or for whom there was no evidence of another cancer type within 5 years prior to their gastric cancer diagnoses. The date of the first observed gastric cancer diagnosis defined the gastric cancer index date. Patients were also required to be 65 years of age or older at the gastric cancer index date, which excluded patients who were, at the gastric cancer index date, enrolled in Medicare because of disability and/or end-stage renal disease. Patients were further required to have continuous Medicare Part A and B enrollment from 6 months prior to the gastric cancer index date through the end of follow-up as defined by death or the end of the database (December 31, 2009), whichever occurred first. Patients with any health maintenance organization enrollment during this period were excluded from the study,1213 as were patients diagnosed with in situ gastric cancer.
In addition to the aforementioned criteria, the cohort was additionally restricted to patients with at least one claim for a chemo-therapy agent following the gastric cancer index date. Patients with evidence of chemotherapy, depending upon disease stage and gastrectomy status at the gastric cancer index date, were required to meet the following additional criteria:
1) Diagnosed with metastatic (distant) disease and received a fluoropyrimidine (i.e., fluorouracil or capecitabine) and/or a platinum agent (i.e., cisplatin, carboplatin, or oxaliplatin) with or without other chemotherapy agents as the first-line chemotherapy; or
2) Diagnosed with early-stage (i.e., localized, regional, unknown) disease, underwent gastrectomy (International Classification of Diseases, 9th Revision, Clinical Modifications [ICD-9-CM] procedure codes 43.5-43.99; CPT codes 43620, 43621, 43622, 43631, 43632, 43775, 43845), and subsequently received a fluoropyrimidine and/or a platinum agent at least 3 months after gastrectomy.
The latter treatment criterion assumed no adjuvant chemotherapy was received within 3 months after gastrectomy. Thus, the subsequent fluoropyrimidine and/or platinum chemotherapy regimen was considered first-line treatment following disease progression.
3. Study measures
1) Patient characteristics
Patient demographic and clinical characteristics assessed at the index date were age, sex, race, SEER region, urban/non-urban status of residence, census region, primary tumor location, stage at initial gastric cancer diagnosis, and site(s) of metastasis. The Charlson Comorbidity Index (excluding gastric cancer) was calculated to obtain a measure of the patients' overall comorbidity burden during the 6-month period preceding the gastric cancer index date.14 The presence of ascites during the follow-up period was also recorded. Human epidermal growth factor receptor 2 (HER2) status was determined via proxy based on the use of either trastuzumab or lapatinib, as the use of these agents is typically limited to patients who are HER2-positive.
In addition to the aforementioned characteristics, overall survival (OS) was assessed as an additional background characteristic and was calculated from the index date to death or the end of the database (December 31, 2009), whichever occurred first. Patients who survived beyond the database end date were censored. OS was also calculated from the completion of first-line chemotherapy.
2) Cancer-related treatment patterns and costs
The number and percentage of patients receiving cancer-related treatments including radiotherapy, chemotherapy, biologic therapy, and palliative surgery were evaluated using the Medicare medical and pharmacy claims data. Among patients receiving chemotherapy, the distribution of first-, second-, and third-line chemotherapy regimens and the chemotherapy agents received within each regimen was assessed. Additionally, for each patient receiving a first-, second-, or third-line regimen, the number of treatment cycles that were completed within each line was estimated. The determination of the line of treatment and number of cycles for a given course of treatment was performed using methods presented in prior published studies, in which a change in chemotherapy agents generally indicated a new line of therapy.5151617 For each line of therapy, the duration of treatment was calculated from the first chemotherapy administration date to the last chemotherapy drug administration date within each line of the chemotherapy regimen.
In addition to evaluating cancer-related treatments, supportive care received during the follow-up period was assessed, including growth factors, iron therapy, antibiotics, antivirals, antiemetics, antifungals, pain medication, and nutritional support. The utilization of injectable formulations of these treatments administered by health care providers was captured on the basis of procedure codes recorded in the Medicare claims under Medicare Part B. However, any self-administered forms of these medications dispensed via outpatient pharmacies were only captured for patients with Medicare Part D enrollment and linked pharmacy claims data in 2007 through 2009, as Medicare Part D prescription claims were unavailable prior to this period. The number and proportion of patients undergoing diagnostic tests, including positron emission tomography, endoscopy, computed tomography, magnetic resonance imaging, radiography, and blood tests, were assessed.
Both cancer-directed and supportive care treatments were defined on the basis of the evidence of relevant Health Care Common Procedure Coding System (HCPCS) procedure codes, ICD-9-CM procedure codes, generic and brand drug names, national drug codes, and certain ICD-9-CM diagnostic codes and administrative revenue codes (code list provided in Appendix 1).
Costs were calculated using the Medicare paid amount in the medical and pharmacy claims database for each gastric cancer-related treatment and supportive care claim observed following the index date. All cost data were adjusted at the claim level to 2012 US currency (United States dollar, USD) using the medical care component of the US Consumer Price Index.
3) Overall health care utilization and costs
Gastric cancer-related and all-cause health care utilization and costs were assessed as a whole and by major care settings, including inpatient, hospital outpatient, emergency department, physician office, skilled nursing facility, hospice, and other ancillary care. Place of service codes associated with each medical claim were used to determine care setting-specific utilization and costs. Gastric cancer-related health care utilization and associated costs were drawn from the following sources: (a) medical claims with a gastric cancer diagnosis (primary or secondary) code (ICD-9-CM: 151. x); (b) outpatient pharmacy claims (i.e., Medicare Part D claims for 2007~2009) for gastric cancer-related supportive care medications (e.g., nutritional supplements); and (c) medical claims for gastric cancer-related therapies covered by Medicare Parts A and B (e.g., intravenous chemotherapy, radiotherapy). All cost data represented the actual amounts paid by Medicare to providers for each service encounter and treatment observed, and as previously described, the data were adjusted at the claim level to 2012 USD.
4. Statistical analyses
All analyses were conducted using SAS ver. 9 (SAS Institute, Cary, NC, USA). Patients were categorized on the basis of treatments received after the completion of first-line chemotherapy. Those receiving additional cancer-related treatments (i.e., chemotherapy, biologics, or radiotherapy) after completing first-line chemotherapy were categorized as 'additionally treated,' and all remaining patients were categorized as 'supportive care only.' The previously described study measures were assessed and reported as a whole and by these two patient groups.
We further analyzed OS, treatment patterns, and heath care utilization and costs over various follow-up periods as follows:
1) Overall follow-up period: the period between the index gastric cancer diagnosis date and death or the end of the database (December 31, 2009), whichever occurred first
2) Post-first-line chemotherapy period: the period between the day immediately following the first-line chemotherapy administration end date and death or the end of the database, whichever occurred first
3) First-line chemotherapy period: the period between the index date and the first-line chemotherapy regimen end date
4) Second-line chemotherapy period: the period between the day immediately following the first-line chemotherapy regimen end date and the last date of the second-line chemotherapy regimen among those who received second-line chemotherapy
The second-line chemotherapy period was not applicable to the supportive care only group, as they did not receive any additional cancer-directed treatment following the completion of their first-line chemotherapy.
Descriptive analyses were conducted, and mean values, standard deviations, median values, and interquartile ranges were reported for continuous variables. Numbers and percentages were used to describe categorical variables. Unadjusted differences between the two groups (i.e., additionally treated vs. supportive care only) were tested using Student's t-test for continuous measures and chi-squared tests for categorical measures. The Kaplan-Meier method was used to descriptively assess OS.
The conduct of this study was approved by the National Cancer Institute and the Institutional Review Board at RTI International (Committee on the Protection of Human Subjects, Federal-Wide Assurance #3331).
Results
1. Patient characteristics
A total of 2,583 patients were identified for analysis after applying all inclusion and exclusion criteria (Table 1). Of these, approximately 55% (n=1,415) received additional cancer-directed therapy after the completion/discontinuation of first-line chemotherapy, and they were classified as 'additionally treated.' The remaining 45% of patients (n=1,168) were classified as 'supportive care only.' The mean patient age at the index date was 74.8±6.0 years. Additionally treated patients were approximately 10 months younger than patients in the supportive care only group (74.4±6.0 years vs. 75.2±5.9 years; P<0.001). Over two-thirds of patients were male, and approximately 80% were white, a trend that remained consistent across the additionally treated and supportive care only groups. Cardia not otherwise specified (NOS) was the most commonly observed (43%) tumor location site, which differed between the additionally treated and supportive care only groups (50% vs. 35%; P<0.001). Slightly more than half (54%) of all patients presented with metastatic (distant) stage disease at the initial gastric cancer diagnosis. Ninety-two percent of patients died during the follow-up period (Fig. 1A). The median survival was 361 days for the post-gastric cancer diagnosis period, compared with 167 days following the completion of first-line chemotherapy. Median survival was longer (272 days) in the additionally treated group than in the supportive care only group (72 days) after the completion of first-line chemotherapy (Fig. 1B). Additional survival estimates are presented in Appendix 2.
2. Cancer-directed treatment and supportive care utilization
Table 2 presents the details on overall cancer-directed treatment and supportive care utilization during the follow-up period. Among all patients, 48% had evidence of radiotherapy, and 2% had evidence of biologic therapy at any time during the overall follow-up period. Among the additionally treated group, 71% received second-line chemotherapy, 64% received radiotherapy, and 4% received biologic therapy. For both the additionally treated and supportive care only groups, fluorouracil (≥58%), cisplatin (≥24%), and carboplatin (≥20%) were the most commonly used first-line chemotherapy agents. Although less commonly utilized in second- and third-line treatment, fluorouracil remained the most common chemotherapy agent used (alone or in combination with other chemotherapies) in the post-first-line setting (37 and 30% of second-and third-line chemotherapy initiators, respectively). Following the gastric cancer index date, the majority of patients received supportive or palliative care medications, with antiemetics (86%) being the most common, followed by growth factors (66%), pain medications (50%), and antibiotics (28%). Additional data on supportive care utilization are provided in Appendix 3.
Among all patients, the distribution of first-, second-, and third-line chemotherapy agents and regimens received within each line of therapy are presented in Table 3. In the first-line setting, 55%, 24%, and 20% of patients received a two-drug combination (doublet therapy), three-drug combination (triplet therapy), and a single drug (monotherapy), respectively. Patients completed a mean of 5.5±6.4) cycles of first-line chemotherapy, with a mean total average therapy duration of 67±83 days. Patients receiving doublet therapy completed a greater mean number of chemotherapy cycles (6.1±6.9) than those receiving triplet therapy (5.5±6.4 cycles) or monotherapy (3.9±3.8 cycles). Among patients initiating first-line chemotherapy with a platinum agent and/or fluoropyrimidine (n=2,583), 39% (n=1,000) initiated second-line chemotherapy. Among these patients, 36%, 40%, and 21% received monotherapy, doublet therapy, and triplet therapy, respectively. Single-agent docetaxel, fluorouracil with leucovorin, and single-agent paclitaxel were the three most commonly observed second-line chemotherapy regimens. Less than half (46%; n=456) of second-line initiators subsequently started third-line chemotherapy. Of these, 42% received monotherapy, and 39% received doublet therapy. Docetaxel monotherapy (10%) and irinotecan monotherapy (7%) were the most commonly used third-line regimens among these patients.
3. Gastric cancer-related utilization and costs
The average per-patient total gastric cancer-related treatment and supportive care cost was USD 26,904±30,071, of which 55% was related to gastric cancer-related treatment (USD 14,668±17,501) and 45% was dedicated to supportive care (USD 12,236± 18,251) (Table 4). Chemotherapy-related costs (including drug and administration costs) accounted for 68% (USD 10,036±15,055) of the total gastric cancer-related treatment costs. The total cost of supportive care was driven by the use of growth factors (49%; USD 6,043±11,421]). The average total cost of treatment was 8-fold higher in the additionally treated group (USD 21,585±26,989) than in the supportive care only group (USD 2,695±14,437; P<0.001), with chemotherapy accounting for nearly 37% of the cost. For both groups, gastric cancer-related treatment costs accounted for approximately 60% of the total costs incurred during the first-line chemotherapy period. This percentage also held across second-and third-line therapy among patients in the additionally treated group. The mean total costs per patient per line for the additionally treated group were USD 15,066±13,834 (first), USD 12,699±15,675 (second), and USD 7,199±14,593 (third).
Overall gastric cancer-related medical resource utilization and costs (inclusive of medical services, cancer-related drugs and administration, and supportive care treatments) incurred during the follow-up period are presented in Table 5. Inpatient medical encounters accounted for 49% (USD 34,401±38,214) of the total gastric cancer-related costs (USD 70,808±56,620). Following the completion of first-line chemotherapy, patients in the additionally treated group had an average 32 more gastric cancer-related medical encounters and incurred an additional USD 25,216 in disease-related costs compared with the supportive care only group (P<0.001). The greater utilization and costs observed in the additionally treated group compared with the supportive care only group was primarily attributable to additional cost incurred in the physician office setting (USD 14,458 greater costs; P<0.001). The mean cost per patient in the additionally treated group steadily declined between first- and second-line therapy (USD 36,810±31,207 and USD 22,332±26,262, respectively). All-cause utilization and costs are presented in Appendix 4.
Discussion
The objective of this study was to document treatment patterns, overall survival, and health care utilization and costs during and after the completion of platinum- and/or fluoropyrimidine-based first-line chemotherapy among Medicare-enrolled patients diagnosed with metastatic and/or unresectable gastric cancer in the SEER registry. Following the completion of first-line chemotherapy, approximately 55% of patients had evidence of further cancer-directed treatment, a finding consistent with data reported by Pasini et al.18 The remaining 45% were administered supportive care only. Consequently, patients in the additionally treated group had more than 6-fold greater treatment-related and supportive care costs than patients in the supportive care only group following the completion of first-line chemotherapy. However, after the completion of first-line chemotherapy, the median survival time among patients in the additionally treated group was approximately 7 months longer than that the supportive care only group, which allowed more time for costs to be incurred for the former group.
The receipt of first-line chemotherapy with a platinum agent and/or fluoropyrimidine was a prerequisite for all patients included in this study. Fluorouracil alone or in combination with other agents was the most commonly used first-line chemotherapy regimen. The recorded first-line agents and combination regimens are consistent with previously published studies and the NCCN recommendations in place during the study period.19202122 However, because of the restrictions on study eligibility other possible first-line regimens that did not contain either a platinum and/or fluoropyrimidine agent were not evaluated. This may account for a percentage of regimens excluded from the present study.
In this study, nearly 40% of patients received second-line che-motherapy, a finding consistent with a prior publication.18 Among patients receiving second-line chemotherapy, docetaxel, paclitaxel, and 5-fluorouracil (alone and in combination with other agents) were the most commonly used second-line chemotherapy regimens. However, even the most frequently occurring second-line regimen, single-agent docetaxel, was used in only 8% of patients, indicating the extent to which second-line treatment selections varied in this study. Limited data supporting the use of second-line chemotherapy regimens exist, with no randomized trials published before 2011, leading to greater variability in utilized second-line chemotherapy agents as reflected in this study. These findings are also consistent with other published data available from this period.23242526272829
In addition to chemotherapy, nearly 50% of patients also had evidence of radiotherapy. However, post-gastric cancer diagnosis radiotherapy use patterns differed between cohorts, with more than two-thirds of patients in the additionally treated group receiving radiotherapy compared to only one-third of patients in the supportive care only group. Overall, differences in disease prognosis between patients in the additionally treated and supportive care groups may have influenced the use of radiotherapy.
For both study cohorts, more than 90% of patients died during the follow-up period, with a median OS of approximately 12 months. This finding is consistent with prior studies assessing OS among patients with metastatic gastric cancer who received first-line chemotherapy.229 As expected, OS varied by stage at initial diagnosis, the receipt of cancer-directed treatment, and the type of cancer-directed treatment received after first-line chemotherapy. Patients diagnosed with early-stage disease (i.e., localized and regional) had longer median OS than those diagnosed with metastatic disease, a finding consistent with previous reports. The median OS following first-line chemotherapy was 5.5 months, which differed by treatment status. Among patients receiving cancer-directed treatment, the median OS was 6.6 months longer than patients receiving only supportive care. These findings support several earlier studies reporting the benefits of second-line chemotherapy compared to no active treatment.252830 However, this finding could be explained by poorer performance status or the prognosis of patients receiving supportive care only after the completion of first-line therapy, limiting their eligibility for additional chemotherapy treatment. Such differences, if they existed, were not controlled for when making these comparisons.
In addition to information on treatment patterns and survival, this study provides details on the direct economic burden associated with gastric cancer-related treatments and supportive care, as well as the distribution of utilization and costs across different care settings (e.g., inpatient, physician office, hospital outpatient). In this study, the per-patient average lifetime all-cause costs exceeded USD 100,000 (Appendix 4), of which approximately 70% (mean, USD 70,808±56,620) comprised gastric cancer-related costs. Inpatient care accounted for more than half of the total all-cause and gastric cancer-related costs. In 2014, 22,220 new cases of gastric cancer were estimated to be diagnosed in the US, of which 62% were expected to occur among elderly patients (≥65 years), and among elderly patients, 34% (approximately 4700) will be diagnosed with metastatic gastric cancer.2 Combining these incidence figures with our estimate of per-patient average lifetime gastric cancer-related costs (i.e., approximately USD 70,000), the estimated total disease-related costs to Medicare could exceed USD 300 million for the lifetimes of these patients. In general, gastric cancer exerts a considerable economic burden on the Medicare system, and these cost estimates could increase as the population in the US continues to age.
Few studies have assessed costs and utilization patterns among patients with gastric cancer. The available data are dated and/or limited in terms of evaluating all aspects of direct costs.3132333435 Thus, we believe the current study provides more comprehensive and complete direct utilization and cost data. These data more accurately reflect the cost of treating this population, and thus, they may help better inform future cost-effectiveness analyses for newer treatments.
Several limitations should be considered when interpreting the findings of this study. The identification of patients with gastric cancer and determination of gastric cancer-directed treatments and supportive care utilization were conducted using relevant codes (e.g., ICD-O-3, ICD-9-CM, and HCPCS). Thus, any coding errors may have led to misclassification of these patients or gastric cancer-directed treatments. We used ICD-O-3 codes (C16.0-C16.9) to identify patients with gastric cancer including patients with GEJ cancer. However, per ICD-O-3 recommendations, patients with GEJ cancer may also be coded using ICD-0-3 code C16.0 (i.e., cardia NOS). Consequently, for the 1,111 patients with a C16.0 diagnosis code, we were unable to distinguish how many specifically had GEJ cancer. Through the Medicare claims data, it was not possible to determine which factors (e.g., disease severity, extent of progression, response to first-line chemotherapy regimen, lack of suitable second-line therapy, or cure) affect the decision to not prescribe a second-line therapy. The lack of oral prescription drug data (i.e., Medicare Part D data are available only for the period of 2007~2009) for the entire study period likely underestimates the use of gastric cancer-related prescription medications. We applied several inclusion and exclusion criteria and further limited the population to patients with evidence of both Medicare and SEER-linked data. Thus, the findings may not be generalizable to all Medicare enrollees with gastric cancer. Finally, this study was descriptive in nature, and statistical tests performed were not adjusted to account for differences in selected covariates between the populations.
Despite the noted limitations, this publication serves as the first documented comprehensive study describing real-world treatment patterns, survival, and health care utilization and costs before and after the completion of platinum- and/or fluoropyrimidine-based first-line chemotherapy among Medicare-enrolled patients with metastatic and/or unresectable gastric cancer. Our findings indicate that this patient population exerts a substantial economic burden on the Medicare system, with primary cost drivers being inpatient, hospital outpatient, and physician office visits. Survival following the completion of first-line chemotherapy remains poor in this population; however, improved survival was observed among patients receiving second-line treatment compared with patients receiving supportive care only. In conclusion, newer treatment options that would help improve survival and lower the overall economic burden are required.
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