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Medical Care Costs for Recurrent versus De Novo Stage IV Cancer by Age at Diagnosis.

Individuals diagnosed with advanced cancer comprise a sizeable proportion of cancer-related deaths and are responsible for substantial morbidity and spending in the United States (USA). There are two ways to develop advanced, noncurable cancer--be diagnosed with de novo metastatic stage IV cancer (i.e., the first occurrence of cancer) or develop recurrent metastatic cancer after previously having been treated for early-stage (i.e., stages I-III) disease. Given that most population-based datasets (including SEER and state-based tumor registries) cannot identify recurrent cancers (Warren and Yabroff 2015), little is known about whether there are cost differences between patients with de novo and recurrent metastatic cancers. In addition, many cost-effectiveness analyses associated with treatment trials for patients with metastatic cancer fail to differentiate between de novo versus recurrent metastatic cancer postdiagnosis cost trajectories (Takeda et al. 2007; Lange et al. 2014).

There are several reasons why the medical care and costs of patients with different types of advanced cancer might differ significantly. In contrast to patients with newly diagnosed cancer, those with a metastatic recurrence have been previously treated with surgery, systemic therapy, and/or radiotherapy and may therefore be ineligible for standard, first-line treatment (Jassem et al. 2009). They may have "late effects" and/or comorbid conditions resulting from their prior disease and treatment (Carver et al. 2007); the treatments and costs for their initial, nonmetastatic cancer diagnosis may extend for many months (Eisen et al. 2015); and surveillance-related utilization and costs after the completion of curative treatment for their initial cancer diagnosis may be significant (Khatcheressian et al. 2006; Backhus et al. 2014; Steele et al. 2015; Hahn et al. 2016). In addition, the experience of having recurrent disease after an attempt of curative therapy may lead to a shift in patients' treatment goals and values (Weeks et al. 2012).

A number of studies have described the variation in utilization and costs associated with the initial treatment for cancer patients diagnosed at late stage versus early stage (Riley et al. 1995; Taplin et al. 1995; Warren et al. 2008; Yabroff et al. 2008, 2011). Several studies have described the high cost of care for breast cancer recurrence (Lamerato et al. 2006; Kamon et al. 2007; Lidgren et al. 2007; Engel-Nitz et al. 2015), and others have generated cost estimates for metastatic disease in patients 65 years and older (Yabroff et al. 2009; Bradley et al. 2017). However, in many of the databases used to generate these estimates, cancer recurrence cannot be identified reliably. This raises concern that cost estimates associated with the surveillance or survivorship phases of care, as well as those associated with the advanced disease phase of care, could be biased. For example, health care costs incurred because of recurrence after definitive treatment for early-stage disease could be attributed to the survivorship phase rather than the advanced disease phase of care. The extent of this potential bias is not well understood (Brown et al. 2002; Mariotto et al. 2011; Yabroff et al. 2011; Guy et al. 2013). In addition, few population-based datasets are available for the estimation of cancer care-related utilization and costs for patients less than 65 years of age. To address the lack of data related to the direct medical costs of cancer recurrence, we estimated average total annual and monthly medical care costs for patients diagnosed with recurrent breast, colorectal, or lung cancer, relative to patients diagnosed with de novo disease. We estimate costs not only among Medicare aged-eligible patients (age [greater than or equal to] 65 years) but also among those under age 65 at diagnosis, a group that we hypothesize will receive more aggressive (and more expensive) treatment for both recurrent and de novo metastatic cancers.

METHODS

Data Sources

Data for this study were obtained from the Cancer Research Network's (CRN) Virtual Data Warehouse (VDW) at the Colorado, Northwest, and Washington (formerly Group Health Cooperative) Kaiser Permanente regions. The CRN (http://cm.cancer.gov/) is a consortium of large health care systems affiliated with the Health Care Systems Research Network and the National Cancer Institute (Chubak et al. 2016). The VDW contains administrative, electronic health record (EHR) and other clinical data that have been extracted, processed, and maintained at each site (Ross et al. 2014). Cancer diagnoses were obtained from the Virtual Tumor Registry (VTR) component of the VDW, which adheres to standards of the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program and the North American Association of Central Cancer Registries (NAACCR) (North American Association of Central Cancer Registries 2011). VTR data are derived from certified tumor registrars' manual review of patients' medical records and include demographics, diagnosis date, and tumor characteristics. VTR and VDW data are linked through a common, unique patient identifier (Ritzwoller et al. 2012, 2013, 2014; Hassett et al. 2014). Diagnosis and procedure-coded events are based on International Classification of Diseases, 9th and 10th revisions, Clinical Modification (ICD9 and ICD10), Healthcare Common Procedure Coding System (HCPCS), and the fourth edition of the Common Procedure Terminology codes (CPT-4). Oral and infused chemotherapy and immunotherapy were captured in the VDW infusion, pharmacy, and procedure files using methods previously described (Ritzwoller et al. 2013, 2014; Carroll et al. 2017). The VDW includes geocoded measures of socioeconomic status (e.g., median family income, and education) where patients' residential addresses are mapped to census block data using geocoding software. Deaths are derived from the tumor registries, membership data, state mortality files, and social security administration data. IRB approval was obtained from all three sites. All analyses were performed using SAS v 9.4 (SAS Inc., Cary, NC).

Study Sample

We identified patients diagnosed with de novo breast, colorectal, or lung cancers between January 1, 2000, and December 31, 2011, and patients who developed recurrent disease between January 1, 2000, and December 31, 2012, after having been initially diagnosed with stages I-III breast, colorectal, or lung cancer between January 1, 2000, and December 31, 2011. All de novo patients were identified from the VTR. Recurrent disease patients from KPCO and KPNW were identified through their respective VTRs, and those from KPWA were identified using our previously reported recurrence detection and timing algorithm (Hassett et al. 2014, 2017; Ritzwoller et al. 2017). Consistent with our previous analyses, eligibility for inclusion in the recurrence group was limited to patients who: (1) had no cancer prior to their incident breast, lung, or colorectal diagnosis; (2) completed definitive local-regional therapy for their incident cancer; and (3) survived and were followed for at least 30 days after definitive therapy. Censoring occurred if the VTR identified a second primary cancer. The date of the de novo or recurrent cancer diagnosis was considered the index date for this analysis. Patients were followed from 1 year prior to index date until death, disenrollment from the health plan, or one-year post-index date, whichever came first. Patients who disenrolled or were alive at the end of the study were censored as of those dates.

Utilization Measures

We examined inpatient, chemotherapy, and hospice use in the 12 months post-index date for de novo and recurrent cases across all three cancer cohorts. For recurrent cases, we also examined the proportion of cases who received chemotherapy and radiotherapy at the initial (i.e., incident stages I-III) diagnosis and in the twelve months after the index date (i.e., the recurrence date).

Costs

Medical care costs were estimated using the standard relative resource cost algorithm (SRRCA) (O'Keeffe-Rosetti et al. 2013). SRRCA applies uniform cost coefficients to standardized claims or EHR-derived utilization data to ensure that observed differences are not a result of differing pricing methods and billing rules (bundling of services). These estimates do not, however, account for variation in patient cost sharing or co-pays. Costs were reported in 2012 U.S. dollars. Average total monthly and annual costs were estimated from 1 year before the index date until disenrollment, death, or 1 year after the index date. For the monthly cost analysis, the calendar month associated with the index date was considered the index month.

Statistical Analysis

Patient characteristics were reported as means, medians, and standard deviations for interval-level variables (pre-index, index month, post-index) and percentages for categorical variables. Wilcoxon's rank-sum tests (for intervallevel variables) and chi-square tests of association (for categorical variables) were used to assess differences between the de novo and recurrent groups for all three cancer cohorts.

Differences in total annual and monthly costs between de novo versus recurrent cases were estimated separately for each cancer site across all age groups (and separately for patients aged <65 vs. [greater than or equal to]65) using generalized linear repeated-measures regression models with a gamma distribution and log link (Manning, Basu, and Mullahy 2005; Basu and Manning 2010; Guy et al. 2013). We also ran the generalized linear repeated-measures regression models where monthly costs were grouped into three-time periods: 12 months pre-index, index month, and 12 months post-index. The following covariates were included in the final adjusted model: age at index date, race/ethnicity, the Quan adaptation of the Charlson comorbidity index modified to exclude cancer diagnoses (Quan et al. 2005), census-based proxy for median family income, health plan (KPCO, KPNW, KPWA), index year, presence of an inpatient event within 12 months post-index date, receipt of chemotherapy within 12 months post-index date, and whether the individual died in the last month for which data were available. We address the potential bias in cost estimates due to differential follow-up among individuals that either disenrolled or died within 12 months following the index date using inverse proportional weights (IPWs), which account for key demographic and clinical factors related to differential follow-up. There were no significant differences in follow-up data among recurrent and de novo breast cancer patients, but there were differences in follow-up time among patients with lung and colorectal cancers.

RESULTS

Demographic and Clinical Characteristics

We identified 352 breast, 1,072 colorectal, and 4,041 lung cancer cases of de novo disease, along with 765 breast, 542 colorectal, and 340 lung cancer cases of recurrent disease after an early-stage initial diagnosis (see Figure SI: Consort Flow Diagram). As described in Table 1, relative to the recurrent cases, de novo colorectal and lung cancer patients were younger, and de novo lung cancer cases were more likely to be male. No clinically significant differences were found in race/ethnicity for de novo versus recurrent cases. Recurrent colorectal and lung cancer patients differed (higher) significandy (p < .054) in based proxies of income distribution. The year of the advanced cancer diagnosis, defined as the index year for this analysis, was relatively evenly distributed for de novo patients across all three cancer types. However, due to the study inclusion criteria (incident stages I-III diagnosis from 2000 to 2011 with a recurrent diagnosis through December 31, 2012), the recurrent cases were more heavily distributed during the latter years of the study. The comorbidity burden was statistically significandy higher only for the de novo lung cancer cases (relative to recurrent cases). A recurrence within 12 months of definitive therapy occurred in 18 percent, 31 percent, and 45 percent of the breast, colorectal, and lung cancer cases, respectively. In addition, relative to the recurrent cases, a larger proportion of the de novo colorectal (50 percent vs. 39 percent) and lung (71 percent vs. 52 percent) cancer cases died before the end of the study. The proportion of de novo cases who had at least one inpatient event after the index date was statistically significandy higher than the recurrent cases with 53 percent versus 42 percent for breast (p < .001), 76 percent versus 57 percent for colorectal (p < .001), and 60 percent versus 50 percent for lung cancers (p < .001), respectively. No statistically significant differences existed in the proportion of de novo versus recurrent cases who received chemotherapy or radiotherapy post-index date, across all three cancer sites. For recurrent cases, receipt of chemotherapy both at the initial (stages I-III) diagnosis and during the 12 months after the index date (recurrence) was higher for breast (51 percent) than colorectal (45 percent) or lung (22 percent). The use of radiotherapy in both time periods was also higher for breast (25 percent) than for colorectal (4 percent) or lung (12 percent). No statistically significant difference in hospice use was found for de novo versus recurrent colorectal or lung cancer cases; however, the hospice use for de novo breast cases was significantly lower than recurrent cases (6 percent vs. 12 percent, p-value .003).

Costs

Adjusted total monthly medical care costs for 12 months before and after the index date for patients with de novo versus recurrent breast, lung, or colorectal cancers appear in Figures 1-3, respectively. Separate estimates are provided for individuals over and under 65. For all cancer types, monthly costs during the pre-index period were significantly higher (p < .0001) for recurrent cancer patients than for de novo patients, through approximately 1 month prior to the index month (Figures 1-3 and Table 2). During the index month, monthly costs were considerably higher for de novo than for recurrent cancer patients for both colorectal cancer age groups (p < .0001) and lung cancer patients aged 65 and older (p < .0001). Higher costs were observed for all de novo breast cancer patients and for lung cancer patients aged less than 65, relative to recurrent patients, although these results did not reach statistical significance. Monthly costs between post-index month 1 and month 12 were statistically significantly higher among de novo than among recurrent patients for all cancers and all age groups. Table S1 describes the final parameter estimates.

Differences in adjusted average total monthly costs were consistent with the adjusted average total annual costs--for both the 12-month period before and the 12-month period after the index diagnosis (Table 2). Recurrent cancer patients had statistically significantly (p < .005) higher annual costs relative to de novo patients in the pre-index period, for all age groups and all three cancer sites. For example, women less than 65 had an average total annual cost of $3,310 [95% CI $2,563-$4,27] in the year prior to a de novo breast cancer diagnosis, compared to $30,531 [95% CI $26,149-$35,649] in the year prior to a recurrence diagnosis, for an estimated annual cost difference of $27,221 (de novo vs. recurrence, p < .0001). For CRC and lung cancer patients less than 65, the average annual cost differential (de novo vs. recurrence) was estimated at $35,703 (p < .0001) and $35,465 (p < .0001), respectively. For patients aged 65 and older, the differentials were not as large, but remained statistically significant, with the exception of lung cancer patients. For the 12-month period starting with and extending beyond the index month, average annual costs were greater for de novo versus recurrent cancer patients for all cancer types and age groups (Figures 1-3); all differences were statistically significant (p < .006) for all groups, except for lung cancer patients aged 65 years and older (-$2,065, p = .33).

DISCUSSION

Our study illuminates the striking differences in overall medical care costs for de novo versus recurrent cancers. Most notable was the difference in annual total costs between the two groups in the months prior to the index advanced cancer diagnosis. For patients less than 65 years of age, estimated medical care costs during the year prior to a diagnosis of a recurrence were approximately five- to ninefold higher than during the year prior to a diagnosis of de novo metastatic disease. Much of this difference may be explained by residual treatment for the initial cancer diagnosis and ongoing surveillance costs (Loggers et al. 2014; Chang and Gould 2017; Merkow et al. 2017), but further analyses are warranted to determine the relative importance of these factors as contributors to this difference. Regardless, the high cost of medical care for patients previously treated for early-stage disease illustrates the need for accessible and assessable guideline-based surveillance care. This is particularly important for patients less than 65 years of age, who are the most vulnerable with respect to access to health insurance (Thorpe and Howard 2003; Davidoff et al. 2015).

Medical care costs during the index month of the advanced cancer diagnosis spiked. This jump was especially notable for de novo patients, relative to those with recurrent cancer. This spike in costs, and the corresponding spike in utilization (Figures 1-3), is consistent with our previous work, which noted a one- to threefold increase in monthly utilization of total medical care services during the months leading up to an initial cancer diagnosis (Hombrook et al. 2013). De novo patients were younger and in the lung and colorectal cohorts less likely to survive for 12 months after the index diagnosis (Table 1) than recurrent patients, but it is not clear that these factors were responsible for the de novo/recurrent cost differential. We identified higher inpatient use for de novo cases, suggesting that the cost differential could be driven by hospitalizations and tests/procedures performed to evaluate the new cancer diagnosis. Patients with recurrent cancer previously had diagnostic studies for their initial cancer diagnosis, so it would not be surprising to expect relatively lower "evaluative" costs at the time of their cancer recurrence diagnosis. While cost differences (de novo vs. recurrent) during the index month were lower for all cancer types, the differences were not statistically significant for breast cancer patients or for lung cancer patients less than 65.

Cost differentials persisted throughout the 12-month post-index period. These differences were reflected in the significantly lower average total annual costs for patients with recurrent versus de novo disease (except for breast cancer patients). Some have suggested that the use of aggressive and expensive initial treatments (Sagar, Lin, and Castel 2017) and/or end-of-life care could be driving costs for de novo cases. However, we found no significant differences between groups with respect to the proportion who received chemotherapy or radiotherapy in the 12 months following the index date. Across all cohorts, a minority of recurrent cases received chemotherapy in both the initial and recurrent settings (Yardley et al. 2014; Rier et al. 2017). Perhaps, providers are less likely to recommend aggressive, expensive therapy for recurrent versus de novo cases, because patients with recurrence may be relatively chemoresistant, whereas de novo cases are inherently chemotherapy naive and may be more likely to benefit from therapy (Malmgren et al. 2018). The average total annual cost estimates further illuminate the cost differences between groups (de novo vs. recurrent) by period (pre-/post-index). Also, we noted higher costs for patients in the younger age group --a finding previously noted by Taplin (Taplin et al. 1995) and Mariotto (Mariotto et al. 2011) in their estimates of initial care costs for patients with distant disease.

We are not aware of previous studies evaluating the medical care costs for patients with recurrent lung or colorectal cancer. For patients with recurrent breast cancer, our estimates of average total annual costs differed from those reported previously. Specifically, for 765 recurrent breast cancer cases (mean age 62.5), we estimated costs before and after recurrence to be $27,038 and $57,549 (2012$U.S., data not shown), respectively. Studying 62 patients with recurrent breast cancer who had at least 12 months of follow-up, Lamearto (Lamerato et al. 2006) reported billed charges of $12,344 before and $79,253 after recurrence (2003$U.S.). However, in addition to a much smaller cohort, this analysis included younger patients, used charges rather than costs, and did not include pharmacy charges. Karnon (Karnon et al. 2007) estimated costs in the year after a metastatic recurrence (2004[pounds sterling]) for patients who died/experienced a subsequent event (n = 56) and for patients who remained alive with no further event (n = 36), to be [pounds sterling]10,003 and [pounds sterling]9,409, respectively. Stokes (Stokes et al. 2008) used SEER/Medicare claims to estimate the 10-year costs of care for patients with recurrent breast cancer, finding that costs ranged from $11,000 to $19,183 (2004$U.S.). Even after adjusting for inflation and exchange rates, most of these other estimates are approximately 50 percent lower than our findings.

Our study begins to fill large gaps in the literature on the variation in medical care costs for patients with recurrent versus de novo metastatic disease, within and across three cancer types that comprise a sizeable proportion of the overall economic burden of cancer in the United States (Yabroff et al. 2011). The strengths of our study include the use of tumor registry data to identify cancer cases and recurrences--supplemented with a validated cancer recurrence detection and timing algorithm (Hassett et al. 2014; Ritzwoller et al. 2017). Second, we captured complete utilization and costs of medical care, both before and after the most important sentinel event in the cancer trajectory. We did not use health plan-specific charges, costs, or payments, given that they can vary for the same service, for the same diagnosis and/or treatment, and even across regions within the Kaiser Permanente program. Instead, we implemented a standardized costing algorithm that is based on Medicare fee schedules (O'Keeffe-Rosetti et al. 2013), thus allowing comparisons between our estimates and other published SEER-/Medicare-based estimates.

However, our study is not without limitations. First, we did not estimate "net" medical care costs relative to matched noncancer controls (Campbell and Ramsey 2009; Guy et al. 2013; Yabroff, Borowski, and Lipscomb 2013; Yabroff et al. 2013); however, findings from our prior work indicate that net costs (i.e., those attributable specifically to cancer) account for the majority of total costs in the year following diagnosis among de novo breast, colorectal, and lung cancer patients (Banegas et al. 2015). We did not decompose all the components driving variation in medical care costs within and between groups. The cost estimates reported in our study reflect utilization patterns of populations diagnosed with cancer between 2000 and 2011 (2012 for recurrent cancers), and thus, our estimates do not account for more recently approved, and often higher-cost, targeted therapies. Also, our study sample was not as racially, ethnically, and geographically diverse as the U.S. population. Further, we present cost estimates from the payer or health system perspective and do not capture patient cost liabilities, which may lead to substantial financial hardship for many patients and their families (Banegas and Yabroff 2013). Assessing the financial burden of patients with recurrent cancer is largely unknown and should be a focus of future research. Lasdy, our study is specific to the experience of patients receiving care from salary-based clinicians within three KP integrated health care systems. Consistent with our previous studies related to treatments and outcomes for patients with advanced cancer (Ritzwoller et al. 2012, 2014), we strongly believe that our findings generalize to other settings. However, given that financial incentives to provide more expensive treatments are mitigated within the KP setting, the cost estimates from this study may actually be less than what one might observe in a fee-forservice setting.

Cost differences between de novo and recurrent cancers reveal heterogeneity in care patterns that merits further investigation. Understanding differences in costs/utihzation for de novo and recurrent cancer patients is critical when developing treatment plans, evaluating factors associated with spending/quality (including assessing overuse and underuse), and studying episode-based reimbursement models. The costs reported by this study may serve as a benchmark for stage-specific phase-of-care oncology episode payment models and future cost-effectiveness studies of treatments for advanced cancer.

ACKNOWLEDGMENTS

Joint Acknowledgment/Disclosure Statement: This work was supported by a grant from the National Cancer Institute (R01 CA172143 DPR/MJH), with additional support from NCI (U2 C171524 to the Cancer Research Network, Lawrence Kushi, PI), R01 CA10527, U01 CA195565; The American Society of Clinical Oncology (Career Development Award) to MJH.

Disclosures: None.

Disclaimer: None.

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SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of the article.

Appendix SA1: Author Matrix.

Figure S1: Qualifying Patients for Recurrence Cost Analysis.

Table S1: Average Total Monthly Cost Model Parameter Estimates by Cancer Site.

Debra P. Ritzwoller [iD], Paul A. Fishman, Matthew P. Banegas, Nikki M. Carroll, Maureen O'Keeffe-Rosetti, Angel M. Cronin, Hajime Uno, Mark C. Hombrook, and Michael J. Hassett

Address correspondence to Debra P. Ritzwoller, Ph.D., Institute for Health Research, Kaiser Permanente Colorado, Waterpark III, 2550 S. Parker Rd., Suite 200, Aurora, CO 80014; e-mail: debra.ritzwoller@kp.org. Paul A. Fishman, Ph.D., is with the Department of Health Services, University of Washington, Seatde, WA; and Kaiser Permanente Washington Health Research Institute, Seattle, WA. Matthew P. Banegas, Ph.D., Maureen O'Keeffe-Rosetti, M.S., and Mark C. Hombrook, Ph.D., are with the Kaiser Permanente Center for Health Research, Portland, OR. Nikki M. Carroll, M.S., is with the Institute for Health Research, Kaiser Permanente Colorado, Aurora, CO. Angel M. Cronin, M.S., is with the Dana-Farber Cancer Institute, Boston, MA. Hajime Uno, Ph.D., and Michael J. Hassett, M.D., M.P.H., are with the Dana-Farber Cancer Institute, Boston, MA; and Harvard Medical School, Boston, MA.

DOI: 10.1111/1475-6773.13014
Table 1: Demographics of De Novo and Recurrent Cohorts by Cancer Site

                                                     Breast Cancer
                                       De Novo       Recurrent
                                       N(%)          N(%)

Total cases                            352           765
Demographics
Race/ethnicity (*)
White                                  297 (84)      638 (83)
Nonwhite                                38 (11)       79 (10)
Unknown                                 17 (5)        48 (6)
Female                                 352 (100)     765 (100)
Age on index date
21-54 years                            113 (32)      238 (31)
55-69 years                            126 (36)      267 (35)
70+ years                              113 (32)      260 (34)
<65 years                              214 (61)      421 (55)
Mean age at index (SD)                  61.6 (13.5)   62.5 (14.7)
Income (census block level based)
<$40,000                                22 (6)        79 (10)
$40,000-$60,000                        125 (36)      252 (33)
$60,000+                               205 (58)      434 (57)
Health Caxe System (HCS)
HCS#1                                  134 (38)      282 (37)
HCS #2                                 110 (31)      231 (30)
HCS #3                                 108 (31)      252 (33)
Clinical characteristics
Diagnosis index year
2000-2003                               93 (26)      109 (14)
2004-2006                               84 (24)      183 (24)
2007-2009                               94 (27)      234 (31)
2010-2012                               81 (23)      239 (31)
Stage ([dagger])
I                                        0 (0)       200 (26)
II                                       0 (0)       348 (46)
III                                      0 (0)       217 (28)
IV                                     352 (100)       0 (0)
Comorbidities
0                                      246 (70)      554 (72)
1                                       64 (18)      134 (18)
2+                                      42 (12)       77 (10)
Recurrence within 12 months of               -       136 (18)
definitive therapy ([double dagger])
Death within 12 months post-index       95 (27)      242 (32)
date
Inpatient event within 12 months       186 (53)      319 (42)
post-index date
Chemotherapy within 12 months          240 (68)      529 (69)
post-index date
Chemotherapy at initial diagnosis and   NA           386 (50)
within 12 months post-index
Radiotherapy within 12 months          137 (39)      327 (43)
post-index
Radiotherapy at initial diagnosis and   NA           194 (25)
within 12 months post-index
Hospice within 12 months post-index     22 (6)        92 (12)

                                                Colorectal Cancer
                                                De Novo
                                       p-Value  N(%)

Total cases                                          1,072
Demographics
Race/ethnicity (*)
White                                  .6241       840 (78)
Nonwhite                                           115 (11)
Unknown                                            117 (11)
Female                                 NA          525 (49)
Age on index date
21-54 years                            .8243       244 (23)
55-69 years                                        379 (35)
70+ years                                          449 (42)
<65 years                              .0708       486 (45)
Mean age at index (SD)                 .3240        66.1 (13.6)
Income (census block level based)
<$40,000                               .0821       110 (10)
$40,000-$60,000                                    397 (37)
$60,000+                                           565 (53)
Health Caxe System (HCS)
HCS#1                                  .7544       356 (33)
HCS #2                                             364 (34)
HCS #3                                             352 (33)
Clinical characteristics
Diagnosis index year
2000-2003                              <.0001      341 (32)
2004-2006                                          270 (25)
2007-2009                                          287 (27)
2010-2012                                          174 (16)
Stage ([dagger])
I                                      NA              0(0)
II                                                     0(0)
III                                                    0(0)
IV                                              1,072 (100)
Comorbidities
0                                      .5873       609 (57)
1                                                  231 (21)
2+                                                 232 (22)
Recurrence within 12 months of                           -
definitive therapy ([double dagger])
Death within 12 months post-index      .1161       532 (50)
date
Inpatient event within 12 months       .0005       819 (76)
post-index date
Chemotherapy within 12 months          .7454       704 (66)
post-index date
Chemotherapy at initial diagnosis and  -            NA
within 12 months post-index
Radiotherapy within 12 months          .2282       165 (15)
post-index
Radiotherapy at initial diagnosis and  -            NA
within 12 months post-index
Hospice within 12 months post-index    .0031       134 (13)

                                                     Lung Cancer
                                       Recurrent
                                       N(%)          p-Value

Total cases                            542
Demographics
Race/ethnicity (*)
White                                  434 (80)      .1070
Nonwhite                                66 (12)
Unknown                                 42 (8)
Female                                 248 (46)      .2217
Age on index date
21-54 years                             76 (14)      .0002
55-69 years                            214 (40)
70+ years                              252 (47)
<65 years                              201 (37)      .0015
Mean age at index (SD)                  68.2 (12.3)  .0032
Income (census block level based)
<$40,000                                47 (9)       .0331
$40,000-$60,000                        190 (35)
$60,000+                               305 (56)
Health Caxe System (HCS)
HCS#1                                  188 (35)      .0180
HCS #2                                 148 (27)
HCS #3                                 206 (38)
Clinical characteristics
Diagnosis index year
2000-2003                              114 (21)      <.0001
2004-2006                              151 (28)
2007-2009                              165 (30)
2010-2012                              112 (21)
Stage ([dagger])
I                                       51 (9)       NA
II                                     165 (30)
III                                    326 (60)
IV                                       0 (0)
Comorbidities
0                                      283 (52)      .1186
1                                      140 (26)
2+                                     119 (22)
Recurrence within 12 months of         170 (31)
definitive therapy ([double dagger])
Death within 12 months post-index      211 (39)      <.0001
date
Inpatient event within 12 months       307 (57)      <.0001
post-index date
Chemotherapy within 12 months          349 (64)      .6099
post-index date
Chemotherapy at initial diagnosis and  241 (44)      _
within 12 months post-index
Radiotherapy within 12 months           88 (16)      .6595
post-index
Radiotherapy at initial diagnosis and   19 (3.5)     -
within 12 months post-index
Hospice within 12 months post-index     54 (10)      .1335

                                       Lung Cancer
                                       De Novo         Recurrent
                                       N(%)            N(%)

Total cases                            4,041           340
Demographics
Race/ethnicity (*)
White                                  3,424 (85)      287 (84)
Nonwhite                                 353 (9)        33 (10)
Unknown                                  264 (7)        20 (6)
Female                                 1,949 (48)      183 (54)
Age on index date
21-54 years                              432 (11)       21 (6)
55-69 years                            1,672 (41)      144 (42)
70+ years                              1,937 (48)      175 (52)
<65 years                              1,450 (36)      109 (32)
Mean age at index (SD)                    68.3 (10.5)   69.0 (9.4)
Income (census block level based)
<$40,000                                 490 (12)       34 (10)
$40,000-$60,000                        1,610 (40)      140 (41)
$60,000+                               1,941 (48)      166 (49)
Health Caxe System (HCS)
HCS#1                                  1,378 (34)      124 (36)
HCS #2                                 1,201 (30)       80 (24)
HCS #3                                 1,462 (36)      136 (40)
Clinical characteristics
Diagnosis index year
2000-2003                              1,268 (31)       68 (20)
2004-2006                              1,074 (27)       93 (27)
2007-2009                              1,018 (25)       94 (28)
2010-2012                                681 (17)       85 (25)
Stage ([dagger])
I                                          0 (0)       177 (52)
II                                         0 (0)        86 (2.5)
III                                        0 (0)        76 (22)
IV                                     4,042 (100)       0 (0)
Comorbidities
0                                      2,047 (51)       96 (28)
1                                        953 (24)      130 (38)
2+                                     1,041 (26)      114 (34)
Recurrence within 12 months of                 -       152 (45)
definitive therapy ([double dagger])
Death within 12 months post-index      2,879 (71)      177 (52)
date
Inpatient event within 12 months       2,414 (60)      170 (50)
post-index date
Chemotherapy within 12 months          2,601 (64)      223 (66)
post-index date
Chemotherapy at initial diagnosis and  NA               76 (22)
within 12 months post-index
Radiotherapy within 12 months          1,997 (49)      157 (46)
post-index
Radiotherapy at initial diagnosis and  NA               39 (11)
within 12 months post-index
Hospice within 12 months post-index      732 (18)       58 (17)



                                       p-Value

Total cases
Demographics
Race/ethnicity (*)
White                                   .7619
Nonwhite
Unknown
Female                                  .0475
Age on index date
21-54 years                             .0292
55-69 years
70+ years
<65 years                               .1573
Mean age at index (SD)                  .2067
Income (census block level based)
<$40,000                                .0541
$40,000-$60,000
$60,000+
Health Caxe System (HCS)
HCS#1                                   .0529
HCS #2
HCS #3
Clinical characteristics
Diagnosis index year
2000-2003                              <.0001
2004-2006
2007-2009
2010-2012
Stage ([dagger])
I                                      NA
II
III
IV
Comorbidities
0                                      <.0001
1
2+
Recurrence within 12 months of
definitive therapy ([double dagger])
Death within 12 months post-index      <.0001
date
Inpatient event within 12 months        .0007
post-index date
Chemotherapy within 12 months           .6509
post-index date
Chemotherapy at initial diagnosis and   -
within 12 months post-index
Radiotherapy within 12 months           .2738
post-index
Radiotherapy at initial diagnosis and   -
within 12 months post-index
Hospice within 12 months post-index     .6283

(*) Nonwhite includes Hispanic, black, Asian, and other races and/or
ethnicities.
([dagger]) For lung cancer cohorts, de novo includes stages IIIB and
IV, while recurrent includes stages I, II, or IIIA (at initial
diagnosis).
([double dagger]) Definitive therapy is defined mastectomy/lumpectomy
for breast cancer, colectomy for CRC, and lobectomy for lung cancer,
with or without radiation.

Table 2: Cost Estimates by Cancer Site and Age Group

                      Adjusted Average Total Monthly Costs
                      [greater than or equal to]65 Years of
                      Age at Index Date
                      Average Monthly Cost [$] (95% CI)


                      De Novo                    Recurrent

Breast
12 months pre            305 (236-394.-)          2,737 (2,337-3,205)
Index month            7,926 (6,564-9,572.-)      7,099 (5,985-8,421)
12 months post         8,559 (7,398-9,904.-)      7,817 (6,896-8,859)
Colorectal cancer
12 months pre            448 (336-595.-)          3,667 (3,067-4,383)
Index month           13,588 (11,838-15,596.-)    5,601 (4,450-7,050)
12 months post         8,694 (7,724-9,785.-)      6,217 (5,334-7,247)
Lung cancer-Outliers
Removed ([dagger])
12 months pre            582 (507-669.-)          3,669 (3,140-4,287)
Index month           10,980 (10,152-11,876.-)    8,724 (6,757-11,263)
12 months post         7,148 (6,722-7,602.-)      5,592 (4,673-6,690)
Breast
12 months              3,310 (2,563-4,274.-)     30,531 (26,149-35,649)
pre
Index                 90,391 (79,197-103,166.-)  72,243 (64,492-80,926)
month +
11 months
post
Colorectal cancer
12 months              4,721 (3,331-6,690.-)     40,424 (33,359-48,991)
pre
Index                 79,809 (70,735-90,048.-)   54,956 (46,859-64,453)
month +
11 months
post
Lung cancer-Outliers
removed ([dagger])
12 months              6,508 (5,628-7,525.-)     41,973 (35,789-49,232)
pre
Index                 64,582 (60,240-69,230.-)   52,759 (45,437-61,261)
month +
11 months
post


                      [greater than or equal to]65 Years of Age at
                      Index Date
                      Average Monthly Cost [$] (95% CI)
                                  p-Value
                      Cost        on Cost
                      Difference  Difference (*)

Breast
12 months pre           2,431     <.0001
Index month              -827      .1087
12 months post           -742      .0690
Colorectal cancer
12 months pre           3,219     <.0001
Index month            -7,987     <.0001
12 months post         -2,476     <.0001
Lung cancer-Outliers
Removed ([dagger])
12 months pre           3,086     <.0001
Index month            -2,256      .0821
12 months post         -1,556      .0071
Breast
12 months              27,221     <.0001
pre
Index                 -18,148      .0005
month +
11 months
post
Colorectal cancer
12 months              35,703     <.0001
pre
Index                 -24,853     <.0001
month +
11 months
post
Lung cancer-Outliers
removed ([dagger])
12 months              35,465     <.0001
pre
Index                 -11,823      .0057
month +
11 months
post


                      [greater than or equal to]65 Years of Age at
                      Index Date
                      Average Monthly Cost [$] (95% CI)


                      De Novo                 Recurrent

Breast
12 months pre            818 (608-1,099)       2,178 (1,843-2,776)
Index month            9,210 (7,309-11,607)    6,530 (5,396-7,903)
12 months post         5,816 (4,852-6,972)     4,772 (4,213-5,406)
Colorectal cancer
12 months pre            878 (749-1,029)       3,125 (2,701-3,616)
Index month           15,500 (13,468-17,836)   7,093 (5,778-8,708)
12 months post         7,024 (6,221-7,932)     5,274 (4,587-$6,063)
Lung cancer-Outliers
Removed ([dagger])
12 months pre          1,025 (938-1,121)       3,286 (2,914-3,705)
Index month           10,314 (9,946-11,029)    6,138 (5,018-7,509)
12 months post         5,498 (5,203-5,811)     4,505 (3,989-5,089)
Breast
12 months              9,596 (7,103-12,964)   24,797 (21,118-29,117)
pre
Index                 55,436 (47,112-65,238)  44,378 (39,703-49,602)
month +
11 months
post
Colorectal cancer
12 months             11,558 (9,730-13,729)   36,702 (31,650-42,565)
pre
Index                 59,623 (53,690-66,210)  43,726 (37,702-50,322)
month +
11 months
post
Lung cancer-Outliers
removed ([dagger])
12 months             11,286 (10,288-12,383)  36,195 (31,758-41,249)
pre
Index                 41,919 (39,410-44,587)  39,854 (35,710-44,480)
month +
11 months
post


                      [greater than or equal to]65 Years of Age at
                      Index Date
                      Average Monthly Cost [$] (95% CI)
                                  p-Value on
                      Cost        Cost
                      Difference  Difference (*)

Breast
12 months pre           1,360     <.0001
Index month            -2,679      .1391
12 months post         -1,043      .0967
Colorectal cancer
12 months pre           2,247     <.0001
Index month            -8,406     <.0001
12 months post         -1,750      .0004
Lung cancer-Outliers
Removed ([dagger])
12 months pre           2,260     <.0001
Index month            -4,175     <.0001
12 months post           -993      .0013
Breast
12 months              15,201     <.0001
pre
Index                 -11,058      .0086
month +
11 months
post
Colorectal cancer
12 months              25,144     <.0001
pre
Index                 -15,897      .0001
month +
11 months
post
Lung cancer-Outliers
removed ([dagger])
12 months              24,909     <.0001
pre
Index                  -2,065      .3236
month +
11 months
post

(*) Differences in cost based on log values.
([dagger]) Outliers removed by adjusting all costs outside of the 99th
percentile to overall mean cost.
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Title Annotation:RESEARCH ARTICLE
Author:Ritzwoller, Debra P.; Fishman, Paul A.; Banegas, Matthew P.; Carroll, Nikki M.; O'Keeffe-Rosetti, Ma
Publication:Health Services Research
Date:Dec 1, 2018
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