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Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System

Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer... R E S E A RC H Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System Nazia Rashid, PharmD, MS; Han A. Koh, MD; Hilda C. Baca, BS; Zhaoliang Li, MS; Susan Malecha, PharmD, MBA; Oyewale Abidoye, MD, MPH; and Anthony Masaquel, PhD, MPH ABSTRACT have more impact on chemotherapy regimens. In our multivariate analy- sis, patients aged > 65 years, having more than 1 comorbidity and having BACKGROUND: Stage IV breast cancer, also known as metastatic breast longer duration in days for each episode of care were all associated with cancer (mBC), is not a curable condition. However, treatment can prolong clinical impact. Black and Hispanic patients were more likely to have a life, delay the progression of the cancer, or improve quality of life. Currently, modification in their chemotherapy compared with white patients. patients with mBC are often treated with chemotherapy. Patients often CONCLUSIONS: This retrospective analysis demonstrates that chemothera- experience adverse events from chemotherapy during the treatment cycle, py-related adverse events in patients with mBC have an impact on the deliv- which leads to chemotherapy modifications such as dose delay, dose reduc- ery of chemotherapy regimens. Having multiple comorbidities, increased tion, or discontinuation of chemotherapy. Previous studies have evaluated age, and prolonged hospitalizations because of adverse events appear to be the rates of adverse events that occur from the use of chemotherapy; how- some of the primary factors related to chemotherapy modification. ever, few studies have evaluated the clinical impact on the chemotherapy regimen once the adverse event occurs. This study evaluates the clinical J Manag Care Spec Pharm. 2015;21(10):863-71 impact on the chemotherapy regimen from chemotherapy-related adverse Copyright © 2015, Academy of Managed Care Pharmacy. All rights reserved. events in patients with mBC in an integrated health care delivery system. OBJECTIVES: To assess the adverse events in patients with mBC and evalu- ate the clinical impact on the chemotherapy regimen from these adverse events in an integrated health care delivery system. What is already known about this subject METHODS: This study is a retrospective cohort of patients with mBC newly initiated on chemotherapy. The first infusion was defined as the index date. • Stage IV breast cancer, also known as metastatic breast cancer Patients were aged > 18 years at time of index date and had 6 months or (mBC), is not a curable condition; however, treatment can prolong more of Kaiser membership and drug eligibility prior to the index date and life, delay the progression of the cancer, or improve quality of life. continuous membership and drug eligibility throughout follow-up. Adverse • Although chemotherapy is given in cycles, patients often experi- events were identified after the index date and during the follow-up using ence adverse events from chemotherapy during the cycle, which ICD-9-CM diagnosis and procedure codes. Single or multiple episodes of leads to chemotherapy modification, such as dose delay, dose care were created from the adverse events. Chart review was conducted to establish whether the adverse event was related to chemotherapy and reduction, or discontinuation of chemotherapy. if any modification to the chemotherapy regimen occurred—a dose delay, • Few retrospective studies have evaluated the clinical impact from dose reduction, or discontinuation was considered a clinical impact on adverse events on chemotherapy treatments, and studies that therapy. Multivariate logistic regression was used to examine factors asso- have did not evaluate chemotherapy modification because of ciated with clinical impact versus no clinical impact from the delivery of chemotherapy adverse events. chemotherapy treatment. What this study adds RESULTS: A total of 1,682 patients with mBC were identified during our time period with an average follow-up of 2.21 years on first-line chemo- • This study used an episode of care method to evaluate chemo- therapy (SD = 1.83). 909 patients (54%) had at least 1 adverse event, and therapy adverse events in order to provide a more real-world 773 patients (46%) did not have any adverse events during follow-up. approach that reflects the common practice of our health care Significant differences at baseline between these 2 groups included race, delivery system. peripheral vascular disease, and length of stay (P < 0.05). From the 909 • A chart review was conducted to determine if the episode of patients who had at least 1 adverse event, 185 patients (20%) experienced care-related adverse event was from chemotherapy or disease an impact on their chemotherapy regimens. Patients with single episodes progression. of care with any chemotherapy regimen impact experienced mostly hema- • Factors such as multiple comorbidities, increased age, and pro- tological, infection/pyrexia, and gastrointestinal-related adverse events. In multiple episodes of care, neurological impact was more frequent than longed hospitalizations because of adverse events appear to be gastrointestinal-related effects. Patients with hospitalizations of > 3 days some of the primary factors related to chemotherapy modification. experienced the most impact, demonstrating that severe adverse events www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 86 3 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System reast cancer is one of the most common malignan- and to evaluate the clinical impact on the chemotherapy cies in women. In 2013, it was estimated that 232,340 regimen from these adverse events in an integrated health Bwomen in the United States were diagnosed with breast care delivery system. We applied an episode of care method cancer, and that 39,620 women died of breast cancer. Breast to provide a more real-world approach, reflecting the common cancer remains a serious health care problem and accounts practice of our health care delivery system, and we conducted a for approximately one third of cancers in the Unites States. chart review to determine if the episode of care-related adverse Overall survival varies by breast cancer stage. People diag- events were from chemotherapy or from disease progression. nosed with stage 0, I, or II breast cancers tend to have higher ■■  Methods overall survival rates than people diagnosed with stage III or IV breast cancer; however, overall survival rates are averages Study Setting and Data and vary depending on each person’s diagnosis and treat- Kaiser Permanente Southern California (KPSC) is an inte- ment. Stage IV, also known as metastatic breast cancer (mBC) grated health care delivery system with approximately 3.6 is not a curable condition; however, treatment can prolong million members. The KPSC membership currently represents life, delay the progression of the cancer, or improve quality of 15% of the population in the Southern California region, 3,4 life. Approximately 6% of women with incident breast cancer and this membership closely mirrors the Southern California have metastatic disease at initial presentation, and the median population; it is racially diverse and includes the entire survival of individuals with mBC is 18 to 24 months, although socioeconomic spectrum. Data were derived from the KPSC the range in survival spans between a few months to many Health Plan (KPSC HP) database and The Kaiser Permanente 4,5 years and depends on the type of breast cancer. Breast can- Regional Cancer Registry (CANREG) database. The KPSC cer can be treated with different modalities. One modality is HP database contains information on patient demographics, chemotherapy, which can be given as a sequential single agent diagnoses, prescriptions, laboratory results, and medical and or in combination to slow, stop, or kill the growth of cancer hospital encounters. KPSC HP has an electronic health medi- cells. Chemotherapy is given in cycles, such as 21 or 28 days, cal record system that allows for more detailed information to which allows the body to recover from the side effects of the be accessed and included in studies. For all reportable cancers, medicines. the CANREG database is a compilation of data collected at the Although chemotherapy is given in cycles, patients often registry level from each of the 14 KPSC hospitals and contains experience adverse events from chemotherapy during the information on patients who are newly diagnosed or who cycle, which leads to a chemotherapy modification that may received at least part of their first course of treatment for can- include dose delay, dose reduction, or discontinuation of cer at a KPSC hospital. The CANREG data are provided to the chemotherapy. Studies have reported that interrupting chemo- Surveillance, Epidemiology, and End Results (SEER) program, therapy cycles or not providing a high percentage of relative a part of the National Cancer Institute that collects cancer data dose intensity will not improve the patient’s disease progres- in the United States and compiles national cancer statistics. 6-9 sion thus decreasing overall survival rates. Few retrospective The diagnoses are validated and confirmed cancer diagnoses, studies have evaluated the clinical impact from adverse events which makes the KPSC CANREG applicable when conducting on chemotherapy. One study used retrospective U.S. data various retrospective or prospective longitudinal studies. The that included the general population; however, the patients institutional review board for KPSC approved this study. were aged less than 63 years and had newly diagnosed breast Design and Study Population cancer during the time period of April 1, 1998, to December 31, 2002. Another study was a population-based assessment A retrospective cohort database analysis was conducted dur- of hospitalizations because of chemotherapy adverse events ing the study enrollment period from January 1, 2007, to within the Medicare population. The patients were aged 65 December 31, 2011. Patients with mBC were either selected years or more and had all stages of breast cancer during the from the KPSC CANREG or by using medical claims from time period of 1991 to 1996, In addition, the study focused the following algorithm (Figure 1) : patients had more than 2 on chemotherapy adverse events in the hospital setting but medical encounters within 90 days between January 1, 2007, did not quantify other health care resource utilization in this and December 31, 2011, with the International Classification population. of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) Although these studies evaluated rates of chemotherapy codes 197.xx-198.xx. The date of metastatic diagnosis was adverse events, they did not evaluate the clinical impact of defined as the metastatic disease index date. We identified adverse events on chemotherapy treatment for patients with patients with breast cancer using the ICD-9-CM codes 174.xx mBC and aged older than 18 years. Consequently, the objec- or 233.0x. These codes had to be identified prior to the mBC tives for this study were to describe chemotherapy-related date starting from January 1, 2002 (5 years prior) or 90 days adverse events in patients with mBC receiving chemotherapy after the mBC date. Patients had to be female and aged more 864 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System FIGURE 1 mBC Study Population Diagram Identify patients who had > 2 medical encounters within 90 days with diagnosis codes for secondary neoplasms (197.xx-198.xx) between January 1, 2007, and December 31, 2011 (N = 18,462) →mBC date Identify patients with > 1 diagnosis code for breast cancer (174.xx or 233.0x) going back to January 1, 2002, before or 90 days after mBC date (N = 3,365) →diagnosis date Exclude patients who are male and aged < 18 years on diagnosis date (N = 244) Female and aged > 18 years (N = 3,121) Exclude patients with other cancers 365 days prior to diagnosis date (140.x-165.x, 170.x-173.x, 175.x-176.x, 179.x-195.x, 196.x, 199.x-209.x, 230.x-234.x [except 233.0x], 235.x-239.x [except 238.3, 239.3], and V10.x [except V10.3]) N = 498 No other cancers prior to diagnosis date (N = 2,623) Add patients from KPSC Cancer Registry using same time period, identified date of mBC, females, and aged ≥18 years, with no overlapping (N = 661) mBC cohort N = 3,284 Exclude patients without continuous membership and drug benefit eligibility 6 months prior to mBC date N= 360 mBC cohort with continuous membership and eligibility N = 2,924 Final mBC cohort with chemotherapy N = 1,682 KPSC = Kaiser Permanente Southern California; mBC = metastatic breast cancer. than 18 years on the date of diagnosis. We excluded patients drug benefit prior to the mBC date and throughout follow-up with any other cancers 12 months prior to the diagnosis date (Figure 1). (140.xx to 165.xx, 170.xx to 173.xx, 175.xx to 176.xx, 179.xx to Identification of Chemotherapy and Patient Follow-Up 195.xx, 196.xx, 199.xx to 209.xx, 230x-234.x [except 233.0x], 235.x-239.x [except 238.3, 239.3], and V10.x [except V10.3]). Once the final cohort of mBC patients was established, Patients had to have 6 months of continuous membership and we used pharmacy and CANREG databases to identify the www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 865 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System first-line chemotherapy for each patient. Chemotherapy was Two types of EOCs were created: a single EOC and a mul- identified using National Drug Code numbers and Generic tiple EOC. A multiple EOC represented repeated health care Product Identifiers if patients were prescribed 1 or more of visits for the management of an adverse event. A single EOC the following: capecitabine, taxanes (docetaxel and paclitaxel), was defined as 1 health care resource encounter for a specific cyclophosphamide, doxorubicin, gemcitabine, epirubicin, adverse event with no other health care encounter within 2 vinorelbine, ixabepilone, and eribulin. Once the chemotherapy weeks from that visit. Thus. single episodes could be an out- was identified for the patient with mBC, we searched the data- patient visit for 1 day or a hospital visit of 3 days. A multiple bases to ensure that no other chemotherapy regimens had been episode EOC was defined as a patient having more than 1 initiated in the prior 12 months. We evaluated use of chemo- health care resource encounter within a 2-week time period. therapy only and did not evaluate hormonal status or examine For example, a patient could have an outpatient visit, then in 3 targeted therapies. If no other chemotherapy regimens were days have another outpatient visit, then in 2 days go to the ER, identified, we categorized the patient by chemotherapy regi- and then be admitted to the hospital for 5 days for the same men and identified the date of the first cycle as the treatment condition. Since there was no 2 week gap between the encoun- index date. Patient follow-up was defined from the index date ters, these episodes were counted as 1 multiple EOC. until disenrollment from the health plan, start of a new chemo- therapy regimen, or end of the study time period (December Defining Clinical Impact 31, 2012), whichever came first. During the follow-up period, Pharmacy claims and chart reviews were used to identify if adverse events were identified while patients were undergoing their first-line chemotherapy regimen. an EOC was related to a patient’s chemotherapy treatment by reading the chart notes available during the time of an adverse Adverse Events event occurrence and then noting if there was a modification of Previous studies and trials were used to identify adverse or clinical impact on the chemotherapy regimen. In this study, 10,11,14 events. The following adverse events were selected based we defined any modification of a patient’s chemotherapy regi- on ICD-9-CM diagnosis and procedure codes and categorized men as a clinical impact. Modifications included dose delay, into the following groups: dermatological (alopecia, injection dose reduction, discontinuation, or no dose impact to the che- site reaction, and rash); dehydration; dyspnea; edema; gastro- motherapy regimen during the EOC. Only patients who had intestinal (constipation, decreased appetite, diarrhea, nausea/ an adverse event EOC related to chemotherapy were included vomiting, and stomatitis); hematological (anemia, leukopenia, in our analysis. neutropenia, and thrombocytopenia); hepatic (increase in liver enzymes and bilirubin); infection or pyrexia; and neurologi- Statistical Analyses cal (arthralgia, myalgia, and peripheral neuropathy). Adverse Unadjusted descriptive statistics were conducted to summarize events were identified using the primary or secondary dis- patient characteristics of patients with mBC who had adverse charge position diagnosis codes and procedure codes for out- events compared with those who did not experience adverse patient visits, hospitalizations, and emergency room (ER) visits events. Differences between these patients groups were tested (Appendix A, available in online article). using two-sided t-tests for continuous variables and the chi- Episodes of Care square statistic for categorical variables. Using descriptive Once adverse events were identified in our cohort, we created statistics, a table was created to evaluate characteristics of episodes of care (EOC) for each event. As defined in the litera- patients who had clinical impact (dose delay, dose reduction, ture, an episode of care is the period initiated by patient pre- discontinuation, or no dose impact) from adverse events. A sentation with a diagnosis of clinical condition and concluded multivariable logistic regression model was used to evaluate 15,16 when the condition is resolved. The theoretical framework factors associated with clinical impact from adverse events on for assessing episodes has been well developed in the lit- the chemotherapy regimens. Factors including age, sex, race, 15,16 erature ; however, the EOC for the management of adverse selected comorbid conditions (using categorical comorbidity events has not been applied to patients with mBC. An EOC index of 0, 1 +), single or combination chemotherapy, duration for the same condition can include single or multiple health of episode of care, and various health care resource scenarios care visits and/or various types of health care visits, including were controlled for in the model. All data were analyzed using hospitalization, ER visits, or outpatient visits. The duration of SAS version 9.2 (SAS Institute, Cary, NC). P values < 0.05 were an EOC is defined as the length of time between the first and considered to be statistically significant. last visit for that clinical condition. We applied a 2-week gap between the date of the last visit to the next visit of the same ■■  Results adverse event to ensure that the EOCs were not overestimated There were 1,682 patients identified as patients with mBC from and were per clinical expert opinion—a 2-week gap would be our selection criteria, database algorithm, and KPSC cancer sufficient to create a unique EOC for each adverse event. 866 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System TABLE 1 Characteristics of Patients with Adverse Events and No Adverse Events Patients with Identified Patients with No Identified Total First-Line Patients AE During First-Line Therapy AE During First-Line Therapy a a Patient Characteristics N = 1,682 n = 909 (54%) n = 773 (46%) Aged < 65 years, n (mean, SD) 1,0 02 (53 ± 8.1) 545 (53 ± 8.2) 457 (53 ± 8.0) Aged > 65 years, n (mean, SD) 680 (73 ± 6.0) 362 (73 ± 5.8) 318 (74 ± 6.2) Single chemotherapy regimen, n (%) 1,547 (91.97) 830 (91.31) 717 (92.76) Multiple chemotherapy regimen, n (%) 135 (8.03) 77 (8.47) 58 (7.5) Race, n (%) Asian/Pacific Islander 150 (8.91) 94 (10.34) 56 (7.24) Black 290 (17.24) 151 (16.61) 139 (17.98) Hispanic 179 (10.64) 110 (12.10) 69 (8.93) Other 100 (5.94) 49 (5.39) 51 (6.6) White 963 (57.25) 503 (55.34) 460 (59.51) Insurance type, n (%) Commercial 1,643 (97.68) 879 (96.70) 764 (98.84) Medicaid 30 (1.78) 20 (2.20) 10 (1.29) Medicare 667 (39.65) 362 (39.82) 305 (39.46) Comorbidities, n (%) Cerebrovascular disease 46 (2.73) 25 (2.75) 21 (2.72) Chronic pulmonary disease 199 (11.83) 113 (12.43) 86 (11.13) Congestive heart failure 64 (3.80) 33 (3.63) 31 (4.01) Diabetes 275 (16.35) 147 (16.17) 128 (16.56) Hypertension 718 (42.69) 401 (44.11) 317 (41.01) Liver disease 14 (0.83) 9 (0.99) 5 (0.65) Myocardial infarction 34 (2.02) 20 (2.20) 14 (1.81) Other 21 (1.25) 11 (1.21) 10 (1.29) Peripheral vascular disease 26 (1.55) 19 (2.09) 7 (0.91) Renal disease 154 (9.16) 87 (9.57) 67 (8.67) Rheumatic disease 30 (1.78) 15 (1.65) 15 (1.94) Health care resource use ER visits, n (%) 622 (36.97) 348 (38.28) 274 (35.44) ER visits (mean, SD) (2.0 ± 1.0) (2.0 ± 1.0) (2.0 ± 1.0) Hospital length of stay (mean, SD) (3.0 ± 4.0) (3.0 ± 5.0) (3.0 ± 3.0) Hospitalization visits, n (%) 622 (36.97) 332 (36.52) 290 (37.52) Hospitalization visits (mean, SD) (2.0 ± 1.0) (2.0 ± 1.0) (2.0 ± 1.0) Outpatient visits, n (%) 1,682 (100.00) 909 (100.00) 773 (100.00) Outpatient visits (mean, SD) (13.0 ± 9.0) (13.0 ± 9.0) (13.0 ± 9.0) Bold values signify statistical significant at P < 0.05. Native Hawaiian/Other Pacific Islander/ Native American/other/unknown. Not mutually exclusive; 1 patient could be counted more than once. Other includes dementia, peptic ulcer disease, and hemiplegia or paraplegia. A E = adverse event; ER = emergency room; SD = standard deviation. registry (Figure 1). Table 1 summarizes the baseline character- cyclophosphamide (9%), doxorubicin (6%); 5% of patients were istics of the mBC cohort and further categorizes the patients started on gemcitabine, epirubicin, vinorelbine, ixabepilone, into a group with 1 or more adverse events (n = 909, 54%) and and eribulin. Patients were predominantly white (57%), and the a group with no adverse events (n = 773, 46%) during follow- most common comorbidities were hypertension (43%), diabetes up. Overall, there was a higher percentage of patients aged less (16%), chronic pulmonary disease (12%), and renal disease than 65 years (60%) with a mean age of 53 years (standard (9%). Statistical differences were shown between the 2 groups at deviation [SD] = 8.1). Patients were initially started with a single baseline with race and peripheral vascular disease. The health chemotherapy agent as opposed to a combination chemotherapy care resource use for the prior 6 months was similar as well; regimen. Patients were divided according to first-line chemo- however, at baseline patients with adverse events had longer therapy treatment as follows: capecitabine (67%), taxane (22%), length of stay compared with patients with no adverse events. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 867 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System TABLE 2 TABLE 3 Adverse Events Identified During Summary of Episode of Care Data First-Line Chemotherapy Treatment During First-Line (Patient-Level Data) AE Episode of Care Summary Therapy During First-Line Number of patients with 1 or more AE episodes 909 Adverse Events and Other Characteristics Therapy Total AE episodes 5,940 Number of unique adverse events, n (%) N = 1,682 AE episodes related to chemotherapy, n (%) 5,475 (92.2) Single episodes, n (%) 4,185 (76.0) 0 773 (46.0) Mean number of single episodes per patient (SD) 4.7 (3.6) 1 322 (19.1) 1-day episode only, n (%) 4,004 (96.0) 2 186 (11.1) > 1-day episode, n (%) 181 (4.3) 3 148 (8.8) Mean duration of days for > 1-day episode (SD) 5.3 (1.7) 4 92 (5.5) Multiple episodes, n (%) 1,290 (24.0) > 5 161 (9.6) Mean number of multiple episodes per patient (SD) 3.0 (4.0) Unique adverse events by category, n (%) N = 909 Mean duration of days per multiple episode (SD) 4.8 (4.6) Dermatological 84 (9.2) Alopecia 5 (0.6) Percentages for single episodes were calculated as follows: 4,185 ÷ 5,475 = 76%. Percentages for multiple episodes were calculated as follows: 1,290 ÷ 5,475 = 24%. Injection site reaction 14 (1.5) A E = adverse event; SD = standard deviation. Rash 65 (7.2) Dehydration 104 (11.4) Dyspnea 108 (11.9) Edema 104 (11.4) Episode of care was applied after adverse events were identi- Gastrointestinal 466 (51.3) fied. During this time, we identified which adverse event episode Constipation 129 (14.2) of care was associated with chemotherapy. There were 5,940 Decreased appetite 37 (4.1) episodes identified: 92.2% (5,475) were chemotherapy related Diarrhea 128 (14.1) (Table 3 and Appendix B, available in online article) and 8% Nausea/vomiting 141 (15.5) (465) were from disease progression or other conditions not Stomatitis 31 (3.4) related to chemotherapy. Chart notes revealed that all the adverse Hematological 592 (65.1) events related to dyspnea were attributed to disease progression Anemia 346 (38.1) and not related to chemotherapy. We also did not identify any Leukopenia 122 (13.4) Neutropenia 88 (9.7) patients with fatigue, which is a common adverse event caused Thrombocytopenia 36 (4) by chemotherapy. Thus, we did not include these EOC events in Hepatic 35 (3.8) our analysis. There were 4,185 (76%) single episodes and 1,290 Liver enzymes increased 29 (3.2) (24%) multiple episodes of care (Table 3). The single episodes Bilirubin increased 6 (0.7) consisted of 4,004 (96%) 1-day single episodes, and 181 (4%) Infection or pyrexia 482 (53.0) less than 1-day single episodes. The mean duration of less than Infection 380 (41.8) 1-day single episodes was 5.3 days (SD = 1.7 days). The duration Pyrexia 102 (11.2) of multiple episodes was 4.8 days (SD = 4.6 days; Table 3). Neurological 322 (35.4) Chart notes were reviewed and pharmacy claims were used Arthralgia 134 (14.7) to evaluate if an EOC for an adverse event had any clinical Myalgia 36 (4.0) Peripheral neuropathy 152 (16.7) impact (dose delay, dose reduction, or discontinuation) on che- motherapy regimens (Table 4). Of the 909 patients, there were Liver enzymes: alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP). 185 patients (20%) who had 1 or more chemotherapy modi- fications as opposed to 724 patients (80%) who did not have any chemotherapy modification. Of the 45 patients who expe- Table 2 summarizes the adverse events identified after first- rienced a single EOC, 34 patients had dose delay; 17 patients line chemotherapy was given during the follow-up period. The had dose reductions; and 14 patients discontinued therapy. Of mean days of being on first-line therapy was 375 days (SD = 262 the patients who experienced a multiple EOC, 116 patients had days). Unique adverse events were defined as a patient having a dose delay; 80 patients had dose reductions; and 48 patients a specific adverse event 1 or more times. More than half of the discontinued therapy. The majority of patients with single patients started on chemotherapy had an adverse event, with 1 episodes who had chemotherapy modification were patients and 2 unique adverse events being the majority (19% and 11%, with hematological (42.3%), gastrointestinal (28.3%), and respectively). Overall, hematological (65%), infection/pyrexia infection/pyrexia (13%) adverse events. Similar results were (53%), and gastrointestinal (51%) episodes were the most shown in patients with multiple EOCs; however, more of these unique adverse events. Neurological (35%) and others (dehy- patients with any chemotherapy modification were shown to have neurological-related adverse events (11.8%) versus dration, dyspnea, and edema) represented 11% of the events. 868 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System TABLE 4 Characteristics of Patients with and Without Clinical Impact on Chemotherapy Regimen During EOC by AE Category Chemotherapy Modification (Dose Delay, Dose Reduction, or Discontinuation) No Chemotherapy Modification AE and Health Care Patients During First-Line Therapy Patients During First-Line Therapy Resource Characteristics N = 185 (20%) N = 724 (80%) a a a a Single EOC Patients, n (%) EOC, n (%) Patients, n (%) EOC, n (%) Total 45 109 724 4,076 Dermatological 2 (4.4) 2 (2.2) 66 (9.1) 111 (2.7) Dehydration 6 (13.3) 7 (7.6) 37 (5.1) 53 (1.3) Edema 1 (2.2) 1 (1.1) 93 (12.8) 158 (3.9) Gastrointestinal 25 (55.6) 26 (28.3) 353 (48.7) 749 (18.4) Hematological 27 (60.0) 39 (42.3) 306 (42.2) 1,348 (33.1) Hepatic 1 (2.2) 1 (1.1) 25 (3.4) 65 (1.6) Infection or Pyrexia 20 (44.5) 29 (31.5) 252 (34.8) 526 (12.9) Neurological 3 (6.7) 4 (4.3) 280 (38.6) 1,066 (26.2) Multiple EOC Total 160 484 400 806 Dermatological 7 (4.4) 7 (1.8) 14 (3.9) 14 (1.7) Dehydration 16 (10.0) 17 (4.3) 69 (19.2) 78 (9.5) Edema 8 (5.0) 9 (2.3) 11 (3.1) 12 (1.5) Gastrointestinal 90 (56.3) 107 (26.8) 129 (35.8) 171 (20.8) Hematological 117 (73.1) 181 (45.3) 138 (38.3) 239 (29.1) Hepatic 1 (0.6) 1 (0.3) 12 (3.3) 12 (1.5) Infection or pyrexia 69 (43.1) 115 (28.7) 135 (33.8) 220 (26.8) Neurological 31 (18.4) 47 (11.8) 41 (11.4) 60 (7.3) HCRU-related to any EOC Total 185 470 724 8,707 Hospital visits 180 (97.3) 70 (14.9) 229 (26.7) 111 (1.3) Hospitalization 1 day + ER visit 1 (0.5) 1 (0.2) 45 (5.2) 81 (0.9) Hospitalization 2 days + ER visit 9 (4.9) 10 (2.1) 63 (7.3) 117 (1.3) Hospitalization 3 days 37 (20.0) 54 (11.5) 56 (6.5) 76 (0.9) Hospitalization > 3 days 152 (82.2) 308 (65.5) 61 (7.1) 60 (0.7) More than 1 outpatient visit 173 (93.5) 445 (94.6) 403 (55.6) 4,773 (54.8) 1 outpatient visit + ER visit 1 (0.5) 2 (0.4) 33 (3.8) 4,328 (49.7) Note: Descriptive statistics were conducted between patients with any chemotherapy modification versus no chemotherapy modification and between EOC for any chemo- therapy modification group versus no chemotherapy modification group. Bold values signify statistical significance at P < 0.05. Patients with ≥ 1 hospital visits versus those with no hospitalizations. Patients with > 1 outpatient visits versus those with 1 outpatient visit. AE = adverse event; EOC = episode of care; ER = emergency room; HCRU = health care resource utilization. infection /pyrexia (7.8%). Table 4 also shows evaluation of health ■■  Discussion care resource utilization for clinical impact. Patients who had The results of this study demonstrate that adverse events related hospital visits with length of stay of 3 or more days (65.5%), to chemotherapy in patients with mBC have significant impact were shown to have the most clinical impact compared with on their chemotherapy regimens in an integrated health care those who stayed less than 3 days. delivery system. This is the first study to apply an EOC frame- Table 5 lists the significant factors associated with any che- work to understand health care delivery for adverse events in motherapy modification versus no chemotherapy modification. mBC women aged more than 18 years and who are undergoing Factors such as age (> 65 years), comorbidity (> 1 comorbidity), chemotherapy. Approximately 23% of patients experienced a and longer duration of days for each EOC were associated with multiple EOC for an adverse event, which was associated with clinical impact. Black and Hispanic patients were more likely to an increased risk of clinical impact. Our study also showed a have a modification in their chemotherapy treatment compared positive association with patients having longer hospital length with white patients. of stays and clinical impact. Adverse events from chemotherapy www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 869 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System pharmacokinetic processes, which could lead to dramatic TABLE 5 Factors Associated with Chemotherapy consequences such as excessive drug levels and unaccept- Regimen Modification and Without able toxicity. Racial/ethnic status was also associated with Chemotherapy Modification from an increased risk of clinical impact in our study. Future Multivariate Logistic Regression in studies will need to examine social and cultural factors that mBC Patients may be responsible for this finding. There was a total of 20% Chemotherapy of patients that had chemotherapy modification to current Modification Versus No Chemotherapy chemotherapy regimens related to an adverse event. A previ- Modification During ous study reported a rate of chemotherapy modification of First-Line Therapy approximately 24.7%. Patient and Clinical Characteristics OR (95% CI) Current existing treatments for patients with mBC are Patient age groups, years effective, but they are associated with many different adverse < 65 years (reference) 1.00 events, and these can cause changes to the patient’s chemo- > 65 years 2.05 (1.57-2.49) therapy regimen. The clinical impact has not been previ- Race ously quantified, and changes in chemotherapy regimens White (reference) 1.00 Black 2.22 (1.75-2.68) can cause clinical, functional, and economic consequences. Hispanic 1.58 (1.11-1.89) These findings can help managed care organizations evalu- Asian/Pacific Islander 0.52 (0.31-1.21) ate the importance of including the side effect profile from Comorbidities various treatment options into clinical decision making and 1 + versus 0 2.01 (1.74-2.82) identify therapies that may be associated with fewer compli- Chemotherapy regimen cations. This could improve patient clinical outcomes and Combination versus single 1.47 (0.33-2.71) reduce changes in chemotherapy regimens and possible costs Duration of EOC related to adverse events. Managed care and other health Single episode 1.24 (1.09-2.07) care systems should always be looking for therapies that Multiple episode 2.81 (2.42-3.56) demonstrate equal or superior efficacy to current standard Health care utilization for any EOC chemotherapy regimens, while decreasing the frequency Hospital visit only 0.88 (0.62-1.63) and severity of adverse events related to these chemotherapy Hospitalization 1 day + ER visit 0.91 (0.73-1.56) Hospitalization 2 days + ER visit 2.88 (2.53-3.57) regimens. Newer therapies can help with economic burden Hospitalization 3 days 5.22 (4.88-6.05) by reducing potential costs incurred from treatment-related Hospitalization > 3 days 8.55 (7.42-9.02) adverse events. 1 outpatient visit 0.28 (0.16-1.05) 1 outpatient visit + ER visit 0.33 (0.14-1.22) Limitations Bold numbers indicate statistical significance. Our study had some limitations. Although we used diagnosis CI = confidence inter val; EOC = episode of care; ER = emergency room; mBC = meta- and procedure codes to identify adverse events, we relied static breast cancer; OR = odds ratio. only on data that were available in our electronic system. All adverse events were identified with diagnosis and procedure codes, and laboratory data were not used to confirm specific reported from other studies showed hematological, infection/ adverse events such as anemia, leukopenia, neutropenia, or pyrexia, and gastrointestinal episodes as the most common thrombocytopenia. Since the health care encounters were adverse events from chemotherapy, which we also found in associated with diagnosis and procedure codes, we thought 10,11 our results. However, the rates in our study were higher, using those codes would suffice; however, there may be pos- which was most likely because our patients were at the meta- sible underestimation in these rates. We also understand static stage rather than an earlier breast cancer stage. The that the adverse event list did not include all adverse events presence of metastatic disease and being initiated on che- caused by chemotherapy; however, by reviewing the litera- motherapy are independently associated with a statistically ture and previous clinical trials, the adverse events included significant increase in the odds of experiencing a serious in this study were the most common in patients using chemo- 10,11 adverse effect. We also found that patients older in age and therapy. A common adverse event is fatigue, and since this is with more comorbidities had a significantly higher likelihood mostly a patient-reported event, we could not identify it using of an impact on chemotherapy treatment. Chemotherapy is diagnosis codes. Our sample consisted of patients on chemo- used in the elderly population; however, oncologists assess therapy only; we did not evaluate the status (positive or nega- age and comorbidities in this population when consider- tive) of human epidermal growth factor receptor 2 (HER2) or ing chemotherapy because of fear of excessive toxicity. evaluate targeted therapies. We used our databases to identify Chemotherapy is known to have a low therapeutic index, first-line chemotherapy regimens 12 months prior to index and with age, there are many changes that could impact the date so could only capture what was found in our pharmacy 870 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System DISCLOSURES databases. Finally, when we evaluated adverse events, we This study was supported by an unrestricted research grant provided by could not report what grade (3 or 4) or apply a scale of sever- Genentech. Rashid, Koh, Li, and Baca do not have any financial interests or ity to them; however, if a patient was admitted to the hospital, potential conf lict of interest with regard to this work. Masaquel, Malecha, and there was an assumption that it had some severity. Overall, Abidoye are employees of Genentech. our rates of health care resource utilization had all severities. Study concept and design were created by Rashid, Koh, Malecha, and Masaquel. Data were collected by Rashid, Baca, and Li and interpreted by all the authors. The manuscript was written by Rashid, Koh, Li, Malecha, and ■■ Conclusions Masaquel and revised by Rashid, Baca, Malecha, and Masaquel. 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Population-based assessment of hos- from patient and societal perspectives. pitalizations for toxicity from chemotherapy in older women with breast cancer. J Clin Oncol. 2002;20(24):4636-42. 12. Koebnick C, Langer-Gould AM, Gould MK, et al. Sociodemographic Authors characteristics of members of a large, integrated health care system: com- parison with U.S. Census Bureau data. Perm J. 2012;16(3):37-41. NAZIA R ASHID, PharmD, MS, is Research Scientist, and 13. Hurvitz S, Guerin A, Brammer M, et al. Investigation of adverse-event- ZHAOLIANG LI, MS, is Biostatistician, Drug Information related costs for patients with metastatic breast cancer in a real-world Services, Kaiser Permanente Southern California, Downey. setting. Oncologist. 2014;19(9):901-08. HAN A. KOH, MD, is Oncologist, Southern California Permanente 14. Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. Medical Group, Kaiser Permanente Southern California, Bellf lower, N Engl J Med. 2001;344(26):1997-2008. and HILDA C. BACA, BS, is Programmer, Pharmacy Analytical 15. Mehta SS, Suzuki S, Glick HA, Schulman KA. Determining an episode of Services, Kaiser Permanente Southern California, Downey. care using claims data. Diabetic foot ulcer. Diabetes Care. 1999;22(7):1110-15. SUSAN MALECHA, PharmD, MBA, is Lead, National Managed 16. Flaherman VJ, Ragins AI, Li SX, Kipnis P, Masaquel A, Escobar GJ. Care Liasion; OYEWALE ABIDOYE, MD, MPH, is Medical Frequency, duration and predictors of bronchiolitis episodes of care among Director; and ANTHONY MASAQUEL, PhD, MPH, is Senior infants ≥32 weeks gestation in a large integrated healthcare system: a retro- Health Economist, Genentech, South San Francisco, California. spective cohort study. BMC Health Serv Res. 2012;12:144-52. AUTHOR CORRESPONDENCE: Nazia Rashid, PharmD, MS, 17. Wildiers H. Mastering chemotherapy dose reduction in elderly cancer Research Scientist, Drug Information Services, Kaiser Permanente patients. Eur J Cancer. 2007;43(15):2235-41. Southern California, 12254 Bellflower Blvd., Downey, CA 90242. 18. Walker MS, Masaquel AS, Kerr J, et al. Early discontinuation and switch- Tel.: 562.658.3952; Fax: 562.658.3843; E-mail: [email protected]. ing in first-line metastatic breast cancer: the role of patient reported symptom burden. Breast Cancer Res Treat. 2014;144(3):673-81. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 871 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System APPENDIX A Diagnosis Codes Used for Identifying Adverse Events Adverse Event ICD-9-CM Code HCPCS/CPT Codes Dermatological Alopecia 704.0x Injection site reaction 999.39 Rash 693.0x, 708.8x, 708.9x,782.1x Dehydration 276.5x Dyspnea 786.0x Edema 782.3x, 514.xx, 518.4x Gastrointestinal Constipation 564.0x Decreased appetite 783.0x, 783.2x Diarrhea 558.9x, 564.5x, 787.91, 007.xx, 009.xx Nausea 787.0x, 787.01, 787.02, 787.03, 536.20 G9021, G9022, G9023, G9024 Stomatitis 528.0x Hematological Anemia 280.xx, 281.xx, 283.xx, 284.xx, 285.xx S3906, S9538, C1010, C1016, C1020, C1021, C9504, C9505, P9016, P9021, P9022, P9038, P9039, P9040, P9051, P9054, P9057, P9058, Q0136, Q4055, J0885, J0886, Q9920-Q9940, Q4054, J0880, J0881, J0882, Q0137, C1774, S0112 Leukopenia 288.5x, 288.8x, 288.9x J1440, J1441, C9119, Q4053, J2505, J2820 Neutropenia 288.0x Thrombocytopenia 287.3x, 287.4x, 287.5x, 444.6x, 289.84, 99.05 P9010, P9031, P9037, P9052, P9053, P9055 Hepatic Liver enzymes increased 790.4x, 790.5x 84450 Bilirubin increased 277.4x 81000, 81001, 81002, 81003, 82248, 82247 Infection or Pyrexia Infection 001.xx-018.xx, 030.xx-041.xx, 045.xx-049.xx, 050.xx- 057.xx, 110.xx-118.xx, 070.xx-079.xx, 130.xx-136.xx, 460.xx-466.xx, 480.xx-488.xx, 038.0x, 038.19, 038.80, 038.9x, 995.91, 995.92 Pyrexia 780.6x Neurological Arthralgia 719.4x, 524.62 Myalgia 729.1x G9025, G9026, G9027, G9028 Peripheral neuropathy 356.xx, 357.xx, 337.0x, 337.1x Other Fatigue 780.72 G9029, G9030, G9031, G9032 Pharyngitis 462.00 CPT = Current Procedural Terminology; HCPCS = Healthcare Common Procedure Coding System; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 871a Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System APPENDIX B Descriptive Data on Chemotherapy-Related EOCs Per AE Category During First-Line Therapy (Episode Level) Total Single 1-Day Single > 1-Day Single Total Multiple Mean Days of During First-Line Total Episodes Episodes Episodes Episodes Episodes Multiple Episode Therapy, n (%) N = 5,475 N = 4,185 n = 4,004 n = 181 N = 1,290 Duration (SD) Dermatological 134 (2.49) 113 (2.71) 111 (2.77) 2 (1.22) 21 (1.72) 5.5 (4.3) Dehydration 155 (2.83) 60 (1.44) 50 (1.25) 10 (6.10) 95 (7.36) 4.3 (3.2) Edema 180 (3.34) 159 (3.81) 157 (3.92) 2 (1.22) 21 (1.72) 5.2 (5.3) Gastrointestinal 1,053 (19.54) 775 (18.59) 741 (18.51) 34 (20.73) 278 (22.75) 5.3 (4.5) Hematological 1,807 (33.53) 1,387 (33.28) 1,317 (32.89) 70 (42.68) 420 (34.37) 6.1 (5.6) Hepatic 79 (1.47) 66 (1.58) 65 (1.62) 1 (0.61) 13 (1.06) 4.3 (2.9) Infections/pyrexia 890 (16.25) 555 (13.26) 498 (12.44) 57 (34.75) 335 (25.96) 4.2 (4.1) Neurological 1,177 (21.84) 1,070 (25.67) 1,065 (26.60) 5 (3.05) 107 (8.76) 4.6 (2.9) A E = adverse event; EOC = episode of care; SD = standard deviation. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 871b http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Managed Care & Specialty Pharmacy Pubmed Central

Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System

Rashid, Nazia; Koh, Han A.; Baca, Hilda C.; Li, Zhaoliang; Malecha, Susan; Abidoye, Oyewale; Masaquel, Anthony
Journal of Managed Care & Specialty Pharmacy , Volume 21 (10) – Oct 1, 2015
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10.18553/jmcp.2015.21.10.863
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Abstract

R E S E A RC H Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System Nazia Rashid, PharmD, MS; Han A. Koh, MD; Hilda C. Baca, BS; Zhaoliang Li, MS; Susan Malecha, PharmD, MBA; Oyewale Abidoye, MD, MPH; and Anthony Masaquel, PhD, MPH ABSTRACT have more impact on chemotherapy regimens. In our multivariate analy- sis, patients aged > 65 years, having more than 1 comorbidity and having BACKGROUND: Stage IV breast cancer, also known as metastatic breast longer duration in days for each episode of care were all associated with cancer (mBC), is not a curable condition. However, treatment can prolong clinical impact. Black and Hispanic patients were more likely to have a life, delay the progression of the cancer, or improve quality of life. Currently, modification in their chemotherapy compared with white patients. patients with mBC are often treated with chemotherapy. Patients often CONCLUSIONS: This retrospective analysis demonstrates that chemothera- experience adverse events from chemotherapy during the treatment cycle, py-related adverse events in patients with mBC have an impact on the deliv- which leads to chemotherapy modifications such as dose delay, dose reduc- ery of chemotherapy regimens. Having multiple comorbidities, increased tion, or discontinuation of chemotherapy. Previous studies have evaluated age, and prolonged hospitalizations because of adverse events appear to be the rates of adverse events that occur from the use of chemotherapy; how- some of the primary factors related to chemotherapy modification. ever, few studies have evaluated the clinical impact on the chemotherapy regimen once the adverse event occurs. This study evaluates the clinical J Manag Care Spec Pharm. 2015;21(10):863-71 impact on the chemotherapy regimen from chemotherapy-related adverse Copyright © 2015, Academy of Managed Care Pharmacy. All rights reserved. events in patients with mBC in an integrated health care delivery system. OBJECTIVES: To assess the adverse events in patients with mBC and evalu- ate the clinical impact on the chemotherapy regimen from these adverse events in an integrated health care delivery system. What is already known about this subject METHODS: This study is a retrospective cohort of patients with mBC newly initiated on chemotherapy. The first infusion was defined as the index date. • Stage IV breast cancer, also known as metastatic breast cancer Patients were aged > 18 years at time of index date and had 6 months or (mBC), is not a curable condition; however, treatment can prolong more of Kaiser membership and drug eligibility prior to the index date and life, delay the progression of the cancer, or improve quality of life. continuous membership and drug eligibility throughout follow-up. Adverse • Although chemotherapy is given in cycles, patients often experi- events were identified after the index date and during the follow-up using ence adverse events from chemotherapy during the cycle, which ICD-9-CM diagnosis and procedure codes. Single or multiple episodes of leads to chemotherapy modification, such as dose delay, dose care were created from the adverse events. Chart review was conducted to establish whether the adverse event was related to chemotherapy and reduction, or discontinuation of chemotherapy. if any modification to the chemotherapy regimen occurred—a dose delay, • Few retrospective studies have evaluated the clinical impact from dose reduction, or discontinuation was considered a clinical impact on adverse events on chemotherapy treatments, and studies that therapy. Multivariate logistic regression was used to examine factors asso- have did not evaluate chemotherapy modification because of ciated with clinical impact versus no clinical impact from the delivery of chemotherapy adverse events. chemotherapy treatment. What this study adds RESULTS: A total of 1,682 patients with mBC were identified during our time period with an average follow-up of 2.21 years on first-line chemo- • This study used an episode of care method to evaluate chemo- therapy (SD = 1.83). 909 patients (54%) had at least 1 adverse event, and therapy adverse events in order to provide a more real-world 773 patients (46%) did not have any adverse events during follow-up. approach that reflects the common practice of our health care Significant differences at baseline between these 2 groups included race, delivery system. peripheral vascular disease, and length of stay (P < 0.05). From the 909 • A chart review was conducted to determine if the episode of patients who had at least 1 adverse event, 185 patients (20%) experienced care-related adverse event was from chemotherapy or disease an impact on their chemotherapy regimens. Patients with single episodes progression. of care with any chemotherapy regimen impact experienced mostly hema- • Factors such as multiple comorbidities, increased age, and pro- tological, infection/pyrexia, and gastrointestinal-related adverse events. In multiple episodes of care, neurological impact was more frequent than longed hospitalizations because of adverse events appear to be gastrointestinal-related effects. Patients with hospitalizations of > 3 days some of the primary factors related to chemotherapy modification. experienced the most impact, demonstrating that severe adverse events www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 86 3 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System reast cancer is one of the most common malignan- and to evaluate the clinical impact on the chemotherapy cies in women. In 2013, it was estimated that 232,340 regimen from these adverse events in an integrated health Bwomen in the United States were diagnosed with breast care delivery system. We applied an episode of care method cancer, and that 39,620 women died of breast cancer. Breast to provide a more real-world approach, reflecting the common cancer remains a serious health care problem and accounts practice of our health care delivery system, and we conducted a for approximately one third of cancers in the Unites States. chart review to determine if the episode of care-related adverse Overall survival varies by breast cancer stage. People diag- events were from chemotherapy or from disease progression. nosed with stage 0, I, or II breast cancers tend to have higher ■■  Methods overall survival rates than people diagnosed with stage III or IV breast cancer; however, overall survival rates are averages Study Setting and Data and vary depending on each person’s diagnosis and treat- Kaiser Permanente Southern California (KPSC) is an inte- ment. Stage IV, also known as metastatic breast cancer (mBC) grated health care delivery system with approximately 3.6 is not a curable condition; however, treatment can prolong million members. The KPSC membership currently represents life, delay the progression of the cancer, or improve quality of 15% of the population in the Southern California region, 3,4 life. Approximately 6% of women with incident breast cancer and this membership closely mirrors the Southern California have metastatic disease at initial presentation, and the median population; it is racially diverse and includes the entire survival of individuals with mBC is 18 to 24 months, although socioeconomic spectrum. Data were derived from the KPSC the range in survival spans between a few months to many Health Plan (KPSC HP) database and The Kaiser Permanente 4,5 years and depends on the type of breast cancer. Breast can- Regional Cancer Registry (CANREG) database. The KPSC cer can be treated with different modalities. One modality is HP database contains information on patient demographics, chemotherapy, which can be given as a sequential single agent diagnoses, prescriptions, laboratory results, and medical and or in combination to slow, stop, or kill the growth of cancer hospital encounters. KPSC HP has an electronic health medi- cells. Chemotherapy is given in cycles, such as 21 or 28 days, cal record system that allows for more detailed information to which allows the body to recover from the side effects of the be accessed and included in studies. For all reportable cancers, medicines. the CANREG database is a compilation of data collected at the Although chemotherapy is given in cycles, patients often registry level from each of the 14 KPSC hospitals and contains experience adverse events from chemotherapy during the information on patients who are newly diagnosed or who cycle, which leads to a chemotherapy modification that may received at least part of their first course of treatment for can- include dose delay, dose reduction, or discontinuation of cer at a KPSC hospital. The CANREG data are provided to the chemotherapy. Studies have reported that interrupting chemo- Surveillance, Epidemiology, and End Results (SEER) program, therapy cycles or not providing a high percentage of relative a part of the National Cancer Institute that collects cancer data dose intensity will not improve the patient’s disease progres- in the United States and compiles national cancer statistics. 6-9 sion thus decreasing overall survival rates. Few retrospective The diagnoses are validated and confirmed cancer diagnoses, studies have evaluated the clinical impact from adverse events which makes the KPSC CANREG applicable when conducting on chemotherapy. One study used retrospective U.S. data various retrospective or prospective longitudinal studies. The that included the general population; however, the patients institutional review board for KPSC approved this study. were aged less than 63 years and had newly diagnosed breast Design and Study Population cancer during the time period of April 1, 1998, to December 31, 2002. Another study was a population-based assessment A retrospective cohort database analysis was conducted dur- of hospitalizations because of chemotherapy adverse events ing the study enrollment period from January 1, 2007, to within the Medicare population. The patients were aged 65 December 31, 2011. Patients with mBC were either selected years or more and had all stages of breast cancer during the from the KPSC CANREG or by using medical claims from time period of 1991 to 1996, In addition, the study focused the following algorithm (Figure 1) : patients had more than 2 on chemotherapy adverse events in the hospital setting but medical encounters within 90 days between January 1, 2007, did not quantify other health care resource utilization in this and December 31, 2011, with the International Classification population. of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) Although these studies evaluated rates of chemotherapy codes 197.xx-198.xx. The date of metastatic diagnosis was adverse events, they did not evaluate the clinical impact of defined as the metastatic disease index date. We identified adverse events on chemotherapy treatment for patients with patients with breast cancer using the ICD-9-CM codes 174.xx mBC and aged older than 18 years. Consequently, the objec- or 233.0x. These codes had to be identified prior to the mBC tives for this study were to describe chemotherapy-related date starting from January 1, 2002 (5 years prior) or 90 days adverse events in patients with mBC receiving chemotherapy after the mBC date. Patients had to be female and aged more 864 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System FIGURE 1 mBC Study Population Diagram Identify patients who had > 2 medical encounters within 90 days with diagnosis codes for secondary neoplasms (197.xx-198.xx) between January 1, 2007, and December 31, 2011 (N = 18,462) →mBC date Identify patients with > 1 diagnosis code for breast cancer (174.xx or 233.0x) going back to January 1, 2002, before or 90 days after mBC date (N = 3,365) →diagnosis date Exclude patients who are male and aged < 18 years on diagnosis date (N = 244) Female and aged > 18 years (N = 3,121) Exclude patients with other cancers 365 days prior to diagnosis date (140.x-165.x, 170.x-173.x, 175.x-176.x, 179.x-195.x, 196.x, 199.x-209.x, 230.x-234.x [except 233.0x], 235.x-239.x [except 238.3, 239.3], and V10.x [except V10.3]) N = 498 No other cancers prior to diagnosis date (N = 2,623) Add patients from KPSC Cancer Registry using same time period, identified date of mBC, females, and aged ≥18 years, with no overlapping (N = 661) mBC cohort N = 3,284 Exclude patients without continuous membership and drug benefit eligibility 6 months prior to mBC date N= 360 mBC cohort with continuous membership and eligibility N = 2,924 Final mBC cohort with chemotherapy N = 1,682 KPSC = Kaiser Permanente Southern California; mBC = metastatic breast cancer. than 18 years on the date of diagnosis. We excluded patients drug benefit prior to the mBC date and throughout follow-up with any other cancers 12 months prior to the diagnosis date (Figure 1). (140.xx to 165.xx, 170.xx to 173.xx, 175.xx to 176.xx, 179.xx to Identification of Chemotherapy and Patient Follow-Up 195.xx, 196.xx, 199.xx to 209.xx, 230x-234.x [except 233.0x], 235.x-239.x [except 238.3, 239.3], and V10.x [except V10.3]). Once the final cohort of mBC patients was established, Patients had to have 6 months of continuous membership and we used pharmacy and CANREG databases to identify the www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 865 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System first-line chemotherapy for each patient. Chemotherapy was Two types of EOCs were created: a single EOC and a mul- identified using National Drug Code numbers and Generic tiple EOC. A multiple EOC represented repeated health care Product Identifiers if patients were prescribed 1 or more of visits for the management of an adverse event. A single EOC the following: capecitabine, taxanes (docetaxel and paclitaxel), was defined as 1 health care resource encounter for a specific cyclophosphamide, doxorubicin, gemcitabine, epirubicin, adverse event with no other health care encounter within 2 vinorelbine, ixabepilone, and eribulin. Once the chemotherapy weeks from that visit. Thus. single episodes could be an out- was identified for the patient with mBC, we searched the data- patient visit for 1 day or a hospital visit of 3 days. A multiple bases to ensure that no other chemotherapy regimens had been episode EOC was defined as a patient having more than 1 initiated in the prior 12 months. We evaluated use of chemo- health care resource encounter within a 2-week time period. therapy only and did not evaluate hormonal status or examine For example, a patient could have an outpatient visit, then in 3 targeted therapies. If no other chemotherapy regimens were days have another outpatient visit, then in 2 days go to the ER, identified, we categorized the patient by chemotherapy regi- and then be admitted to the hospital for 5 days for the same men and identified the date of the first cycle as the treatment condition. Since there was no 2 week gap between the encoun- index date. Patient follow-up was defined from the index date ters, these episodes were counted as 1 multiple EOC. until disenrollment from the health plan, start of a new chemo- therapy regimen, or end of the study time period (December Defining Clinical Impact 31, 2012), whichever came first. During the follow-up period, Pharmacy claims and chart reviews were used to identify if adverse events were identified while patients were undergoing their first-line chemotherapy regimen. an EOC was related to a patient’s chemotherapy treatment by reading the chart notes available during the time of an adverse Adverse Events event occurrence and then noting if there was a modification of Previous studies and trials were used to identify adverse or clinical impact on the chemotherapy regimen. In this study, 10,11,14 events. The following adverse events were selected based we defined any modification of a patient’s chemotherapy regi- on ICD-9-CM diagnosis and procedure codes and categorized men as a clinical impact. Modifications included dose delay, into the following groups: dermatological (alopecia, injection dose reduction, discontinuation, or no dose impact to the che- site reaction, and rash); dehydration; dyspnea; edema; gastro- motherapy regimen during the EOC. Only patients who had intestinal (constipation, decreased appetite, diarrhea, nausea/ an adverse event EOC related to chemotherapy were included vomiting, and stomatitis); hematological (anemia, leukopenia, in our analysis. neutropenia, and thrombocytopenia); hepatic (increase in liver enzymes and bilirubin); infection or pyrexia; and neurologi- Statistical Analyses cal (arthralgia, myalgia, and peripheral neuropathy). Adverse Unadjusted descriptive statistics were conducted to summarize events were identified using the primary or secondary dis- patient characteristics of patients with mBC who had adverse charge position diagnosis codes and procedure codes for out- events compared with those who did not experience adverse patient visits, hospitalizations, and emergency room (ER) visits events. Differences between these patients groups were tested (Appendix A, available in online article). using two-sided t-tests for continuous variables and the chi- Episodes of Care square statistic for categorical variables. Using descriptive Once adverse events were identified in our cohort, we created statistics, a table was created to evaluate characteristics of episodes of care (EOC) for each event. As defined in the litera- patients who had clinical impact (dose delay, dose reduction, ture, an episode of care is the period initiated by patient pre- discontinuation, or no dose impact) from adverse events. A sentation with a diagnosis of clinical condition and concluded multivariable logistic regression model was used to evaluate 15,16 when the condition is resolved. The theoretical framework factors associated with clinical impact from adverse events on for assessing episodes has been well developed in the lit- the chemotherapy regimens. Factors including age, sex, race, 15,16 erature ; however, the EOC for the management of adverse selected comorbid conditions (using categorical comorbidity events has not been applied to patients with mBC. An EOC index of 0, 1 +), single or combination chemotherapy, duration for the same condition can include single or multiple health of episode of care, and various health care resource scenarios care visits and/or various types of health care visits, including were controlled for in the model. All data were analyzed using hospitalization, ER visits, or outpatient visits. The duration of SAS version 9.2 (SAS Institute, Cary, NC). P values < 0.05 were an EOC is defined as the length of time between the first and considered to be statistically significant. last visit for that clinical condition. We applied a 2-week gap between the date of the last visit to the next visit of the same ■■  Results adverse event to ensure that the EOCs were not overestimated There were 1,682 patients identified as patients with mBC from and were per clinical expert opinion—a 2-week gap would be our selection criteria, database algorithm, and KPSC cancer sufficient to create a unique EOC for each adverse event. 866 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System TABLE 1 Characteristics of Patients with Adverse Events and No Adverse Events Patients with Identified Patients with No Identified Total First-Line Patients AE During First-Line Therapy AE During First-Line Therapy a a Patient Characteristics N = 1,682 n = 909 (54%) n = 773 (46%) Aged < 65 years, n (mean, SD) 1,0 02 (53 ± 8.1) 545 (53 ± 8.2) 457 (53 ± 8.0) Aged > 65 years, n (mean, SD) 680 (73 ± 6.0) 362 (73 ± 5.8) 318 (74 ± 6.2) Single chemotherapy regimen, n (%) 1,547 (91.97) 830 (91.31) 717 (92.76) Multiple chemotherapy regimen, n (%) 135 (8.03) 77 (8.47) 58 (7.5) Race, n (%) Asian/Pacific Islander 150 (8.91) 94 (10.34) 56 (7.24) Black 290 (17.24) 151 (16.61) 139 (17.98) Hispanic 179 (10.64) 110 (12.10) 69 (8.93) Other 100 (5.94) 49 (5.39) 51 (6.6) White 963 (57.25) 503 (55.34) 460 (59.51) Insurance type, n (%) Commercial 1,643 (97.68) 879 (96.70) 764 (98.84) Medicaid 30 (1.78) 20 (2.20) 10 (1.29) Medicare 667 (39.65) 362 (39.82) 305 (39.46) Comorbidities, n (%) Cerebrovascular disease 46 (2.73) 25 (2.75) 21 (2.72) Chronic pulmonary disease 199 (11.83) 113 (12.43) 86 (11.13) Congestive heart failure 64 (3.80) 33 (3.63) 31 (4.01) Diabetes 275 (16.35) 147 (16.17) 128 (16.56) Hypertension 718 (42.69) 401 (44.11) 317 (41.01) Liver disease 14 (0.83) 9 (0.99) 5 (0.65) Myocardial infarction 34 (2.02) 20 (2.20) 14 (1.81) Other 21 (1.25) 11 (1.21) 10 (1.29) Peripheral vascular disease 26 (1.55) 19 (2.09) 7 (0.91) Renal disease 154 (9.16) 87 (9.57) 67 (8.67) Rheumatic disease 30 (1.78) 15 (1.65) 15 (1.94) Health care resource use ER visits, n (%) 622 (36.97) 348 (38.28) 274 (35.44) ER visits (mean, SD) (2.0 ± 1.0) (2.0 ± 1.0) (2.0 ± 1.0) Hospital length of stay (mean, SD) (3.0 ± 4.0) (3.0 ± 5.0) (3.0 ± 3.0) Hospitalization visits, n (%) 622 (36.97) 332 (36.52) 290 (37.52) Hospitalization visits (mean, SD) (2.0 ± 1.0) (2.0 ± 1.0) (2.0 ± 1.0) Outpatient visits, n (%) 1,682 (100.00) 909 (100.00) 773 (100.00) Outpatient visits (mean, SD) (13.0 ± 9.0) (13.0 ± 9.0) (13.0 ± 9.0) Bold values signify statistical significant at P < 0.05. Native Hawaiian/Other Pacific Islander/ Native American/other/unknown. Not mutually exclusive; 1 patient could be counted more than once. Other includes dementia, peptic ulcer disease, and hemiplegia or paraplegia. A E = adverse event; ER = emergency room; SD = standard deviation. registry (Figure 1). Table 1 summarizes the baseline character- cyclophosphamide (9%), doxorubicin (6%); 5% of patients were istics of the mBC cohort and further categorizes the patients started on gemcitabine, epirubicin, vinorelbine, ixabepilone, into a group with 1 or more adverse events (n = 909, 54%) and and eribulin. Patients were predominantly white (57%), and the a group with no adverse events (n = 773, 46%) during follow- most common comorbidities were hypertension (43%), diabetes up. Overall, there was a higher percentage of patients aged less (16%), chronic pulmonary disease (12%), and renal disease than 65 years (60%) with a mean age of 53 years (standard (9%). Statistical differences were shown between the 2 groups at deviation [SD] = 8.1). Patients were initially started with a single baseline with race and peripheral vascular disease. The health chemotherapy agent as opposed to a combination chemotherapy care resource use for the prior 6 months was similar as well; regimen. Patients were divided according to first-line chemo- however, at baseline patients with adverse events had longer therapy treatment as follows: capecitabine (67%), taxane (22%), length of stay compared with patients with no adverse events. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 867 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System TABLE 2 TABLE 3 Adverse Events Identified During Summary of Episode of Care Data First-Line Chemotherapy Treatment During First-Line (Patient-Level Data) AE Episode of Care Summary Therapy During First-Line Number of patients with 1 or more AE episodes 909 Adverse Events and Other Characteristics Therapy Total AE episodes 5,940 Number of unique adverse events, n (%) N = 1,682 AE episodes related to chemotherapy, n (%) 5,475 (92.2) Single episodes, n (%) 4,185 (76.0) 0 773 (46.0) Mean number of single episodes per patient (SD) 4.7 (3.6) 1 322 (19.1) 1-day episode only, n (%) 4,004 (96.0) 2 186 (11.1) > 1-day episode, n (%) 181 (4.3) 3 148 (8.8) Mean duration of days for > 1-day episode (SD) 5.3 (1.7) 4 92 (5.5) Multiple episodes, n (%) 1,290 (24.0) > 5 161 (9.6) Mean number of multiple episodes per patient (SD) 3.0 (4.0) Unique adverse events by category, n (%) N = 909 Mean duration of days per multiple episode (SD) 4.8 (4.6) Dermatological 84 (9.2) Alopecia 5 (0.6) Percentages for single episodes were calculated as follows: 4,185 ÷ 5,475 = 76%. Percentages for multiple episodes were calculated as follows: 1,290 ÷ 5,475 = 24%. Injection site reaction 14 (1.5) A E = adverse event; SD = standard deviation. Rash 65 (7.2) Dehydration 104 (11.4) Dyspnea 108 (11.9) Edema 104 (11.4) Episode of care was applied after adverse events were identi- Gastrointestinal 466 (51.3) fied. During this time, we identified which adverse event episode Constipation 129 (14.2) of care was associated with chemotherapy. There were 5,940 Decreased appetite 37 (4.1) episodes identified: 92.2% (5,475) were chemotherapy related Diarrhea 128 (14.1) (Table 3 and Appendix B, available in online article) and 8% Nausea/vomiting 141 (15.5) (465) were from disease progression or other conditions not Stomatitis 31 (3.4) related to chemotherapy. Chart notes revealed that all the adverse Hematological 592 (65.1) events related to dyspnea were attributed to disease progression Anemia 346 (38.1) and not related to chemotherapy. We also did not identify any Leukopenia 122 (13.4) Neutropenia 88 (9.7) patients with fatigue, which is a common adverse event caused Thrombocytopenia 36 (4) by chemotherapy. Thus, we did not include these EOC events in Hepatic 35 (3.8) our analysis. There were 4,185 (76%) single episodes and 1,290 Liver enzymes increased 29 (3.2) (24%) multiple episodes of care (Table 3). The single episodes Bilirubin increased 6 (0.7) consisted of 4,004 (96%) 1-day single episodes, and 181 (4%) Infection or pyrexia 482 (53.0) less than 1-day single episodes. The mean duration of less than Infection 380 (41.8) 1-day single episodes was 5.3 days (SD = 1.7 days). The duration Pyrexia 102 (11.2) of multiple episodes was 4.8 days (SD = 4.6 days; Table 3). Neurological 322 (35.4) Chart notes were reviewed and pharmacy claims were used Arthralgia 134 (14.7) to evaluate if an EOC for an adverse event had any clinical Myalgia 36 (4.0) Peripheral neuropathy 152 (16.7) impact (dose delay, dose reduction, or discontinuation) on che- motherapy regimens (Table 4). Of the 909 patients, there were Liver enzymes: alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP). 185 patients (20%) who had 1 or more chemotherapy modi- fications as opposed to 724 patients (80%) who did not have any chemotherapy modification. Of the 45 patients who expe- Table 2 summarizes the adverse events identified after first- rienced a single EOC, 34 patients had dose delay; 17 patients line chemotherapy was given during the follow-up period. The had dose reductions; and 14 patients discontinued therapy. Of mean days of being on first-line therapy was 375 days (SD = 262 the patients who experienced a multiple EOC, 116 patients had days). Unique adverse events were defined as a patient having a dose delay; 80 patients had dose reductions; and 48 patients a specific adverse event 1 or more times. More than half of the discontinued therapy. The majority of patients with single patients started on chemotherapy had an adverse event, with 1 episodes who had chemotherapy modification were patients and 2 unique adverse events being the majority (19% and 11%, with hematological (42.3%), gastrointestinal (28.3%), and respectively). Overall, hematological (65%), infection/pyrexia infection/pyrexia (13%) adverse events. Similar results were (53%), and gastrointestinal (51%) episodes were the most shown in patients with multiple EOCs; however, more of these unique adverse events. Neurological (35%) and others (dehy- patients with any chemotherapy modification were shown to have neurological-related adverse events (11.8%) versus dration, dyspnea, and edema) represented 11% of the events. 868 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System TABLE 4 Characteristics of Patients with and Without Clinical Impact on Chemotherapy Regimen During EOC by AE Category Chemotherapy Modification (Dose Delay, Dose Reduction, or Discontinuation) No Chemotherapy Modification AE and Health Care Patients During First-Line Therapy Patients During First-Line Therapy Resource Characteristics N = 185 (20%) N = 724 (80%) a a a a Single EOC Patients, n (%) EOC, n (%) Patients, n (%) EOC, n (%) Total 45 109 724 4,076 Dermatological 2 (4.4) 2 (2.2) 66 (9.1) 111 (2.7) Dehydration 6 (13.3) 7 (7.6) 37 (5.1) 53 (1.3) Edema 1 (2.2) 1 (1.1) 93 (12.8) 158 (3.9) Gastrointestinal 25 (55.6) 26 (28.3) 353 (48.7) 749 (18.4) Hematological 27 (60.0) 39 (42.3) 306 (42.2) 1,348 (33.1) Hepatic 1 (2.2) 1 (1.1) 25 (3.4) 65 (1.6) Infection or Pyrexia 20 (44.5) 29 (31.5) 252 (34.8) 526 (12.9) Neurological 3 (6.7) 4 (4.3) 280 (38.6) 1,066 (26.2) Multiple EOC Total 160 484 400 806 Dermatological 7 (4.4) 7 (1.8) 14 (3.9) 14 (1.7) Dehydration 16 (10.0) 17 (4.3) 69 (19.2) 78 (9.5) Edema 8 (5.0) 9 (2.3) 11 (3.1) 12 (1.5) Gastrointestinal 90 (56.3) 107 (26.8) 129 (35.8) 171 (20.8) Hematological 117 (73.1) 181 (45.3) 138 (38.3) 239 (29.1) Hepatic 1 (0.6) 1 (0.3) 12 (3.3) 12 (1.5) Infection or pyrexia 69 (43.1) 115 (28.7) 135 (33.8) 220 (26.8) Neurological 31 (18.4) 47 (11.8) 41 (11.4) 60 (7.3) HCRU-related to any EOC Total 185 470 724 8,707 Hospital visits 180 (97.3) 70 (14.9) 229 (26.7) 111 (1.3) Hospitalization 1 day + ER visit 1 (0.5) 1 (0.2) 45 (5.2) 81 (0.9) Hospitalization 2 days + ER visit 9 (4.9) 10 (2.1) 63 (7.3) 117 (1.3) Hospitalization 3 days 37 (20.0) 54 (11.5) 56 (6.5) 76 (0.9) Hospitalization > 3 days 152 (82.2) 308 (65.5) 61 (7.1) 60 (0.7) More than 1 outpatient visit 173 (93.5) 445 (94.6) 403 (55.6) 4,773 (54.8) 1 outpatient visit + ER visit 1 (0.5) 2 (0.4) 33 (3.8) 4,328 (49.7) Note: Descriptive statistics were conducted between patients with any chemotherapy modification versus no chemotherapy modification and between EOC for any chemo- therapy modification group versus no chemotherapy modification group. Bold values signify statistical significance at P < 0.05. Patients with ≥ 1 hospital visits versus those with no hospitalizations. Patients with > 1 outpatient visits versus those with 1 outpatient visit. AE = adverse event; EOC = episode of care; ER = emergency room; HCRU = health care resource utilization. infection /pyrexia (7.8%). Table 4 also shows evaluation of health ■■  Discussion care resource utilization for clinical impact. Patients who had The results of this study demonstrate that adverse events related hospital visits with length of stay of 3 or more days (65.5%), to chemotherapy in patients with mBC have significant impact were shown to have the most clinical impact compared with on their chemotherapy regimens in an integrated health care those who stayed less than 3 days. delivery system. This is the first study to apply an EOC frame- Table 5 lists the significant factors associated with any che- work to understand health care delivery for adverse events in motherapy modification versus no chemotherapy modification. mBC women aged more than 18 years and who are undergoing Factors such as age (> 65 years), comorbidity (> 1 comorbidity), chemotherapy. Approximately 23% of patients experienced a and longer duration of days for each EOC were associated with multiple EOC for an adverse event, which was associated with clinical impact. Black and Hispanic patients were more likely to an increased risk of clinical impact. Our study also showed a have a modification in their chemotherapy treatment compared positive association with patients having longer hospital length with white patients. of stays and clinical impact. Adverse events from chemotherapy www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 869 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System pharmacokinetic processes, which could lead to dramatic TABLE 5 Factors Associated with Chemotherapy consequences such as excessive drug levels and unaccept- Regimen Modification and Without able toxicity. Racial/ethnic status was also associated with Chemotherapy Modification from an increased risk of clinical impact in our study. Future Multivariate Logistic Regression in studies will need to examine social and cultural factors that mBC Patients may be responsible for this finding. There was a total of 20% Chemotherapy of patients that had chemotherapy modification to current Modification Versus No Chemotherapy chemotherapy regimens related to an adverse event. A previ- Modification During ous study reported a rate of chemotherapy modification of First-Line Therapy approximately 24.7%. Patient and Clinical Characteristics OR (95% CI) Current existing treatments for patients with mBC are Patient age groups, years effective, but they are associated with many different adverse < 65 years (reference) 1.00 events, and these can cause changes to the patient’s chemo- > 65 years 2.05 (1.57-2.49) therapy regimen. The clinical impact has not been previ- Race ously quantified, and changes in chemotherapy regimens White (reference) 1.00 Black 2.22 (1.75-2.68) can cause clinical, functional, and economic consequences. Hispanic 1.58 (1.11-1.89) These findings can help managed care organizations evalu- Asian/Pacific Islander 0.52 (0.31-1.21) ate the importance of including the side effect profile from Comorbidities various treatment options into clinical decision making and 1 + versus 0 2.01 (1.74-2.82) identify therapies that may be associated with fewer compli- Chemotherapy regimen cations. This could improve patient clinical outcomes and Combination versus single 1.47 (0.33-2.71) reduce changes in chemotherapy regimens and possible costs Duration of EOC related to adverse events. Managed care and other health Single episode 1.24 (1.09-2.07) care systems should always be looking for therapies that Multiple episode 2.81 (2.42-3.56) demonstrate equal or superior efficacy to current standard Health care utilization for any EOC chemotherapy regimens, while decreasing the frequency Hospital visit only 0.88 (0.62-1.63) and severity of adverse events related to these chemotherapy Hospitalization 1 day + ER visit 0.91 (0.73-1.56) Hospitalization 2 days + ER visit 2.88 (2.53-3.57) regimens. Newer therapies can help with economic burden Hospitalization 3 days 5.22 (4.88-6.05) by reducing potential costs incurred from treatment-related Hospitalization > 3 days 8.55 (7.42-9.02) adverse events. 1 outpatient visit 0.28 (0.16-1.05) 1 outpatient visit + ER visit 0.33 (0.14-1.22) Limitations Bold numbers indicate statistical significance. Our study had some limitations. Although we used diagnosis CI = confidence inter val; EOC = episode of care; ER = emergency room; mBC = meta- and procedure codes to identify adverse events, we relied static breast cancer; OR = odds ratio. only on data that were available in our electronic system. All adverse events were identified with diagnosis and procedure codes, and laboratory data were not used to confirm specific reported from other studies showed hematological, infection/ adverse events such as anemia, leukopenia, neutropenia, or pyrexia, and gastrointestinal episodes as the most common thrombocytopenia. Since the health care encounters were adverse events from chemotherapy, which we also found in associated with diagnosis and procedure codes, we thought 10,11 our results. However, the rates in our study were higher, using those codes would suffice; however, there may be pos- which was most likely because our patients were at the meta- sible underestimation in these rates. We also understand static stage rather than an earlier breast cancer stage. The that the adverse event list did not include all adverse events presence of metastatic disease and being initiated on che- caused by chemotherapy; however, by reviewing the litera- motherapy are independently associated with a statistically ture and previous clinical trials, the adverse events included significant increase in the odds of experiencing a serious in this study were the most common in patients using chemo- 10,11 adverse effect. We also found that patients older in age and therapy. A common adverse event is fatigue, and since this is with more comorbidities had a significantly higher likelihood mostly a patient-reported event, we could not identify it using of an impact on chemotherapy treatment. Chemotherapy is diagnosis codes. Our sample consisted of patients on chemo- used in the elderly population; however, oncologists assess therapy only; we did not evaluate the status (positive or nega- age and comorbidities in this population when consider- tive) of human epidermal growth factor receptor 2 (HER2) or ing chemotherapy because of fear of excessive toxicity. evaluate targeted therapies. We used our databases to identify Chemotherapy is known to have a low therapeutic index, first-line chemotherapy regimens 12 months prior to index and with age, there are many changes that could impact the date so could only capture what was found in our pharmacy 870 Journal of Managed Care & Specialty Pharmacy JMCP October 2015 Vol. 21, No. 10 www.amcp.org Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System DISCLOSURES databases. Finally, when we evaluated adverse events, we This study was supported by an unrestricted research grant provided by could not report what grade (3 or 4) or apply a scale of sever- Genentech. Rashid, Koh, Li, and Baca do not have any financial interests or ity to them; however, if a patient was admitted to the hospital, potential conf lict of interest with regard to this work. Masaquel, Malecha, and there was an assumption that it had some severity. Overall, Abidoye are employees of Genentech. our rates of health care resource utilization had all severities. Study concept and design were created by Rashid, Koh, Malecha, and Masaquel. Data were collected by Rashid, Baca, and Li and interpreted by all the authors. The manuscript was written by Rashid, Koh, Li, Malecha, and ■■ Conclusions Masaquel and revised by Rashid, Baca, Malecha, and Masaquel. 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Medical Group, Kaiser Permanente Southern California, Bellf lower, N Engl J Med. 2001;344(26):1997-2008. and HILDA C. BACA, BS, is Programmer, Pharmacy Analytical 15. Mehta SS, Suzuki S, Glick HA, Schulman KA. Determining an episode of Services, Kaiser Permanente Southern California, Downey. care using claims data. Diabetic foot ulcer. Diabetes Care. 1999;22(7):1110-15. SUSAN MALECHA, PharmD, MBA, is Lead, National Managed 16. Flaherman VJ, Ragins AI, Li SX, Kipnis P, Masaquel A, Escobar GJ. Care Liasion; OYEWALE ABIDOYE, MD, MPH, is Medical Frequency, duration and predictors of bronchiolitis episodes of care among Director; and ANTHONY MASAQUEL, PhD, MPH, is Senior infants ≥32 weeks gestation in a large integrated healthcare system: a retro- Health Economist, Genentech, South San Francisco, California. spective cohort study. BMC Health Serv Res. 2012;12:144-52. AUTHOR CORRESPONDENCE: Nazia Rashid, PharmD, MS, 17. Wildiers H. Mastering chemotherapy dose reduction in elderly cancer Research Scientist, Drug Information Services, Kaiser Permanente patients. Eur J Cancer. 2007;43(15):2235-41. Southern California, 12254 Bellflower Blvd., Downey, CA 90242. 18. Walker MS, Masaquel AS, Kerr J, et al. Early discontinuation and switch- Tel.: 562.658.3952; Fax: 562.658.3843; E-mail: [email protected]. ing in first-line metastatic breast cancer: the role of patient reported symptom burden. Breast Cancer Res Treat. 2014;144(3):673-81. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 871 Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System APPENDIX A Diagnosis Codes Used for Identifying Adverse Events Adverse Event ICD-9-CM Code HCPCS/CPT Codes Dermatological Alopecia 704.0x Injection site reaction 999.39 Rash 693.0x, 708.8x, 708.9x,782.1x Dehydration 276.5x Dyspnea 786.0x Edema 782.3x, 514.xx, 518.4x Gastrointestinal Constipation 564.0x Decreased appetite 783.0x, 783.2x Diarrhea 558.9x, 564.5x, 787.91, 007.xx, 009.xx Nausea 787.0x, 787.01, 787.02, 787.03, 536.20 G9021, G9022, G9023, G9024 Stomatitis 528.0x Hematological Anemia 280.xx, 281.xx, 283.xx, 284.xx, 285.xx S3906, S9538, C1010, C1016, C1020, C1021, C9504, C9505, P9016, P9021, P9022, P9038, P9039, P9040, P9051, P9054, P9057, P9058, Q0136, Q4055, J0885, J0886, Q9920-Q9940, Q4054, J0880, J0881, J0882, Q0137, C1774, S0112 Leukopenia 288.5x, 288.8x, 288.9x J1440, J1441, C9119, Q4053, J2505, J2820 Neutropenia 288.0x Thrombocytopenia 287.3x, 287.4x, 287.5x, 444.6x, 289.84, 99.05 P9010, P9031, P9037, P9052, P9053, P9055 Hepatic Liver enzymes increased 790.4x, 790.5x 84450 Bilirubin increased 277.4x 81000, 81001, 81002, 81003, 82248, 82247 Infection or Pyrexia Infection 001.xx-018.xx, 030.xx-041.xx, 045.xx-049.xx, 050.xx- 057.xx, 110.xx-118.xx, 070.xx-079.xx, 130.xx-136.xx, 460.xx-466.xx, 480.xx-488.xx, 038.0x, 038.19, 038.80, 038.9x, 995.91, 995.92 Pyrexia 780.6x Neurological Arthralgia 719.4x, 524.62 Myalgia 729.1x G9025, G9026, G9027, G9028 Peripheral neuropathy 356.xx, 357.xx, 337.0x, 337.1x Other Fatigue 780.72 G9029, G9030, G9031, G9032 Pharyngitis 462.00 CPT = Current Procedural Terminology; HCPCS = Healthcare Common Procedure Coding System; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 871a Clinical Impact of Chemotherapy-Related Adverse Events in Patients with Metastatic Breast Cancer in an Integrated Health Care System APPENDIX B Descriptive Data on Chemotherapy-Related EOCs Per AE Category During First-Line Therapy (Episode Level) Total Single 1-Day Single > 1-Day Single Total Multiple Mean Days of During First-Line Total Episodes Episodes Episodes Episodes Episodes Multiple Episode Therapy, n (%) N = 5,475 N = 4,185 n = 4,004 n = 181 N = 1,290 Duration (SD) Dermatological 134 (2.49) 113 (2.71) 111 (2.77) 2 (1.22) 21 (1.72) 5.5 (4.3) Dehydration 155 (2.83) 60 (1.44) 50 (1.25) 10 (6.10) 95 (7.36) 4.3 (3.2) Edema 180 (3.34) 159 (3.81) 157 (3.92) 2 (1.22) 21 (1.72) 5.2 (5.3) Gastrointestinal 1,053 (19.54) 775 (18.59) 741 (18.51) 34 (20.73) 278 (22.75) 5.3 (4.5) Hematological 1,807 (33.53) 1,387 (33.28) 1,317 (32.89) 70 (42.68) 420 (34.37) 6.1 (5.6) Hepatic 79 (1.47) 66 (1.58) 65 (1.62) 1 (0.61) 13 (1.06) 4.3 (2.9) Infections/pyrexia 890 (16.25) 555 (13.26) 498 (12.44) 57 (34.75) 335 (25.96) 4.2 (4.1) Neurological 1,177 (21.84) 1,070 (25.67) 1,065 (26.60) 5 (3.05) 107 (8.76) 4.6 (2.9) A E = adverse event; EOC = episode of care; SD = standard deviation. www.amcp.org Vol. 21, No. 10 October 2015 JMCP Journal of Managed Care & Specialty Pharmacy 871b

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Journal of Managed Care & Specialty Pharmacy – Pubmed Central

Published: Oct 1, 2015

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