Jim M. Koeller, MS

: The costs of diagnostic, treatment, and end-of-life phases for advanced squamous cell carcinoma of the head and neck (SCCHN) are unknown, particularly after the approval of the first biologic agent for treatment, cetuximab. We aimed to characterize costs for each of the 3 disease phases and total cost of care for patients with advanced SCCHN before and after the approval of cetuximab.

: Retrospective, observational, cohort study.

: This was a retrospective analysis of the PharMetrics Choice insurance claims database. Patients 20 years or older with International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes suggestive of advanced SCCHN between March 1, 2003, and March 1, 2008, were included. Patients were divided into 2 cohorts by date of diagnosis: a “prebiologic” period and a “postbiologic” period. Descriptive statistics were used to summarize baseline patient characteristics, monthly and total medical costs, and cost drivers. The Mann-Whitney U test was used to compare medical costs between segments and cohorts.

: A total of 365 patients with SCCHN met the study criteria. Median monthly medical costs were: diagnosis ($2199), treatment ($4161), end-of-life ($6614), and total ($4167). Total medical costs were driven primarily by outpatient costs (23%), inpatient costs (18%), and the cost of radiation therapy (16%). In the treatment segment, median monthly costs were significantly lower in the prebiologic era compared with the postbiologic era ($3301 vs $4381; P = .0024).

: Median total costs exceeded $4000 per month for patients with SCCHN, driven primarily by the end-of-life segment. The median monthly costs of the treatment segment increased by approximately $1000 following cetuximab’s approval.

Head and neck cancers account for approximately 3% of all cancer diagnoses and 2% of cancer-related deaths in the United States.

 In 2015, an estimated 45,780 Americans were diagnosed with head and neck cancers, of which 90% were of squamous cell histology.

Currently, the estimated 5-year survival rate for all patients diagnosed with squamous cell carcinoma of the head and neck (SCCHN) is 60%. Of those diagnosed with SCCHN, 60% are diagnosed with locally or regionally advanced disease, generally denoting a poorer prognosis.

Fortunately, recent data from the American Cancer Society demonstrate a steady annual decrease in SCCHN mortality of approximately 2% for women. Mortality in men has since stabilized.

The decrease in mortality is likely attributable to advances in the management of head and neck cancers.

 The National Comprehensive Cancer Network clinical practice guidelines recommend combined modality therapy for patients diagnosed with locally or regionally advanced disease.

Currently, first-line recommendations include combining radiation therapy with chemotherapy (eg, cisplatin) or with biologic therapy.

 Cetuximab is a biologic therapy, an epidermal growth factor receptor inhibitor approved in 2006 for use in patients with locally or regionally advanced SCCHN in combination with radiation therapy.

Second-line options include surgery, radiation (if not previously given), or systemic therapy with various single-agent chemotherapeutic options: cisplatin, carboplatin, docetaxel, cetuximab, or fluorouracil.

With the rising cost of cancer care in the United States, new therapies must be critically evaluated in regard to their economic value. Multiple factors, including extent of care, advancements in diagnostic capabilities, and increases in cancer prevalence rates, have contributed to this rise in recent years.

 The growing use of newer drug therapies, such as biologic agents, is often cited as one of the primary drivers of increasing cancer costs.

 However, available cost analyses of head and neck cancers have been limited to time periods preceding approval of these newer treatment modalities.

Differing patterns of care across disease segments (ie, diagnosis, treatment, end-of-life) make it difficult to quantify the costs of managing specific cancers

; however, a longitudinal evaluation of incidence-based direct medical costs for specific cancers can be used to estimate long-term costs for managing patients with cancer.

 The objective of this study was to describe the segmented (diagnosis, treatment, end-of-life) and total direct medical costs associated with the management of SCCHN.

This was a retrospective, observational, cohort study utilizing data from a private payer claims database (PharMetrics Choice) spanning the period from September 1, 2002, through March 1, 2010. The study was approved by the institutional review board at the University of Texas Health Science Center at San Antonio.

The PharMetrics database is an integrated patient-level database of pharmacy and medical claims from more than 90 commercial health plans in the United States. The database is representative of commercially insured patients across the United States and captures various claims rendered, such as laboratory and diagnostic tests, outpatient physician visits, hospitalizations, outpatient clinic visits, and pharmacy-related costs.

The PharMetrics Choice database (derived from the PharMetrics database) excludes claims for carve-outs, patients who lack integrated pharmacy and medical benefits, plans that have failed to submit data for the previous 2 years, and plans that lack membership tables. In 2010, more than 55 million patients were included in the PharMetrics Choice database.

All patients 20 years or older and enrolled in an eligible health plan for more than 1 day between March 1, 2003, and March 1, 2008, (the enrollment period) were considered for initial sampling. Individuals with advanced or locally advanced SCCHN were identified using an algorithm developed for use with healthcare claims data (Figure 1).

Diagnosis of new SCCHN cases was determined by the presence of at least 1 inpatient or 2 outpatient claims suggestive of head and neck malignancies at sites with a high proportion of squamous cell histology. These claims were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 140.X to 148.X, 161.X, 195.0, and 196.0. The date of the first claim for SCCHN was assigned as the index date.

Eligible patients were required to have 6 months of continuous enrollment preindex date and 24 months of continuous enrollment postindex date to account for patient progression through all segments of disease. Additionally, patients were required to have claims and procedure codes indicative of receipt of therapy for squamous cell histology and recurrent and/or advanced disease (ie, stage II, III, IV). Patients with another primary malignancy, as evidenced by at least 1 inpatient or 2 outpatient claims, were excluded.

Variables evaluated at the time of the index date included patient age, sex, geographic region, and National Cancer Institute (NCI) Comorbidity Index score. This score was derived from the Charlson Comorbidity Index and numerically represents the risk of impending mortality according to the presence of various chronic diseases at the time of cancer diagnosis.

 Additional data, such as race, ethnicity, tobacco and alcohol use, and human papilloma virus status, were not reported for the study population due to a lack of reporting of such information in the claims database.

Patients were followed from the index date until patient death, end of continuous enrollment, or end of the study period (March 1, 2010). Patient follow-up was evaluated in total and as segments (ie, diagnosis, treatment, and end-of-life). These 3 disease segments were derived from prior published studies evaluating the economic burden of cancer across phases of care.

The diagnosis segment was defined as the period 90 days immediately preceding the index date plus the time until the receipt of active treatment, identified as claims for surgery, radiation therapy, biologic therapy, or chemotherapy.

The treatment segment consisted of all claims identified following the initiation of active treatment until the study's end or the start of the end-of-life segment. The end-of-life segment was defined as the period 90 days preceding death. As reporting of mortality in healthcare claims is limited, we used a previously published algorithm for identifying deaths within insurance claims databases.

Patients with claims ending prior to the study end (March 1, 2010) and coding of a “likely fatal event” (eg, hospitalization, hospice, emergency department [ED], resuscitation, or cardiac arrest) within 30 days of the last date of active enrollment were considered to have died. Those patients who did not experience a likely fatal event during the study period would have remained in the treatment phase and not experienced the end-of-life phase.

The primary outcome was direct medical costs of SCCHN from the payer perspective, according to the specific disease segment: diagnosis, treatment, and end-of-life. Cost estimates were based on direct medical costs paid and included total reimbursed amounts and all paid medical and pharmacy claims.

Claims for hospitalization, ED visits, outpatient physician visits, outpatient treatments, skilled nursing care, hospice direct costs, radiation therapy, and drug costs made during the follow-up period were included. Costs were reported as monthly costs for each segment. Secondary outcomes included total monthly cost, cost per disease segment and total cost, percentage of costs for individual claims, and cost comparison among the prebiologic and postbiologic cohorts.

The approval of new treatments allowed stratification across 2 time periods. Patients were categorized into cohorts surrounding the approval of the biologic agent, cetuximab. Patients with an index date between March 1, 2003, and February 28, 2006, were assigned to the prebiologic cohort whereas patients with an index date on or following March 1, 2006, were assigned to the postbiologic cohort. Costs were compared among individuals according to prespecified cohort.

Additionally, those patients who experienced all segments of care (ie, diagnosis, treatment, and end-of-life) were assessed separately. This analysis was performed to evaluate costs incurred in patients with a likely fatal event, as these costs may differ from those for patients experiencing only the first 2 of the 3 segments of care associated with advanced SCCHN. These patients were referred to as the “full-care” group.

Categorical data were reported as numbers and percentages. Data were compared using the 

2 method. Continuous data were reported using descriptive methods and compared across cohorts using the Mann-Whitney U test. All costs were adjusted to 2009 US dollars based on the medical services component of the Consumer Price Index and were presented as medians and interquartile ranges (IQRs).

All statistical analyses were conducted using JMP version 9.0 (SAS Corporation; Cary, North Carolina).

Initial sampling identified 38,601 patients with head and neck malignancies. A total of 365 patients met the study inclusion criteria for SCCHN: 100 in the prebiologic period and 265 in the postbiologic period (Figure 1). The eAppendix (available at www.ajpb.com) describes patient demographics for the study population in composite and among the prebiologic and postbiologic cohorts. Patients were predominately male (78%), with a median age of 57 years. The mean NCI Comorbidity Index score was 0.53 (SD = 1.04).

The median duration of follow-up after the index date for all patients with SCCHN was 30.1 months (eAppendix), predominated by the treatment segment (median = 27.3 months). Overall, the total median cost incurred for patients with SCCHN was $110,793 (IQR, $73,769-$156,836) (Table 1). The median cost for care of patients with SCCHN incurred in this study was $4167 per month over the follow-up period.

The end-of-life segment was associated with the highest monthly cost (median = $6614; IQR, $3172-$17,158), followed by the treatment segment (median = $4161; IQR, $2540-$7915); however, total costs (median = $99,247; IQR, $63,117-$142,653) were highest in the treatment segment due to the longer duration of follow-up. The diagnostic segment incurred the lowest total (median = $6341; IQR, $2749-$11,121) and monthly (median = $2199; IQR, $1077-$4677) costs.

Outpatient clinic visits, radiation, and inpatient therapy costs were the 3 main cost drivers, representing 23%, 18%, and 16% of total medical costs, respectively. During the treatment segment, outpatient visits (23%) were the primary cost driver (

Radiation therapy, when combined with intensity-modulated radiation therapy (IMRT), accounted for 39.5% of the total costs incurred. Composite oncology drug (chemotherapy plus cetuximab) claims accounted for 7% of treatment costs, with chemotherapy accounting for 2.6% and biologics 4.4%. Surgery accounted for only 0.6%.

Patient characteristics were similar for prebiologic and postbiologic cohorts, with the exception of geographic region (P <.0036) (eAppendix). The overall duration of diagnostic and end-of-life segments (if present) were similar, with median durations of 2.8 and 2.9 months, respectively (Table 2). Patients in the prebiologic period had a significantly longer median duration of treatment, resulting in a longer observation period compared with the postbiologic period (29.1 vs 26.8 months; P = .0023).

Median monthly costs in the treatment segment were increased in the postbiologic cohort compared with the prebiologic cohort ($3301 vs $4381; P = .0024), whereas costs in the diagnostic and end-of-life segments were not statistically different (Table 2). Total monthly costs were higher in the postbiologic cohort compared with the prebiologic cohort ($3236 vs $4421; P = .0006). Medical claims between cohorts remained unchanged, with the exception of IMRT (8% vs 14%; P <.0001), chemotherapy (4% vs 2%; P = .001), and cetuximab (0% vs 4%; P <.0001) use.

Twelve percent of patients (n = 44) in this study were included in the full-care group: 14 prebiologic patients and 30 postbiologic patients. Baseline characteristics of patients in the full-care group were similar to patients in the non—full-care group: median age (58.5 vs 57 years; P = .0943), percentage male (81.8% vs 77.8%; P =.5521), and mean NCI comorbidity index score (0.73 vs 0.50; P = .1476). Full-care patients in the prebiologic and postbiologic cohorts had similar baseline characteristics.

Median monthly costs in the full-care group according to segment were: diagnostic segment ($1733; IQR, $660-$3614), treatment segment ($8265; IQR, $3946-$17,851), and end-of-life segment ($6614; IQR, $3172-$17,157). Total median costs for the follow-up period were $122,041 (IQR, $73,582-$168,461), with the highest proportion of costs incurred in the treatment segment ($89,281; IQR, $46,598-$121,067).

In comparing prebiologic and postbiologic cohorts, median monthly costs and median total costs were similar across all disease segments. The total median monthly cost for the follow-up period ($7817; IQR, $4053-$12,243) was higher compared with the non—full care group, ($3889; IQR, $2549-$6757; P = .0002).

To our knowledge, this is the first study to characterize the segmented direct medical costs of SCCHN across disease segments during the era of biologic therapy. The results of this study illustrate the economic impact of SCCHN across different segments of care and capture the impact of cetuximab by evaluating the time surrounding the approval of this agent.

Earlier studies evaluated the cost of head and neck cancers utilizing data from the 1990s.13,14 In a study by Lang et al, the economic cost of SCCHN in patients 65 years or older used data collected from the Surveillance, Epidemiology, and End Results database.

The study results demonstrated a significant increase in the median cost of SCCHN compared with controls ($1428 vs $446 per month; P < .001), with most costs incurred from hospitalization. The investigators found that patients with regional and distant disease had higher average costs ($2059-$2547); however, chemotherapy and radiation accounted for only 8% and 10% of regional and distant disease costs, respectively.

In comparison, the median cost of care of patients with SCCHN incurred in this study was $4167 per month over the follow-up period. When converted to 2009 dollars, the median cost per month incurred for advanced-stage disease in the study by Lang et al

 would be approximately $3300, which is comparable with the costs incurred in our study.

Although our study is the first to our knowledge to evaluate the segmented costs of SCCHN, other studies have conducted similar analyses in other malignancies.

 Song et al evaluated the costs incurred for metastatic colorectal cancer during the era of biologic therapy.

Articles

The cost of squamous cell cancer of the head and neck is driven primarily by the end-of-life phase. Treatment costs increased following the approval of cetuximab.

Cost of Squamous Cell Cancer of the Head and Neck

: We assessed chemotherapy use in patients with chronic myelogenous leukemia (CML) to determine how use of CML-specific tests impacted drug selection and modification. We compared real-world data with National Comprehensive Cancer Network (NCCN) guideline recommendations.

: This was a longitudinal, retrospective analysis of a commercial insurer database.

: Patients with at least 2 claims associated with CML between July 1, 2006, and June 30, 2008, were included. Time from diagnosis to first chemotherapy treatment was measured. We identified the use of karyotyping/fluorescent in situ hybridization (FISH), reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative polymerase chain reaction (Q-PCR), and kinase domain mutation analysis and compared use with NCCN recommendations.

: Sixty patients with a CML diagnosis had specialty tests and received drug therapy. Median age was 55 years and 57% of patients were male. For 48 patients, the median time from diagnosis to therapy initiation was 3.7 months. Twelve patients had no CML-specific tests drawn prior to initiation. Forty-eight patients (80%) had CML-specific tests drawn every 3 months during drug therapy; however, 12 patients had at least one 3-month period with no labs. Overall, 85% received Q-PCR, 13% received RT-PCR, 2% received FISH, and no patients had karyotyping or mutation analysis. Imatinib was the initial chemotherapy in 87% of patients. Every patient who received a second-line drug (n = 9) had labs within 30 days of drug change.

: It appears that use of CML-specific molecular tests met 2008 NCCN guidelines. PCR testing was carried our prior to chemotherapy change; however, the use of mutation analysis was not identified. Educational efforts to promote the use of karyotyping/FISH analysis and to use molecular tests with appropriate frequency should be considered.

Chronic myelogenous leukemia (CML) is a slow-progressing form of leukemia characterized by increased and unregulated growth of myeloid cells in the bone marrow. CML occurs in 3 phases: chronic phase (during which most patients are diagnosed), accelerated phase (a transitional phase), and blast-crisis phase. Blastcrisis phase is the terminal phase of CML, often occurring within 3 to 5 years post diagnosis.

In 2009, the National Cancer Institute estimated that 5050 patients would be diagnosed with CML in the United States each year.

 This disease has a widespread age range; the median age at diagnosis is 67 years, and the median age at death is 73 years. This disease is more prevalent in men. CML is characterized by identification (cytogenetically or via molecular methodology) of the chromosomal translocation (9:22) referred to as the “Philadelphia chromosome” (Ph+). This translocation results in the head-tail fusion of the break point cluster region (BCR) (chromosome 22 at band 11) and the Abelson murine leukemia (ABL) gene (chromosome 9 at band q34).

The product of this translocated gene plays a central role in the development of CML. Studies have shown that the fusion gene product, BCR-ABL, deregulates tyrosine kinase activity, which is thought to be integral to the development of CML.

 CML is often suspected in patients with an irregular complete blood count (CBC), when granulocytes, basophils, and eosinophils are increased. CML is diagnosed by detecting the Ph+ chromosome in blood or bone marrow.

Detection is generally accomplished through routine cytogenetics (normal karyotyping). If bone marrow collection is not possible, then cytogenetic determination may be achieved via fluorescent in situ hybridization (FISH), which measures the percent of Ph+ metaphases. BCR-ABL transcripts can be measured by conventional qualitative reverse-transcriptase polymerase chain reaction (RT-PCR). RT-PCR generates a positive or negative reading. A real-time quantitative polymerase chain reaction (Q-PCR) can report the actual number of mRNA transcripts. Although the Q-PCR test is highly sensitive and specific, it is also expensive; thus, Q-PCR is generally not obtained unless patients are Ph+ negative by cytogenetic testing or have a low level of FISH positivity.

Conventional cytogenetics is a microscopic examination of genetic material that screens for Ph+ cells among a minimum of 20 metaphase samples. A complete cytogenetic response (CCR) is defined by the absence (0%) of Ph+ chromosomes; CCR may be a possible surrogate marker for survival.

 Molecular responses are primarily measured using the Q-PCR test. A complete molecular response is the absence of BCR-ABL mRNA transcripts. In 2001, imatinib was the first selective inhibitor of the BCR-ABL tyrosine kinase approved by the FDA. However, despite high complete response rates, resistance to imatinib occurred in up to 37% of patients treated over a 6-year period.

 It was also reported that 13% to 14% of patients discontinued imatinib therapy due to resistance or intolerance in the same period.

 For those who remain on imatinib therapy, some continue to test positive for the BCR-ABL gene mutation.

 Clinical evidence suggests the importance of achieving early cytogenetic and molecular response for optimal long-term outcomes.

The molecular basis of CML is heterogeneous, with some patients initially resistant or rapidly acquiring resistance to imatinib. Physiological changes in the patient or molecular changes in the BCR-ABL kinase domain (KD) may lead to imatinib resistance. More than 100 different point mutations in this domain can result in resistance.

Ernst and colleagues found that 53 of 95 patients (55.8%) with imatinib resistance in various disease stages had detectable mutations; 22 different mutations were seen within these individuals. Patients’ responses to dose increases were poor.

 While not all point mutations may confer imatinib resistance, disease progression is associated with improperly treated resistance.

 The BCR-ABL mutation T315I is of particular concern, since it mediates resistance to other tyrosine kinase inhibitors (TKIs), including dasatinib and nilotinib.

Dasatinib and nilotinib are each indicated for first-line treatment of CML and in patients with resistance or intolerance to prior therapy, including imatinib.

The effectiveness of dasatinib is based on hematologic and cytogenetic response rates. Early detection of imatinib failure allows for therapeutic switch to dasatinib, which has shown favorable results for major molecular response in imatinib resistance.

 Bosutinib and ponatinib are newer TKIs reserved for use when a patient fails therapy with a first-line CML TKI. Conventional laboratory work, along with special cytogenetic and molecular testing, plays a critical role in the diagnosis, treatment, and follow-up of CML patients. The National Comprehensive Cancer Network (NCCN) constructed CML monitoring guidelines.

Initial diagnosis should include a CBC, platelet count, bone marrow cytogenetics (including fluorescence in situ hybridization [FISH]), and baseline Q-PCR. Definitions of complete hematologic response, cytogenetic responses, and partial hematologic response as defined by the NCCN are listed in Table 1. When peripheral blood counts are normalized, a patient is in hematologic remission.

Cytogenetic remission can be determined via bone marrow aspiration and cytogenetic evaluation. In a patient with CML, evaluation of therapy response should be carried out every 3 months for the remainder of the patient’s life.

 Testing every 3 months promotes early detection of resistance; this allows treatment maximization for each patient. BCR-ABL analysis should be performed every 3 months, while cytogenetic testing should be performed at treatment months 6, 12, and 18.

 If a patient experiences imatinib failure, a mutational analysis is warranted.

Our aim was to utilize data from CML patients within Horizon Blue Cross Blue Shield (Horizon BCBS) and establish whether the patterns of care adhered to the 2008 NCCN CML clinical practice guidelines for the following outcomes: time from initial diagnosis to initiation of drug therapy, choice of initial treatment regimen, and patterns of follow-up monitoring of drug therapy (completion rates of the specific recommended specialty tests).

This retrospective longitudinal cohort study used a hybrid database that included data from Horizon BCBS and their primary laboratory. The study period ranged from July 1, 2006, through June 30, 2008. Eligibility criteria included presence of the diagnostic code for CML (International Classification of Diseases, Ninth Revision, Clinical Modification code 205.1), being 18 years or older, insurance enrollment for 6 months or more, 90 days or more of designated specialty laboratory data, and 2 or more CML drug claims. Patients were required to have a new diagnosis of CML after July 1, 2006, for inclusion in the study. Patients without 2 or more designated specialty laboratory tests from the primary laboratory were not included.

The primary measures were the times from initial diagnosis of CML to initiation of cancer therapy, to initial drug treatment, and to completion of specialty cytogenetic and molecular tests. Cytogenetic and molecular tests included normal bone marrow karyotyping, chromosomal analysis by FISH, BCR-ABL RT-PCR, BCR-ABL Q-PCR, and BCRABL KD mutational analysis. Per NCCN 2008 CML guidelines, bone marrow cytogenetics or FISH were indicated along with polymerase chain reaction monitoring of BCRABL transcript number. For patients responding, BCR-ABL transcript numbers should have been monitored every 3 months. Bone marrow cytogenetics should have been performed at months 6 and 12 post therapy initiation, and at 18 months if CCR was not achieved at 12 months. With disease progression, drug resistance, or changing BCR-ABL transcripts, patients should have been followed monthly with the possibility of additional testing using KD mutational analysis prior to drug change.

Statistical analyses were performed using JMP version 7.0 (SAS Institute, Cary, North Carolina). Descriptive statistics (percents, mean SDs) were used to characterize the CML population based on patient age, gender, and comorbidities. Comorbidities included coronary artery disease, diabetes, heart failure, hypertension, and chronic obstructive pulmonary disease Time-to-treat was defined as time (in days) from initial diagnosis to first CML drug treatment; this outcome was reported as mean SD. Length of treatment was also reported as mean SD and defined as time (in months) from start of CML drug until cessation. The length of treatment was reported for each drug a patient received.

Follow-up for each patient included any therapy changes and all CML special tests throughout the study period. We calculated the number of special tests performed for patients with a change in drug or dosage during the study period. Patients in this subgroup included those with intolerance (such as toxicity) or those who experienced overt progression (resistance to particular drug therapy). We also identified the percentage of patients that did not have recommended special tests completed prior to drug therapy change.

This study was conducted in accordance with the ethical principles that have their origin in the current Declaration of Helsinki and were consistent with the International Conference on Harmonization Good Clinical Practice, Good Epidemiology Practices, and all applicable regulatory requirements.

Of 145 CML patients identified in the hybrid database, 60 met inclusion criteria. The Figure shows the breakdown of patient eligibility for study inclusion. See Table 2 for demographic results of the 60 patients included in the study.

CML diagnosis was assumed with the first identified primary lab specialty laboratory test. Forty-eight patients had a primary lab specialty test prior to their first dose of CML treatment. For 43 of these 48 patients (90%) the primary lab specialty lab test was performed 30 days or less (median 8.5 days) prior to the first dose of treatment. For 48 patients (80% of patients in study) with a confirmed primary lab specialty test, time to first drug claim from first specialty test was a median of 3.7 months (mean = 5.7 months; SD = 6.1 months). Twelve patients had no primary lab specialty test identified prior to first dose. Four of these 12 patients had no labs within 30 days of drug treatment.

The remaining 8 patients had a specialty lab within 30 days of drug therapy, but not prior to therapy initiation. If these 8 patients were included in the secondary analysis (by giving them a value of 0 for the time-to-first drug), median time would be 2.2 months and mean time would be 4.9 months.

A majority of patients (87% [n = 52]) received imatinib as first-line therapy; dasatinib was the first-line therapy for 5 patients (8%). Cytarabine, hydroxyurea, and nilotinib were each used for 1 patient. This patient received interferon alfa-2b initially, but was switched to cytarabine in less than a month. Hydroxyurea was used for 2 other patients. There were a mean of 10.6 drug claims per patient (median = 8) for a total of 635; 91% of all drug claims were for imatinib. The median time between first and last drug claim was 17.4 months (15.8 mean) and ranged from 0.9 to 24.2 months based on a 28-day (4 week) month The median and mean number of days between drug claims were 34 days and 46.2, respectively.

During the study period, 9 patients were switched to second-line therapy. All 9 patients had a specialty lab performed within 30 days of change. Q-PCR was the primary test used. Five of those 9 patients had been on imatinib and switched to another TKI (4 to dasatinib, 1 to nilotinib). Mean time to switch was 10.1 months. Three patients received hydroxyurea as first-line therapy, but were subsequently switched to imatinib. The mean time for these switches was 0.6 months.

Specialty laboratory tests were analyzed for type and frequency and then compared with NCCN guidelines. Forty-eight patients (80%) consistently had specialty labs performed every 3 months or more frequently, meeting NCCN guidelines. However, 12 patients had at least 1 3-month period without a specialty lab test. Overall, 51 patients (85%) had Q-PCR performed, while 8 patients (13%) had RT-PCR. One patient had FISH performed. No bone marrow karyotyping or ABL KD mutational analysis was identified. The 1 patient in whom the use of FISH was identified, had 19 drug and 35 laboratory claims for FISH over a 22-month period. Before each drug claim for this patient, a mean of 1.8 FISH tests were identified. For the 8 patients in whom RT-PCR was performed, the median number of RTPCR tests performed per patient was 26. Before each drug claim, RT-PCR testing ranged from 0.7 to 7.5 tests. For the 51 patients who had the Q-PCR test performed, a median of 38 tests were performed per patient. Before each drug claim, patients averaged between 0.4 and 5.0 Q-PCR tests.

Our study sample correlated with the average CML population in the United States. In 2009, the National Cancer Institute estimated that 5050 patients in the United States would receive a diagnosis of CML each year.

 The age range of patients in our study corresponded with the age range of the US CML population. Nationally, the median age at diagnosis was 66 years; the median age in our study was 11 years lower. The sample in our study had more male patients than females, which correlates with CML population national trends. Demographically, our study sample follows the statistics of the US population of CML patients, which allows for extrapolation of study results to the larger national population. A majority of patients in this study had a diagnosis of CML established prior to any CML drug claims. Our study showed a high compliance rate with the NCCN guidelines on testing in regards to initiation of chemotherapy, with a majority of patients having a specialty test prior to first drug claim. This compliance increased in the secondary analysis, when patients who received treatment prior to specialty test were included.

In our study, 80% of patients consistently had a specialty lab performed every 3 months. The most frequent test was the Q-PCR, performed an average of 3.8 times per patient. We did not know the actual disease status of these patients; therefore, it was hard to determine if the frequency of these specialty labs was justified. However, it appeared some patients received more molecular tests than guidelines recommend. We also identified 12 patients with at least one 3-month period without a specialty lab test. Again, without knowing the clinical status of these patients, it was difficult to determine if circumstances existed that precluded the use of a specialty test.

Although cytogenetic evaluation is part of the NCCN guidelines, we only identified 1 patient with FISH evaluation. We expected to identify additional patients with bone marrow and or FISH analysis. The reason for lack of cytogenetic determination was not clear. Certainly, educational efforts aimed at physicians to highlight current CML monitoring guidelines would be prudent. Indications for ABL KD mutation analysis should be performed according to the CML stage of the patient. For patients in the chronic phase of CML, ABL KD mutation screening is indicated at several points: without complete hematologic response at 3 months, minimal cytogenetic response at 6 months, or major cytogenetic response at 12 months. This screening is also indicated in chronic phase if there is any sign indicating loss of response to treatment (hematological, Ph+, or transcript relapse). In the accelerated and blast crisis phases of CML, the testing for ABL KD mutations should be routinely performed at 3-month intervals in high-risk patients, regardless of their response level to the TKIs. Again, we did not identify any ABL KD mutational analysis performed. This may be explained by the fact that this test had been relatively recently accepted as an addition to the 2008 NCCN guidelines at the time of the study; physicians may not have been familiar with this test or may have been hesitant to utilize it routinely.

The limitations of this analysis are primarily related to availability of specialty laboratory data. The hybrid database was generated using specialty laboratory results obtained from the primary contracted lab of the health insurer. Specialty lab values were not available for this analysis if these labs were performed in a different “off-contract” laboratory. Additionally, the contracted laboratory only recalled 2 years’ worth of the requested specialty lab data, which limited the study time frame. Sample size was limited to the patients included in the hybrid database. Medicare patients may not have been included, which may be why our median age was lower than the national average. While impact of this research may be greater with a larger study group, we did not have access to additional hybrid databases at the time of this study.

It appears that the use of CML-specific molecular tests met 2008 NCCN guidelines. PCR testing was carried our prior to chemotherapy change; however, the use of mutation analysis was not identified. Educational efforts to promote the use of karyotyping/FISH analysis and to use molecular tests with appropriate frequency should be considered.

: Department of Pharmacy Practice, The University of Mississippi School of Pharmacy (AMB), Jackson, MS; Center for Pharmacoeconomic Studies, Health Outcomes and Pharmacy Practice Division (KMR), The University of Texas at Austin College of Pharmacy (CRF, JMK), Austin, TX; The University of Texas Health Science Center San Antonio (CRF, JMK), San Antonio, TX.

: Partial funding by Bristol-Myers Squibb.

: Mr Koeller received a CML grant from Bristol-Myers Squibb for this, and other studies. Dr Frei has a grant pending from Forest, and has received a research grant from Bristol-Myers Squibb for a different study. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

: Concept and design (JMK); acquisition of data (JMK); analysis and interpretation of data (AMB, KMR, CRF, JMK); drafting of the manuscript (AMB, JMK); critical revision of the manuscript for important intellectual content (AMB, KMR, CRF, JMK); statistical analysis (KMR); obtaining funding (JMK); administrative, technical, or logistic support (CRF, JMK); and supervision (CRF, JMK).

: Jim M. Koeller, MS, Pharmacotherapy Education and Research Center (PERC), The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, MC-6220, San Antonio, TX 78229-3900. E-mail: koeller@uthscsa.edu.

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Study assessed chemotherapy use in patients with chronic myelogenous leukemia (CML) to determine how use of CML-specific tests impacted drug selection and modification.