Quality of Treatment Selection for Medicare Beneficiaries With Cancer.

PURPOSE: The Medicare part D Low-Income Subsidy (LIS) improves access to oral cancer drugs, but provides no assistance for clinician-administered/part B drugs. This analysis assessed the association between LIS participation and receipt of optimal cancer treatment. METHODS: We investigated initial systemic therapy using SEER-Medicare data (2015-2017) and National Comprehensive Cancer Network (NCCN) Evidence Blocks (EB) as the standard for treatment recommendations. We included cancer clinical scenarios wherein (1) ≥one treatment was optimal (higher efficacy and safety scores) versus other treatments; (2) identifiable in SEER-Medicare (eg, not defined by clinical data unavailable in registry data or claims); and (3) both EB and ASCO Value Framework agreed regarding optimal treatment. We fit logistic regression models to assess the association between receipt of systemic therapy (v no therapy) and patient and provider characteristics. Contingent on receipt of treatment, we modeled the likelihood of receiving a treatment ranked (by EB scores) within the highest or lowest quartile for that cancer type. RESULTS: Nine thousand two hundred and ninety patients were included across 11 clinical scenarios. Fifty-seven percent (5,336) of patients received any systemic therapy and 43% (3,954) received no systemic therapy. Compared with non-LIS participants, LIS participants were less likely to receive any systemic therapy versus no systemic therapy (odds ratio, 0.64 [95% CI, 0.57 to 0.72]). Contingent on receiving systemic therapy, LIS participants received treatment ranked within the worst quartile 24.8% of the time, compared with 21.9% of non-LIS patients (adjusted prevalence difference, 4.3% [95% CI, 0.5 to 8.2]). CONCLUSION: LIS participants were less likely to receive systemic therapy at all and were more likely to receive treatments that receive low NCCN EB scores.

The landscape of use of NCCN-guideline chemotherapy regimens in stage I-IIIA breast cancer in an integrated healthcare delivery system.

PURPOSE: The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedules for the treatment of early-stage breast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time. METHODS: In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time. RESULTS: Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR (both in terms of administration schedule and drug combination) and TDR have decreased, although patterns vary by drug combination. CONCLUSION: Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings.

Patient Characteristics Associated with Intended Nonguideline Chemotherapy in Women with Stage I to IIIA Breast Cancer.

BACKGROUND: Guidelines informing chemotherapy regimen selection are based on clinical trials with participants who do not necessarily represent general populations with breast cancer. Understanding who receives nonguideline regimens is important for understanding real-world chemotherapy administration and how it relates to patient outcomes. METHODS: Using data from the Optimal Breast Cancer Chemotherapy Dosing (OBCD) study, based at Kaiser Permanente Northern California (2006-2019) and Kaiser Permanente Washington (2004-2015), we use logistic regression to examine the associations between patient characteristics and receipt of nonguideline chemotherapy regimens among 11,293 women with primary stage I to IIIA breast cancer receiving chemotherapy. RESULTS: The use of nonguideline regimens was strongly associated with several factors, including older age [≥80 vs. 18-39 years: OR, 5.25; 95% confidence interval (CI), 3.06-9.00; P-trend = 0.002] and HER2 status (HER2+ vs. HER2-: OR, 3.44; 95% CI, 3.06-3.87) and was less likely in women with larger tumor size (>5 cm vs. 0.1 to ≤0.5 cm: OR, 0.56; 95% CI, 0.36-0.87; P-trend = 0.01) and diagnosed in later years (2012-2019 vs. 2005-2011: OR, 0.80; 95% CI, 0.71-0.90). Factors associated varied by type of nonguideline regimens. For example, women with comorbidity and older age were more likely to receive nonguideline drug combinations in particular, whereas women with larger tumor size were less likely to receive nonguideline administration schedules. CONCLUSIONS: Nonguideline chemotherapy regimens are more likely in certain patient populations. IMPACT: These associations highlight that vulnerable patient populations may be less likely to receive guideline care, and thus, real-world studies are essential for understanding how the use of nonguideline regimens impacts patient outcomes in these groups.

Patient characteristics associated with delayed time to adjuvant chemotherapy among women treated for stage I-IIIA breast cancer.

For patients with breast cancer, delays in chemotherapy initiation have been adversely associated with recurrence and survival. We evaluated patient-level factors associated with delayed chemotherapy initiation, from both diagnosis and surgery, in a community-based cohort of women with early-stage breast cancer. For the Optimal Breast Cancer Chemotherapy Dosing study, we identified a cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at two U.S. integrated healthcare delivery systems between 2004 and 2019. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) to identify patient factors associated with delays in chemotherapy initiation after diagnosis (≥90 days) and surgery (≥60 days). Among 10,968 women receiving adjuvant chemotherapy, 21.1% experienced delays in chemotherapy initiation after diagnosis and 21.3% after surgery. Older age, non-Hispanic Black and Hispanic race and ethnicity, and ER+ and/or PR+ disease were associated with increased likelihood of delays to chemotherapy initiation after diagnosis and surgery. People diagnosed in 2012-2019 (vs. 2005-2011), with a higher grade and larger tumor size were less likely to experience delays. Other factors were associated with a higher likelihood of delays specifically from diagnosis (earlier stage, mastectomy vs. breast-conserving surgery), or surgery (higher comorbidity, increased nodal number). Women diagnosed with breast cancer who were at highest risk of progression and recurrence were less likely to experience delays in chemotherapy initiation after diagnosis and surgery. Understanding reasons for chemotherapy delays beyond patient factors may be potentially important to reduce risk of breast cancer recurrence and progression.

Trends in chemotherapy use for early-stage breast cancer from 2006 to 2019.

BACKGROUND: Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington). FINDINGS: Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend < 0.001). Among 13,089 women receiving chemotherapy, neoadjuvant treatment increased (4.1-14.7%; p-trend < 0.001), as did receipt of anti-HER2 therapies (20.8-30.9%) (p-trend < 0.001). The average treatment duration increased (5.3 to 6.0 months; p-trend < 0.001), as did the number of infusion visits (10.8 to 12.5; p-trend < 0.001). For those receiving anti-HER2 therapies, treatment duration and average number of visits decreased; among those not receiving anti-HER2 therapies, number of visits increased, with no change in duration. CONCLUSIONS: While the prevalence of chemotherapy receipt has decreased over time, the use of neoadjuvant chemotherapy has increased, as has use of anti-HER2 therapies; duration and number of administration visits have also increased. Understanding these trends is useful to inform clinical and administrative planning.

Methodology for Using Real-World Data From Electronic Health Records to Assess Chemotherapy Administration in Women With Breast Cancer.

PURPOSE: Identification of patients' intended chemotherapy regimens is critical to most research questions conducted in the real-world setting of cancer care. Yet, these data are not routinely available in electronic health records (EHRs) at the specificity required to address these questions. We developed a methodology to identify patients' intended regimens from EHR data in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) study. METHODS: In women older than 18 years, diagnosed with primary stage I-IIIA breast cancer at Kaiser Permanente Northern California (2006-2019), we categorized participants into 24 drug combinations described in National Comprehensive Cancer Network guidelines for breast cancer treatment. Participants were categorized into 50 guideline chemotherapy administration schedules within these combinations using an iterative algorithm process, followed by chart abstraction where necessary. We also identified patients intended to receive nonguideline administration schedules within guideline drug combinations and nonguideline drug combinations. This process was adapted at Kaiser Permanente Washington using abstracted data (2004-2015). RESULTS: In the OBCD cohort, 13,231 women received adjuvant or neoadjuvant chemotherapy, of whom 10,213 (77%) had their intended regimen identified via the algorithm, 2,416 (18%) had their intended regimen identified via abstraction, and 602 (4.5%) could not be identified. Across guideline drug combinations, 111 nonguideline dosing schedules were used, alongside 61 nonguideline drug combinations. A number of factors were associated with requiring abstraction for regimen determination, including: decreasing neighborhood household income, earlier diagnosis year, later stage, nodal status, and human epidermal growth factor receptor 2 (HER2)+ status. CONCLUSION: We describe the challenges and approaches to operationalize complex, real-world data to identify intended chemotherapy regimens in large, observational studies. This methodology can improve efficiency of use of large-scale clinical data in real-world populations, helping answer critical questions to improve care delivery and patient outcomes.

Clinical Trial Participation Among Older Adult Medicare Fee-for-Service Beneficiaries With Cancer.

Importance: Clinical trials play a critical role in the development of novel cancer therapies, and precise estimates of the frequency with which older adult patients with cancer participate in clinical trials are lacking. Objective: To estimate the proportion of older adult Medicare Fee-for-Service (FFS) beneficiaries with cancer who participate in interventional cancer clinical trials, using a novel population-based methodology. Design, Setting, and Participants: In this retrospective cohort study evaluating clinical trial participation among older adult patients with cancer from January 1, 2014, through June 30, 2020, claims data from Medicare FFS were linked with the ClinicalTrials.gov to determine trial participation through the unique National Clinical Trial (NCT) identifier. The proportion of patients with newly diagnosed or newly recurrent cancer in 2015 participating in an interventional clinical trial and receiving active cancer treatment from January 2014 to June 2020 was estimated. Data analysis was performed from November 18, 2020, to November 1, 2021. Exposures: Patients with cancer aged 65 years or older with Medicare FFS insurance, with and without active cancer treatment. Main Outcomes and Measures: Enrollment in clinical trials among all patients with cancer 65 years and older and among patients receiving active cancer treatments as defined by the presence of at least 1 NCT identifier corresponding to an interventional cancer clinical trial in Medicare claims. Results: Among 1 150 978 patients (mean [SD] age, 75.7 [8.4] years; 49.9% men and 50.1% women) with newly diagnosed or newly recurrent cancer in 2015, 12 028 (1.0%) patients had a billing claim with an NCT identifier indicating enrollment in an interventional cancer clinical trial between January 2014 and June 2020. In a subset of 429 343 patients with active cancer treatment, 8360 (1.9%) were enrolled in 1 or more interventional trials. Patients enrolled in a trial tended to be younger, male, a race other than Black, and residing in zip codes with high median incomes. Conclusions and Relevance: Findings of this cohort study show that clinical trial enrollment among older adult patients with cancer remains low, with only 1.0% to 1.9% of patients with newly diagnosed or recurrent cancer in 2015 participating in an interventional cancer clinical trial as measured by the presence of NCT identifiers in Medicare claims. These data provide a contemporary estimate of trial enrollment, persistent disparities in trial participation, and only limited progress in trial access over the past 2 decades.

Validation of a Population-Based Data Source to Examine National Cancer Clinical Trial Participation.

Importance: The Centers for Medicare & Medicaid Services requires health care organizations to report the National Clinical Trial (NCT) identifier on claims for items and services related to clinical trials that qualify for coverage. This same NCT identifier is used to identify clinical trials in the ClinicalTrials.gov registry. If linked, this information could facilitate population-based analyses of clinical trial participation and outcomes. Objective: To evaluate the validity of a linkage between fee-for-service (FFS) Medicare claims and ClinicalTrials.gov through the NCT identifier for patients with cancer enrolled in clinical trials. Design, Setting, and Participants: This cohort study included 2 complementary retrospective analyses for a validation assessment. First, billing data from 3 health care institutions were used to estimate the missingness of the NCT identifier in claims by calculating the proportion of known participants in cancer clinical trials with no NCT identifier on any submitted Medicare claims. Second, the Surveillance Epidemiology and End Results-Medicare data set, which includes a subset of all FFS Medicare beneficiaries for whom health insurance claims are linked with cancer registry data, was used to identify adult patients diagnosed with cancer between 2006 and 2015 with an NCT identifier in claims corresponding to an interventional cancer clinical trial. To estimate the accuracy of the NCT identifier when present, the proportion of NCT identifiers that corresponded to trials that were aligned with the patients' known primary or secondary diagnoses was calculated. Data were analyzed from March 2020 to March 2021. Exposures: An NCT identifier present in Medicare claims. Main Outcomes and Measures: The main outcome was participating in a clinical trial relevant to patient's cancer diagnosis. Results: A total of 1 171 816 patients were included in analyses. Across the 3 participating institutions, there were 5061 Medicare patients enrolled in a clinical trial, including 3797 patients (75.0%) with an NCT identifier on at least 1 billing claim that matched the clinical trial on which the patient was participating. Among 1 171 816 SEER-Medicare patients, 29 138 patients (2.5%) had at least 1 claim with a value entered in the NCT identifier field corresponding to 32 950 unique patient-NCT identifier pairs. There were 26 694 pairs (81.0%) with an NCT identifier corresponding to a clinical trial registered in ClinicalTrials.gov, of which 10 170 pairs (38.1%) were interventional cancer clinical trials. Among these, 9805 pairs (96.4%) were considered appropriate. Conclusions and Relevance: In this cohort study, this data linkage provided a novel data source to study clinical trial enrollment patterns among Medicare patients with cancer on a population level. The presence of the NCT identifiers in claims for Medicare patients participating in clinical trials is likely to improve over time with increasing adherence with the Centers for Medicare & Medicaid Services mandate.

Are Financial Payments From the Pharmaceutical Industry Associated With Physician Prescribing? : A Systematic Review.

BACKGROUND: Financial payments from the drug industry to U.S. physicians are common. Payments may influence physicians' clinical decision making and drug prescribing. PURPOSE: To evaluate whether receipt of payments from the drug industry is associated with physician prescribing practices. DATA SOURCES: MEDLINE (Ovid), Embase, the Cochrane Library, Web of Science, and EconLit were searched without language restrictions. The search had no limiting start date and concluded on 16 September 2020. STUDY SELECTION: Studies that estimated the association between receipt of industry payments (exposure) and prescribing (outcome). DATA EXTRACTION: Pairs of reviewers extracted the primary analysis or analyses from each study and evaluated risk of bias (ROB). DATA SYNTHESIS: Thirty-six studies comprising 101 analyses were included. Most studies (n = 30) identified a positive association between payments and prescribing in all analyses; the remainder (n = 6) had a mix of positive and null findings. No study had only null findings. Of 101 individual analyses, 89 identified a positive association. Payments were associated with increased prescribing of the paying company's drug, increased prescribing costs, and increased prescribing of branded drugs. Nine studies assessed and found evidence of a temporal association; 25 assessed and found evidence of a dose-response relationship. LIMITATION: The design was observational, 21 of 36 studies had serious ROB, and publication bias was possible. CONCLUSION: The association between industry payments and physician prescribing was consistent across all studies that have evaluated this association. Findings regarding a temporal association and dose-response suggest a causal relationship. PRIMARY FUNDING SOURCE: National Cancer Institute.

Association Between Clinical Value and Financial Cost of Cancer Treatments: A Cross-Sectional Analysis.

BACKGROUND: The cost of cancer treatment has increased significantly in recent decades, but it is unclear whether these costs have been associated with commensurate improvement in clinical value. This study aimed to assess the association between the cost of cancer treatment and 4 of the 5 NCCN Evidence Blocks (EB) measures of clinical value: efficacy of regimen/agent, safety of regimen/agent, quality of evidence, and consistency of evidence. METHODS: This is a cross-sectional, observational study. We obtained NCCN EB ratings for all recommended, first-line, and/or maintenance treatments for the 30 most prevalent cancers in the United States and calculated direct pharmacologic treatment costs (drug acquisition, administration fees, guideline-concordant supportive care medications) using Medicare reimbursement rates in January 2019. We used generalized estimating equations to estimate the association between NCCN EB measures and treatment cost with clustering at the level of the treatment indication. RESULTS: A total of 1,386 treatments were included. Among time-unlimited treatments (those administered on an ongoing basis without a predetermined stopping point), monthly cost was positively associated with efficacy ($3,036; 95% CI, $1,782 to $4,289) and quality of evidence ($1,509; 95% CI, $171 to $2,847) but negatively associated with safety (-$1,470; 95% CI, -$2,790 to -$151) and consistency of evidence (-$2,003; 95% CI, -$3,420 to -$586). Among time-limited treatments (those administered for a predetermined interval or number of cycles), no NCCN EB measure was significantly associated with treatment cost. CONCLUSIONS: An association between NCCN EB measures and treatment cost was inconsistent, and the magnitude of the association was small compared with the degree of cost variation among treatments with the same EB scores. The clinical value of cancer treatments does not seem to be a primary determinant of treatment cost.

The Accuracy and Usefulness of the National Comprehensive Cancer Network Evidence Blocks Affordability Rating.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) Guidelines' Evidence Blocks has the broadest scope of the several oncology value assessment frameworks. The Evidence Blocks includes the Affordability criterion, which reflects the financial cost of each treatment on a 1-5 scale. The accuracy of Affordability is unknown. METHODS: We calculated Medicare costs for all first-line and maintenance treatments for the 30 cancers with the highest incidence in the USA that had published NCCN Evidence Blocks as of 31 December 2018. We assessed the accuracy and consistency of Affordability across different treatments and cancer types. Among different treatments for the same indication, we determined the frequency with which the Affordability assessment was consistent with calculated treatment costs. RESULTS: There were a total of 1386 treatments in our sample. Lower Affordability scores were associated with higher costs. There was significant variation in cost at each level of Affordability; for treatments with Affordability = 1 (very expensive), costs ranged from $US4551 to $US43,794 per month for treatments administered over an undefined time period and from $US2865 to $US500,982 per course of therapy for treatments administered over a defined time period. Among treatments for the same indication, Affordability was discrepant with calculated treatment costs in 7.9% of pairwise comparisons, identifying the higher-cost treatment as being more affordable. Discrepancies were reduced when we reassigned Affordability scores based on calculated treatment costs. CONCLUSIONS: Evidence Blocks Affordability generally correlated with treatment costs but contained discrepancies, which may limit its usefulness to clinicians in comparing costs. This study suggests that the Affordability score may be improved by indexing more directly to specified dollar value thresholds.

Evolution and assembly of ESCRTs.

The AAA (ATPase associated with various cellular activities) proteins participate in membrane trafficking, organelle biogenesis, DNA replication, intracellular locomotion, cytoskeletal remodelling, protein folding and proteolysis. The AAA Vps (vacuolar protein sorting) 4 is central to traffic to lysosomes, retroviral budding and mammalian cell division. It dissociates ESCRTs (endosomal sorting complexes required for transport) from endosomal membranes, enabling their recycling to the cytosol, and plays a role in fission of intraluminal vesicles within MVBs (multivesicular bodies). The mechanism of Vps4-catalysed disassembly of ESCRT networks is unknown; however, it requires interaction between Vps4 and ESCRT-III subunits. The 30 C-terminal residues of Vps2 and Vps46 (Did2) subunits are both necessary and sufficient for interaction with the Vps4 N-terminal MIT (microtubule-interacting and transport) domain, and the crystal structure of the Vps2 C-terminus in a complex with the Vps4 MIT domain shows that MIT helices alpha2 and alpha3 recognize a (D/E)XXLXXRLXXL(K/R) MIM (MIT-interacting motif). These Vps2-MIT interactions are essential for vacuolar sorting and for Vps4-catalysed disassembly of ESCRT-III networks in vitro. Electron microscopy of ESCRT-III filaments assembled in vitro has enabled us to identify surfaces of the Vps24 subunit that are critical for protein sorting in vivo. The ESCRT-III-Vps4 interaction predates the divergence of Archaea and Eukarya. The Crenarchaea have three classes of ESCRT-III-like subunits, and one of these subunits interacts with an archaeal Vps4-like protein in a manner closely related to the human Vps4-human ESCRT-III subunit Vps20 interaction. This archaeal Vps4-ESCRT-III interaction appears to have a fundamental role in cell division in the Crenarchaea.

Structure and disassembly of filaments formed by the ESCRT-III subunit Vps24.

The ESCRT machinery mediates sorting of ubiquitinated transmembrane proteins to lysosomes via multivesicular bodies (MVBs) and also has roles in cytokinesis and viral budding. The ESCRT-III subunits are metastable monomers that transiently assemble on membranes. However, the nature of these assemblies is unknown. Among the core yeast ESCRT-III subunits, Snf7 and Vps24 spontaneously form ordered polymers in vitro. Single-particle EM reconstruction of helical Vps24 filaments shows both parallel and head-to-head subunit arrangements. Mutations of regions involved in intermolecular assembly in vitro result in cargo-sorting defects in vivo, suggesting that these homopolymers mimic interactions formed by ESCRT-III heteropolymers during MVB biogenesis. The C terminus of Vps24 is at the surface of the filaments and is not required for filament assembly. When this region is replaced by the MIT-interacting motif from the Vps2 subunit of ESCRT-III, the AAA-ATPase Vps4 can both bundle and disassemble the chimeric filaments in a nucleotide-dependent fashion.

Structural basis for selective recognition of ESCRT-III by the AAA ATPase Vps4.

The AAA+ ATPases are essential for various activities such as membrane trafficking, organelle biogenesis, DNA replication, intracellular locomotion, cytoskeletal remodelling, protein folding and proteolysis. The AAA ATPase Vps4, which is central to endosomal traffic to lysosomes, retroviral budding and cytokinesis, dissociates ESCRT complexes (the endosomal sorting complexes required for transport) from membranes. Here we show that, of the six ESCRT--related subunits in yeast, only Vps2 and Did2 bind the MIT (microtubule interacting and transport) domain of Vps4, and that the carboxy-terminal 30 residues of the subunits are both necessary and sufficient for interaction. We determined the crystal structure of the Vps2 C terminus in a complex with the Vps4 MIT domain, explaining the basis for selective ESCRT-III recognition. MIT helices alpha2 and alpha3 recognize a (D/E)xxLxxRLxxL(K/R) motif, and mutations within this motif cause sorting defects in yeast. Our crystal structure of the amino-terminal domain of an archaeal AAA ATPase of unknown function shows that it is closely related to the MIT domain of Vps4. The archaeal ATPase interacts with an archaeal ESCRT-III-like protein even though these organisms have no endomembrane system, suggesting that the Vps4/ESCRT-III partnership is a relic of a function that pre-dates the divergence of eukaryotes and Archaea.