High Compliance With Choosing Wisely Breast Surgical Guidelines at a Safety-Net Hospital.

BACKGROUND: Professional organizations recently set guidelines for avoiding surgeries of low utility and overutilization for the Choosing Wisely campaign. These include re-excision for invasive cancer close to margins, double mastectomy in patients with unilateral breast cancer, axillary lymph node dissection in patients with limited nodal disease, and sentinel lymph node biopsy (SLNB) in patients ≥70 years with early-stage breast cancer. Variable adherence to these recommendations led us to evaluate implementation rates of low-value surgical guidelines at a safety-net hospital. METHODS: We retrospectively analyzed breast cancer patients who underwent surgery from 2015 to 2020. Each patient was assessed for eligibility for omission of the listed surgeries. Trends were evaluated by cohorts before and after a fellowship-trained breast surgeon joined the faculty in 2018. Outcomes were compared using Fisher's exact test. RESULTS: Among 195 patients, none underwent re-excision for close margins of invasive cancer. Only 6.7% of patients (3/45) received contralateral mastectomy and 1.8% of eligible patients (3/169) received axillary lymph node dissection. Overall, 60% of patients ≥ 70 years with stage 1 hormone-positive breast cancer (9/15) received SLNB. There was a downward trend from 71% of eligible patients receiving SLNB in 2015-2018 to 50% in 2019-2020. CONCLUSIONS: De-implementation of traditional surgical practices, deemed as low-value care, toward newer guidelines is achievable even at community hospitals serving a low socioeconomic community. By avoiding overtreatment, hospitals can achieve effective resource allocation which allow for social distributive justice among patients with breast cancer and ensure strategic use of scarce health economic resources while preserving patient outcomes.

Factors delaying chemotherapy in patients with breast cancer at a safety-net hospital.

BACKGROUND: Despite advances in healthcare and improved chemotherapy, disparities in breast cancer outcomes continue to persist. Our aim was to evaluate socioeconomic factors that may impact timing of treatment for patients receiving chemotherapy in underserved communities. METHODS: A review of patients with breast cancer who received neoadjuvant or adjuvant chemotherapy from 2015-2019 was conducted at a safety-net hospital. The primary outcomes were times from diagnosis to chemotherapy and surgery. Clinicodemographic factors including race, age, clinical stage, primary language, comorbidities, and median income by zip code were collected. Multivariable regression analysis was performed to evaluate for factors associated with the primary outcomes. RESULTS: One hundred patients were identified. For the neoadjuvant group, median time from diagnosis to chemotherapy and surgery was 52 ± 34 days and 256 ± 59 days, respectively. For the adjuvant group, median time from diagnosis to surgery and chemotherapy was 24.5 ± 18 days and 94.5 ± 53 days, respectively. Non-English language and older age were associated with increased time to chemotherapy in the adjuvant group (p < 0.05). Language and age were not associated with increased time to surgery in both groups. Race, age, comorbidities, and income were not associated with delay in treatment in either groups. CONCLUSIONS: Older age and non-English language were associated with prolonged time from surgery to adjuvant chemotherapy. Targeted interventions directed at patient education and decreasing language barriers especially post-operatively may decrease delays in treatment and subsequently reduce disparities seen in the breast cancer population.

Health Equity Within Inequity: Timing of Diagnostic Breast Cancer Care in an Underserved Medical Population.

BACKGROUND/AIM: We evaluated timeliness of care at a safety-net hospital after implementation of a multidisciplinary breast program. PATIENTS AND METHODS: A prospective database of patients with breast cancer was created after multidisciplinary breast program initiation in 2018. Patients were tracked to obtain time to completion of diagnostic imaging, biopsy, and treatment initiation. Patients with breast cancer diagnosed from 2015-2017 were reviewed for comparison. RESULTS: A total of 102 patients were identified. There was no statistical difference in time to completion of imaging, biopsy, and initial treatment between the 2018 and the 2015-2017 cohorts (p>0.05). No statistical difference was observed in time to completion of imaging, biopsy, and initial treatment between different races (p>0.05). CONCLUSION: Within the same socioeconomic status, there was no differential delivery of screening, work-up, and treatment by race. Despite protocol implementations, efficiency of care remained limited in a safety-net hospital with lack of financial resources.

Primary undifferentiated pleomorphic cardiac sarcoma presenting as right heart failure.

Right-sided heart failure is a common sequela of left heart failure and seldom presents as a primary disorder. The differential diagnosis of right heart failure includes a cardiac tumor. Cardiac malignancies are rare tumors with an overall poor prognosis. We evaluated a 69-year-old man who presented with a 3-week history of progressive lower extremity swelling, ascites, and scrotal swelling. Laboratory studies were significant only for mildly elevated liver function tests. CT scan of the abdomen and pelvis showed ascites, hepatic swelling, and a bland clot in the inferior vena cava extending from the level of the kidneys to the right atrium. A large mass originating from the right atrium was identified, and biopsy confirmed an undifferentiated pleomorphic cardiac sarcoma. Given the extensive tumor and clot burden, he was not an operative candidate. He developed portal hypertension with esophageal varices and expired due to variceal bleeding.

End of an era of administering erythropoiesis stimulating agents among Veterans Administration cancer patients with chemotherapy-induced anemia.

Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003-2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p<0.01). Following REMS in 2010, mean hematocrit levels at ESA initiation decreased from 30% to 21% (p<0.01). Black box warnings preceded decreased ESA use among VA cancer patients with CIA. REMS was followed by reduced hematocrit levels at ESA initiation. Our findings contrast with privately- insured and Medicaid insured cancer patient data on chemotherapy-induced anemia where ESA use decreased to 3% to 7% by 2010-2012. By 2012, the era of ESA administration to VA to cancer patients had ended but the warnings remain relevant and significant. In 2019, oncology/hematology national guidelines (ASCO/ASH) recommend that cancer patients with chemotherapy-induced anemia should receive ESAs or red blood cell transfusions after risk-benefit evaluation.

End of an era for erythropoiesis-stimulating agents in oncology.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration. We evaluated ESA utilization from 2003 to 2012 and obtained private health insurer claims data for persons with lung, colorectal, or breast cancer from 2001 to 2012. ESA use for CIA was determined by an ESA claim after chemotherapy, up to 6 months after treatment. We identified 839,948 commercially insured patients, including 24,785 patients with ESA-treated CIA (3.2%). Darbepoetin use increased 3.9-fold from 2003 to 2007 (12.3% to 48.7%) and then decreased 95% to 2.6% by 2012. Epoetin use decreased 90% from 2003 to 2012 (30.3% to 3.1%). Between 2003 and 2012, mean epoetin dosing decreased 0.8-fold (244,979 in 2003 vs. 196,216 units in 2012), but increased 1.8-fold for darbepoetin-treated CIA (262 in 2003 to 467 µg in 2012). Among CIA patients, transfusions were low (4.5%) in 2002-2007, then increased 2.2-fold between 2008 and 2012. Safety initiatives between 2007 and 2010 facilitated reductions in ESA use combined with changes in coverage. These data show the efficacy of regulatory efforts, publication of adverse events and changes in reimbursement in reducing use of ESAs. Future studies are warranted to optimize deimplementation strategies to improve patient safety.

An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin-association neuropsychiatric toxicities, long-term disability, and aortic aneurysms/dissections disseminated by the Food and Drug Administration and the European Medicines Agency.

Introduction: Ciprofloxacin, levofloxacin, and moxifloxacin belong to the fluoroquinolone class of antibiotics and are amongst the most commonly prescribed antibiotics. In 2018 and 2019, Food and Drug Administration (FDA) and the European Medicine Agency (EMA) requested that manufacturers harmonize FQ safety information related to neuropsychiatric, aortic dissection, and long-term disability. The authors hypothesize that FDA and EMA epidemiologists support a strong association between these drugs and the three toxicities. Areas covered: Studies of FQ-associated neuropsychiatric toxicity, long-term disability, and aortic ruptures/dissections. Clinical sources include FDA Advisory Committee documents, a 2014 Citizen Petition filed with the FDA requesting safety information additions to FQ labels for neuropsychiatric toxicities (partially granted in 2018), an under-review Citizen Petition under review by the FDA requesting a FQ Risk Evaluation and Mitigation Strategy, and safety notifications from the EMA. Expert opinion: FDA and the EMA report state that neuropsychiatric toxicity, long-term disability, and aortic dissections//aneurysms occur with all FQs. Disability and neuropsychiatric toxicity can occur after one dose or several months after FQs. United States' and European' regulators warn physicians not to prescribe FQs for uncomplicated acute urinary tract infection, sinusitis, or bronchitis, unless other possible choices are tried first, as risks outweigh benefits in these settings.

Caveat Medicus: Clinician experiences in publishing reports of serious oncology-associated adverse drug reactions.

Oncology-associated adverse drug/device reactions can be fatal. Some clinicians who treat single patients with severe oncology-associated toxicities have researched case series and published this information. We investigated motivations and experiences of select individuals leading such efforts. Clinicians treating individual patients who developed oncology-associated serious adverse drug events were asked to participate. Inclusion criteria included having index patient information, reporting case series, and being collaborative with investigators from two National Institutes of Health funded pharmacovigilance networks. Thirty-minute interviews addressed investigational motivation, feedback from pharmaceutical manufacturers, FDA personnel, and academic leadership, and recommendations for improving pharmacovigilance. Responses were analyzed using constant comparative methods of qualitative analysis. Overall, 18 clinicians met inclusion criteria and 14 interviewees are included. Primary motivations were scientific curiosity, expressed by six clinicians. A less common theme was public health related (three clinicians). Six clinicians received feedback characterized as supportive from academic leaders, while four clinicians received feedback characterized as negative. Three clinicians reported that following the case series publication they were invited to speak at academic institutions worldwide. Responses from pharmaceutical manufacturers were characterized as negative by 12 clinicians. One clinician's wife called the post-reporting time the "Maalox month," while another clinician reported that the manufacturer collaboratively offered to identify additional cases of the toxicity. Responses from FDA employees were characterized as collaborative for two clinicians, neutral for five clinicians, unresponsive for negative by six clinicians. Three clinicians endorsed developing improved reporting mechanisms for individual physicians, while 11 clinicians endorsed safety activities that should be undertaken by persons other than a motivated clinician who personally treats a patient with a severe adverse drug/device reaction. Our study provides some of the first reports of clinician motivations and experiences with reporting serious or potentially fatal oncology-associated adverse drug or device reactions. Overall, it appears that negative feedback from pharmaceutical manufacturers and mixed feedback from the academic community and/or the FDA were reported. Big data, registries, Data Safety Monitoring Boards, and pharmacogenetic studies may facilitate improved pharmacovigilance efforts for oncology-associated adverse drug reactions. These initiatives overcome concerns related to complacency, indifference, ignorance, and system-level problems as barriers to documenting and reporting adverse drug events- barriers that have been previously reported for clinician reporting of serious adverse drug reactions.

Quality Initiative in Clinical Practice: A Single-Institution Appraisal of Quality Metrics in the Management of Newly Diagnosed Diffuse Large B-Cell Lymphoma.

OBJECTIVE: To assess our adherence to treatment guidelines for diffuse large B-cell lymphoma (DLBCL) established by the American Society of Hematology in 2014 through implementation of a quality improvement initiative (QII) at our institution in 2015. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL treated from January 1, 2006, through December 31, 2017, were identified. Electronic medical records were reviewed for documentation of American Society of Hematology Practice Improvement Module quality measures (eg, key pathologic features of DLBCL, lymphoma staging, and screening for hepatitis B virus [HBV] infection in patients receiving rituximab-based chemotherapy). We also reviewed assessment of prognosis by revised International Prognostic Index score, testing for hepatitis C virus, HBV, and HIV, chemotherapy education, and the addition of rituximab in the treatment regimen of CD20+ DLBCL. RESULTS: Following QII implementation, we saw improvements in most metrics, including reporting of key molecular features (fluorescence in situ hybridization for c-MYC, BCL2, and BCL6, from 45.5% [75 of 165 patients] before QII to 91.7% [22 of 24 patients] after QII; P<.001), screening for HBV (41.8% [69 of 165 patients] to 91.7% [22 of 24 patients]; P<.001) and HIV infections (33.9% [56 of 165 patients] to 87.5% [21 of 24 patients]; P<.0001), providing chemotherapy education (92.7% [153 of 165 patients] to 100%), and use of rituximab for CD20+ DLBCL (83.6% [138 of 165 patients] to 100%; P=.05). All patients had positron emission tomography-computed tomography for DLBCL staging, and there was significantly lower use of bone marrow biopsy (P=.011). CONCLUSION: Implementating a QII and employing standardized metrics can aid in improving quality of care for patients with newly diagnosed DLBCL and allow opportunities to build and ensure better adherence to evolving patient care guidelines.

Live-cell phenotypic-biomarker microfluidic assay for the risk stratification of cancer patients via machine learning.

The risk stratification of prostate cancer and breast cancer tumours from patients relies on histopathology, selective genomic testing, or on other methods employing fixed formalin tissue samples. However, static biomarker measurements from bulk fixed-tissue samples provide limited accuracy and actionability. Here, we report the development of a live-primary-cell phenotypic-biomarker assay with single-cell resolution, and its validation with prostate cancer and breast cancer tissue samples for the prediction of post-surgical adverse pathology. The assay includes a collagen-I/fibronectin extracellular-matrix formulation, dynamic live-cell biomarkers, a microfluidic device, machine-vision analysis and machine-learning algorithms, and generates predictive scores of adverse pathology at the time of surgery. Predictive scores for the risk stratification of 59 prostate cancer patients and 47 breast cancer patients, with values for area under the curve in receiver-operating-characteristic curves surpassing 80%, support the validation of the assay and its potential clinical applicability for the risk stratification of cancer patients.

Tale of Two Erythropoiesis-Stimulating Agents: Utilization, Dosing, Litigation, and Costs of Darbepoetin and Epoetin Among South Carolina Medicaid-Covered Patients With Cancer and Chemotherapy-Induced Anemia.

PURPOSE: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. METHODS: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. RESULTS: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. CONCLUSION: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Characteristics and treatment patterns among US patients with hairy cell leukemia: a retrospective claims analysis.

AIM: Describe hairy cell leukemia (HCL) treatment patterns using a large, nationally representative US database. PATIENTS & METHODS: Adults newly diagnosed with HCL (1 January 2006 to 30 June 2014) with continuous health plan enrollment ≥180 days pre- and 90 days post-diagnosis were identified from the QuintilesIMS PharMetrics Plus Health Plan Claims Database. Treatment patterns by line of therapy were assessed over the variable follow-up. RESULTS: Among 749 HCL patients (77.4% male; mean age 55.6; mean 32.3 months follow-up), only 37.7% initiated first-line therapy during the available follow-up in a mean of 4.4 months following diagnosis; the majority (75.5%) received cladribine (mean duration 7.3 days). Thirty-eight patients (5.1%) received second-line treatment. CONCLUSION: Over 2.7 years follow-up, more than a third of patients initiated first-line therapy which appeared to provide a long-lasting response.

Live-single-cell phenotypic cancer biomarkers-future role in precision oncology?

The promise of precision and personalized medicine is rooted in accurate, highly sensitive, and specific disease biomarkers. This is particularly true for cancer-a disease characterized by marked tumor heterogeneity and diverse molecular signatures. Although thousands of biomarkers have been described, only a very small number have been successfully translated into clinical use. Undoubtedly, there is need for rapid, quantitative, and more cost effective biomarkers for tumor diagnosis and prognosis, to allow for better risk stratification and aid clinicians in making personalized treatment decisions. This is particularly true for cancers where specific biomarkers are either not available (e.g., renal cell carcinoma) or where current biomarkers tend to classify individuals into broad risk categories unable to accurately assess individual tumor aggressiveness and adverse pathology potential (e.g., prostate cancer), thereby leading to problems of over-diagnosis and over-treatment of indolent cancer and under-treatment of aggressive cancer. This perspective highlights an emerging class of cancer biomarkers-live-single-cell phenotypic biomarkers, as compared to genomic biomarkers, and their potential application for cancer diagnosis, risk-stratification, and prognosis.

Economic Burden of Tyrosine Kinase Inhibitor Treatment Failure in Chronic Myeloid Leukemia.

BACKGROUND: The economic burden of tyrosine kinase inhibitor (TKI) treatment failure in chronic myeloid leukemia (CML) is not well understood. The objective of this study was to quantify the economic burden associated with treatment failure versus successfully remaining on TKI therapy. METHODS: Treatment episodes for adult CML patients initiating a TKI of interest (imatinib, dasatinib, or nilotinib; index TKI) during July 1, 2008, to December 31, 2011, with continuous enrollment for ≥ 120 days before and 1 year after the initiation were identified from the IMS PharMetrics Plus Health Plan Claims Database. Eligible episodes of TKI treatment failure were matched to those without failure using propensity scores based on patients' baseline demographic and clinical characteristics. Treatment failure was defined as a switch to a nonindex TKI or discontinuation (gap in pharmacy claims ≥ 60 days) of index TKI over the 1-year follow-up. Mean all-cause health care resource utilization and costs per episode (in 2012 US dollars) over follow-up were compared between failures and nonfailures. RESULTS: Among 1774 eligible episodes, 547 failures were matched to 547 nonfailures. Failures had fewer TKI prescription fills but higher utilization of all other services versus nonfailures. Consequently, failures incurred lower pharmacy costs ($51,238 vs. $72,450; Δ-$21,212) but higher medical costs ($52,619 vs. $18,180; Δ$34,439) than nonfailures, resulting in higher total costs ($103,857 vs. $90,630; Δ$13,227) (all P < .05). CONCLUSION: Total health care costs are higher for episodes of TKI treatment failure than those of ongoing treatment, largely as a result of costly medical (nonpharmacologic) services. Avoiding treatment failure by optimal CML management may reduce health care costs.

Meta-analysis of the efficacy and safety of bortezomib re-treatment in patients with multiple myeloma.

INTRODUCTION: Bortezomib is administered for a finite course; thus, patients might remain sensitive to bortezomib-based therapy at relapse. We report a meta-analysis of bortezomib-based retreatment in relapsed/refractory myeloma. PATIENTS AND METHODS: A systematic literature review identified studies of bortezomib-based retreatment in relapsed/refractory myeloma. Proportions of bortezomib-refractory patients and additional prognostic factors were extracted and used in weighted stratified analyses of TTP and OS. Random-effect pooled estimates were calculated for overall response rate (ORR) and rates of common AEs. RESULTS: Twenty-three studies (n = 1051 patients) were identified. Bortezomib was administered intravenously in all studies. Across studies in which data were available, pooled, weighted average ORR was 39.1% (95% confidence interval, 30.8%-47.4%), and pooled, weighted average median TTP and OS were 7.5 and 16.6 months, respectively. Patients with fewer previous therapies (≤ 4) and relapsed (not refractory) patients achieved higher ORRs, of 43.4% and 57.2%, respectively. Random-effects meta-regression analysis confirmed that relapsed patients were associated with a higher ORR by 28 to 41 percentage points versus refractory patients. In relapsed patients, median TTP and OS were 8.5 and 19.7 months, respectively. Common Grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%). CONCLUSION: Based on these findings, bortezomib retreatment is well tolerated and appears efficacious in relapsed patients. In an era of new and emerging treatment options for relapsed and/or refractory myeloma, these data indicate that bortezomib retreatment might be a highly effective option in previously treated patients.

The safety of bendamustine in patients with chronic lymphocytic leukemia or non-Hodgkin lymphoma and concomitant renal impairment: a retrospective electronic medical record database analysis.

Abstract This retrospective study compared adverse-event rates in patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), with and without renal impairment, receiving bendamustine alone or with rituximab. Patients (n = 940) were stratified into a renally impaired group (creatinine clearance [CrCL] < 40 mL/min) and two comparator groups (CrCL ≥ 40 mL/min and CrCL ≥ 60 mL/min). Renally impaired patients with NHL had a significantly greater incidence of grade 3-4 thrombocytopenia compared with the CrCL ≥ 60 mL/min group (hazard ratio [HR], 2.57; p = 0.025). For CLL and NHL together, grade 3-4 increased blood urea nitrogen was significantly higher in the renally impaired group than in the CrCL ≥ 40 mL/min (HR, 2.36; p = 0.02) and CrCL ≥ 60 mL/min (HR, 4.46; p = 0.001) groups. Based on these results, monitoring blood counts (including platelets) and renal function would be prudent in the management of patients with renal dysfunction and NHL or CLL who receive bendamustine-based regimens.