Acquired Resistance to KRASG12C Inhibition in Cancer.

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).

An analysis of medical malpractice claims against medical oncologists from a national database: Implications for safer practice.

Malpractice claims data include valuable information about patient safety. We used mixed methods to analyze claims against medical oncologists (MO) from 2008 to 2019 using a national database. MO claims were compared to a group of other internal medicine subspecialties (OIMS). Logistic regression was used to examine correlates of closing with an indemnity payment. A subset of claims against MO were thematically analyzed using a validated safety incident taxonomy as a framework. 456 claims against MO were compared with 5771 claims against OIMS. MO claims closed with indemnity payments 29.8% of the time versus OIMS 30.3% (p = 0.87). Median MO and OIMS indemnity payments were similar ($190,591 vs. $233,432; p = 0.20). Correlates of MO claims closing with payment included patient assessment, communication among providers, and safety and security as contributing factors. Thematic analysis identified provider cognitive error, adverse drug events and relational problems as the most common safety incidents. MO malpractice claims have similar outcomes to OIMS. We demonstrate the proof-of-concept of applying a safety incident taxonomy to medical malpractice. Finding ways to reduce patient exposure to provider cognitive errors, adverse drug reactions, and communication breakdowns should be strategic priorities for safer cancer care.

Design and Implementation of an Opt-Out, End-to-End, Preemptive DPYD Testing Program for Patients Planned for a Systemic Fluoropyrimidine.

PURPOSE: Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine. METHODS: The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record-based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. RESULTS: At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non-fluoropyrimidine-based regimen was accomplished in 96%. CONCLUSION: Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it.

Improving the quality of bone marrow assessment: Impact of operator techniques and use of a specimen preparation checklist.

BACKGROUND: Successful bone marrow assessment is essential to the diagnosis and staging of hematologic malignancies. The objective of this study was to determine whether specific operator techniques and/or use of a specimen preparation checklist could impact the quality of bone marrow assessment by reducing the frequency of nonspicular aspirates, small cores, and nondiagnostic samples. METHODS: All bone marrow biopsies performed at the Dana-Farber Cancer Institute from April, 2012 to September, 2012 were eligible for inclusion. Six operator techniques were linked with specimen quality in a preintervention cohort. Next, a specimen preparation checklist was implemented, and outcomes were compared from the preintervention and postintervention cohorts. RESULTS: In total, 830 procedures performed by 41 operators were prospectively observed and analyzed. In the preintervention cohort (n = 413), no operator technique was associated with specimen quality in multivariable models accounting for patient characteristics and operator. Compared with the preintervention cohort, in multivariable analyses, the postintervention cohort (n = 417) had decreased odds of nondiagnostic specimens (odds ratio, 0.49; 95% confidence interval, 0.28-0.87; P = .01) and core lengths ≤1 cm (odds ratio, 0.67; 95% confidence interval, 0.50-0.90; P = .009), but there was no significant difference in spicularity. CONCLUSIONS: Variation in the operator techniques studied did not have an impact on specimen quality, but implementation of a specimen preparation checklist significantly improved core length and frequency of diagnostic samples.

Care Fragmentation, Faulty Communication, and Documentation Lapses Derail a Treatment Plan.

This is the second Cancer Morbidity, Mortality, and Improvement Rounds, a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. This case describes the care of a patient who was diagnosed with locally advanced lung cancer during the COVID-19 pandemic; it highlights how gaps in communication and care coordination caused the patient to receive care that did not reflect the consensus of his multidisciplinary team. The discussion highlights the importance of multidisciplinary care, particularly for patients with stage III non-small-cell lung cancer, discusses factors that led to communication gaps, and examines how we should assign accountability across dispersed health care systems.Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.

Uncovering the Risks of Anticancer Therapy Through Incident Report Analysis Using a Newly Developed Medical Oncology Incident Taxonomy.

BACKGROUND: Incident reporting systems were developed to identify possible and actual harm in healthcare facilities. They have the potential to capture important safety trends and to enable improvements that can mitigate the risk of future patient harm and suffering. We recently developed and validated a taxonomy specific for medical oncology designed to enhance the identification, tracking, and trending of incidents that may lead to patient harm. The current project was designed to test the ability of such a taxonomy to be applied across different organizations delivering medical oncology care and to identify specific risks that could result in future harm. METHODS: We analyzed 309 randomly selected medical oncology-related incident reports from 3 different cancer centers that had been posted between January 2019 and December 2020. Each report was assigned up to 2 incident categories. We used a 2-step process to reconcile reviewer discrepancies. In a secondary analysis, each of the incidents was reviewed and recoded to identify events which may result in major or catastrophic harm. RESULTS: Three hundred four incidents met criteria for inclusion. Three hundred incidents (98.7%) were successfully coded. Sixty-seven percent of incidents were encompassed by the following 4 of 21 categories: prescriber ordering (22%), nursing care (15%), pharmacy (14%), and relational/communication issues (15%). Of 297 evaluable incidents, 47% did not reach the patient, 44.7% reached the patient without harm, 7.7% caused minor injury, and 0.7% caused severe injury or death. Submission rates by physicians varied between the 3 sites accounting for 1.7%, 10.7%, and 16.1% of reports. Secondary analysis identified 9 distinct scenarios that may result in major or catastrophic patient harm. CONCLUSIONS: A medical oncology-specific incident reporting taxonomy has the potential to increase our understanding of inherent risks and may lead to process improvements that improve patient safety.

How Safe Is Cancer Care?

Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.

A Perfect Storm Averted: Flawed Systems, a Dropped Ball, and Cognitive Biases Delay a Critical Diagnosis.

This is the first case of Cancer Morbidity, Mortality, and Improvement Rounds, a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. This case highlights how multiple overlapping factors contributed to a delay in diagnosing disseminated tuberculosis in a patient with lung cancer. The discussion focuses on the ways that cognitive biases contributed to the delayed diagnosis in a patient who, with the benefit of hindsight, exhibited several signs and symptoms suggesting tuberculosis.Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.1.

Early Findings on the Use of Clinical Pathways for Management of Unwarranted Variation in Cancer Care.

Clinical pathways have the potential to improve complex clinical decision-making in cancer care. The authors implemented pathways with customized content to assist oncologists to select treatments, aiming for an on-pathway rate of 70%-85%. Treatment decisions were captured as on or off pathway, and metrics were shared monthly with users. Oncologists were categorized into quintiles based on on-pathway performance during the first 90 days of use. On-pathway rates were then calculated for days 91-360 (N = 121). Median on-pathway quintile rates varied from 50% to 100% in the initial 90-day period. During follow-up, median on-pathway rates shifted into the prespecified goal range for all groups. Clinical pathways resulted in greater uniformity in medical oncology practice. Monthly feedback about usage, familiarity with the electronic platform, and regular content updates are some factors that may influence on-pathway rates. Clinical pathways hold promise to manage unwarranted variation in cancer care.

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib.

Introduction: The central nervous system (CNS) is a common site of progression among patients with ROS1-rearranged lung cancer receiving crizotinib. We conducted a phase 2 study to evaluate the intracranial efficacy of lorlatinib in patients with ROS1-rearranged lung cancer who developed CNS-only progression on crizotinib. Methods: Patients with metastatic ROS1-rearranged lung cancer with CNS-only progression on crizotinib received lorlatinib 100 mg daily. The primary end point was intracranial disease control rate at 12 weeks per modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included intracranial and extracranial progression-free survival, intracranial objective response rate, and safety/tolerability. Results: A total of 16 patients were enrolled between November 2016 and January 2019. Nine patients (56%) had received prior CNS radiation, with a median of 10.9 months between radiation and lorlatinib. At 12 weeks, the intracranial disease control rate was 100% and intracranial objective response rate was 87%. While on study, the complee intracranial response rate was 60%. With median follow-up of 22 months, seven patients experienced disease progression, including five patients with CNS relapse. The median intracranial and extracranial progression-free survivals were 38.8 months (95% confidence interval: 16.9-not reported) and 41.1 months (95% confidence interval: 17.6-not reported), respectively. Molecular analysis of plasma or tissue from patients with extracranial progression on lorlatinib revealed ROS1 G2032R (n = 1), ROS1 L2086F (n = 1), and CCDC6-RET fusion plus ROS1 G2032R (n = 1). The safety profile of lorlatinib was consistent with prior studies. There were 11 patients (69%) who required dose reduction, including one patient who discontinued treatment for grade 3 edema. No grade greater than or equal to 4 adverse events were observed. Conclusions: Lorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.

Chemotherapy-related hospitalization among community cancer center patients.

PURPOSE: To describe the frequency, nature, trends, predictors, and outcomes of chemotherapy-related hospitalizations (CRHs) among a nonselected population of cancer patients treated at a community cancer center, and to explore the feasibility of implementing continuous quality improvement methodologies in routine oncology practice. METHODS: We conducted a prospective cohort study of consecutive adult cancer patients who received chemotherapy at a community cancer center January 2003 to December 2006. Demographic, comorbidity, diagnosis, treatment, and laboratory data were collected via medical record abstraction. Hospitalizations were classified as chemotherapy related or unrelated by a multidisciplinary panel. Patients who experienced CRHs were compared with those who did not. Using a randomly sampled subset of cases and controls, we built a logistic regression model to identify independent predictors of CRH. RESULTS: Of 2,068 chemotherapy recipients, 179 (8.7%) experienced 262 CRHs. Most hospitalizations were not chemotherapy related (73.7%). The mean monthly rate of CRH was 1.5%, the median length of stay was 5 days, the most common type of CRH was gastrointestinal (46.1%) followed by infectious (31.4%), and 0.9% of chemotherapy recipients had a fatal CRH. Significant predictors of CRH included having a comorbidity score of 3-4 versus 0 and having a higher creatinine level. CONCLUSIONS: Although the vast majority of chemotherapy recipients did not experience a CRH, these events were, unfortunately, not without serious consequences. Care should be taken when offering chemotherapy to patients with multiple comorbid conditions. Systematic efforts to monitor toxicity can lead directly to improvements in quality of care.

Improving the Delivery of High-Quality Cancer Care in Medically Underserved Communities: A Formative Evaluation Method.

BACKGROUND AND OBJECTIVES: In 2015, the American Society of Clinical Oncology launched a new program: Improving Quality of Care in Underserved Communities with the overarching aim of serving patients with cancer who have traditionally had difficulty accessing the care they need. Cancer care requires intense coordination of complex services to provide safe, effective, timely, and equitable care. If chemotherapy and/or radiation is needed, patients must navigate a complex system of care many times, a formidable challenge for many disadvantaged patients. Many practices believe that these patients face such significant issues that it is almost impossible to provide high-quality care. A grant from the Stavros Niarchos Foundation allowed us to select 4 oncology practices serving high proportions of racial minorities and persons of low socioeconomic status to participate in the new American Society of Clinical Oncology program. The program had 2 objectives: (1) to improve the capacity and capability of the participating practices to provide evidence-based, high-quality care; and (2) to identify and disseminate lessons learned for improving quality of care among oncology practices serving underserved patients. METHODS: The program leveraged existing programs including the Quality Oncology Practice Initiative, which is a national performance measurement and improvement program that collects data about processes of care provided in the outpatient medical oncology setting, and the American Society of Clinical Oncology Quality Training Program, which provides training in how to apply the tools and methods of quality improvement in routine care settings. Training was provided in face-to-face and virtual meetings and participants were provided mentors throughout the program. At the conclusion, a formative evaluation method was used to assess whether the goals had been achieved. Objectives, activities, and desired outcomes were identified for each of the goals and thus became the framework for the evaluation. RESULTS: The program met the stated goals and objectives. The evaluation revealed many successes, some surprises, and a list of improvements that were incorporated in the next iteration of this program. Based on data from the evaluation, the Niarchos Foundation provided funds for an additional 10 practices to participate in a similar program in 2020. CONCLUSION: This article outlines the evaluation of a new program demonstrating that medical oncology practices can make improvements in the care of their underserved populations if provided with the proper tools, methods, and coaching. The use of formative evaluation methodology also identified opportunities for improvement and ultimately resulted in additional funding for more practices to participate in the program.

Identifying Actionable Causes of Potentially Avoidable Readmissions to an Oncology Service at a Safety Net Hospital.

PURPOSE: Hospital readmissions occur commonly in those receiving cancer care and result in impaired quality of life and increased costs. Causes of readmission in safety net hospitals that serve vulnerable populations are not well understood. The primary goal of this project was to identify potentially avoidable and intervenable causes of readmissions to an urban safety net hospital. METHODS: A retrospective chart review was performed on patients who were readmitted within 30 days of discharge from the hematology and oncology service at Boston Medical Center over the 6-month period between October 2018 and March 2019. Charts were reviewed by three internal medicine residents and discussed under the supervision of an attending oncologist. RESULTS: Two hundred ninety-one patient encounters involving 203 unique patients were identified in the 6-month study period. Of these 291 encounters, 80 encounters (27.5%) were followed by a readmission within 30 days and occurred in 61 (30.0%) unique patients. Nineteen (31.1%) of these 61 patients experienced two readmissions within 30 days of discharge. Twenty-five readmissions (31.3%) were classified as potentially avoidable, with the most common cause of potentially avoidable readmissions attributed to ascitic or pleural fluid reaccumulation (8, 32%). The majority of presumed nonpreventable readmissions were due to expected complications of cancer progression and treatment-related side effects. DISCUSSION: In conclusion, readmissions were common, and a modifiable reason for 30-day readmissions was identified. Addressing recurrent ascitic and pleural fluid reaccumulation in the outpatient setting could help to reduce inpatient hospital readmission on an inpatient oncology service.

Impact of Clinical Process Improvement Training in an Integrated Delivery System.

Multiple integrated health systems use frontline staff training in quality and process improvement, although the optimal method to determine training success remains unknown. The authors assessed the Partners Clinical Process Improvement Leadership Program's short-term impact by evaluating data in project presentations during 14 courses between 2010 and 2016. Long-term impact was assessed via a graduate survey. Among 262 interprofessional teams, 180 (69%) achieved short-term improvement, including 78 (30%) achieving and 102 (39%) demonstrating improvement toward their project goal. Projects implementing ≥2 interventions were more likely to succeed. Of 231 graduates surveyed, 79% reported the ability to lead and 67% reported actual work on additional quality improvement projects. Ninety-seven percent of alumni reported a positive career impact. Hospital leadership support of clinical process improvement training meets short-term improvement needs and promotes long-term capacity for learning health systems.

Physician alerts to prevent symptomatic venous thromboembolism in hospitalized patients.

BACKGROUND: Venous thromboembolism (VTE) prophylaxis remains underused among hospitalized patients. We designed and carried out a large, multicenter, randomized controlled trial to test the hypothesis that an alert from a hospital staff member to the attending physician will reduce the rate of symptomatic VTE among high-risk patients not receiving prophylaxis. METHODS AND RESULTS: We enrolled patients using a validated point score system to detect hospitalized patients at high risk for symptomatic VTE who were not receiving prophylaxis. We randomized 2493 patients (82% on Medical Services) from 25 study sites to the intervention group (n=1238), in which the responsible physician was alerted by another hospital staff member, or the control group (n=1255), in which no alert was issued. The primary end point was symptomatic, objectively confirmed VTE within 90 days. Patients whose physicians were alerted were more than twice as likely to receive VTE prophylaxis as control subjects (46.0% versus 20.6%; P<0.0001). The symptomatic VTE rate was lower in the intervention group (2.7% versus 3.4%; hazard ratio, 0.79; 95% CI, 0.50 to 1.25), but the difference did not achieve statistical significance. The rate of major bleeding at 30 days in the alert group was similar to that in the control group (2.1% versus 2.3%; P=0.68). CONCLUSIONS: A strategy of direct notification of the physician by a staff member increases prophylaxis use and leads to a reduction in the rate of symptomatic VTE in hospitalized patients. However, VTE prophylaxis continues to be underused even after physician notification, especially among Medical Service patients.

Evolution and elements of the quality oncology practice initiative measure set.

BACKGROUND: Over the past 5 years, the American Society of Clinical Oncology (ASCO) has supported the development of a Web-based quality-reporting tool in response to a recognized need to provide medical oncologists the opportunity to demonstrate the quality of care that they are providing to patients. METHODS: The development of quality measures, their basis in the literature, and the descriptions and organizational structure of the measures are discussed. RESULTS: Specific results are the property of practices and are not shared outside of the practices except in aggregate. The system allows collection of information concerning a wide range of quality measures in a short period of time. In the last data collection period in the fall of 2008, information was submitted concerning 81 measures of quality divided into one required and six optional modules from over 250 practices concerning 15,000 patients. CONCLUSIONS: The timely collection of information on a wide range of quality measures regarding cancer patients can be efficiently collected using a Web-based data collection tool allowing for practice self-examination and comparison with other practices.

Managing Cancer Patients' Expectations Amid Hope And Hype.

How patients view oncologists-and how oncologists view themselves-„matters when difficult decisions must be made.