Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Malignant Pleural Effusions in the Era of Immunotherapy and Antiangiogenic Therapy.

Malignant pleural effusions (MPE) have historically been associated with a poor prognosis, and patients often require a series of invasive procedures and hospitalizations that significantly reduce quality of life at the terminus of life. However, advances in the management of MPE have coincided with the era of immunotherapies, and to a lesser extent, antiangiogenic therapies for the treatment of lung cancer. Landmark studies have shown these drugs to improve overall survival and progression-free survival in patients with lung cancer, but a paucity of phase III trial data exists for the impact of immune checkpoint inhibitors (ICI) on lung cancers associated with MPE. This review will focus on the leading studies investigating the impact of ICI and antiangiogenic therapies in patients with lung cancer and MPE. The diagnostic and prognostic values of vascular endothelial growth factor and endostatin expression levels in malignancy will also be discussed. These advancements are changing the paradigm of MPE management from palliation to treatment for the first time since 1767 when MPE was first reported. The future holds the promise of durable response and extended survival in patients with MPE.

Health Through Activity: Initial Evaluation of an In-Home Intervention for Older Adults With Cancer.

OBJECTIVE: The objective of this study was to assess the feasibility of conducting a future full-scale trial to test the efficacy of an in-home occupational therapy intervention designed to reduce disability in older adult cancer survivors. METHOD: Participants reporting activity limitations during or after cancer treatment were enrolled in a Phase 1 pilot randomized controlled trial comparing the 6-wk intervention (n = 30) to usual care (n = 29). Descriptive data on retention rates were collected to assess feasibility of intervention and study procedures. Potential efficacy was explored through participants' self-reported disability, quality of life, activity level, and behavioral activation at 0, 8, and 16 wk after enrollment. RESULTS: Retention rates were high regarding completion of the intervention (90%) and outcome assessments (90% of usual-care participants and 80% of intervention participants). Outcomes consistently favored the intervention group, although group differences were small. CONCLUSION: The procedures were feasible to implement and acceptable to participants.

Root Cause Analysis of Oncology Adverse Events in the Veterans Health Administration.

PURPOSE: Oncology providers are leaders in patient safety. Despite their efforts, oncology-related medical errors still occur, sometimes resulting in patient injury or death. The Veterans Health Administration (VHA) National Center of Patient Safety used data obtained from root cause analysis (RCA) to determine how and why these adverse events occurred in the VHA, and how to prevent future reoccurrence. This study details the types of oncology adverse events reported in VHA hospitals and their root causes and suggests actions for prevention and improvement. METHODS: We searched the National Center for Patient Safety adverse event reporting database for RCA related to oncology care from October 1, 2013, to September 8, 2017, to identify event types, root causes, severity of outcomes, care processes, and suggested actions. Two independent reviewers coded these variables, and inter-rater agreement was calculated by κ statistic. Variables were evaluated using descriptive statistics. RESULTS: We identified 48 RCA reports that specifically involved an oncology provider. Event types included care delays (39.5% [n = 19]), issues with chemotherapy (25% [n = 12]) and radiation (12.5% [n = 6]), other (12.5% [n = 6]), and suicide (10.5% [n = 5]). Of the 48 events, 27.1% (n = 13) resulted in death, 4.2% (n = 2) in severe harm, 18.8% (n = 9) in temporary harm, 20.8% (n = 10) in minimal harm, and 2.1% (n = 1) in no harm. The majority of root causes identified a need to improve care processes and policies, interdisciplinary communication, and care coordination. CONCLUSION: This analysis highlights an opportunity to implement system-wide changes to prevent similar events from reoccurring. These actions include comprehensive cancer clinics, usability testing of medical equipment, and standardization of processes and policies. Additional studies are necessary to assess oncologic adverse events across specialties.

Tumor-stage mycosis fungoides in palmoplantar localization with large-cell transformation and partial CD30 expression shows complete response to brentuximab vedotin.

Mycosis fungoides in palmoplantar localization (MFPP) is a rare variant of MF that is confined to the hands and feet. Patients commonly receive treatment over many years for suspected palmoplantar dermatitis before the diagnosis is made. Most MFPP patients remain at patch or plaque stage, and often respond to treatment with radiotherapy. Herein, we describe a 77-year-old man who suffered 6 years of hand and foot dermatitis that failed multiple treatments, most notably TNF-α inhibitors and mycophenolate mofetil. He eventually developed a tumor on the hand, which was biopsied to reveal a dense dermal infiltrate of large lymphocytes (CD3+/CD4-/CD8-/TCR-BetaF1+/partial CD30+). A subsequent biopsy of an eczematous patch from his hand revealed an epidermotropic and syringotropic infiltrate comprised of smaller lymphocytes with a concordant immunophenotype and matching clonal peak with TCR gene rearrangement. He was diagnosed with MFPP and started on radiotherapy with a modest response; therefore, a decision was made to start brentuximab vedotin, which resulted in a complete response. MFPP is an exceedingly rare variant of MF that can show large-cell transformation and progress in stage. We highlight a possible association between disease progression and immunosuppressants and the potential role for treatment with brentuximab.

A phase I trial and in vitro studies combining ABT-751 with carboplatin in previously treated non-small cell lung cancer patients.

BACKGROUND: ABT-751 is a novel antimitotic agent that exerted cytotoxic effects in preclinical studies. Carboplatin has efficacy in treating advanced non-small cell lung cancer (NSCLC) in combination with other drugs. METHODS: Lung cancer cell lines were treated with ABT-751 and/or carboplatin to investigate their impact on cell growth. A phase I study with an expansion cohort was conducted in previously treated NSCLC patients. The primary objective was the maximum tolerated dose (MTD); secondary objectives were objective response rates, median survival, time to tumor progression, dose-limiting toxicities (DLTs), and pharmacodynamic evaluation of buccal swabs. RESULTS: Combining ABT-751 with carboplatin significantly reduced growth and induced apoptosis of lung cancer cell lines. Twenty advanced NSCLC patients were enrolled. MTD was ABT-751 125 mg orally twice daily for 7 days with carboplatin AUC 6. DLTs included fatigue, ileus, neutropenia and pneumonitis. Two patients had confirmed partial responses. Median overall survival was 11.7 months (95% CI 5.9-27.0). Time to tumor progression was 2.8 months (95% CI 2.0-2.7). Four of 6 patients showed decreased cyclin D1 protein in posttreatment versus pretreatment buccal swabs. CONCLUSION: Combining ABT-751 with carboplatin suppressed growth of lung cancer cell lines and had modest clinical antitumor activity in advanced NSCLC previously treated predominantly with carboplatin. Further studies of this combination are not recommended while investigations of biomarkers in different patient populations, alternative schedules and combinations may be pursued.

The impact of residents, interns, and attendings on inpatient laboratory ordering patterns: a report from one university's hospitalist service.

PURPOSE: To examine the laboratory test ordering patterns of interns to determine the effects of more senior residents' and attendings' supervision on trainees' patterns and residents' perceptions of control in test ordering. METHOD: In a 2007 cohort study of 2,066 patients cared for by 85 interns, 56 residents, and 27 attendings on the University of Pennsylvania general medical hospitalist service, the authors studied variation in laboratory test utilization and costs in 10,908 patient-days. Ordinary least squares regression was used to partition variance among supervised and supervising physicians. Interns and residents were surveyed about their perceived control over lab test ordering. RESULTS: Forty-five percent (95% confidence interval [CI]: 39-53) of the variation in laboratory test utilization was attributable to interns' ordering, 26% (95% CI: 21-34) to residents, and 9% (95% CI: 7-16) to attendings; 20% (95% CI: 6-25) could not be uniquely attributed to a particular level of the care team. Similar results were obtained for variation in laboratory costs. Interns underestimated their control over laboratory test utilization, residents overestimated their control, and both groups had inaccurate assessments of their utilization relative to peers. CONCLUSIONS: Attending faculty had relatively little impact on laboratory ordering patterns. This may reflect a consistent baseline impact of attending physicians on laboratory use, but it may also represent a missed opportunity to reduce practice variation and improve patient care. Observing variation in trainee practice patterns in the face of different supervisors represents a new approach to measuring the supervision in clinical settings.

Pemetrexed in advanced non-small-cell lung cancer.

IMPORTANCE OF THE FIELD: Current therapeutic options for advanced non-small-cell lung cancer (NSCLC) yield relatively modest improvements in survival leading to an ongoing search for new active treatment agents. In the past decade, pemetrexed has had an increasingly established role in the treatment of advanced NSCLC in both first- and second-line settings. AREAS COVERED IN THIS REVIEW: Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of pemetrexed in the treatment of advanced NSCLC are described. Peer-reviewed publications on the development of pemetrexed and its clinical use in NSCLC were reviewed (1995 - 2009). WHAT THE READER WILL GAIN: Pemetrexed is a multitargeted antifolate cytotoxic agent. Key Phase II and Phase III trials are described that have shown pemetrexed's efficacy in both the first- and second-line treatment of advanced NSCLC. The efficacy of pemetrexed seems to vary between squamous and nonsquamous histologies. Possible reasons for this are explored. Additionally, the potential role of pemetrexed in maintenance therapy is discussed. TAKE HOME MESSAGE: Pemetrexed is an effective treatment for advanced NSCLC, with an overall favorable toxicity profile. There is growing evidence that, in patients treated with pemetrexed, nonsquamous tumors have improved outcomes compared to squamous cell tumors. Pemetrexed may also have a role in maintenance therapy for NSCLC.

Educating Physicians-in-Training About Resource Utilization and Their Own Outcomes of Care in the Inpatient Setting.

BACKGROUND: Despite significant policy concerns about the role of inpatient resource utilization on rising medical costs, little information is provided to residents regarding their practice patterns and the effect on resource use. Improved knowledge about their practice patterns and costs might reduce resource utilization and better prepare physicians for today's health care market. METHODS: We surveyed residents in the internal medicine residency at the Hospital of the University of Pennsylvania. Based on needs identified via the survey, discussions with experts, and a literature review, a curriculum was created to help increase residents' knowledge about benchmarking their own practice patterns and using objective performance measures in the health care market. RESULTS: The response rate to our survey was 67%. Only 37% of residents reported receiving any feedback on their utilization of resources, and only 20% reported receiving feedback regularly. Even fewer (16%) developed, with their attending physician, a concrete improvement plan for resource use. A feedback program was developed that included automatic review of the electronic medical record to provide trainee-specific feedback on resource utilization and outcomes of care including number of laboratory tests per patient day, laboratory cost per patient day, computed tomography scan ordering rate, length of stay, and 14-day readmission rate. Results were benchmarked against those of peers on the same service. Objective feedback was provided biweekly by the attending physician, who also created an action plan with the residents. In addition, an integrated didactic curriculum was provided to all trainees on the hospitalist service on a biweekly basis. CONCLUSIONS: Interns and residents do not routinely receive feedback on their resource utilization or ways to improve efficiency. A method for providing objective data on individual resource utilization in combination with a structured curriculum can be implemented to help improve resident knowledge and practice. Ongoing work will test the impact on resource utilization and outcomes.