Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.

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Sorafenib in Advanced Hepatocellular Carcinoma

BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

/pdf/pd-1-blockade-in-tumors-with-mismatch-repair-deficiency-1eb0ztv7j7.pdf

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.07-9574LSF

Dose translation from animal to human studies revisited

Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

/pdf/idh1-and-idh2-mutations-in-gliomas-1er88anbwg.pdf

IDH1 and IDH2 Mutations in Gliomas

BackgroundWe assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non–small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. MethodsWe assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. ResultsCommon side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1501824

Pembrolizumab for the treatment of non-small cell lung cancer

Purpose: Endothelin receptors, particularly the ETA receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ETA receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. Patients and Methods: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. Results: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination halflife was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. Conclusion: Adverse events were consistent with atrasentan’s pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed. J Clin Oncol 20:2171-2180. © 2002 by American Society of Clinical Oncology.

Atrasentan, a n E ndothelin-Recep tor A ntagonist f or Refractory A denocarcinomas: S afety a nd P harmacokinetics

365 Background: An important factor contributing to a resident’s interest in oncology training is early and consistent exposure to the field. Currently, completing an inpatient oncology rotation is associated with a decreased interest in pursuing a career in oncology and low resident satisfaction. The reasons for this are multi-factorial, including high task burden and limited dedicated teaching time. Fortunately, prior work has revealed that interest in oncology fellowship training increases when residents receive targeted educational material during their oncology rotations. As part of a multifaceted approach to improve the inpatient curriculum, we conducted a targeted needs assessment at our institution. Our goal is to improve resident satisfaction, clinical competency, and interest in pursuing subspecialty training in oncology by implementing a focused educational intervention. Methods: The Johns Hopkins Hospital is an urban academic medical center where the Osler Internal Medicine Residency Program of approximately 156 housestaff complete their training. A majority of these residents rotate through the inpatient solid tumor service. We performed a targeted needs assessment designed with the ABIM Blueprint, the solid tumor service learning objectives, and ACGME data specific to our program. The survey was created using Qualtrics software and distributed via email to all PGY-1, PGY-2, and PGY-3 residents. Results: 42.9% of residents participated in the survey. 79% of participants indicated they planned to pursue subspecialty training after residency with 21% of those in oncology. Approximately half of participants (45%) had rotated on the solid tumor service. 51% of participants reported barriers to education; the most common barriers identified were patient census and high resident task burden. “On the fly teaching” was the preferred instructional strategy by 70% of participants, followed by in-person didactics and asynchronous videos. The top three areas of interest for content creation were: basics of antineoplastic therapy, tumor lysis syndrome, and immune checkpoint inhibitor toxicities. Conclusions: Resident educational experiences on subspecialty rotations plays a strong role in the ultimate decision to pursue further training. Given the rising need for oncologists nationally, it is imperative that programs identify and address gaps in the educational experience on oncology rotations. Our needs assessment identified several concrete ways to improve resident experience on the Johns Hopkins inpatient solid tumor service. Next steps will include development and implementation of a high-yield resident inpatient curriculum for oncology (RICO), with focused assessments planned throughout the academic year to measure clinical competency, resident satisfaction and ultimately identify areas for further improvement.

Resident Inpatient Curriculum for Oncology (RICO): Results of a targeted needs assessment performed in the Osler Internal Medicine Residency Program.

e23014 Background: As the oncology patient population grows, continued recruitment of talented individuals is essential. Meaningful and highly educational clinical exposures play a crucial role in a resident’s decision to pursue fellowship in oncology. Currently, the majority of oncology exposure occurs in the inpatient setting, where trainees are confronted with many competing clinical demands, leaving minimal time for teaching. Prior work has demonstrated that dedicated time for teaching supplemented with high-yield educational material improves trainee satisfaction and interest in a particular field. We hypothesize that implementing an asynchronous inpatient video oncology curriculum will improve resident clinical competency and satisfaction. Methods: This is an ongoing, single institution educational intervention using the Kern method for curriculum development in the Johns Hopkins Osler Internal Medicine Residency (IRB00307077). A targeted needs assessment has been developed to identify gaps in medical knowledge, assess preparedness in managing common solid tumor inpatient diagnoses, and explore satisfaction with prior educational experiences on this service. Based on these results, ten educational videos will be created by content experts and aligned with the learning objectives of the Osler residency program and ABIM blueprint. Trainees will have dedicated time to watch the videos during their solid tumor rotation. We plan to evaluate effectiveness of our curriculum by measuring completion rates and pre- and post-video multiple choice responses. We will also assess knowledge retention and resident satisfaction at three and six months post-rotation with online questionnaires. Results: Annual Osler program ACGME survey data review revealed a high level of resident dissatisfaction with the oncology clinical experience compared with other rotations. While 83.3% of residents rated their general internal medicine experience as “excellent,” only 52.4% rated their oncology experience as “excellent.” Needs assessment data collection has been delayed by the COVID-19 pandemic but is ongoing. Following topic selection, videos will be created in April 2022 with plans for video curriculum implementation in July 2022. Conclusions: In order to attract and retain trainees in the field of oncology, it is imperative that educational curricula adapts to meet learners’ needs. Efficient, evidence-based instructional strategies designed to promote clinical competency for internal medicine residents on an inpatient solid tumor service may foster engagement and rotation satisfaction. We are currently evaluating how an asynchronous video inpatient oncology curriculum may significantly improve the inpatient internal medicine trainee experience. If successful, this curriculum can be adapted for other trainees and practitioners new to the field of oncology.

Ross C. Donehower

Papers

Atrasentan, a n E ndothelin-Recep tor A ntagonist f or Refractory A denocarcinomas: S afety a nd P harmacokinetics

Resident Inpatient Curriculum for Oncology (RICO): Results of a targeted needs assessment performed in the Osler Internal Medicine Residency Program.

Improving resident education on the inpatient solid tumor oncology rotation through development of an asynchronous video curriculum.