Updated Review Article: Cyclin-Dependent Kinase 4/6 Inhibitor Impact, FDA Approval, and Resistance Pathways.

Objective: To describe the mechanism of cyclin-dependent kinase (CDK) 4/6 inhibitors, mechanisms of resistance, and summarize various clinical trials used to determine the efficacy and safety of CDK4/6 inhibitor used for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer. Data Sources: An extensive literature search using PubMed and notable sources was performed (2016 to February 2022) using the following search terms: CDK4/6 inhibitors, palbociclib, abemaciclib, ribociclib, CDK4/6 inhibitor resistance, FAT1 gene, luminal A breast cancer, luminal B breast cancer, HR+/HER2- breast cancer. Abstracts from conferences, national clinical trials, and drug monographs were reviewed. Study Selection and Data Extraction: Relevant clinical studies or those conducted in humans and updated clinical trials were considered. Data synthesis: The various clinical trials reviewed and results have led to numerous studies and expansions of U.S. Food and Drug Administration (FDA) approval. Although the use of CDK4/6 inhibitors has improved progression-free survival in patients with HR+, HER2- breast cancer, studies have shown that resistance pathways can cause cells to be insensitive to CDK4/6 inhibitors, leading to continued cell proliferation. Conclusions: CDK4/6 inhibitors are recommended as first-line therapy in combination with endocrine therapy for patients with HR+/HER2- advanced breast cancer. However, mutations and acquired resistance can occur that affect a patient's response to treatment. Additional research needs to be conducted on strategies to overcome resistance and determine how ethnicity plays a role in resistance pathways.

Partnering With Patients to Bridge Gaps in Consent for Acute Care Research.

Clinical trials for acute conditions such as myocardial infarction and stroke pose challenges related to informed consent due to time limitations, stress, and severe illness. Consent processes should be sensitive to the context in which trials are conducted and to needs of patients and surrogate decision-makers. This manuscript describes a collaborative effort between ethicists, researchers, patients, and surrogates to develop patient-driven, patient-centered approaches to consent for clinical trials in acute myocardial infarction and stroke.Our group identified important ways in which existing consent processes and forms for clinical trials fail to meet patients' and surrogates' needs in the acute context. We collaborated to create model forms and consent processes that are substantially shorter and, hopefully, better-matched to patients' and surrogates' needs and expectations from the perspective of content, structure, and tone. These changes, however, challenge some common conventions regarding consent.

Adjunct Histamine Blockers as Premedications to Prevent Carboplatin Hypersensitivity Reactions.

OBJECTIVE: The objective of this study was to evaluate the impact of premedications given as an adjunct to carboplatin on the incidence of hypersensitivity reactions in women with ovarian cancer. Medications of interest include a histamine1 (H1 ) and histamine2 (H2 ) blocker in addition to dexamethasone. METHODS: This was a retrospective chart review evaluating the addition of an H1 and H2 blocker in addition to dexamethasone as standard premedications on the incidence of carboplatin hypersensitivity reactions (CHRs) in women with ovarian cancer. MAIN RESULTS: The odds ratio for premedication use was 0.46 with a 95% confidence interval (0.17-1.27), suggesting that patients with premedication use had approximately half the risk of CHR compared with patients without premedication. The overall incidence of CHRs decreased from 7.9% at baseline to 3.2% after the addition of premedications. The incidence of CHRs was 5.2% in 58 patients with recurrent or progressive disease compared with 2.1% in 96 newly diagnosed patients. Lifetime dose greater than 3377 mg, number of cycles more than six, and progressive or recurrent disease were predictive factors of CHR in women with ovarian cancer. PRINCIPAL CONCLUSIONS: Total lifetime exposure to carboplatin remains the greatest predictive factor of CHR in women with ovarian cancer. Although data analysis indicates the addition of premedications for all ovarian cancer patients receiving carboplatin did not result in a statistically significant reduction in CHRs, a patient benefit in CHR reduction was observed. A prospective study is needed to confirm these findings.

Evaluation of intervention to prevent hypomagnesemia in cervical cancer patients receiving combination cisplatin and radiation treatment.

PURPOSE: The purpose of this study was to evaluate the impact of increasing the magnesium (Mg(2+)) supplementation in the pre- and posthydration of patients receiving cisplatin plus radiation (CisXRT) to prevent chemotherapy-induced hypomagnesemia (CIH) events. MATERIALS AND METHODS: The study was conducted on newly diagnosed cervical cancer patients receiving CisXRT. The first prospective intervention to prevent CIH was to increase the pre- and posthydration Mg(2+) from 1 to 2 g. After completion of the first intervention, the analysis demonstrated the persistent occurrence of CIH on cycle 3, and later, a second intervention was implemented to increase Mg(2+) to 3 g in the pre- and posthydration. Patients that failed to complete at least five cycles or received cisplatin in combination with another chemotherapy regimen were excluded from the study. Baseline group included 70 patients that had received CisXRT prior to any changes in magnesium supplementation. RESULTS: There were 62.8% (44/70) and 32.6% (22/70) of patients with episodes of CIH in the baseline and first intervention groups, respectively (P = 0.007). In the second intervention group, a 49.6% decrease in the total number of episodes compared to control group was observed. Patients in the second intervention group showed a 100% improvement incidence of persistent CIH over the two other cohorts (P = 0.001). CONCLUSIONS: The increase of Mg(2+) to 2 g for the initial two cycles and then to 3 g with the third cycle of CisXRT therapy prevented episodes of CIH and decreased associated treatment delays.

Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA).

Obesity is a chronic disease that has increased dramatically in the past few decades worldwide. More concerning, obesity is linked to many other disease states including cancer and has been shown to increase mortality. Unfortunately, oncology drug development and most clinical trials fail to address the problem of appropriate chemotherapy dosing in obese patients. This can potentially lead to either increased toxicity or decreased efficacy. Although dosing schemas may vary among practices and institutions, many oncologists tend to remain conservative and empirically dose-reduce obese patients despite data suggesting otherwise. The goals of this review were to consider the various aspects of pharmacokinetics in obese patients, to examine the existing literature regarding chemotherapy dosing in obese patients, and to determine the most appropriate weight estimation for body surface area (BSA) dose calculations. Based upon the current clinical data of obesity and chemotherapy dosing it can be concluded there is very limited if any data to support the perception that capping the doses of obese patients is beneficial and more likely this practice may have negative implications on survival outcomes. Under dosing patients with treatable or even curable disease to prevent toxicities could be costing the obese oncology patient population months to years of overall survival.