Citation: ESMO Open. 2021, 6(3), 100162. Epub 2021 Jun 5
Author: C Palmieri, I R Macpherson
Abstract: As the liver is vital for the metabolism of many anticancer drugs, determining the correct starting doses in cancer patients with liver impairment is key to safe prescription and prevention of unnecessary adverse effects. Clinicians typically use liver function tests when evaluating patients; however, prescribing information and summaries of product characteristics often suggest dosing of anticancer drugs in patients with liver impairment based on the Child-Pugh criteria, even though the criteria were not developed for this purpose. In this review, we assessed all the oncological small molecule and cytotoxic drugs approved by the United States Food and Drug Administration (FDA) over a 5-year period from 2014 to 2018. The various entry criteria related to these drugs-with respect to hepatic function-in key pivotal studies were compared with their approved dosing recommendations found in prescribing information and summaries of product characteristics. We found that 46% of drugs have dosing recommendations based on Child-Pugh criteria alone, despite the fact that only 8% of these drugs were tested within studies that used the Child-Pugh criteria as entry criteria. Moreover, we note that the data used to make recommendations based on Child-Pugh criteria are typically from small studies that may lack an appropriate patient population. We propose that these findings, along with details surrounding the development of the Child-Pugh criteria, call into question the validity and appropriateness of using Child-Pugh criteria for dosing recommendations of anticancer drugs.
Keywords: Child-Pugh criteria; anticancer drugs; dosing; liver impairment.
Citation: Radiation Oncology. 2021, 16(1), 95
Author: Louise Turtle, Neeraj Bhalla, Andrew Willett, Robert Biggar, Jonathan Leadbetter, Georgios Georgiou, James M Wilson, Sindu Vivekanandan, Maria A Hawkins, Michael Brada, John D Fenwick
Abstract: Background: We have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC).
Materials and methods: Baseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MDHeart). Reductions in MDHeart achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving ≥ 50 Gy (VHeart-50-Gy) and left atrial wall volume receiving ≥ 63 Gy (VLAwall-63-Gy).
Results: Following re-optimization, mean MDHeart, VHeart-50-Gy and VLAwall-63-Gy values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MDHeart is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including VHeart-50-Gy and VLAwall-63-Gy, providing some insurance against survival being more strongly related to these measures than to MDHeart. The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MDHeart was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MDHeart values exceeded the median value in a published series, the average MDHeart reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MDHeart values.
Conclusions: Cardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MDHeart led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MDHeart levels, for whom larger reductions in heart doses can be achieved.
Keywords: Cardiac-sparing; Heart; NSCLC; Radiotherapy; Survival.
Citation: International Journal of Radiation Oncology, Biology, Physics. 2021, 110(2), 596-608. Epub 2021 Jan 4.
Author: Douglas H Brand, Sarah C Brüningk, Anna Wilkins, Katie Fernandez, Olivia Naismith, Annie Gao, Isabel Syndikus, David P Dearnaley, Alison C Tree, Nicholas van As, Emma Hall, Sarah Gulliford, CHHiP Trial Management Group
Abstract: Purpose: Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy.
Methods and materials: The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models.
Results: Late rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/β, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1 + α/β ratio = 2.4 Gy; G2 + α/β ratio = 2.3 Gy.
Conclusions: We estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy.
Citation: Transplantation. 2021, 105(7), e76
Author: Avinash R Odugoudar, Hemant Sharma, Meghana Hipparagi, Bhavesh Devkaran, Ajay Sharma
Citation: Journal of Geriatric Cardiology. 2021, 18(5), 319-26
Author: Yau-Lam Alex Chau, Ji Won Yoo, Ho Chuen Yuen, Khalid Bin Waleed, Dong Chang, Tong Liu, Fang Zhou Liu, Gary Tse, Sharen Lee, Ka Hou Christien Li
Abstract: Background: Post-operative atrial fibrillation (POAF) is a common yet understudied clinical issue after coronary artery bypass graft (CABG) leading to higher mortality rates and stroke. This systematic review and meta-analysis evaluated the rates of adverse outcomes between patients with and without POAF in patients treated with CABG or combined procedures.
Methods: The search period was from the beginning of PubMed and Embase to May 18th, 2020 with no language restrictions. The inclusion criteria were: (1) studies comparing new onset atrial fibrillation before or after revascularization vs. no new onset AF before or after revascularization. The outcomes assessed included all-cause mortality, cardiac death, cerebral vascular accident (CVA), myocardial infarction (MI), repeated revascularization, major adverse cardiac event (MACE), and major adverse cardiac and cerebrovascular events (MACCEs).
Results: Of the 7,279 entries screened, 11 studies comprising of 57,384 patients were included. Compared to non-POAF, POAF was significantly associated with higher risk of all-cause mortality (Risk Ratio (RR) = 1.58; 95% Confidence Interval (CI): 1.42-1.76, P < 0.00001) with accompanying high level of heterogeneity ( I 2 = 62%).
Conclusions: Patients with POAF after CABG or combined procedures are at an increased risk of all-cause mortality or CVAs. Therefore, POAF after such procedures should be closely monitored and treated judiciously to minimize risk of further complications. While there are studies on POAF versus no POAF on outcomes, the heterogeneity suggests that further studies are needed.
Citation: British Journal of Nursing. 2021, 30(Sup7), 1-7
Author: Dave Wynne
Citation: Endoscopy. 2021 Jun 17. Online ahead of print
Author: Konstantinos Triantafyllou, Paraskevas Gkolfakis, Ian M Gralnek, Kathryn Oakland, Gianpiero Manes, Franco Radaelli, Halim Awadie, Marine Camus Duboc, Dimitrios Christodoulou, Evgeny Fedorov, Richard J Guy, Marcus Hollenbach, Mostafa Ibrahim, Ziv Neeman, Daniele Regge, Enrique Rodriguez de Santiago, Tony C Tham, Peter Thelin-Schmidt, Jeanin E van Hooft
Link to PubMed record
