Case Report: Durable Response to Very Low Dose Tyrosine Kinase Inhibitors in Advanced Hepatocellular Carcinoma

The oral tyrosine kinase inhibitors (TKI) sorafenib, regorafenib, and cabozantinib are approved for advanced hepatocellular carcinoma (aHCC) and improve survival. However, patients on these medications frequently require dose reductions or discontinuation due to multiple side effects leading to poor tolerability. Here we report three different aHCC patients with clinical responses outlasting those reported in their corresponding Phase 3 clinical trials on 1/8th the target dose for sorafenib, 1/4th the target dose for regorafenib and 1/6th the target dose for cabozantinib respectively. As these doses are below the minimal recommended doses on the FDA labels, this case series provides a preliminary demonstration that low dose TKI therapy can be effective and patients on TKIs should first assess for clinical response before empirically discontinuing TKI therapy on the basis of tolerating only a low dose.

Impact of prescription isodose level and collimator selection on dose homogeneity and plan quality in robotic radiosurgery

Purpose In stereotactic radiosurgery (SRS), prescription isodoses and resulting dose homogeneities vary widely across different platforms and clinical entities. Our goal was to investigate the physical limitations of generating dose distributions with an intended level of homogeneity in robotic SRS. Methods Treatment plans for non-isocentric irradiation of 4 spherical phantom targets (volume 0.27–7.70 ml) and 4 clinical targets (volume 0.50–5.70 ml) were calculated using Sequential (phantom) or VOLOTM (clinical) optimizers (Accuray, Sunnyvale, CA, USA). Dose conformity, volume of 12 Gy isodose (V12Gy) as a measure for dose gradient, and treatment time were recorded for different prescribed isodose levels (PILs) and collimator settings. In addition, isocentric irradiation of phantom targets was examined, with dose homogeneity modified by using different collimator sizes. Results Dose conformity was generally high (nCI ≤ 1.25) and varied little with PIL. For all targets and collimator sets, V12Gy was highest for PIL ≥ 80% and lowest for PIL ≤ 65%. The impact of PIL on V12Gy was highest for isocentric irradiation and lowest for clinical targets (VOLOTM optimization). The variability of V12Gy as a function of collimator selection was significantly higher than that of PIL. V12Gy and treatment time were negatively correlated. Plans utilizing a single collimator with a diameter in the range of 70–80% of the target diameter were fastest, but showed the strongest dependence on PIL. Conclusion Inhomogeneous dose distributions with PIL ≤ 70% can be used to minimize dose to normal tissue. PIL ≥ 90% is associated with a marked and significant increase in off-target dose exposure. Careful selection of collimators during planning is even more important.

379 Contemporary use of guideline directed medical therapy in dilated cardiomyopathy: therapeutic optimization and prognostic benefits

Aims Therapy with antineurohormonal drugs at target doses has a prognostic benefits in heart failure with reduced ejection fraction. Dilated cardiomyopathy (DCM) represents a particular setting where the possible benefit of target doses of antineurohormonal drugs is unexplored. Methods and results All patients enrolled from 1/1/1992 to 1/3/2020 in the Trieste Muscle Heart Disease register affected by DCM with data on the dosage of therapy available both enrollment and at follow-up visit (i.e., 6–12 month) were included. The population was divided according to the percentage of recommended dose prescribed (0–49%, 50–99%, 100%) of both renin-angiotensin system inhibitors (RASi) and beta blockers (BB). A composite of death/heart transplant/hospitalization for heart failure was considered as the primary endpoint; a composite of sudden cardiac death/major ventricular arrythmias/defibrillator intervention was evaluated as a secondary endpoint. Prognostic associations were explored with uni- and multivariate analyses, Cox regressions, Kaplan–Meier, cumulative incidence curves and propensity score matching. 826 patients were included. At baseline 789 (96%) were taking a RASi and 627 (76%) a BB. The target dose of RASi was prescribed in 29% and 36% of patients at enrolment and at follow-up visit, respectively. The percentage of patients taking the maximum recommended dose of BB was 10% at baseline and 17% after optimization. Predictors of reaching target dose for RASi were BMI < 25 kg/m2, male sex [HR: 1.798 (95% CI: 1.073–3.012), P = 0.026] and higher systolic blood pressure [HR per mmHg 1.038 (95% CI: 1.025–1.051), P < 0.001]. Target dose predictors of BB were age [HR per year 0.527 (95% CI: 0.347–0.802), P = 0.003] and highest systolic blood pressure [HR per mmHg 1.024 (95% CI: 1.013–1.035), P < 0.001]. After adjustment target dose of RASi or BB did not show a significant association with the risk of primary outcome occurrence compared to those taking less than 50% (P = 0.550 for RASi and P = 0.921 for BB). The incidence of arrhythmic events was significantly lower in patients taking 100% of recommended dose of BB compared to those taking less than 50% (P = 0.009), after adjustment for confounders. The target dose of RASi was not associated with an arrhythmic events risk change (P = 0.688). Conclusions In DCM a significant number of patients do not tolerate maximal therapy doses, mainly due to hypotension. The achievement of the target dose of RASi and BB, after adjustment for confounders had a neutral effect on the incidence of heart failure-related events. Uptitration of BB to the recommended dose has a strong protective effect on arrhythmic events.

Patients with Kidney Transplant: Maximizing Mycophenolic Acid Submission with Target Dose Intervention

Background: Mycophenolate, an immunosuppressive agent choice. It is used readily in the transplantation of kidneys. Aim: To find out utilization of this drug is considered safe but the exact dosage of this drug varies according to the choice. Methods: It alters from fixed-dose to the dose optimization to the drug exposure target. It is the area under the concentration and time curve graph. This graph gives inconsistent results of concentration-controlled dosing in prospective studies. In this research paper, the evidence helping mycophenolate has been analyzed. The research includes finding out the pharmacological features, toxicities, and efficacy of this chemical ingredient. Randomized controlled trials along with dose optimization procedure and exposure have also been achieved. Results: A fixed dose of mycophenolate continuously leads to either less exposure associated with unapproved strategy or over-exposure leading to toxicity. When concentration controlled dosing is measured via pharmacokinetic measurement to target concentration intervention, mycophenolate exposure is controlled successfully and clinical benefits are visible. There is a need for agreement on practical aspects of drug-target concentration intervention in normal tacrolimus containing dosage and research to find maintenance phase subjection targets. Conclusion: More preference should be given to the effects of over suppression and under suppression in transplantation of kidney affecting short term as well as long term benefits. A single dose should be given to the mycophenolate target concentration intervention. Keywords: Mycophenolate, immunosuppressive agent, kidney transplant, target dose intervention

Comparative dosimetry of brachytherapy treatment planning between a volume-based plan by CT and a point-based plan by TAUS in CT datasets for brachytherapy

Aim: To evaluate comparative dosimetry of brachytherapy treatment planning between a volume-based plan by computed tomography (CT) and a point-based plan by transabdominal ultrasound (TAUS) in CT datasets for brachytherapy. Materials and methods: From 2019 to 2021, 59 different datasets of CT images were collected from 38 patients treated by intracavitary brachytherapy with tandem ovoid or tandem ring applicators. At that time, TAUS was performed to prevent uterine perforation and to evaluate topography of the cervix during application. In volume-based planning by CT, the target dose was used to keep the dose at 90% of high-risk clinical target volume (HR-CTV), to give a dose of at least 7Gy, while in the point-based plan by TAUS, the target dose was used to keep the minimum dose to eight cervix reference points (measured by TAUS), to give a dose of at least 7Gy. The doses to targets and organs at risk were evaluated and compared between volume-based planning by CT and the point-based plan by TAUS. Results: Of 59 fractions, a tandem ovoid applicator was used in 48 fractions (81·3%). In the volume-based plan by CT, the mean doses to HR-CTV(D90), intermediate-risk clinical target volume (IR-CTV)(D90), bladder(D2cc), rectum(D2cc) and sigmoid colon(D2cc) were 7·0, 3·9, 4·9, 2·9 and 3·3 Gy, respectively, while in the point-based plan by TAUS, the mean doses to HR-CTV(D90), IR-CTV(D90), bladder(D2cc), rectum(D2cc) and sigmoid colon(D2cc) were 8·2, 4·6, 5·9, 3·4 and 3·9 Gy, respectively. The percentages of mean dose differences between TAUS and CT of HR-CTV(D90), IR-CTV(D90), bladder(D2cc), rectum(D2cc) and sigmoid colon(D2cc) were 17·7, 19·5, 20·5, 19·5, 21·3 and 19·8%, respectively. With the target dose to the point-based plan by TAUS (7 Gy to the cervix reference points), this was close to D98 of HR-CTV with a mean percentage of difference of 0·6%. Findings: The point-based plan by TAUS showed higher values to targets and organs at risk than the volume-based plan by CT. With the point-based plan by TAUS, it was close to D98 of HR-CTV.

Brexucabtagene Autoleucel (Tecartus)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses Brexucabtagene autoleucel (Tecartus) cell suspension in a patient-specific single infusion bag for IV use at a target dose of 2 × 106 chimeric antigen receptor T cells per kilogram Indication: Tecartus is a CD19-directed genetically modified autologous T-cell immunotherapy indicated for: The treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after 2 or more lines of systemic therapy including a Bruton’s tyrosine kinase (BTK) inhibitor.

Influence of target dose heterogeneity on dose sparing of normal tissue in peripheral lung tumor stereotactic body radiation therapy

Objective To evaluate the influence of target dose heterogeneity on normal tissue dose sparing for peripheral lung tumor stereotactic body radiation therapy (SBRT). Methods Based on the volumetric-modulated arc therapy (VMAT) technique, three SBRT plans with homogeneous, moderate heterogeneous, and heterogeneous (HO, MHE, and HE) target doses were compared in 30 peripheral lung tumor patients. The prescription dose was 48 Gy in 4 fractions. Ten rings outside the PTV were created to limit normal tissue dosage and evaluate dose falloff. Results When MHE and HE plans were compared to HO plans, the conformity index of the PTV was increased by approximately 0.08. The median mean lung dose (MLD), V5, V10, V20 of whole lung, D2%, D1cc, D2cc of the rib, V30 of the rib, D2% and the maximum dose (Dmax) of the skin, and D2% and Dmax of most mediastinal organs at risk (OARs) and spinal cord were reduced by up to 4.51 Gy or 2.8%. Analogously, the median Dmax, D2% and mean dose of rings were reduced by 0.71 to 8.46 Gy; and the median R50% and D2cm were reduced by 2.1 to 2.3 and 7.4% to 8.0%, respectively. Between MHE and HE plans there was little to no difference in OARs dose and dose falloff beyond the target. Furthermore, the dose sparing of rib V30 and the mean dose of rings were negatively correlated with the rib and rings distance from tumor, respectively. Conclusions For peripheral lung tumor SBRT, target conformity, normal tissue dose, and dose falloff around the target could be improved by loosening or abandoning homogeneity. While there was negligible further dose benefit for the maximum target dose above 125% of the prescription, dose sparing of normal tissue derived from a heterogeneous target decreased as the distance from the tumor increased.