Significant Change In Dose Research Articles

Use of a 3D camera for automated patient positioning for chest-abdomen-pelvis CT scans: Effect on positioning accuracy and patient dose

Introduction3D positioning cameras that automate the positioning of patients with respect to the CT isocentre have been developed and are in common use in CT departments. This study aimed to compare the performance of radiographers and a 3D camera system with respect to positioning accuracy and the effect on patient radiation dose for chest-abdomen-pelvis scans. MethodsPatient positioning and dose data obtained from a dose management system was evaluated over a two-month period for patients positioned with (CAMon) and without (CAMoff) the positioning camera. Median vertical and lateral offset values were compared between the groups whilst doses were evaluated as a function of patient water equivalent diameter (WED) for the thorax and abdomen-pelvis acquisitions for both cohorts. ResultsRadiographers demonstrated high levels of positioning accuracy, however significant improvements in median vertical offset were identified for the CAMon cohort for both thorax (8 mm vs. 17 mm (p = 0.001)) and abdomen-pelvis (7 mm vs. 16 mm (p = 0.003)) scans. The percentage of patients positioned within 5 mm of the isocentre was 39.0% and 16.1% for the CAMon and CAMoff cohorts. For CAMoff scans, 77.4% of patients were positioned below the isocentre, but this was reduced to 45.8% for CAMon scans. No significant changes in dose as a function of WED were identified related to the camera use (thorax: p = 0.569, abdomen-pelvis: p = 0.760). ConclusionUse of a 3D camera delivered significant improvements in the accuracy and reproducibility of patient positioning when compared with radiographers. Implications for practiceImprovements in positioning accuracy were observed at the research site and hence positioning camera use has the potential to become standard practice in CT to help ensure appropriate doses are delivered to patients according to their size.

Evaluation of the Treatment Planning and Delivery for Hip Implant Cases on Tomotherapy.

The metal present in the implant creates artifacts during the treatment simulation, which impacts the treatment planning and delivery of the prescribed dose to the target and sparing normal tissues. This retrospective study evaluated the uncertainties in the planning and delivery of doses for prosthesis cases with dedicated phantom. In this retrospective study, 11 patients with a hip prosthesis having cervix carcinoma were selected. Two treatment plans were generated on treatment planning system (TPS) for each case. Plan_No_Res was without any beam restriction, and Plan_exit_only was the plan with restricted beam entry through the metallic implant. An indigenous phantom was utilized to verify the accuracy of the treatment. In the phantom, some groves were present, which could be filled by implants that mimic the patient's geometries, like left, right and bilateral femur implants. The delivered doses were recorded using optically stimulated luminescence dosimeters (OSLDs), which were placed at different positions in the phantom. The plans were further calculated using megavoltage computed tomography (MVCT) scans acquired during treatment. The patient data showed no significant dose changes between the two planning methods. The treatment time increases from 412.18 ± 86.65 to 427.36 ± 104.80 with P = 0.03 for Plan_No_Res and Plan_exit_only, respectively. The difference between planned and delivered doses of various points across phantom geometries was within ± 9.5% in each case as left, right, and bilateral implant. The variations between OSLDs and MVCT calculated doses were also within ± 10.8%. The study showed the competency of tomotherapy planning for hip prosthesis cases. The phantom measurements demonstrate the errors in dosimetry near the implant material, suggesting the need for precise methods to deal with artifact-related issues.

Do HDR Tandem and Ring Interfractional Displacements Predict the Need to Re-Plan?

<h3>Purpose/Objective(s)</h3> To evaluate the effect of changes in HDR tandem and ring applicator position on doses to nearby organs at risk. <h3>Materials/Methods</h3> CT imaging studies (29) and dosimetry of 6 women ages 44 to 86 undergoing tandem/ring based HDR for cervical cancer were used retrospectively. Measures of applicator positional changes (translation and rotation) relative to the pelvis were obtained using image fusion in a commercial image analysis software. Dosimetric data were calculated in the commercial image analysis software using the original (first fraction) dose distribution applied to organs at risk (rectum and bladder) via deformable registration of the original contours. The new contours were examined visually for appropriateness. Differences in translation and rotation between the planning CT and subsequent individual fractions were recorded and plotted against dose changes between each fraction of treatment and the original (first) fraction. Percent differences in positional shifts vs dosimetric changes were calculated and a correlation coefficient between dose parameters and measured positional shifts of the applicator was determined. <h3>Results</h3> Dosimetric parameters for rectum and bladder (D_2cc and V₅₀) calculated using a commercial treatment planning system for HDR brachytherapy and commercial image analysis software gave similar results within 1% of the original plan (Fraction 1 of 5). A summary of positional changes and average and maximum dose changes for each dosimetric endpoint is found in Table 1. Average percent difference between planned dose and fractional doses obtained through deformable registration were 12%, 16%, 4% and 49% for bladder D_2cc, Bladder V₅₀, Rectum D_2cc and Rectum D₅₀, respectively. Correlation between dose parameters and measured positional changes for bladder D₅₀ and displacement and bladder D₅₀ and sagittal plane rotation gave an r² of 0.3. Applicator displacement of approximately 1.6 times greater than average applicator displacement across all plans studied have shown a significant increase in bladder dose. Bladder dose increased by a maximum of 30 Gy and 54.5 Gy for bladder D_2cc and bladder V₅₀, respectively for the patient with the largest catheter shifts. <h3>Conclusion</h3> We have quantified the effects of applicator positional changes on dose differences for bladder and rectum. Even large changes did not result in significant changes in dose to organs at risk, meaning adaptive re-planning is not required in most cases below a certain displacement threshold.

Impact of intrafraction changes in delivered dose of the day for prostate cancer patients treated with stereotactic body radiotherapy via MR-Linac.

The purpose of this study is to evaluate the impact of intrafraction pelvic motion by comparing the adapted plan dose (APD) and the computed delivered dose of the day (DDOTD) for patients with prostate cancer (PCa) treated with SBRT on the MR-Linac. Twenty patients with PCa treated with MR-guided adaptive SBRT were included. A 9-field IMRT distribution was adapted based on the anatomy of the day to deliver a total prescription dose of 3000cGy in 5 fractions to the prostate plus a 5mm isotropic margin. Prostate, bladder, and rectum were re-contoured on the MR-image acquired during treatment delivery (MRBO). DDOTD was computed by propagating the dose from the daily adapted plan generated during treatment onto the MRBO. Target coverage was met for all fractions, however, computed DDOTD was significantly less than the APD (p<0.05). During an average treatment of 53min, mean bladder volume increased by 116%, which led to a significant decrease in the DDOTD bladder D40% (p<0.001). However, DDOTD to bladder 5cc was significantly higher (p<0.001) than APD. Rectum intrafraction changes were observed based on a volume change of -20% to 83% and presence of significant dose changes from APD to DDOTD for rectum D20% (p<0.05) and D1cc (p<0.0001). Intrafraction motion observed during prostate SBRT treatment on the MR-Linac have dosimetric impacts on both the target and organs at risk. Post-treatment computation using DDOTD may inform adaptation beyond anatomic changes in subsequent treatment fractions to best capitalize on MR-Linac technology and widen the therapeutic index of SBRT for PCa.

Effective radiation dose of skeletal surveys performed for suspected physical abuse.

A skeletal survey is an important diagnostic tool for patients presenting with suspected physical abuse. A relatively recent change in guidelines for skeletal surveys by the Royal College of Radiologists (RCR) in 2017 has led to more initial and follow-up images for these patients, which would be expected to have led to an increase in effective radiation dose. To estimate the effective dose following the change in guidelines and to ascertain the difference between doses before and after the change in guidelines. Data were collected retrospectively on children younger than 3years old referred for skeletal surveys for suspected physical abuse at a tertiary paediatric centre. A Monte Carlo radiation patient dose simulation software, PCXMC v 2.0.1, was used to estimate the effective dose, expressed in millisieverts (mSv). Sixty-eight children underwent skeletal surveys for suspected physical abuse. The total estimated effective dose for skeletal surveys with the previous RCR guidelines was found to be 0.19mSv. For initial skeletal surveys with the current RCR guidelines, the estimated effective radiation dose was 0.19mSv. Eighteen children had both initial and follow-up skeletal surveys as indicated by the current RCR guidelines, with an estimated effective total radiation dose of 0.26mSv. Skeletal surveys deliver a relatively low estimated effective radiation dose equivalent to 1month of United Kingdom background radiation, with no significant change in dose following the change in guidelines. Therefore, the benefits of having a skeletal survey outweigh the main radiation risk. However, accurate data regarding the radiation dose are important for clinicians consenting parents/guardians for imaging in suspected physical abuse.

A mask-compatible, radiolucent, 8-channel head and neck receive array for MRI-guided radiotherapy treatments and pre-treatment simulation

Immobilization masks are used to prevent patient movement during head and neck (H&N) radiotherapy. Motion restriction is beneficial both during treatment, as well as in the pre-treatment simulation phase, where magnetic resonance imaging (MRI) is often used for target definition. However, the shape and size of the immobilization masks hinder the use of regular, close-fitting MRI receive arrays. In this work, we developed a mask-compatible 8-channel H&N array that consists of a single-channel baseplate, on which the mask can be secured, and a flexible 7-channel anterior element that follows the shape of the mask. The latter uses high impedance coils to achieve its flexibility and radiolucency. A fully-functional prototype was manufactured, its radiolucency was characterized, and the gain in imaging performance with respect to current clinical setups was quantified. Dosimetry measurements showed an overall dose change of −0.3%. Small, local deviations were up to −2.7% but had no clinically significant impact on a full treatment plan, as gamma pass rates (3%/3 mm) only slightly reduced from 97.9% to 97.6% (clinical acceptance criterion: ≥95%). The proposed H&N array improved the imaging performance with respect to three clinical setups. The H&N array more than doubled (+123%) and tripled (+246%) the signal-to-noise ratio with respect to the clinical MRI-simulation and MR-linac setups, respectively. G-factors were also lower with the proposed H&N array. The improved imaging performance resulted in a clearly visible signal-to-noise ratio improvement of clinically used TSE and DWI acquisitions. In conclusion, the 8-channel H&N array improves the imaging performance of MRI-simulation and MR-linac acquisitions, while dosimetry suggests that no clinically significant dose changes are induced.

Abstract CT211: Personalized, rational, efficacy-driven chemotherapy dosing via an artificial intelligence system (PRECISE): A protocol for the PRECISE CURATE.AI pilot clinical trial

Abstract Background: Faced with a trade-off between efficacy and toxicity, oncologists have conventionally administered the maximum tolerated doses in chemotherapy on an assumption that higher doses increase efficacy. However, multiple studies have shown that this method of toxicity-guided dosing may result in more frequent toxicities and potentially suboptimal efficacy. With the advent of artificial intelligence (AI), personalized dosing in chemotherapy may be considered to optimize patient care. CURATE.AI is an efficacy-driven, indication-agnostic and mechanism-independent personalized dosing platform that may offer an optimal solution. In contrast to traditional AI approaches based on massive volumes of population data, CURATE.AI requires only the individual patient's medical profile for dose recommendations. Based on the observation that the relationship between a drug dose and a phenotypic response in a human system can be modelled by a dynamic quadratic surface, CURATE.AI continually guides dosing throughout the treatment duration to optimize efficacy. While CURATE.AI has been used in various clinical settings, there are no prior randomized controlled trials (RCTs) on CURATE.AI-guided chemotherapy dosing for solid tumors. Therefore, we are conducting a pilot study to assess the technical and logistical feasibility of an RCT for CURATE.AI-guided solid tumor chemotherapy dosing. We aim to collect exploratory data on efficacy and toxicity, and on the use of longitudinal blood tumor marker measurements, including ctDNA, to inform dose guidance decision. Methods: PRECISE is an open-label, single-arm, multi-centre, prospective pilot clinical trial on using CURATE.AI to achieve personalized, efficacy-driven and dynamically optimized chemotherapy dosing for solid tumors (NCT04522284). Adults with metastatic solid tumors and raised baseline tumor marker levels who are planned for palliative-intent, capecitabine-based chemotherapy will be recruited. CURATE.AI will guide drug dosing for each participant based only on their own tumor marker levels and drug doses as input data. The primary outcome is the proportion of participants in whom CURATE.AI is successfully applied. Secondary outcomes include the timeliness of dose recommendations, participant and physician adherence to CURATE.AI-recommended doses, and the proportion of clinically significant dose changes. As an exploratory outcome, we will analyze the utility of tumor markers including CEA, CA19-9 and ctDNA in high frequency serial measurements. We aim to initially enroll 10 participants from 2 hospitals in Singapore, perform an interim analysis, and consider either cohort expansion or a RCT based on initial pilot data. Recruitment of patients began in August 2020. As of December 2020, 2 participants have been enrolled with recruitment planned for 1 year. Citation Format: Chong Boon Teo, Benjamin Kye Jyn Tan, Xavier Tadeo, Siyu Peng, Hazel Pei Lin Soh, Sherry De Xuan Du, Vilianty Wen Ya Luo, Aishwarya Bandla, Raghav Sundar, Dean Ho, Theodore Kee, Agata Blasiak. Personalized, rational, efficacy-driven chemotherapy dosing via an artificial intelligence system (PRECISE): A protocol for the PRECISE CURATE.AI pilot clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT211.

A first radiotherapy application of functional bulboclitoris anatomy, a novel female sexual organ-at-risk, and organ-sparing feasibility study.

The bulboclitoris (clitoris and vestibular bulbs) is the primary organ responsible for female sexual arousal and orgasm. Effects of radiotherapy on the bulboclitoris are unknown, as its structure/function has yet to be described in radiotherapy, and it overlaps only partially with the external genitalia structure. Our aim was to: describe bulboclitoris structure, function and delineation; compare volume of and dose delivered to the bulboclitoris vs external genitalia; and, compare bulboclitoris-sparing IMRT (BCS-IMRT) to standard IMRT (S-IMRT) to determine reoptimization feasibility. Our expert team (anatomist, pelvic radiologist, radiation oncologist) reviewed bulboclitoris anatomy and developed contouring guidance for radiotherapy. 20 female patients with anal cancer treated with chemoradiation were analyzed. Sexual organs at risk (OARs) included the external genitalia and the bulboclitoris. Volumes, dice similarity coefficients (DSCs) and dose received using S-IMRT were compared. Plans were reoptimized using BCS-IMRT. Dose-volume histograms (DVHs) for PTVs and all OARs were compared for BCS-IMRT vs S-IMRT. Bulboclitoris structure, function and delineation are described herein. The bulboclitoris occupies 20cc (IQR:12-24), largely distinct from the external genitalia (DSC <0.05). BCS-IMRT was superior to S-IMRT in reducing the dose to the bulboclitoris, with the greatest reductions in V30 and V40, with no significant changes in dose to other OARs or PTV 1/V95. The bulboclitoris can be contoured on planning imaging, largely distinct from the external genitalia. Compared with S-IMRT, BCS-IMRT dramatically reduced dose to the bulboclitoris in anal cancer planning. BCS-IMRT might safely reduce sexual toxicity compared with standard approaches. The structure and function of the bulboclitoris, the critical primary organ responsible for female sexual arousal and orgasm, has yet to be described in the radiotherapy literature. Structure, function and delineation of the bulboclitoris are detailed, delineation and bulboclitoris-sparing IMRT were feasible, and sparing reduces the dose to the bulboclitoris nearly in half in female patients receiving IMRT for anal cancer, warranting further clinical study.

Personalised, Rational, Efficacy-Driven Cancer Drug Dosing via an Artificial Intelligence SystEm (PRECISE): A Protocol for the PRECISE CURATE.AI Pilot Clinical Trial.

Introduction: Oncologists have traditionally administered the maximum tolerated doses of drugs in chemotherapy. However, these toxicity-guided doses may lead to suboptimal efficacy. CURATE.AI is an indication-agnostic, mechanism-independent and efficacy-driven personalised dosing platform that may offer a more optimal solution. While CURATE.AI has already been applied in a variety of clinical settings, there are no prior randomised controlled trials (RCTs) on CURATE.AI-guided chemotherapy dosing for solid tumours. Therefore, we aim to assess the technical and logistical feasibility of a future RCT for CURATE.AI-guided solid tumour chemotherapy dosing. We will also collect exploratory data on efficacy and toxicity, which will inform RCT power calculations.Methods and analysis: This is an open-label, single-arm, two-centre, prospective pilot clinical trial, recruiting adults with metastatic solid tumours and raised baseline tumour marker levels who are planned for palliative-intent, capecitabine-based chemotherapy. As CURATE.AI is a small data platform, it will guide drug dosing for each participant based only on their own tumour marker levels and drug doses as input data. The primary outcome is the proportion of participants in whom CURATE.AI is successfully applied to provide efficacy-driven personalised dosing, as judged based on predefined considerations. Secondary outcomes include the timeliness of dose recommendations, participant and physician adherence to CURATE.AI-recommended doses, and the proportion of clinically significant dose changes. We aim to initially enrol 10 participants from two hospitals in Singapore, perform an interim analysis, and consider either cohort expansion or an RCT. Recruitment began in August 2020. This pilot clinical trial will provide key data for a future RCT of CURATE.AI-guided personalised dosing for precision oncology.Ethics and dissemination: The National Healthcare Group (NHG) Domain Specific Review Board has granted ethical approval for this study (DSRB 2020/00334). We will distribute our findings at scientific conferences and publish them in peer-reviewed journals.Trial registration number: NCT04522284

Comparison of the Dosimetric Influence of Applicator Displacement on 2D and 3D Brachytherapy for Cervical Cancer Treatment

To compare the dosimetric influence of applicator displacement on two-dimensional brachytherapy (2D-BT) and three-dimensional brachytherapy (3D-BT) for cervical cancer. Nineteen patients who received computed tomography-guided tandem-and-ovoid (T&O) brachytherapy were retrospectively selected. Both 2D (point-based) and 3D (volume-based) plans with and without virtual applicator displacement in the 3 axes were created for each patient. Dose changes at point A, D90 of the high-risk clinical target volume (HR-CTV) and intermediate-risk CTV (IR-CTV), and the D0.1cc, D1cc, D2cc, and D5cc of organs-at-risk (OARs) caused by applicator displacement were evaluated. Both 2D-BT and 3D-BT plans were sensitive to T&O applicator displacement. The D90 of the CTV and the dose at point A were very sensitive to applicator displacement in the right–left direction (X-axis). An applicator shift of >2 mm in the X-axis resulted in a change of >5% in the dose at point A and D90 of HR-CTV and IR-CTV. In addition, the doses to the OARs were mostly affected by applicator displacement in the anterior–posterior direction (Z-axis). A displacement of <1.5 mm in the Z-axis was required to avoid a dose change of >10% for OARs. For both 2D-BT and 3D-BT plans, T&O displacement greater than ± 2 mm in the X-axis or T&O applicator displacement ± 1.5 mm in the Z-axis resulted in significant dose changes to the tumor and OARs. In comparison with 3D-BT plans, 2D-BT plans delivered a higher dose to the tumor, and the OARs received more undesirable doses when applicator displacement occurred. The influence of applicator displacement on the doses to the tumor and OARs differed between 2D-BT and 3D-BT. Physicians should take individual patient differences into account when selecting a brachytherapy plan to mitigate the influence of applicator displacement.

Utilization of PCSK-9 Inhibitors in Statin Intolerant Cardiac Transplant Patients

Background HMG CoA Reductase Inhibitors, commonly referred to as statins, are widely used in heart transplant patients as dyslipidemia is common after cardiac transplantation and increases the risk of cardiovascular adverse events including cardiac allograft vasculopathy (CAV). However, not all patients can tolerate statins or see an adequate lowering of the low density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors have been shown to be effective at lowering LDL with great tolerance and excellent safety profiles in the general population. Yet, there is limited data regarding effect of PCSK9 inhibitors in heart transplant patients. Objective To study the effect of PSCK-9 inhibitors in post-cardiac transplant patients. Method We reviewed post heart transplant patients who received PCSK9 inhibitors at our University Medical Center from 2017 to March 2020. We found four patients who were eligible. Results The mean age of the four patients was 65.75± 4.7 years (3 Females). Indication for PCSK9 inhibitors in three patients was statin intolerance due to myopathy; the fourth patient had familial hypercholesterolemia that required more aggressive therapy. Average time for initiation of the medication since heart transplant was 10.25 years. The average duration of treatment was 18.25 months. Two patients were on Evolocumab 140mg subcutaneously once every 2 weeks, and the other two were on Alirocumab 75mg every 2 weeks. All four patients continued the medicine with no side effects. Mean LDL-C prior to initiation of the drug was 125.75± 24.42 mg/dL. At 8-12 week follow up there was significant reduction in the LDL 35.75 ±13.74mg/dL (p=0.006).There was no significant dose changes to the immunosuppressive medications. None of the four patients experienced rejection of the transplanted heart. Only one patient with familial hypercholesterolemia had mild CAV on heart catheterization prior to initiation of the drug and there was no progression of the CAV at one year follow up. Conclusion PCSK9-inhibitors were effective in reducing low-density lipoprotein levels in post-cardiac transplant patients and were well tolerated without any rejection or modifications to the transplant medications in this small cohort of patients. The study findings are promising and highlight the need for larger, prospective, multicenter studies.

Relationships Between Opioid Dosing, Pain Severity, and Disability in a Community-Based Chronic Pain Population: An Exploratory Retrospective Analysis

To determine the relationship between opioid dose change, pain severity, and function in patients with chronic pain. Retrospective cohort study. Community interdisciplinary pain management practice. A total of 778 patients with chronic pain prescribed opioids for three or more consecutive months between April 1, 2013, and March 1, 2015. Changes in opioid dose, pain severity rating, modified Roland Morris Disability Questionnaire score, and opioid risk data were extracted from medical records and analyzed for associations. Two hundred forty-three subjects (31.2%) had an overall dose decrease, 223 (28.7%) had a dose increase, and 312 (40.1%) had no significant change in dose (<20% change). There was a weak negative correlation between change in opioid dose and change in pain severity (r = -0.08, P = 0.04) but no association between change in disability scores and dose change (N = 526, P = 0.13). There was a weak positive correlation between change in pain severity rating and change in disability scores (r = 0.16, P < 0.001). The results suggest that escalating opioid doses may not necessarily result in clinically significant improvement of pain or disability. Similarly, significant opioid dose reductions may not necessarily result in worsened pain or disability. This exploratory investigation raised questions of possible subgroups of patients who might demonstrate improvement of pain and disability with opioid dose adjustments, and further research should prospectively explore this potential, given the limitations inherent in retrospective analyses. Prescribers should still consider reduction of opioid doses as recommended by current guidelines, in an effort to mitigate the potential risks associated with high-dose treatment.

Use of high and very high dose radiotherapy after radical prostatectomy for prostate cancer in the United States

BackgroundThe cost-benefit tradeoff of radiation dose-intensification for prostate cancer in the post-prostatectomy setting is difficult to predict and is ideally studied in randomized trials. The purpose of this study was to assess the use of dose-escalated post-operative radiation (PORT) for prostate cancer in the United States, during a period in which there were no published level 1 studies on dose-escalation.MethodsWe performed analyses on pT2-3, N0, M0 prostate cancer patients who received PORT after an R0-1 resection within the National Cancer Data Base (NCDB), 2003–2012. We classified patients according to the use of high dose (>66.60 cGy) and very high dose (>70.20 cGy) radiation. We used regression analysis to assess the association of year of treatment with use of high and very high dose PORT. To demonstrate the potential of a registry-based network like the NCDB to prospectively monitor changes in radiation dosing patterns, we determined the year in which a significant change in dose could have been first detected had dose been actively monitored.ResultsBetween 2003 and 2012, the use of high dose PORT increased from 29.9% CI (26.7–33.1) to 63.5% CI (60.6–66.5) and very high dose PORT from 4.5% CI (3.1–5.9) to 10.8% CI (8.9–12.6) (adjusted p < 0.01, for both trends). Patients diagnosed at community centers were less likely to be treated with high dose PORT compared to those at academic or comprehensive centers (p < 0.01 for both comparisons). Had the NCDB network been prospectively monitoring PORT dose, significant increases in dose would have been detected as early as 2004 and after every year of the study period.ConclusionsThe use of both high dose and very high dose PORT increased two-fold from 2003 to 2012 in the absence of randomized studies. This change in practice may be exposing patients to excess toxicity without cancer control benefits. Monitoring dosing patterns using cancer registries is feasible.

Cumulative dose of radiation therapy of hepatocellular carcinoma patients and its deterministic relation to radiation-induced liver disease

This study aimed to investigate the relationship between dose and radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) receiving 3-dimensional conformal radiotherapy (3DCRT). Twenty-three patients with HCC who received conventional fractionated 3DCRT, including 7 who were diagnosed with classic RILD, were enrolled in this retrospective investigation. Cone-beam computed tomography (CBCT) scans were acquired at the time of treatment for each patient. The beams from each patient's treatment plan were applied to each pretreatment CBCT (the modified CBCT or mCBCT) to construct the delivered dose distribution of the day considering inter-treatment anatomy changes. The daily doses were summed together with the help of deformable image registration (DIR) to obtain the adjusted cumulative dose (Dadjusted). The dose changes to the normal liver between the original planned dose (Dplan) and Dadjusted were evaluated by V20, V30, V40, and the mean dose to normal liver (MDTNL). Univariate analysis was performed to identify the significant dose changes. Among the 23 patients, the liver V20, V30, V40, and MDTNL showed significant differences between Dplan and Dadjusted, with average values of these parameters increased by 4.1%, 4.7%, 4.5%, and 3.9 Gy, respectively (p < 0.05). The adjusted liver dose in 21 patients (91%) was higher than the planned value. For patients without and with RILD,the MDTNL was increased on average by 3.5 Gy and 4.7 Gy, and normal tissue complication probability (NTCP) increased on average by 2.8% and 7.5%, respectively. Our study found that the adjusted cumulative dose based on calculations using pretreatment mCBCT differs significantly from planned dose; the use of the dosimetric results of the initial plan was found to be less predictive of RILD as compared with Dadjusted. Determination of a reconstructed Dadjusted using the mCBCT scans are more accurate in predicting RILD and has the potential to reduce the risk of RILD.

Longitudinal Pharmacokinetics of Everolimus When Combined With Low-level of Tacrolimus in Elderly Renal Transplant Recipients.

Although the proportion of elderly patients among renal transplant recipients has increased, pharmacokinetic (PK) studies of immunosuppressants rarely include older patients. We studied 12-hour everolimus (EVL) PK in 16 elderly renal transplant recipients (all whites; 10 men; mean age, 64 ± 2 years (61-71 years), in 4 separate timepoints (at 7, 30, 60, and 150 days) after EVL introduction, corresponding to a mean postrenal transplantation day: PK1 (43 ± 4 days), PK2 (65 ± 7 days), PK3 (106 ± 17 days), and PK4 (206 ± 40 days). Patients received EVL (target trough level (Ctrough, 3-8 ng/mL), prednisone, and tacrolimus (TCL) (target Ctrough, 2-5 ng/mL). Mean TCL-Ctrough was 7.2 ± 3.8, 4.9 ± 2.2, 4.9 ± 2.2, and 4.5 ± 1.2 ng/mL at PK1, PK2, PK3, and PK4, respectively. There were no differences among timepoints for mean EVL daily dose (data shown as PK3) (3.5 ± 1.3 mg/d), Ctrough (4.7 ± 2.5 ng/mL), AUC0-12h (106 ± 51 ng/h per mL), Caverage (8.8 ± 4.2 ng/mL), Cmax (19.2 ± 9.7 ng/mL), apparent Half-life (11.7 ± 4.2 hours), estimated total body clearance (0.39 ± 0.27 L/h), or fluctuation (166 ± 65%). Also, none of those PK parameters differed statistically when adjusted for body weight. EVL-Ctrough showed a very high correlation (r = 0.849) with AUC0-12h. Our data indicate that elderly renal transplant recipients starting EVL 1 month after transplantation along with a steady-state TCL level, present stable EVL-PK parameters without significant changes in dose or exposure during the first 6 months after renal transplantation.

Dosimetric impact of intrafraction changes in MR-guided high-dose-rate (HDR) brachytherapy for prostate cancer

PurposeTo assess changes in implant and treatment volumes through the course of a prostate high-dose-rate brachytherapy procedure and their impact on plan quality metrics. Methods and MaterialsSixteen MRI-guided high-dose-rate procedures included a post-treatment MR (ptMR) immediately after treatment delivery (135 min between MR scans). Target and organs at risk (OARs) were contoured, and catheters were reconstructed. The delivered treatment plan was applied to the ptMR image set. Volumes and dosimetric parameters in the ptMR were evaluated and compared with the delivered plan using a paired two-tailed t-test with p < 0.05 considered statistically significant. ResultsAn average increase of 8.9% in prostate volume was observed for whole-gland treatments, resulting in reduction in coverage for both prostate and planning target volume, reflected in decreased V100 (mean 3.3% and 4.6%, respectively, p < 0.05), and D90 (mean 7.1% and 7.6%, respectively, of prescription dose, p < 0.05). There was no significant change in doses to OARs. For partial-gland treatments, there was an increase in planning target volume (9.1%), resulting in reduced coverage and D90 (mean 3.6% and 12.4%, respectively, p < 0.05). A decrease in D0.5cc for bladder (3%, p < 0.05) was observed, with no significant changes in dose to other OARs. ConclusionsVolumetric changes were observed during the time between planning MR and ptMR. Nonetheless, treatment plans for both whole- and partial-gland therapies remained clinically acceptable. These results apply to clinical settings in which patients remain in the same position and under anesthesia during the entire treatment process.

Impact of safety warnings on domperidone prescribing in Ireland.

This study aimed to investigate the impact of the 2014 safety warnings on use of domperidone, on subsequent prescribing patterns in Ireland. The Irish HSE-PCRS pharmacy claims database was used to identify the study cohort (aged 18+), prescribed domperidone from Jan 2014 to Oct 2015. Dosage was available for each claim; concomitant prescription with the following drug classes was identified and calculated as a percentage of the total number of claims: anti-arrhythmics, macrolide antimicrobials and the selective serotonin receptor inhibitors (SSRIs) citalopram and escitalopram. Segmented regression analysis was used to examine the changes in prescribing before and after the issue of safety warnings in May 2014. A total of 397,572 claims for domperidone were identified from Jan 2014 to Oct 2015. Overall, there was a significant decline in numbers receiving domperidone during the study period (from 22,226 to 15,691 claims, p=0.012), with no significant change over time. In addition, no significant change in co-prescribed SSRIs or anti-arrhythmic agents was observed over time; co-prescribed macrolide antimicrobials significantly increased after the safety advisory compared to trends before (p=0.031). In those aged 60+years, 10% of claims (n=1332) were for doses >30mg/day at the start of the study with no significant change in dose after the May advisory. Safety warnings concerning domperidone appeared to have had little effect on prescribing patterns in Ireland. Of concern is the continuing co-prescription with drugs known to increase the risk of QT prolongation, in all ages, including the 60+ year age group.

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

Survey of EKG Monitoring Practices: A Necessity or Prolonged Nuisance?

The use of dose-escalated radiation for locally advanced non-small cell lung cancer in the U.S., 2004\u20132013

Purpose/ObjectivesThe clinical effects of radiation dose-intensification in locally advanced non-small cell lung (NSCLCa) and other cancers are challenging to predict and are ideally studied in randomized trials. The purpose of this study was to assess the use of dose-escalated radiation for locally advanced NSCLCa in the U.S., 2004–2013, a period in which there were no published level 1 studies on dose-escalation.Materials/MethodsWe performed analyses on two cancer registry databases with complementary strengths and weaknesses: the National Oncology Data Alliance (NODA) 2004–2013 and the National Cancer Database (NCDB) 2004–2012. We classified locally advanced patients according to the use of dose-escalation (>70 Gy). We used adjusted logistic regression to assess the association of year of treatment with dose-escalated radiation use in two periods representing time before and after the closure of a cooperative group trial (RTOG 0617) on dose-escalation: 2004–2010 and 2010–2013. To determine the year in which a significant change in dose could have been detected had dose been prospectively monitored within the NODA network, we compared the average annual radiation dose per year with the forecasted dose (average of the prior 3 years) adjusted for patient age and comorbidities.ResultsWithin both the NODA and NCDB, use of dose-escalation increased from 2004 to 2010 (p < 0.0001) and decreased from 2010 to 2013 (p = 0.0018), even after controlling for potential confounders. Had the NODA network been monitoring radiation dose in this cohort, significant changes in average annual dose would have been detected at the end of 2008 and 2012.ConclusionsPatterns of radiation dosing in locally advanced NSCLCa changed in the U.S. in the absence of level 1 evidence. Monitoring radiation dose is feasible using an existing national cancer registry data collection infrastructure.

Individualized Dosing of Hydroxyurea for Children with Sickle Cell Anemia Using a Population Pharmacokinetic-Based Model: The TREAT Study

Background: Hydroxyurea is the primary disease modifying therapy for patients with sickle cell anemia (SCA). The clinical and laboratory benefits of hydroxyurea are the greatest when escalated to the maximum tolerated dose (MTD). The process of dose escalation to MTD requires expertise and can be tedious, often taking 6-12 months to titrate to the optimal dose. In addition, due in part to inter-patient variability in hydroxyurea pharmacokinetics (PK), the MTD varies among patients with a range of 15-35 mg/kg/day. We utilized a population PK model in combination with Bayesian estimation and a sparse sampling strategy, to individualize dosing of children starting hydroxyurea treatment.Methods: The Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154) is a prospective study of hydroxyurea for children with SCA. The primary objective is to develop and evaluate a population PK-based model to predict hydroxyurea MTD through an individualized dosing strategy. A sparse sampling approach was developed to allow practical sampling from young children with SCA. The sampling strategy includes administering a single oral 20 mg/kg dose followed by collection of small quantities of blood (~100uL) at three post-dosing time points (15-20 minutes, 50-60 minutes, and ~3 hours). Baseline labs (including liver and renal function) are typically collected by venipuncture, while the other two samples are drawn by fingerstick or heelstick. Plasma hydroxyurea concentrations are measured using HPLC using an internal standard of methylurea. Using the population PK model with Bayesian estimation and hydroxyurea concentrations measured at the three specified time points, hydroxyurea exposure is estimated using specialized therapeutic drug monitoring software (MWPharm, Mediware, Prague, Czech Republic). Using the area under the curve (AUC0-inf) estimated by the model, we calculate a starting dose that is predicted to achieve an AUC of 115 ug*h/mL, which was the mean AUC value at MTD for a large cohort of children from a previous study (Dong M et al. Br J Clin Pharmacol 2016). The primary objective is to select a starting dose that is close to actual MTD, to reduce the time to maximum therapeutic effect and need for dose modifications before achieving MTD.Results: From December 2014 through June 2016, 20 children taking taking hydroxyurea for the first time were enrolled in TREAT. Seventeen of the 20 participants had all 3 post-treatment PK samples collected and processed to allow calculation of an individualized PK-based dose, while 3 had difficulties in sampling or processing that prevented a safe PK-guided dose recommendation. These 3 participants were started at the standard hydroxyurea dose of 20 mg/kg/day. The Table summarizes baseline characteristics for the initial study population, notable for a very young starting age with 13/20 (65%) less than two years of age.Twelve children with PK-based initial dosing have been treated with hydroxyurea for at least six months. Despite the young starting age, after six months of hydroxyurea, children have documented increases in total Hb (1.4+/-1.9 g/dL), HbF (11.3+/-6.4%), and MCV (15+/-8 fL) and decreases in absolute reticulocyte count (-217+/-128 x 109/L) and absolute neutrophil count (-1.0+/-1.9 x 109/L). In 9 of 12 participants, the PK-guided initial dose remained the best clinical dose at six months without significant dose changes except for minor adjustments for weight. Two patients required a single dose escalation due to inadequate marrow suppression, while one required a dose hold and decrease due to neutropenia during and following a viral infection.Conclusions: These data demonstrate that a sparse sampling approach, requiring only 3 blood samples over 3 hours, is able to accurately estimate hydroxyurea exposure in children with SCA. Hydroxyurea exposure, as defined by AUC, was similar with this sparse sampling approach as previous studies that relied upon a more standard and prolonged PK sampling approach. This population PK model is then able to predict a safe starting dose of hydroxyurea that approximates the actual MTD, with clinically significant improvements in laboratory parameters following six months of therapy. This individualized PK-guided dosing regimen should simplify hydroxyurea dosing and reduce the time interval to reach MTD and maximal clinical benefits. [Display omitted] DisclosuresKalfa:Baxter/Baxalta/Shire: Research Funding. Quinn:Silver Lake Research Corporation: Consultancy; Amgen: Research Funding; Eli Lilly: Research Funding. Ware:Nova Laboratories: Consultancy; Addmedica: Research Funding; Global Blood Therapeutics: Consultancy; Bayer Pharmaceuticals: Consultancy; Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding.