Liver Dose Research Articles

The feasibility of transcatheter arterial chemoembolization following radiation therapy for hepatocellular carcinoma.

BackgroundTechnological developments have led to an increased usage of external-body radiotherapy (RT) for the treatment of hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) may be required later in patients treated with RT because of the high recurrence rate and multinodular presentation of HCC. However, despite the risk of liver function impairment, the cumulative liver damage correlated with TACE following a hepatic RT has not been adequately assessed.PurposeTo evaluate the feasibility of TACE following RT for HCC.Materials and methodsSixty-seven patients with HCC who underwent TACE after RT were retrospectively evaluated between 2012 and 2018. We assessed increases in Child–Turcotte–Pugh (CTP) by ≥2 points at 1 month, the incidence of major complications, survival duration, and short-term mortality within 6 months after TACE. Furthermore, we evaluated the predictive factors for liver function impairment and short-term mortality.ResultsEight patients experienced a CTP increase ≥2 points at 1 month. There were no cases of liver abscesses or bilomas. Nine patients died within 6 months following TACE. The mean liver dose (MLD) was a significant predictor of liver function impairment at 1 month (p = 0.042). Low liver functional reserve, distant metastasis (p = 0.037), MLD (p = 0.046), TACE type (p = 0.025), and TACE within 3 months following RT (p = 0.007) were significant predictors of short-term mortality.ConclusionsDespite the feasibility of TACE following RT, clinicians should pay attention to impaired pretreatment liver function, following high dose RT, and the short duration between RT and TACE.

Impact of adjuvant radiotherapy on biological and clinical parameters in right-sided breast cancer

PurposeIn patients with right-sided breast cancer (BC) the liver might be partially irradiated during adjuvant radiotherapy (RT). Thus, we performed a prospective observational study to evaluate the dose delivered to the liver, and its potential biological impact. Patients and methodsWe enrolled 34 patients with right-sided BC treated with adjuvant RT. The RT schedules were either the Canadian (42.5Gy in 16 fx) or standard fractionated (50Gy in 25 fx) regimen respectively with 9 (26.5%) and 25 (73.5%) patients each, ± a boost of 10–16Gy. Each patient had a complete blood count and liver enzymes analysis, before starting and during the last week of treatment. ResultsA significant decrease in white blood cells and thrombocytes counts was observed during RT. We observed a significant correlation between certain hepatic parameters and the volume of the irradiated liver and/or the mean liver dose. A significant correlation between the volume of the right lung and the liver mean dose was found (P=0.008). In the bivariate analysis, a significant correlation between fatigue and the white blood cell count's evolution was observed (P<0.025). ConclusionWith the standard RT technique, incidental irradiation of the liver was documented in a large number of patients, and some significant hepatic parameters alterations were observed, without an apparent clinical impact, but this study cannot exclude them. The liver mean dose was correlated with the right lung volume suggesting that deep inspiration breath hold (DIBH) techniques may represent a way to decrease the liver dose. These findings need to be evaluated in further larger studies.

Comparable Efficacy of Reduced Dose Radiation Therapy for the Treatment of Early Stage Gastric Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue

PurposeThis study compares reduced (<27 Gy) to standard dose (≥30 Gy) radiation therapy (RT) in the treatment of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (gMALT lymphoma). Methods and MaterialsForty-two patients with stage I or II disease were retrospectively reviewed. Response to RT was assessed with endoscopy after RT. Complete response rate (CR), freedom from treatment failure, and overall survival (OS) were calculated. ResultsAll patients were stage I (n = 40) or II (n = 2). All patients had residual biopsy proven gMALT lymphoma before RT. Twenty-six patients (61.9%) were treated with standard dose RT, 30 to 36 Gy, and 16 (38.1%) with the reduced dose RT, 23.5 to 27 Gy. The median follow-up was 29.5 months (range, 6-85). Thirty-six patients (86%) achieved complete response (CR), and 6 patients (14%) achieved partial response (PR). The complete response rate (CR) at the first endoscopic assessment, median time of 3 months, was 81% (95% confidence interval, 0.61%-0.93%) for standard RT, and 94% (confidence interval, 0.69%-0.99%) for reduced RT. Among CR patients, one patient had locally relapsed disease at 50 months. The 1-year overall survival (OS) was 100% in both groups. The 1-year freedom from treatment failure (FFTF) was 100% in the reduced RT group and 92% in the standard RT group. The 2-year FFTF and OS of the whole cohort were 92% and 96%, respectively. There was no significant difference in the OS, FFTF, and CR between the 2 treatment groups (P = .38, P = .18, and P = .267, respectively). For toxicity, the mean liver dose and the mean V20 heart dose were significantly lower in the reduced RT group (P <.001 and P = .001, respectively). However, incidence and severity of reported toxicities were similar between the 2 groups. ConclusionsReduced dose RT (23.5-27 Gy) achieved excellent complete response rates with minimal toxicity, comparable with standard dose RT (30-36 Gy), for gMALT.

Validation of dose distribution for liver tumors treated with real-time-image gated spot-scanning proton therapy by log data based dose reconstruction.

In spot scanning proton therapy (SSPT), the spot position relative to the target may fluctuate through tumor motion even when gating the radiation by utilizing a fiducial marker. We have established a procedure that evaluates the delivered dose distribution by utilizing log data on tumor motion and spot information. The purpose of this study is to show the reliability of the dose distributions for liver tumors treated with real-time-image gated SSPT (RGPT). In the evaluation procedure, the delivered spot information and the marker position are synchronized on the basis of log data on the timing of the spot irradiation and fluoroscopic X-ray irradiation. Then a treatment planning system reconstructs the delivered dose distribution. Dose distributions accumulated for all fractions were reconstructed for eight liver cases. The log data were acquired in all 168 fractions for all eight cases. The evaluation was performed for the values of maximum dose, minimum dose, D99, and D5–D95 for the clinical target volumes (CTVs) and mean liver dose (MLD) scaled by the prescribed dose. These dosimetric parameters were statistically compared between the planned dose distribution and the reconstructed dose distribution. The mean difference of the maximum dose was 1.3% (95% confidence interval [CI]: 0.6%—2.1%). Regarding the minimum dose, the mean difference was 0.1% (95% CI: −0.5%—0.7%). The mean differences of D99, D5–D95 and MLD were below 1%. The reliability of dose distributions for liver tumors treated with RGPT-SSPT was shown by the evaluation of the accumulated dose distributions.

Assessment of the confidence interval in the multivariable normal tissue complication probability model for predicting radiation-induced liver disease in primary liver cancer.

We developed a confidence interval-(CI) assessing model in multivariable normal tissue complication probability (NTCP) modeling for predicting radiation-induced liver disease (RILD) in primary liver cancer patients using clinical and dosimetric data. Both the mean NTCP and difference in the mean NTCP (ΔNTCP) between two treatment plans of different radiotherapy modalities were further evaluated and their CIs were assessed. Clinical data were retrospectively reviewed in 322 patients with hepatocellular carcinoma (n = 215) and intrahepatic cholangiocarcinoma (n = 107) treated with photon therapy. Dose–volume histograms of normal liver were reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose. The most predictive variables were used to build the model based on multivariable logistic regression analysis with bootstrapping. Internal validation was performed using the cross-validation leave-one-out method. Both the mean NTCP and the mean ΔNTCP with 95% CIs were calculated from computationally generated multivariate random sets of NTCP model parameters using variance–covariance matrix information. RILD occurred in 108/322 patients (33.5%). The NTCP model with three clinical and one dosimetric parameter (tumor type, Child–Pugh class, hepatitis infection status and MLD) was most predictive, with an area under the receiver operative characteristics curve (AUC) of 0.79 (95% CI 0.74–0.84). In eight clinical subgroups based on the three clinical parameters, both the mean NTCP and the mean ΔNTCP with 95% CIs were able to be estimated computationally. The multivariable NTCP model with the assessment of 95% CIs has potential to improve the reliability of the NTCP model-based approach to select the appropriate radiotherapy modality for each patient.

An estimate of 90Y dosimetry for bremsstrahlung SPECT/CT imaging in liver therapy with 90Y microspheres

ObjectiveBremsstrahlung SPECT/CT (bSPECT/CT) is one of the most common methods for post-therapy imaging in 90Y microspheres selective internal radiation therapy (SIRT) of liver cancers. Here, we are proposing a simple approach using bSPECT/CT to estimate mean absorbed dose to the liver in patients undergoing treatment with 90Y microspheres. Materials and methodsIn our previous study comparing 90Y dosimetry obtained using bSPECT/CT vs PET/CT, we found that there was a large difference between the mean absorbed dose values to the whole-liver. However, there was a high linear correlation between the doses, which presented an opportunity for quantitative assessment using bSPECT/CT 90Y imaging. In this study, after treatment with 90Y microspheres, 43 patients were immediately imaged on a dual-head Infinia SPECT/CT gamma camera and on a mCT PET/CT system. Images from 25 of the patients, randomly selected, were used to calculate the correlation of mean liver doses obtained from bSPECT/CT vs. PET/CT. For the remaining 18 patients, the calculated correlation was used to estimate doses obtained from bSPECT/CT, and these estimations were then compared to the doses obtained from PET/CT, considered the gold standard for quantitative analysis. ResultsFrom the 25 selected patients, the calculated linear correlation between bSPECT/CT and PET/CT 90Y mean absorbed doses in whole liver was high (r^2 = 0.97), with a slope of 2.80 and an intercept of -0.63. This linear fit was used to calculate the bSPECT/CT doses for the remaining 18 patients. For these patients, the mean whole-liver dose obtained from bSPECT/CT fitted data vs that obtained from PET/CT were 50.59 Gy and 50.81 Gy, respectively. The average dose difference was 0.2 ± 5.4 Gy (range −18.2%–13.0%). The repeatability coefficient was 10.5 (20.8 % of the mean). ConclusionAlthough quantitative bremsstrahlung imaging is difficult, it is possible to calculate adequate estimates of whole-liver dosimetry from bSPECT/CT imaging that is calibrated using its correlation with post-therapy PET/CT 90Y images.

Hepatic Arterial Buffer Response in Liver Radioembolization and Potential Use for Improved Cancer Therapy.

Simple SummaryRadioembolization of hepatic tumors is performed by injecting 90Y or 166Ho loaded spheres into the hepatic artery. A twofold tumor to normal liver absorbed dose ratio is commonly obtained. In order to improve tumoral cell killing while preserving lobule function, co-injection of arterial vasoconstrictor has been proposed, but without success: the hepatic arterial buffer response quickly inhibits the arterioles vasoconstriction. The aim of the study is to investigate whether it is possible to take benefit from this buffer response, by co-infusing a mesenteric arterial vasodilator in order to dump the hepatic lobules arterial flow. Animal studies evidencing such mechanism are reviewed. Some potential mesenteric vasodilators are identified and their safety profile discussed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in hepatocellular carcinoma (HCC), more frequent in obese subjects, and where ultra-selective spheres delivery is often not possible.Liver radioembolization is a treatment option for unresectable liver cancers, performed by infusion of 90Y or 166Ho loaded spheres in the hepatic artery. As tumoral cells are mainly perfused via the liver artery unlike hepatic lobules, a twofold tumor to normal liver dose ratio is commonly obtained. To improve tumoral cell killing while preserving lobules, co-infusion of arterial vasoconstrictor has been proposed but with limited success: the hepatic arterial buffer response (HABR) and hepatic vascular escape mechanism hamper the arterioles vasoconstriction. The proposed project aims to take benefit from the HABR by co-infusing a mesenteric arterial vasodilator: the portal flow enhancement inducing the vasoconstriction of the intra sinusoids arterioles barely impacts liver tumors that are mainly fed by novel and anarchic external arterioles. Animal studies were reviewed and dopexamine was identified as a promising safe candidate, reducing by four the hepatic lobules arterial flow. A clinical trial design is proposed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in HCC where ultra-selective spheres delivery is often not possible.

Volumetric arc therapy: A viable option for right-sided breast with comprehensive regional nodal irradiation in conjunction with deep inspiration breath hold

Abstract Purpose Deep inspiration breath hold (DIBH) is an innovative technique routinely used for left-sided breast radiotherapy to significantly reduce harmful dose to the heart and ipsilateral lung. Currently, there is scant literature exploring DIBH for right-sided whole breast and regional nodal irradiation (WB & RNI). The purpose of this study is to examine if DIBH produces a clinically significant reduction in organ at risk (OAR) dose for right-sided WB + RNI, whilst comparatively analysing the use of volumetric arc therapy (VMAT) versus tangential inverse modulated radiotherapy (t-IMRT). Methods and Materials Ten patients, previously treated for left sided breast cancer (with a FB and DIBH CT scan), were selected from our database to be retrospectively replanned to the right breast and nodal regions. Planning target volumes (PTV) were marked to include the whole right breast and regional nodes, encompassing the supraclavicular fossa (SCF) and internal mammary nodes (IMN). PTVs and OARs were contoured on the Pinnacle workstation according to the Radiation Therapy Oncology Group (RTOG) guidelines. VMAT and t-IMRT plans were generated to a prescribed dose of 50 Gy in 25 fractions on both the DIBH and FB data sets for dosimetric analysis. Results Coverage of the right breast (mean, D95%) and SCF (D95%) were significantly improved with VMAT in comparison to t-IMRT, with no statistically significant variation on the IMN PTV (D95%). The use of DIBH did not impact PTV coverage compared with FB. VMAT reduced dose to the ipsilateral lung (mean, V20Gy), combined lungs (mean, V20Gy) and liver (D2cc); conversely dose to the heart (mean), left lung (mean, V5Gy) and contralateral breast (mean) were increased. For both techniques DIBH significantly improved dose to OARs including the ipsilateral lung (mean, V20Gy, V5Gy), total lung (mean, V20Gy), heart (mean, V25Gy) and liver (D2cc) when compared to FB. Conclusion DIBH could be considered for patients treated with right-sided WB and RNI due to a significant decrease in heart, ipsilateral lung, total lung and liver doses. VMAT significantly improves PTV coverage over t-IMRT whilst reducing dose to the ipsilateral lung and liver, albeit to the detriment of the left lung, contralateral breast and heart. The increase in heart dose can be mitigated by the use of DIBH. We recommend if VMAT is utilised for superior target volume coverage, DIBH should also be implemented to reduce OAR toxicity.

Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy.

Lipophilicity is explored in the biodistribution (BD), pharmacokinetics (PK), radiation dosimetry (RD), and toxicity of an internally administered targeted alpha-particle therapy (TAT) under development for the treatment of metastatic melanoma. The TAT conjugate is comprised of the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated to melanocortin receptor 1 specific peptidic ligand (MC1RL) using a linker moiety and chelation of the 225Ac radiometal. A set of conjugates were prepared with a range of lipophilicities (log D 7.4 values) by varying the chemical properties of the linker. Reported are the observations that higher log D 7.4 values are associated with decreased kidney uptake, decreased absorbed radiation dose, and decreased kidney toxicity of the TAT, and the inverse is observed for lower log D 7.4 values. Animals administered TATs with lower lipophilicities exhibited acute nephropathy and death, whereas animals administered the highest activity TATs with higher lipophilicities lived for the duration of the 7 month study and exhibited chronic progressive nephropathy. Changes in TAT lipophilicity were not associated with changes in liver uptake, dose, or toxicity. Significant observations include that lipophilicity correlates with kidney BD, the kidney-to-liver BD ratio, and weight loss and that blood urea nitrogen (BUN) levels correlated with kidney uptake. Furthermore, BUN was identified as having higher sensitivity and specificity of detection of kidney pathology, and the liver enzyme alkaline phosphatase (ALKP) had high sensitivity and specificity for detection of liver damage associated with the TAT. These findings suggest that tuning radiopharmaceutical lipophilicity can effectively modulate the level of kidney uptake to reduce morbidity and improve both safety and efficacy.

DOSE OPTIMIZATION ON LIVER CANCER PROTON THERAPY AND BORON NEUTRON CAPTURE THERAPY USING PARTICLE AND HEAVY IONS TRANSPORT CODE SYSTEM

Liver cancer was the third leading cause of death from cancer in 2020 with 830,180 deaths worldwide. Radiotherapy is a common treatment method for liver cancer. Technological advances presented proton therapy and boron neutron capture therapy (BNCT) as alternatives with a lower dose on healthy organs. The objective of this research is to get a good dose distribution with higher tumor dose and lower healthy organ dose in proton therapy. A comparison with BNCT is done to get a better understanding of how both methods deliver the dose to treat the cancer while minimizing healthy organ doses. The research simulated proton therapy for cancer liver with Particle and Heavy Ions Transport Code System (PHITS), and a literature review for BNCT. The effectiveness of both methods were compared by tumor dose and liver dose. The optimal tumor dose for proton therapy is 86.01 Gy (W) with 0.67 Gy (W) liver dose. Proton therapy can replace conventional radiotherapy for tumors with complex shapes in dose delivery by utilizing its dose profile, while BNCT can give better tumor control on patients previously treated with conventional radiotherapy.

Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial

BackgroundTo investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC).MethodsThis phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local–regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS).ResultsTotal nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months.ConclusionsAxitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort.Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461

Intraindividual comparison of [177Lu]Lu-DOTA-EB-TATE and [177Lu]Lu-DOTA-TOC

PurposeThe radiolabelled somatostatin analogue [177Lu]Lu-DOTA-EB-TATE binds to albumin via Evans blue, thereby increasing the residence time in the blood and potentially allowing more therapeutic agent to be absorbed into the target tissue during peptide receptor radionuclide therapy. It was tested in selected patients whether the substance is superior to [177Lu]Lu-DOTA-TOC.MethodsActivity kinetics in organs and tumours after [177Lu]Lu-DOTA-EB-TATE and [177Lu]Lu-DOTA-TOC were compared intraindividually in five patients with progressive somatostatin receptor-positive disease scheduled for radionuclide therapy.ResultsIn comparison to [177Lu]Lu-DOTA-TOC, tumour doses per administered activity were higher for [177Lu]Lu-DOTA-EB-TATE in 4 of 5 patients (median ratio: 1.7; range: 0.9 to 3.9), kidney doses (median ratio: 3.2; range: 1.6 to 9.8) as well as spleen doses (median ratio: 4.7; range 1.2 to 6.2) in all patients, and liver doses in 3 of 4 evaluable patients (median ratio: 4.0; range: 0.7 to 4.9). The tumour to critical organs absorbed dose ratios were higher after [177Lu]Lu-DOTA-TOC in 4 of 5 patients.ConclusionsPrior to a treatment with [177Lu]Lu-DOTA-EB-TATE, it should be assessed individually whether the compound is superior to established substances.

Proton beam therapy can achieve lower vertebral bone marrow dose than photon beam therapy during chemoradiation therapy of esophageal cancer.

Chemoradiation therapy plays an important role in both the neoadjuvant and definitive management of esophageal cancer (EC). Prior studies have suggested that advanced planning techniques can better spare organs at risk including the heart. Although multiple toxicities can result from esophageal radiotherapy, one less studied acute toxicity is that of myelosuppression, which can result, in part, from the combination of chemotherapy and incidental radiotherapy administration to the vertebral bodies (VBs), which abut the posterior aspect of the esophagus, especially in the lower thoracic esophagus. Traditionally, VB bone marrow doses are not accounted during EC radiation therapy planning. We sought to compare the doses to VBs between proton and photon radiation therapy as part of chemoradiation therapy for EC treatment. By reducing doses to the vertebrae, radiation therapy can decrease treatment-related myelosuppression, which can avoid delays or chemotherapy dose reductions in therapy, which likely affect long-term patient survival. Dose constraints are not routinely employed for bone marrow in radiation treatment planning. In our previous work, we identified thresholds to avoid grade ≥3 leukopenia, including VB V10Gy, VB V20Gy, and a mean VB dose (MVD) of 18.8 Gy. Herein we perform a retrospective dosimetric planning study comparing passive- or double-scattering proton beam therapy (PS-PBT), volumetric-modulated arc therapy (VMAT) (photon-based), and intensity-modulated radiation therapy (IMRT) (photon-based) in 25 patients with locally advanced EC who were treated originally with photon RT at our institution between 2011 and 2016. The aforementioned dose constraints were included in the retrospective planning process for PS-PBT, VMAT, and IMRT to determine the feasibility of achieving these VB constraints while maintaining reasonable target coverage and planned, consistent constraints to other organs at risk including lungs, spinal cord, and stomach. PS-PBT plans were found to achieve lower doses for VB V10Gy, V20Gy, and MVD than VMAT and static IMRT plans while achieving the same target coverage. PS-PBT resulted in lower organs at risk dosimetric parameters than the photon plans, with p < 0.0001. Student's paired t-test p-values in favor of proton therapy's ability to spare organs were as follows: for PS-PBT vs VMAT and PS-PBT vs IMRT in mean doses for lung, liver, and VB and VB V10Gy and VB V20Gy were all <0.001 (Bonferroni corrected α=0.017). One-way ANOVA found that VB doses (VB V10Gy, VB V20Gy, and MVD) were significantly lower for proton therapy (p < 0.006) among the 3 planning techniques.

Dosimetric comparison of constant dose rate volumetric modulated arc therapy (CDR-VMAT) and intensity-modulated radiation therapy (IMRT) for gallbladder cancer

AbstractAim:To study the feasibility of constant dose rate volumetric modulated arc therapy (CDR-VMAT) in radiotherapy for gallbladder cancer by comparing dosimetric parameter suggested by International Commission on Radiation Units and Measurements-83 (ICRU-83) with step and shoot intensity-modulated radiation therapy (SS IMRT).Methods:For this study, we selected 21 post-operative gallbladder cancer patients, which were treated with the IMRT technique from 2016 to 2019. For each patient, we generated SS IMRT plan and CDR-VMAT plan and were dosimetrically compared by parameters suggested by ICRU-83 for PTV. Homogeneity Index (HI) and Conformity Index (CI) were also calculated. For evaluation of Organ at Risk (OAR), we compared the mean doses, volume doses to the right kidney, left kidney, both kidneys combined, liver and max dose to the spinal cord. Monitor units (MUs) and treatment delivery time were also compared.Results:On comparing, we found that CDR-VMAT plans were highly conformed as CI and PCI (CI define by Paddick) were found more (0·98 ± 0·01 vs. 0·97 ± 0·03 and 0·86 ± 0·05 vs. 0·85 ± 0·05) than IMRT plans but not statistically significant. Better dose HI was found for IMRT plans with statistical significant difference (p &lt; 0·001). The tumour coverage was found similar 98·24% and 97·83% for SS IMRT and CDR-VMAT, respectively. For D2%, the maximum dose to PTV was significantly lower in IMRT (p = 0·001). D50% and mean dose to PTV were also comparable to IMRT with no statistically significant difference. The OAR parameters were comparable in both the techniques. The mean doses and volume doses V10, V20 and V30 to the right kidney, left kidney and liver were also comparable with no significant difference (p &gt; 0·05) was noted among them. However, the maximum dose to the spinal cord was significantly less in CDR-VMAT (21·1 Gy vs. 25·1Gy) than SS IMRT with p = 0·006. More MUs were associated with the CDR-VMAT technique, but shorter treatment delivery time than the IMRT technique.Conclusions:On dosimetric comparison of two treatment techniques, we conclude that CDR-VMAT can be a valid option in radiotherapy as it achieved highly conformed dose distribution, comparable tumour coverage and OAR sparing as IMRT technique for gallbladder cancer.

TNFR1 and the TNFα axis as a targetable mediator of liver injury from stereotactic body radiation therapy

IntroductionRadiation therapy for the management of intrahepatic malignancies can adversely affect liver function. Liver damage has been associated with increased levels of inflammatory cytokines, including tumor necrosis factor alpha (TNFα). We hypothesized that an inflammatory state, characterized by increased soluble TNFα receptor (sTNFR1), mediates sensitivity of the liver to radiation. Materials/MethodsPlasma samples collected during 3 trials of liver radiation for liver malignancies were assayed for sTNFR1 level via enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression and longitudinal models were used to characterize associations between liver toxicity (defined as a ≥2-point increase in Child-Pugh [CP] score within 6 months of radiation treatment) and sTNFR1 levels, ALBI score, biocorrected mean liver dose (MLD), age, and baseline laboratory values. ResultsSamples from 78 patients given liver stereotactic body radiation therapy [SBRT] (92%) or hypofractionated radiation were examined. There was a significant association between liver toxicity and sTNFR1 levels, and higher values were associated with increased toxicity over a range of mean liver doses. When ALBI score and biocorrected dose were included in the model with sTNFR1, baseline ALBI score and change in ALBI (ΔALBI) were significantly associated with toxicity, but sTNFR1 was not. Baseline aminotransferase levels also predicted toxicity but not independently of ALBI score. ConclusionsElevated plasma sTNFR1 levels are associated with liver injury after liver radiation, suggesting that elevated inflammatory cytokine activity is a predictor of radiation-induced liver dysfunction. Future studies should determine whether administration of agents that decrease inflammation prior to treatment is warranted.

Internal dosimetry of [99m Tc]NTP15-5 radiotracer for cartilage imaging in preclinical and clinical models using the GATE Monte Carlo platform.

This study aims to perform dosimetry for [99m Tc]NTP15-5 radiotracer used in imaging of articular cartilage in rabbits and humans. The radiotracer (covered by a world patent WO 01/00621 A1) has been proposed in the previous years for the study of cartilage in osteoarthritis diseases. A sensitive imaging approach is essential to quantify osteoarthritis progression and monitor response to new therapies. [99m Tc]NTP15-5 binds to cartilage proteoglycans whose decreased content is associated to a loss of biomedical function of cartilage. We have implemented the whole dosimetry study concerning this new radiotracer for rabbits and humans using the GATE Monte Carlo platform. Absorbed doses to critical organs are determined using the MIRD formalism. Biodistribution data are obtained by organ sampling, measuring the activity in organs for three rabbits sacrificed at various times postadministration, and by SPECT/CT imaging at different times after injection. Most important sources are cartilages (in knees and intervertebral discs), due to localization together with the liver and kidneys due to excretion of the agent. S-values are calculated from rabbit's CT scan and human CT scan using the GATE v8.0 Monte Carlo platform. Cumulated activity in humans is extrapolated from animals using the %kg-dose/g method. Particular attention is given to dose calculation in bones, bone marrow and organs at risk. The dosimetry performed in rabbits shows highest absorbed doses for liver and kidneys with respectively 22.5 and 43.8µGy per MBq of injected activity. In humans, we found absorbed doses for a maximum injected activity of 15MBq/kg, that is, 1050MBq for an adult of 70kgs of 9.03mGy for kidneys and 4.16mGy for knee cartilages. Effective dose is 2.69µSv/MBq. The dosimetry profile of [99m Tc]NTP15-5 in the context of preclinical trials is of major importance in order to make sure that organs at risk are not overexposed. GATE provides all the capability needed to calculate dose profiles for internal dosimetry. The extrapolation of the dose for a human model is a first step towards clinical trials.

Analysis of Incidence Risk for Different Types of Stroke among the Mayak Worker Cohort

The incidence risk estimates for different types of strokes among the cohort of 22 377 Mayak workers occupationally exposed to prolonged radiation and followed up until the end of 2013 are presented. Information about the work histories and estimates of the liver absorbed doses from external and internal radiations were obtained from the “Mayak Worker Dosimetry System—2013” database; medical data and lifestyle factors were obtained from the “Clinic” medical and dosimetry database. Over the entire follow-up period, 221 cases of intracerebral hemorrhage (ICH), 1463 cases of brain cerebral infarction (BI), and 342 cases of nonspecified stroke (NS) were registered in the study cohort. It was shown that the ICH, BI, and NS incidence risks in the study cohort were significantly associated with nonradiation factors such as gender, age, calendar period, duration of employment at the main plants, smoking, alcohol assumption, body mass index, and comorbidities (arterial hypertension and diabetes), which agreed with the literature data. Analyses did not reveal an effect of external γ-ray exposure on the ICH and BI incidence. However, NS relative risk (RR) was statistically significantly below the one in the groups of workers exposed to external γ-rays at the total absorbed liver doses above 0.20 Gy as compared with workers exposed at doses below 0.10 Gy. BI incidence RR was statistically significantly above the one in the groups of workers exposed to internal α-radiation at the total absorbed liver dose above 0.10 Gy as compared with workers exposed at lower doses. There was no effect of internal exposure on the ICH and NS incidence. These findings agreed with the results obtained earlier for the Mayak worker cohort.

VMAT Based TBI Prior to BMT in Malignant & Non-malignant Disorders – Single Institution Experience

The purpose of this paper is to report the feasibility of Total Body Irradiation (TBI) by multiple Iso-centric Volumetric Modulated Arc Therapy (VMAT) technique before Bone Marrow Transplant (BMT) in malignant & Non-malignant, hematological & non-hematological disorders. Total of 5 patients, 3 with ALL, 1each with Hurlor syndrome and Thalasemia Major were recruited for the TBI in our hospital from April 2018 to May 2019 before going for BMT. Immobilizations were done with thermoplastic masks and vaclocs for all patients in SBRT Multi-board. HFS&FFS two sets of CT scans done for 4 patients having more than 120 cm in heights with dosimetric reference marker in junction and only HFS scan done for a patient less than 120 cm in height. Dose prescribed to PTV excluding lung and kidneys was 12Gy in 6 fractions over 3 days (2 fractions per day) for ALL, single dose of 3 Gy for Hurler syndrome and 4 Gy in 2 fractions for Thalasemia Major. Treatment planning was done using VMAT technique in a treatment planning system. It consisted of average of 13 arcs for ALL and 8 arcs for other two patients with multiple isocenters and small static fields used to enhance the dose coverage. The best treatment plans were selected ensuring 90% PTV dose coverage and acceptable dose to OARs. Treatment executed with Linear accelerator equipped with OBI, CBCT used as Image Guided Radiation Therapy (IGRT) for each VMAT delivery. Quality assurance performed with mini-phantom and point dose measurements done with slab phantom and CC13 ion chamber followed by in vivo dosimetry performed with Optically Stimulated Luminescence Dosimeter nano chips. Contouring and planning time took 15-20 hours and quality assurance took 4-5 hours for each patient. PTV coverage of 90% achieved with PTV Dmean of 12.54 Gy for ALL patients and 3.02&4.32 respectively in other two cases. OAR average doses of lungs, kidneys and liver reduced to 9.8, 9.5 & 10.3 Gy respectively and lens restricted to 6 Gy for ALL patients and no OAR constraints for single and dual fraction low dose prescription patients. On couch treatment time on day one was 2.5 hours including setup and mounting of OSLD chips and irradiation for all cases. Further fractions time reduced to 1.5 hrs. 3 sets of CBCT performed for head first with average setup error of ±0.5 mm and two CBCT scans performed for feet first with average setup error of ±0.3 mm. OSLD dosimeter readings showed the results of within ±5% deviation. TBI by VMAT technique is feasible and provides satisfactory 3D dose distribution within PTV and reducing the dose to the critical OARs. VMAT provides a homogenous dose to the whole body, verified & confirmed by in vivo dosimetry. VMAT-TBI has advantage over extended SSD based conventional TBI methods in resource limited community as it can be used in regular radiotherapy department without requiring dedicated accessories.

Impact of Prior Y90 Dosimetry on Toxicity and Outcomes Following SBRT for Hepatocellular Carcinoma

Stereotactic body radiation therapy (SBRT) is the only non-invasive local therapy for the treatment of hepatocellular carcinoma (HCC) and is often utilized following transarterial embolization. There is a paucity of data reporting safety and outcomes of patients (pts) receiving SBRT after yttrium-90 (Y90). We evaluated the impact of Y90 and SBRT composite plan dosimetry on toxicity and outcomes of HCC pts. An IRB-approved registry of 260 liver SBRT pts was used. Pts included in analysis received Y90 prior to SBRT and had post-90Y PET imaging (measuring Bremsstrahlung component of Y90). Volume of ablated liver was estimated using the sharp edge of PET gradient and the SBRT volume receiving at least 30 Gy (V30). Characteristics between groups were compared using Chi-square and independent t-test. Clinical, imaging, and laboratory follow up are reported. Twenty eights pts with median follow up of 14 m (4.6-49.6) were included. Pts received 1 (N = 15), 2 (N = 10), or 3 (N = 3) prior Y90 treatments, to a median volume of 286 cm3 (21-1512) a median 4.4 m (1.1-82.9) prior to SBRT. SBRT dose ranged from 24-50 Gy in 3-5 fractions with a median PTV of 117 cm3 (26-857). Y90 and V30 overlap ranged from 0-577 cm3 with a median of 80 cm3. Treatment intent was definitive in 23 pts, to downstage within transplant criteria in 4 pts, and as a bridge to transplant in 1 pt. Baseline Child-Pugh (CP) score was A, B, and C in 23, 3, 2 pts, respectively. At a median 9 m (1.5-46.4) after SBRT local control was 93%. Liver, nodal, and distant failure had an incidence of 11%, 3.6%, and 11%, respectively. Change in CP score was analyzed at 1-2 m and 3 m post SBRT. Twenty-six patients had at least one calculable time point. Change in CP class from A to B was seen in 6 pts (26%), of which two recovered back to CP A by 3 m. The 3 CP B pts did not change class, and the 2 CP C pts received successful liver transplants 2-3 m after SBRT downstaging. Factors associated with an increase in CP score within 3 m of SBRT include SBRT mean liver dose (P = 0.001), SBRT V30 (P = 0.049), and <1200 cm3 of un-ablated liver (P = 0.003). Volume of liver treated by Y90 and time between Y90 and SBRT was not associated with an increase in CP score within 3 m of SBRT. Non-hematologic toxicity includes 2 acute biliary stricture (grade 2-3), 1 late biliary stricture (grade 2), 1 late chest wall pain (grade 1), and 1 late grade 2 radiographic myonecrosis. One CP A pt died 4 weeks after SBRT of cardiopulmonary comorbidities. Time between Y90 and SBRT, volume of liver exposed to prior Y90, and overlap between V30 and Y90 volumes do not appear to adversely impact CP score within 3 m of SBRT. In addition to known dosimetric properties including mean liver dose, and V30, we found that un-ablated liver volume <1200 cm3 was associated with an increase in CP score within 3 m of SBRT in this cohort of pts. Pts with HCC previously treated with Y90 appear to tolerate SBRT well with no clinically significant change in CP score, minimal toxicity, and excellent local control.

Cone Beam CT-Based Daily Adaptive Planning or Defined-Filling Protocol for Neoadjuvant Gastric Cancer Radiation Therapy: A Comparison

PurposeThis study aimed to investigate, in the setting of neoadjuvant gastric irradiation with integrated boost, whether cone beam computed tomography (CBCT)-based adaptive radiation therapy compared with a defined-filling protocol would be beneficial in terms of feasibility and achieving daily reproducible dose volume indexes of the planning target volume (PTV) and organs at risk (OARs) and workflow. Methods and materialsPlanning computed tomography (PCT) and 25 CBCT scans of a previously treated patient were used, and neoadjuvant therapy of gastric carcinoma was simulated offline. PTVs and OARs were defined per the TOPGEAR protocol (PTV: 45 Gy/1.8 Gy), and an integrated boost (gross tumor volume [GTV]: 50.4 Gy/2.016 Gy) was added. The patient followed a filling regimen consisting of 12-hour fasting followed by 200 mL of water intake (2 glasses of water) immediately before irradiation. OARs and PTVs were newly contoured on each CBCT. Nonrigid registration of PCT and CBCT scans was performed. Nonadapted plans were recalculated on each CBCT (R-CBCT). Furthermore, an adapted plan was created for the new anatomy (A-CBCT). Dose parameters and comparison of R-CBCT and A-CBCT for the kidneys, liver, and heart were analyzed using a paired t test. ResultsA total of 200 plans for R-CBCT and A-CBCT were obtained. Mean gastric volumes were 277.32 cm3 (±54.40 cm3) in CBCT scans and 519.2 cm3 in PCT. Mean doses to the PTV did not differ meaningfully within the CBCT scans, with an average of 1.54%. The D95 improved in GTV coverage by 5.26% compared with the R-CBCT plan. Mean heart, liver, and right kidney doses were reduced with the A-CBCT plan by 35.74%, 10.71% and 29.47%, respectively. The R- and A-CBCT comparison for GTV and OARs was significantly different in all cases (P < .0001). ConclusionsAdaptive radiation therapy through deformable registration represents an important tool in neoadjuvant gastric irradiation, encompassing daily variability and organ motion, compared with the defined-filling protocol while improving OAR sparing.