Mean Liver Dose Research Articles

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.

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

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.

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.

Clinical implementation of pencil beam scanning proton therapy for liver cancer with forced deep expiration breath hold

PurposeTo present our technique for liver cancer treatments with proton therapy in pencil beam scanning mode and to evaluate the impact of uncertainties on plan quality. Materials and MethodsSeventeen patients affected by liver cancer were included in this study. Patients were imaged and treated in forced breath-hold using the Active Breathing Coordinator system and monitored with an optical tracking system. Three simulation CTs were acquired to estimate the anatomical variability between breath-holds and generate an internal target volume (ITV). The treatment plans were optimized with a Single Field Optimization technique aimed at minimizing the use of range shifter. Plan robustness was tested simulating systematic range and setup uncertainties, as well as the interplay effect between breath-holds. The appropriateness of margin was further verified based on the actual positioning data acquired during treatment. ResultsThe dose distributions of the nominal plans achieved a satisfactory target coverage in 11 out of 17 patients, while in the remaining 6 D95 to the PTV was affected by the constraint on mean liver dose. The constraints for all other organs at risk were always within tolerances.The interplay effect had a limited impact on the dose distributions: the worst case scenario showed a D95 reduction in the ITV < 3.9 GyRBE and no OAR with D1 > 105% of the prescription dose.The robustness analysis showed that for 13 out of 17 patients the ITV coverage in terms of D95 was better than D95 of the PTV in the nominal plan. For the remaining 4 patients, the maximum difference between ITV D95 and PTV D95 was ≤0.7% even for the largest simulated setup error and it was deemed clinically acceptable. Hot spots in the OARs were always lower than 105% of the prescription dose.Positioning images confirmed that the breath hold technique and the PTV margin were adequate to compensate for inter- and intra-breath-hold variations in liver position. ConclusionWe designed and clinically applied a technique for the treatment of liver cancer with proton pencil beam scanning in forced deep expiration breath-hold. The initial data on plan robustness and patient positioning suggest that the choices in terms of planning technique and treatment margins are able to reach the desired balance between target coverage and organ at risk sparing.

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-Y90 PET imaging (measuring Bremsstrahlung component of Y90). Volume of ablated liver was the sum of Y90 ablation region (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 3 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 include 2 acute biliary strictures (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. As expected, dosimetric properties including mean liver dose, V30, and un-ablated liver volume <1200 cm3 are associated with an increase in CP score within 3 m of SBRT. 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.

Individualized Adaptive Radiation Therapy Allows for Safe Treatment of Hepatocellular Carcinoma in Patients With Child-Turcotte-Pugh B Liver Disease

Previous reports of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) suggest unacceptably high rates of toxicity in patients with Child-Turcotte-Pugh (CTP) B liver disease. We hypothesized that an individualized adaptive treatment approach based on midtreatment liver function would maintain good local control while limiting toxicity in this population. Patients with CTP-B liver disease and HCC were treated on prospective trials of individualized adaptive SBRT between 2006 and 2018. Patients underwent pre- and midtreatment liver function assessments using indocyanine green. Treatment-related toxicity was defined as a ≥2-point increase in CTP score from pretreatment within 6 months of treatment. In addition, we performed analyses with a longitudinal model to assess changes in CTP score over 12 months after SBRT. Eighty patients with CTP-B (median tumor size, 2.5 cm) were treated: 37 patients were CTP-B-7, 28 were CTP-B-8, and 15 were CTP-B-9. The median treatment dose was 36 Gy in 3 fractions. One-year local control was 92%. In a multivariate model controlling for tumor size, treatment dose, and baseline CTP score, higher treatment dose was associated with improved freedom from local progression (hazard ratio: 0.97; 95% confidence interval, 0.94-1.00; P = .04). Eighteen patients (24%) had a ≥2-point increase in CTP score within 6 months of SBRT. In a longitudinal model assessing changes in CTP score over 12 months after SBRT, controlling for baseline CTP and tumor size, increasing mean liver dose was associated with larger increases in CTP score (P = .04). An individualized adaptive treatment approach allows for acceptable toxicity and effective local control in patients with HCC and CTP-B liver disease. Because increasing dose may increase both local control and toxicity, further work is needed to optimize treatment in patients with compromised liver function.

A randomized phase II feasibility study of individualized stereotactic body radiation therapy (SBRT) versus transarterial chemoembolization (TACE) with DEBDOX beads as a bridge to transplant in hepatocellular carcinoma (HCC).

4586 Background: For HCC pts undergoing LT, loco-regional treatment as a "bridge" is standard. The best bridging modality is unclear. SBRT is safe and effective when used in pts with advanced HCC. We prospectively compared SBRT to TACE as a bridge for HCC pts undergoing LT. Methods: From 9/2014-10/2019, 60 pts within Milan Criteria with CTP Class A/B8 cirrhosis were consented. 54 pts were randomized to TACE vs. SBRT. TACE pts (n =30) were scheduled to receive 2 treatments one month apart utilizing DEBDOX beads. TACE pts were hospitalized after each TACE. Pts receiving SBRT (n =24) received a median total dose of 45Gy delivered over 5 fractions using fiducials. Mean liver dose, Veff, and NTCP determined prescription dose. Pts were assessed by using mRECIST criteria at 2 months and every 3 months thereafter until LT or death. Toxicity and QOL were assessed before treatment, during treatment, two weeks post-treatment, and then every three months using the PIQ-6 Pain Impact Questionnaire and the SF-36v2 Health Survey. The 1° endpoint was time to recurrent or residual dz. Secondary endpoints were toxicity, pathologic response, radiologic response, number of subsequent treatments, cost, and QOL. 50 pts are evaluable for review. Results: See table. Conclusions: For early stage HCC patients with CTP Class A/B liver cirrhosis, SBRT appears as effective as TACE at controlling HCC prior to LT, may engender less toxicity, and eliminates the need for hospitalization. A larger multi-center trial is ongoing. Clinical trial information: NCT02182687. [Table: see text]

HOW MANY DOSEMETERS ARE NEEDED FOR CORRECT MEAN ORGAN DOSE ASSESSMENT WHEN PERFOMING PHANTOM DOSIMETRY? A PHANTOM STUDY EVALUATING LIVER ORGAN DOSE AND INVESTIGATING TLD NUMBERS AND WAYS OF DOSEMETER PLACEMENT.

This study evaluated repeated mean organ dose measurements of the liver by phantom dosimetry and statistical modelling in order to find a way to reduce the number of dosemeters needed for precise organ dose measurements. Thermoluminescent dosemeters were used in an adult female phantom exposed to a biplanar x-ray source at three different axial phantom rotations. Generalised mixed linear effect modelling was used for statistical analysis. A subgroup of five to six organ-specific locations out of 28 yielded mean liver organ doses within 95% confidence intervals of measurements based on all 28 liver-specific dosemeter locations. No statistical difference of mean liver dose was observed with rotation of the phantom either 10° clockwise or counter-clockwise as opposed to the coronal plane. Phantom dosimetry handling time during organ dose measurements can be markedly reduced, in this case the liver, by 79% (22/28), while still providing precise mean organ dose measurements.

The impact of the effective dose to immune cells on lymphopenia and survival of esophageal cancer after chemoradiotherapy

PurposeTo test the hypothesis that effective dose to circulating immune cells (EDIC) impacts the severity of radiation-induced lymphopenia and clinical outcomes of esophageal cancer patients treated with concurrent chemoradiotherapy (CCRT). Material and methods488 esophageal cancer patients treated with CCRT with and without surgery were analyzed. The EDIC model considers the exposure of circulating immune cells as the proportion of blood flow to lung, heart, liver, and the volume of the exposed area of the body, with the basis of mean lung dose (MLD), mean heart dose (MHD), mean liver dose (MlD), and integral dose (ITD) of the body region scanned, calculated as:EDIC=0.12∗MLD+0.08∗MHD+0.15∗0.85∗MlD∗n451/2+0.45+0.35∗0.85∗nk1/2∗ITD62∗103Where n is the fraction number. Correlations of EDIC with overall survival (OS), progression free survival (PFS), distant metastasis free survival (DMFS), and locoregional control (LRC) rates were analyzed using both univariable and multivariable Cox models. Lymphopenia during CCRT was graded according to Common Terminology Criteria for Adverse Events version 4.0. ResultsGrade 4 lymphopenia resulted in inferior clinical outcomes, including OS, PFS, and DMFS. The median EDIC was 3.6 Gy (range, 0.8–6.0 Gy). Higher EDIC was strongly associated with severe lymphopenia, particularly when EDIC was above 4 Gy. Patients with EDIC > 4.0 Gy had more G4 lymphopenia than those with EDIC ≤ 4.0 Gy (67.3% vs. 40.8%; P < 0.001). On multivariate analysis, increasing EDIC was independently and inversely associated with worse OS, PFS, and DMFS. ConclusionEDIC can be recommended as a useful tool to predict lymphopenia and inferior clinical outcomes, and it should be minimized below 4 Gy.

Proton beam therapy for liver cancers.

Proton beam therapy (PBT) delivers less dose to nearby normal organs compared to X-ray therapy (XRT), which is particularly relevant for treating liver cancers given that both mean and low liver dose are among the most significant predictors of radiation induced liver disease (RILD). High-dose PBT has been shown to achieve excellent long-term tumor control with minimal toxicity in hepatocellular carcinoma (HCC) patients. Increasing data support ablative PBT for patients with unresectable cholangiocarcinoma or liver metastases, especially those with larger tumors not suitable for XRT.

Liver dose reduction by deep inspiration breath hold technique in right-sided breast irradiation

PurposeDeep inspiration breath hold (DIBH) is a well-established technique that enables efficient cardiac sparing in patients with left-sided breast cancer. The aim of the current study was to determine if DIBH is effective for reducing radiation exposure of of liver and other organs at risk in right breast radiotherapy (RT).Materials and MethodsTwenty patients with right-sided breast cancer were enrolled in this study. Three-dimensional conformal RT plans were generated for each patient, with two different computed tomography scans of free breathing (FB) and DIBH. Nodes were contoured according to the Radiation Therapy Oncology Group contouring guidelines. Dose-volume histograms for the target volume coverage and organs at risk were evaluated and analyzed.ResultsDIBH plans showed significant reduction in mean liver dose (5.59 ± 2.07 Gy vs. 2.54 ± 1.40 Gy; p = 0.0003), V20Gy (148.38 ± 73.05 vs. 64.19 ± 51.07 mL; p = 0.0003) and V10Gy (195.34 ± 93.57 vs. 89.81 ± 57.28 mL; p = 0.0003) volumes compared with FB plans. Right lung doses were also significantly reduced in DIBH plans. Heart and left lung doses showed small but statistically significant improvement with application of the DIBH technique.ConclusionWe report that the use of DIBH for right-sided breast cancer significantly reduces the radiation doses to the liver, lungs, and heart.

Real-time Magnetic Resonance-guided Liver Stereotactic Body Radiation Therapy: An Institutional Report Using a Magnetic Resonance-Linac System.

BackgroundStereotactic body radiation therapy (SBRT) is a proven and effective modality for treatment of hepatic primary and metastatic tumors. However, these lesions are challenging for planning and treatment execution due to natural anatomic changes associated with respiration. Magnetic resonance imaging (MRI) offers superior soft tissue contrast resolution and the ability for real-time image-guided treatment delivery and lesion tracking.ObjectiveTo evaluate the plan quality, treatment delivery, and tumor response of a set of liver SBRT cancer treatments delivered with magnetic resonance (MR)-guided radiotherapy on a MR-linear accelerator (MR-linac).MethodsTreatment data from 29 consecutive patients treated with SBRT were reviewed. All treatments were performed using a step and shoot technique to one or more liver lesions on an MR-linac platform. Patients received 45 to 50 Gy prescribed to at least 95% of the planning target volume (PTV) in five fractions except for two patients who received 27-30 Gy in three fractions. Computed tomography and MRI simulation were performed in the supine position prior to treatment in the free-breathing, end exhalation, and end inhalation breath-hold positions to determine patient tolerability and potential dosimetric advantages of each technique. Immobilization consisted of using anterior and posterior torso MRI receive coils embedded in a medium-sized vacuum cushion. Gating was performed using sagittal cine images acquired at 4 frames/second. Gating boundaries were defined in the three major axes to be 0.3 to 0.5 cm. An overlapping region of interest, defined as the percentage volume allowed outside the boundary for beam-on to occur, was set between 1 and 10%. The contoured target was assigned a 5-mm PTV expansion. Organs at risk constraints adopted by the American Association of Physicists in Medicine Task Group 101 were used during optimization.ResultsTwenty-nine patients, with a total of 34 lesions, successfully completed the prescribed treatment with minimal treatment breaks or delays. Twenty-one patients were treated at end-exhale, and six were treated at end-inhale. Two patients were treated using a free-breathing technique due to poor compliance with breath-hold instructions. The reported mean liver dose was 5.56 Gy (1.39 - 10.43; STD 2.85) and the reported mean liver volume receiving the prescribed threshold dose was 103.1 cm3 (2.9 - 236.6; STD 75.2). Follow-up imaging at one to 12 months post treatment confirmed either stable or decreased size of treated lesions in all but one patient. Toxicities were mild and included nausea/vomiting, abdominal pain and one case of bloody diarrhea. Four patients died due to complications from liver cirrhosis unrelated to radiation effect.ConclusionSBRT treatment using a gated technique on an MR-linac has been successfully demonstrated. Potential benefits of this modality include decreased liver dose leading to decreased toxicities. Further studies to identify the benefits and risks associated with MR-guided SBRT are necessary.

Albi and Mean Liver Dose Are Predictive of Overall Survival in Hepatocellular Carcinoma Patients Treated with SBRT

Albi and Mean Liver Dose Are Predictive of Overall Survival in Hepatocellular Carcinoma Patients Treated with SBRT

Hypofractionated Radiation Therapy for Unresectable/Locally Recurrent Intrahepatic Cholangiocarcinoma

To evaluate outcomes for patients with unresectable/locally recurrent intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated proton or photon radiation therapy (HF-RT). We retrospectively identified 66 patients with ICC who were treated with HF-RT from 2008-18. 51 patients had intrahepatic disease only, and 15 patients had extrahepatic disease at time of RT but received RT for biliary control. Median age at RT was 76 years (range: 30-92), including 27 patients (41%) ≥ 80 years. Median RT dose was 58.05 Gy (range: 37.5-67.5), all delivered in 15 daily fractions. 32 patients received proton RT, and 34 patients received photon RT. Rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated with the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the Cox proportional hazards method. For multivariate analyses, variables with p < 0.5 on univariate analysis were evaluated by backwards selection. Median follow-up times from diagnosis and RT start were 21 months and 14 months, respectively. In total, 5 patients (7.6%) developed local failure. Only 1 patient developed isolated local failure. The 2-yr outcomes were 93% LC, 37% PFS, and 55% OS. Among the 51 patients treated with definitive intent, the 2-yr LC was 96%, PFS 35%, OS 60%. Receipt of protons was significantly associated with younger age (p = 0.02), but not gender, race, ECOG status, metastatic disease at presentation, mean liver dose, cumulative GTV, or number of lesions. There were no significant predictors of LC or PFS, including RT dose. On UVA for OS, younger age, female gender, prior chemotherapy, and prior surgery were significantly associated with improved OS (p < 0.05). On MVA, female gender (HR: 0.33, p = 0.001), prior chemotherapy (HR: 0.38, p = 0.002), and proton vs. photon RT (HR: 0.50, p = 0.05) remained significantly associated with OS. The rate of overall Grade 3+ toxicity was 11%. Radiation-induced liver disease (RILD) was documented in 1 patient who underwent glucocorticoid treatment. HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent ICC. HF-RT is well tolerated and should be considered as a treatment option for elderly patients who are considered medically inoperable. Proton RT and chemotherapy may further improve outcomes.

Treatment Outcome and Treatment Plan Comparisons with X-ray for HCC Patients with Small Pretreatment Liver Volume and Treated by Proton Beam

Patients with hepatocellular carcinoma (HCC) often have liver volume (LV) reduction caused by cirrhosis and are frequently ineligible for ablative photon radiotherapy. This study is to report the outcomes in HCC patients with small LV treated with high-dose hypofractionated proton beam therapy (PBT) and to elucidate the dosimetric advantages of protons versus photons. Sixty-two HCC patients with pretreatment LV < 1000 ml undergoing curative-intent PBT (with unirradiated LV to standard LV ratios [ULV/SLV] >30% for Child-Pugh [CP] class A and >40% for CP class B ) were included in this study. The most common dose-fractionation schedules were 72.6 GyE/22 fx. for central tumors (≤1 cm of gastrointestinal tract and porta hepatis [PH], N = 42) and 66 GyE/10 fx. for peripheral tumors (>1 cm from gastrointestinal tract/PH, N = 15). Photon treatment plans was performed in all patients using the same dose schedules as those of PBT, and the dosimetric parameters were compared. Additional photon plans with 36 Gy/3 fx were performed to investigate the eligibility of stereotactic body radiotherapy (SBRT) based on the safety threshold that >700 ml of LV receiving ≤15 Gy. The median pretreatment liver volume was 829 ml (range, 595-995 ml), whereas the median tumor size was 6.0 cm (range, 0.8-22.7 cm). After a median follow-up of 12 months, the 1-year LC, PFS, and OS in patients treated with definitive PBT were 96%, 57%, and 86%, respectively. Radiation-induced liver disease (RILD) was recorded in 3 (4.8%) patients. In the treatment plan comparison using the same hypofractionated dose schedules, proton plans were associated with significantly lower mean doses of liver (16.5 vs. 22.3 Gy, P <0.001), stomach (2.4 vs. 8.4 Gy, P <0.001), duodenum (4.3 vs. 7.2 Gy, P <0.001), lower third esophagus (4.6 vs. 13.9 Gy, P <0.001), heart (3.7 vs. 6.7 Gy, P <0.001), left kidney (2.3 vs. 2.9 Gy, P <0.001), spinal cord (from T9 to L3, 4.5 vs. 7.4, P <0.001), and body (from T9 to L3, 6.4 vs. 9.5, P <0.001), mean D2cc of stomach (9.9 vs. 20.7 Gy, P <0.001), duodenum (16.5 vs. 21.3 Gy, P = 0.002), lower third esophagus (10.8 vs. 22.3 Gy, P <0.001), and mean maximum dose of spinal cord (15.3 vs. 22.7 Gy, P <0.001), compared with the photon plans. As converting the dose-volume histogram (DVH) dose-bins to equivalent doses in 2 Gy (EQD2), 21 (34%) patients had mean liver dose >28 Gy in their photon plans and thereof necessitated target dose de-escalation. In the SBRT plans with 36 Gy in 3 fractions, 50 (81%) patients failed to comply with the constraint that >700 ml of LV receiving ≤15 Gy. The majority of HCC patients with LV <1000 ml were ineligible to SBRT and frequently required dose compromization for hypofractionated photon radiotherapy. Strikingly, PBT permitted these patients to undergo ablative radiation treatment and offered substantial local control benefits with <5% of RILD risk.

Individualized Adaptive Radiation Therapy Allows for Safe Treatment of Hepatocellular Carcinoma in Patients with Child-Pugh B Liver Disease

Liver stereotactic body radiation therapy (SBRT) is an effective treatment for hepatocellular carcinoma (HCC). However, previous reports suggest unacceptably high rates of treatment related toxicity in patients with Child Pugh B (CPB) liver disease. Our approach to limit toxicity in these patients has been to treat with an individualized adaptive approach, based on baseline and mid-treatment liver function. We hypothesized that this approach would maintain good local control while limiting toxicity in CPB patients receiving SBRT for HCC. Eighty patients with CPB liver disease and HCC were treated on prospective clinical trials of individualized adaptive radiation therapy at a single institution from 2006-2018. Patients underwent pre and mid-treatment liver function assessment using indocyanine green, a water soluble compound cleared exclusively by the liver, thereby providing a dynamic assessment of liver function. The mid-treatment assessment was typically performed one month after the delivery of the first 60% of the total intended dose, with the potential to receive 0-40% of the remaining dose after the 1 month break. Treatment related toxicity was defined as a ≥2 point rise in CP score from pre-treatment. Logistic regression models were used to assess predictors of toxicity and linear mixed models were used to assess longitudinal changes in CP score over time. Overall survival (OS) was assessed using Cox proportional hazard models. In total, 80 CPB patients with HCC were treated. Median follow-up was 13.1 months and median survival was 17.1 months. 37 patients were CPB-7, 28 CPB-8, and 15 CPB-9. Median tumor size was 2.6 cm. Median treatment dose was 36 Gy delivered in 3 fractions with a median mean liver dose (MLD) of 11.0 Gy. 2-year local control was 89.3%. Overall, 18 patients (22.5 %) had a ≥2 point rise in CP score within 6 months of SBRT. In a multivariate model assessing predictors of toxicity, baseline CP, tumor size, and MLD were not associated with toxicity (all p>0.35). In a longitudinal model assessing changes in CP score over 12 months post-SBRT, controlling for baseline CP and tumor size, increasing MLD was associated with an increased risk of eventual increase in CP score (p=0.04). In a multivariate model for OS controlling for tumor size and baseline CP score, increasing MLD was associated with decreased OS (HR: 1.04, 95% CI: 1.00-1.12, p=0.04). Tumor size and baseline CP score were not significantly associated with OS. Our individualized adaptive treatment approach allows for safe and effective treatment of patients with CPB liver disease. Our rates of treatment related toxicity in these high-risk patients is comparable to reported series in patients with Child-Pugh A liver dysfunction, and substantially less than those reported to date in CPB patients.

The Use of Dual-Energy CT to Eliminate the Need of Pre-Contrast CT and Registration Error for Contrast CT-Based Radiation Treatment Planning

The delineation of targets for CT based radiation treatment (RT) planning frequently utilizes contrast enhancement via Iodine bolus. However, dose calculations should not be performed on a CT with a contrast agent because the patient won’t receive bolus during treatment. Hence it is typical to acquire CT twice during RT simulation: once before the injection of bolus and once after. The registration between these two CT sets can introduce error, particularly for abdominal and thoracic tumor sites, due to the motion between the two acquisitions. In this work, we investigate the feasibility of using virtual non-contrast (VNC) images derived from dual-energy CT (DECT) to eliminate the pre-contrast CT and the registration error. CT datasets, including DECT and conventional 120 kVp pre- and post-contrast CTs, acquired for 10 pancreatic cancer patients were used. The DECT sets were acquired simultaneously using a dual source CT simulator. For each case, a VNC was derived from the DECT and was registered to the pre-contrast CT. The gross tumor volume (GTV) and organs at risk (OAR) were delineated on the contrast CT and then populated to the pre-contrast CT. An IMRT plan of 50.4 Gy to the GTV in 28 fractions was calculated on the pre-contrast CT. The dose distribution was reconstructed on the VNC image. Dose volume parameters (DVP) of the original plan on the pre-contrast CT were compared to reconstructed plan on the VNC. The motion related differences between the pre- and post-contrast CTs were assessed in the target region. The CT number in the bone of the VNC sets dropped an average of 65 HU in comparison to the pre-contrast CTs. On average, the distance between the centroids of the duodenum differs by an average of 6.7 ± 4.0 mm and as much as 13.3 mm as measured on the pre- and post-contrast CTs. The dose distributions on the pre-contrast CT and VNC are almost identical. The GTV mean dose and GTV maximum dose differ by 0.1% and 0.2% respectively between the two plans for the cases analyzed. For organs at risk the maximum point dose difference is 0.3% and 0.5% for the duodenum and cord respectively; the liver mean dose differs by 0.1%; the kidney V15Gy differs by 1.0%. The VNC images derived from DECT can be used to replace the conventional pre-contrast CT for RT planning, eliminating the need for a pre-contrast CT scan and subsequently eliminating the error in the registration of pre- and post-contrast CT. The use of VNC improves clinical workflow and reduces imaging dose to the patient.