Tobias R. Chapman

ACR Appropriateness Criteria® non-spine bone metastases.

Bone is one of the most common sites of metastatic spread of malignancy, with possible deleterious effects including pain, hypercalcemia, and pathologic fracture. External beam radiotherapy (EBRT) remains the mainstay for treatment of painful bone metastases. EBRT may be combined with other local therapies like surgery or with systemic treatments like chemotherapy, hormonal therapy, osteoclast inhibitors, or radiopharmaceuticals. EBRT is not commonly recommended for patients with asymptomatic bone metastases unless they are associated with a risk of pathologic fracture. For those who do receive EBRT, appropriate fractionation schemes include 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. Single fraction treatment maximizes convenience, while fractionated treatment courses are associated with a lower incidence of retreatment. The appropriate postoperative dose fractionation following surgical stabilization is uncertain. Reirradiation with EBRT may be safe and provide pain relief, though retreatment might create side effect risks which warrant its use as part of a clinical trial. All patients with bone metastases should be considered for concurrent management by a palliative care team, with patients whose life expectancy is less than six months appropriate for hospice evaluation. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Differential hepatic avoidance radiation therapy: Proof of concept in hepatocellular carcinoma patients

PURPOSE To evaluate the feasibility of a novel planning concept that differentially redistributes RT dose away from functional liver regions as defined by (99m)Tc-sulphur colloid (SC) uptake on patient SPECT/CT images. MATERIALS AND METHODS Ten HCC patients with different Child-Turcotte-Pugh scores (A5-B9) underwent SC SPECT/CT scans in treatment position prior to RT that were registered to planning CT scans. Proton pencil beam scanning (PBS) therapy plans were optimized to deliver 37.5-60.0Gy (RBE) over 5-15 fractions using single field uniform dose technique robust to range and setup uncertainty. Photon volumetrically modulated arc therapy (VMAT) plans were optimized to the same prescribed dose and minimum target coverage. For both treatment modalities, differential hepatic avoidance RT (DHART) plans were generated to decrease dose to functional liver volumes (FLV) defined by a range of thresholds relative to maximum SC uptake (43-90%) in the tumor-subtracted liver. Radiation dose was redistributed away from regions of increased SC uptake in each FLV by linearly scaling mean dose objectives during PBS or VMAT optimization. DHART planning feasibility was assessed by a significantly negative Spearmans rank correlation (RS) between dose difference and SC uptake. Patient, tumor, and treatment planning characteristics were tested for association to DHART planning feasibility using non-parametric Kruskal-Wallis ANOVA. RESULTS Compared to conventional plans, DHART plans achieved a 3% FLV dose reduction for every 10% SC uptake increase. DHART planning was feasible in the majority of patients with 60% of patients having RS<-0.5 (p<0.01, range -1.0 to 0.2) and was particularly effective in 30% of patients (RS<-0.9). Mean dose to FLV was reduced by up to 20% in these patients. Only fractionation regimen was associated with DHART planning feasibility: 15 fraction courses were more feasible than 5-6 fraction courses (RS<-0.93 vs. RS>-0.60, p<0.02). CONCLUSION Differential avoidance of functional liver regions defined on sulphur colloid SPECT/CT is achievable with either photon VMAT or proton PBS therapy. Further investigation with phantom studies and in a larger cohort of patients may validate the utility of DHART planning for HCC radiotherapy.

Proton beam therapy for hepatocellular carcinoma

ABSTRACT Introduction: Radiation therapy is an effective treatment option for hepatocellular carcinoma (HCC) patients. However, radiotherapy for HCC still has limited recognition as a standard treatment option in international consensus guidelines due to a paucity of randomized controlled trials and the risk of hepatotoxicity, which is primarily mediated by baseline liver function and dose delivered to non-tumor liver cells. Proton beam therapy (PBT) may offer advantages over photon-based radiation treatments through its dosimetric characteristic of sparing more liver volume at low to moderate doses. PBT has the potential to reduce radiation-related hepatotoxicity and allow for tumor dose escalation. Areas covered: This article reviews the clinical rationale for using PBT for HCC patients and clinical outcome and toxicity data from retrospective and prospective studies. PBT-specific technical challenges for these tumors and appropriate selection of patients to be treated with PBT are discussed. Expert commentary: Local control, overall survival, and toxicity results are promising for liver PBT. Future studies, including ongoing randomized cooperative group trials, will aim to determine the incremental benefit of PBT over photons and which patients are most suitable for PBT.

Assessment of functional liver reserve: old and new in 99mTc-sulfur colloid scintigraphy

Purpose A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (99mTc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected 99mTc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease. Patients and methods Thirty patients with chronic liver disease and primary liver cancers underwent 99mTc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction 99mTc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned 99mTc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of 99mTc-SC biodistribution to liver function parameters and liver disease scoring systems (Child–Pugh) were evaluated by Spearman rank correlation. Results Percentages of 99mTc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman’s correlation coefficient showed a significant statistical association between Child–Pugh score and bone marrow uptake at 0.55 (P⩽0.05), liver uptake at 0.71 (P⩽0.001), spleen uptake at 0.56 (P⩽0.05), and spleen plus bone marrow uptake at 0.71 (P⩽0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P⩽0.05) compared with bone marrow uptake percentage. Conclusion We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of 99mTc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the 99mTc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages.

Functional imaging of radiation liver injury in a liver metastasis patient: imaging and pathologic correlation

BACKGROUND Radiation therapy (RT) is increasingly being utilized as a treatment modality for the treatment of primary and metastatic liver malignancies. Accurate assessment of liver function and prediction of radiation induced liver disease (RILD) remains a challenge with conventional laboratory tests and imaging. Imaging-pathology correlation of hepatic injury after RT has been described with computer tomography (CT) imaging that depicts perfusion changes. However, these imaging changes may not directly characterize the functional capacity of the liver. CASE PRESENTATION This case report describes a patient that received preoperative chemoradiation and surgical resection for a liver metastasis from endometrial cancer. Sulfur colloid (SC) single photon emission computed tomography (SPECT/CT) was obtained post-chemoradiation and prior to surgery. Imaging-pathology correlation between radiation changes depicted on functional imaging using SC SPECT/CT and corresponding histopathology is described. DISCUSSION Quantitative SC SPECT/CT may allow non-invasive assessment of global and spatial liver function before treatment and enable personalized treatment approaches for liver-directed therapies.

Chest wall toxicity after hypofractionated proton beam therapy for liver malignancies

PURPOSE Normal liver-sparing with proton beam therapy (PBT) allows for dose escalation in the treatment of liver malignancies, but it may result in high doses to the chest wall (CW). CW toxicity (CWT) data after PBT for liver malignancies are limited, with most published reports describing toxicity after a combination of hypofractionated proton and photon radiation therapy. We examined the incidence and associated factors for CWT after hypofractionated PBT for liver malignancies. METHODS AND MATERIALS We retrospectively reviewed the charts of 37 consecutive patients with liver malignancies (30 hepatocellular carcinoma, 6 intrahepatic cholangiocarcinoma, and 1 metastasis) treated with hypofractionated PBT. CWT was scored using Common Terminology Criteria for Adverse Events, version 4. Receiver-operating characteristic curves were used to identify patient and dosimetric factors associated with CWT and to determine optimal dose-volume histogram parameters/cutoffs. Cox regression univariate analysis was used to associate factors to time-dependent onset of CWT. RESULTS Thirty-nine liver lesions were treated with a median dose of 60 GyE (range, 35-67.5) in 15 fractions (range, 13-20). Median follow-up was 11 months (range, 2-44). Grade ≥2 and 3 CW pain occurred in 7 (19%) and 4 (11%) patients, respectively. Median time to onset of pain was 6 months (range, 1-14). No patients had radiographic rib fracture. On univariate analysis, CW equivalent 2 Gy dose with an α/β = 3 Gy (EQD2α/β=3), V57 >20 cm3 (hazard ratio [HR], 2.7; P = .004), V63 >17 cm3 (HR, 2.7; P = .003), and V78 >8 cm3 (HR, 2.6; P = .003) had the strongest association with grade ≥2 CW pain, as did tumor dose of >75 Gy EQD2α/β=10 (HR, 8.7; P = .03). No other patient factors were associated with CWT. CONCLUSIONS CWT after hypofractionated PBT for liver malignancies is clinically relevant. For a 15-fraction regimen, V47 >20 cm3, V50 >17 cm3, and V58 >8 cm3 were associated with higher rates of CWT. Further investigation of PBT techniques to reduce CW dose are warranted.

Neutron radiation therapy for advanced thyroid cancers

Purpose The aim of this study was to review institutional outcomes for advanced thyroid cancers treated with fast neutron radiation therapy (FNRT) and photon radiation therapy (RT). Methods and materials In all, 62 consecutive patients were analyzed. Fifty-nine had stage IV disease. Twenty-three were treated with FNRT and 39 with photon RT. Median follow-up was 14 months. The primary endpoint was overall survival (OS). Results There was no significant difference in median OS between FNRT and photon RT (26 vs 16 months; P = .49). Patients with well-differentiated histologies had superior median OS with photon RT (17 vs 69 months; P = .04). There was a nonsignificant trend toward improved OS with FNRT for medullary and anaplastic histologies. Conclusions Outcomes in this study are in line with historical results. There is an apparent detriment in OS with FNRT for well-differentiated histologies and a trend toward improved OS with medullary and anaplastic histologies that warrants further investigation.

Proton Beam Therapy for Hepatic Malignancies

Proton beam therapy (PBT) has emerged as a promising radiation treatment modality option for primary and metastatic hepatobiliary cancer patients due to its dosimetric advantages in sparing normal liver tissue from radiation. In this chapter, the rationale for using PBT for liver cancer patients, treatment planning and delivery including special considerations specific to PBT, and toxicities of liver PBT are discussed.

Defining radiation induced liver toxicity in the treatment of hepatocellular carcinoma: Which metric is most predictive for survival?

361 Background: Radiation induced liver disease (RILD) is of critical concern in the treatment of hepatocellular carcinoma (HCC) with radiation therapy (RT). Variability exists in metrics used to define RILD with no consensus on which best predict for overall survival (OS) and RILD-specific survival (RILDSS). We examined the correlation between toxicity metrics and clinical outcomes in a heavily pre-treated population that received RT. Methods: The charts of 37 HCC patients treated from 2013 - 2015 were reviewed retrospectively. At baseline, 62% were Child-Pugh (CP)-A, 32% CP-B and 5% CP-C. The majority (59%) had prior liver-directed therapy (LDT), 43% received stereotactic body RT and 49% proton RT. Pre-treatment, toxicity ( ≤ 6 months from treatment) and outcomes data were collected. Deaths from RILD were scored. Pre-treatment factors and toxicity outcomes were assessed by univariate Cox models for association with OS and RILDSS. Statistically significant predictors formed the basis for stepwise multiva...