Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and its incidence is on the rise. The primary therapy is resection or liver transplant, but only a minority of patients ...present with resectable disease. Historically, radiotherapy has not played a significant role in the treatment of liver malignancies because of the low tolerance of the whole liver to radiation. With improvements in 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy, higher doses of radiation can be delivered to target lesions with low doses to the noninvolved liver; thus, experience in the use of radiation for the treatment of focal HCC has increased. At the same time, our understanding of the relationships between radiation dose and volume and the risk of classic radiation-induced liver disease and other toxicities more likely to occur in HCC patients has improved considerably. These developments have led to a body of evidence that now supports the careful use of radiotherapy for unresectable HCC. The rationale for studying radiotherapy in a randomized trial is strong.
A substantial barrier to the single- and multi-institutional aggregation of data to supporting clinical trials, practice quality improvement efforts, and development of big data analytics resource ...systems is the lack of standardized nomenclatures for expressing dosimetric data. To address this issue, the American Association of Physicists in Medicine (AAPM) Task Group 263 was charged with providing nomenclature guidelines and values in radiation oncology for use in clinical trials, data-pooling initiatives, population-based studies, and routine clinical care by standardizing: (1) structure names across image processing and treatment planning system platforms; (2) nomenclature for dosimetric data (eg, dose–volume histogram DVH-based metrics); (3) templates for clinical trial groups and users of an initial subset of software platforms to facilitate adoption of the standards; (4) formalism for nomenclature schema, which can accommodate the addition of other structures defined in the future. A multisociety, multidisciplinary, multinational group of 57 members representing stake holders ranging from large academic centers to community clinics and vendors was assembled, including physicists, physicians, dosimetrists, and vendors. The stakeholder groups represented in the membership included the AAPM, American Society for Radiation Oncology (ASTRO), NRG Oncology, European Society for Radiation Oncology (ESTRO), Radiation Therapy Oncology Group (RTOG), Children's Oncology Group (COG), Integrating Healthcare Enterprise in Radiation Oncology (IHE-RO), and Digital Imaging and Communications in Medicine working group (DICOM WG); A nomenclature system for target and organ at risk volumes and DVH nomenclature was developed and piloted to demonstrate viability across a range of clinics and within the framework of clinical trials. The final report was approved by AAPM in October 2017. The approval process included review by 8 AAPM committees, with additional review by ASTRO, European Society for Radiation Oncology (ESTRO), and American Association of Medical Dosimetrists (AAMD). This Executive Summary of the report highlights the key recommendations for clinical practice, research, and trials.
Stereotactic Body Radiation Therapy (SBRT) is a non-invasive ablative treatment for hepatocellular carcinoma (HCC). This report aimed to address the limited availability of long-term outcomes after ...SBRT for HCC from North America.
Localized HCC patients without vascular invasion, who were ineligible for other liver-directed therapies and treated with SBRT at the University of Toronto or University of Michigan, were pooled to determine overall survival (OS), cumulative recurrence rates, and ≥ grade-3 toxicity. Multivariable analysis determined factors affecting OS and local recurrence rates.
In 297 patients with 436 HCCs (42% > 3 cm), one-, three- and five-year OS was 77·3%, 39·0% and 24·1%, respectively. On Cox proportional hazards regression analysis, liver transplant after SBRT, Child–Pugh A liver function, alpha-fetoprotein ≤ 10 ng/ml, and Eastern Co-operative Oncology Group performance status 0 significantly improved OS (hazard ratio HR = 0·06, 95% confidence interval CI- 0·02–0·25; p<0·001; HR = 0·42, 95% CI = 0·29–0·60, p<0·001; HR = 0·61, 95% CI- 0·44–0·83; p=0·002 and HR = 0·71, 95% CI = 0·51–0·97, p=0·034, respectively). Cumulative local recurrence was 6·3% (95% CI = 0.03–0.09) and 13·3% (95% CI = 0.06–0.21) at one and three years, respectively. Using Cox regression modelling, local control was significantly higher using breath-hold motion management and in HCC smaller than 3 cm (HR = 0.52, 95% CI = 0.58–0.98; p=0.042 and HR = 0.53, 95% CI = 0.26–0.98; p=0.042, respectively). Worsening of Child–Pugh score by ≥2 points three months after SBRT was seen in 15.9%.
SBRT confers high local control and long-term survival in a substantial proportion of HCC patients unsuitable for, or refractory to standard loco-regional treatments. Liver transplant should be considered if appropriate downsizing occurs after SBRT.
•Stereotactic radiation provides durable tumour control in early hepatocellular cancer.•Patients unsuitable or refractory to other local therapies too had good outcomes.•Good liver function and performance status at baseline predicted for better survival.•Down-staged tumours may be considered for liver transplant which improves survival.
The purpose of this study was to assess the dosimetric accuracy of synthetic CT (MRCT) volumes generated from magnetic resonance imaging (MRI) data for focal brain radiation therapy.
A study was ...conducted in 12 patients with gliomas who underwent both MR and CT imaging as part of their simulation for external beam treatment planning. MRCT volumes were generated from MR images. Patients' clinical treatment planning directives were used to create 12 individual volumetric modulated arc therapy (VMAT) plans, which were then optimized 10 times on each of their respective CT and MRCT-derived electron density maps. Dose metrics derived from optimization criteria, as well as monitor units and gamma analyses, were evaluated to quantify differences between the imaging modalities.
Mean differences between planning target volume (PTV) doses on MRCT and CT plans across all patients were 0.0% (range: -0.1 to 0.2%) for D(95%); 0.0% (-0.7 to 0.6%) for D(5%); and -0.2% (-1.0 to 0.2%) for D(max). MRCT plans showed no significant changes in monitor units (-0.4%) compared to CT plans. Organs at risk (OARs) had average D(max) differences of 0.0 Gy (-2.2 to 1.9 Gy) over 85 structures across all 12 patients, with no significant differences when calculated doses approached planning constraints.
Focal brain VMAT plans optimized on MRCT images show excellent dosimetric agreement with standard CT-optimized plans. PTVs show equivalent coverage, and OARs do not show any overdose. These results indicate that MRI-derived synthetic CT volumes can be used to support treatment planning of most patients treated for intracranial lesions.
Stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) are widely used therapies for the treatment of intrahepatic metastases; however, direct comparisons are lacking. We sought ...to compare outcomes for these 2 modalities.
From 2000 to 2015, 161 patients with 282 pathologically diagnosed unresectable liver metastases were treated with RFA (n = 112) or SBRT (n = 170) at a single institution. The primary outcome was freedom from local progression (FFLP). The effect of treatment and covariates on FFLP was modeled using a mixed-effects Cox model with application of inverse probability treatment weighting to adjust for potential imbalances in treatment modality.
The median follow-up period was 24.6 months. Patients receiving SBRT had larger tumors than those treated with RFA (median, 2.7 cm vs 1.8 cm; P < .01). On univariate analysis, tumor size was associated with worse FFLP for RFA (hazard ratio HR; 1.57; 95% confidence interval CI, 1.15-2.14; P < .01) but not for SBRT (HR, 1.38; 95% CI, 0.76-2.51; P = .3). The 2-year FFLP rate was 88.2% compared with 73.9%, favoring SBRT (P = .06). For tumors ≥2 cm in diameter, SBRT was associated with improved FFLP (HR, 0.28; 95% CI, 0.09-0.93; P < .01). On multivariate analysis, treatment with SBRT (HR, 0.21; 95% CI, 0.07-0.62; P = .005) and smaller tumor size (HR, 0.65; 95% CI, 0.47-0.91; P = .01) were associated with improved FFLP. The 2-year overall survival rate was 51.1%, with no difference between groups (P = .8). Grade ≥3 treatment-related toxicity was rare, with no difference between SBRT (n = 4) and RFA (n = 3).
Treatment with SBRT or RFA is well tolerated and provides excellent and similar local control for intrahepatic metastases <2 cm in size. For tumors ≥2 cm in size, treatment with SBRT is associated with improved FFLP and may be the preferable treatment.
Accurate interpretation of posttherapeutic images obtained in radiation oncology patients requires familiarity with modern radiation therapy techniques and their expected effects on normal tissues. ...Three-dimensional conformal external-beam radiation therapy techniques (eg, intensity-modulated radiation therapy, stereotactic body radiation therapy), although they are designed to reduce the amount of normal tissue exposed to high-dose radiation, inevitably increase the amount of normal tissue that is exposed to low-dose radiation, with the potential for resultant changes that may evolve over time. Currently available internal radiation therapy techniques (eg, arterial radioembolization for hepatic malignancies, brachytherapy for prostate cancer and gynecologic cancers) also carry risks of possible injury to adjacent nontargeted tissues. The sensitivity of tissues to radiation exposure varies according to the tissue type but is generally proportional to the rate of cellular division, with rapidly regenerating tissues such as intestinal mucosa being the most radiosensitive. The characteristic response to radiation-induced injury likewise varies according to tissue type, with atrophy predominating in epithelial tissue whereas fibrosis predominates in stromal tissue. Moreover, changes in irradiated tissues evolve over time: In the liver, decreased attenuation at computed tomography and increased signal intensity at T2-weighted magnetic resonance imaging reflect hyperemia and edema in the early posttherapeutic period; later, veno-occlusive changes alter the hepatic enhancement pattern; and finally, fibrosis develops in some patients. In the small bowel, wall thickening and mucosal hyperenhancement predominate initially, whereas luminal narrowing is the most prominent feature of chronic enteropathy. Correlation of posttherapeutic images with images used for treatment planning may be helpful when interpreting complex cases.
Use of highly conformal radiation for prostate cancer can lead to both overtreatment of surrounding normal tissues and undertreatment of the prostate itself. In this retrospective study we analyzed ...the radiographic and anatomic basis of common errors in computed tomography (CT) contouring and suggest methods to correct them.
Three hundred patients with prostate cancer underwent CT and magnetic resonance imaging (MRI). The prostate was delineated independently on the data sets. CT and MRI contours were compared by use of deformable registration. Errors in target delineation were analyzed and methods to avoid such errors detailed.
Contouring errors were identified at the prostatic apex, mid gland, and base on CT. At the apex, the genitourinary diaphragm, rectum, and anterior fascia contribute to overestimation. At the mid prostate, the anterior and lateral fasciae contribute to overestimation. At the base, the bladder and anterior fascia contribute to anterior overestimation. Transition zone hypertrophy and bladder neck variability contribute to errors of overestimation and underestimation at the superior base, whereas variable prostate-to-seminal vesicle relationships with prostate hypertrophy contribute to contouring errors at the posterior base.
Most CT contouring errors can be detected by (1) inspection of a lateral view of prostate contours to detect projection from the expected globular form and (2) recognition of anatomic structures (genitourinary diaphragm) on the CT scans that are clearly visible on MRI. This study shows that many CT prostate contouring errors can be improved without direct incorporation of MRI data.
To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma.
Outcomes were analyzed from 58 patients with 64 instances of treatment for ...adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival.
Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030).
Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.
Dynamic gadoxetic acid‐enhanced magnetic resonance imaging (MRI) allows the investigation of liver function through the observation of the perfusion and uptake of contrast agent in the parenchyma. ...Voxel‐by‐voxel quantification of the contrast uptake rate (k1) from dynamic gadoxetic acid‐enhanced MRI through the standard dual‐input, two‐compartment model could be susceptible to overfitting of variance in the data. The aim of this study was to develop a linearized, but more robust, model. To evaluate the estimated k1 values using this linearized analysis, high‐temporal‐resolution gadoxetic acid‐enhanced MRI scans were obtained in 13 examinations, and k1 maps were created using both models. Comparison of liver k1 values estimated from the two methods produced a median correlation coefficient of 0.91 across the 12 scans that could be used. Temporally sparse clinical MRI data with gadoxetic acid uptake were also employed to create k1 maps of 27 examinations using the linearized model. Of 20 scans, the created k1 maps were compared with overall liver function as measured by indocyanine green (ICG) retention, and yielded a correlation coefficient of 0.72. In the 27 k1 maps created via the linearized model, the mean liver k1 value was 3.93 ± 1.79 mL/100 mL/min, consistent with previous studies. The results indicate that the linearized model provides a simple and robust method for the assessment of the rate of contrast uptake that can be applied to both high‐temporal‐resolution dynamic contrast‐enhanced MRI and typical clinical multiphase MRI data, and that correlates well with the results of both two‐compartment analysis and independent whole liver function measurements.
This study used the uptake of gadoxetic acid contrast into the hepatocytes as a means of quantifying liver function. A linearized form of the dual‐input two‐compartment model was developed to estimate the uptake robustly and efficiently. The resulting function maps were compared to the full dual‐input two‐compartment model, and to whole liver function quantified via indocyanine green.
To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive ...treatment planning.
Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model.
There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT.
This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.
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