To perform an individual patient data (IPD) meta-analysis of randomized controlled trials evaluating stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT) for patients ...presenting with 1 to 4 brain metastases.
Three trials were identified through a literature search, and IPD were obtained. Outcomes of interest were survival, local failure, and distant brain failure. The treatment effect was estimated after adjustments for age, recursive partitioning analysis (RPA) score, number of brain metastases, and treatment arm.
A total of 364 of the pooled 389 patients met eligibility criteria, of whom 51% were treated with SRS alone and 49% were treated with SRS plus WBRT. For survival, age was a significant effect modifier (P=.04) favoring SRS alone in patients ≤50 years of age, and no significant differences were observed in older patients. Hazard ratios (HRs) for patients 35, 40, 45, and 50 years of age were 0.46 (95% confidence interval CI = 0.24-0.90), 0.52 (95% CI = 0.29-0.92), 0.58 (95% CI = 0.35-0.95), and 0.64 (95% CI = 0.42-0.99), respectively. Patients with a single metastasis had significantly better survival than those who had 2 to 4 metastases. For distant brain failure, age was a significant effect modifier (P=.043), with similar rates in the 2 arms for patients ≤50 of age; otherwise, the risk was reduced with WBRT for patients >50 years of age. Patients with a single metastasis also had a significantly lower risk of distant brain failure than patients who had 2 to 4 metastases. Local control significantly favored additional WBRT in all age groups.
For patients ≤50 years of age, SRS alone favored survival, in addition, the initial omission of WBRT did not impact distant brain relapse rates. SRS alone may be the preferred treatment for this age group.
Most randomized comparison trials (RCTs) investigating treatments for brain metastases (BM) have included BM from any origin; as a result, more than half (52.4–77.0%) of the BM in these trials ...originated from the lungs (mostly non-small-cell lung cancer, NSCLC), with the breasts being the origin in only 6.8–19.0% of cases. In addition, patients with poor systemic status (KPS < 70) were not included in these trials. Hence, before we can apply RCT-based information to the daily clinical treatment of BM from breast cancers, it will be crucial to differentiate the characteristics of BM originating from NSCLC and BM originating from breast cancer. Although stereotactic radiosurgery (SRS) is widely used in Japan, level-1 evidence suggests that the benefit of using SRS in addition to whole-brain radiation therapy (WBRT) has been proven only for patients with a single BM. Treatment with SRS alone, which is widely used in Japan, seems attractive because it could avoid the risk of long-term adverse effects of WBRT. However, level-1 evidence suggests that the omission of WBRT results in a high frequency of brain tumor recurrence (BTR). In an RCT between SRS-alone and SRS + WBRT conducted in Japan, we found that patients who had a single BM and no extracranial metastases had a low risk of developing BTR after initial brain management (low-risk group) compared with those who had 2 or more BM and extracranial metastases (high-risk group). In order to meet the criteria of “low-risk” BTR, patients also should have good systemic status (KPS ≧ 70). Epidemiologic data suggest that the prognosis is twice as likely to be poor in patients with BM from breast cancer (RPA III = KPS < 70) than in patients with BM from NSCLC (40 vs. 20%); in addition, the probability of brain-only metastases in patients with breast cancer is less than half that in patients with NSCLC (20–25 vs. 60–75%). Considering these findings, we should be aware that most patients with BM from breast cancer are not good candidates for SRS alone, and, therefore, the role of WBRT is still important in the era of modern radiation techniques.
In urethra-sparing radiation therapy, prostatic urinary tract visualization is important in decreasing the urinary side effect. A methodology has been developed to visualize the prostatic urinary ...tract using post-urination magnetic resonance imaging (PU-MRI) without a urethral catheter. This study investigated whether the combination of PU-MRI and super-resolution (SR) deep learning models improves the visibility of the prostatic urinary tract. We enrolled 30 patients who had previously undergone real-time-image-gated spot scanning proton therapy by insertion of fiducial markers. PU-MRI was performed using a non-contrast high-resolution two-dimensional T2-weighted turbo spin-echo imaging sequence. Four different SR deep learning models were used: the enhanced deep SR network (EDSR), widely activated SR network (WDSR), SR generative adversarial network (SRGAN), and residual dense network (RDN). The complex wavelet structural similarity index measure (CW-SSIM) was used to quantitatively assess the performance of the proposed SR images compared to PU-MRI. Two radiation oncologists used a 1-to-5 scale to subjectively evaluate the visibility of the prostatic urinary tract. Cohen's weighted kappa (k) was used as a measure of agreement of inter-operator reliability. The mean CW-SSIM in EDSR, WDSR, SRGAN, and RDN was 99.86%, 99.89%, 99.30%, and 99.67%, respectively. The mean prostatic urinary tract visibility scores of the radiation oncologists were 3.70 and 3.53 for PU-MRI (k = 0.93), 3.67 and 2.70 for EDSR (k = 0.89), 3.70 and 2.73 for WDSR (k = 0.88), 3.67 and 2.73 for SRGAN (k = 0.88), and 4.37 and 3.73 for RDN (k = 0.93), respectively. The results suggest that SR images using RDN are similar to the original images, and the SR deep learning models subjectively improve the visibility of the prostatic urinary tract.
To determine how the omission of whole brain radiotherapy (WBRT) affects the neurocognitive function of patients with one to four brain metastases who have been treated with stereotactic radiosurgery ...(SRS).
In a prospective randomized trial between WBRT+SRS and SRS alone for patients with one to four brain metastases, we assessed the neurocognitive function using the Mini-Mental State Examination (MMSE). Of the 132 enrolled patients, MMSE scores were available for 110.
In the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and Karnofsky performance status. Of the 92 patients who underwent the follow-up MMSE, 39 had a baseline MMSE score of < or =27 (17 in the WBRT+SRS group and 22 in the SRS-alone group). Improvements of > or =3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (p = 0.85) were observed. Of the 82 patients with a baseline MMSE score of > or =27 or whose baseline MMSE score was < or =26 but had improved to > or =27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free rate of the 3-point drop in the MMSE was 76.1%, 68.5%, and 14.7% in the WBRT+SRS group and 59.3%, 51.9%, and 51.9% in the SRS-alone group, respectively. The average duration until deterioration was 16.5 months in the WBRT+SRS group and 7.6 months in the SRS-alone group (p = 0.05).
The results of the present study have revealed that, for most brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effects of WBRT on neurocognitive function might not be negligible.
Purpose
To quantitatively evaluate the achievable performance of volumetric imaging based on lung motion modeling by principal component analysis (PCA).
Methods
In volumetric imaging based on PCA, ...internal deformation was represented as a linear combination of the eigenvectors derived by PCA of the deformation vector fields evaluated from patient‐specific four‐dimensional‐computed tomography (4DCT) datasets. The volumetric image was synthesized by warping the reference CT image with a deformation vector field which was evaluated using optimal principal component coefficients (PCs). Larger PCs were hypothesized to reproduce deformations larger than those included in the original 4DCT dataset. To evaluate the reproducibility of PCA‐reconstructed volumetric images synthesized to be close to the ground truth as possible, mean absolute error (MAE), structure similarity index measure (SSIM) and discrepancy of diaphragm position were evaluated using 22 4DCT datasets of nine patients.
Results
Mean MAE and SSIM values for the PCA‐reconstructed volumetric images were approximately 80 HU and 0.88, respectively, regardless of the respiratory phase. In most test cases including the data of which motion range was exceeding that of the modeling data, the positional error of diaphragm was less than 5 mm. The results suggested that large deformations not included in the modeling 4DCT dataset could be reproduced. Furthermore, since the first PC correlated with the displacement of the diaphragm position, the first eigenvector became the dominant factor representing the respiration‐associated deformations. However, other PCs did not necessarily change with the same trend as the first PC, and no correlation was observed between the coefficients. Hence, randomly allocating or sampling these PCs in expanded ranges may be applicable to reasonably generate an augmented dataset with various deformations.
Conclusions
Reasonable accuracy of image synthesis comparable to those in the previous research were shown by using clinical data. These results indicate the potential of PCA‐based volumetric imaging for clinical applications.
Background
Online adaptation during intensity‐modulated proton therapy (IMPT) can minimize the effect of inter‐fractional anatomical changes, but remains challenging because of the complex workflow. ...One approach for fast and automated online IMPT adaptation is dose restoration, which restores the initial dose distribution on the updated anatomy. However, this method may fail in cases where tumor deformation or position changes occur.
Purpose
To develop a fast and robust IMPT online adaptation method named “deformed dose restoration (DDR)” that can adjust for inter‐fractional tumor deformation and position changes.
Methods
The DDR method comprises two steps: (1) calculation of the deformed dose distribution, and (2) restoration of the deformed dose distribution. First, the deformable image registration (DIR) between the initial clinical target volume (CTV) and the new CTV were performed to calculate the vector field. To ensure robustness for setup and range uncertainty and the ability to restore the deformed dose distribution, an expanded CTV‐based registration to maintain the dose gradient outside the CTV was developed. The deformed dose distribution was obtained by applying the vector field to the initial dose distribution. Then, the voxel‐by‐voxel dose difference optimization was performed to calculate beam parameters that restore the deformed dose distribution on the updated anatomy. The optimization function was the sum of total dose differences and dose differences of each field to restore the initial dose overlap of each field. This method only requires target contouring, which eliminates the need for organs at risk (OARs) contouring. Six clinical cases wherein the tumor deformation and/or position changed on repeated CTs were selected. DDR feasibility was evaluated by comparing the results with those from three other strategies, namely, not adapted (continuing the initial plan), adapted by previous dose restoration, and fully optimized.
Results
In all cases, continuing the initial plan was largely distorted on the repeated CTs and the dose‐volume histogram (DVH) metrics for the target were reduced due to the tumor deformation or position changes. On the other hand, DDR improved DVH metrics for the target to the same level as the initial dose distribution. Dose increase was seen for some OARs because tumor growth had reduced the relative distance between CTVs and OARs. Robustness evaluation for setup and range uncertainty (3 mm/3.5%) showed that deviation in DVH‐bandwidth for CTV D95% from the initial plan was 0.4% ± 0.5% (Mean ± S.D.) for DDR. The calculation time was 8.1 ± 6.4 min.
Conclusions
An online adaptation algorithm was developed that improved the treatment quality for inter‐fractional anatomical changes and retained robustness for intra‐fractional setup and range uncertainty. The main advantage of this method is that it only requires target contouring alone and saves the time for OARs contouring. The fast and robust adaptation method for tumor deformation and position changes described here can reduce the need for offline adaptation and improve treatment efficiency.
Although chemoradiotherapy (CRT) is one of the curative treatments for thoracic esophageal squamous cell carcinoma (ESCC) with submucosal invasion, the risk of local recurrence after CRT remains a ...clinical problem. This retrospective study aimed to analyze the predictive factors for local recurrence after CRT.
Ninety-one patients with clinical or pathological (c/p) T1bN0M0 thoracic ESCC who underwent CRT from 2004 to 2017 in our institution were analyzed retrospectively. Sixty-three patients were diagnosed with pathological T1b after undergoing initial endoscopic resection (ER) and treated with additional CRT; meanwhile, 28 patients were clinically diagnosed with T1b and underwent definitive CRT. We investigated the predictors of disease-specific survival (DSS) and local recurrence-free survival (LRFS) by performing univariate and multivariate analyses.
The median observation period was 59.8 months. The 5-year DSS and LRFS rates were 84.3% (95% confidence interval CI: 76.1-92.5) and 87.1% (95% CI: 79.1-95.1), respectively. The multivariate analysis revealed no significant predictors associated with DSS. On the contrary, ER (hazard ratio HR: 0.11, 95% CI: 0.02-0.48, p = 0.003) and tumor length (HR: 6.78, 95% CI: 1.28-36.05, p = 0.025) were recognized as independent predictive factors for LRFS. During follow-up, recurrence was observed in 18 patients (19.8%). With regard to the patterns of relapse, local recurrence was the most common in 11 patients, and salvage ER was performed in 9 of 11 patients.
ER and tumor length were independent predictive factors for LRFS. Our study suggested that performance of ER prior to CRT improved the local control in patients with c/p T1bN0M0 ESCC. In addition, most of the patients who experienced local recurrence were treated with salvage ER, which contributed to preserving the organs.
Background
It is important to have precise image guidance throughout proton therapy in order to take advantage of the therapy's physical selectivity.
Purpose
We evaluated the effectiveness of ...computed tomography (CT)‐image guidance in proton therapy for patients with hepatocellular carcinoma (HCC) by assessing daily proton dose distributions. The importance of daily CT image‐guided registration and daily proton dose monitoring for tumors and organs at risk (OARs) was investigated.
Methods
A retrospective analysis was conducted using 570 sets of daily CT (dCT) images throughout whole treatment fractions for 38 HCC patients who underwent passive scattering proton therapy with either a 66 cobalt gray equivalent (GyE)/10 fractions (n = 19) or 76 GyE/20 fractions (n = 19) protocol. The actual daily delivered dose distributions were estimated by forward calculation using the dCT sets, their corresponding treatment plans, and the recorded daily couch correction information. We then evaluated the daily changes of the dose indices D99%, V30GyE, and Dmax for the tumor volumes, non‐tumorous liver, and other OARs, that is, stomach, esophagus, duodenum, colon, respectively. Contours were created for all dCT sets. We validated the efficacy of the dCT‐based tumor registrations (hereafter, “tumor registration”) by comparing them with the bone registration and diaphragm registration as a simulation of the treatment based on the positioning using the conventional kV X‐ray imaging. The dose distributions and the indices of three registrations were obtained by simulation using the same dCT sets.
Results
In the 66 GyE/10 fractions, the daily D99% value in both the tumor and diaphragm registrations agreed with the planned value with 3%–6% (SD), and the V30GyE value for the liver agreed within ±3%; the indices in the bone registration showed greater deterioration. Nevertheless, tumor‐dose deterioration occurred in all registration methods for two cases due to daily changes of body shape and respiratory condition. In the 76 GyE/20 fractions, in particular for such a treatment that the dose constraints for the OARs have to be cared in the original planning, the daily D99% in the tumor registration was superior to that in the other registration (p < 0.001), indicating the effectiveness of the tumor registration. The dose constraints, set in the plan as the maximum dose for OARs (i.e., duodenum, stomach, colon, and esophagus) were maintained for 16 patients including seven treated with re‐planning. For three patients, the daily Dmax increased gradually or changed randomly, resulting in an inter‐fractional averaged Dmax higher than the constraints. The dose distribution would have been improved if re‐planning had been conducted. The results of these retrospective analyses indicate the importance of daily dose monitoring followed by adaptive re‐planning when needed.
Conclusions
The tumor registration in proton treatment for HCC was effective to maintain the daily dose to the tumor and the dose constraints of OARs, particularly in the treatment where the maintenance for the dose constraints needs to be considered throughout the treatment. Nevertheless daily proton dose monitoring with daily CT imaging is important for more reliable and safer treatment.
Purpose
In the scanning beam delivery of protons, different portions of the target are irradiated with different linear energy transfer protons with various time intervals and irradiation times. This ...research aimed to evaluate the spatially dependent biological effectiveness of protracted irradiation in scanning proton therapy.
Methods
One and two parallel opposed fields plans were created in water phantom with the prescribed dose of 2 Gy. Three scenarios (instantaneous, continuous, and layered scans) were used with the corresponding beam delivery models. The biological dose (physical dose × relative biological effectiveness) was calculated using the linear quadratic model and the theory of dual radiation action to quantitatively evaluate the dose delivery time effect. In addition, simulations using clinical plans (postoperative seminoma and prostate tumor cases) were conducted to assess the impact of the effects on the dose volume histogram parameters and homogeneity coefficient (HC) in targets.
Results
In a single‐field plan of water phantom, when the treatment time was 19 min, the layered‐scan scenario showed a decrease of <0.2% (almost 3.3%) in the biological dose from the plan on the distal (proximal) side because of the high (low) dose rate. This is in contrast to the continuous scenario, where the biological dose was almost uniformly decreased over the target by approximately 3.3%. The simulation with clinical geometry showed that the decrease rates in D99% were 0.9% and 1.5% for every 10 min of treatment time prolongation for postoperative seminoma and prostate tumor cases, respectively, whereas the increase rates in HC were 0.7% and 0.2%.
Conclusions
In protracted irradiation in scanning proton therapy, the spatially dependent dose delivery time structure in scanning beam delivery can be an important factor for accurate evaluation of biological effectiveness.
The effect of transient tumor expansion after conventionally fractionated stereotactic radiation therapy (SRT) on the symptomatic outcomes is not well-known.
This study enrolled 201 consecutive ...patients who received SRT for vestibular schwannoma. A conventional fractionation schedule was applied in 194 patients (97%), and 142 (71%) received a total dose of 50 Gy. The median follow-up time was 72 months.
The maximum diameter was 9 mm or less in 13 patients, 10-19 mm in 79 patients, 20-29 mm in 87 patients, and 30 mm or greater in 22 patients. At presentation, tumor size of 20 mm or greater was significantly associated with loss of serviceable hearing and trigeminal neuropathy. After SRT, tumor expansion was observed in 42 patients (21%). By tumor size, tumor expansion was observed in 0%, 11.4%, 25.6%, and 50% of patients with tumors of 9 mm or less, 10-19 mm, 20-29 mm, and 30 mm or greater, respectively, in diameter. The tumor expansion was significantly associated with an increased risk of hydrocephalus requiring shunt placement (P=.004), loss of serviceable hearing (P=.0064), and worsening of facial (P<.0001) and trigeminal nerve (P<.0001) functions. Spontaneous tumor shrinkage was observed in 29 of those 42 patients, mostly within 2 years after the expansion, and the majority of the worsened symptoms except for hearing resolved once the tumor had shrunk. As a result, salvage surgical resection for symptomatic relief was required in only 5% of patients.
Fractionated SRT could be safely applied even for medium- to large-sized (≥20 mm) tumors. However, greater knowledge of the risks and consequences, including transient symptomatic worsening, and the time span of expansion will be required for the follow-up of patients after SRT to avoid unnecessary surgical intervention.
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