Spinal Cord Dose Tolerance to Stereotactic Body Radiation Therapy.

Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following spinal cord point maximum doses (Dmax) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD22) Dmax ≤70 Gy; SBRT thecal sac EQD22 Dmax ≤25 Gy, thecal sac SBRT EQD22 Dmax to cumulative EQD22 Dmax ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates.

Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer.

INTRODUCTION: The management of prostate cancer has undergone significant advances since the introduction of 68 Ga-prostate-specific membrane antigen (68 Ga-PSMA) positron emission tomography (PET) scans. Data on the use of 68 Ga-PSMA PET scans in the setting of biochemical recurrence is widely available. Data on the use of 68 Ga-PSMA PET as an initial staging modality, however, is limited. The aim of this retrospective study was to compare the staging of patients with newly diagnosed prostate cancer between 68 Ga-PSMA PET and current conventional imaging modalities. The potential impact of any change in stage will be analysed. METHODS: Details of all patients who underwent 68 Ga-PSMA PET in South Australia between March 2016 and March 2017 were obtained. One hundred and thirty-one patients with newly diagnosed prostate cancer who had 68 Ga-PSMA PET prior to consideration of definitive treatment were included in this study. The stage pre-68 Ga-PSMA PET (based on conventional imaging) and post-68 Ga-PSMA PET was recorded. The stage was classified as A - localised disease, B - presence of regional lymphadenopathy, C - oligometastatic disease (up to three metastases) and D - widespread metastases. Management plans were recorded. RESULTS: This study showed that the use of 68 Ga-PSMA PET resulted in a change of stage in 37 (28%) patients with an upstage in 17 (13%) patients and a downstage in 20 (15%) patients (P < 0.001). 68 Ga-PSMA PET excluded oligometastatic disease in 11 (8%) patients who had suspicious oligometastatic disease based on a single conventional imaging modality. These 68 Ga-PSMA PET findings impacted on management in at least 24 (18%) patients. CONCLUSION: The use of 68 Ga-PSMA PET scans in initial staging can have a significant impact on staging and management when compared to current conventional imaging modalities.

The safety and effectiveness of stereotactic body radiotherapy for central versus ultracentral lung tumors.

BACKGROUND AND PURPOSE: Recent studies have postulated that patients undergoing lung stereotactic body radiotherapy (SBRT) for ultracentral tumors have higher toxicity and mortality rates than those with central tumors. Our aim was to compare the outcomes after lung SBRT for central versus ultracentral tumors in our own series. MATERIAL AND METHODS: This was a retrospective review of patients with primary and metastatic lung tumors treated with SBRT from 1 September 2009 to 30 June 2015. Patients were included if they were treated with five-fraction SBRT to central or ultracentral tumors. Central tumors were defined as tumors where the closest point was within 2 cm of (but not abutting) the proximal bronchial tree, or within 2 cm of (whether abutting or not) mediastinal structures. Ultracentral tumors were defined as tumors abutting the proximal bronchial tree. The 2-year overall survival (OS), 2-year local failure (LF), and 2-year grade ≥3 toxicity rates were compared between patients with central and ultracentral tumors. RESULTS: A total of 107 patients were included in this study. There were no significant differences in 2-year OS between the two groups, with 2-year OS 57.7% for central tumors, and 50.4% for ultracentral tumors (p = 0.10). There were no significant differences in 2-year LF between the two groups, with 2-year LF 3.4% for central tumors and 4.3% for ultracentral tumors (p = 0.92). There were no significant differences in 2-year grade ≥3 toxicity rate for the two groups, with 3.5% with central tumors and 8.7% with ultracentral tumors (p = 0.23). CONCLUSIONS: There were no significant differences in OS, LF, or grade ≥3 toxicity between patients with central and ultracentral lung tumors. Although these results indicate that SBRT for ultracentral tumors may be safe, caution should be applied in selecting and treating these patients until the completion of large prospective trials.

Post-operative stereotactic radiotherapy for the treatment of intracranial haemangiopericytoma: 'A Study of Dose and Outcome'.

INTRODUCTION: This study was performed to assess the relationship between tumour response and radiation dose in equivalent 2 Gy per fraction (EQD2). METHOD: A retrospective cohort analysis of 21 patients with a diagnosis of intracranial haemangiopericytoma between 2000 and 2013 was included in this study. A total of 39 lesions were analysed. The equivalent dose in 2 Gy per fraction was calculated by assigning an alpha-beta ratio of 12 Gy. A paired t-test compared dose (EQD2) and tumour response, and as the outcome was binary, a logistic regression analysis was performed. RESULTS: In total, there were 14 cases of progression and 25 cases of non-progression. It was estimated that for a one unit increase in EQD2, the odds of non-progression were increased by a factor of 1.13 (P = 0.026). After adjusting for PTV volume, the estimated effect of EQD2 (min) on tumour response was stronger, with an estimated odds ratio of 1.36 for an increase of one unit and an odds ratio of 21.6 for an increase of 10 units (P = 0.015). The dose range varied with varying PTV volumes. Based on the logistic model, the probability of having non-progression is larger than 50% for EQ2Dmin doses larger than 30-40 Gy, in particular for volumes larger than 3.67 cm3 . CONCLUSION: This study demonstrates that there is a relationship between dose (EQD2) and outcome. With increasing dose, the likelihood of regression is higher. When adjusted for PTV volume, the response appeared stronger. The dose varied significantly with changes in the size of the PTV.

Positional Accuracy of Treating Multiple Versus Single Vertebral Metastases With Stereotactic Body Radiotherapy.

The aim of this study is to determine whether stereotactic body radiotherapy for multiple vertebral metastases treated with a single isocenter results in greater intrafraction errors than stereotactic body radiotherapy for single vertebral metastases and to determine whether the currently used spinal cord planning organ at risk volume and planning target volume margins are appropriate. Intrafraction errors were assessed for 65 stereotactic body radiotherapy treatments for vertebral metastases. Cone beam computed tomography images were acquired before, during, and after treatment for each fraction. Residual translational and rotational errors in patient positioning were recorded and planning organ at risk volume and planning target volume margins were calculated in each direction using this information. The mean translational residual errors were smaller for single (0.4 (0.4) mm) than for multiple vertebral metastases (0.5 (0.7) mm; P = .0019). The mean rotational residual errors were similar for single (0.3° (0.3°) and multiple vertebral metastases (0.3° (0.3°); P = .862). The maximum calculated planning organ at risk volume margin in any direction was 0.83 mm for single and 1.22 for multiple vertebral metastases. The maximum calculated planning target volume margin in any direction was 1.4 mm for single and 1.9 mm for multiple vertebral metastases. Intrafraction errors were small for both single and multiple vertebral metastases, indicating that our strategy for patient immobilization and repositioning is robust. Calculated planning organ at risk volume and planning target volume margins were smaller than our clinically employed margins, indicating that our clinical margins are appropriate.

Stereotactic Body Radiotherapy for Spinal Metastases: What are the Risks and How Do We Minimize Them?

STUDY DESIGN: Systematic literature review. OBJECTIVES: To summarize the risks of 3 key complications of stereotactic body radiotherapy (SBRT) for spinal metastases, that is, radiation myelopathy (RM), vertebral compression fracture (VCF), and epidural disease progression, and to discuss strategies for minimizing them. SUMMARY OF BACKGROUND DATA: RM, VCF and epidural disease progression are now recognized as important risks following SBRT for spine metastases. It is unclear at this stage exactly how large these risks are and what strategies can be employed to minimize these risks. METHODS: A systematic review of the literature using MEDLINE and a review of the bibliographies of reviewed articles on SBRT for spinal metastases were conducted. RESULTS: The initial literature search revealed a total of 376 articles, of which 38 were pertinent to the study objectives. The risk of RM following SBRT was found to be dependent on the maximum dose to the spinal cord and estimated to be ≤5% if the recommended published thecal sac dose constraints are adhered to. The crude risk of VCF was 13.7% (range: 0.7%-40.5%), and, on average, 45% were surgically salvaged. It has been shown that the risk of VCF is dependent on several anatomic and tumor-related factors including the SBRT dose per fraction. The crude risk of local failure at 1 year was 21.4% (range: 12%-27%) of which 67% (range: 38%-96%) occurred within the epidural space. The grade of epidural disease has been shown to be associated with the risk of local failure. CONCLUSION: The risk of RM after spinal SBRT is low in particular if recommended dose metrics are adhered to. There is a significant risk of both VCF and epidural disease progression after spinal SBRT. These risks can potentially be minimized by identifying the risk factors for these complications, and performing careful radiotherapy and surgical planning. LEVEL OF EVIDENCE: 2.

RADBIOMOD: A simple program for utilising biological modelling in radiotherapy plan evaluation.

PURPOSE: Radiotherapy plan evaluation is currently performed by assessing physical parameters, which has many limitations. Biological modelling can potentially allow plan evaluation that is more reflective of clinical outcomes, however further research is required into this field before it can be used clinically. METHODS: A simple program, RADBIOMOD, has been developed using Visual Basic for Applications (VBA) for Microsoft Excel that incorporates multiple different biological models for radiotherapy plan evaluation, including modified Poisson tumour control probability (TCP), modified Zaider-Minerbo TCP, Lyman-Kutcher-Burman normal tissue complication probability (NTCP), equivalent uniform dose (EUD), EUD-based TCP, EUD-based NTCP, and uncomplicated tumour control probability (UTCP). RADBIOMOD was compared to existing biological modelling calculators for 15 sample cases. RESULTS: Comparing RADBIOMOD to the existing biological modelling calculators, all models tested had mean absolute errors and root mean square errors less than 1%. CONCLUSIONS: RADBIOMOD produces results that are non-significantly different from existing biological modelling calculators for the models tested. It is hoped that this freely available, user-friendly program will aid future research into biological modelling.

Comparison of [(11)C]choline Positron Emission Tomography With T2- and Diffusion-Weighted Magnetic Resonance Imaging for Delineating Malignant Intraprostatic Lesions.

PURPOSE: The purpose of this study was to compare the accuracy of [(11)C]choline positron emission tomography (CHOL-PET) with that of the combination of T2-weighted and diffusion-weighted (T2W/DW) magnetic resonance imaging (MRI) for delineating malignant intraprostatic lesions (IPLs) for guiding focal therapies and to investigate factors predicting the accuracy of CHOL-PET. METHODS AND MATERIALS: This study included 21 patients who underwent CHOL-PET and T2W/DW MRI prior to radical prostatectomy. Two observers manually delineated IPL contours for each scan, and automatic IPL contours were generated on CHOL-PET based on varying proportions of the maximum standardized uptake value (SUV). IPLs identified on prostatectomy specimens defined reference standard contours. The imaging-based contours were compared with the reference standard contours using Dice similarity coefficient (DSC), and sensitivity and specificity values. Factors that could potentially predict the DSC of the best contouring method were analyzed using linear models. RESULTS: The best automatic contouring method, 60% of the maximum SUV (SUV60) , had similar correlations (DSC: 0.59) with the manual PET contours (DSC: 0.52, P=.127) and significantly better correlations than the manual MRI contours (DSC: 0.37, P<.001). The sensitivity and specificity values were 72% and 71% for SUV60; 53% and 86% for PET manual contouring; and 28% and 92% for MRI manual contouring. The tumor volume and transition zone pattern could independently predict the accuracy of CHOL-PET. CONCLUSIONS: CHOL-PET is superior to the combination of T2W/DW MRI for delineating IPLs. The accuracy of CHOL-PET is insufficient for gland-sparing focal therapies but may be accurate enough for focal boost therapies. The transition zone pattern is a new classification that may predict how well CHOL-PET delineates IPLs.

MRI scans significantly change target coverage decisions in radical radiotherapy for prostate cancer.

INTRODUCTION: Conventional clinical staging for prostate cancer has many limitations. This study evaluates the impact of adding MRI scans to conventional clinical staging for guiding decisions about radiotherapy target coverage. METHODS: This was a retrospective review of 115 patients who were treated between February 2002 and September 2005 with radical radiotherapy for prostate cancer. All patients had MRI scans approximately 2 weeks before the initiation of radiotherapy. The T stage was assessed by both conventional clinical methods (cT-staging) as well as by MRI (mT-staging). The radiotherapy target volumes were determined first based on cT-staging and then taking the additional mT staging into account. The number of times extracapsular extension or seminal vesicle invasion was incorporated into target volumes was quantified based on both cT-staging and the additional mT-staging. RESULTS: Extracapsular extension was incorporated into target volumes significantly more often with the addition of mT-staging (46 patients (40%) ) compared with cT-staging alone (37 patients (32%) ) (P = 0.002). Seminal vesicle invasion was incorporated into target volumes significantly more often with the addition of mT-staging (21 patients (18%) ) compared with cT-staging alone (three patients (3%) ) (P < 0.001). A total of 23 patients (20%) had changes to their target coverage based on the mT-staging. CONCLUSIONS: MRI scans can significantly change decisions about target coverage in radical radiotherapy for prostate cancer.

Diffusion-weighted MRI, 11C-choline PET and 18F-fluorodeoxyglucose PET for predicting the Gleason score in prostate carcinoma.

OBJECTIVES: To evaluate the accuracy of transrectal ultrasound-guided (TRUS) biopsy, diffusion-weighted (DW) magnetic resonance imaging (MRI), (11)C-choline (CHOL) positron emission tomography (PET), and (18)F-fluorodeoxyglucose (FDG) PET in predicting the prostatectomy Gleason risk (GR). METHODS: The study included 21 patients who underwent TRUS biopsy and multi-technique imaging before radical prostatectomy. Values from five different tests (TRUS biopsy, DW MRI, CHOL PET, FDG PET, and combined DW MRI/CHOL PET) were correlated with the prostatectomy GR using Spearman's ρ. Tests that were found to have significant correlations were used to classify patients into GR groups. RESULTS: The following tests had significant correlations with prostatectomy GR: TRUS biopsy (ρ = 0.617, P = 0.003), DW MRI (ρ = -0.601, P = 0.004), and combined DW MRI/CHOL PET (ρ = -0.623, P = 0.003). CHOL PET alone and FDG PET only had weak correlations. The correct GR classification rates were 67% with TRUS biopsy, 67% with DW MRI, and 76% with combined DW MRI/CHOL PET. CONCLUSIONS: DW MRI and combined DW MRI/CHOL PET have significant correlations and high rates of correct classification of the prostatectomy GR, the strength and accuracy of which are comparable with TRUS biopsy. KEY POINTS: • Accurate determination of the Gleason score is essential for prostate cancer management. • DW MRI ± CHOL PET correlated significantly with prostatectomy Gleason score. • These correlations are similar to that between TRUS biopsy and prostatectomy.

Hypoxia-targeted radiotherapy dose painting for head and neck cancer using (18)F-FMISO PET: a biological modeling study.

BACKGROUND: This study investigates the use of (18)F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP). RESULTS: The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138). CONCLUSION: Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation.

Intensity modulated radiation therapy dose painting for localized prostate cancer using ¹¹C-choline positron emission tomography scans.

PURPOSE: To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using (11)C-choline positron emission tomography PET scans in patients with localized prostate cancer. METHODS AND MATERIALS: This was an RT planning study of 8 patients with prostate cancer who had (11)C-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV(60%) and SUV(70%)). Three IMRT plans were generated for each patient: PLAN(78), which consisted of whole-prostate radiation therapy to 78 Gy; PLAN(78-90), which consisted of whole-prostate RT to 78 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy; and PLAN(72-90), which consisted of whole-prostate RT to 72 Gy, a boost to the SUV(60%) to 84 Gy, and a further boost to the SUV(70%) to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCP(PET)) and on prostatectomy-defined volumes (TCP(path)), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. RESULTS: All plans for all patients reached prescription doses while adhering to dose constraints. TCP(PET) values for PLAN(78), PLAN(78-90), and PLAN(72-90) were 65%, 97%, and 96%, respectively. TCP(path) values were 71%, 97%, and 89%, respectively. Both PLAN(78-90) and PLAN(72-90) had significantly higher TCP(PET) (P=.002 and .001) and TCP(path) (P<.001 and .014) values than PLAN(78). PLAN(78-90) and PLAN(72-90) were not significantly different in terms of TCP(PET) or TCP(path). There were no significant differences in rectal NTCPs between the 3 plans. CONCLUSIONS: IMRT dose painting for localized prostate cancer using (11)C-choline PET scans is technically feasible. Dose painting results in higher TCPs without higher NTCPs.

Histopathological correlation of (11)C-choline PET scans for target volume definition in radical prostate radiotherapy.

BACKGROUND AND PURPOSE: To evaluate the accuracy of (11)C-choline PET scans in defining dominant intraprostatic lesions (DILs) for radiotherapy target volume definition. MATERIAL AND METHODS: Eight men with prostate cancer who had (11)C-choline PET scans prior to radical prostatectomy were studied. Several methods were used to contour the DIL on the PET scans: visual, PET Edge, Region Grow, absolute standardised uptake value (SUV) thresholds and percentage of maximum SUV thresholds. Prostatectomy specimens were sliced in the transverse plane and DILs were delineated on these by a pathologist. These were then compared with the PET scans. The accuracy of correlation was assessed by the Dice similarity coefficient (DSC) and the Youden index. RESULTS: The contouring method resulting in both the highest DSC and the highest Youden index was 60% of the maximum SUV (SUV(60%)), with values of 0.64 and 0.51, respectively. However SUV(60%) was not statistically significantly better than all of the other methods by either measure. CONCLUSIONS: Although not statistically significant, SUV(60%) resulted in the best correlation between (11)C-choline PET and pathology amongst all the methods studied. The degree of correlation shown here is consistent with previous studies that have justified using imaging for DIL radiotherapy target volume definition.

Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells.

Dendritic cell (DC)-based vaccination represents a promising approach to harness the specificity and potency of the immune system to combat cancer. Finding optimal strategies for tumor Ag preparation and subsequent pulsing of DC, as well as improving the immunogenicity of weak tumor Ags remain among the first challenges of this approach. In this report, we use a prophylactic vaccine consisting of DC loaded with whole, nonmanipulated B16-F10 melanoma cells that had been stressed by heat shock and gamma irradiation. Stressed B16-F10 cells underwent apoptosis and were internalized by bone marrow-derived DC during coculture. Surprisingly, coculture of DC with stressed B16-F10 undergoing apoptosis and necrosis did not induce DC maturation. However, a marked retardation in tumor growth was observed in C57BL/6 mice immunized using DC loaded with stressed B16-F10 cells and subsequently challenged with B16-F10 cells. Growth retardation was further increased by treating DC with LPS before in vivo administration. In vivo depletion studies revealed that both CD8(+) and CD4(+) T cells played a critical role in retarding tumor growth. In addition, treatment with anti-CD25 Ab to deplete CD4(+)CD25(+) regulatory T cells before DC vaccination considerably improved the effect of the vaccine and allowed the development of long-lived immune responses that were tumor protective. Our results demonstrate that depletion of regulatory T cells is an effective approach to improving the success of DC-based vaccination against weakly immunogenic tumors. Such a strategy can be readily applied to other tumor models and extended to therapeutic vaccination settings.