Prediction of Acute Radiation-Induced Lung Toxicity After Stereotactic Body Radiation Therapy Using Dose-Volume Parameters From Functional Mapping on Gallium 68 Perfusion Positron Emission Tomography/Computed Tomography.

PURPOSE: The aim of this work was to compare anatomic and functional dose-volume parameters as predictors of acute radiation-induced lung toxicity (RILT) in patients with lung tumors treated with stereotactic body radiation therapy. METHODS AND MATERIALS: Fifty-nine patients treated with stereotactic body radiation therapy were prospectively included. All patients underwent gallium 68 lung perfusion positron emission tomography (PET)/computed tomography (CT) imaging before treatment. Mean lung dose (MLD) and volumes receiving x Gy (VxGy, 5-30 Gy) were calculated in 5 lung volumes: the conventional anatomic volume (AV) delineated on CT images, 3 lung functional volumes (FVs) defined on lung perfusion PET imaging (FV50%, FV70%, and FV90%; ie, the minimal volume containing 50%, 70%, and 90% of the total activity within the AV), and a low FV (LFV; LFV = AV - FV90%). The primary endpoint of this analysis was grade ≥2 acute RILT at 3 months as assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Dose-volume parameters in patients with and without acute RILT were compared. Receiver operating characteristic curves assessing the ability of dose-volume parameters to discriminate between patients with and without acute RILT were generated, and area under the curve (AUC) values were calculated. RESULTS: Of the 59 patients, 10 (17%) had grade ≥2 acute RILT. The MLD and the VxGy in the AV and LFV were not statistically different between patients with and without acute RILT (P > .05). All functional parameters were significantly higher in acute RILT patients (P < .05). AUC values (95% CI) for MLD AV, LFV, FV50%, FV70%, and FV90% were 0.66 (0.46-0.85), 0.60 (0.39-0.80), 0.77 (0.63-0.91), 0.77 (0.64-0.91), and 0.75 (0.58-0.91), respectively. AUC values for V20Gy AV, LFV, FV50%, FV70%, and FV90% were 0.65 (0.44-0.87), 0.64 (0.46-0.83), 0.82 (0.69-0.95), 0.81 (0.67-0.96), and 0.75 (0.57-0.94), respectively. CONCLUSIONS: The predictive value of PET perfusion-based functional parameters outperforms the standard CT-based dose-volume parameters for the risk of grade ≥2 acute RILT. Functional parameters could be useful for guiding radiation therapy planning and reducing the risk of acute RILT.

Impact of age on the Quadrella index assessing oncological and functional results after prostate brachytherapy: A 6-year analysis.

Purpose: As the oncological results of prostate brachytherapy (BT) are excellent for low-risk (LR) or favorable intermediate-risk (FIR) prostate cancer (PCa), evaluating the side effects has become a major issue, especially for young men. The objective of the study was to compare the oncologic and functional results of BT using Quadrella index for patients aged 60 or less compared with older patients. Material and methods: From June, 2007 to June, 2017, 222 patients, including 70 ≤ 60 years old and 152 > 60 years old, underwent BT for LR-FIR PCa, with good erectile function at baseline according to International Index of Erectile Function-5 (IIEF-5) > 16. Quadrella index was achieved under the following circumstances: 1) Absence of biological recurrence (Phoenix criteria); 2) Absence of erectile dysfunction (ED) (IIEF-5 > 16); 3) No urinary toxicity (international prostate score symptom) IPSS < 15 or IPSS > 15, and ΔIPSS < 5; 4) No rectal toxicity (RT) (Radiation Therapy Oncology Group, RTOG = 0). Patients were treated on demand with phosphodiesterase inhibitors (PDE5i) post-operatively. Results: The Quadrella index was satisfied for about 40-80% of patients ≤ 60 years vs. 33-46% for older patients during 6-year follow-up (significant difference from the second year). At year 5, 100% of evaluable patients aged ≤ 60 and 91.8% > 60 (p = 0.29) reached Phoenix criteria. The criterion of ED (IIEF-5 < 16) largely explained the validity rate of Quadrella alone. There was no ED for 67.2-81.4% of patients ≤ 60 years compared with 40.0-56.1% for patients > 60 (significant difference since year 4 in favor of young men). After two years of follow-up, more than 90% of patients in both the groups showed neither urinary nor rectal toxicities. Conclusions: For young men displaying LR-FIR PCa, BT appears to be a first-class therapeutic option, as the oncological results were at least equivalent to those of older patients with good long-term tolerance.

A Feasibility Study of Functional Lung Volume Preservation during Stereotactic Body Radiotherapy Guided by Gallium-68 Perfusion PET/CT.

The aim of this study was to assess the feasibility of sparing functional lung areas by integration of pulmonary functional mapping guided by 68Ga-perfusion PET/CT imaging in lung SBRT planification. Sixty patients that planned to receive SBRT for primary or secondary lung tumors were prospectively enrolled. Lung functional volumes were defined as the minimal volume containing 50% (FV50%), 70% (FV70%) and 90% (FV90%) of the total activity within the anatomical volume. All patients had a treatment planning carried out in 2 stages: an anatomical planning blinded to the PET results and then a functional planning respecting the standard constraints but also incorporating "lung functional volume" constraints. The mean lung dose (MLD) in functional volumes and the percentage of lung volumes receiving xGy (VxGy) within the lung functional volumes using both plans were calculated and compared. SBRT planning optimized to spare lung functional regions led to a significant reduction (p < 0.0001) of the MLD and V5 to V20 Gy in all functional volumes. Median relative difference of the MLD in the FV50%, FV70% and FV90% was -8.0% (-43.0 to 1.2%), -7.1% (-34.3 to 1.2%) and -5.7% (-22.3 to 4.4%), respectively. Median relative differences for VxGy ranged from -12.5% to -9.2% in the FV50%, -11.3% to -7.2% in the FV70% and -8.0% to -5.3% in the FV90%. This study shows the feasibility of significantly decreasing the doses delivered to the lung functional volumes using 68Ga-perfusion PET/CT while still respecting target volume coverage and doses to other organs at risk.

Re-Irradiation by Stereotactic Radiotherapy of Brain Metastases in the Case of Local Recurrence.

PURPOSE: To evaluate the efficacy and safety of a second course of stereotactic radiotherapy (SRT2) treatment for a local recurrence of brain metastases previously treated with SRT (SRT1), using the Hypofractionated Treatment Effects in the Clinic (HyTEC) reporting standards and the European Society for Radiotherapy and Oncology guidelines. METHODS: From December 2014 to May 2021, 32 patients with 34 brain metastases received salvage SRT2 after failed SRT1. A total dose of 21 to 27 Gy in 3 fractions or 30 Gy in 5 fractions was prescribed to the periphery of the PTV (99% of the prescribed dose covering 99% of the PTV). After SRT2, multiparametric MRI, sometimes combined with 18F-DOPA PET-CT, was performed every 3 months to determine local control (LC) and radionecrosis (RN). RESULTS: After a median follow-up of 12 months (range: 1-37 months), the crude LC and RN rates were 68% and 12%, respectively, and the median overall survival was 25 months. In a multivariate analysis, the performance of surgery was predictive of a significantly better LC (p = 0.002) and survival benefit (p = 0.04). The volume of a normal brain receiving 5 Gy during SRT2 (p = 0.04), a dose delivered to the PTV in SRT1 (p = 0.003), and concomitant systemic therapy (p = 0.04) were associated with an increased risk of RN. CONCLUSION: SRT2 is an effective approach for the local recurrence of BM after initial SRT treatment and is a potential salvage therapy option for well-selected people with a good performance status. Surgery was associated with a higher LC.

A machine-learning approach based on 409 treatments to predict optimal number of iodine-125 seeds in low-dose-rate prostate brachytherapy.

PURPOSE: Low-dose-rate brachytherapy is a key treatment for low-risk or favorable intermediate-risk prostate cancer. The number of radioactive seeds inserted during the procedure depends on prostate volume, and is not easy to predict without pre-planning. Consequently, a large number of unused seeds may be left after treatment. The objective of the present study was to predict the exact number of seeds for future patients using machine learning and a database of 409 treatments. MATERIAL AND METHODS: Database consisted of 18 dosimetric and efficiency parameters for each of 409 cases. Nine predictive algorithms based on machine-learning were compared in this database, which was divided into training group (80%) and test group (20%). Ten-fold cross-validation was applied to obtain robust statistics. The best algorithm was then used to build an abacus able to predict number of implanted seeds from expected prostate volume only. As an evaluation, the abacus was also applied on an independent series of 38 consecutive patients. RESULTS: The best coefficients of determination R 2 were given by support vector regression, with values attaining 0.928, 0.948, and 0.968 for training set, test set, and whole set, respectively. In terms of predicted seeds in test group, mean square error, median absolute error, mean absolute error, and maximum error were 2.55, 0.92, 1.21, and 7.29, respectively. The use of obtained abacus in 38 additional patients resulted in saving of 493 seeds (393 vs. 886 remaining seeds). CONCLUSIONS: Machine-learning-based abacus proposed in this study aims at estimating the necessary number of seeds for future patients according to past experience. This new abacus, based on 409 treatments and successfully tested in 38 new patients, is a good alternative to non-specific recommendations.

Minimal channel GreenLight photovaporization before permanent implant prostate brachytherapy for patients with obstructive symptoms: Technically feasible and safe.

PURPOSE: Brachytherapy (BrT) is a standard treatment for low-risk to favorable-intermediate-risk prostate cancer but is a relative contraindication for patients with obstructive symptoms. We aimed to assess the feasibility and urinary toxicity of a minimal photovaporization (mPVP) before implantation. MATERIALS AND METHODS: Between 04/2009 and 08/2016, 50 patients candidates for BrT but with International Prostate Symptom Score (IPSS)>15, uroflowmetry <15 mL/s, obstructive prostate or large median lobe underwent a mPVP (GreenLight Laser) at least 6 weeks (median 8.5) before permanent seed implantation (loose seeds, 125I, 160 Gy). RESULTS: Two patients (4%) did not have sufficient improvement and did not undergo BrT, although it would have been possible at 3 months. For the 48 (96%) other patients, at the baseline, mean IPSS was 15.5 (±5.3), vs. 8.6 (±4.4) after mPVP (p = 1 × 10-6), and uroflowmetry 11.7 mL/s (±4), vs. 17.4 (±5.4) (p = 1.4 × 10-5). We did not experience any difficulty for BrT. Mean IPSS did not significantly increase 1, 3, or 6 months after BrT. With a median followup of 60 months [30-120], (92% assessed at last followup), only 4 patients (4/48 = 8.3%) experienced urinary retention and 5 (10.4%) needed surgery for urinary toxicity. In addition, only 2 patients (4%) needed medical treatment at last followup. Considering the 8 patients with de novo incontinence at 1 year, only 2 (4%) had persistent mild symptoms at last followup (36 months) (ICS1-2). CONCLUSIONS: These results suggest that a two-step approach with an mPVP at least 6 weeks before BrT is feasible, with no excessive urinary toxicity, and may be a good strategy for obstructive patients seeking BrT.

Impact of concomitant systemic treatments on toxicity and intracerebral response after stereotactic radiotherapy for brain metastases.

BACKGROUND: The aim of this study was to determine the safety and efficacy of fractionated stereotactic radiotherapy (SRT) in combination with systemic therapies (ST) for brain metastases (BM). METHODS: Ninety-nine patients (171 BM) received SRT and concurrent ST (group 1) and 95 patients (131 BM) received SRT alone without concurrent ST (group 2). SRT was planned on a linear accelerator, using volumetric modulated arc therapy. All ST were allowed including chemotherapy (CT), immunotherapy (IT), targeted therapy (TT) and hormonotherapy (HT). Treatment was considered to be concurrent if the timing between the drug administration and SRT did not exceed 1 month. Local control (LC), freedom for distant brain metastases (FFDBM), overall survival (OS) and radionecrosis (RN) were evaluated. RESULTS: After a median follow-up of 11.9 months (range 0.7-29.7), there was no significant difference between the two groups. However, patients who received concurrent IT (n = 30) had better 1-year LC, OS, FFDBM but a higher RN rate compared to patients who did not: 96% versus 78% (p = 0.02), 89% versus 77% (p = 0.02), 76% versus 53% (p = 0.004) and 80% versus 90% (p = 0.03), respectively. In multivariate analysis, concurrent IT (p = 0.022) and tumor volume < 2.07 cc (p = 0.039) were significantly correlated with improvement of LC. The addition of IT to SRT compared to SRT alone was associated with an increased risk of RN (p = 0.03). CONCLUSION: SRT delivered concurrently with IT seems to be associated with improved LC, FFDBM and OS as well as with a higher rate of RN.

Toxicity in patients treated with permanent prostate brachytherapy using intraoperatively built custom-linked seeds versus loose seeds.

PURPOSE: Low-dose-rate brachytherapy (BT) with permanent iodine-125 radioactive seeds is a highly effective treatment option for low- and favorable intermediate-risk prostate cancer. However, optimal implantation is not always achieved due to edema or seeds loss. One way to improve seed placement is the use of stranded seeds called "intraoperatively built custom-linked seeds (IBCLS)" in an opposition to loose seeds (LS). To date, there are few data comparing toxicity rates between these two techniques. The aim of this study was to compare dosimetric parameters and toxicity rates at 2 years between both procedures in a matched-paired population. MATERIAL AND METHODS: Patients were considered for BT according to European guidelines. Among 548 patients treated at our institution, 105 patients in the loose seeds cohort were individually matched to 105 patients in the IBCLS group according to age, prostate volume, pre-operative international prostate symptom score (IPSS), clinical stage, and Gleason score. Erectile function was scored using the five-item international index of erectile function (IIEF-5) score. A multivariable linear mixed-effects model was applied to examine the association between total and individual scores (repeated measures) and covariates. RESULTS: Overall, 61 (29%) patients presented with a favorable intermediate-risk prostate cancer. There were no significant changes in IPSS over time (p = 0.57). During follow-up, the IIEF-5 was similar in the two groups, except at one month, where it was lower in the IBCLS group (10.9 vs. 6.9, p = 0.029). Also, there was no difference in grade ≥ 2 rectal toxicity. At 1 month, D90Gy, V150%, and V100% were higher in the LS group compared to the IBCLS group. CONCLUSIONS: Low-dose-rate prostate brachytherapy using IBCLS is a safe technique, with comparable toxicity profiles at 2 years compared to LS brachytherapy.

Dose to the penile bulb and individual patient anatomy are predictive of erectile dysfunction in men treated with 125I low dose rate brachytherapy for localized prostate cancer.

Background: To evaluate the occurrence of erectile dysfunction at 3 years (3yED) after prostate brachytherapy (BT) and to predict 3yED after treatment based on patients and treatments characteristics. Material and methods: From September 2007 to July 2015, 117 men with mild or no ED [International Index of Erectile Function (IIEF-5) > 16] underwent 125Iodine real-time ultrasound-guided low-dose rate BT to a total dose of 160 Gy for low-risk or favorable intermediate-risk prostate adenocarcinoma, and were followed prospectively during 3 years. Median age was 63 years (51-79). The post-implant dosimetric parameters on the postoperative computer tomography were derived from the dose-volume histogram of the prostate and the penile bulb (PB), crura, neurovascular bundles (NVBs) and internal pudendal arteries (IPAs). Potential clinical confounding factors were collected. Additionally, anatomical indexes reflecting the prostate anatomical location within the pelvis were studied. These variables were compared between patients with and without 3yED. 3yED was defined as an IIEF-5 score change to the lower category between baseline, with or without medication. Results: The 3yED rate was 59% (62% maintained an IIEF-5 > 16). On multivariate analysis, prostate D90% (p > .5) and pretreatment characteristics including age (p > .5), pre-implant potency (p > .5), diabetes (p = .08) and high cardiovascular risk rates (p = .1) did not influence the occurrence of 3yED. Only the PB dose especially the D10% > 51 Gy was associated with 3yED (p = .005). Conversely, dose to the crura, IPAs or NVBs did not seem to impact the erectile function. The prostate position, especially the apex location varied significantly between potent and impotent patients and 3yED was significantly associated with close position of the prostate apex to PB (p = .008). Conclusion: The most predictive factor of 3yED was the dose to the PB. This may be explained by variation in individual patients' anatomy and this could allow for the development of better strategies to prevent ED.

Inhomogeneous tumor dose distribution provides better local control than homogeneous distribution in stereotactic radiotherapy for brain metastases.

INTRODUCTION: The aim of this study was to analyze the impact of inhomogeneous versus homogeneous dose distribution on local control (LC) and radionecrosis (RN) in patients treated with fractionated stereotactic radiotherapy (SRT) for newly-diagnosed brain metastases (BM). PATIENTS AND METHODS: From 2014 to 2017, 134 patients (median age 61 years) underwent SRT for BM (n = 114 with ≤2, n = 20 with 3-6 BM) at our institution. Treatment was delivered using volumetric modulated arc therapy on a linear accelerator. Ninety-one consecutive patients (BM = 136) were irradiated at a dose of 21-23.1 Gy in 3 fractions delivered homogeneously (99% of the dose had to cover 99% of the planning target volume (PTV)) (group 1) whereas the following 43 patients (BM = 72) received an inhomogeneous dose of 10 or 11 Gy prescribed to the isocenter with the 70% isodose line covering the PTV (group 2). Variables analyzed included dose distribution, age, gender, histology, diagnosis-specific Graded Prognostic Assessment score, number of brain metastases, presence of extracranial metastases, and tumor volumes. RESULTS: After a median follow-up of 12.4 months (range, 1.4-33.1), the 1-year LC and RN rate were 78% and 7.5% in group 1 and 93% and 0% in group 2, respectively (p = 0.005). In multivariate analysis, improved LC was significantly correlated with SRT dose distribution (p = 0.009) and tumor volume (p = 0.03). The number of metastases (p = 0.03) and SRT dose distribution (p = 0.04) were both associated with increased risk of RN. CONCLUSION: SRT delivered with inhomogeneous dose distribution resulted in better LC and a lower risk of RN compared to homogeneous distribution.

Evaluation of the "Quadrella" at 3 years: New index to assess functional and oncological performance specific to prostate brachytherapy.

PURPOSE: "Quadrella" index has been recently developed to assess oncological and functional outcomes after prostate brachytherapy (PB). We aimed to evaluate this index at 1, 2, and 3 years, using validated questionnaires, assessed prospectively. METHODS AND MATERIALS: From 08/2007 to 01/2013, 193 patients underwent 125Iodine PB for low-risk or favorable intermediate-risk prostate adenocarcinoma. Inclusion criteria were as follows: no incontinence (International Continence Society Index initial score = 0) and good erectile function (International Index of Erectile Function-5 items: >16). One hundred patients were included (mean age: 64 y). Postimplantation intake of phosphodiesterase inhibitors was not considered as failure. The "Quadrella" index was defined by the absence of biochemical recurrence (Phoenix criteria), significant erectile dysfunction (ED) (Index of Erectile Function-5 items: >16), urinary toxicity (UT) (International Prostate Score Symptom [IPSS] <15 or IPSS> 15 with ΔIPSS <5), and rectal toxicity (RT) (Radiation Therapy Oncology Group = 0). RESULTS: At 12 months, 90 patients were evaluable: 42/90 (46.7%) achieved Quadrella. The main criteria for failure were as follows: ED in 77.1% (37/48) of cases, RT in 20.8% (10/48) of cases, and UT in 12.5% (9/57) of cases. At 24 and 36 months, 59.3% (48/81) and 61.1% (44/72) of patients achieved Quadrella, respectively. The main cause of failure was ED in 69.7% (23/33) and 85.7% (24/28) of cases, while RT was involved in 21.2% (7/33) and in 3.6% (1/28) of cases, and UT in 9.1% (3/33) and 3.6% (1/28) of cases. Only one case of biochemical recurrence was observed (i.e., 1/28 = 3.6% at 3 y). CONCLUSIONS: The Quadrella can be used at 1, 2, and 3 years after PB. It allows to take into account the urinary and RT specific to PB. ED was the main cause of failure. This index will be useful to assess midterm and long-term results.