Median Target Dose Research Articles

Introducing yttrium-90 radioembolization to atezolizumab and bevacizumab regimen for intermediate and advanced stage hepatocellular carcinoma: A preliminary report of safety and effectiveness.

e16231 Background: The IMbrave150 Phase III trial demonstrated superiority of atezolizumab and bevacizumab (Atezo/Bev) over sorafenib in unresectable hepatocellular carcinoma (HCC). Combined radiotherapy and immune checkpoint inhibitors have been shown to induce synergistic effects in treatment of HCC and other solid tumors. Barcelona Clinic Liver Cancer 2022 updated guidelines recommend consideration of transarterial radioembolization (TARE) for early stage and very early stage HCC. The present study sims to evaluate the safety and effectiveness of combining TARE and the Atezo/Bev regimen for intermediate and advanced stage HCC. Methods: Retrospective review at a single institution was performed between May 2021 and December 2022. Patients who received TARE using yttrium-90 (Y90) with concomitant or sequential Atezo/Bev systemic treatment were included. The following outcomes were retrieved: overall survival (OS), radiologic tumor response, progression-free survival, technical adverse events related to TARE, and toxicity based on the National Cancer Institute–Common Terminology Criteria for Adverse Events version 5.0. Results: Ten consecutive patients (9 male, 1 female) with unresectable HCC received TARE and Atezo/Bev were included. A total 21 of doses of Y90 were administered with a median target dose of 156 Gy. Tumor control was achieved in all target lesions (100%) based on modified Response Evaluation Criteria in Solid Tumors criteria. Overall disease progression occurred in 4 patients after TARE with a 6- month PFS of 80% (95%CI: 40.9-95.6%) and 12-month PFS of 53.3% (17.3%-79.8%). Two patients died during follow-up, with 6-month and 12-month OS rates of 88.9% (95%CI: 43.3-98.4%) and 76.2% (95%CI: 33.2-93.5%), respectively. One patient developed grade 3 transaminitis and hypoglobulinemia. Atezo/Bev was switched to Lenvatinib in one patient due to myositis. Bevacizumab was held in one patient due to suspected transient ischemic attack. Conclusions: This small patient cohort demonstrated preliminary safety and effectiveness of TARE in combination with Atezo/Bev in treating intermediate and advanced stage HCC. Further prospective and comparative studies with large sample sizes are warranted.

Effective clinical applications of Monte Carlo-based independent secondary dose verification software for helical tomotherapy

PurposeTo investigate the scope of the effective clinical application of Monte Carlo (MC)-based independent dose verification software for helical tomotherapy. MethodsDoseCHECK was selected as the MC-based dose calculation software. First, the dose calculation accuracy of DoseCHECK was evaluated with film and chamber measurements in a water-equivalent phantom. Second, the dose calculation accuracy was examined in several heterogeneous materials. Finally, dosimetric comparisons between DoseCHECK and the treatment planning system (TPS) were performed for clinical patient plans. Prostate IMRT, head and neck IMRT (HN), total body irradiation (TBI), and brain stereotactic radiotherapy (SRT) were evaluated. ResultThe DoseCHECK calculations agreed with the chamber and film measurements in the homogenous phantom. For heterogeneous phantom cases, the dose differences between DoseCHECK and TPS were within 3 %, except in air, in which large dose differences of 20 % were observed. In clinical patient plans, the median dose differences between the lung Dmean in TBI cases and the normal brain Dmean in brain SRT cases were significantly >3 %. For HN and brain SRT cases, the median target dose differences were >3 %. ConclusionOur results show that independent dose verification with the MC algorithm can detect systematic errors caused by the lack of heterogeneity correction in the TPS. In particular, MC-based independent dose verification is required for HN, TBI, and brain SRT cases in helical tomotherapy.

Volume staging for arteriovenous malformation SRS treatment using VMAT.

Volume staging involves dividing the target volume into smaller parts and treating each part separately. In this study, the feasibility of volume-staged stereotactic radiosurgery (VS-SRS) on a linear accelerator using volumetric modulated arc therapy (VMAT) and a frameless patient positioning system is investigated. Ten patients, previously treated with hypofractionated stereotactic radiotherapy with arteriovenous malformation (AVM) sized from 1.6 to 4.0cm in diameter, were selected. VS-SRS plans were created with the VMAT technique on the Varian Eclipse treatment planning system (TPS) using the TrueBeam STx linear accelerator. For each patient, an AVM-VMAT set was planned with the AVM as the target and a PTV-VMAT set using the (PTV=AVM+1mm) as the target. All targets were divided into two sub-volumes. The TPS data from the AVM-VMAT plans was compared to Gamma Knife (GK) VS-SRS plan data available in the literature. The AVM-VMAT and PTV-VMAT plans were compared to investigate the effect of a 1mm PTV margin on normal brain (NB) dose. End-to-end testing was performed using a GaFchromic EBT3 film and point-dose measurements. Dosimetric effects of multiple setups were investigated through film-to-film comparisons. Median target dose coverage, NB V12Gy , and conformity index for the AVM-VMAT plans were 97.5%, 17cm3 , and 0.8, respectively. PTV-VMAT plans attained comparable target dose coverage, but the average NB V12Gy increased by 48.9% when compared to the AVM-VMAT plans. Agreement of point-dose measurements with TPS calculations was -0.6% when averaged over all patients. Gamma analysis passing rates were above 90% for all film-to-film comparisons (2%/1mm criteria), and for the film to TPS comparison (5%/1mm). This work suggests that VMAT is capable of producing VS-SRS plans with similar dose falloff characteristics as GK plans. NB dose depends on PTV margin size, and two-stage treatment setups do not appear to contribute additional uncertainty to treatment delivery.

Can CBCT-Based Delta Radiomics Predict Normal Lung Toxicity during Thoracic Radiation?

<h3>Purpose/Objective(s)</h3> Delta radiomics which refers to longitudinal changes of radiomic features over time has shown the potential to predict treatment response. However, its role in predicting normal lung toxicity has not been studied extensively. This study evaluates the potential for CBCT based delta radiomics in predicting radiotherapy induced lung parenchymal changes during thoracic radiotherapy. <h3>Materials/Methods</h3> Sixty-two patients were selected who underwent thoracic radiation with volume-modulated-arc-therapy. CBCT images from treatment weeks 1, 3 and 6 (CBCTfirst, CBCTmid, CBCTend) were included. An experienced radiologist reviewed the serial lung changes and geographic location. 19 patients had radiological confirmed early pneumonitis. The normal lung was delineated into regions receiving dose between 5-10 Gy(V5-10), 10-20 Gy(V10-20), above 20 Gy (V20) on the planning CT and structures were transferred to CBCT following rigid registration using the treatment planning system. Each CBCT was processed with resampling (2mm3 isotropic), feature extraction (103 Pyradiomic features) and normalization (z-score). Optimal delta features were selected following a forward sequential selection method. Dataset was resampled with synthetic minority oversampling technique. Support vector machine classifier was used to build a machine-learning-based model to pick up incidence of early pneumonitis. The models used were built using 80:20 training/testing data split and performance was evaluated by the area-under-the-receiver-operating-characteristic-curve (AUC). <h3>Results</h3> The median target dose received by the patients during thoracic radiation was 54 Gy. The delta features selected for model training following the sequential feature selection technique were SurfaceArea, Contrast, RootMeanSquared, MeanAbsoluteDeviation, SmallAreaHighGrayLevelEmphasis (GLZSM). At CBCTmid, support vector machine classifier resulted in the best performance in predicting early pneumonitis in the region V5-10, AUC being 0.89 (95% CI 0.89-0.903) and 0.76 (0.74-0.78) in the training and testing datasets, respectively. This was followed by V20 region in the CBCTend with AUC of 0.904(0.89-0.92) and 0.71(0.69-0.74) in the training and testing datasets, respectively. <h3>Conclusion</h3> This study supports a potential role of delta radiomics to predict incidence of early pneumonitis changes with reasonable accuracy in patients undergoing thoracic radiation. Future studies with more patients and external validation are needed to confirm these results and for clinical implementation. In future, prediction models for clinical pneumonitis using CBCT based delta radiomics will be explored.

Feasibility, Tolerability, and Patient-Reported Outcomes with Pharmacokinetic (PK)-Directed Dosing of Evomela® (propylene glycol free melphalan) for Multiple Myeloma and AL Amyloidosis Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT)

Background: For multiple myeloma (MM) and AL amyloidosis (AL) patients undergoing autologous hematopoietic stem cell transplant (AHCT), high-dose melphalan is given at a fixed dose based on body surface area with five-fold inter-patient variability in exposure, as measured by area under the curve (AUC). Patients with higher than the median AUC (12.85mg/L*h) have prolonged survival, but increased toxicity (Shaw et al., BBMT 2012). Pharmacokinetically (PK)-directed dosing has the potential to achieve an optimal concentration in each patient. We prospectively evaluated the feasibility of PK-directed dosing of propylene glycol free melphalan (Evomela®, PGF-MEL), a more stable and possibly less toxic intravenous formulation of melphalan, to personalize therapy for maximum efficacy and tolerability.Methods: MM and AL patients age 18-75 received a 10mg/m2 test dose of PGF-MEL within 14 days of AHCT. Serum samples were drawn at 5, 15, 30, 40, 75, and 150 min after PGF-MEL administration. Liquid chromatography tandem mass spectrometry was used to measure MEL concentrations. AUC PK modeling with Phoenix WinNonlin v6.4 was used to determine a target dose to achieve an AUC of 13.5mg/L*h (+/-1), which was given on day -2 prior to AHCT. PK samples were collected after the target dose at the same time points as after the test dose. AHCT with 3-10 x10^6 CD34+ cells/kg was conducted per institutional guidelines. Patient-reported symptom burden was collected prospectively using the MD Anderson Symptom Inventory - MM (MDASI-MM) on day +1, 6, 11, 30, 60, and 90. Toxicities were collected by chart review through day +100 after AHCT and compared using either a T-test or Fisher's exact test between patients above and below AUC 14.5 mg/L*h.Results: Ten patients (7 MM, 3 AL) with 50% male, median age 67yr (range 53-74), and median body surface area 1.95 (range 1.56-2.35) had a median of 4.5 days (range 1-24) between the test and target doses of PGF-MEL. Target doses were calculated for 90% of patients and 70% received the calculated dose. The reasons for not administering the calculated dose were inability to calculate a test dose AUC (N=1), toxicity after the test dose (N=1), and target dose outside study safety parameters (N=1). Median test and target dose AUCs were 0.655 (range 0.447-0.869) and 15.65mg/L*h (range 10.1-17.2, Figure 1), respectively. No patients receiving the calculated target dose had an AUC within the goal range. MDASI-MM AUCs were calculated for fatigue, pain, sleep, appetite, drowsiness, and the average of these 5 symptoms. Overall, higher scores were seen in patients with MEL AUCs above 14.5mg/L*h compared with below (Figure 2). More patients with higher AUCs had fevers (83 vs 50%), ≥500ml of diarrhea per day (83 vs 75%), grade ≥3 mucositis (50 vs 25%), and need for patient-controlled analgesia (33 vs 25%), but these were not statistically significantly different between the groups (Table 1). Neutrophil engraftment occurred at a median of 10 (range 9-11) days post AHCT in both groups; patients with AUCs above 14.5mg/L*h required more pRBC and platelet transfusions. With a median follow-up of 217 days (range 179-250) in surviving patients, no patients progressed, and one AL patient died of failure to thrive at 134 days post AHCT.Conclusion: Collection of PK levels and calculation of a target dose was feasible. However, using a 10mg/m2 test dose we did not achieve the target AUC in our patients. This could be due to the small test dose which may have been insufficient to saturate the two-compartment model, rendering the PK analysis inaccurate. Patients with higher AUCs required more transfusions, had more toxicities, and had prolonged patient-reported symptom burden. Due to the small number of patients, these differences were not statistically significant, but suggest there may be an ideal concentration to minimize toxicity and maximize efficacy. Disease response and outcome data continue to be collected. Further study is needed to determine the optimum test dose and schedule, and modifications to the schema are ongoing. [Display omitted] DisclosuresKoehne:Atara: Consultancy, Patents & Royalties. Landau:Janssen: Honoraria; Takeda: Research Funding; Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board; Pfizer: Honoraria; Karyopharm: Consultancy; Amgen: Research Funding.

Clinical and Imaging Response to Trigeminal Schwannoma Radiosurgery: A Retrospective Analysis of a 28-Year Experience.

Objective The purpose of this study was to evaluate long-term clinical outcomes and tumor control after stereotactic radiosurgery (SRS) for trigeminal schwannoma (TS). Methods During a 28-year period (1989-2017), 50 patients underwent SRS for TS. The median patient age was 51 years (range: 15-87 years). A total of 17 patients had a previous tumor resection: 10 had a single procedure, 5 had two procedures, and 2 had three procedures. The median and mean times between tumor resection and SRS were 12 and 24 months (range: 1-90 months), respectively. Four patients had neurofibromatosis II (NF2). Based on location, tumors were classified as root type (7), ganglion type (22), or dumbbell type (21). The median radiosurgery target volume was 3.4 cm 3 (range: 0.10-18 cm 3 ), median target dose was 14 Gy (range: 12-20 Gy), and the median number of isocenters was 6 (range: 1-15). The median and mean times to last follow-up was 36.9 and 55.2 months (range: 4-205 months), respectively. Eighteen patients (36%) had longer than 5-year follow-up, and seven patients (14%) had longer than 10-year follow-up. Results The tumor control rate was 92% and the clinical improvement or stabilization rate was 94%. After SRS, the rates of progression free survival (PFS) at 1, 5, and 10 years were 98, 84, and 84%, respectively. Factors associated with improved PFS were female sex ( p = 0.014) and smaller tumor volume ( p = 0.022). In this series, we did not find that tumor type (root, ganglion, and dumbbell) had a statistically significant correlation to PFS. Forty-seven patients had neurological signs or symptoms at presentation. At last follow-up, neurological signs or symptoms improved in 22/47 (47%), remained unchanged in 24/50 (48%), and worsened due to tumor progression in 3/50 (6%). One patient (2%) developed temporary symptomatic adverse radiation effect (ARE) and three additional patients (6%) had transient imaging evidence of peritumoral reactive edema but no new symptoms. Conclusion As a single outpatient procedure, SRS was associated with long-term freedom from additional management in 84% of patients. Nearly half the treated patients experienced improvement in neurological symptoms or signs.

Oral Immunotherapy for Peanut Allergy (PACE): A Systematic Review and Meta–analysis of Efficacy and Safety

To systematically review the efficacy and safety of peanut oral immunotherapy (OIT) compared with allergen avoidance or placebo OIT for peanut allergy.The population included individuals with peanut allergy (61% male, 39% female), the majority of whom were children (median age: 8.7 years; interquartile range [IQR]: 5.9–11.2 years) participating in peanut OIT trials in North America, Australia, and Western Europe.This systematic review and meta-analysis included a comprehensive search of international health care databases from the United States, Latin America, Europe, and China through December 2018. Authors performed searches for randomized controlled trials comparing peanut OIT to no OIT for the treatment of peanut allergy. The authors screened studies, extracted data, assessed risk of bias, and assessed quality of evidence by the Grading of Recommendations Assessment, Development, and Evaluation approach. The main outcomes included treatment efficacy (ie, proportion of patients passing an oral food challenge), anaphylaxis, allergic or adverse reactions, epinephrine use, and quality of life.Twelve randomized controlled trials were included, with 1041 participants in total undergoing peanut OIT for a median follow-up of 1.0 year (IQR: 0.8–1.4), achieving a median target dose of 2000 mg of peanut protein (IQR: 375–4000). Passing a supervised, in-clinic oral food challenge was more likely in the OIT group. Subjects undergoing peanut OIT had increased anaphylaxis risk (risk ratio: 3.12 [95% confidence interval (CI): 1.76–5.55]), anaphylaxis frequency (incidence rate ratio: 2.72 [95% CI: 1.57–4.72]), and epinephrine use (risk ratio: 2.21 [95% CI: 1.27–3.83]). Peanut OIT increased serious adverse events and nonanaphylactic reactions. These findings were irrespective of OIT protocol, proprietary formulation or not, and phase of OIT (build-up versus maintenance). Quality of life was not different between groups.High-quality evidence shows that current peanut OIT regimens effectively achieve a modest level of desensitization but clinically result in a net increase in anaphylaxis and other allergic reactions compared with avoidance or placebo, rather than preventing them, as intended. These data support the need for improved food allergy treatment approaches with an enhanced safety profile.Hesitancy to implement OIT in routine clinical practice centers around concerns for safety, standardization of approach, practicality of long-term therapy maintenance, and identification of patients who will respond best with the fewest side effects. Although most adverse effects from OIT are mild and do not prevent patients from continuing therapy, the potential for life-threatening anaphylaxis exists. Despite the safety concerns outlined in this report, OIT is being offered in some clinical practices and is expected be available on a larger scale in the near future. It is important to remember that OIT may not be the best fit for many food-allergic patients, and as we near the likely acceptance of a US Food and Drug Administration–approved peanut OIT product, patients will seek advice from their pediatrician before talking to an allergist to help them navigate the pros and cons of interventional therapy versus the traditional approach of maintaining strict allergen avoidance. Salient points for the pediatrician to remember include the following. (1) OIT and all other products currently under investigation for treatment of food allergy provide benefit while on therapy but do not appear to induce sustained remission for the majority of allergic patients. (2) There are no surrogate biomarkers to identify which patients will receive the greatest benefit with the fewest side effects. (3) Anaphylaxis while on therapy is a potential side effect, and patients must continue to carry autoinjectable epinephrine at all times. Shared decision-making and an open and honest discussion with families considering therapeutic options are necessary in providing comprehensive care of our patients with food allergy and their families.

Sensitivity study of the microdosimetric kinetic model parameters for carbon ion radiotherapy

In carbon ion therapy treatment planning, the relative biological effectiveness (RBE) is accounted for by optimization of the RBE-weighted dose (biological dose). The RBE calculation methods currently applied clinically in carbon ion therapy are derived from the microdosimetric kinetic model (MKM) in Japan and the local effect model (LEM) in Europe. The input parameters of these models are based on fit to experimental data subjected to uncertainties. We therefore performed a sensitivity study of the MKM input parameters, i.e. the domain radius (rd), the nucleus radius (Rn) and the parameters of the linear quadratic (LQ) model (αx and β). The study was performed with the FLUKA Monte Carlo code, using spread out Bragg peak (SOBP) scenarios in water and a biological dose distribution in a clinical patient case. Comparisons were done between biological doses estimated applying the MKM with parameters based on HSG cells, and with HSG parameters varied separately by ±{5, 25, 50}%. Comparisons were also done between parameter sets from different cell lines (HSG, V79, CHO and T1), as well as versions of the LEM. Of the parameters, rd had the largest impact on the biological dose distribution, especially on the absolute dose values. Increasing this parameter by 25% decreased the biological dose level at the center of a 3 Gy(RBE) SOBP by 14%. Variations in Rn only influenced the biological dose distribution towards the particle range, and variations in αx resulted in minor changes in the biological dose, with an increasing impact towards the particle range. β had the overall smallest influence on the SOBPs, but the impact could become more pronounced if alternative (LET dependent) implementations are used. The resulting percentage change in the SOBPs was generally less than the percentage change in the parameters. The patient case showed similar effects as with the SOBPs in water, and parameter variations had similar impact on the biological dose when using the clinical MKM and the general MKM. The clinical LEM calculated the highest biological doses to both tumor and surrounding healthy tissues, with a median target dose (D50%) of 40.5 Gy(RBE), while the MKM with HSG and V79 parameters resulted in a D50% of 34.2 and 36.9 Gy(RBE), respectively. In all, the observed change in biological dose distribution due to parameter variations demonstrates the importance of accurate input parameters when applying the MKM in treatment planning.

Synthetic CT for MRI-based liver stereotactic body radiotherapy treatment planning

A technique for generating MRI-derived synthetic CT volumes (MRCTs) is demonstrated in support of adaptive liver stereotactic body radiation therapy (SBRT). Under IRB approval, 16 subjects with hepatocellular carcinoma were scanned using a single MR pulse sequence (T1 Dixon). Air-containing voxels were identified by intensity thresholding on T1-weighted, water and fat images. The envelope of the anterior vertebral bodies was segmented from the fat image and fuzzy-C-means (FCM) was used to classify each non-air voxel as mid-density, lower-density, bone, or marrow in the abdomen, with only bone and marrow classified within the vertebral body envelope. MRCT volumes were created by integrating the product of the FCM class probability with its assigned class density for each voxel. MRCTs were deformably aligned with corresponding planning CTs and 2-ARC-SBRT-VMAT plans were optimized on MRCTs. Fluence was copied onto the CT density grids, dose recalculated, and compared. The liver, vertebral bodies, kidneys, spleen and cord had median Hounsfield unit differences of less than 60. Median target dose metrics were all within 0.1 Gy with maximum differences less than 0.5 Gy. OAR dose differences were similarly small (median: 0.03 Gy, std:0.26 Gy). Results demonstrate that MRCTs derived from a single abdominal imaging sequence are promising for use in SBRT dose calculation.

Radioembolization with 90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: final report of a prospective pilot study.

This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of radioembolization of liver-dominant metastatic gastrointestinal cancer using 90Y glass microspheres. Between June 2010 and October 2013, 42 adult patients (26 men, 16 women; median age 60 years) with metastatic chemotherapy-refractory unresectable colorectal (n=21), neuroendocrine (n=11), intrahepatic bile duct (n=7), pancreas (n=2), and esophageal (n=1) carcinomas underwent 60 lobar or segmental administrations of 90Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for up to 5.5 years after radioembolization. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Time to maximum response, response duration, progression-free survival (PFS) (hepatic and extrahepatic), and overall survival (OS) were measured. Median target dose and activity were 109.4 Gy and 2.6 GBq per treatment session, respectively. Majority of clinical AE were grade 1 or 2 in severity. Patients with colorectal cancer had hepatic objective response rate (ORR) of 25% and a hepatic disease control rate (DCR) of 80%. Median PFS and OS were 1.0 and 4.4 months, respectively. Patients with neuroendocrine tumors (NET) had hepatic ORR and DCR of 73% and 100%, respectively. Median PFS was 8.9 months for this cohort. DCR and median PFS and OS for patients with cholangiocarcinoma were 86%, 1.1 months, and 6.7 months, respectively. 90Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.

Leksell Gamma Knife treatment for pilocytic astrocytomas: long-term results.

OBJECTIVE The purpose of this study was to evaluate long-term treatment results, radiation-related toxicity, and prognostic factors for the progression-free survival (PFS) of patients with pilocytic astrocytomas treated by means of stereotactic radiosurgery with a Leksell Gamma Knife. METHODS A total of 25 patients with pilocytic astrocytomas underwent Gamma Knife surgery during the period 1992-2002. The median target volume was 2700 mm(3) (range 205-25,000 mm(3)). The 18 patients treated with 5 daily fractions received a median minimum target dose of 25 Gy. Doses for the 2 patients treated with 10 fractions over 5 days (2 fractions delivered on the same day at least 6 hours apart) were 23 and 28 Gy. For the 5 patients treated with a single fraction, the minimum target dose ranged from 13 to 20 Gy (median 16 Gy). RESULTS Complete regression occurred in 10 patients (40%) and partial regression in 10 patients (40%). The 10-year overall survival rate was 96% and the 10-year PFS rate was 80%. Target volume appeared to be a significant prognostic factor for PFS (p = 0.037). Temporary Grade 3 toxicity appeared in 2 patients (8%), and these patients were treated with corticosteroids for 2 months. Permanent Grade 4 toxicity appeared in 2 patients (8%) and was associated with neurocognitive dysfunction. In these 2 individuals, the neurocognitive dysfunction was also felt to be in part the result of the additional therapeutic interventions (4 in one case and 6 in the other) required to achieve durable control of their tumors. CONCLUSIONS Radiosurgery represents an alternative treatment modality for small residual or recurrent volumes of pilocytic astrocytomas and provides long-term local control. Target volume appears to be the most important factor affecting PFS.

Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy.

IntroductionWe investigated the clinical outcome and the toxicity of trimodal therapy of malignant pleural mesothelioma (MPM) treated with neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant intensity-modulated radiotherapy (IMRT).MethodsChemotherapy regimens included Cisplatin/Pemetrexed, Carboplatin/Pemetrexed and Cisplatin/Gemcitabine, followed by EPP. 62 patients completed the adjuvant radiotherapy. IMRT was carried out in two techniques, either step&shoot or helical tomotherapy. Median target dose was 48 Gy to 54 Gy. Toxicity was scored with the Common Terminology Criteria (CTC) for Adverse Events. We used Kaplan-Meier method to estimate actuarial rate of locoregional control (LRC), distant control (DC) and overall survival (OS), measured from the date of surgery. Rates were compared using the logrank test. For multivariate analysis the Cox proportional hazard model was used.ResultsThe median OS, LRC and DC times were 20.4, 31.4 and 21.4 months. The 1-, 2-, 3-year OS rates were 63, 42, 28 %, the LRC rates were 81, 60, 40 %, and the DC rates were 62, 48, 41 %. We observed no CTC grade 4 or grade 5 toxicity. Step&shoot and helical tomotherapy were equivalent both in dosimetric characteristics and clinical outcome. Biphasic tumor histology was associated with worse clinical outcome compared to epitheloid histology.ConclusionsMature clinical results of trimodal treatment for MPM were presented. They indicate that hemithoracic radiotherapy after EPP can be safely administered by either step&shoot IMRT and tomotherapy. However, the optimal prospective patient selection for this aggressive trimodal therapy approach remains unclear. This study can serve as a benchmark for current and future therapy concepts for MPM.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0575-5) contains supplementary material, which is available to authorized users.

Whole-Field Sequential Intensity–Modulated Radiotherapy for Local-Regional Advanced Head-and-Neck Squamous Cell Carcinoma

There is little published data on the technique and results of whole-field (WF) sequential intensity-modulated radiotherapy (S-IMRT) for patients with head-and-neck squamous cell carcinoma (HNSCC). We report the treatment outcomes, adverse events (AEs), and dosimetric parameters in local-regional advanced (LRA) HNSCC patients treated with the WF S-IMRT technique. The IRB approved this retrospective study. Patients received WF S-IMRT with or without concomitant chemotherapy. Three separate IMRT plans corresponding to 3 planning target volumes were generated. This study reports patient and tumor characteristics, treatment-induced acute AEs based on CTCAE version 3.0, chronic AEs according to RTOG scale and treatment outcomes, local-regional control (LRC), distant metastases (DM), relapse-free survival (RFS), and overall survival (OS). Between January 2003 and December 2010, 103 patients with LRA HNSCC were treated either definitively or postoperatively with WF S-IMRT, with (99 patients) or without (4 patients) concurrent chemotherapy. The median age was 55 years (range, 30 to 89 y). The median cumulative target dose was 70 Gy (range, 60 to 75 Gy). At a median follow-up of 40 months (range, 4 to 95 mo), the 2- and 5-year rates of OS were 94% and 77%, RFS were 90% and 84%, LRC were 97% and 93%, and DM were 9% and 11%, respectively. Grade 3 acute AEs included mucositis (68%), dysphagia (35%), weight loss (19.6%), and xerostomia (7.8%). Chronic worst grade 3 AEs included xerostomia (21.9%), weight loss (12.8%), and dysphagia (12.5%). Chronic grade 3 AEs at last follow-up included weight loss (6.25%), dysphagia (6.2%), and xerostomia (6.2%). No patient had an acute or chronic grade 4 AE, brachial plexopathy, or spinal cord injury. WF S-IMRT results in excellent tumor control and an acceptable toxicity profile in LRA HNSCC patients treated with this technique.

Repeat Gamma-Knife Radiosurgery for Refractory or Recurrent Trigeminal Neuralgia with Consideration About the Optimal Second Dose

To investigate adequate radiation doses for repeat Gamma Knife radiosurgery (GKS) for trigeminal neuralgia in our series and meta-analysis. Fourteen patients treated by ipsilateral repeat GKS for trigeminal neuralgia were included. Median age of patients was 65 years (range, 28-78), the median target dose, 140-180). Patients were followed a median of 10.8 months (range, 1-151) after the second gamma-knife surgery. Brainstem dose analysis and vote-counting meta-analysis of 19 studies were performed. After the second gamma-knife radiosurgeries, pain was relieved effectively in 12 patients (86%; Barrow Neurological Institute Pain Intensity Score I-III). Post-gamma-knife radiosurgery trigeminal nerve deficits were mild in 5 patients. No serious anesthesia dolorosa was occurred. The second GKS radiation dose ≤ 60 Gy was significantly associated with worse pain control outcome (P = 0.018 in our series, permutation analysis of variance, and P = 0.009 in the meta-analysis, 2-tailed Fisher's exact test). Cumulative dose ≤ 140-150 Gy was significantly associated with poor pain control outcome (P = 0.033 in our series and P = 0.013 in the meta-analysis, 2-tailed Fisher's exact test). A cumulative brainstem edge dose >12 Gy tended to be associated with trigeminal nerve deficit (P = 0.077). Our study suggests that the second GKS dose is a potentially important factor.

Yttrium-90 Glass-Based Microsphere Radioembolization in the Treatment of Hepatocellular Carcinoma Secondary to the Hepatitis B Virus: Safety, Efficacy, and Survival

PurposeTo evaluate outcomes of yttrium-90 radioembolization performed with glass-based microspheres in the treatment of hepatocellular carcinoma (HCC) secondary to the hepatitis B virus (HBV). Materials and MethodsA total of 675 patients treated between January 2006 and July 2014 were reviewed, of which 45 (age 62 y ± 10; 91% male) received glass-based radioembolization for HCC secondary to HBV. All patients were stratified according to previous therapy (naive, n = 14; 31.1%), Child–Pugh class (class A, n = 41; 91%), Eastern Cooperative Oncology Group (ECOG) performance status (PS; < 1, n = 21; 47%), solitary (n = 26; 58%) and unilobar (n = 37; 82%) tumor distribution, tumor size < 5 cm (n = 29; 64%), portal vein thrombosis (n = 14; 31%), α-fetoprotein level > 400 ng/mL (n = 17; 38%), and Barcelona Clinic Liver Cancer stage (A, n = 8; B, n = 9; C, n = 28). ResultsA total of 50 radioembolization treatments were performed, with a 100% technical success rate (median target dose, 120 Gy). Clinical toxicities included pain (16%), fatigue (12%), and nausea (4%). Grade 3/4 laboratory toxicities included bilirubin (8%) and aspartate aminotransferase (4%) toxicities. Observed toxicities were independent of treatment dose. The objective response rates were 55% per modified Response Evaluation Criteria In Solid Tumors and 21% per World Health Organization criteria, and the disease control rate was 63%. Disease progression was secondary to new, nontarget HCC in 45% of cases. Median time to progression and overall survival were 6.0 mo (95% confidence interval [CI], 4.4–8.0 mo) and 19.3 mo (95% CI, 11.2–22.7 mo), respectively. Multivariate analysis demonstrated ECOG PS ≥ 1 and AFP level > 400 ng/mL to be independent predictors of inferior overall survival. ConclusionsGlass-based radioembolization for HCC secondary to HBV can be safely performed, with favorable target lesion response and overall survival.

90Y Glass Microspheres for the Treatment of Unresectable Metastatic Liver Disease from Chemotherapy-Refractory Gastrointestinal Cancers: A Pilot Study

This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of treatment of liver-dominant metastatic gastrointestinal cancer using (90)Y glass microspheres. Between June 2010 and November 2012, 30 adult patients (22 men, eight women; median age 61 years) with metastatic chemotherapy-refractory unresectable colorectal (n = 15), neuroendocrine (n = 9), intrahepatic cholangiocarcinoma (n = 3), pancreas (n = 2), and esophageal (n = 1) carcinomas underwent 45 lobar or segmental administrations of (90)Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for 6 months after each treatment. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1. Time to maximum response, response duration, progression-free survival (hepatic and extrahepatic), and overall survival were measured. Median target dose and activity were 111.6 Gy and 2.5 GBq per treatment session, respectively. All but three clinical AE were grade 1 or 2 in severity. Serious AE included an unplanned hospital admission for carcinoid crisis, grade 3 vomiting, and grade 4 gastric ulcer. Patients with colorectal cancer had hepatic objective response rate (ORR) of 27 % and a disease control rate (DCR) of 73 %. Median progression-free and overall survival were 1.0 and 4.9 months, respectively. Patients with neuroendocrine tumors had hepatic ORR and DCR of 78 % and 100 %, respectively. Median progression-free survival was 18.5 months for this cohort. Y glass microspheres device has a favorable safety profile and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.

90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: A pilot study.

359 Background: This prospective single-institution pilot study was undertaken to document the feasibility, safety, and efficacy of treatment of liver-dominant metastatic gastrointestinal cancer using 90Y glass microspheres. Methods: Between June 2010 and November 2012, 30 adult patients (22 men, 8 women; median age 61 years) with metastatic chemotherapy-refractory unresectable colorectal (n=15), neuroendocrine (n=9), biliary tract (n=3), pancreas (n=2), and esophageal (n=1) carcinomas underwent 45 lobar or segmental administrations of 90Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for 6 months after each treatment. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1. Time to maximum response, response duration, progression-free survival (hepatic and extrahepatic), and overall survival were measured. Results: Median target dose and activity were 111.6Gy and 2.5GBq per treatment session, respectively. All but 3 clinical AE were grade 1 or 2 in severity. The most frequent clinical AE were fatigue (83%), anorexia (50%), nausea (50%), abdominal pain (40%), vomiting (20%), fever (17%), and sweating (17%). Common metabolic and laboratory AE included hypoalbuminemia (50%), transaminitis (63%), and hyperbilirubinemia (27%). Serious AE included an unplanned hospital admission for carcinoid crisis, grade 3 vomiting, and grade 4 gastric ulcer. Patients with colorectal cancer had hepatic objective response rate (ORR) of 27% and a disease control rate (DCR) of 73%. Median progression-free and overall survival were 1.0 and 4.9 months, respectively. Patients with neuroendocrine tumors had hepatic ORR and DCR of 78% and 100%, respectively. Median progression-free survival was 18.5 months for this cohort. Conclusions: 90Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort. Clinical trial information: NCT01290536.

A plea for the GTV median dose reporting in SBRT/can the ICRU 83 reporting way be applied to SBRT plans?

Purpose Plan comparison is difficult with various prescriptions (80% of maximum dose, on the 70% or 50%). In 2010 the AAPM TG 101 suggests to report SBRT with prescription ICRU reference point or isodose covering PTV to a particular percentage. At the same time ICRU report 83 for IMRT was published, the ICRU point is abandoned and prescription is based on median target dose. Can we conciliate these 2 reports? Methods Theoretical plans with Cyberknife for spherical GTV of from 2 to 60 mm were created with prescription of 10 Gy with based on % of maximum dose perfectly adjusted to cover 95% of PTV. GTV median doses were collected. Plans with a shift equal to the PTV margin, in the direction of the minimum observed in the dose distribution, were created and the GTV D50% were again collected. Three different clinical situations: brain metastases, prostate and lung lesion were assessed with different percentage of maximum dose used for prescription and again applying a shift. Results The GTV median dose is little sensitive to the minimum in the PTV, and thus remains almost constant in all cases i.e. when we imagine a systematic error equal to the PTV margin. With the 6 mm PTV and a prescription isodose of 54%, i.e. with a fall-off of 20%/mm at the edge of the PTV, the GTV median dose is 14.77 Gy and 14.75 Gy with the shift. For the particular case of lung where the PTV includes a low density region, using Monte-Carlo calculation, the GTV median dose is also stable. Conclusions The GTV median dose appears to be a convenient way to describe the dose distribution delivered, whatever the % of maximum dose used for prescription. For a better understanding of the dose distributions, every team should report PTV D98%, PTV D95%, PTV D2% and GTV median dose like ICRU report 83 recommends for IMRT, in order to compare clinical studies.

Role of Early Proctoscopy in Predicting Late Symptomatic Proctitis After External Radiation Therapy for Prostate Carcinoma

To determine whether acute radiation-proctitis, diagnosed by proctoscopy after radiation therapy for prostate cancer, can predict late clinical proctitis. A prospective study of 130 patients who underwent external radiation therapy (RT) for stage T1 to T4 prostate cancer between 1997 and 2008 was performed. Treatments were conventional (2-dimensional [2D]) in 61 patients and 3D conformal in 69, with a median target dose of 72 Gy (70-74 Gy). Within 1 week after RT, proctoscopy was performed to detect possible acute endoscopic proctitis (AEP). Acute clinical proctitis (ACP) and late clinical proctitis (LCP) were also evaluated. The median follow-up was 84 months (20-180 months). The influence of AEP and ACP on LCP occurrence was studied using the Cox model controlling for age, dose, prostatectomy, RT technique (2D vs 3D), and hormone therapy. AEP was detected in 15 patients (11.5%) and ACP in 67 (51.5%); in 13 cases (10%) AEP and ACP occurred simultaneously. Thirty-five cases of LCP were recorded. The 5-year probability of developing LCP was highest in patients with AEP and ACP (77%, 95% confidence interval [CI] 53%-94%) and lowest in asymptomatic patients (14%, 95% CI 7%-26%; P<.001). Compared to asymptomatic patients, the 5-year probability also was slightly increased in patients with ACP only (26%, 95% CI 16%-40%; P=.052). In multivariable analysis, the combination of AEP and ACP was the main predictor of LCP: compared to asymptomatic patients, the hazard ratio was 5.6 (2.1-15.2) in patients with AEP plus ACP (P=.001) and 2.1 (0.9-4.9) in those with ACP only (P=.103). In patients with AEP and ACP, the risk of LCP was more than 5-fold increased compared to those who were asymptomatic, while a much smaller increase in risk occurred in patients with ACP only. Early proctoscopy can provide valuable information regarding the likelihood of late proctitis.

Perspectives on key articles in neurosurgery

Park, Kyung-Jae MD, PhD*,‡; Kondziolka, Douglas MD*; Berkowitz, Oren RPA-C, MSPH*; Kano, Hideyuki MD, PhD*; Novotny, Josef Jr PhD*; Niranjan, Ajay MS, MCh*; Flickinger, John C. MD*; Lunsford, L. Dade MD* Neurosurgery, 2012 Feb;70(2):295-305 Study Question: What is the efficacy of repeat radiosurgery on patients with recurrent trigeminal neuralgia? Methods: Park et al. performed a retrospective study on 119 patients who were previously treated with the gamma knife for trigeminal neuralgia. Patients were treated with a median target dose for 70 Gy (dose ranging between 50 and 90 Gy). The endpoints used were pain relief according to the Barrow Neurological Institute pain score and facial sensory dysfunction. Results: The authors reported that their median follow-up was 48 months (ranging between 6 and 187 months). Their median interval for treatment was 26 months. The authors reported that 87% of their patients experienced initial pain relief. At 1 year, 3 years, and 5 years, the pain relief rates were 87.8%, 69.8%, and 44.2%, respectively. The authors found that patients who presented with recurrent facial pain in a distribution smaller than their initial presentation had a more favorable prognosis. Facial sensory dysfunction rates were 21% within 18 months; however, facial sensory dysfunction was a favorable indicator for pain relief. The authors also found that having a higher dose of radiation to the brainstem correlated with sensory dysfunction. Conclusion: Park et al. conclude that repeat radiosurgery for trigeminal neuralgia can be as effective as the initial treatment in terms of pain relief. Perspective: Radiosurgery for trigeminal neuralgia was initially reserved for patients who were not good candidates for a microvascular decompression. However, there are an increasing number of patients with trigeminal neuralgia who are treated with radiosurgery. Given that radiosurgery is not as durable as a microvascular decompression for pain relief, there are an increasing number of patients who present with recurrent pain. Park et al. report that repeat treatments can be just as effective in pain control. However, the rate of facial sensory dysfunction is higher for the second treatment. Interestingly, for repeat treatments, sensory dysfunction appears to correlate with pain relief. Despite the fact that the rate of facial numbness is higher with a second treatment, the authors also point out that rhizotomies also carry a significant risk for facial sensory changes. Finally, the time to pain relief took 1.5 months which is similar to the latency for a first treatment. This paper suggests that we can safely use repeat radiosurgery for patients with recurrent TN. Summary written by: Michael Lim