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Purpose: The vitamin E analog γ-tocotrienol (GT3) is a powerful radioprotector. GT3 reduces postradiation vascular peroxynitrite production, an effect dependent on inhibition of hydroxy-methylglutaryl–coenzyme A reductase. Hydroxy-methylglutaryl–coenzyme A reductase inhibitors mediate their pleiotropic effects via endothelial nitric oxide synthase that requires the cofactor tetrahydrobiopterin (BH4). This study investigated the effects of radiation on BH4 bioavailability and of GT3 on BH4 metabolism. Methods and Materials: Mice were exposed to 8.5 Gy of total body irradiation (TBI). Lung BH4 and total biopterin concentrations were measured 0, 3.5, 7, 14, and 21 days after TBI by use of differential oxidation followed by high-performance liquid chromatography. The effect of exogenous GT3 and BH4 treatment on postradiation vascular oxidative stress and bone marrow colony–forming units were assessed in vivo. The effect of GT3 on endothelial cell apoptosis and endothelial expression of guanosine triphosphate (GTP) cyclohydrolase 1 (GTPCH), GTPCH feedback regulatory protein (GFRP), GFRP transcription, GFRP protein levels, and GFRP–GTPCH protein binding was determined in vitro. Results: Compared with baseline levels, lung BH4 concentrations decreased by 24% at 3.5 days after TBI, an effect that was reversed by GT3. At 14 and 21 days after TBI, compensatory increases in BH4 (58% and 80%, respectively) were observed. Relative to vehicle-treated controls, both GT3 and BH4 supplementation reduced postirradiation vascular peroxynitrite production at 3.5 days (by 66% and 33%, respectively), and BH4 resulted in a 68% increase in bone marrow colony–forming units. GT3 ameliorated endothelial cell apoptosis and reduced endothelial GFRP protein levels and GFRP–GTPCH binding by decreasing transcription of the GFRP gene. Conclusions: BH4 bioavailability is reduced in the early postradiation phase. Exogenous administration of BH4 reduces postirradiation vascular oxidative stress. GT3 potently reduces the expression of GFRP, one of the key regulatory proteins in the BH4 pathway, and may thus exert some of its beneficial effects on postradiation free radical production partly by counteracting the decrease in BH4. [Copyright &y& Elsevier]

Purpose: Pathologic complete tumor response after chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with a favorable prognosis and allows organ-sparing treatment strategies. In the RECTAL-BOOST trial, we aimed to investigate the effect of an external radiation boost to the tumor before chemoradiation on pathologic or sustained clinical complete tumor response in LARC.Methods and Materials: This multicenter, nonblinded, phase 2 randomized controlled trial followed the trials-within-cohorts design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can either accept or refuse this), whereas patients in the control group are not notified about the randomization. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of 2 radiation therapy centers were eligible. Patients were randomized to no boost or an external radiation boost (5 × 3 Gy) without concurrent chemotherapy, directly followed by standard pelvic chemoradiation (25 × 2 Gy with concurrent capecitabine). The primary outcome was pathologic complete response (ie, ypT0N0) in patients with planned surgery at 12 weeks, or, as surrogate for pathologic complete response, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCT01951521.Results: Between September 2014 and July 2018, 128 patients were randomized. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4 stage and a low rectal tumor (31.3% vs 17.2% and 56.3% vs 45.3%, respectively), and more patients had a cN2 stage (59.4% vs 70.3%, respectively). Rate of pathologic or sustained clinical complete tumor response was similar between the groups: 23 of 64 (35.9%; 95% confidence interval [CI], 24.3-48.9) in the intervention group versus 24 of 64 (37.5%; 95% CI, 25.7-50.5) in the control group (odds ratio [OR] = 0.94; 95% CI, 0.46-1.92). Near-complete or complete tumor regression was more common in the intervention group (34 of 49; 69.4%) than in the control group (24 of 53; 45.3%; (OR = 2.74, 95% CI 1.21-6.18). Grade ≥3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR = 1.22; 95% CI, 0.35-4.22).Conclusions: Dose escalation with an external radiation therapy boost to the tumor before neoadjuvant chemoradiation did not increase the pathologic or sustained clinical complete tumor response rate in LARC. [ABSTRACT FROM AUTHOR]

Even though High Dose Rate (HDR) brachytherapy has good treatment outcomes in different treatment sites, treatment verification is far from widely implemented because of a lack of easily available solutions. Previously it has been shown that an imaging panel (IP) near the patient can be used to determine treatment parameters such as the dwell time and source positions in a single material pelvic phantom. In this study we will use a heterogeneous head phantom to test this IP approach, and simulate common treatment errors to assess the sensitivity and specificity of the error-detecting capabilities of the IP. A heterogeneous head-phantom consisting of soft tissue and bone equivalent materials was 3D-printed to simulate a base of tongue treatment. An High Dose Rate treatment plan with 3 different catheters was used to simulate a treatment delivery, using dwell times ranging from 0.3 s to 4 s and inter-dwell distances of 2 mm. The IP was used to measure dwell times, positions and detect simulated errors. Measured dwell times and positions were used to calculate the delivered dose. Dwell times could be determined within 0.1 s. Source positions were measured with submillimeter accuracy in the plane of the IP, and average distance accuracy of 1.7 mm in three dimensions. All simulated treatment errors (catheter swap, catheter shift, afterloader errors) were detected. Dose calculations show slightly different distributions with the measured dwell positions and dwell times (gamma pass rate for 1 mm/1% of 96.5%). Using an IP, it was possible to verify the treatment in a realistic heterogeneous phantom and detect certain treatment errors. [ABSTRACT FROM AUTHOR]

The various rectal endoluminal radiation techniques all have steep, but different, dose gradients. In rectal contact brachytherapy (CXB) doses are typically prescribed and reported to the applicator surface and not to the gross tumor volume (GTV), clinical target volume (CTV) or organs at risk (OAR), which is crucial to understand tumor response and toxicity rates. To quantify the above-described problem, we performed a dose modeling study using a fixed prescription dose at the surface of the applicator and varied tumor response scenarios. Endorectal ultrasound-based 3D-volume-models of rectal tumors and the rectal wall were used to simulate the delivered dose to GTV, CTV and the rectal wall layers, assuming treatment with Maastro HDR contact applicator for rectal cancer with a fixed prescription dose to the applicator surface (equivalent to 3 × 30 Gy CXB) and various response scenarios. An identical prescribed dose to the surface of the applicator resulted in a broad range of doses delivered to the GTV, CTV and the uninvolved intestinal wall. For example, the equieffective dose in 2 Gy per fraction (EQD2) D90% of the GTV varied between 63 and 231 Gy, whereas the EQD2 D2cc of the rectal wall varied between 97 and 165 Gy. Doses prescribed at the surface are not representative of the dose received by the tumor and the bowel wall. This stresses the relevance of dose reporting and prescription to GTV and CTV volumes and OAR in order to gain insight between delivered dose, local control and toxicity and to optimize treatment protocols. [ABSTRACT FROM AUTHOR]

Purpose: Dose-escalated chemoradiation (CRT) for locally advanced rectal cancer did not result in higher complete response rates but initiated more tumor regression in the randomized RECTAL-BOOST trial (Clinicaltrials.gov NCT01951521). This study compared patient reported outcomes between patients who received dose-escalated CRT (5 × 3 gray boost + CRT) or standard CRT for 2 years after randomization.Methods and Materials: Patients with locally advanced rectal cancer who were participating in the RECTAL-BOOST trial filled out European Organisation for Research and Treatment of Cancer QLQ-C30 and CR29 questionnaires on quality of life (QoL) and symptoms at baseline, 3, 6, 12, 18, and 24 months after start of treatment. Between-group differences in functional QoL domains were estimated using a linear mixed-effects model and expressed as effect size (ES). Symptom scores were compared using Mann-Whitney U test.Results: Patients treated with dose-escalated CRT (boost group, n = 51) experienced a significantly stronger decline in global health at 3 and 6 months (ES -0.4 and ES -0.4), physical functioning at 6 months (ES -1.1), role functioning at 3 and 6 months (ES -0.8 and ES -0.6), and social functioning at 6 months (ES -0.6), compared with patients treated with standard CRT (control group, n = 64). The boost group reported significantly more fatigue at 3 and 6 months (83% vs 66% respectively 89% vs 76%), pain at 3 and 6 months (67% vs 36% respectively 80% vs 44%), and diarrhea at 3 months (45% vs 29%) compared with the control group. From 12 months onwards, QoL and symptoms were similar between groups, apart from more blood/mucus in stool in the boost group.Conclusions: In patients with locally advanced rectal cancer, dose-escalated CRT resulted in a transient deterioration in global health, physical, role, and social functioning and more pain, fatigue and diarrhea at 3 and 6 months after start of treatment compared with standard CRT. From 12 months onwards, the effect of dose-escalated CRT on QoL largely resolved. [ABSTRACT FROM AUTHOR]

Highlights from the article: We appreciate the response of the HERBERT study group regarding our review on toxicity of various endorectal boosting techniques and are pleased that they agree with our conclusions [1], [2]. In our review, it is written: "The dose limiting-toxicity was set at 7 Gy after 3 of 10 patients (30%) experienced acute Grade 3 radiation proctitis" (2, page 83). In this sentence, we refer to the fact that the dose considered to be safe was set at 7 Gy as in the 8 Gy dose group, Grade 3 toxicity was observed in 3 of 10 patients.

Abstract: Purpose: To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients. Material and methods: A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade ⩾2 within 6months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC). Results: Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p <0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p <0.001) on the training set, and 0.67 (p <0.001) on the validation set. Conclusion: Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients. [Copyright &y& Elsevier]

Abstract Purpose A clinical complete response is seen after neoadjuvant chemoradiation for rectal tumors in 15%–20% of patients. These patients can potentially be spared mutilating total mesorectal excision surgery through a watch-and-wait policy. Recent studies show that dose escalation by a radiation boost increases the clinical complete response rate. The boost dose to the tumor can be administered through external beam radiotherapy or through internal radiotherapy using techniques like contact therapy, low-dose-rate or high-dose-rate brachytherapy (BT). However, limited information is available concerning treatment-related toxicity of these techniques. With this systematic review, we aim to summarize and compare published data concerning acute and late toxicity after contact X-ray therapy (CXT) and BT for rectal cancer. Methods and Materials/Results Thirty-eight studies reporting toxicity after endorectal radiation techniques for rectal cancer were included, resulting in 3682 patients for analysis. Direct comparison of toxicity by the different radiation modes was hampered by various combinations of endorectal techniques, a lack of clear reporting of toxicity scores, dose prescription, technique used, and treated volumes. ≥ Grade 3 rectal toxicity was reported in 2.9% of patients having received only CXT; 6.3% of patients who received only BT had Grade 3 rectal toxicity, and BT also caused Grade 3 urinary toxicity in 1 patient. Conclusion All techniques reported some ≥ Grade 3 toxicity. Toxicity after CXT was confined to the rectum, whereas after BT, urogenital toxicity and skin toxicity were seen as well. Unfortunately, few specific conclusions could be drawn regarding the dose-related risk of toxicity for the various techniques due to nonuniform reporting strategies and missing information. To enable future comparisons and improvements, the endorectal radiation field urgently needs consensus guidelines on dose reporting, dose prescription, treatment volume specification, and toxicity reporting. [ABSTRACT FROM AUTHOR]