T. Dijkema

Brief report: enzyme inducers reduce elimination half-life after a single dose of nevirapine in healthy women.

Objective:Single-dose nevirapine (SD-NVP) to prevent mother-to-child transmission (MTCT) of HIV is associated with development of NVP resistance, probably because of its long half-life in combination with a low genetic barrier to resistance. The objective of this study was to find enzyme inducers to reduce the NVP half-life. Design:The design of this phase 1 pharmacokinetic study was a single-center, open-label, 2-period, 9-group study. Methods:After administration of a single 200-mg dose of NVP to HIV-seronegative nonpregnant women in periods 1 and 2, blood was sampled twice a week for 21 days. In period 2, additional interventions (single-dose carbamazepine, phenobarbital, or phenytoin; phenytoin for 3 or 7 days; or St. Johns wort, vitamin A, or cholecalciferol for 14 days) were administered to all subjects except for the control group. Results:Thirty-six subjects participated. In 3 intervention groups, the T-half ratio (nevirapine half-life in period 2/half-life in period 1) differed significantly from that in the control group: a single 400-mg dose of carbamazepine (P = 0.021) or 184 mg of phenytoin once daily for 3 (P = 0.021) or 7 days (P = 0.021). The median decreases in the NVP half-life were 18.8, 19.0, and 16.9 hours, respectively. Conclusions:Interventions with a single dose of 400 mg of carbamazepine or 184 mg of phenytoin for 3 or 7 days effectively reduced the NVP half-life. Appropriately powered safety and feasibility end point studies are warranted before these interventions can be tested in the setting of single-dose NVP for prevention of mother-to-child transmission (PMTCT) of HIV to reduce the development of NVP resistance.

Cross-institutional knowledge-based planning (KBP) implementation and its performance comparison to Auto-Planning Engine (APE)

BACKGROUND AND PURPOSEnTo investigate (1) whether a plan library established at one institution can be applied for another institutions knowledge-based planning (KBP); (2) the performance of cross-institutional KBP compared to Auto-Planning Engine (APE).nnnMATERIAL AND METHODSnRadboud University Medical Center (RUMC) provided 35 oropharyngeal cancer patients (68Gy to PTV68 and 50.3Gy to PTV50.3) with clinically-delivered and comparative APE plans. The Johns Hopkins University (JHU) contributed a three-dose-level plan library consisting of 179 clinically-delivered plans. MedStar Georgetown University Hospital (MGUH) contributed a KBP approach employing overlap-volume histogram (OVH-KBP), where the JHU library was used for guiding RUMC patients KBP. Since clinical protocols adopted at RUMC and JHU are different and both approaches require protocol-specific planning parameters as initial input, 10 randomly selected patients from RUMC were set aside for deriving them. The finalized parameters were applied to the remaining 25 patients for OVH-KBP and APE plan generation. A Wilcoxon rank-sum test was used for statistical comparison.nnnRESULTSnPTV68 and PTV50.3s V95 in OVH-KBP and APE were similar (p>0.36). Cords D0.1 cc in OVH-KBP was reduced by 5.1Gy (p=0.0001); doses to other organs were similar (p>0.2).nnnCONCLUSIONnAPE and OVH-KBPs plan quality is comparable. Institutional-protocol differences can be addressed to allow cross-institutional library sharing.

Patterns of Recurrence in Electively Irradiated Lymph Node Regions After Definitive Accelerated Intensity Modulated Radiation Therapy for Head and Neck Squamous Cell Carcinoma

PURPOSEnTo provide a comprehensive risk assessment on the patterns of recurrence in electively irradiated lymph node regions after definitive radiation therapy for head and neck cancer.nnnMETHODS AND MATERIALSnTwo hundred sixty-four patients with stage cT2-4N0-2M0 squamous cell carcinoma of the oropharynx, larynx, or hypopharynx treated with accelerated intensity modulated radiation therapy between 2008 and 2012 were included. On the radiation therapy planning computed tomography (CT) scans from all patients, 1166 lymph nodes (short-axis diameter ≥5xa0mm) localized in the elective volume were identified and delineated. The exact sites of regional recurrences were reconstructed and projected on the initial radiation therapy planning CT scan by performing coregistration with diagnostic imaging of the recurrence.nnnRESULTSnThe actuarial rate of recurrence in electively irradiated lymph node regions at 2xa0years was 5.1% (95% confidence interval 2.4%-7.8%). Volumetric analysis showed an increased risk of recurrence with increasing nodal volume. Receiver operating characteristic analysis demonstrated that the summed long- and short-axis diameter is a good alternative for laborious volume calculations, using ≥17xa0mm as cut-off (hazard ratio 17.8; 95% confidence interval 5.7-55.1; P<.001).nnnCONCLUSIONSnAn important risk factor was identified that can help clinicians in the pretreatment risk assessment of borderline-sized lymph nodes. Not overtly pathologic nodes with a summed diameter ≥17xa0mm may require a higher than elective radiation therapy dose. For low-risk elective regions (all nodes <17xa0mm), the safety of dose de-escalation below the traditional 45 to 50xa0Gy should be investigated.

Reirradiation of head and neck cancer: Long‐term disease control and toxicity

The purpose of this study was to report long‐term disease control and late radiation toxicity for patients reirradiated for head and neck cancer.

Automated IMRT planning in Pinnacle

PurposeThis study evaluates the performance and planning efficacy of the Auto-Planning (AP) module in the clinical version of Pinnacle 9.10 (Philips Radiation Oncology Systems, Fitchburg, WI, USA).Methods and materialsTwenty automated intensity-modulated radiotherapy (IMRT) plans were compared with the original manually planned clinical IMRT plans from patients with oropharyngeal cancer.ResultsAuto-Planning with IMRT offers similar coverage of the planning target volume as the original manually planned clinical plans, as well as better sparing of the contralateral parotid gland, contralateral submandibular gland, larynx, mandible, and brainstem. The mean dose of the contralateral parotid gland and contralateral submandibular gland could be reduced by 2.5u2009Gy and 1.7u2009Gy on average. The number of monitor units was reduced with an average of 143.9 (18%). Hands-on planning time was reduced from 1.5–3u2009h to less than 1u2009h.ConclusionsThe Auto-Planning module was able to produce clinically acceptable head and neck IMRT plans with consistent quality.ZusammenfassungZieleDiese Studie untersucht die Leistungsfähigkeit und Planungseffektivität des Auto-Planning-Moduls in der klinischen Version von Pinnaclexa09.10 (Philips Radiation Oncology Systems, Fitchburg, WI, USA).Methoden und MaterialZwanzig automatisch erstellte Pläne für die intensitätsmodulierte Strahlentherapie (IMRT) wurden mit den ursprünglichen manuell erstellten klinischen IMRT-Plänen von Patienten mit Oropharynxkarzinom verglichen.ErgebnisseDie automatisch erstellten IMRT-Pläne bieten eine vergleichbare Deckung des Planungszielvolumens (PTV) wie die ursprünglichen, manuell erstellten klinischen Pläne sowie eine verbesserte Schonung der kontralateralen Ohrspeicheldrüse, der kontralateralen Unterkieferspeicheldrüse, des Kehlkopfs, des Unterkiefers und des Hirnstamms. Die mittlere Dosis der kontralateralen Ohr- und kontralateralen Unterkieferspeicheldrüse konnte um durchschnittlich 2,5 bzw. 1,7u2009Gy reduziert werden. Die Anzahl der Monitoreinheiten wurde im Durchschnitt um 143,9 (18u2009%) reduziert. Die praktische Planungszeit wurde von 1,5–3u2009h auf weniger als 1u2009h minimiert.SchlussfolgerungDas Auto-Planning-Modul war in der Lage, klinisch akzeptable Kopf-Hals-IMRT-Pläne mit konsistenter Qualität zu produzieren.

Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma

BackgroundIn definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called ‘elective dose’ in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary.Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment.MethodsUPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial.Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4xa0N0-2xa0M0 squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors.In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level.Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5xa0weeks. The primary endpoint is ‘normalcy of diet’ at 1xa0year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2xa0years after treatment (safety).DiscussionThe objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck.Trial registrationClinicalTrials.gov Identifier: NCT02442375.

Tumor to cervical spinal cord standardized uptake ratio (SUR) improves the reproducibility of 18 F-FDG-PET based tumor segmentation in head and neck squamous cell carcinoma in a multicenter setting

BACKGROUNDnIn quantitative FDG-PET data analysis, normalization of the standardized uptake value (SUV) with an internal image-derived standard improves its reproducibility. In this study, the cervical spinal cord is proposed as an internal standard that is within the field of view of the radiotherapy planning PET/CT-scan in head and neck cancer. The aim is to evaluate if the tumor to cervical spinal cord standardized uptake ratio (SUR) can improve the reproducibility of a model to determine the metabolic tumor volume (MTV) on FDG-PET/CT in a multicenter setting.nnnMATERIALS AND METHODSnNinety-five radiotherapy planning FDG-PET/CT-scans of patients with head and neck cancer were analyzed using the Bland-Altman method to evaluate differences in FDG-uptake in the cervical spinal cord and the mediastinal blood pool. Non-linear regression analysis was used to determine the optimal MTV using the gross tumor volume (GTV) as ground truth and a spatial overlap-index as statistical validation metric. Reproducibility was evaluated using the Bland-Altman method and external validation was performed in an independent dataset consisting of 62 patients.nnnRESULTSnBland-Altmans analyses demonstrated equivalence of FDG-uptake in the mediastinal blood pool and the cervical spinal cord. Reproducibility of the models improved when using SUR instead of SUV. These results were confirmed in the validation cohort.nnnCONCLUSIONnThe use of the tumor to cervical spinal cord SUR instead of SUV improves the reproducibility of a model to determine the MTV on FDG-PET/CT in a multicenter setting. This study indicates that SUR may be preferred over SUV based approaches.

Correction to: Automated IMRT planning in Pinnacle—A study in head-and-neck cancer

Correction to:Strahlenther Onkol 2017https://doi.org/10.1007/s00066-017-1187-9n Unfortunately, parts of the ‘Materials and Methods section’ and axa0sentence in the ‘Discussion section’ had to be corrected.On pagexa03, left column, the complete first paragraph was corrected and now reads as follows:Auto-P

EP-1099: Re-irradiation for head and neck tumors: efficacy versus late toxicity in 137 patients

Material and Methods: Patients with head and neck cancer that had completed IMRT to unilateral or bilateral neck with a minimum of 2 years of follow up were identified from a prospective database. All patients underwent clinical review as per local protocol which was commonly 6 weekly. The brachial plexus was contoured based on RTOG Atlas. Maximum dose (Dmax) to brachial plexus was recorded from DVH. All doses were converted to BED using an α/β ratio of 2. A review of electronic records was performed to determine brachial plexus toxicity using CTCAE v 3.0.

MO-G-201-01: A Multi-Institutional Study Investigating the Performance of a Knowledge-Based Planning System Against Pinnacle Auto-Planning Engine in SIB-IMRT for the Head-And-Neck Cancer

PURPOSEnKnowledge-based Planning (KBP) founded on prior planning experience and Auto-Planning Engine (APE; commercialized in Pinnacle v9.10 TPS) based on progressive optimization algorithm both aim to eliminate the trial-and-error process in radiotherapy inverse planning. This study investigates the performance of the approaches in a multi-institutional setting to evaluate their functionalities in oropharyngeal cancer and offers suggestions how they can be implemented in the clinic.nnnMETHODSnRadboud University Medical Center (RUMC) provided 35 oropharyngeal cancer patients (SIB-IMRT with two-dose-level prescription: 68 Gy to PTV68 and 50.3 Gy to PTV50.3) with corresponding comparative APE plans. Johns Hopkins University (JHU) contributed to a three-dose-level (70 Gy 63 Gy and 58.1 Gy) plan library for RUMCs patient KBP generation. MedStar Georgetown University Hospital (MGUH) contributed to a KBP approach employing overlap-volume histogram (OVH-KBP) for generating RUMCs patient KBP plans using JHUs plan library. Since both approaches need their own user-defined parameters as initial inputs the first 10 patients were set aside as training set to finalize them. Meanwhile cross-institutional comparisons and adjustments were implemented for investigating institutions protocol discrepancies and the approaches user-defined parameters were updated accordingly. The finalized parameters were then applied to the remaining 25 patients for OVH-KBP and APE generation. A Wilcoxon rank-sum test was used for statistical comparison with significance level of p<0.05.nnnRESULTSnOn average PTV68s V95 was 96.5% in APE plans vs. 97% in OVH-KBP plans (p=0.36); PTV50.3s V95 in APE plans was 97.8% vs.97.6% in OVH-KBP plans (p=0.6); cords D0.1 cc was 38.6 Gy in OVH-KBP plans vs. 43.7 Gy in APE plans (p=0.0001); mean doses to larynxes oral cavities parotids and submandibular glands were similar with p>0.2.nnnCONCLUSIONSnThe study demonstrates that KBP and APE can generate plans of comparable quality in a multi-institutional setting. Variations in clinical protocols can be effectively addressed for cross-institutional adaptations. Binbin Wu and Todd McNutt are the co-inventors of a patent associated with the proposed knowledge-based planning system which was licensed to Varian Medical Systems in 2015; This research was in part supported by Philips Radiation Oncology Systems.