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Is Hippocampal Avoidance During Whole-Brain Radiotherapy Risky for Patients With Small-Cell Lung Cancer? Hippocampal Metastasis Rate and Associated Risk Factors.

ABSTRACT: Hippocampal avoidance during whole-brain radiotherapy is performed to prevent neural stem cell injury causing neurocognitive dysfunction. Nevertheless, the estimated risk of metastases in hippocampal avoidance area in small-cell lung cancer is unknown. The current study aimed to characterize the metastatic distribution within the brain relative to the hippocampus, estimate the incidence of hippocampal metastasis in patients with small-cell lung cancer, and identify clinical and radiographic variables that may be associated with the risk of hippocampal avoidance area metastasis.Patients with small-cell lung cancer treated with therapeutic whole-brain radiotherapy between January 2010 and December 2015 were reviewed. T1-weighted, postcontrast axial magnetic resonance images obtained just before therapeutic cranial irradiation were retrieved and reviewed for each patient. The hippocampal avoidance area was defined as hippocampus and 5-mm ring area adjacent to the hippocampus to account for necessary dose falloff between the hippocampus and the whole-brain planning target volume. Metastatic lesions within hippocampal avoidance area were defined as hippocampal metastasis. Hippocampal metastasis rate and characteristics of patients with hippocampal metastasis were analyzed and compared to patients without hippocampal metastasis.Fifty-four patients evaluated with cranial magnetic resonance imaging were enrolled. Hippocampal metastasis rate was 32% (17 patients). A total of 4.4% of all metastases involved the hippocampal avoidance area. The most common location was frontal lobe. Being younger than 65 years of age was found to be an independent risk factor for HM (odds ratio: 4.8, 95% confidence interval: 1-23.2, P = .049). The number of brain metastases was significantly higher in patients with hippocampal metastasis ( P = .027), and hippocampal metastasis rate was also higher in patients having larger hippocampus ( P = .026) and larger brain volumes ( P = .02).Hippocampal metastasis might be more common in small-cell lung cancer. Reducing the dose to the hippocampus by hippocampal avoiding whole-brain radiotherapy plan in small-cell lung cancer may be risky for the development of HM compared with other malignant solid tumors.

SUBMITTER: Korkmaz Kirakli E

PROVIDER: S-EPMC5762091 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Is Hippocampal Avoidance During Whole-Brain Radiotherapy Risky for Patients With Small-Cell Lung Cancer? Hippocampal Metastasis Rate and Associated Risk Factors.

Korkmaz Kirakli Esra E Oztekin Ozgur O

Technology in cancer research & treatment 20171121 6

<h4>Objectives</h4>Hippocampal avoidance during whole-brain radiotherapy is performed to prevent neural stem cell injury causing neurocognitive dysfunction. Nevertheless, the estimated risk of metastases in hippocampal avoidance area in small-cell lung cancer is unknown. The current study aimed to characterize the metastatic distribution within the brain relative to the hippocampus, estimate the incidence of hippocampal metastasis in patients with small-cell lung cancer, and identify clinical an ...[more]

PMID: 29332467

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Project description:BackgroundMelanoma brain metastases (MBM) often cause morbidity and mortality for stage IV melanoma patients. An ongoing randomised phase III trial (NCT01503827 - WBRT-Mel) evaluates the role of adjuvant whole brain radiotherapy (WBRT) following local treatment of MBM. Hippocampal avoidance during WBRT (HA-WBRT) has shown memory and neurocognitive function (NCF) preservation in the RTOG-0933 phase II study. This study assessed the quality assurance of HA-WBRT within the WBRT-Mel trial according to RTOG-0933 study criteria.MethodsHippocampal avoidance was allowed in approved centres with intensity-modulated radiotherapy capability. Patients treated by HA-WBRT were not randomized within the WBRT arm. The RTOG 0933 contouring Atlas was used to contour hippocampi. In the trial co-ordinating centre, patients were treated with volumetric modulated arc therapy using complementary arcs; similar techniques were used at other sites. Dosimetric data were extracted retrospectively and analysed in accordance with RTOG 0933 study constraints criteria.ResultsAmong the 215 patients accrued to the WBRT-Mel study between April 2009 and September 2017, 107 were randomized to the WBRT arm, 22 were treated by HA-WBRT in 4 centers. Eighteen patients were treated in the same centre. The median age was 65 years. The commonest (91%) HA-WBRT schema was 30 Gy in 10 fractions. Prior to HA-WBRT, 10 patients had been treated by surgery alone, six by radiosurgery alone, four by surgery and radiosurgery and two exclusively by simultaneous integrated boost concurrent to HA-WBRT. Twenty patients were treated with intention to spare both hippocampi and two patients had MBM close to one hippocampus and were treated with intention to spare the contralateral hippocampus. According to RTOG-0933 study criteria, 18 patients (82%) were treated within constraints and four patients (18%) had unacceptable deviation in just one hippocampus.ConclusionsThis dosimetric quality assurance study shows good compliance (82%) according to RTOG-0933 study dosimetric constraints. Indeed, all patients respected RTOG hippocampal avoidance constraints on at least one hippocampus. In the futureanalysis of the WBRT-Mel trial, the NCF of patients on the observation arm, WBRT arm and with HA-WBRT arm will be compared.

Project description:Respiratory motion management techniques in radiotherapy (RT) planning are primarily focused on maintaining tumor target coverage. An inadequately addressed need is accounting for motion in dosimetric estimations in smaller serial structures. Accurate dose estimations in such structures are more sensitive to motion because respiration can cause them to move completely in or out of a high dose-gradient field. In this work, we study three motion management strategies (m1-m3) to find an accurate method to estimate the dosimetry in airways. To validate these methods, we generated a 'ground truth' digital breathing model based on a 4DCT scan from a lung stereotactic ablative radiotherapy (SAbR) patient. We simulated 225 breathing cycles with ±10% perturbations in amplitude, respiratory period, and time per respiratory phase. A high-resolution breath-hold CT (BHCT) was also acquired and used with a research virtual bronchoscopy software to autosegment 239 airways. Contours for planning target volume (PTV) and organs at risk (OARs) were defined on the maximum intensity projection of the 4DCT (CTMIP) and transferred to the average of the 10 4DCT phases (CTAVG). To design the motion management methods, the RT plan was recreated using different images and structure definitions. Methods m1 and m2 recreated the plan using the CTAVG image. In method m1, airways were deformed to the CTAVG. In m2, airways were deformed to each of the 4DCT phases, and union structures were transferred onto the CTAVG. In m3, the RT plan was recreated on each of the 10 phases, and the dose distribution from each phase was deformed to the BHCT and summed. Dose errors (mean [min, max]) in airways were: m1: 21% (0.001%, 93%); m2: 45% (0.1%, 179%); and m3: 4% (0.006%, 14%). Our work suggests that accurate dose estimation in moving small serial structures requires customized motion management techniques (like m3 in this work) rather than current clinical and investigational approaches.

Project description:BackgroundDespite the clinical benefit of whole brain radiotherapy (WBRT), patients and physicians are concerned by the long-term impact on cognitive functioning. Many studies investigating the molecular and cellular impact of WBRT have used rodent models. However, there has not been a rodent protocol comparable to the recently reported Radiation Therapy Oncology Group (RTOG) protocol for WBRT with hippocampal avoidance (HA) which is intended to spare cognitive function. The aim of this study was to develop a hippocampal-sparing WBRT protocol in Wistar rats.MethodsThe technical and clinical challenges encountered in hippocampal sparing during rat WBRT are substantial. Three key challenges were identified: hippocampal localization, treatment planning, and treatment localization. Hippocampal localization was achieved with sophisticated imaging techniques requiring deformable registration of a rat MRI atlas with a high resolution MRI followed by fusion via rigid registration to a CBCT. Treatment planning employed a Monte Carlo dose calculation in SmART-Plan and creation of 0.5 cm thick lead blocks custom-shaped to match DRR projections. Treatment localization necessitated the on-board image-guidance capability of the XRAD C225Cx micro-CT/micro-irradiator (Precision X-Ray). Treatment was accomplished with opposed lateral fields with 225 KVp X-rays at a current of 13 mA filtered through 0.3 mm of copper using a 40x40 mm square collimator and the lead blocks. A single fraction of 4 Gy was delivered (2 Gy per lateral field) with a 41 second beam on time per field at a dose rate of 304.5 cGy/min. Dosimetric verification of hippocampal sparing was performed using radiochromic film. In vivo verification of HA was performed after delivery of a single 4 Gy fraction either with or without HA using ?-H2Ax staining of tissue sections from the brain to quantify the amount of DNA damage in rats treated with HA, WBRT, or sham-irradiated (negative controls).ResultsThe mean dose delivered to radiochromic film beneath the hippocampal block was 0.52 Gy compared to 3.93 Gy without the block, indicating an 87% reduction in the dose delivered to the hippocampus. This difference was consistent with doses predicted by Monte Carlo dose calculation. The Dose Volume Histogram (DVH) generated via Monte Carlo simulation showed an underdose of the target volume (brain minus hippocampus) with 50% of the target volume receiving 100% of the prescription isodose as a result of the lateral blocking techniques sparing some midline thalamic and subcortical tissue. Staining of brain sections with anti-phospho-Histone H2A.X (reflecting double-strand DNA breaks) demonstrated that this treatment protocol limited radiation dose to the hippocampus in vivo. The mean signal intensity from ?-H2Ax staining in the cortex was not significantly different from the signal intensity in the cortex of rats treated with WBRT (5.40 v. 5.75, P = 0.32). In contrast, the signal intensity in the hippocampus of rats treated with HA was significantly lower than rats treated with WBRT (4.55 v. 6.93, P = 0.012).ConclusionDespite the challenges of planning conformal treatments for small volumes in rodents, our dosimetric and in vivo data show that WBRT with HA is feasible in rats. This study provides a useful platform for further application and refinement of the technique.

Dataset Information

Is Hippocampal Avoidance During Whole-Brain Radiotherapy Risky for Patients With Small-Cell Lung Cancer? Hippocampal Metastasis Rate and Associated Risk Factors.

Publications

Is Hippocampal Avoidance During Whole-Brain Radiotherapy Risky for Patients With Small-Cell Lung Cancer? Hippocampal Metastasis Rate and Associated Risk Factors.

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