Whole brain radiotherapy: Consequences for personalized medicine

Several studies focusing on brain irradiation are in progress. Reflecting updates of relevant outcomes in palliative treatment of patients suffering from brain metastases, the primary objective of these studies is the evaluation of neurocognitive function and quality of life. Improvements of technology in radiation oncology allows us to spare the hippocampal region while appropriately irradiating other parts of brain tissue. Irradiation of the hippocampus region is likely to lead to manifestations of adverse events with a subsequent impact on patient''s quality of life, which is in fact an improper approach in palliative medicine. Ongoing studies evaluate results of hippocampus avoiding radiotherapy compared to standard whole brain radiotherapy. Incorporation of neurocognitive function assessment may result in the confirmation of superiority of sparing the region of hippocampus and thus change current style of providing brain irradiation.     

Hippocampal dose during Linac-based stereotactic radiotherapy for brain metastases: An observational study

IntroductionAim of the present study is to evaluate homolateral and contralateral hippocampus (H-H, C-H, respectively) dose during Fractionated Stereotactic Radiotherapy (FSRT) or Radiosurgery (SRS) for brain metastases (BM).Materials & methodsPatients with BM < 5, size ≤ 30 mm, KPS ≥ 80 and a life expectancy > 3 months, were considered for SRS/FSRT (total dose 15–30 Gy, 1–5 fractions). For each BM, a Flattening Filter Free (FFF) Volumetric Modulated Arc Therapy (VMAT) plan was generated with one or two arcs. Hippocampi were not considered during optimizations phase and were contoured and evaluated retrospectively in terms of dose: the Dmedian, Dmean, D0.1cc and the V1Gy, V2Gy, V5Gy and V10Gy were analyzed.ResultsFrom April 2014 to December 2015, 81 BM were treated with FFF-FSRT/SRS. For the H-H, the average values of Dmedian, Dmean and D0.1cc were 1.5Gy, 1.54Gy and 2.2Gy, respectively, while the V1Gy, V2Gy, V5Gy and V10Gy values were 25%, 8.9%, 8.9% and 2.1%, respectively. For the C–H, the average Dmedian, Dmean and D0.1 cc were 0.7Gy, 0.7Gy, 0.9Gy, respectively, while the average values of V1Gy, V2Gy, V5Gy and V10Gy were 18%, 10.2%, 2.8% and 1.4%, respectively. Tumor dimension, tumor cranial-caudal length and the distance between BM and H-H were correlated to Dmedian, Dmean and D0.1cc. For C-H, only the distance from PTV was correlated with a dose reduction.ConclusionDuring FFF-FSRT/SRS, hippocampus received a negligible dose. Despite its clinical significance is still under evaluation, in patients with a long life expectancy, H-H should be considered during Linac-based FSRT/SRS.     

Quality of life improvement in patients with bone metastases undergoing palliative radiotherapy

BackgroundThe aim of the study was to analyze the impact of palliative radiotherapy on quality of life (QoL) in patients with symptomatic bone metastases.Materials and methodsWe present the results from a prospective multicentric study including 128 patients who provided pre- and post-radiotherapy (one month after treatment) brief pain inventory (BPI) assessments. Worst pain was recorded using the BPI (range: 0–10). Pain response was described according to the International Bone Metastases Consensus on palliative radiation. Regarding QoL, for each pre- and post-radiation BPI-questionnaire, scores from the interference domains were summed and averaged to obtain an overall interference score.ResultsThere was a significant correlation between radiation treatment response and improvement in all functional interference domains except sleeping. Patients > 75 years old presented a significantly higher improvement in general activity, mood and relationships with others compared to patients ≤ 75 years old. Patients presenting a baseline pain score ≥ 8 showed a higher improvement in the general activity item (p = 0.049). There was no statistically significant association between pretreatment ECOG, chemotherapy, primary tumor location and radiation schedule with any of the functional interference items.ConclusionsPatients who report pain relief after palliative radiotherapy also present a better quality of life including physical and psychosocial aspects.     

Stereotactic radiotherapy for brain metastases in patients with lung cancer; outcome and toxicity in clinical practice

BackgroundStereotactic radiotherapy (SRT) is an established modality for treating limited brain metastases (BMs). This study aimed to assess the real-life treatment outcome and associated prognostic factors for survival in a consecutive lung cancer cohort receiving SRT for BMs.Materials and methodsA retrospective review and analysis of patients with lung cancer with BMs treated with SRT in western Sweden between 2002 and 2017 were performed. Data were collected from patient charts and the radiotherapy dose planning system.ResultsOne hundred nine patients corresponding to 139 lesions were assessed; the majority were treated with single-fractionated SRT with 20 Gy. The median overall survival (OS) was 6.1 months, with a 12-month survival rate of 24%. The estimated overall disease control rate (DCR) was 84% at a median time of three months. On multivariate analysis, WHO performance status (PS) (p = 0.002) and smoking status (p = 0.005) were significant predictive factors for survival. Four percent of the patients experienced possible grade III–IV toxicity, and previously administered cranial radiation therapy was a significant independent factor (p = 0.03) associated with the risk of developing acute toxicity.ConclusionsSRT due to brain metastases from lung cancer is a well-tolerated treatment. When selecting patients suitable for treatment, PS and extracranial disease progression should be considered. Smoking cessation is probably of value even in this palliative setting. The goal of SRT for BMs is not only to improve survival but also to provide symptom relief, and future studies on SRT should assess patient-reported outcomes in addition to survival.     

Stereotactic radiotherapy for brain oligometastases

Brain metastases, the most common metastases in adults, will develop in up to 40% of cancer patients, accounting for more than one-half of all intracranial tumors. They are most associated with breast and lung cancer, melanoma and, less frequently, colorectal and kidney carcinoma.Magnetic resonance imaging (MRI) is the gold standard for diagnosis. For the treatment plan, computed tomography (CT ) images are co-registered and fused with a gadolinium-enhanced T1-weighted MRI where tumor volume and organs at risk are contoured. Alternatively, plain and contrast-enhanced CT scans are co-registered. Single-fraction stereotactic radiotherapy (SRT ) is used to treat patients with good performance status and up to 4 lesions with a diameter of 30 mm or less that are distant from crucial brain function areas. Fractionated SRT (2–5 fractions) is used for larger lesions, in eloquent areas or in proximity to crucial or surgically inaccessible areas and to reduce treatment-related neurotoxicity. The single-fraction SRT dose, which depends on tumor diameter, impacts local control. Fractionated SRT may encompass different schedules. No randomized trial data compared the safety and efficacy of single and multiple fractions. Both single-fraction and fractionated SRT provide satisfactory local control rates, tolerance, a low risk of transient acute adverse events and of radiation necrosis the incidence of which correlated with the irradiated brain volume.     

Biology of brain metastases and novel targeted therapies: Time to translate the research

Brain metastases (BM) occur in 20% to 40% of patients with cancer and result in significant morbidity and poor survival. The main therapeutic options include surgery, whole brain radiotherapy, stereotactic radiosurgery and chemotherapy. Although significant progress has been made in diagnostic and therapeutic methods, the prognosis in these patients remains poor. Furthermore, the poor penetrability of chemotherapy agents through the blood brain barrier (BBB) continues to pose a challenge in the management of this disease. Preclinical evidence suggests that new targeted treatments can improve local tumor control but our clinical experience with these agents remains limited. In addition, several clinical studies with these novel agents have produced disappointing results. This review will examine the knowledge of targeted therapies in BM. The preclinical and clinical evidence of their use in BM induced by breast cancer, non-small cell lung cancer and melanoma will be presented. In addition, we will discuss the role of antiangiogenic and radiosensitising agents in the treatment of BM and the current strategies available to increase BBB permeability. A better understanding of the mechanism of action of these agents will help us to identify the best targets for testing in future clinical studies.     

Significant impact on the oncologic outcomes with intensity modulated radiotherapy and conformational radiotherapy over conventional radiotherapy in cervix cancer patients treated with radiotherapy

ObjectiveWe designed a retrospective cohort of women with cervix cancer treated by radiation therapy with an extended follow-up to evaluate if the incorporation of modern radiation techniques was a prognostic factor.Material and methodsWe studied a cohort of patients with cervix cancer FIGO stage I-IVa treated in the last fifteen years. Patients were treated with radiotherapy alone (RT) or chemoradiation alone (CRT) using conventional radiotherapy (2DRT), conformational radiotherapy (3DRT), or intensity-modulated radiotherapy (IMRT) followed by high dose rate brachytherapy. Univariate and multivariate analysis was conducted to identify significant prognostic factors (p < 0.05).Results228 patients with cervix cancer were included. The treatment groups were CRT (64.8%), and RT (34.2%), with 31.6% submitted to 2DRT and 68.4% to IMRT/3DRT. The median follow-up was 6.3 years, the OS in 5 years according to the treatment groups was 48% for CRT, and 27.8% for RT (p < 0.001). The early-stage I-IIa (p = 0.001), CRT, and IMRT/3DRT were significant factors for better overall survival (OS) in the multivariate analysis. For the cancer-specific survival (CSS), chemoradiation, age <60 years, and IMRT/3DRT were significant. Treatment with IMRT/3DRT was the only prognostic factor associated with event-free survival (EFS).ConclusionIn a long-term follow-up, chemoradiation, early-clinical stage, and age <60 years were significant factors associated with better OS and CSS at 5 and 8 years. The incorporation of new radiation techniques, such as IMRT/3DRT, over time has a significant impact on all endpoints (EFS, OS, and CSS) of this cohort. These outcomes are useful to decide about the radiation technique to achieve satisfactory oncological results outside a clinical trial.     

Long-term survival results after treatment for oligometastatic brain disease

AimThe aim of this study was to characterize the survival results of patients with up to four brain metastases after intense local therapy (primary surgery or stereotactic radiotherapy) if extracranial metastases were absent or limited to one site, e.g. the lungs.BackgroundOligometastatic disease has repeatedly been reported to convey a favorable prognosis.Material and methodsThis retrospective study included 198 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. Uni- and multivariate tests were performed.ResultsMedian survival was 16.5 months (single brain metastasis) and 9.8 months (2–4, comparable survival for 2, 3 and 4), respectively (p = 0.001). After 5 years, 15 and 2% of the patients were still alive. In patients alive after 2 years, added median survival was 23 months and the probability of being alive 5 years after treatment was 26%. In multivariate analysis, extracranial metastases were not significantly associated with survival, while primary tumor control was.ConclusionLong-term survival beyond 5 years is possible in a minority of patients with oligometastatic brain disease, in particular those with a single brain metastasis. The presence of extracranial metastases to one site should not be regarded a barrier towards maximum brain-directed therapy.     

唑来膦酸延缓骨转移癌放射治疗的临床研究

目的以帕米膦酸二钠为对照,研究唑来膦酸对延缓骨转移癌放射治疗事件发生的临床疗效。方法对118例骨转移癌患者,随机分为病例组60例,对照组58例,以疼痛持续加重,X线或CT证实骨转移病灶进展或有可能导致病理性骨折而行放射治疗为观察终点,研究唑来膦酸延缓骨转移癌放射治疗事件出现时间的临床疗效。结果近期止痛有效率和获益率在唑来膦酸组分别为55.36%,65.18%;帕米膦酸组为35.19%,44.44%,P<0.05;放疗事件发生率在唑来膦酸组为34.21%,帕米膦酸钠组为54.28%,P>0.05;发生放疗事件中位时间在唑来膦酸组为121天,帕米膦酸钠组为189天,P=0.041。结论唑来膦酸近期止痛的临床有效率、获益率和总体骨相关事件(SRE)危险性降低的比例均高于帕米膦酸二钠。     

肝转移癌放射治疗进展

过去的几十年,在肝转移癌的治疗方面,放疗已经越来越多的应用于临床。对于局部肝转移癌,临床上往往采取加大剂量已提高局部控制率,以期提高患者生产期。但是,对于有症状的广泛性肝转移患者则给以全肝低剂量照射。放疗已成为不适合手术或化疗等方式的肝转移癌患者的有效治疗手段。放疗靶区勾画及放疗技术进步更好的保护了高剂量靶区周围的正常肝脏组织,使得提高靶区放疗剂量的手段很好的应用于临床。关于肝转移癌的适形与立体定向放疗治疗的提高局控率及生存期的临床研究不断出现。本文就局部肝转移的根治放疗与全肝的姑息放疗临床数据做相关综述,认为放疗在肝转移癌的治疗中是安全,有效的。但是,肝转移癌的临床随机试验研究仍较匮乏。     

A practical methodology to improve the dosimetric accuracy of MR-based radiotherapy simulation for brain tumors

PurposeTo investigate the dosimetric accuracy of synthetic computed tomography (sCT) images generated by a clinically-ready voxel-based MRI simulation package, and to develop a simple and feasible method to improve the accuracy.Methods20 patients with brain tumor were selected to undergo CT and MRI simulation. sCT images were generated by a clinical MRI simulation package. The discrepancy between planning CT and sCT in CT number and body contour were evaluated. To resolve the discrepancies, an sCT specific CT-relative electron density (RED) calibration curve was used, and a layer of pseudo-skin was created on the sCT. The dosimetric impact of these discrepancies, and the improvement brought about by the modifications, were evaluated by a planning study. Volumetric modulated arc therapy (VMAT) treatment plans for each patient were created and optimized on the planning CT, which were then transferred to the original sCT and the modified-sCT for dose re-calculation. Dosimetric comparisons and gamma analysis between the calculated doses in different images were performed.ResultsThe average gamma passing rate with 1%/1 mm criteria was only 70.8% for the comparison of dose distribution between planning CT and original sCT. The mean dose difference between the planning CT and the original sCT were −1.2% for PTV D₉₅ and −1.7% for PTV D_max, while the mean dose difference was within 0.7 Gy for all relevant OARs. After applying the modifications on the sCT, the average gamma passing rate was increased to 92.2%. Mean dose difference in PTV D₉₅ and D_max were reduced to −0.1% and −0.3% respectively. The mean dose difference was within 0.2 Gy for all OAR structures and no statistically significant difference were found.ConclusionsThe modified-sCT demonstrated improved dosimetric agreement with the planning CT. These results indicated the overall dosimetric accuracy and practicality of this improved MR-based treatment planning method.     

Whole abdominal radiotherapy in ovarian cancer

Objectives

The aim of the study was to evaluate the clinical outcome and toxicity after adjuvant whole abdominal radiotherapy (WART) in patients with ovarian cancer.

Material and methods

Ten patients with optimal cytoreduced ovarian cancer, with a mean age of 58 years (40–70) and stage Ic: 4, stage II: 2, stage III: 4, were treated with WART and adjuvant chemotherapy (9/10). The total radiation dose was 22.5 Gy in the whole abdomen and 42–45 Gy in the pelvis.

Results

The mean follow-up was 8 years. The 5-year actuarial disease-free survival (DFS) was 60%, and the overall survival (OS) was 70%. Four patients had disease recurrence. The sites of recurrence were the abdomen in 2 patients and distant metastases in the other 2 patients (liver and brain metastasis). Gastrointestinal toxicity was as follows: acute 3/10 grades I and II, and late toxicity: 2/10 grades I and II, and only 1 patient developed small bowel obstruction (SBO) that required surgery.

Conclusions

Whole abdominal radiotherapy after surgery and platinum-based chemotherapy achieves high locoregional disease control with an acceptable risk of acute toxicity.     

In vitro radiotherapy and chemotherapy alter migration of brain cancer cells before cell death

Although radiotherapy and most cancer drugs target the proliferation of cancer cells, it is metastasis, the complex process by which cancer cells spread from the primary tumor to other tissues and organs of the body where they form new tumors, that leads to over 90% of all cancer deaths. Thus, there is an urgent need for anti-metastasis strategies alongside chemotherapy and radiotherapy. An important step in the metastatic cascade is migration. It is the first step in metastasis via local invasion. Here we address the question whether ionizing radiation and/or chemotherapy might inadvertently promote metastasis and/or invasiveness by enhancing cell migration. We used a standard laboratory irradiator, Faxitron CellRad, to irradiate both non-cancer (HCN2 neurons) and cancer cells (T98G glioblastoma) with 2 Gy, 10 Gy and 20 Gy of X-rays. Paclitaxel (5 μM) was used for chemotherapy. We then measured the attachment and migration of the cells using an electric cell substrate impedance sensing device. Both the irradiated HCN2 cells and T98G cells showed significantly (p < 0.01) enhanced migration compared to non-irradiated cells, within the first 20–40 h following irradiation with 20 Gy. Our results suggest that cell migration should be a therapeutic target in anti-metastasis/anti-invasion strategies for improved radiotherapy and chemotherapy outcomes.     

Bystander effects and radiotherapy

Radiation-induced bystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. These effects include DNA damage, chromosomal instability, mutation, and apoptosis. There is considerable evidence that ionizing radiation affects cells located near the site of irradiation, which respond individually and collectively as part of a large interconnected web. These bystander signals can alter the dynamic equilibrium between proliferation, apoptosis, quiescence or differentiation. The aim of this review is to examine the most important biological effects of this phenomenon with regard to areas of major interest in radiotherapy. Such aspects include radiation-induced bystander effects during the cell cycle under hypoxic conditions when administering fractionated modalities or combined radio-chemotherapy. Other relevant aspects include individual variation and genetics in toxicity of bystander factors and normal tissue collateral damage. In advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), the high degree of dose conformity to the target volume reduces the dose and, therefore, the risk of complications, to normal tissues. However, significant doses can accumulate out-of-field due to photon scattering and this may impact cellular response in these regions. Protons may offer a solution to reduce out-of-field doses. The bystander effect has numerous associated phenomena, including adaptive response, genomic instability, and abscopal effects. Also, the bystander effect can influence radiation protection and oxidative stress. It is essential that we understand the mechanisms underlying the bystander effect in order to more accurately assess radiation risk and to evaluate protocols for cancer radiotherapy.     

Radiation therapy for the management of painful bone metastases: Results from a randomized trial

AimThe aim of this study was to compare the effectiveness of two radiotherapy schedules in patients with bone metastases.BackgroundWe analyzed the need for re-irradiation, rates of pain control, pathological fractures, and functionality in patients randomized to single-fraction (8 Gy 1×) or multiple-fraction radiotherapy (3 Gy 10×) with at least 12 months follow-up, during five years. The hypothesis was that the two radiotherapy schedules are equally effective.Materials and methodsNinety patients with painful skeletal metastases were randomized to receive single fraction (8 Gy) or multiple fraction (3 Gy 10×) radiotherapy.ResultsIn the single-fraction group, seven pathological fractures occurred (15.5%) versus two (4.4%) in the multiple-fraction group. There was no statistically significant difference between the time it took to suffer a pathological fracture in both groups (p = 0.099). Patients in the single-fraction group received twelve re-irradiations (26.6%), four in the multiple-fraction group (8.8%), with no significant difference between time elapsed before the first re-irradiation (p = 0.438).ConclusionThis study shows no difference between the two groups for the majority of patients with painful bone metastases. Patients were followed up during five years, and the trial showed no disadvantage for 8 Gy 1× compared to 3 Gy 10×. Despite the fact that the pathological fracture rate is 3.75 times higher in the single-fraction group, this schedule is considered more convenient for patients and more cost-effective for radiotherapy departments.     

记忆训练联合电针疗法对全脑放疗患者认知功能、健康相关生命质量和颅脑磁共振灌注成像参数的影响

摘要 目的：探讨记忆训练联合电针疗法对全脑放疗患者认知功能、健康相关生命质量和颅脑磁共振灌注成像参数的影响。方法：选择江南大学附属医院2020年3月～2022年1月期间收治的全脑放疗患者94例,根据随机数字表法分为研究组（常规干预、记忆训练联合电针疗法）和对照组（常规干预）,各为47例。对比两组认知功能、健康相关生命质量和颅脑磁共振灌注成像参数的变化。结果：治疗1周、2周、3周、4周后,两组蒙特利尔认知功能检查量表（MoCA）和简易精神状态量表（MMSE）评分均较治疗前逐渐下降,但研究组各时间点MoCA、MMSE评分高于对照组（P<0.05）。治疗4周后,两组健康相关生命质量量表（HRQoL）各维度评分及总分均较治疗前升高,且研究组上述评分均高于对照组（P<0.05）。治疗4周后,两组颅脑平均脑血容量（CBV）值和平均脑血流量（CBF）值均较治疗前下降,但研究组上述值高于对照组（P<0.05）。结论：记忆训练联合电针疗法可减缓全脑放疗后导致的认知功能损害,并提升患者的健康相关生命质量,可能与调节脑血容量、脑血流量有关。     

Comparison of PRIMO Monte Carlo code and Eclipse treatment planning system in calculation of dosimetric parameters in brain cancer radiotherapy

BackgroundIt is important to evaluate the dose calculated by treatment planning systems (TPSs) and dose distribution in tumor and organs at risk (OARs). The aim of this study is to compare dose calculated by the PRIMO Monte Carlo code and Eclipse TPS in radiotherapy of brain cancer patients.Materials and methodsPRIMO simulation code was used to simulate a Varian Clinac 600C linac. The simulations were validated for the linac by comparison of the simulation and measured results. In the case of brain cancer patients, the dosimetric parameters obtained by the PRIMO code were compared with those calculated by Eclipse TPS. Gamma function analysis with 3%, 3 mm criteria was utilized to compare the dose distributions. The evaluations were based on the dosimetric parameters for the planning target volume (PTV) and OAR including D_min, D_mean, and D_max, homogeneity index (HI), and conformity index (CI).ResultsThe gamma function analysis showed a 98% agreement between the results obtained by the PRIMO code and measurement for the percent depth dose (PDD) and dose profiles. The corresponding value in comparing the dosimetric parameters from PRIMO code and Eclipse TPS for the brain patients was 94%, on average. The results of the PRIMO simulation were in good agreement with the measured data and Eclipse TPS calculations.ConclusionsBased on the results of this study, the PRIMO code can be utilized to simulate a medical linac with good accuracy and to evaluate the accuracy of treatment plans for patients with brain cancer.