Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable risks for normal tissue injury and the hazards of physical tumor miss. A first-of-its-kind SBRT platform achieves high-precision ablative radiation treatment through a combination of versatile real-time imaging solutions and sophisticated tumor tracking capabilities. It uses dual-diagnostic kV x-ray units for stereoscopic open-loop feedback of cancer target intrafraction movement occurring as a consequence of respiratory motions and heartbeat. Image-guided feedback drives a gimbaled radiation accelerator (maximum 15 x 15 cm field size) capable of real-time ±4 cm pan-and-tilt action. Robot-driven ±60° pivots of an integrated ±185° rotational gantry allow for coplanar and non-coplanar accelerator beam set-up angles, ultimately permitting unique treatment degrees of freedom. State-of-the-art software aids real-time six dimensional positioning, ensuring irradiation of cancer targets with sub-millimeter accuracy (0.4 mm at isocenter). Use of these features enables treating physicians to steer radiation dose to cancer tumor targets while simultaneously reducing radiation dose to normal tissues. By adding respiration correlated computed tomography (CT) and 2-[¹⁸F] fluoro-2-deoxy-ᴅ-glucose (¹⁸F-FDG) positron emission tomography (PET) images into the planning system for enhanced tumor target contouring, the likelihood of physical tumor miss becomes substantially less¹. In this article, we describe new radiation plans for the treatment of moving lung tumors.     

Stereotactic Body Radiation Therapy as an Alternative Treatment for Small Hepatocellular Carcinoma

Background

Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment.

Materials and Methods

A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT.

Results

The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients’ survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%).

Conclusions

SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.     

The Time Course of Dynamic Computed Tomographic Appearance of Radiation Injury to the Cirrhotic Liver Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

This study aimed to evaluate the dynamic computed tomographic (CT) appearance of focal radiation injury to cirrhotic liver tissue around the tumor following stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). Seventy-seven patients with 92 HCCs were observed for >6 months. Sixty-four and 13 patients belonged to Child–Pugh class A and B, respectively. The median SBRT dose was 48 Gy/4fr. Dynamic CT scans were performed in non–enhanced, arterial, portal, and venous phases. The median follow-up period was 18 months. Dynamic CT appearances were classified into 3 types: type 1, hyperdensity in all enhanced phases; type 2, hypodensity in arterial and portal phases; type 3, isodensity in all enhanced phases. Half of the type 2 or 3 appearances significantly changed to type 1, particularly in patients belonging to Child–Pugh class A. After 3–6 months, Child–Pugh class B was a significant factor in type 3 patients. Thus, dynamic CT appearances were classified into 3 patterns and significantly changed over time into the enhancement group (type 1) in most patients belonging to Child–Pugh class A. Child–Pugh class B was a significant factor in the non–enhancement group (type 3).     

Inter-Fraction Tumor Volume Response during Lung Stereotactic Body Radiation Therapy Correlated to Patient Variables

PurposeAnalyze inter-fraction volumetric changes of lung tumors treated with stereotactic body radiation therapy (SBRT) and determine if the volume changes during treatment can be predicted and thus considered in treatment planning.ResultsAll tumors studied experienced volume change during treatment. Tumor increased in volume by an average of 15% and regressed by an average of 11%. The overall volume increase during treatment is contained within the planning target volume (PTV) for all tumors. Larger tumors increased in volume more than smaller tumors during treatment (q = 0.0029). The volume increase on CBCT was correlated to the treatment planning gross target volume (GTV) as well as internal target volumes (ITV) (q = 0.0085 and q = 0.0039 respectively) and could be predicted for tumors with a GTV less than 22 mL. The volume increase was correlated to the integral dose (ID) in the ITV at every fraction (q = 0.0049). The peak inter-fraction volume occurred at an earlier fraction in younger patients (q = 0.0122).ConclusionsWe introduced a new analysis method to follow inter-fraction tumor volume changes and determined that the observed changes during lung SBRT treatment are correlated to the initial tumor volume, integral dose (ID), and patient age. Furthermore, the volume increase during treatment of tumors less than 22mL can be predicted during treatment planning. The volume increase remained significantly less than the overall PTV expansion, and radiation re-planning was therefore not required for the purpose of tumor control. The presence of the studied correlations suggests that the observed volumetric changes may reflect some underlying biologic process rather than random fluctuations.     

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Prognostic Factors of Local Control,Overall Survival,and Toxicity

Purpose

Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been evaluated in several recent studies. The CyberKnife^® is an SBRT system that allows for real-time tracking of the tumor. The purpose of this study was to evaluate the prognostic factors for local control and overall survival following this treatment.

Patients and Methods

75 patients with 96 liver-confined HCC were treated with SBRT at the Oscar Lambret Comprehensive Cancer Center. Fiducials were implanted in the liver before treatment and were used as markers to track the lesion’s movement. Treatment response was scored according to RECIST v1.1. Local control and overall survival were calculated using the Kaplan and Meier method. A stepwise multivariate analysis (Cox regression) of prognostic factors was performed for local control and overall survival.

Results

There were 67 patients with Child-Turcotte-Pugh (CTP) Class A and eight patients with CTP Class B. Treatment was administered in three sessions. A total dose of 40–45 Gy to the 80% isodose line was delivered. The median follow-up was 10 months (range, 3–49 months). The local control rate was 89.8% at 1 and 2 years. Overall survival was 78.5% and 50.4% at 1 and 2 years, respectively. Toxicity mainly consisted of grade 1 and grade 2 events. Higher alpha-fetoprotein (aFP) levels were associated with less favorable local control (HR=1.001; 95% CI [1.000, 1.002]; p=0.0063). A higher dose was associated with better local control (HR=0.866; 95% CI [0.753, 0.996]; p=0.0441). A Child-Pugh score higher than 5 was associated with worse overall survival (HR= 3.413; 95% CI [1.235, 9.435]; p=0.018).

Conclusion

SBRT affords good local tumor control and higher overall survival rates than other historical controls (best supportive care or sorafenib). High aFP levels were associated with lesser local control, but a higher treatment dose improved local control.     

射波刀立体定向放疗技术治疗结直肠癌肝转移癌的疗效观察

目的:探讨射波刀立体定向放疗技术治疗结直肠癌肝转移癌的疗效观察。方法:选择2014年1月至2016年2月我院收治的64例结直肠癌肝转移癌患者为研究对象,按照随机数字表法随机分为对照组(32例)和治疗组(32例),对照组患者给予FOLFOX6全身化疗方案,治疗组患者给予FOLFOX6全身化疗和肝脏病灶立体定向放疗(射波刀)治疗。观察患者的治疗3个月后的近期临床疗效和不良反应,6个月后患者生存率和局部控制率,并评价患者的生活质量。结果:治疗3个月后,治疗组患者的总有效率为78.13%,高于对照组的53.13%,差异有统计学意义(P0.05);治疗6个月后,治疗组的生存率(96.88%)和局部控制率(87.50%)均高于对照组(81.25%和65.63%),差异有统计学意义(P0.05);治疗6个月后,治疗组患者的情绪功能、认知功能、角色功能、躯体功能、社会功能评分均高于对照组,差异有统计学意义(P0.05)。两组患者的不良反应发生率比较差异无统计学意义(P0.05)。结论:射波刀立体定向放疗技术治疗结直肠癌肝转移癌具有较好的近期临床疗效,可提高患者的生存率和局部控制率,改善患者生活质量,且不良反应发生率低,值得临床推广应用。     

Delayed Contrast Extravasation MRI for Depicting Tumor and Non-Tumoral Tissues in Primary and Metastatic Brain Tumors

The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution MRI-based delayed enhancement subtraction maps may be applied for clear depiction of tumor and non-tumoral tissues in patients with primary brain tumors and patients with brain metastases.     

Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development.     

Time-Dependent Effect of Hypoxia on Tumor Progression and Liver Progenitor Cell Markers in Primary Liver Tumors

Background & Aims

Expression of liver progenitor cell (LPC) characteristics has been proposed as a negative prognostic marker in primary liver tumors. Hypoxia has been linked to activation of the Notch pathway which is responsible for activation and proliferation of LPCs and hypoxia-induced LPC activation has been shown in hepatocellular carcinoma. Our aim was to elucidate the time-dependent effects of hypoxia on the LPC niche in hepatocellular carcinoma which could aid in determining a safe time frame for use of hypoxia inducing therapies.

Methods

We used dimethyloxaloylglycine to mimic a hypoxic reaction in mice by stabilizing hypoxia-inducible factor 1 alpha at three distinct time points in diethylnitrosamine induced hepatocarcinogenesis. LPC, metastasis and Notch pathway markers were determined by quantitative PCR and (immune)histochemistry (heamatoxillin-eosin, reticulin, Sirius red and cytokeratin 19 staining).

Results

Activating the hypoxia inducible pathway early in hepatocarcinogenesis resulted in an increased incidence of both cholangioma and hepatocellular lesions, associated with high expression of LPC, metastatic and Notch pathway markers. Adversely, activating the hypoxic response during tumor development resulted in decreased incidence of hepatocellular lesions and increased cholangioma incidence, with an unaltered gene expression profile of LPC-, Notch pathway- and metastatic markers. A hypoxic insult at advanced stages of hepatocarcinogenesis severely increased the expression of LPC characteristics, however without increased expression of actors of the Notch pathway and metastatic markers and minor changes in incidence of hepatocellular and cholangioma lesions.

Conclusion

Our results indicate that increased hypoxia at the onset of tumor development has detrimental effects on tumor progression; patients with HCC developed in a background of fibrosis/cirrhosis might therefore represent a more difficult treatment group. In contrast, hypoxia during tumor development appears to favor tumor outcome, highlighting the importance of early detection. Finally, hypoxia in advanced stages resulted in increased expression of LPC characteristics indicating poor outcome.     

非小细胞肺癌体部寡转移的立体定向放射治疗

非小细胞肺癌(Non-small cell lung cancer, NSCLC)寡转移是NSCLC转移过程中的一种中间状态,是肿瘤生物侵袭过程中较温和的一个阶段,它介于原发灶与远处广泛转移之间,转移瘤数目≦5个,受累器官≦2个,此时肿瘤细胞尚不具备全身播散的倾向。晚期恶性肿瘤患者很大部分处于寡转移状态,而约30%的非小细胞肺癌(NSCLC)患者死于寡转移,目前对于寡转移的治疗以局部治疗为主(包括手术、放疗以及射频消融)。治疗隐匿性转移灶、寡转移灶及全身化学治疗结束后清除残留局部病灶成为治疗寡转移的关键,越来越得到专家共识。在无法手术或者拒绝手术的患者中,局部放放射治疗凸显巨大优势,尤其是体部立体定向放射治疗(Stereotactic Body Radiation Therapy, SBRT),大量临床研究结果显示体部立体定向放射治疗NSCLC寡转移是安全有效的,并能提高转移灶的局部控制率。本文旨在对SBRT治疗非小细胞肺癌寡转移的临床进展做一综述。     

三氧化二砷栓塞联合肝动脉介入治疗转移性肝癌的疗效并33例临床观察

目的：观察并探讨三氧化二砷碘油栓塞联合置管介入化疗治疗转移性肝癌的临床效果。方法：选取辽宁省肿瘤医院介入治疗科2008-2010年收治的转移性肝癌患者33例,进行肝动脉造影及间接门脉造影,根据肝动脉造影或门脉造影结果,根据肝动脉供血情况分别采取肝动脉化疗栓塞及肝动脉灌注化疗方法治疗,3．4周为1治疗周期,共完成4个治疗周期,治疗结束后评价患者,陆床有效率,随访半年、1年、2年患者生存率。结果：①介入治疗后,患者,临床症状均改善,KPS得分明显高于化疗前（P〈0．05）,临床总有效率81．82％。②随访半年、1年、2年生存率分别为90．9l％、66．67％、33.33％,肝动脉化疗栓塞组患者中远期生存率明显高于肝动脉灌注化疗的患者。结论：三氧化二砷可从多角度抑制癌细胞,临床应用安全有效;对于不能手术和不适宜手术的转移性肝癌患者,根据肝动脉供血情况和特点选择合适的介入治疗,可获得满意疗效。     

Low Incidence of Chest Wall Pain with a Risk-Adapted Lung Stereotactic Body Radiation Therapy Approach Using Three or Five Fractions Based on Chest Wall Dosimetry

Purpose

To examine the frequency and potential of dose-volume predictors for chest wall (CW) toxicity (pain and/or rib fracture) for patients receiving lung stereotactic body radiotherapy (SBRT) using treatment planning methods to minimize CW dose and a risk-adapted fractionation scheme.

Methods

We reviewed data from 72 treatment plans, from 69 lung SBRT patients with at least one year of follow-up or CW toxicity, who were treated at our center between 2010 and 2013. Treatment plans were optimized to reduce CW dose and patients received a risk-adapted fractionation of 18 Gy×3 fractions (54 Gy total) if the CW V30 was less than 30 mL or 10–12 Gy×5 fractions (50–60 Gy total) otherwise. The association between CW toxicity and patient characteristics, treatment parameters and dose metrics, including biologically equivalent dose, were analyzed using logistic regression.

Results

With a median follow-up of 20 months, 6 (8.3%) patients developed CW pain including three (4.2%) grade 1, two (2.8%) grade 2 and one (1.4%) grade 3. Five (6.9%) patients developed rib fractures, one of which was symptomatic. No significant associations between CW toxicity and patient and dosimetric variables were identified on univariate nor multivariate analysis.

Conclusions

Optimization of treatment plans to reduce CW dose and a risk-adapted fractionation strategy of three or five fractions based on the CW V30 resulted in a low incidence of CW toxicity. Under these conditions, none of the patient characteristics or dose metrics we examined appeared to be predictive of CW pain.     

Pituitary Hormone Dysfunction After Proton Beam Radiation Therapy in Children with Brain Tumors

Objectiveo characterize endocrine dysfunction in pediatric patients with brain tumors who received proton beam (PB) radiation therapy and to compare those treated with PB radiotherapy only versus combined conventional and PB irradiation.MethodsA retrospective review of medical records of patients ≤ 18 years of age who received PB radiation therapy for a brain tumor between 2000 and 2008 was performed. Variables analyzed included patient demographics, tumor type, therapeutic modalities, radiation doses, and types and timing of endocrine dysfunction.ResultsThirty-eight patients were identified, of whom 31 (19 boys and 12 girls; mean age, 11.9 ± 3.3 years) had undergone endocrine evaluation. Of these patients, 19 received PB radiotherapy only and 12 received conventional plus PB irradiation. Before irradiation, a cranial surgical procedure was performed in 28 study subjects, and 22 received chemotherapy. The mean duration of follow-up after radiation therapy was 1.8 ± 0.8 years. Nine patients (47%) in the PB only group and 4 (33%) in the conventional plus PB group developed endocrine dysfunction (no significant difference) after cranial irradiation. Children with endocrine sequelae treated with PB irradiation alone received fewer cobalt gray equivalents than those treated with conventional plus PB irradiation (5,384 ± 268 versus 5,775 ± 226, respectively; P < .02), and pituitary hormone deficiencies were detected later during follow-up in those who received PB radiotherapy only versus conventional plus PB irradiation (1.17 ± 0.4 years versus 0.33 ± 0.11 year, respectively; P < .01).ConclusionA high rate of endocrine sequelae was seen in our study. Children with brain tumors treated with conventional plus PB irradiation developed endocrine dysfunction faster and received a higher radiation dose than those receiving PB radiotherapy only. Prior surgical treatment and chemotherapy were additional risk factors. Large prospective studies are needed to evaluate further the incidence of endocrine sequelae after PB irradiation in children. (Endocr Pract. 2011;17:891-896)     

三氧化二砷栓塞联合肝动脉介入治疗转移性肝癌的疗效并33 例 临床观察*

摘要目的：观察并探讨三氧化二砷碘油栓塞联合置管介入化疗治疗转移性肝癌的临床效果。方法：选取辽宁省肿瘤医院介入治 疗科2008-2010 年收治的转移性肝癌患者33 例,进行肝动脉造影及间接门脉造影,根据肝动脉造影或门脉造影结果,根据肝动脉 供血情况分别采取肝动脉化疗栓塞及肝动脉灌注化疗方法治疗,3-4 周为1 治疗周期,共完成4 个治疗周期,治疗结束后评价患 者临床有效率,随访半年、1 年、2 年患者生存率。结果：①介入治疗后,患者临床症状均改善,KPS得分明显高于化疗前（P＜ 0.05）,临床总有效率81.82%。②随访半年、1 年、2 年生存率分别为90.91%、66.67%、33.33%,肝动脉化疗栓塞组患者中远期生存 率明显高于肝动脉灌注化疗的患者。结论：三氧化二砷可从多角度抑制癌细胞,临床应用安全有效;对于不能手术和不适宜手术 的转移性肝癌患者,根据肝动脉供血情况和特点选择合适的介入治疗,可获得满意疗效。     

MR Imaging Evaluation of Intracerebral Hemorrhages and T2 Hyperintense White Matter Lesions Appearing after Radiation Therapy in Adult Patients with Primary Brain Tumors

The purpose of our study was to determine the frequency and severity of intracerebral hemorrhages and T2 hyperintense white matter lesions (WMLs) following radiation therapy for brain tumors in adult patients. Of 648 adult brain tumor patients who received radiation therapy at our institute, magnetic resonance (MR) image data consisting of a gradient echo (GRE) and FLAIR T2-weighted image were available three and five years after radiation therapy in 81 patients. Intracerebral hemorrhage was defined as a hypointense dot lesion appearing on GRE images after radiation therapy. The number and size of the lesions were evaluated. The T2 hyperintense WMLs observed on the FLAIR sequences were graded according to the extent of the lesion. Intracerebral hemorrhage was detected in 21 (25.9%) and 35 (43.2) patients in the three- and five-year follow-up images, respectively. The number of intracerebral hemorrhages per patient tended to increase as the follow-up period increased, whereas the size of the intracerebral hemorrhages exhibited little variation over the course of follow-up. T2 hyperintense WMLs were observed in 27 (33.3%) and 32 (39.5) patients in the three and five year follow-up images, respectively. The age at the time of radiation therapy was significantly higher (p < 0.001) in the patients with T2 hyperintense WMLs than in those without lesions. Intracerebral hemorrhages are not uncommon in adult brain tumor patients undergoing radiation therapy. The incidence and number of intracerebral hemorrhages increased over the course of follow-up. T2 hyperintense WMLs were observed in more than one-third of the study population.     

食管癌三维适形放疗和常规放疗比较

目的对比研究三维适形放疗（3DCRT）和常规模拟机定位放疗两种不同方法在食管癌放射治疗中的优缺点。方法 20例食管癌患者采用3DCRT方法进行治疗,应用同一治疗计划系统,制定适形放疗和常规模拟机定位放疗方案。结果与常规模拟定位机定位放疗相比,食管癌照射中3DCRT有最好的剂量分布,既可明显提高靶区的剂量,同时能较好地保护正常组织。结论食管癌的适形放疗技术能降低正常组织的放射损伤和并发症,提高放疗治疗的适形度,改善靶区的剂量分布。     

低剂量放疗缓解骨关节炎

骨关节炎（osteoarthritis,OA）是一种慢性退行性关节疾病,也是最常见的关节炎类型,几乎涉及任何关节,可导致患者慢性疼痛和残疾。19世纪末期伦琴发现了X射线,到20世纪80年代Luckey认为低水平辐射（LDRT）对生物可能有益,逐步应用于一些疾病的治疗,但目前LDRT的运用并未得到普及。本文介绍了OA的流行病学、危险因素、临床表现、治疗方法以及发病机制,重点讨论了LDRT缓解OA的可能机制以及临床研究进展,还探讨了LDRT治疗OA引起的不良反应（急性反应和致癌风险）。在临床上,LDRT本身具有非侵入性、不良反应较小等优势,在治疗OA展现出疼痛缓解、运动改善等疗效,因此LDRT在治疗OA中有广阔的应用前景。