Emerging application of stereotactic body radiation therapy for gynecologic malignancies

Stereotactic body radiation therapy (SBRT) involves delivery of image-guided, ablative radiation doses to planning treatment volume(s) using sophisticated dosimetric planning and target localization. Early on, clinical investigators pursued SBRT for the treatment of early stage non-small-cell lung cancer, lung and liver oligometastases and spinal metastases. As a result of its clinical efficacy in these disease sites, SBRT has been explored in the management of persistent or recurrent gynecological cancers. This article will consider indications for SBRT application in gynecological cancer management, will reflect on outcomes from key SBRT clinical trials and will discuss new therapeutic roles of SBRT for gynecological cancers.     

立体定向放疗在治疗肝转移癌中的应用现状及研究进展

肝脏是大多数实体恶性肿瘤转移的常见部位,研究证实,对于合并肿瘤肝转移的患者,除积极针对原发病灶进行综合治疗外,对肝转移癌进行局部治疗亦可提高患者的生存潜能.立体定向放疗(SBRT)作为一种无创的肿瘤局部治疗方式,具有生物等效剂量(BED)高、正常组织反应轻、治疗时间短等优势.现有研究在应用人群、剂量和分割方式、临床疗效...     

Regorafenib-induced transverse myelopathy after stereotactic body radiation therapy

Stereotactic body radiation therapy (SBRT) delivers large doses of radiation with great accuracy, but is known to have deleterious effects on the vascular compartment of irradiated tissues. Combining SBRT with targeted anti-angiogenesis agents, while able to increase therapeutic efficacy, may unexpectedly precipitate vascular-based toxicities. In this report, we describe a patient with colon cancer who developed transverse myelopathy from regorafenib 2 years after receiving SBRT for three metastatic liver lesions. Regorafenib (Stivarga), formerly BAY 73-4506, (Bayer HealthCare Pharmaceuticals, Montville, NJ) is a multiple receptor tyrosine kinase inhibitor with anti-angiogenic effects used in metastatic colon cancer. Its most common side effects are fatigue, diarrhea and hypertension. However, severe neurologic toxicity has not been previously recognized. Here, we illustrate a case in which the patient developed hyperalgesia and radicular pain 2 weeks after starting regorafenib. Several studies report an increased neurological toxicity when angiogenesis inhibitors are given after radiation therapy, and we postulate that the angioinhibitory effects of regorafenib accelerated subclinical microvascular injury from SBRT. This unexpected toxicity may be clinically relevant when giving targeted angiogenesis inhibitors after SBRT.     

Guidelines for safe practice of stereotactic body (ablative) radiation therapy

The uptake of stereotactic ablative body radiation therapy (SABR)/stereotactic body radiation therapy (SBRT) worldwide has been rapid. The Australian and New Zealand Faculty of Radiation Oncology (FRO) assembled an expert panel of radiation oncologists, radiation oncology medical physicists and radiation therapists to establish guidelines for safe practice of SABR. Draft guidelines were reviewed by a number of international experts in the field and then distributed through the membership of the FRO. Members of the Australian Institute of Radiography and the Australasian College of Physical Scientists and Engineers in Medicine were also asked to comment on the draft. Evidence‐based recommendations (where applicable) address aspects of departmental staffing, procedures and equipment, quality assurance measures, as well as organisational considerations for delivery of SABR treatments. Central to the guidelines is a set of key recommendations for departments undertaking SABR. These guidelines were developed collaboratively to provide an educational guide and reference for radiation therapy service providers to ensure appropriate care of patients receiving SABR.     

A prospective trial of stereotactic body radiation therapy for unresectable pancreatic cancer testing ablative doses

BackgroundWe explored the safety and efficacy of ablative doses of stereotactic body radiation therapy (SBRT) for unresectable pancreatic cancer.MethodsThis phase I/II trial included patients with unresectable pancreatic cancer previously treated with any number of cycles of induction chemotherapy. Patients were enrolled according to a 3+3 dose escalation design at 10, 12.5, and 15 Gy ×3, with subsequent patients at the maximally tolerated dose (MTD). Treatment was delivered to gross tumor delineated with MRI fusion using image-guidance to fiducial markers. Dose-limiting toxicity (DLT) was defined as grade 3+ toxicity within 30 days. Secondary endpoints included late gastrointestinal (GI) toxicity, freedom from local failure (FFLF), and survival.ResultsFifteen patients received a median 10 cycles of chemotherapy. There were no DLTs, and the MTD was 15 Gy ×3. Thirty-day toxicity included grade 2 nausea (46%) and grade 2 diarrhea (7%). Median survival after SBRT was 12.8 months (23 months after diagnosis) and median relapse-free survival was 7 months. At 1-year, FFLF was 80%. Four patients had grade 3+ GI bleeding after 30 days (median 6 months). Grade 3+ GI bleeding was associated with tumor volume (P=0.01), heterogeneity of dose within the planning target volume (PTV) (V120, P=0.03), and duodenal dose (V26–30 Gy, P<0.2).ConclusionsThis aggressive SBRT regimen demonstrated limited 30-day morbidity, a moderate degree of local control, and a moderate risk for late GI bleeding. Further work is necessary to define the most appropriate hypofractionated radiation therapy (RT) regimen in the ablative dose range.     

立体定向放疗联合免疫治疗晚期恶性肿瘤进展

晚期肺转移癌或黑素瘤中放疗联合免疫检测点抑制剂,封闭免疫抑制通路,增强抗肿瘤免疫应答,在临床上明显改善生存。体部立体定向放疗大剂量精准照射到肿瘤靶区,最大程度避免周围正常组织损伤,同时还诱导相关细胞因子和免疫分子表达,较常规放疗更能诱导强烈的免疫反应及远隔效应,更适合与免疫联合。已有研究表明总剂量和分割模式是调节放疗免疫反应的重要参数;放疗与免疫序贯时机显著影响疗效,肿瘤浸润淋巴细胞、PD-L1表达水平和MMR缺陷可能是预测放疗免疫治疗的重要指标。采用合理的放疗剂量和分割模式,选择最佳序贯时机和有效的预测标记物,SBRT联合免疫可以最大程度激活全身免疫反应,发挥远隔效应协同作用晚期恶性肿瘤。     

Complications of pelvic radiation in patients treated for gynecologic malignancies

Radiation therapy is a critical treatment modality in the management of patients with gynecologic tumors. New highly conformal external‐beam and brachytherapy techniques have led to important reductions in recurrence and patient morbidity and mortality. However, patients who receive pelvic radiation for gynecologic malignancies may experience a unique constellation of toxicity because of the anatomic locations, combination with concurrent chemotherapy and/or surgery, as well as potential surgical interventions. Although side effects are often categorized into acute versus late toxicities, several late toxicities represent continuation and evolution of the same pathologic process. Comorbidities and radiation dose can significantly increase the risk of morbidity. Current understanding of the incidence of various morbidities in patients treated with current radiation techniques for gynecologic malignancies, the impact of chemotherapy and surgery, treatment options for those effects, and future areas of research are highlighted. Cancer 2014;120:3870–3883. © 2014 American Cancer Society.     

Proton stereotactic body radiation therapy for liver metastases—results of 5-year experience for 81 hepatic lesions

BackgroundTo report on our institutional experience using Proton stereotactic body radiation therapy (SBRT) for patients with liver metastases.MethodsAll patients with liver metastases treated with Proton SBRT between September 2012 and December 2017 were retrospectively analyzed. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method calculated from the time of completion of Proton SBRT. LC was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.ResultsForty-six patients with 81 lesions were treated with Proton SBRT. The median age was 65.5 years old (range, 33–86 years) and the median follow up was 15 months (range, 1–54 months). The median size of the gross tumor volume (GTV) was 2.5 cm (range, 0.7–8.9 cm). Two or more lesions were treated in 56.5% of patients, with one patient receiving treatment to a total of five lesions. There were 37 lesions treated with a biologically effective dose (BED) ≤60, 9 lesions with a BED of 61–80, 22 lesions with a BED of 81–100, and 13 lesions with a BED >100. The 1-year and 2-year LC for all lesions was 92.5% (95% CI, 82.7% to 96.8%). The grade 1 and grade 2 toxicity rates were 37% and 6.5%, respectively. There were no grade 3 or higher toxicities and no cases of radiation-induced liver disease (RILD).ConclusionsProton SBRT for the treatment of liver metastases has promising LC rates with the ability to safely treat multiple liver metastases. Accrual continues for our phase II trial treating liver metastases with Proton SBRT to 60 GyE (Gray equivalent) in 3 fractions.     

Use of stereotactic body radiation therapy for oligometastatic recurrent prostate cancer: A systematic review

The purpose of this study is to evaluate the effectiveness and safety of stereotactic body radiation therapy (SBRT) in the management of oligometastatic recurrent prostate cancer (PCa) by means of a systematic review. Six databases were searched (CENTRAL, Embase, LILACS, PubMed, Scopus and Web of Science). Additionally, hand‐searching and grey literature search were performed. The main outcomes were progression‐free survival (PFS) and toxicity rates. Androgen deprivation therapy‐free survival (ADT‐FS), local control, pattern of recurrence, cancer‐specific survival and overall survival were also assessed. Risk of bias and quality of evidence were judged with the aid of specific tools. Fourteen studies were included, involving 661 patients and 899 lesions (561 nodal, 336 bone, 2 liver). Median PFS and ADT‐FS were around 1 to 3 years. Local control rates varied from 82 to 100% among researches with low risk of bias. Acute and late grade 2 toxicity was observed in 2.4% and 1.1% of the patients, respectively. One case of acute and two cases of late grade 3 toxicity were registered. Only one randomized study addresses this topic. Although it does not meet all the eligibility criteria, it is useful for the discussion. A quantitative analysis was not possible, nor were subgroup analyses, due to the significant heterogeneity of the interventions and outcomes reported. Longer follow‐up period is required. SBRT seems to be a safe approach to metastatic lesions that might provide disease control and defer androgen deprivation therapy (ADT). Local control is better when higher radiation doses are employed.     

Radiation therapy for intrahepatic malignancies

Historically, radiation was not used in the management of hepatocellular carcinoma and liver metastasis because of the low tolerance of the liver to radiation. More recently, improvements in radiation delivery using advanced techniques, such as 3D conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, stereotactic body radiation therapy, proton-beam therapy and internal radiation therapy, have enabled partial and selective irradiation of the liver with promising response rates and toxicity profiles. This review will discuss the different techniques of radiation that can now be used to treat intrahepatic malignancies and the important clinical studies in the medical literature.     

Stereotactic body radiation therapy for nonpulmonary primary tumors

Stereotactic body radiation therapy (SBRT) represents a novel treatment modality for cancer and has been used to treat various types of primary cancer with curative intent. Data on the use of SBRT for various primary sites are emerging. While the largest body of data is concerned with early-stage lung cancer, there is also a fair amount of experience in the treatment of nonpulmonary primary sites with SBRT. This article will provide an overview of radiobiologic, technical and clinical aspects of the use of this emerging treatment modality for various nonpulmonary primary tumors.     

Stereotactic body radiation therapy for metastasis to the adrenal glands

Many primary cancers can metastasize to the adrenal glands. Adrenalectomy via an open or laparoscopic approach is the current definitive treatment, but not all patients are eligible or wish to undergo surgery. There are only limited studies on the use of conventional radiation therapy for palliation of symptoms from adrenal metastasis. However, the advent of stereotactic body radiation therapy (SBRT) – also named stereotactic ablative radiotherapy for primary lung cancer, metastases to the lung, and metastases to the liver – have prompted some investigators to consider the use of SBRT for metastases to the adrenal glands. This review focuses on the emerging data on SBRT of metastasis to the adrenal glands, while also providing a brief discussion of the overall management of adrenal metastasis.     

Dose discrepancy between planning system estimation and measurement in spine stereotactic body radiation therapy: A case report

Stereotactic body radiation therapy (SBRT) to treat spinal metastases has shown excellent clinical outcomes for local control. High dose gradients wrapping around spinal cord make this treatment technically challenging. In this work, we present a spine SBRT case where a dosimetric error was identified during pre‐treatment dosimetric quality assurance (QA). A patient with metastasis in T7 vertebral body consented to undergo SBRT. A dual arc volumetric modulated arc therapy plan was generated on the Pinnacle treatment planning system (TPS) with a 6 MV Elekta machine using gantry control point spacing of 4°. Standard pre‐treatment QA measurements were performed, including ArcCHECK, ion chamber in CTV and spinal cord (SC) region and film measurements in multiple planes. While the dose measured at CTV region showed good agreement with TPS, the dose measured to the SC was significantly higher than reported by TPS in the original and repeat plans. Acceptable agreement was only achieved when the gantry control point spacing was reduced to 3°. A potentially harmful dose error was identified by pre‐treatment QA. TPS parameter settings used safely in conventional treatments should be re‐assessed for complex treatments.     

3D-CRT联合主动脉呼吸控制主体定向放射治疗剂量学分析

目的:探讨高剂量率三维适形放疗(three-dimensional conformal radiation therapy,3D-CRT)联合主动呼吸控制技术(active breathing control,ABC)进行早期非小细胞肺癌(non-small cell lung cancer,NSCLC)立体定向放射治疗(ste-reotactic body radiation therapy,SBRT)的剂量学特点。方法:选取接受放射治疗的早期NSCLC患者8例,分别在ABC辅助下适度深吸气末屏气(moderate deep inspiration breath-hold,mDIBH,触发阈值设定为峰值的80%)和自由呼吸(free breathing,FB)状态下行模拟定位CT扫描,分别在2套CT图像上采用高剂量率(剂量率为1 000 Mu/min)的3D-CRT设计SBRT计划。比较2种呼吸状态下大体肿瘤体积(gross tumor volume,GTV)、计划靶体积(planning targetvolume,PTV)、双肺的体积、2种计划方式下PTV的最大剂量(D1%)和最小剂量(D99%)、靶区剂量分布的均匀指数(HI)和适形指数(CI)、正常组织的相关体积-剂量(Vx、Dmean、Dmax)及机器跳数(MU)的差异。结果:PTV体积由FB下平均158.04cm3减少到了mDIBH下的76.90cm3,减少51.34%,P=0.006;GTV FB体积较GTV mDIBH平均减少了约3cm3,差异无统计学意义,P=0.658;mDIBH状态下患侧肺、健侧肺和双肺平均体积分别由FB状态下的1 978.77、1 762.55和3 745.26cm3增加到了2 910.88、2 671.13和5 615.85cm3,分别增加了32.02%、35.36%和33.31%,P值均<0.05。FB及mDIBH状态下的靶区剂量的CI、HI、D1%和D99%均基本相当,P>0.05;mDIBH下3D-CRT计划中患侧肺V5～V40、双侧肺V5～V40及Dmean、胸壁V5～V40及Dmean、脊髓Dmax、绝对剂量体积V60-50、V50-40均小于FB状态,P<0.05;mDIBH下的健侧肺V5～V15、心脏V20～V40、Dmean以及绝对剂量体积V40-30、V30-20较FB略有降低,绝对剂量体积V20-10、V10～V5略有增大,P>0.05;3D-CRT mDIBH的MU及照射时间与3D-CRT FB基本相当,P>0.05。结论:高剂量率的3D-CRT联合ABC技术在早期NSCLC SBRT中可在不影响靶区剂量分布的同时,更好的降低肺组织、胸壁受照剂量。     

体部肿瘤立体定向放疗(SBRT或SABR)的临床应用现状

体部肿瘤的立体定向放疗(SBRT)因其疗效好,副作用低,在临床上的应用越来越广泛。根据肿瘤特征、位置和大小,采用不同的放疗分割模式,但最佳分隔模式和OAR的剂量限制仍不清楚,需要进一步研究和观察长期的不良反应。     

Stereotactic body radiation therapy for liver metastases

Over the years, early diagnosis of metastatic disease has improved and the prevalence of oligometastatic patients is increasing. Liver is a most common site of progression from gastrointestinal, lung and breast cancer and in the setting of oligometastatic patients, surgical resection is associated with increased survival. Approximately 70-90% of liver metastases, however, are unresectable and an effective and safe alternative therapeutic option is necessary for these patients. The role of stereotactic body radiation therapy (SBRT) was investigated in the treatment of oligometastatic patients with promising results, thanks to the ability of this procedure to deliver a conformal high dose of radiation to the target lesion and a minimal dose to surrounding critical tissues. This paper was performed to review the current literature and to provide the practice guidelines on the use of stereotactic body radiotherapy in the treatment of liver metastases. We performed a literature search using Medical Subject Heading terms “SBRT” and “liver metastases”, considering a period of ten years.     

准直器角度对肺癌SBRT-VMAT治疗计划的影响

目的:研究准直器角度对中央型非小细胞肺癌(NSCLC)患者体部立体定向放射治疗(SBRT)容积旋转调强(VMAT)计划剂量学影响。方法:选取10名中央型NSCLC患者进行VMAT计划设计。使用Varian Eclipse系统,6 MV FFF X射线,最大剂量率1400 MU/min。机架角度:CCW 179°~181°、CW 181°~179°,双弧准直器角度互组,0°~90°每间隔10°设置准直器角度,即为(0°,0°)、(10°,350°)、(20°,340°)、(30°,330°)、(40°,320°)、(50°,310°)、(60°,300°)、(70°,290°)、(80°,280°)和(90°,270°)制定十个计划。在处方剂量相同并且处方剂量线包绕相同靶区体积的前提下(归一至80%),比较计划靶区参数:D 95%、V 90%、适形度指数(CI)、梯度指数(GI)、D 2 cm以及机器跳数(MU),危及器官参数:双肺(D 1500 cm³、D 1000 cm³)、心脏(D 15 cm³)、脊髓(D 1.2 cm³、D 0.35 cm³)。用SPSS软件对每个分析指标做Wilcoxon符号秩检验,判断差异是否具有统计学意义。结果:在有统计学意义的基础上,10组计划中,准直器角度为60°时(P<0.05),靶区D 95%剂量最高,准直器角度为50°时(P<0.05),靶区V 90%最高。CI和GI在0°最佳。危及器官双肺(D 1500 cm³、D 1000 cm³)、心脏(D 15 cm³)、脊髓(D 1.2 cm³)受照剂量均在0°最低,脊髓D 0.35 cm³在整个角度范围内不具有统计学差异。此外,所有计划中危及器官受照剂量均远远低于计划规定值,其中双肺(D 1500 cm³)在50°的剂量与最低值仅相差4.1%(P<0.05),心脏(D 15 cm³)在60°的剂量与最低值仅相差3.4%(P<0.05)。结论:改变准直器角度对肺癌SBRT-VMAT计划剂量有明显的影响。选择合适的准直器角度,正常组织受照剂量远远低于计划限量时,靶区体积剂量明显提高,但计划复杂度也略有提升。在临床计划设计过程中,应充分考虑准直器角度的影响,制定更合适的治疗计划。     

体部立体定向放疗的放射生物学进展

相比常规照射方式,SBRT照射次数少(1~5次),单次剂量较高(8~30 Gy)。然而在低剂量、多分割方案中适用的LQ模型并不能准确评价大剂量射线的放射生物效应。有学者提出了USC、LQL、gLQ等修正模型,希望能更好地预测SBRT的放射生物学效应。目前SBRT成为肺部、肝脏、脊柱、胰腺等部位原发病灶或少发转移病灶的重要治疗手段之一。放射生物学的进展可以更深入地探索SBRT的临床应用,对提高肿瘤放疗疗效有重要作用。     

Hyperbaric oxygen therapy for late radiation tissue injury in gynecologic malignancies

Background

Late radiation tissue injury is a serious complication of radiotherapy for patients with gynecologic malignancies. Strategies for managing pain and other clinical features have limited efficacy; however, hyperbaric oxygen therapy (HBO₂) may be an effective option for some patients.

Methods

In a systematic review of the literature, the Ovid medline, embase, Cochrane Library, National Guidelines Clearinghouse, and Canadian Medical Association Infobase databases were searched to June 2009 for clinical practice guidelines, systematic reviews, randomized controlled trials, or other relevant evidence. Studies that did not evaluate soft tissue necrosis, cystitis, proctitis, bone necrosis, and other complications were excluded.

Results

Two randomized trials, eleven nonrandomized studies, and five supporting documents comprise the evidence base. In addition, information on the harms and safety of treatment with HBO₂ were reported in three additional sources. There is modest direct evidence and emerging indirect evidence that the use of HBO₂ is broadly effective for late radiation tissue injury of the pelvis in women treated for gynecologic malignancies.

Conclusions

Based on the evidence and expert consensus opinion,

• HBO₂ is likely effective for late radiation tissue injury of the pelvis, with demonstrated efficacy specifically for radiation damage to the anus and rectum;
• the main indication for HBO₂ therapy in gynecologic oncology is in the management of otherwise refractory chronic radiation injury;
• HBO₂ may provide symptomatic benefit in certain clinical settings (for example, cystitis, soft-tissue necrosis, and osteonecrosis); and
• HBO₂ may reduce the complications of gynecologic surgery in patients undergoing surgical removal of necrosis.