Technical description, phantom accuracy, and clinical feasibility for single-session lung radiosurgery using robotic image-guided real-time respiratory tumor tracking

To describe the technological background, the accuracy, and clinical feasibility for single session lung radiosurgery using a real-time robotic system with respiratory tracking. The latest version of image-guided real-time respiratory tracking software (Synchrony, Accuray Incorporated, Sunnyvale, CA) was applied and is described. Accuracy measurements were performed using a newly designed moving phantom model. We treated 15 patients with 19 lung tumors with robotic radiosurgery (CyberKnife, Accuray) using the same treatment parameters for all patients. Ten patients had primary tumors and five had metastatic tumors. All patients underwent computed tomography-guided percutaneous placement of one fiducial directly into the tumor, and were all treated with single session radiosurgery to a dose of 24 Gy. Follow up CT scanning was performed every two months. All patients could be treated with the automated robotic technique. The respiratory tracking error was less than 1 mm and the overall shape of the dose profile was not affected by target motion and/or phase shift between fiducial and optical marker motion. Two patients required a chest tube insertion after fiducial implantation because of pneumothorax. One patient experienced nausea after treatment. No other short-term adverse reactions were found. One patient showed imaging signs of pneumonitis without a clinical correlation. Single-session radiosurgery for lung tumor tracking using the described technology is a stable, safe, and feasible concept for respiratory tracking of tumors during robotic lung radiosurgery in selected patients. Longer follow-up is needed for definitive clinical results.     

Quantitative measurement of CyberKnife robotic arm steering

Respiratory motion is a significant and challenging problem for radiation medicine. Without adequate compensation for respiratory motion, it is impossible to deliver highly conformal doses to tumors in the thorax and abdomen. The CyberKnife frameless stereotactic radiosurgery system with Synchrony provides respiratory motion adaptation by monitoring skin motion and dynamically steering the beam to follow the moving tumor. This study quantitatively evaluated this beam steering technology using optical tracking of both the linear accelerator and a ball-cube target. Respiratory motion of the target was simulated using a robotic motion platform and movement patterns recorded from previous CyberKnife patients. Our results show that Synchrony respiratory tracking can achieve sub-millimeter precision when following a moving object.     

CyberKnife stereotactic ablative radiotherapy for lung tumors

Stereotactic ablative radiotherapy (SABR) has emerged as a promising treatment for early stage non-small cell lung cancer, particularly for patients unable to tolerate surgical resection. High rates of local tumor control have been demonstrated with acceptable toxicity and the practical advantage of a short course of treatment. The CyberKnife image-guided robotic radiosurgery system has unique technical characteristics that make it well suited for SABR of tumors that move with breathing, including lung tumors. We review the qualities of the CyberKnife platform for lung tumor SABR, and provide a summary of clinical data using this system specifically.     

Four-dimensional stereotactic radiotherapy for early stage non-small cell lung cancer: a comparative planning study

In this study we sought to assess the potential of the respiratory tumor tracking system of the CyberKnife to administer 3 fractions of 15 Gy in the treatment of early stage non-small cell lung cancer (NSCLC). The CyberKnife plans were compared to those developed for 3-D conformal radiotherapy (3-D CRT) administering 20 fractions of 3 Gy based on a slow CT. Ten patients with stage I NSCLC, who were previously treated with 3-D CRT, were re-planned with the CyberKnife treatment planning system. In the 3-D CRT plan, the planning target volume (PTV) included the gross tumor volume (GTV)(slow) and a 15-mm margin, whereas in the CyberKnife plan the margin was 8 mm. The physical doses from both treatment plans were converted to normalized total doses (NTD) using the linear quadratic model with an alpha/beta(tumor) of 10 Gy and alpha/beta(organs at risk (OAR)) of 3 Gy. The average minimal and mean doses administered to the PTV with the CyberKnife and 3-D CRT were 93 and 115.8 Gy and 61 and 66 Gy, respectively (p<0.0001). The mean V(20) of the CyberKnife and 3-D CRT plans were 8.2% and 6.8%, respectively (p=0.124). Both plans complied with the OAR constraints. In conclusion, 4-dimensional stereotactic radiotherapy can increase the minimal and mean biological dose with 51% and 75%, in comparison with 3-D CRT without significantly increasing the V(20), respectively.     

临床肿瘤医师如何善用放射外科的新利器

目的:阐述放射外科的新进展,并建议临床肿瘤医师应采取的应用态度。方法:回顾放射外科的发展史,包括伽马刀、X刀的应用,以及射波刀的特点、优点和目前的临床应用经验。结果:资料显示射波刀自2001年获美国FDA核准作为全身放射外科治疗仪器后,至2006年底在美、欧、亚洲国家已有90家医院,约两万五千个临床病例使用过射波刀治疗颅内、脊椎、躯干良性和恶性肿瘤以及颅内和脊髓动静脉畸形、三叉神经痛。由于临床精准度达1mm以下,治疗中能靠影像导引多次修正患者体位移动,能1～5次大剂量照射而获得良好的治疗成效。射波刀还能治疗随呼吸而移动的肿瘤如肝、肺、胰、前列腺、肾等不必照射大体积的正常组织,是放射外科非常独特和优良的利器。结论:射波刀是放射外科非常卓越的新利器。     

CyberKnife放射治疗肿瘤的临床研究

CyberKnife是一种影像引导下的无框架立体定向放射治疗肿瘤的国际前沿性新技术。它可使其放射线到达传统立体定向放射外科治疗技术无法接近的病变部位;在放射治疗前和放疗的过程中,其先进的影像导航系统可对病灶进行准确的实时监控和跟踪;目标如有移动,会补偿性的自动修正治疗床的位置或射束的方向;非等中心照射特征可使放射线的剂量分布在病变部位达到最大程度的均匀性和适形度,消除以往传统立体定向放射外科治疗技术在靶区剂量分布方面存在的冷点和热点问题;既可以实施单次治疗,也可以进行分次照射,是真正意义上的全新概念的肿瘤立体定向放射外科治疗系统。     

Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomography-based treatment planning

PURPOSE: The aim of this study was to assess the outcomes of patients treated with stereotactic body radiation therapy (SBRT) in patients with primary, recurrent, or metastatic lung lesions, with a focus on positron emission tomography (PET)/computed tomography (CT)-based management. PATIENTS AND METHODS: Fifty-one patients with primary stage I non-small-cell lung cancer (NSCLC; n = 26), recurrent lung cancer after definitive treatment (n = 12), or solitary lung metastases (n = 13) were treated with SBRT between 2005 and 2007. Patients were treated with the CyberKnife Robotic Radiosurgery System with Synchrony respiratory tracking. A dose of 60 Gy was delivered in 3 fractions. All patients had CT or PET/CT performed at approximately 3-month intervals after treatment. RESULTS: The median follow-up was 12 months. Local control at median follow-up was 85% in patients with stage I NSCLC, 92% in patients with recurrent lung cancer, and 62% in the patients with solitary lung metastasis. Analysis of the 28 patients with pre- and post-treatment PET/CT scans demonstrated that those with stable disease (n = 4) had a mean standardized uptake value (SUV) decrease of 28%, partial responders (n = 11) had a decrease of 48%, and patients with a complete response (n = 11) had a decrease of 94%. Patients with progressive disease (n = 2) had an SUV decrease of only 0.4%. Only 2 patients (7%) who had reduced fluorodeoxyglucose avidity later progressed locally. No correlations were found between pretreatment SUV and tumor response, disease progression, or survival. Overall 1-year survival rates were 81%, 67%, and 85% among the patients with primary NSCLC, recurrent lung cancer, and solitary lung metastases, respectively. CONCLUSION: Stereotactic body radiation therapy with CyberKnife is an effective treatment for patients with medically inoperable recurrent or metastatic lung cancer. Positron emission tomography/CT is valuable in staging, planning, and evaluating treatment response and might predict long-term outcome.     

CyberKnife Frameless Radiosurgery for the treatment of extracranial benign tumors

Limited data exists for the use of radiosurgery for benign extracranial tumors. The purpose of this study was to evaluate the feasibility, toxicity, and local control of patients with benign extracranial lesions treated with the CyberKnife Frameless Radiosurgery System. From September 2001 thru January 2004, 59 benign tumors in 44 patients were treated using the CyberKnife a frameless image-guided radiosurgery system. Of these tumors, there were 21 neurofibromas, ten schwannomas, eight meningiomas, eight hemangioblastomas, seven paragangliomas, two hemangiopericytomas, one pseudotumor, one ependymoma, and one arteriovenous malformation (AVM). The anatomic locations of these tumors were spinal (25 cervical, four thoracic, 14 lumbar, and two sacral), neck (eight), orbital (three), brainstem (one), and foramen magnum (one). All patients were treated in a single fraction except three lesions were treated in a fractionated manner. The median treatment delivery time per fraction was 59 minutes (range 11-194). Twenty three lesions initially underwent surgical resection. Ten lesions received prior external beam radiation with a median dose 48 Gy (range 40-54 Gy), and one lesion received two prior CyberKnife treatments for a total dose of 32 Gy to the 80% isodose line. The median follow-up was eight months (range 1-25 months). Acute and late toxicity was graded using the National Cancer Institute Common Toxicity Criteria (CTC) scale. Symptomatic response was documented as "improved," "stable," or "progression". The median tumor dose delivered was 16.0 Gy to the 80% isodose line (range 10-31 Gy). The median tumor volume was 4.3 cc (range 0.14-98.6 cc). The median spinal cord volume receiving more than 8 Gy was 0.035 cc (range 0-2.5 cc) and the median maximum spinal cord dose 11.5 Gy (range 0-19.8 Gy). There were no patients that suffered a significant (Grade 3, 4, or 5) acute toxicity. There was no observed late toxicity. 78% of patients experienced an improvement of their pre-treatment symptoms while only one patient experienced symptom progression. Of the 26 patients who underwent follow-up imaging, the local control rate was 96%. This study suggests that CyberKnife Radiosurgery is a safe and efficacious treatment modality for benign tumors, even for those patients with recurrent previously irradiated lesions.     

射波刀治疗老年早期肺癌患者的初步临床疗效观察

  目的  探讨采用射波刀(CyberKnife?)立体定向放射治疗技术治疗70岁以上老年早期肺癌患者的有效性和安全性。  方法  回顾性分析天津医科大学附属肿瘤医院放疗科2006年11月至2010年9月间34例不能手术的老年早期肺癌患者(T₁N₀M₀ 20例, T₂N₀M₀ 14例), 中位年龄78(70~88)岁, 18例患者采用肿瘤内植入1~2枚金标的呼吸同步追踪技术(Synchrony?), 16例患者采用椎体追踪技术(X-Sight?)。处方剂量45~60 Cy, 中位剂量60 Gy, 分3~6次给予。  结果  25例病变完全缓解(73.5%), 9例部分缓解(26.5%)。中位随访期29(11~59)个月, 原发肿瘤局部控制率97.1%, 1、2、3年无进展生存率分别为85.3%、81.6%、70.0%, 总生存率分别为97.1%、86.6%、80.0%。31例患者(91.1%)出现治疗后的轻度乏力, 15例患者(44.1%)发生Ⅰ~Ⅱ级放射性肺炎, 未发现Ⅲ级及以上的不良反应。1例患者(2.9%)在经胸腔穿刺植入金标后发生严重气胸, 经胸腔闭式引流后缓解。  结论  射波刀立体定向放射治疗技术疗效确切, 不良反应轻, 为无法手术的老年早期肺癌患者的较好选择。      

CyberKnife在颅内外肿瘤治疗中的临床应用

CybcrKnifie（赛博刀）是一种肿瘤证体定向放射外科／治疗（SRS／SRT）领域的新技术．具有实时影像引导、无榧架定位及高精确度等优势，近年来已被应用存全身帅瘤的治疗上.本文综述了国外使用CyberKnife治疗颅内外肿瘤的进展.     

Image-guided robotic radiosurgery for spinal metastases.

BACKGROUND AND PURPOSE: To determine the effectiveness and safety of image-guided robotic radiosurgery for spinal metastases. MATERIALS/METHODS: From 1996 to 2005, 74 patients with 102 spinal metastases were treated using the CyberKnife at Stanford University. Sixty-two (84%) patients were symptomatic. Seventy-four percent (50/68) of previously treated patients had prior radiation. Using the CyberKnife, 16-25 Gy in 1-5 fractions was delivered. Patients were followed clinically and radiographically for at least 3 months or until death. RESULTS: With mean follow-up of 9 months (range 0-33 months), 36 patients were alive and 38 were dead at last follow-up. No death was treatment related. Eighty-four (84%) percent of symptomatic patients experienced improvement or resolution of symptoms after treatment. Three patients developed treatment-related spinal injury. Analysis of dose-volume parameters and clinical parameters failed to identify predictors of spinal cord injury. CONCLUSIONS: Robotic radiosurgery is effective and generally safe for spinal metastases even in previously irradiated patients.     

Toxicity and Efficacy of Stereotactic Ablative Body Radiotherapy for Moderately Central Non-small Cell Lung Cancers Using 50 Gy in Five Fractions

AimsStereotactic ablative body radiotherapy doses for peripheral lung lesions caused high toxicity when used for central non-small cell lung cancer (NSCLC). To determine a safe stereotactic ablative body radiotherapy dose for central tumours, the phase I/II Radiation Therapy Oncology Group RTOG 0813 trial used 50 Gy/five fractions as a baseline. From 2013, 50 Gy/five fractions was adopted at the Beatson West of Scotland Cancer Centre for inoperable early stage central NSCLC. We report our prospectively collected toxicity and efficacy data.Materials and methodsPatient and treatment characteristics were obtained from electronic medical records. Tumours were classed as moderately central or ultra-central tumours using published definitions. Toxicity was assessed in a centralised follow-up clinic at 2 weeks, 6 weeks, 3 months, 6 months, 1 year and 2 years after treatment.ResultsFifty patients (31 women, 19 men, median age 75.1 years) were identified with T1-2N0M0 moderately central NSCLC; one patient had both an ultra-central and a moderately central tumour. Eighty-four per cent were medically unfit for surgery. Forty per cent had biopsy-proven NSCLC and 60% were diagnosed radiologically using 18-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Fifty-six per cent of patients were Eastern Cooperative Oncology Group (ECOG) performance status 2 or worse. All patients received 50 Gy/five fractions on alternate days on schedule. Two patients died within 90 days of treatment, one from a chest infection, the other cause of death was unknown. There was one episode of early grade 3 oesophagitis and one grade 3 late dyspnoea. There was no grade 4 toxicity. Over a median follow-up of 25.2 months (range 1–70 months), there were 34 deaths: 18 unrelated to cancer and 16 due to cancer recurrence. The median overall survival was 27.0 months (95% confidence interval 20.6–35.9) and cancer-specific survival was 39.8 months (95% confidence interval 28.6, not reached).ConclusionThis study has shown that 50 Gy/five fractions is a safe dose and fractionation for early stage inoperable moderately central NSCLC, with outcomes comparable with other series, even with patients with a poor performance status.     

An Overview of CyberKnife Radiosurgery

Stereotactic radiosurgery is a non-invasive procedure that utilizes precisely targeted radiation as an ablative surgical tool. Conventional radiosurgery devices, such as the Gamma Knife, rely upon skeletally attached Stereotactic frames to immobilize the patient and precisely determine the 3D spatial position of a tumor. A relatively new instrument, the CyberKnife (Accuray, Inc., Sunnyvale, CA), makes it possible to administer radiosurgery without a frame. The CyberKnife localizes clinical targets using a very accurate image-to-image correlation algorithm, and precisely cross-fires high-energy radiation from a lightweight linear accelerator by means of a highly manipulable robotic arm. CyberKnife radiosurgery is an effective alternative to conventional surgery or radiation therapy for a range of tumors and some non-neoplastic disorders. This report will describe CyberKnife technology and oncologic applications in neurosurgery and throughout the body.     

Lung tumor tracking during stereotactic radiotherapy treatment with the CyberKnife: Marker placement and early results

Lung tumor tracking during stereotactic radiotherapy with the CyberKnife requires the insertion of markers in or close to the tumor. To reduce the risk of pneumothorax, three methods of marker placement were used: 1) intravascular coil placement, 2) percutaneous intrathoracal, and 3) percutaneous extrathoracal placement. We investigated the toxicity of marker placement and the tumor response of the lung tumor tracking treatment. Markers were placed in 20 patients with 22 tumors: 13 patients received a curative treatment, seven a palliative. The median Charlson Comorbidity Score was 4 (range: 1-8). Platinum fiducials and intravascular embolisation coils were used as markers. In total, 78 markers were placed: 34 intrathoracal, 23 intravascular and 21 extrathoracal. The PTV equaled the GTV + 5 mm. A median dose of 45 Gy (range: 30-60 Gy, in 3 fractions) was prescribed to the 70-85% isodose. The response was evaluated with a CTscan performed 6-8 weeks after the last treatment and routinely thereafter. The median follow-up was 4 months (range: 2-11). No severe toxicity due to the marker placement was seen. Pneumothorax was not seen. The local control was 100%. Four tumors in four patients showed a complete response, 15 tumors in 14 patients a partial response, and three tumors in two patients with metastatic disease had stable disease. No severe toxicity of marker placement was seen due to the appropriate choice of one of the three methods. CyberKnife tumor tracking with markers is feasible and resulted in excellent tumor response. Longer follow-up is needed to validate the local control.     

Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: phase I study

PURPOSE: A Phase I dose escalation study of stereotactic body radiation therapy to assess toxicity and local control rates for patients with medically inoperable Stage I lung cancer. METHODS AND MATERIALS: All patients had non-small-cell lung carcinoma, Stage T1a or T1b N0, M0. Patients were immobilized in a stereotactic body frame and treated in escalating doses of radiotherapy beginning at 24 Gy total (3 x 8 Gy fractions) using 7-10 beams. Cohorts were dose escalated by 6.0 Gy total with appropriate observation periods. RESULTS: The maximum tolerated dose was not achieved in the T1 stratum (maximum dose = 60 Gy), but within the T2 stratum, the maximum tolerated dose was realized at 72 Gy for tumors larger than 5 cm. Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4/19 T1 and 6/28 T2 patients. Nine local failures occurred at doses < or =16 Gy and only 1 at higher doses. Local failures occurred between 3 and 31 months from treatment. Within the T1 group, 5 patients had distant or regional recurrence as an isolated event, whereas 3 patients had both distant and regional recurrence. Within the T2 group, 2 patients had solitary regional recurrences, and the 4 patients who failed distantly also failed regionally. CONCLUSIONS: Stereotactic body radiation therapy seems to be a safe, effective means of treating early-stage lung cancer in medically inoperable patients. Excellent local control was achieved at higher dose cohorts with apparent dose-limiting toxicities in patients with larger tumors.     

非小细胞肺癌伽玛刀治疗后并发放射性肺不张分析

目的：回顾分析伽玛刀大分割适形放射治疗非小细胞肺癌（non small cell lung cancer,NSCLC）后并发非肿瘤性肺不张的原因,进一步完善大分割适形放射治疗。方法：488例非小细胞肺癌（NSCLC）分为中央型（262例）和周围型（226例）,分别进行了伽玛刀分次治疗,剂量3Gy-8Gy/次,处方剂量50%-70%剂量线,1次/日,5次/周,连续照射,总次数5-16次,总剂量35Gy-60Gy。结果：非小细胞肺癌中央型伽玛刀治疗3-6月后共出现20例放射性肺不张,而周围型未出现放射性肺不张,两组差异明显。结论：放射性肺不张是肺癌大分割适形放射治疗中很少报道的严重并发症,区分中央型和周围型分别实施治疗可能有效减轻治疗的严重并发症,中央型肺癌进行精确放疗时有必要将1,2级支气管作为剂量限制性器官。     

CyberKnife radiotherapy for localized prostate cancer: rationale and technical feasibility

There is a clear dose response for localized prostate cancer radiotherapy and there probably is a radiobiological rationale for hypo-fractionation. Combining the two should maximize tumor control and increase the therapeutic ratio. This study examines the rationale and technical feasibility of CyberKnife radiotherapy (a robotic arm-driven linear accelerator) for localized prostate cancer. Its ability to deliver non-coplanar non-isocentric arcs can yield maximally conformal isodoses. It is the only integrated system capable of target position verification and real-time tracking during delivery of conformal stereotactic radiotherapy. Inverse planning with the CyberKnife is used to design a course of radiotherapy for localized prostate cancer. Fiducial markers within the gland are used to verify organ position and track organ motion via an orthogonal pair of electronic x-ray imaging devices and provide real-time feedback correction to the robotic arm during delivery. Conformal isodose curves and dose volume histograms (DVH) are used to compare with an optimized Intensity-Modulated Radiotherapy (IMRT) plan actually delivered to the study patient based upon CT scan-derived organ volumes. The CyberKnife can produce superior DVHs for sparing of rectum and bladder and excellent DVHs for target coverage compared with IMRT, and possesses dose heterogeneities to the same degree as IMRT plans. Because of the significantly longer delivery times required it would be best suited for hypo-fractionated regimens. Such dose regimens might allow for biologically equivalent dose escalation without increased normal tissue toxicity. Since the CyberKnife can verify organ position and motion and correct for this in real-time it is the ideal means of achieving such excellent DVHs without a compromise in doses to normal tissues. These capabilities are essential if one contemplates hypo-fractionated regimens with large dose-per-fraction sizes (>5Gy to 10Gy) and dose-escalation.     

Survival following CyberKnife radiosurgery and hypofractionated radiotherapy for newly diagnosed glioblastoma multiforme

Current therapeutic goals for treatment of Glioblastoma Multiforme (GBM) involve gross total resection followed by multifractionated focal external beam radiation therapy (EBRT). Patients treated with optimal therapy have a median survival of approximately 12-15 months. In the present study, we sought to determine whether a hypofractionated dosing schedule using CyberKnife is at least as effective as multifractionated focal EBRT. A retrospective analysis was conducted on 20 histopathologically confirmed GBM patients treated with CyberKnife at Okayama Kyokuto Hospital in Japan after gross total resection (n=11), subtotal resection (n=8), or biopsy (n=1). Eight patients also received adjuvant ACNU and Vincrisitine chemotherapy according to local protocol; however, no patient received any other form of radiation besides post surgical/biopsy CyberKnife treatment. The treated tumor volumes ranged from 9.62 cm(3)-185.81 cm(3) (mean: 86.08 cm(3)). The marginal dose (D90) ranged from 19.99 Gy-41.47 Gy (mean: 34.58 Gy) with a maximum mean dose of 43.99 Gy (range: 23.33 Gy-56.89 Gy). The prescribed isodose line ranged from 50.38%-85.68% with a mean of 79.25%. Treatment was delivered in 1-8 fractions (mean: 5.65). Patients were followed from 2-36 months (mean: 16.45 months). Overall median survival was 16 months with 55% of patients alive at 12 months and 34% of patients alive at 24 months. Median survival of patients in Recursive Partitioning Analysis (RPA) classes III or IV was 32 months versus 12 months for those in RPA class V. Median survival for patients who received gross total resection was 36 months versus 8 months for those who underwent subtotal resection or biopsy. The results of this study using CyberKnife stereotactic radiosurgery (SRS) and hypofractionated radiotherapy compared favorably to historic data using focal EBRT in newly diagnosed post surgical GBM patients. A larger prospective analysis that compares CyberKnife SRS and hypofractionated radiotherapy to focal EBRT is warranted.     

Solutions that enable ablative radiotherapy for large liver tumors: Fractionated dose painting,simultaneous integrated protection,motion management,and computed tomography image guidance

The emergence and success of stereotactic body radiation therapy (SBRT) for the treatment of lung cancer have led to its rapid adoption for liver cancers. SBRT can achieve excellent results for small liver tumors. However, the vast majority of physicians interpret SBRT as meaning doses of radiation (range, 4‐20 Gray [Gy]) that may not be ablative but are delivered within about 1 week (ie, in 3‐6 fractions). Adherence to this approach has limited the effectiveness of SBRT for large liver tumors (>7 cm) because of the need to reduce doses to meet organ constraints. The prognosis for patients who present with large liver tumors is poor, with a median survival ≤12 months, and most of these patients die from tumor‐related liver failure. Herein, the authors present a comprehensive solution to achieve ablative SBRT doses for patients with large liver tumors by using a combination of classic, modern, and novel concepts of radiotherapy: fractionation, dose painting, motion management, image guidance, and simultaneous integrated protection. The authors discuss these concepts in the context of large, inoperable liver tumors and review how this approach can substantially prolong survival for patients, most of whom otherwise have a very poor prognosis and few effective treatment options. Cancer 2016;122:1974–86 . © 2016 American Cancer Society.