GOECP/SEOR radiotheraphy guidelines for non-small-cell lung cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease accounting for approximately 85% of all lung cancers. Only 17% of patients are diagnosed at an early stage. Treatment is multidisciplinary and radiotherapy plays a key role in all stages of the disease. More than 50% of patients with NSCLC are treated with radiotherapy (curative-intent or palliative). Technological advances-including highly conformal radiotherapy techniques, new immobilization and respiratory control systems, and precision image verification systems-allow clinicians to individualize treatment to maximize tumor control while minimizing treatment-related toxicity. Novel therapeutic regimens such as moderate hypofractionation and advanced techniques such as stereotactic body radiotherapy (SBRT) have reduced the number of radiotherapy sessions. The integration of SBRT into routine clinical practice has radically altered treatment of early-stage disease. SBRT also plays an increasingly important role in oligometastatic disease. The aim of the present guidelines is to review the role of radiotherapy in the treatment of localized, locally-advanced, and metastatic NSCLC. We review the main radiotherapy techniques and clarify the role of radiotherapy in routine clinical practice. These guidelines are based on the best available evidence. The level and grade of evidence supporting each recommendation is provided.     

Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer

The oligometastatic state represents a distinct entity among those with metastatic disease and consists of patients with metastases limited in number and location, representing an intermediate state between locally confined and widely metastatic cancer. Although similar, “oligorecurrence” (limited number of metachronous metastases under conditions of a controlled primary lesion) and “oligoprogressive” (disease progression at a limited number of sites with disease controlled at other disease sites) states are distinct entities. In non–small cell lung cancer (NSCLC), the oligometastatic state is relatively common, with 20% to 50% of patients having oligometastatic disease at diagnosis. This subgroup of patients when receiving ablative therapy, such as surgery or stereotactic body radiation radiotherapy, can obtain markedly long progression-free and overall survival. The role of radical treatment for intracranial oligometastases is well established. Fewer data exist regarding radical treatment of extracranial metastases in lung cancer; however, retrospective series using surgery or stereotactic body radiotherapy for extracranial oligometastatic disease in NSCLC have shown excellent local control, with a suggestion of improvement in progression-free survival. In the present report, we have reviewed the data on the treatment of brain metastases in oligometastatic NSCLC and the results of ablative treatment of extracranial sites. Recently, the first randomized trial comparing ablative treatment versus control in oligometastatic disease was reported, and those data are reviewed in the context of smaller series. Finally, areas of controversy are discussed and a therapeutic approach for patients with oligometastatic disease is proposed.     

Oligometastases in prostate cancer: Ablative treatment

Technological advances in radiotherapy have led to the introduction of techniques such as stereotactic body radiation therapy (SBRT), allowing the administration of ablative doses. The hypothesis that oligometastatic disease may be cured through local eradication therapies has led to the increasing use of SBRT in patients with this type of disease. At the same time, scientific advances are being made to allow the confirmation of clinically suspected oligometastatic status at molecular level. There is growing interest in identifying patients with oligometastatic prostate cancer (PCa) who may benefit from curative intent metastasis-directed therapy, including SBRT. The aim is to complement, replace or delay the introduction of hormone therapy or other systemic therapies. The present review aims to compile the evidence from the main ongoing studies and results on SBRT in relation to oligometastatic PCa; examine aspects where gaps in knowledge or a lack of consensus persist (e.g., optimum schemes, response assessment, identification and diagnosis of oligometastatic patients); and document the lack of first-level evidence supporting the use of such techniques.     

Stereotactic Radiosurgery and Stereotactic Body Radiotherapy in the Management of Oligometastatic Disease

Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) represent non-invasive, efficacious and safe radiation treatments for the ablation of intracranial and extracranial metastases. Although the use of SRS has been established by level 1 evidence for patients presenting with up to three or four brain metastases for at least a decade, the paradigm of ablating a limited number of extracranial metastases (typically up to five, known as oligometastatic disease) has yet to be proven beyond the few reported but highly encouraging phase II randomised trials. In this overview, we summarise the phase III randomised controlled trials evaluating SRS for intact brain metastases and postoperative surgical cavities and introduce the limited literature and future concepts for treating patients with more than five intracranial metastases. Next, we summarise the published phase II randomised controlled trials specific to SBRT and oligometastatic disease, while briefly describing and contrasting the technical principles and biological mechanisms of SBRT versus conventional radiation. Phase III evidence for SBRT is needed, and we summarise ongoing trials in this overview. Ultimately, SRS and SBRT have become cornerstone therapeutic options for patients with oligometastatic disease and the future is bright for these patients, considering that not so long ago they were considered incurable and relegated to palliation alone.     

Evolution of treatment strategies for oligometastatic NSCLC patients – A systematic review of the literature

BackgroundThe concept of oligometastatic disease (OMD) has expanded the scope of potentially curative therapy for metastatic NSCLC. However, large uncertainties remain regarding its definition and optimal management strategies. We therefore conducted a systematic review to investigate the value of various multimodality treatment concepts.MethodsWe searched the available literature in Pubmed, Medline and EMBASE using the terms “oligomet*”, “synchron*”, “oligorec*”, “metachr*” “NSCLC”, “lung cancer” and “stage IV” and included studies reporting treatment regimens and outcomes on radically treated patients with either “synchronous”, “metachronous” or “mixed” OMD. Only de-novo diagnosis of OMD was considered. The impact of patient and treatment characteristics on overall survival (OS) and time trends in patterns of care were investigated.Results54 studies published between 1987 and 2018 were included. Despite a wide range of OMD definitions, 90.1% of patients were treated for a single metastasis. Systemic therapy was used as backbone treatment for most patients. Although surgery was the preferred local treatment in earlier studies, the use of stereotactic radiotherapy increased rapidly after 2011. No OS difference was observed between surgery or radiotherapy as the treatment of primary tumor or metastases, respectively. A time trend towards improved OS after 2011 could be detected.ConclusionsWhile evidence in favor of radical treatment is emerging, most studies remain retrospective and mainly evaluate patients with singular metastases. While surgery, stereotactic radiotherapy and chemotherapy are the cornerstones of current treatment strategies, future clinical trials need to address the high risk of distant metastases by integrating targeted or immunotherapy.     

体部立体定向放射治疗早期可手术非小细胞肺癌

体部立体定向放疗是指应用单次或少数多次给予靶区高剂量照射的治疗方式。和常规放疗相比，该技术具有分割剂量大、精度高等特点。对于因高龄或合并严重心肺等内科疾病不能手术或不愿接受手术的早期非小细胞肺癌患者，SBRT已被确立为标准治疗。对于可手术病灶，SBRT能达到与手术相似的局部控制率。本研究将对SBRT用于早期可手术NSCLC患者的研究进展作一综述。     

Radiothérapie stéréotaxique extracrânienne et oligométastases

In stage IV cancers, locoregional management of primitive tumours as surgery and/or radiotherapy improved both progression-free survival and overall survival. Among metastatic cancer patients, some of them are considered as oligometastatic stage as they present few metastatic sites associated with low tumor aggressiveness. For those patients, metastatic local control, and therefore prolonged time to progression should be reached through local treatments as surgery and/or radiofrequency ablation and/or stereotactic radiotherapy. Here we propose a review of oligometastatic stage and results from extracranial stereotactic radiotherapy in terms of efficacy and tolerance.     

SBRT治疗早期非小细胞肺癌的研究进展

肺癌仍处于恶性肿瘤发病率和死亡率的首位,非小细胞肺癌(NSCLC)是肺癌的主体,NSCLC患者中有15%~25%可以被早期发现(ⅠA或ⅠB期),而且随着影像诊断技术的发展,这个比例在不断升高。目前针对能够耐受手术的早期NSCLC患者的标准治疗仍然是手术。但是,早期NSCLC患者中只有约60%可以耐受根治性手术。对于不能耐受手术的早期NSCLC患者,以往,认为传统放疗(1.8~2.0 Gy/次,1次/天,6~7周)是其标准治疗方法,但是疗效欠佳;有研究证明传统放疗效果不佳是由于局部剂量不足。目前,几项长期随访研究都证明体部立体定向放射治疗(SBRT)对不能手术的Ⅰ/Ⅱ期NSCLC患者有效并且安全,SBRT已经成为不能手术的早期NSCLC患者的标准治疗方法。对于能够手术的病人,SBRT也逐步成为一种可以替代手术的治疗方法。     

Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature

Objectives

Long-term survival has been observed in patients with oligometastatic non-small cell lung cancer (NSCLC) treated with locally ablative therapies to all sites of metastatic disease. We performed a systematic review of the evidence for the oligometastatic state in NSCLC.

Materials and Methods

A systematic review of MEDLINE, EMBASE and conference abstracts was undertaken to identify survival outcomes and prognostic factors for NSCLC patients with 1–5 metastases treated with surgical metastatectomy, Stereotactic Ablative Radiotherapy (SABR), or Stereotactic Radiosurgery (SRS), according to PRISMA guidelines.

Results

Forty-nine studies reporting on 2176 patients met eligibility criteria. The majority of patients (82%) had a controlled primary tumor and 60% of studies included patients with brain metastases only. Overall survival (OS) outcomes were heterogeneous: 1 year OS: 15–100%, 2 year OS: 18–90% and 5 year OS: 8.3–86%. The median OS range was 5.9–52 months (overall median 14.8 months; for patients with controlled primary, 19 months). The median time to any progression was 4.5–23.7 months (overall median 12 months). Highly significant prognostic factors on multivariable analyses were: definitive treatment of the primary tumor, N-stage and disease-free interval of at least 6–12 months.

Conclusions

Survival outcomes for patients with oligometastatic NSCLC are highly variable, and half of patients progress within approximately 12 months; however, long-term survivors do exist. Definitive treatment of the primary lung tumor and low-burden thoracic tumors are strongly associated with improved long-term survival. The only randomized data to guide management of oligometastatic NSCLC pertains to patients with brain metastases. For other oligometastatic NSCLC patients, randomized trials are needed, and we propose that these prognostic factors be utilized to guide clinical decision making and design of clinical trials.     

Ⅰ期非小细胞肺癌治疗研究进展

肺癌是导致癌症相关死亡的主要原因之一，在所有恶性肿瘤中发病率和死亡率最高。其中，非小细胞肺癌（non-small cell lung cancer，NSCLC）占肺癌患者的80%以上。Ⅰ期NSCLC（ⅠA、ⅠB期）占NSCLC患者的15%~20%，手术切除是Ⅰ期NSCLC的主要治疗方案，但ⅠA、ⅠB期NSCLC患者术后5年总生存率（overall survival，OS）分别为仅83%和71%。对于无法耐受手术或不愿意接受手术的患者，放疗可能达到与手术切除术相同的治疗效果，目前也有许多新型的治疗方法出现，如消融、粒子放疗等。本文将对Ⅰ期NSCLC的治疗方法及其预后进行综述。      

Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; Systematic review and comparison with a surgical cohort

Background and purpose

To assess the efficacy of stereotactic ablative radiotherapy (SABR) for the treatment of non-small cell lung cancer (NSCLC) through a systematic review of all relevant publications from 2006 to the present compared to controls treated with surgery. In the absence of Grade I evidence, the objective outcome data should form the basis for planning future studies and commissioning SABR services.

Materials and methods

Standard systematic review methodology extracting patient and disease characteristics, treatment and outcome data from published articles reporting patient data from populations of 20 or more Stage I NSCLC patients treated with SABR with a median follow up of minimum of 1 year. The individual outcome measures were corrected for stage and summary weighted outcome data were compared to outcome data from a large International Association for the Study of Lung Cancer (IASLC) cohort matched for stage of disease with survival as the principal endpoint and local control (local progression free survival – local PFS) as the secondary endpoint.

Results

Forty-five reports containing 3771 patients treated with SABR for NSCLC were identified that fulfilled the selection criteria; both survival and staging data were reported in 3171 patients. The 2 year survival of the 3201 patients with localized stage I NSCLC treated with SABR was 70% (95% CI: 67–72%) with a 2 year local control of 91% (95% CI: 90–93%). This was compared to a 68% (95% CI: 66–70) 2 year survival of 2038 stage I patients treated with surgery. There was no survival or local PFS difference with different radiotherapy technologies used for SABR.

Conclusions

Systematic review of a large cohort of patients with stage I NSCLC treated with SABR suggests that survival outcome in the short and medium term is equivalent to surgery for this population of patients regardless of co-morbidity. As selection bias cannot be assessed from the published reports and treatment related morbidity data are limited, a direct comparison between the two treatment approaches should be a priority. In the meantime, SABR can be offered to stage I patients with NSCLC as an alternative to surgery.     

Current treatment landscape for oligometastatic non-small cell lung cancer

The management of patients with advanced non-small cell lung carcinoma (NSCLC) has undergone major changes in recent years. On the one hand, improved sensitivity of diagnostic tests, both radiological and endoscopic, has altered the way patients are staged. On the other hand, the arrival of new drugs with antitumoral activity, such as targeted therapies or immunotherapy, has changed the prognosis of patients, improving disease control and prolonging survival. Finally, the development of radiotherapy and surgical and interventional radiology techniques means that radical ablative treatments can be performed on metastases in any location in the body. All of these advances have impacted the treatment of patients with advanced lung cancer, especially in a subgroup of these patients in which all of these treatment modalities converge. This poses a challenge for physicians who must decide upon the best treatment strategy for each patient, without solid evidence for one optimal mode of treatment in this patient population. The aim of this article is to review, from a practical and multidisciplinary perspective, published evidence on the management of oligometastatic NSCLC patients. We evaluate the different alternatives for radical ablative treatments, the role of primary tumor resection or radiation, the impact of systemic treatments, and the therapeutic sequence. In short, the present document aims to provide clinicians with a practical guide for the treatment of oligometastatic patients in routine clinical practice.     

The Role of Thoracic Surgery in the Therapeutic Management of Metastatic Non–Small Cell Lung Cancer

IntroductionIn most patients with NSCLC, the disease is diagnosed in an advanced stage, the prognosis is poor, and survival is typically measured in months. Standard therapeutic treatment regimens for patients with stage IV NSCLC typically include chemotherapy and palliative radiation. Despite newer regimens that may include molecularly targeted therapy and immunotherapy, the overall 5-year survival for stage IV disease remains low at 4% to 6%. Although therapeutic surgery is performed in a minority of cases, accumulating data suggest that thoracic surgery may play several beneficial roles for these patients.MethodsIn this narrative review, we summarize the literature on surgical intervention in the multimodality management of stage IV NSCLC, focusing on the potential evidence for and against therapeutic or curative intent procedures to affect outcomes for patients with oligometastatic disease and pleural metastasis.ResultsIn selected patients, surgical resection can result in a 5-year survival rate of 30% to 50%, but this is heavily influenced by the presence of mediastinal nodal disease, which should be evaluated before therapeutic surgical procedures are undertaken. Additionally, diagnostic or palliative surgical procedures can play an important role in the personalized management of stage IV disease. These data suggest that for carefully selected patients with advanced stage NSCLC, surgical intervention can be an important component of combined modality treatment.ConclusionsGiven the advances in molecular targeted therapy and immunotherapy, further studies should focus on the possible use of surgery as a strategy of therapeutic “consolidation” for appropriately selected patients with stage IV NSCLC who are receiving combined modality care.     

非小细胞肺癌寡转移的立体定向放射治疗研究

非小细胞肺癌(Non-small cell lung cancer,NSCLC)是除小细胞肺癌以外所有类型的肺癌,脑、骨、肝及肾上腺为最常见的远处转移部位。在NSCLC远处转移患者中,并非都是多发的、广泛的,有近7%的患者表现为肺外孤立性转移。这种特殊形式的晚期肿瘤转移状态称之为NSCLC寡转移。寡转移的治疗以局部治疗为主,局部治疗主要措施包括立体定向放疗、手术切除、射频消融等。本文主要探讨立体定向放射治疗(Stereotactic radiotherapy,SRT)对NSCLC在常见远处转移脏器寡转移的作用。     

Radiologie interventionnelle et tumeurs des tissus mous : du diagnostic au traitement

Interventional radiology plays an increasing role in the management of soft tissue tumors. For initial diagnosis, precise and safe image-guided biopsies; soft tissue tumor biopsies must be performed in accordance with international guidelines. Then, in a therapeutic phase, interventional radiology, particularly with thermal ablation techniques (radiofrequency, cryoablation), can be proposed for specific indications like salvage treatment of recurrent tumor after surgery and radiotherapy, focal ablation for oligometastatic sarcomas, or treatment of benign locally aggressive tumors such as symptomatic hemangiomas or desmoid tumors. A multidisciplinary approach remains mandatory to achieve optimal patient selection for interventional radiology techniques.     

Improved Overall Survival With Comprehensive Local Consolidative Therapy in Synchronous Oligometastatic Non–Small-Cell Lung Cancer

BackgroundLocal consolidative therapy (LCT) to optimize disease control is an evolving management paradigm in non–small-cell lung cancer (NSCLC) patients who present with a limited metastatic disease burden. We hypothesized that LCT to all sites of disease would be associated with improved overall survival (OS) among patients with synchronous oligometastatic NSCLC.Patients and MethodsPatients presenting to a single institution (2000-2017) with stage IV NSCLC and ≤ 3 synchronous metastases were identified. Intrathoracic nodal disease was counted as one site. Landmark and propensity-adjusted Cox regression analyses were performed to identify factors associated with OS.ResultsOf 194 patients, 143 (74%) had 2 or 3 sites of metastasis. LCT was delivered to all sites of disease in 121 patients (62%), to some but not all sites in 52 (27%), and were not used in 21 (11%). Comprehensive LCT was independently associated with improved OS (hazard ratio [HR] = 0.67; 95% confidence interval [CI], 0.46-0.97; P = .034), with the greatest therapeutic effect among patients without thoracic nodal disease, bone metastases, or > 1 metastatic site. Among patients who underwent comprehensive LCT, tumor histology (squamous: HR = 2.32; 95% CI, 1.28-4.22; P = .006), intrathoracic disease burden (T3-4: HR = 1.67; 95% CI, 0.97-2.86; P = .065; N3: HR = 1.90; 95% CI, 0.90-4.03; P = .093), and bone metastases (HR = 1.74; 95% CI, 1.02-3.00; P = .044) were associated with poor OS.ConclusionComprehensive LCT was associated with improved OS in this large cohort of patients with synchronous oligometastatic NSCLC. These results support ongoing prospective efforts to characterize the therapeutic benefits associated with this management strategy.     

When Should we Irradiate the Primary in Metastatic Lung Cancer?

Metastatic lung cancer encompasses a heterogenous group of patients in terms of burdens of disease, ranging from patients with extensive metastases to those with a limited number of metastatic lesions (oligometastatic disease). Histopathological heterogeneity also exists within two broad categories, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), portraying different patterns and evolution of disease. Local consolidative therapy to the primary tumour and metastatic sites, including surgery and/or radical dose radiotherapy, is increasingly being used to improve survival outcomes, particularly in the context of oligometastatic disease, with or without the use of molecular targeted therapy and immunotherapy. Recently, randomised studies in oligometastatic NSCLC have shown that local consolidative therapy may confer a survival advantage. This review explores whether treating just the primary tumour with radiotherapy may similarly produce improved clinical outcomes. Such a treatment strategy may carry less potential toxicity than treating multiple sites upfront. The biological rationale behind the potential benefits of treating just the primary in metastatic malignancy is discussed. The clinical evidence of such an approach across tumour sites, such as breast and prostate cancer, is also explored. Then the review focuses on treating the primary in NSCLC and SCLC with radiotherapy, by first exploring patterns of failure in metastatic NSCLC and second exploring evidence on survival outcomes from studies in metastatic NSCLC and SCLC. It is challenging to draw conclusions on the clinical benefit of treating the primary cancer in isolation from the evidence available. This highlights the need to collect data within the ongoing clinical trials on the clinical outcome and toxicity of radiotherapy delivery to primary thoracic disease specifically. This challenge also identifies the need to design future clinical trials to produce randomised evidence for such an approach.     

基于CT或PET/CT的影像组学信息预测Ⅰ期非小细胞肺癌立体定向消融放疗疗效的初步研究

背景与目的:影像组学作为极具潜力的新领域,是指从影像图像中提取有价值的图像特征,并将这些特征数据定量化并转换成可挖掘的数据矿用以指导临床.该回顾性研究应用影像组学的方法初步探索PET/CT对比常规CT在Ⅰ期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者接受立体定向消融放疗(stereotactic ablative radiotherapy,SABR)后疗效预测方面的可行性.方法:回顾性收集经病理证实并在复旦大学附属肿瘤医院行SABR治疗的Ⅰ期NSCLC患者,提取治疗前PET/CT和定位CT图像,由放疗科医师勾画病灶,运用影像组学的方法进行特征值的提取、分析和总结,采用NMF聚类法(non-negative matrix factorization)分析这些特征值是否能够对有无局部进展的患者进行区分,所有统计学算法都在R平台(R Development Core Team)上实现.结果:16例患者纳入最终分析,在PET/CT的影像组学PET特征中发现两个差异有统计学意义的特征值(灰度共生矩阵最大相关系数和灰度游程共生矩阵长行程加重),可以用以区分患者是否出现局部进展,而在所有定位CT图像提取的特征值中并没有类似发现.结论:在经过SABR治疗后的Ⅰ期NSCLC患者中应用基线PET/CT及胸部定位CT提供的信息进行影像组学分析后,PET/CT似乎能够提供更具统计效能的PET特征值用以预测疗效,对比胸部定位CT提供的信息,PET/CT所提取的特征值可能更敏感、更全面甚至更具特征性.     

Irradiation de la maladie primitive des cancers de la prostate avec métastases synchrones

The management of early metastatic prostate cancer is based on systemic treatment by androgen deprivation therapy with or without chemotherapy or next-generation anti-androgen therapies. Local treatment of the prostate was initially used only to alleviate local symptoms. However, local radiotherapy of the prostate has been the subject of retrospective and prospective studies in patients with better prognostic factors, particularly in oligometastatic status. The results of these studies support that prostate radiotherapy can prolong the survival of patients with a low metastatic burden. This article states the biological bases, the main published and future published studies aimed to embed this strategy to optimize therapeutic management.     

Radiothérapie stéréotaxiques des métastases osseuses des lésions vertébrales

Stereotactic radiotherapy is an ever more common technique, regardless of the location treated. However, spinal stereotactic radiotherapy requires a particular technicality in order to ensure its proper realization. There is now a large literature defining the type of imaging to be used, the dose to be delivered and the delineation of target volumes. This technique can achieve a significant local control and an interesting analgesic efficiency. However, its place in relation to conventional radiotherapy remains limited because it requires MRI imaging and a significantly longer patient management during the treatment fraction. In this context, it is currently mainly restricted to oligometastatic patients or for re-irradiations.