Current challenges of lung cancer care in an aging population

Local control for advanced non-small cell lung cancer (NSCLC) remains a significant problem with chemoradiation local failure rates in the chest of 30–50%. Despite attempts at dose escalation with conventional radiation therapy techniques, toxicities limit the amount of radiation that can be delivered. For stage I NSCLC, mounting evidence supports the use of hypofractionated radiation therapy (SBRT) to gain high local control rates with acceptable toxicity. For healthy patients with stage II/III NSCLC, the National Comprehensive Cancer Network guidelines suggest surgery is the preferred standard of care for patients with <N2 nodes or T3 tumors. In select patients who are surgical candidates or have more extensive disease, guidelines may include pre-operative chemoradiation followed by surgery, although this remains controversial and is the subject of a current national clinical trial (RTOG 0839). Dose escalation through conventional radiation therapy planning suggests that we can improve outcomes in stage III patients, but toxicity remains problematic. It follows that with improvements in imaging and delivery of radiotherapy, dose escalation with SBRT incorporation may improve local control in stage II/III NSCLC for medically inoperable patients. The rationale for dose escalation and some of the considerations for incorporation of SBRT dose escalation in stage III lung cancer are reviewed here.     

多病灶SBRT联合免疫检查点抑制剂在晚期NSCLC寡转移中应用进展

近年来,免疫检查点抑制剂（PD‐1/PD‐L1/CTLA‐4等）在非小细胞肺癌（NSCLC）治疗中的应用发展迅速。但是单独使用免疫检查点抑制剂的响应率低至15%~30%,在临床中仍存在获益人群有限、缺乏有效的生物标志物、治疗耐药等诸多问题。与常规分割放疗相比,立体定向放疗（SBRT）具有单次剂量高、照射次数少、免疫激活能力更强大等特点,已在晚期NSCLC寡转移患者中显示出了良好的抗肿瘤作用。在免疫治疗时代,将免疫检查点抑制剂与SBRT联合是肿瘤治疗的发展趋势,临床前以及临床研究显示SBRT能增强NSCLC患者的免疫治疗效果。最初的研究为了减轻潜在的不良反应,优先考虑单病灶SBRT。然而,越来越多的研究证实了多病灶SBRT的可行性和必要性。本综述介绍了晚期NSCLC寡转移SBRT与免疫检查点抑制剂联合使用的机制和最新进展,更深入探讨了多病灶SBRT联合免疫治疗的基础和临床研究,以指导临床实践。     

多病灶SBRT联合免疫检查点抑制剂在晚期NSCLC寡转移中应用进展北大核心CSCD

近年来,免疫检查点抑制剂(PD-1/PD-L1/CTLA-4等)在非小细胞肺癌(NSCLC)治疗中的应用发展迅速。但是单独使用免疫检查点抑制剂的响应率低至15%~30%,在临床中仍存在获益人群有限、缺乏有效的生物标志物、治疗耐药等诸多问题。与常规分割放疗相比,立体定向放疗(SBRT)具有单次剂量高、照射次数少、免疫激活能力更强大等特点,已在晚期NSCLC寡转移患者中显示出了良好的抗肿瘤作用。在免疫治疗时代,将免疫检查点抑制剂与SBRT联合是肿瘤治疗的发展趋势,临床前以及临床研究显示SBRT能增强NSCLC患者的免疫治疗效果。最初的研究为了减轻潜在的不良反应,优先考虑单病灶SBRT。然而,越来越多的研究证实了多病灶SBRT的可行性和必要性。本综述介绍了晚期NSCLC寡转移SBRT与免疫检查点抑制剂联合使用的机制和最新进展,更深入探讨了多病灶SBRT联合免疫治疗的基础和临床研究,以指导临床实践。     

中国非小细胞肺癌放射治疗临床指南(2020版)

随着先进技术的迅速发展,放射治疗已进入精确放疗时代,精确放疗显著提高了肿瘤控制效果、降低了不良反应,对非小细胞肺癌(NSCLC)不同期别均发挥着重要作用。近年来,靶向治疗、免疫治疗等新疗法取得了突破性进展,为患者带来了生存获益。中华医学会放射肿瘤治疗学分会、中国医师协会放射肿瘤治疗医师分会、中国抗癌协会放射治疗专业委员会和中国临床肿瘤学会肿瘤放疗专家委员会联合组织相关专家,在NSCLC现有医学证据基础上,结合专家意见制订了《中国非小细胞肺癌放射治疗临床指南(2020版)》,内容主要包括概述、诊断、早中晚期治疗原则、放疗技术和随访等,以期为中国临床医生和患者提供针对放疗的NSCLC循证医学指南,指导临床实践。     

Stereotactic body radiation therapy (SBRT) for early-stage lung cancer in the elderly

Early-stage non-small cell lung cancer (NSCLC) is on the rise due to the implementation of screening guidelines for patients at risk for developing lung cancer. It is anticipated that as the US population continues to age, there will be a higher percentage of medically inoperable early-stage lung cancer patients. For this reason, noninvasive ablative therapies are necessary. Stereotactic body radiation therapy (SBRT) is an effective modality in addressing early-stage NSCLC. SBRT consists of high-dose radiation delivered over 3–5 treatments. Several randomized trials comparing surgery to SBRT in early-stage operable patients have unfortunately closed early due to poor accrual. However, a recent pooled analysis from 2 randomized trials (StereoTActic Radiotherapy and Radiosurgery Or Surgery for operable Early-stage non–small cell Lung cancer) comparing surgery to SBRT did show comparable local control and overall survival rates between surgery and SBRT, offering a very effective, noninvasive modality for older adult patients with early-stage NSCLC. In this review, we summarize the role of SBRT in early-stage NSCLC, in particularly applied to the older adult population.     

Radiotherapy With Curative Intent in Patients With Early-stage,Medically Inoperable,Non–Small-cell Lung Cancer: A Systematic Review

Patients with early-stage non–small-cell lung cancer (NSCLC) who are unable to undergo surgery can be offered radiation therapy (RT). Previously, conventional RT was offered; however, newer techniques such as stereotactic body RT (SBRT) have become available. The objective of the present systematic review was to investigate the effectiveness of RT with curative intent in patients with early-stage medically inoperable NSCLC. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing stereotactic RT with curative intent compared with observation or other types of RT for early-stage, medically inoperable, NSCLC. Comparisons of radiation dosing or fractionation schedules for SBRT were included. We include 4 systematic reviews and 52 observational studies. The evidence suggests that SBRT compared with observation or other forms of RT, such as accelerated hypofractionated RT, 3-dimensional conformal RT, conventional fractionated RT, external beam RT, proton beam therapy, and carbon ion therapy, could have similar or improved results in survival or local control, with similar or fewer adverse effects. Evidence also suggests that local tumor control and survival were associated with the biologically effective dose (BED) for SBRT. Several studies suggested a cutoff of approximately 100 BED correlated significantly with patient outcomes. The presented evidence suggests that SBRT compared with other forms of RT is a reasonable treatment option for patients with medically inoperable early-stage NSCLC.     

Definitive Radiotherapy for Inoperable Stage IIB Non–small-cell Lung Cancer: Patterns of Care and Comparative Effectiveness

BackgroundThe purpose of this study was to analyze practice patterns and perform comparative effectiveness of definitive radiotherapy techniques for inoperable stage IIB (American Joint Committee on Cancer eighth edition) non–small-cell lung cancer (NSCLC).Materials and MethodsAdults in the National Cancer Database diagnosed with T3N0M0 or T1-2N1M0 NCSLC between 2004 and 2015 who received definitive radiotherapy were identified. Cases were divided as stereotactic body radiotherapy (SBRT), hypofractionated radiotherapy (HFRT), or conventionally fractionated radiotherapy (CFRT) and stratified by systemic therapy (ST). Cox proportional hazards models evaluated the effect of covariates on overall survival (OS). Subgroup analysis by tumor size, chest wall invasion, multifocality, and ST use was performed with Kaplan-Meier estimates of OS.ResultsA total of 10,081 subjects met inclusion criteria: 4401 T3N0M0 (66.5% CFRT, 11.0% HFRT, and 22.5% SBRT) and 5680 T1-2N1M0 (92.5% CFRT and 7.5% HFRT). For T3N0M0 NSCLC, SBRT utilization increased from 3.7% in 2006% to 35.4% in 2015. Subjects treated with SBRT were more likely to have smaller tumors, multifocal tumors, or adenocarcinoma histology. SBRT resulted in similar or superior OS compared with CFRT for tumors > 5 cm, tumors invading the chest wall, or multifocal tumors. SBRT was significantly associated with improved OS on multivariate analysis (hazard ratio, 0.715; P < .001). For T1-2N1M0 NSCLC, patients treated with HFRT were significantly older and less likely to receive ST; nevertheless, there was no difference in OS between HFRT and CFRT on multivariate analysis.ConclusionCFRT + ST is utilized most frequently to treat stage IIB NSCLC in the United States when surgery is not performed, though it is decreasing. SBRT utilization for T3N0M0 NSCLC is increasing and was associated with improved OS.     

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。     

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.     

早期非小细胞肺癌的体部立体定向放射治疗进展

体部立体定向放射治疗（stereotactic body radiotherapy,SBRT）成为医学上不能手术的早期非小细胞肺癌（non-small cell lung cancer,NSCLC）的标准治疗方式。近十年的临床证据表明SBRT替代手术治疗效果可观。由于毒副作用小,SBRT同样适用于肺功能差、患有某些严重并发症的老年患者。最近针对可手术早期NSCLC患者的对比研究中发现SBRT可能同样适用于这一群体,但这些可观的结果仍需要长期随访的前瞻性实验的验证。本文就SBRT治疗早期非小细胞肺癌的临床进展做一综述。     

立体定向放射治疗Ι期非小细胞肺癌的临床研究进展

目前体部立体定向放射治疗（ Stereotactic body radiation therapy ,SBRT）越来越多地应用于无法手术早期非小细胞肺癌患者的治疗,有替代外科作为标准治疗手段的趋势。大量临床研究结果显示SBRT治疗早期肺癌是安全的,临床局部控制率达到90％以上。本文对SBRT治疗Ⅰ期非小细胞肺癌的临床研究进展做一综述。     

Stereotaktische Strahlentherapie im Stadium I des nichtkleinzelligen Lungenkarzinoms

For patients with inoperable stage I non-small cell lung cancer (NSCLC) stereotactic body radiotherapy (SBRT) has evolved as the standard of care. As a non-invasive method, SBRT has led to a significant progress with high local control rates regularly amounting to nearly 90% and a high disease-specific (actuarial) survival after 5 years of approximately 75%. The application of SBRT has now been widely adopted in many radiation units; however, its use places high demands on the technical apparative equipment and a sophisticated quality assurance in the individual centers. The choice of appropriate fractionation schemes depends primarily on the distinction between a central and a peripheral tumor location. With appropriately adjusted dose regimens very good treatment tolerance can be achieved. In comparison to sublobar resection for patients with advanced chronic obstructive pulmonary disease (COPD, GOLD III or IV), SBRT is superior in terms of post-interventional morbidity and mortality. For the operable stage I the results of SBRT treatment in small collectives are as effective as those of patients who received a guideline-conform lobar resection. This is the conclusion of the analysis of two prospective randomized trials, which were terminated early; however, clinical evidence is still limited in this context. Promising currently running clinical trials are examining the application of SBRT as a boost after chemoradiotherapy in stage III NSCLC and also the combination of SBRT and immunotherapeutic approaches in stage I.     

EGFR敏感突变的晚期非小细胞肺癌TKI联合肺部病灶SBRT的临床研究进展

目前表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)已作为EGFR突变的晚期非小细胞肺癌(NSCLC)患者的标准一线治疗,但EGFR-TKI治疗后不可避免的会产生获得性耐药而导致疾病进展,其中约50%患者为肺部原发灶和/或初始转移灶进展。放疗作为主要的局部治疗手段,在晚期肿瘤患者的管理中有着不可替代作用。应用射波刀实施的体部立体定向放疗(SBRT)是最先进的放疗技术,能够更好地满足临床需求。近年来,基于上述复发模式的思考,采用肺部病灶SBRT联合EGFR-TKI改善患者无瘤进展生存的治疗模式备受关注,本文将对该联合治疗策略的临床研究进展进行综述。     

Strategies for Translating Evidence-Based Medicine in Lung Cancer into Community Practice

The landscape of non-small cell lung cancer (NSCLC) treatment has rapidly evolved over the past decade. This is exemplified by the use of molecular targeted agents, immunotherapies, and newer technologies such as stereotactic body radiotherapy (SBRT). As the translation of preclinical discoveries into clinical practice continues, the effective dissemination and implementation of evidence-based treatment of NSCLC will remain a foremost challenge for oncologists. To further extend evidence-based medicine into the community setting, community oncologists are being engaged on multiple fronts including leadership and participation in national clinical trials and utilization of internet-based resources.     

Feasibility of Stereotactic Body Radiation Therapy on Unresectable Stage III NSCLC with Peripheral Primary Tumor: A Prospective Study (GFPC 01-14)

Concomitant radiochemotherapy (RTCT) is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). However, in patients with a peripheral primary tumor, the irradiated volume may include a large portion of normal lung and RT-CT is not possible. This multicenter phase II trial in unresectable stage III NSCLC with peripheral primary tumor evaluated the feasibility of stereotactic body radiation therapy (SBRT) in peripheral tumor after concomitant radio-chemotherapy (RT-CT). Nineteen patients were included and analyzed (median age, 60.9 years; male, 78%; adenocarcinoma, 74%; median size of peripheral primary tumor, 19 mm). At 6 months, the disease control rate was 79% (15/19). SBRT toxicity was generally mild with one (5%) patient having grade 3 lung toxicity. Recruitment for this study was stopped prior to completion, firstly due to the approval of adjuvant durvalumab after RT-CT, which was not anticipated in the design, and secondly due to the small number of stage III NSCLC patients with a peripheral tumor that was accessible to SBRT. Nevertheless, the combination of RT-CT and SBRT appeared to be feasible and safe.     

中国小细胞肺癌放射治疗临床指南(2020版)

小细胞肺癌(SCLC)是严重威胁患者生命的常见恶性肿瘤之一。为了充分发挥好放疗在SCLC综合治疗中的重要作用,为患者带来生存获益,中华医学会放射肿瘤治疗学分会、中国医师协会放射肿瘤治疗医师分会、中国抗癌协会放射治疗专业委员会和中国临床肿瘤学会肿瘤放疗专家委员会,组织相关专家,在SCLC现有临床研究证据的基础上,结合专家意见,制订了本指南。内容主要包括概述、诊断、不同分期SCLC的放疗和综合治疗原则、放疗技术等方面,以期为我国临床医生和患者提供针对SCLC放疗的循证医学指南,指导临床实践。     

Radiation therapy for lung cancer

Radiation therapy is one of the most important modalities for the treatment of lung cancer. Current progress of radiation therapy in cooperation with the development of physics and biology is remarkable. The techniques of three-dimensional treatment planning and three-dimensional conformal radiotherapy (3D-CRT) have facilitated the use of higher radiation doses. Patients with early-stage non-small cell lung cancer (NSCLC) are candidates for curative surgical resection. However, the number of elderly patients has been increasing, and these patients often have medical contraindications that prevent curative surgery. Recently, several clinical trials on stereotactic body radiotherapy (SBRT) using the 3D-CRT technique for solitary lung tumors have been reported. The local control rate for stage I disease is more than 90%, and survival rates are promising. Now a prospective multi-institutional trial is ongoing to determine whether this modality can become a standard treatment for inoperable patients or an alternative to lobetectomy. For locally advanced NSCLC, unfortunately, recent studies have demonstrated that conventional therapies may have reached a therapeutic plateau. Now several radiation dose escalation studies utilizing conventional fractionation and 3D-CRT techniques are ongoing. The strategies of almost all of these trials are to eliminate elective nodal irradiation and deliver a higher dose of radiation to gross tumor volume while sparing normal tissues. Preliminary experience has resulted in promising survival, but should be developed to integrate into the combined treatment to completely control both local disease and other microscopically involved lesions. The combination of novel chemotherapeutic agents and molecular targeting therapies with radiation therapy is being investigated. Development of molecular imaging techniques is expected to facilitate more selective dose escalation in tumors.     

FDG-PET and stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer

PURPOSE: To investigate the utility of positron emission tomography (PET) in patients treated with stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) on prospective institutional trials. PATIENTS AND METHODS: Fifty-eight patients with medically inoperable stage I NSCLC who participated in prospective phase I and II trials of SBRT, had >or=2 years of follow-up, and received FDG-PET imaging are the focus of this evaluation. Fifty-seven of 58 patients received pre-SBRT FDG-PET to confirm stage I status. All patients received stereotactic body frame immobilization and treatment with 7-10 photon beams. SBRT total doses ranged from 24 to 72Gy in three fractions. No elective nodal irradiation was undertaken. Regular follow-up with planned CT imaging was performed on all patients. Post-SBRT FDG-PET was not mandated by protocol and was typically ordered upon concern for disease recurrence. Thirty-eight post-SBRT PET studies were performed in 28 patients at a median 17.3 months following SBRT. RESULTS: With a median follow-up of 42.5 months, the 3-year actuarial overall survival and local control for this select subset of our SBRT experience were 48.9% and 74.8%, respectively. Pre-SBRT FDG-PET SUV did not predict 3-year overall survival or local control. Fourteen of 57 patients eventually failed in nodal stations by CT and/or PET. Isolated first site of failure was nodal in 6 patients (10%). Out of 28 patients with post-SBRT PET, 4 (14%) had delayed PET imaging (22-26 months after SBRT) showing moderate hypermetabolic activity (SUV 2.5-5.07), but no evidence of local, nodal, or distant recurrence by clinical examination and conventional imaging performed 20-26 months following these concerning PET findings. CONCLUSIONS: Isolated nodal recurrence following PET-staged I NSCLC treated with SBRT is uncommon. Moderate post-SBRT PET hypermetabolic activity may persist 2 years following treatment without definite evidence of recurrence. Further study is needed to confirm these results in larger populations with longer follow-up.     

New radiotherapy approaches in locally advanced non-small cell lung cancer

Radiotherapy plays a major role in the treatment of patients with locally advanced non-small cell lung cancer (NSCLC), particularly since most patients are not suitable for surgery due to the extent of their disease, advanced age and multiple co-morbidities. Despite advances in local and systemic therapies local control and survival remain poor and there is a sense that a therapeutic plateau has been reached with conventional approaches. Strategies for the intensification of radiotherapy such as dose escalation have shown encouraging results in phase I–II trials, but the outcome of the phase III Radiation Therapy Oncology Group 0617 trial was surprisingly disappointing. Hyperfractionated and/or accelerated fractionating schedules have demonstrated superior survival compared to conventional fractionation at the expense of greater oesophageal toxicity. Modern radiotherapy techniques such as the integration of 4-dimensional computed tomography for planning, intensity modulated radiotherapy and image-guided radiotherapy have substantially enhanced the accuracy of the radiotherapy delivery through improved target conformality and incorporation of tumour respiratory motion. A number of studies are evaluating personalised radiation treatment including the concept of isotoxic radiotherapy and the boosting of the primary tumour based on functional imaging. Proton beam therapy is currently under investigation in locally advanced NSCLC. These approaches, either alone or in combination could potentially allow for further dose escalation and improvement of the therapeutic ratio and survival for patients with NSCLC.