Nonsurgical therapy for stages I and II non-small cell lung cancer

For patients who have stages I and II non-small cell lung cancer (NSCLC) and who are unable or unwilling to undergo surgical resection, nonsurgical treatment modalities have been used with curative intent. Conventionally fractionated radiotherapy has been the mainstay of nonsurgical therapy; however, advances in technology and the clinical application of radiobiologic principles have allowed more accurately targeted treatment that delivers higher effective doses to the tumor, while respecting the tolerance of surrounding normal tissues. This article discusses nonsurgical approaches to the treatment of early-stage NSCLC, including several promising techniques, such as radiation dose escalation, altered radiation fractionation, stereotactic radiotherapy, and radiofrequency ablation.     

Chimioradiothérapie concomitante pour le traitement des cancers bronchiques non à petites cellules, localisés au thorax, inopérables ou non résécables

Concomitant chemoradiation is the standard strategy for unresectable locally advanced non-small cell lung cancer (NSCLC). Its modalities used currently include three-dimensional conformal techniques, allowing dose escalation and sequential and concurrent combination with new generation cytotoxic agents. Phase III trials have not demonstrated any benefit from induction and consolidation chemotherapy in this setting. New techniques of radiation may also increase the efficacy and the feasibility of radiation. The integration of targeted therapies in the management of stage III NSCLC is also under investigation. This constant progress makes chemoradiation one of the most promising combined treatments in thoracic oncology.     

The impact of three-dimensional radiation on the treatment of non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) patients with locally advanced unresectable disease have a grim prognosis. Radiotherapeutic strategies are necessary to improve the permanent eradication of thoracic disease. The poor results achieved with conventional external beam radiation therapy reflect in part, the inadequacy of such therapy in achieving its primary objective of achieving local control. The impact of three-dimensional conformal radiation therapy (3-DCRT) on local disease eradication and its potential role in improving survival is assessed. DESIGN: This review addresses aspects of the software and hardware technology of 3-DCRT, the clinical and technical aspects of target volume definition, the use of 3-DCRT to predict radiation pneumonitis, strategies for dose escalation in NSCLC, and analyses the clinical results to date. RESULTS: Initially investigators compared the best treatment techniques devised with conventional planning techniques to those devised with 3-DCRT. These analyses showed that 3-DCRT had the potential to deliver high dose radiation (>70 Gy) with minimal underdosing and with a concomitant relative sparing of normal tissues. This technical demonstration of enhanced therapeutic ratio is the basis for the evolving clinical utilization of 3-DCRT for NSCLC. Software and hardware developments continue to develop and have the potential to solve evolving clinical issues. Dose-volume-histograms have been used to accurately quantify lung dose and derived parameters have the potential to predict the risk of pneumonitis for individual patients before treatment. Initial clinical results have been promising and strategies for further dose escalation are emerging. CONCLUSION: Preliminary experience has resulted in promising survival following three-dimensional conformal radiation therapy alone for locally advanced NSCLC. More follow-up and experience will determine late toxicity, maximum dose, and efficacy of dose escalation with three-dimensional conformal radiation therapy. Strategies should be developed to integrate this modality into the combined treatment of locally advanced non-small cell lung cancer.     

Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer

PURPOSE: To compare dose-volume histograms (DVH) in patients with non-small-cell lung cancer (NSCLC) treated by photon or proton radiotherapy. METHODS AND MATERIALS: Dose-volume histograms were compared between photon, including three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and proton plans at doses of 66 Gy, 87.5 Gy in Stage I (n=10) and 60-63 Gy, and 74 Gy in Stage III (n=15). RESULTS: For Stage I, the mean total lung V5, V10, and V20 were 31.8%, 24.6%, and 15.8%, respectively, for photon 3D-CRT with 66 Gy, whereas they were 13.4%, 12.3%, and 10.9%, respectively, with proton with dose escalation to 87.5 cobalt Gray equivalents (CGE) (p=0.002). For Stage III, the mean total lung V5, V10, and V20 were 54.1%, 46.9%, and 34.8%, respectively, for photon 3D-CRT with 63 Gy, whereas they were 39.7%, 36.6%, and 31.6%, respectively, for proton with dose escalation to 74 CGE (p=0.002). In all cases, the doses to lung, spinal cord, heart, esophagus, and integral dose were lower with proton therapy even compared with IMRT. CONCLUSIONS: Proton treatment appears to reduce dose to normal tissues significantly, even with dose escalation, compared with standard-dose photon therapy, either 3D-CRT or IMRT.     

Intensity modulated radiation therapy and proton radiotherapy for non-small cell lung cancer

Local failure of non-small-cell lung cancer (NSCLC) radiotherapy may cause continuous tumor seeding and death. Radiotherapy dose escalation has been shown to improve local control and survival. However, the toxicities associated with dose escalation are significant and limit the potential of dose escalation. Intensity modulated radiotherapy (IMRT) may have the potential to improve the therapeutic ratio for photon treatment of lung cancer by sparing surrounding normal tissues. However, lowdose exposure to normal lung and organ motion is a major concern. We have conducted several studies to address these issues and started clinical studies to evaluate the potential benefit of IMRT in patients with NSCLC. Proton radiotherapy may have greater potential to spare normal tissue and allow for further dose escalation and acceleration. We are conducting preclinical and clinical studies for imaging-guided proton radiotherapy in NSCLC. In this paper, we discuss the preliminary data, IMRT treatment guidelines, and ongoing studies for proton therapy in NSCLC.     

The rush to judgment: does the evidence support the enthusiasm over three-dimensional conformal radiation therapy and dose escalation in the treatment of prostate cancer?

PURPOSE: To discuss the assumptions behind and current clinical evidence on three-dimensional conformal radiation therapy (3D-CRT) and dose escalation in the treatment of prostate cancer. METHODS: We first define 3D-CRT in comparison to standard radiation therapy and discuss the assumptions on which the technology of 3D-CRT and dose escalation are based. We then examine the evidence on the benefits and limitations from the current most commonly cited studies on dose-escalation trials to treat prostate cancer. RESULTS: The assumption that 3D-CRT can provide a tighter margin around the tumor area to allow for dose escalation is not yet proven by studies that show continual difficulty in defining the planning treatment volume because of extrinsic and intrinsic difficulties, such as imaging variabilities and patient and organ movement. Current short-term dose-escalation studies on the use of 3D-CRT to treat prostate cancer are limited in their ability to prove that increasing dose improves survival and does not incur potential long-term complications to normal tissue. CONCLUSION: Although 3D-CRT is a promising technology that many radiation oncologists and clinics are quickly adopting to treat such tumors as prostate cancer, the long-term evidence on the benefits and limitations of this technology is still lacking. Until we have solid long-term evidence on the true clinical potential of this new technology, let us not rush to judgment, but exercise caution, diligence, and thoughtfulness in using this new technology to treat our patients.     

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.     

Gross tumor volume and clinical target volume in radiotherapy: lung cancer]

Radiotherapy plays a major role as a curative treatment of various stages non-small cell lung cancers (NSCLC): as an exclusive treatment in curative attempt for patients with unresectable stages I and II; as a preoperative treatment, which is often associated with chemotherapy, for patients with surgically stage IIIA NSCLC in clinical trials; in association with chemotherapy for unresectable stages IIIA and IIIB patients. Currently, three-dimensional conformal radiotherapy allows for some dose escalation, increasing radiation quality. However, the high inherent conformality of this radiotherapy technique requires a rigorous approach and an optimal quality of the preparation throughout the treatment procedure and specifically of the accurate definition of the safety margins (GTV, CTV...). Different questions remain specific to lung cancers: 1) Despite the absence of randomized trials, the irradiated lymph nodes volume should be only, for the majority of the authors, the visible macroscopically involved lymph nodal regions. However, local control remains low and solid arguments suggest the poor local control is due to an insufficient delivered dose. Therefore the goal of radiotherapy, in this particular location, is to improve local control by increasing the dose until the maximum normal tissue tolerance is achieved, which essentially depends on the dose to the organs at risk (OAR) and specifically for the lung, the esophagus and the spinal cord. For this reason, the irradiated volume should be as tiny as possible, leading to not including the macroscopically uninvolved lymph nodes regions in prophylactic view in the target volume; 2) The lung is one of the rare organs with extensive motion within the body, making lung tumors difficult to treat. This particular point is not specifically considered in the GTV and CTV definitions but it is important enough to be noted; 3) When radiation therapy starts after a good response to chemotherapy, the residual tumoral volume should be defined as the target volume in place of the initial tumor volume. These different elements are discussed in this paper.     

Cooperative Group Portfolio in Locally Advanced Non–Small-Cell Lung Cancer: Are We Making Progress?

Combined-modality therapy has emerged as the standard of care for fit patients with unresectable, locally advanced non-small-cell lung cancer (NSCLC). Concurrent chemotherapy/radiation has demonstrated therapeutic superiority compared with sequential or asynchronous chemotherapy and radiation in this setting. The role of consolidation or maintenance therapy with targeted agents or conventional cytotoxic agents remains unclear. We explore the portfolio of clinical trials being conducted in locally advanced NSCLC by North American cooperative oncology groups as well as ongoing trials in Europe and Japan. These efforts focus on radiation dose escalation using image-guided radiation therapy as well as newer cytotoxic agents (eg, pemetrexed) and targeted therapies (eg, cetuximab, bevacizumab, and etc) thus far unexplored in this setting.     

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.     

增强CT定位对非小细胞肺癌三维适形放疗计划参数的影响

[目的]观察非小细胞肺癌(NSCLC)三维适形放疗(3D-CRT)中增强CT定位对放疗计划参数的影响.[方法]对97例在CT定位下拟行根治性3D-CRT的NSCLC患者,分别以CT平扫图像、增强CT图像勾画大体肿瘤靶区 (GTVCT和GTVCT+),分别制定放疗计划.[结果]增强CT明显改变35例(36.1％)患者PTV和/或GTV.增强CT组与平扫CT组的计划参数GTV的体积(VGTV)、受照射量≥45Gy的食管占全食管体积的比例(VE45)和脊髓最大受照射剂量(SCM)差异有统计学意义(P均＜0.001).[结论]利用增强CT定位能更加准确地确定靶区,据此制定3D-CRT 可更优的覆盖靶区,降低脊髓、食管的受照射剂量.     

Stereotactic body radiotherapy (SBRT)

The techniques of three-dimensional conformal radiotherapy (3 D-CRT) and patient immobilization have recently been developed, enabling us to focus high doses on the target with relatively less irradiation of normal tissues. In radiotherapy for solitary lung tumors, the local control may be safely improved by delivering a higher dose at only the target volume using these techniques. Recently, several clinical studies on stereotactic body radiotherapy (SRT) using the 3 D-CRT technique for solitary lung tumors have been reported. The single dose used is 10-15 Gy, and the total sessions are three to five. The local control rate is more than 90% and complication rates are very low. Therefore, this treatment is a promising new non-invasive treatment for early stage lung cancer. A multi-institutional clinical study, JCOG 0403, in now underway.     

第15届世界肺癌大会非小细胞肺癌放疗研究进展

第15届世界肺癌大会（WCLC）共收到约210篇放疗相关研究的摘要。内容涉及早期非小细胞肺癌（NSCLC）应用体部立体定向放疗（SBRT）的疗效和安全性、评价手段和剂量分割探讨;局部晚期NSCLC同步放化疗中高剂量与标准放疗剂量、不同化疗方案以及是否联合西妥昔单抗的对照研究;经全切的ⅢA～N2期NSCLC患者术后采用三维适行放疗（3D-CRT）的临床意义;NSCLC多发脑转移行全脑放疗（WBRT）同步联合酪氨酸激酶抑制剂（TKI）的疗效和安全性以及表皮生长因子受体（EGFR）突变状态对疗效的影响。另外关于放疗的防护、毒性、疗效、预后及生活质量评估也多有报告。     

PET/CT对非小细胞肺癌三维适形放疗中治疗计划参数的影响

目的:观察PET/CT对非小细胞肺癌(NSCLC)三维适形放疗(3D-CRT)中治疗计划参数的影响.方法:对83例在PET/CT定位下拟行根治性3D-CRT的NSCLC患者,分别以CT图像和PET/CT融合图像勾画大体肿瘤靶区(GTVCT和GTVPET/CT),分别制定放疗计划,并对两者进行比较.结果:PET/CT明显改变44例(53.01％)患者GTV或PTV,31例PTV和(或)GTV减小,13例PTV和(或)GTV增加.根据PET/CT和CT分别制定的放疗计划在VGTV、VE50、SCM和ESM的差异有统计学意义,P值分别为0.001、0.001、0.000和0.002.结论:应用PET/CT制定NSCLC3D-CRT治疗计划可降低食管和脊髓的受照射剂量,从而有利于放疗剂量的提升.     

Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma.

PURPOSE: Three-dimensional conformal radiation therapy (3D-CRT) has recently become widely available with applications for patients with non-small-cell lung cancer (NSCLC). These techniques represent a significant advance in the delivery of radiotherapy, including improved ability to delineate target contours, choose beam angles, and determine dose distributions more accurately than were previously available. The purpose of this study is to identify prognostic factors in a population of NSCLC patients treated with definitive 3D-CRT. METHODS AND MATERIALS: Between March 1991 and December 1998, 207 patients with inoperable NSCLC were treated with definitive 3D-CRT. Tumor targets were contoured in multiple sections from a treatment planning computed tomography (CT) scan. Three-dimensional treatment volumes and normal structures were reconstructed. Doses to the International Commission on Radiation Units and Measurements (ICRU) reference point ranged from 60 to 83.85 Gy with a median dose of 70 Gy. The median dose inhomogeneity was +/- 5% across planning target volume. Outcome was analyzed by prognostic factors for NSCLC including pretreatment patient and tumor-related factors (age, gender, race, histology, clinical stage, tumor [T] stage, and node [N] stage), parameters from our 3D-CRT system (gross tumor volume [GTV] in cm3), irradiation dose prescribed to isocenter, volume of normal lung exceeding 20 Gy (V20), and treatment with or without chemotherapy. The median follow-up time was 24 months (range, 7.5 months to 7.5 years). RESULTS: One and two-year overall survival rates for the entire group were 59% and 41%, respectively. Overall survival, cause-specific survival, and local tumor control were most highly correlated with the GTV in cm3. On multivariate analysis the independent variable most predictive of survival was the GTV. Traditional staging such as T, N, and overall clinical staging were not independent prognostic factors. Patients receiving ICRU reference doses > or =70 Gy had better local control and cause-specific survivals than those treated with lower doses (p = 0.05). Increased irradiation dose did not improve overall survival. CONCLUSIONS: GTV as determined by CT and 3D-CRT planning is highly prognostic for overall and cause-specific survival and local tumor control and may be important in stratification of patients in prospective therapy trials. T, N, and overall stage were not independent prognostic factors in this population of patients treated nonsurgically. The value of dose escalation beyond 70 Gy should be tested prospectively by clinical trial.     

Ⅲ期~Ⅳ期非小细胞肺癌三维不同空间位置胸内靶区精确放射治疗的研究

目的：探讨非小细胞肺癌（non-small cell lung cancer,NSCLC）胸内不同三维空间位置原发肿瘤靶区选择精确放射治疗的优势.方法：2006年11月至2009年7月完成调强适形放疗（IMRT）或三维适形放疗（3D-CRT）的51例初治的Ⅲ期＋Ⅳ期NSCLC患者,将已完成的IMRT和3D-CRT计划病例分别重新设计三维适形放疗（r3D-CRT）和调强放疗（rIMRT）计划,统计分析两组放射性肺损伤发生率,在射野数目、方向、靶区和危及器官的剂量体积相似时的正常肺剂量体积变化.结果：按＂坐标＂分区后不论3D-CRT组还是IMRT组,IMRT的肺V20显著低于3D-CRT（均P＜0.05）,多数空间分布病灶的平均肺剂量也显著降低;IMRT组在内区、中区病灶的肺V50显著降低（均P＜0.05）,而外区、上下区相似;rIMRT的肺V5在外区、中区、内区显著低于3D-CRT（均P＜0.05）;两组放射性肺损伤发生率无显著性差异.结论：对Ⅲ＋Ⅳ期NSCLC不同三维空间位置胸内病灶,相同计划设计参数条件下IMRT显著降低正常肺剂量体积,尤其是原发肿瘤位于内区和中区时的优势更明显.     

肿瘤体积和放疗剂量对局部晚期非小细胞肺癌预后的影响

  目的  探讨肿瘤体积和放疗剂量对接受三维适形放疗的非小细胞肺癌患者长期预后的影响。  方法  对三维适形放疗的87例非小细胞肺癌患者进行分析, 利用三维适形放疗计划系统及CT扫描勾画相应靶区, 分别定义为GTV-P、GTV-N及GTV-T。  结果  全组患者原发肿瘤最大直径 < 5.0 cm者生存率明显高于≥5.0 cm者(χ2=4.29, P=0.000 7);GTV-P < 90.00 cm3者生存率高于≥90.00 cm3者(χ2=4.94, P=0.0262);GTV-T < 100.00 cm3者生存率明显高于≥100.00cm3者(χ2=5.47, P=0.0194), 且GTV-T < 100.00 cm3组患者局控率明显高于≥100.00 cm3者(χ2=6.46, P=0.0110)。剂量≤66Gy组患者中GTV-T < 100.00 cm3亚组预后明显好于≥100.00 cm3亚组(χ2=4.59, P=0.032 2), 而在剂量 > 66 Gy组患者中GTV-T大小对生存率无明显影响。多因素分析结果显示N分期、GTV-T及放疗疗效为影响患者预后独立影响因素。  结论  大体肿瘤体积为预测接受三维适形放疗的非小细胞肺癌患者长期预后的一个可靠指标, 建议在以后接受放疗的非小细胞肺癌患者分析中常规加入该指标; 对体积小的肿瘤行大剂量放疗可能对局部晚期非小细胞肺癌患者生存有益。      

Cost-Benefit Analysis of 3D Conformal Radiation Therapy: Treatment of Prostate Cancer as a Model

Three-dimensional conformal radiation therapy (3D-CRT) is a promising new treatment technique based on the principle that improved precision in both tumor definition and dose delivery will enhance outcomes by maximizing dose to the tumor area while minimizing dose to normal tissue. Using a cost-benefit analysis, in terms of outcomes, we first examined the overall risks and benefits of 3D-CRT. We then used the treatment of prostate cancer as a model to compare actual clinical outcomes reported between 3D-CRT and standard radiation therapy (SRT). Our analysis shows that application of 3D-CRT to the clinical setting remains difficult because of the continual difficulties of target definition, and that dose escalation cannot yet be justified on the basis of the lack of benefit found, and suggested increased late toxicity, in most of the dose escalation series compared with SRT.     

Induction or consolidation systemic therapy in the multimodality treatment of unresectable locally advanced non-small cell lung cancer

Chemoradiotherapy has been shown to improve survival over radiation alone for unresectable locally advanced non-small cell lung cancer (NSCLC). Large randomized trials comparing sequential to concomitant platinum based chemoradiotherapy have demonstrated improved median survival times in favor of concomitant treatment. Recent phase II trials have evaluated the integration of advanced radiotherapy techniques, novel chemotherapy combinations, induction chemotherapy, and consolidation chemotherapy with concomitant chemoradiotherapy. On-going or recently completed phase III trials are evaluating whether the promising regimens from phase II studies are superior to concomitant chemoradiotherapy alone. Molecular therapies now need to be integrated with chemoradiotherapy.     

Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer

The relative inability of conventional radiotherapy to control localized prostate cancer results from resistance of subpopulations of tumor clonogens to dose levels of 65 to 70 Gy, the maximum feasible with traditional two-dimensional (2D) treatment planning and delivery techniques. Several technological advances have enhanced the precision and improved the outcome of external-beam radiotherapy. The three-dimensional conformal radiotherapy (3D-CRT) approach has permitted significant increases in the tumor dose to levels beyond those feasible with conventional techniques. Intensity-modulated radiotherapy (IMRT), an advanced form of conformal radiotherapy, has resulted in reduced rectal toxicity, permitting tumor dose escalation to previously unattainable levels with a concomitant improvement in local tumor control and disease-free survival. The combination of androgen deprivation and conventional-dose radiotherapy, tested mainly in patients with locally advanced disease, has also produced significant outcome improvements. Whether androgen deprivation will preclude the need for dose escalation or whether high-dose radiotherapy will obviate the need for androgen deprivation remains unknown. In some patients, both approaches may be necessary to maximize the probability of cure. In view of the favorable benefit-risk ratio of high-dose IMRT, the design of clinical trials to resolve these critical questions is essential.