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Br J Radiol. July 2015; 88(1051): 20150036.
Published online 2015 May 15. doi:  10.1259/bjr.20150036
PMCID: PMC4628529

LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective

Abstract

Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113—LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided.

Stereotactic body radiotherapy (SBRT) is a technique in which high doses of radiotherapy are very precisely delivered with steep dose gradients and a short overall treatment time (OTT). This achieves a very high biological dose.1 Evidence supports SBRT as a curative treatment option for inoperable early stage non-small-cell-lung cancer (NSCLC).25 High-precision, hypofractionated dose delivery enables a significant reduction in both target volume size and exposure of normal tissue (NT) to high doses, resulting in a decreased toxicity risk and high rates of local control.68 However, promising results are mainly derived from the SBRT of small peripheral pulmonary lesions with low risk of treatment-related toxicity, as these tumours are surrounded by parallel organs at risk (OARs), specifically lung tissue. In contrast, the SBRT for central tumours can lead to severe, potentially life-threatening radiation sequelae owing to the spatial proximity to serial OARs. As robust, prospective and multicentre data on the tolerance of mediastinal structures to high-dose hypofractionated radiation is limited, there is generally caution in implementing SBRT for central lung tumours. Current published data are rather inconsistent regarding the definition of “central tumour”, SBRT techniques, dose prescription and reporting, calculation algorithms, image guidance and evaluation of outcome. A recent systematic review has summarized the current limited evidence on this topic, mainly from single-centre experiences,9 but there are still many open questions regarding patient selection, efficiency, safety and response assessment, which hamper the use of SBRT for central lung tumours in routine practice.10 A prospective study sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113–LungTech) was launched in late 2014 and is expected to answer the question of the efficacy and toxicity of SBRT in inoperable and centrally located early stage NSCLC in a multicentre setting.

NSCLC: TREATMENT OPTIONS FOR EARLY STAGE NSCLC

The incidence and mortality of lung cancer in the European Union are 52/100.000 and 47/100.000 per year, respectively.11 The NSCLC accounts for approximately 80%11 of all cases with a poor 5-year survival rate of 16%, mainly owing to patients being diagnosed at advanced stages. If diagnosed at an earlier stage, 5-year survival for NSCLC can be as high as up to 80%.12,13 The current standard of care for early stage tumours is anatomic surgical resection in medically fit patients, consisting of lobectomy or pneumonectomy accompanied by a systematic mediastinal lymph node sampling or lymphadenectomy.1315 Associated 5-year survival rates are commonly accepted to be 60–80% for Stage I and 40–50% for Stage II NSCLC.13 The efficacy of routine sublobar resections for tumours <2 cm is currently being investigated worldwide. This technique spares lung tissue and preserves pulmonary function when compared with lobectomy. However, the results of a randomized controlled trial indicate that this is associated with inferior oncological outcome.16 In contrast to peripheral tumours, those located centrally often show compression and/or invasion in vessels, major bronchi or other critical mediastinal structures and, therefore, require more extensive surgical procedures associated with higher mortality and morbidity.1719 Approximately 20% of all patients with NSCLC Stage I are medically inoperable because of poor general condition or coexisting morbidities such as chronic obstructive pulmonary disease and/or heart disease,20 and <50% of all patients with early stage NSCLC older than 75 years undergo surgery.21 It is expected that as the global population ages and lung cancer screening of high-risk populations is implemented,22 the proportion of inoperable patients with lung cancer with comorbidities will increase.2325 In Stage I patients with NSCLC who refuse surgery and do not receive other treatments such as radiotherapy, 5-year overall survival (OS) and cancer-specific survival (CSS) are low, 6% and 16%, respectively.26 The standard of care treatment option for medically inoperable patients with early stage NSCLC has been conventionally fractionated radiotherapy (CFRT), superior to best supportive care with CSS rates of about 30% after 5 years27,28 and 5-year OS of 29–37% for T1 tumours.29 Evidence supports a clear dose effect for local control and survival in NSCLC,30,31 however, traditional CFRT-planning and delivery techniques are associated with low accuracy and broad safety margins resulting in increased toxicity rates,32 therefore, limiting the delivery of higher doses in inoperable patients with early stage NSCLC. Although advanced techniques and positron emission tomography (PET) staging allow modern three dimensional (3D)-CFRT the application of high biological doses, resulting in local control rates >85% in Stage I patients with NSCLC,33,34 the implementation of such 3D-CFRT regimes leads to longer OTT of approximately 3–6 weeks,33,34 whereas SBRT usually can be performed in OTT of days rather than weeks.

SBRT AS AN EFFICIENT TREATMENT MODALITY FOR PERIPHERALLY LOCATED NSCLC

In the past two decades, SBRT has been accepted as a curative treatment alternative for inoperable patients with small (<5 cm) peripheral early stage NSCLC.25 Several prospective studies reported excellent local tumour control rates of up to approximately 90%,5,6,8,35,36 in the same range as those obtained with surgery.37,38 Low rates of toxicity have been observed, including elderly, medically, inoperable patients with severe comorbidities.6,8,35,36,39,40 Survival after SBRT is modest (approximately 50% at 3 years) but has to be interpreted in the context of patients with multiple comorbidities. As expected, survival after SBRT is higher in fitter, operable patients who refused surgery.41 Furthermore, population-based studies indicated improved OS in medically inoperable patients following the introduction of SBRT.42 Based on these data, SBRT for patients with early stage NSCLC has been recommended as the standard of care for medically inoperable cases by the European Society For Medical Oncology, Lugano, Switzerland,43 the National Comprehensive Cancer Network, Fort Washington, PA14 and by the Deutsche Gesellschaft für Radioonkologie e.V., Berlin, Germany.20

Although histological or cytological confirmation of NSCLC is recommended before performing SBRT, biopsy is sometimes not feasible or associated with an unacceptably high risk because of the severe comorbidities of the patient. Thus, an inevitable percentage of patients are treated based on clinical suspicion and imaging criteria of malignancy only. However, in Western Europe, the likelihood of having NSCLC has been demonstrated to be well over 90% using a calculation based on clinical parameters, CT characteristics of malignancy and significant uptake of fluorine-18 fludeoxyglucose (18F-FDG) on PET scan.43 Moreover, when malignancy is highly likely based on these imaging criteria, SBRT without pathological confirmation was shown to lead to the same outcome as in pathology-proven NSCLC.44

With regard to dose/fractionation, there is vast heterogeneity in the SBRT regimes used routinely. Internationally, 3 × 18 Gy is one of the most frequently used regimes, whereas in Germany for small peripheral lesions, lower doses of 3 × 13.5–15.0 Gy are recommended20 and have been demonstrated to result in local control rates of >90%.45 Local tumour control has repeatedly been reported to show a dose-dependent increase with a minimum biologically effective dose (BED; α/β ratio, 10 Gy) of 100 Gy to the planning target volume (PTV) surrounding isodose resulting in local tumour control rates >90%,46,47 that even translates into improved OS.46,48 Interestingly, in a recent meta-analysis, Zhang et al49 demonstrated a plateau effect with regard to OS with doses of 83.2–146.0 Gy BED and a detrimental effect on OS with doses >146 Gy.

SBRT FOR CENTRALLY LOCATED NSCLC

The major difference between peripherally and centrally located NSCLC is the spatial proximity to centrally located serial OARs, such as, main airways, large blood vessels, the heart, the oesophagus, the phrenic nerves or the brachial plexus, where hypofractionated high doses might lead to severe, potentially life-threatening consequences. Several articles have reported high rates of toxicity after SBRT of centrally located NSCLC. A prospective study by Timmerman et al50 from the Indiana University reported a 2-year freedom from severe toxicity of only 54% for central tumours compared with 83% for peripheral tumours, in 70 patients treated with 60–66 Gy total in three fractions. Furthermore, SBRT may have contributed to the events leading to the death of six patients (four patients from bacterial pneumoniae; one patient from pericardial effusion; and one patient owing to massive haemoptysis), of which four of the six patients had central tumours.50 These deaths occurred after a median of 10.4 months following SBRT (range, 1–20 months). The 2-year incidence of toxicity grade ≥3 was 17% and 46% for peripherally and centrally tumours, respectively. The observation of severe toxicity after SBRT of centrally located NSCLC was subsequently confirmed by two studies: grade 5 toxicity was observed in 1 out of 17 patients after treatment with 60 Gy in 4 fractions36 and in 1 out of 9 patients after irradiation with 48 Gy in 4 fractions51 delivered on consecutive days. Moreover, a case report was published by the University of Pennsylvania, Philadelphia, PA, reporting on a fatal central airway necrosis more than 8 months after 50 Gy in five fractions was delivered to a central lung tumour.52 Conversely, investigators from the Free University in Amsterdam demonstrated that the use of “risk-adapted SBRT” using a more fractionated regime (60 Gy in eight fractions) did not result in excess toxicity for centrally located early stage lung tumours (n = 63), and clinical outcomes were comparable with those seen for peripheral tumours.53 However, none of the retrospective data included detailed dose–volume histogram/toxicity analyses. A PRISMA structured literature review published in 2013 identified 20 publications reporting outcomes for 563 central lung tumours treated with SBRT, including 315 patients with early stage NSCLC.9 The majority of these studies were retrospective and conducted at single institutions. Only four studies were prospective and reported on 68 patients with central tumours. Local control was 85% when the prescribed BED10 was >100 Gy. Tumour location (central vs peripheral) did not impact on OS, and treatment-related mortality was 2.7% overall. Grade 3/4 toxicities following SBRT for central tumours were more common than for peripheral tumours, and occurred in <9% of patients. It should however be noted that there was heterogeneity in the common toxicity criteria used to define toxicities and treatment–response criteria. Furthermore, the follow-up of these studies was relatively short (median, 18 months), and long-term toxicity data are needed given the high dose and hypofractionated nature of the treatments delivered. The BED10 delivered ranged between 60 and 180 Gy. It is important to note that published studies vary widely in their reporting of dose/fractionation as well as dose specifications and calculations. Only 11 of the 20 reviewed studies used tissue heterogeneity correction, and the prescription isodoses ranged between 50% and 100%.

In summary, there is a clear need for a prospective, multicentre study using standardized RT techniques, treatment–response criteria and toxicity assessment. As the maximum tolerated doses and optimal fractionation schemes for SBRT near mediastinal structures are currently unknown, collective knowledge of the complex relationship between the radiation dose and the volume of irradiated tissue for each mediastinal structure is a pre-requisite to the safe future routine use of SBRT for central tumours. The lack of high-quality evidence to support SBRT in centrally located tumours is reflected in international guidelines that only recommend SBRT for peripheral and medically inoperable early stage NSCLC.43,54 We therefore advocate that treatment of central lesions should preferably be performed within the context of a well-conducted prospective trial.

EORTC 22113-08113 LungTech: CONCEPT OF THE TRIAL

The LungTech trial aims to evaluate the efficiency and toxicity of SBRT for patients with histologically or cytologically proven early stage, centrally located, inoperable NSCLC in a multicentre setting. The primary end point will be freedom from local progression at 3 years as assessed by serial CT scans and confirmed by 18F-FDG-PET/CT. If still unclear, biopsies or 3 monthly repeated imaging will be performed. Using one-sided 5% Type I error and 80% power, 150 patients (included so far from 23 planned centres in Belgium, France, Germany, Poland, Switzerland and UK) should be sufficient to reject the hypothesis of freedom from the local progression rate at 3 years of ≤80% under the assumption that SBRT is expected to achieve a freedom from local progression rate of 90%. The trial will also investigate acute and late toxicities as well as patterns of local and distant recurrence, including mediastinal failure, assessed by serial CT scans and confirmed by 18F-FDG-PET/CT and subsequent repeat imaging or biopsy, if necessary. Moreover, this study offers a unique opportunity to evaluate the role of 18F-FDG-PET/CT to monitor disease progression and toxicity, as translational research end points, including staging comparison between 3D- and four-dimensional (4D) 18F-FDG-PET/CT assessment, possible impact of 4D 18F-FDG-PET/CT on target volume contouring and external validation of Huang et al55 response criteria.

Recently, the Radiation Therapy Oncology Group (RTOG) has performed a dose-escalation Phase I/II study (RTOG 0813) in centrally located NSCLC.56 Derived from the North American standard, the study is based on a five-fraction regime, the results are awaited. Although the RTOG study includes only T1/T2 tumours, the LungTech study will also include a limited population of T3 tumours and therefore supplement the available data pool. In Europe, owing to the risk of toxicity with three- to five-fraction regimes as described above, it was decided to investigate a less hypofractionated “risk-adapted” approach (60 Gy in eight fractions) as reported by the Free University in Amsterdam.53 To ensure the feasibility and safety of the planned treatment, only those centres that have used SBRT for a period of at least 12 months and have treated a minimum of 20 patients will be eligible. The study will be conducted only within EORTC centres and will benefit from the EORTC and Radiation Oncology Group Quality Assurance infrastructure. A pooled data analysis of both studies maybe an interesting future option.

Some essential features of the protocol are outlined below.

Definition of central tumour

In current literature, the definition of what constitutes a “central” tumour varies widely and further hampers the comparison between trials. Only 11 out of the 20 studies reviewed by Senthi et al9 used the same definition as RTOG 0813;56 Modh et al57 even included two different definitions of “central tumours” within the same publication of their study.

Haasbeek et al53 defined central tumours as located within a 1-cm zone from the mediastinal envelope. In RTOG 0236,58 the following definition is used: a tumour within 2 cm of the proximal bronchial tree (carina, right and left main bronchi, and bronchial tree to the second bifurcation), whereas RTOG 0813 sticks to the definition of Timmerman et al:50 a tumour located within 2 cm in all directions around the proximal bronchial tree and immediately adjacent to mediastinal or pericardial pleura with a PTV expected to touch or include the pleura. This definition has also been slightly modified in the LungTech trial: “Centrally located tumour defined as tumour within 2 cm or touching the zone of the proximal bronchial tree or tumour that is immediately adjacent to the mediastinal or pericardial pleura, with a PTV expected to touch or include the pleura.”

Some tumours might be “too central” to be safely treated with SBRT when applying BED >100 Gy. Even using the “risk-adapted” LungTech regime, there will be central tumours, for example, invading the proximal bronchial tree and/or hilar structures, which will not be treatable within the trial owing to a very high risk of severe toxicity (Figure 1). In current literature, a selection bias with regard to the inclusion of certain anatomical subgroups within the SBRT “danger zone” cannot be excluded. Indeed, the examples and description of patient cohorts, for example, in the Haasbeek's study53 show that “very central” tumours have not been included in the larger published series. However, a clear definition of what constitutes “too central tumours” is lacking. In the LungTech protocol, T3 tumours >7 cm, all T4 tumours and tumours abutting the oesophagus or presenting with separate tumour nodule(s) in the same lobe are excluded to increase the safety of this treatment. Furthermore, all potential LungTech cases will undergo a central expert review of eligibility relating to tumour anatomical location and treatment planning before enrolment in the study treatment, thus confirming central tumour localization and excluding tumours that are “too central” according to the eligibility criteria and dose constraints (e.g. proximity to the central bronchi, Figure 1).

Figure 1.
(a) An 81-year-old patient with centrally located non-small-cell lung cancer (NSCLC), T1N0M0, meeting the eligibility criteria for inclusion in the LungTech trial. Delineation of tumour: gross tumour volume (GTV) (purple), internal target volume (ITV) ...

Prescribed dose, normal tissue constraints

In order to define dose/fractionation and NT constraints for the LungTech trial, current literature and experiences in other trials were reviewed (Tables 1 and and22).9,36,5053,56,57,5975

Table 1.
Literature review of severe radiation induced toxicities for central lung tumors for definition of normal tissue (NT) constraints for the LungTech trial
Table 2.
Normal tissue (NT) constraints for the LungTech trial derived from literature review of severe toxicities (Table 1) and used NT constraints

In terms of tumour dose, the LungTech protocol will investigate a medium hypofractionated approach, applying 8.0 × 7.5 Gy to a total dose of 60 Gy; this is equal to a BED of 105 Gy (α/β = 10). Referring to report 83 of the International Commission on Radiation Units and Measurements (ICRU), 95% of the PTV has to receive at least the nominal fraction dose, and 99% of the PTV receives a minimum of 90% of the nominal dose. The maximum dose within the PTV should not be <110%, nor should it exceed 130% of the prescribed dose. Gross tumour volume (GTV) delineation is based on 4D-CT in treatment position, mandatory 3D-PET/CT scan and supplementary clinical information, for example, results of bronchoscopy. To account for tumour motion during the breathing cycle, the protocol allows the individual internal target volume (ITV) and the average mean position approach. The PTV margin based on the ITV concept is primarily meant to take into account patient set-up uncertainties, thus requiring an isotropic ITV expansion of 3–5 mm. For PTV generation, based on the average mean position of the tumour, the margin should take into account both the set-up error and breathing-induced motion and should not be <3 mm. All patients treated in this trial will receive image-guided SBRT. Further details on the technical aspects of the radiotherapy planning including dose specification and radiation therapy quality assurance (RTQA) procedures will be reported elsewhere.

Defining NT constraints for thoracic OARs, in the context of SBRT, is a major challenge, as the maximum-tolerated doses and optimum fractionation for mediastinal structures are currently unknown. Another challenge is the assessment of treatment-related toxicity in patients with multiple comorbidities, which may be a confounding factor. Whilst toxicity for SBRT delivered to peripheral tumours is well documented, this is not the case for central tumours, and long-term data are necessary given that late effects can become apparent more than 1 year post treatment.65 For this reason, patients will be prospectively assessed for at least 3 years after treatment in the LungTech study.

Although the linear quadratic model (LQM) has been criticized for not being applicable to SBRT,76 data from Guckenberger et al77 suggested accurate modelling of local tumour control in fractionated SBRT for Stage I NSCLC with the traditional linear-quadratic formalism. Brown et al78 reported that there is compelling in vitro and in vivo NT evidence that the LQM provides a reasonable estimate of dose–response relationships including single high doses. Therefore, the NT constraints defined in LungTech have been derived from the available literature on SBRT coupled with LQM estimates related to CFRT experience (Tables 1 and and22).

While translating stated dose/fraction from the varying data to comparable equivalent dose in 2 Gy fractions (EqD2), wide ranges of allegedly comparable equivalent doses become apparent (Tables 1 and and2).2). This is most likely because different α/β ratios have been used and/or other factors than LQM estimates might have contributed to dose calculation or recommendation. This obvious heterogeneity underlines the need for systemically collected data for defining maximum-tolerated doses and optimum fractionation for mediastinal structures, and thus robust NT constraints for thoracic OARs. The dose constraints and possible deviations chosen for the LungTech trial are presented in the EORTC 22113-8113RTQA guidelines (Table 3).

Table 3.
EORTC 221133 LungTech trial: dose constraints for organs at risk (OARs)

Primary end point assessment

Clinical symptoms of acute radiation-induced lung injury develop within approximately 3–6 months after treatment. A proportion of patients will subsequently develop radiation fibrosis (from 6 months after SBRT). The assessment of tumour response after SBRT by CT-based criteria [response evaluation criteria in solid tumour (RECIST)] is therefore challenging, as such changes are typically seen within the high dose area. However, some changes, independently of the tumour size change, have been identified as more reliable indicators of local recurrence (e.g. opacity with a convex border, disappearance of air bronchograms55). In order to confirm a suspicion of local recurrence, it has been shown that 18F-FDG-PET/CT may play an important role in increasing the sensitivity of the diagnosis. In a systematic review of the literature, Huang et al55 proposed a set of criteria for the evaluation of local recurrence with CT and PET findings in patients with primary lung tumours or lung metastases treated with SBRT. A value of maximum standard value uptake (SUVmax) > 5 was suggested79,80 for the differential diagnosis between local recurrence and post-treatment changes. However, the quantitative measurement criteria set by Huang et al,55 are derived from various single-centre studies with heterogeneous PET imaging protocols. Therefore, Huang et al55 recommend conducting all PET scans for a specific patient on the same machine and with a standardized scanner. This is obviously not possible in the context of a multicentre trial.

In the LungTech trial, 18F-FDG-PET/CT will be requested in case of equivocal findings or progressive soft-tissue abnormalities. The integration of quantitative measurement criteria would require the standardization of all the 18F-FDG-PET/CT scanners. Given that such standardization, e.g. the “European Association of Nuclear Medicine” (EANM) accreditation, is not used in all the participating centres, a modified Huang et al55 criterion is being applied with local progression defined as “focal 18F-FDG accumulation significantly above the mediastinal blood pool” (Figure 2). However, quantitative assessment (SUVmax) of the treated tumour and regional lymph nodes will also be measured and collected in order to prospectively evaluate the robustness of the criteria set by Huang et al55 in a subset of centres that have EANM accreditation. In difficult cases, reimaging or biopsy will be requested to confirm progression if clinically indicated.

Figure 2.
Local progression evaluation based on modified Huang et al55 criteria. 18F-FDG, fluorine-18 fludeoxyglucose; PET, positron emission tomography. yr, year. a Repeat imaging should be performed no later than 3 months after the first abnormal CT. b Biopsy ...

Toxicity assessment

An important secondary end point of the LungTech trial is the prospective evaluation of toxicity. As previously described, there is a paucity of prospective data regarding the relationship of dose fractionation, irradiated volume and toxicity of SBRT in centrally located tumours. One of the objectives of LungTech is to elaborate on such coherences and thus be able to provide robust recommendations on central NT constraints in patients treated with SBRT. In order to make recommendations that will be applicable to other SBRT dose/fractionation, pooling the data of LungTech and RTOG 081356 (five-fraction regime) is furthermore an interesting future option. Adverse events are assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4 at baseline, at the end of treatment, 6 weeks after SBRT, 3 monthly for the first 3 years, 6 monthly for up to 5 years and yearly thereafter. Additionally, CT imaging is performed and pulmonary function tests recommended. Serious Adverse Event and Suspected Unexpected Serious Adverse Reactions reporting are conducted according to the Good Clinical Practice.81

Radiation therapy quality assurance and imaging quality control

Differences in delivery of care between institutions may induce variations affecting trial outcome. These variations may be multifactorial such as failure to adhere to protocol guidelines or differences in the equipment quality and/or its use. To prevent these biases, a high-technology quality assurance (QA) procedure has been developed. The RTQA procedure aims to ensure for each treatment plan an acceptable level of conformity to the protocol guidelines.82 The process includes the requirement to submit a benchmark case for review prior to entry of the first patient in the trial (Figure 3). During the recruitment phase, all treatment plans are sent for a prospective central review by a team of experts, who will decide whether the patient is allowed to be treated based on the treatment plan provided (Figure 4).83 Another aspect of RTQA is the verification of the correct use of RT techniques within the trial. End-to-end tests will be performed during site visits using a specific breathing phantom (carrying films and an ionization chamber). Owing to the moving nature of the target, the RTQA procedure also includes an evaluation of the PET/CT, CT and 4D-CT techniques to assess the impact of potential motion artefacts on target volume accuracy. Furthermore, the LungTech QA evaluation will also include the assessment of consistency of Hounsfield units and SUV values, which is of particular relevance given the use of PET/CT data in this study.

Figure 3.
A 54-year-old patient with centrally located non-small-cell lung cancer, T1N0M0, meeting the eligibility criteria for inclusion in the LungTech trial (benchmark case). (a) Delineation of tumour: gross tumour volume (GTV) (purple), internal target volume ...
Figure 4.
Design of the LungTech trial [European Organization for Research and Treatment of Cancer (EORTC) 22113-08113]. 3D, three dimensional; 4D-CT, four-dimensional CT; 18F-FDG, Fluorine-18 Fludeoxyglucose; CBCT, cone beam CT; fr, fractions; NSCLC, non-small-cell ...

Integration of technology advancement techniques in prospective trials

With technology advancement, the conduct of modern clinical research requires a major upgrade of clinical research organizations and the infrastructure for performing such sophisticated trials. Indeed, implementing this high-technology research brings new challenges to international multicentre clinical trials in terms of QA and standardization. For instance, imaging technologies such as PET scans have existed for decades and are widely available, their full use in clinical research, however, remains challenging. The quality and comparability of images collected within international multicentre clinical trials are not always optimal. Reliable clinical research involving imaging or radiotherapy can only be achieved within quality-assured, multicentre trials supported by robust methodology and operational infrastructures, allowing the processing, storage and analysis of imaging or treatment plan data by experienced researchers to be fully integrated with clinical and biological data (Figure 5). Maintaining quality-assured clinical trials infrastructure is a cornerstone of independent clinical research, which will guarantee consistent, long-term and reliable research to patients. To have the necessary academic clinical research infrastructure available, skilled, experienced staff must be retained.

Figure 5.
European organization for research and treatment of cancer (EORTC) infrastructure to support new generation clinical trials. ORTA (online randomized trials access), web-based application designed to facilitate the registration and randomization of patients ...

PERSPECTIVES/CONCLUSIONS

In summary, the LungTech trial is expected to provide high-quality, prospective, multicentre data on the efficacy and toxicity of moderately hypofractionated SBRT for central early stage NSCLC. The data generated by this trial will inform future recommendations on technique, prescription, risk estimation and response assessment for the routine use of this promising new radiotherapy technology. This is of particular importance given the likelihood of an increase in the proportion of patients with lung cancer diagnosed at an earlier stage through screening programs.

ACKNOWLEDGMENTS

The authors thank Sally Falk for language support.

FUNDING

This publication was supported by the EORTC Academic Fund, the Deutsche Krebshilfe e.V., the EORTC Charitable Trust and Cancer Research UK.

REFERENCES

1 . De Ruysscher D, , Nakagawa K, , Asamura H.. Surgical and nonsurgical approaches to small-size nonsmall cell lung cancer. Eur Respir J 2014 ; 44: 483–94. doi: 10.1183/09031936.00020214 [PubMed] [Cross Ref]
2 . Lagerwaard FJ, , Verstegen NE, , Haasbeek CJ, , Slotman BJ, , Paul MA, , Smit EF., et al. . Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2012 ; 83: 348–53. doi: 10.1016/j.ijrobp.2011.06.2003 [PubMed] [Cross Ref]
3 . Guckenberger M.. What is the current status of stereotactic body radiotherapy for stage I non-small cell lung cancer? J Thorac Dis 2011 ; 3: 147–9. doi: 10.3978/j.issn.2072-1439.2011.06.04 [PMC free article] [PubMed] [Cross Ref]
4 . Duncker-Rohr V, , Nestle U, , Momm F, , Prokic V, , Heinemann F, , Mix M., et al. . Stereotactic ablative radiotherapy for small lung tumors with a moderate dose. Favorable results and low toxicity. Strahlenther Onkol 2013 ; 189: 33–40. doi: 10.1007/s00066-012-0224-y [PubMed] [Cross Ref]
5 . Timmerman R, , Paulus R, , Galvin J, , Michalski J, , Straube W, , Bradley J., et al. . Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010 ; 303: 1070–6. doi: 10.1001/jama.2010.261 [PMC free article] [PubMed] [Cross Ref]
6 . Baumann P, , Nyman J, , Hoyer M, , Wennberg B, , Gagliardi G, , Lax I., et al. . Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009 ; 27: 3290–6. doi: 10.1200/JCO.2008.21.5681 [PubMed] [Cross Ref]
7 . Onishi H, , Shirato H, , Nagata Y, , Hiraoka M, , Fujino M, , Gomi K., et al. . Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery? Int J Radiat Oncol Biol Phys 2011 ; 81: 1352–8. doi: 10.1016/j.ijrobp.2009.07.1751 [PubMed] [Cross Ref]
8 . Ricardi U, , Filippi AR, , Guarneri A, , Giglioli FR, , Ciammella P, , Franco P., et al. . Stereotactic body radiation therapy for early stage non-small cell lung cancer: results of a prospective trial. Lung Cancer 2010 ; 68: 72–7. doi: 10.1016/j.lungcan.2009.05.007 [PubMed] [Cross Ref]
9 . Senthi S, , Haasbeek CJ, , Slotman BJ, , Senan S.. Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 2013 ; 106: 276–82. doi: 10.1016/j.radonc.2013.01.004 [PubMed] [Cross Ref]
10 . Schanne DH, , Nestle U, , Allgäuer M, , Andratschke N, , Appold S, , Dieckmann U., et al. . Stereotactic body radiotherapy for centrally located stage I NSCLC: a multicenter analysis. Strahlenther Onkol 2015 ; 191: 125–32. doi: 10.1007/s00066-014-0739-5 [PubMed] [Cross Ref]
11 . D'Addario G, , Felip E.; ESMO Guidelines Working Group. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009 ; 20(Suppl. 4): 68–70. doi: 10.1093/annonc/mdp132 [PubMed] [Cross Ref]
12 . Gibbs IC, , Loo BW., Jr. CyberKnife stereotactic ablative radiotherapy for lung tumors. Technol Cancer Res Treat 2010 ; 9: 589–96. doi: 10.1177/153303461000900607 [PubMed] [Cross Ref]
13 . Scott WJ, , Howington J, , Feigenberg S, , Movsas B, , Pisters K.; American College of Chest Physicians. Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007 ; 132(Suppl. 3): 234S–42S. [PubMed]
14 . The National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version 3, 2012. [Updated 15 August 2012.] Available from: http://www.nccn.com.
15 . Goeckenjan G, , Sitter H, , Thomas M, , Branscheid D, , Flentje M, , Griesinger F., et al. . Prevention, diagnosis, therapy, and follow-up of lung cancer interdisciplinary guideline of the German Respiratory Society and the German Cancer Society—abridged version. [In German.] Pneumologie 2011 ; 65: e51–75. doi: 10.1055/s-0030-1256562 [PubMed] [Cross Ref]
16 . Ginsberg RJ, , Rubinstein LV.. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995 ; 60: 615–22; discussion 22–3. doi: 10.1016/0003-4975(95)00537-U [PubMed] [Cross Ref]
17 . Lausberg HF, , Graeter TP, , Tscholl D, , Wendler O, , Schäfers HJ.. Bronchovascular versus bronchial sleeve resection for central lung tumors. Ann Thorac Surg 2005 ; 79: 1147–52; discussion 1147–52. doi: 10.1016/j.athoracsur.2004.09.009 [PubMed] [Cross Ref]
18 . Chen C, , Bao F, , Zheng H, , Zhou YM, , Bao MW, , Xie HK., et al. . Local extension at the hilum region is associated with worse long-term survival in stage I non-small cell lung cancers. Ann Thorac Surg 2012 ; 93: 389–96. doi: 10.1016/j.athoracsur.2011.09.079 [PubMed] [Cross Ref]
19 . Spiguel L, , Ferguson MK.. Sleeve lobectomy versus pneumonectomy for lung cancer patients with good pulmonary function. In: Ferguson MK, editor. , ed. Difficult decisions in thoracic surgery: an evidence-based approach. 3rd edn. London, UK: Springer; 2007 . pp. 103–9.
20 . Guckenberger M, , Andratschke N, , Alheit H, , Holy R, , Moustakis C, , Nestle U., et al. ; Deutschen Gesellschaft für Radioonkologie (DEGRO). Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer. Strahlenther Onkol 2014 ; 190: 26–33. doi: 10.1007/s00066-013-0450-y [PMC free article] [PubMed] [Cross Ref]
21 . Haasbeek CJ, , Palma D, , Visser O, , Lagerwaard FJ, , Slotman B, , Senan S.. Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in the Netherlands. Ann Oncol 2012 ; 23: 2743–7. doi: 10.1093/annonc/mds081 [PubMed] [Cross Ref]
22 . National Lung Screening Trial Research Team; Church TR, , Black WC, , Aberle DR, , Berg CD, , Clingan KL., et al. . Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 2013 ; 368: 1980–91. doi: 10.1056/NEJMoa1209120 [PMC free article] [PubMed] [Cross Ref]
23 . Janssen-Heijnen ML, , Smulders S, , Lemmens VE, , Smeenk FW, , van Geffen HJ, , Coebergh JW.. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax 2004 ; 59: 602–7. doi: 10.1136/thx.2003.018044 [PMC free article] [PubMed] [Cross Ref]
24 . Asmis TR, , Ding K, , Seymour L, , Shepherd FA, , Leighl NB, , Winton TL., et al. ; National Cancer Institute of Canada Clinical Trials Group. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: a review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol 2008 ; 26: 54–9. doi: 10.1200/JCO.2007.12.8322 [PubMed] [Cross Ref]
25 . Jemal A, , Bray F, , Center MM, , Ferlay J, , Ward E, , Forman D.. Global cancer statistics. CA Cancer J Clin 2011 ; 61: 69–90. doi: 10.3322/caac.20107 [PubMed] [Cross Ref]
26 . Raz DJ, , Zell JA, , Ou SH, , Gandara DR, , Anton-Culver H, , Jablons DM.. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest 2007 ; 132: 193–9. doi: 10.1378/chest.06-3096 [PubMed] [Cross Ref]
27 . Sibley GS, , Jamieson TA, , Marks LB, , Anscher MS, , Prosnitz LR.. Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 1998 ; 40: 149–54. [PubMed]
28 . Jeremic B, , Classen J, , Bamberg M.. Radiotherapy alone in technically operable, medically inoperable, early stage (I/II) non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002 ; 54: 119–30. doi: 10.1016/s0360-3016(02)02917-6 [PubMed] [Cross Ref]
29 . Rowell NP, , Williams CJ.. Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable). Cochrane Database Syst Rev 2001 : CD002935. doi: 10.1002/14651858.CD002935 [PubMed] [Cross Ref]
30 . Willner J, , Baier K, , Caragiani E, , Tschammler A, , Flentje M.. Dose, volume, and tumor control prediction in primary radiotherapy of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002 ; 52: 382–9. doi: 10.1016/s0360-3016(01)01823-5 [PubMed] [Cross Ref]
31 . Martel MK, , Ten Haken RK, , Hazuka MB, , Kessler ML, , Strawderman M, , Turrisi AT., et al. . Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer 1999 ; 24: 31–7. doi: 10.1016/s0169-5002(99)00019-7 [PubMed] [Cross Ref]
32 . Seppenwoolde Y, , Lebesque JV, , de Jaeger K, , Belderbos JS, , Boersma LJ, , Schilstra C., et al. . Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability. Int J Radiat Oncol Biol Phys 2003 ; 55: 724–35. doi: 10.1016/S0360-3016(02)03986-X [PubMed] [Cross Ref]
33 . Bogart JA, , Hodgson L, , Seagren SL, , Blackstock AW, , Wang X, , Lenox R., et al. . Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol 2010 ; 28: 202–6. doi: 10.1200/jco.2009.25.0753 [PMC free article] [PubMed] [Cross Ref]
34 . van Baardwijk A, , Wanders S, , Boersma L, , Borger J, , Ollers M, , Dingemans AM., et al. . Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer. J Clin Oncol 2010 ; 28: 1380–6. doi: 10.1200/jco.2009.24.7221 [PubMed] [Cross Ref]
35 . Nagata Y, , Takayama K, , Matsuo Y, , Norihisa Y, , Mizowaki T, , Sakamoto T., et al. . Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2005 ; 63: 1427–31. doi: 10.1016/j.ijrobp.2005.05.034 [PubMed] [Cross Ref]
36 . Bral S, , Gevaert T, , Linthout N, , Versmessen H, , Collen C, , Engels B., et al. . Prospective, risk-adapted strategy of stereotactic body radiotherapy for early stage non-small-cell lung cancer: results of a Phase II trial. Int J Radiat Oncol Biol Phys 2011 ; 80: 1343–9. doi: 10.1016/j.ijrobp.2010.04.056 [PubMed] [Cross Ref]
37 . Crabtree TD, , Denlinger CE, , Meyers BF, , El Naqa I, , Zoole J, , Krupnick AS., et al. . Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2010 ; 140: 377–86. doi: 10.1016/j.jtcvs.2009.12.054 [PubMed] [Cross Ref]
38 . Grills IS, , Mangona VS, , Welsh R, , Chmielewski G, , McInerney E, , Martin S., et al. . Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol 2010 ; 28: 928–35. doi: 10.1200/JCO.2009.25.0928 [PubMed] [Cross Ref]
39 . Haasbeek CJ, , Lagerwaard FJ, , Antonisse ME, , Slotman BJ, , Senan S.. Stage I nonsmall cell lung cancer in patients aged > or =75 years: outcomes after stereotactic radiotherapy. Cancer 2010 ; 116: 406–14. doi: 10.1002/cncr.24759 [PubMed] [Cross Ref]
40 . Louie AV, , Rodrigues G, , Hannouf M, , Lagerwaard F, , Palma D, , Zaric GS., et al. . Withholding stereotactic radiotherapy in elderly patients with stage I non-small cell lung cancer and co-existing COPD is not justified: outcomes of a Markov model analysis. Radiother Oncol 2011 ; 99: 161–5. doi: 10.1016/j.radonc.2011.04.005 [PubMed] [Cross Ref]
41 . Shelkey J, , Fakiris A, , DeCamp MM, , Medford-Davis LN, , Flickinger JC, , Recht A., et al. . Matched-pair comparison of outcome of patients with clinical stage I non-small cell lung cancer treated with resection or stereotactic radiosurgery. J Clin Oncol 2012 ; 30.
42 . Palma D, , Visser O, , Lagerwaard FJ, , Belderbos J, , Slotman BJ, , Senan S.. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: a population-based time-trend analysis. J Clin Oncol 2010 ; 28: 5153–9. doi: 10.1200/JCO.2010.30.0731 [PubMed] [Cross Ref]
43 . Vansteenkiste J, , De Ruysscher D, , Eberhardt WE, , Lim E, , Senan S, , Felip E., et al. ; ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 ; 24(Suppl. 6): vi89–98. doi: 10.1093/annonc/mdt241 [PubMed] [Cross Ref]
44 . Verstegen NE, , Lagerwaard FJ, , Haasbeek CJ, , Slotman BJ, , Senan S.. Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: comparison with a contemporaneous cohort with pathologically proven disease. Radiother Oncol 2011 ; 101: 250–4. doi: 10.1016/j.radonc.2011.09.017 [PubMed] [Cross Ref]
45 . Guckenberger M, , Allgauer M, , Appold S, , Dieckmann K, , Ernst I, , Ganswindt U., et al. . Safety and efficacy of stereotactic body radiotherapy for stage 1 non-small-cell lung cancer in routine clinical practice: a patterns-of-care and outcome analysis. J Thorac Oncol 2013 ; 8: 1050–8. doi: 10.1097/JTO.0b013e318293dc45 [PubMed] [Cross Ref]
46 . Onishi H, , Araki T, , Shirato H, , Nagata Y, , Hiraoka M, , Gomi K., et al. . Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 2004 ; 101: 1623–31. doi: 10.1002/cncr.20539 [PubMed] [Cross Ref]
47 . Guckenberger M, , Wulf J, , Mueller G, , Krieger T, , Baier K, , Gabor M., et al. . Dose–response relationship for image-guided stereotactic body radiotherapy of pulmonary tumors: relevance of 4D dose calculation. Int J Radiat Oncol Biol Phys 2009 ; 74: 47–54. doi: 10.1016/j.ijrobp.2008.06.1939 [PubMed] [Cross Ref]
48 . Onimaru R, , Fujino M, , Yamazaki K, , Onodera Y, , Taguchi H, , Katoh N., et al. . Steep dose-response relationship for stage I non-small-cell lung cancer using hypofractionated high-dose irradiation by real-time tumor-tracking radiotherapy. Int J Radiat Oncol Biol Phys 2008 ; 70: 374–81. doi: 10.1016/j.ijrobp.2007.06.043 [PubMed] [Cross Ref]
49 . Zhang J, , Yang F, , Li B, , Li H, , Liu J, , Huang W., et al. . Which is the optimal biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell lung cancer? A meta-analysis. Int J Radiat Oncol Biol Phys 2011 ; 81: e305–16. doi: 10.1016/j.ijrobp.2011.04.034 [PubMed] [Cross Ref]
50 . Timmerman R, , McGarry R, , Yiannoutsos C, , Papiez L, , Tudor K, , DeLuca J., et al. . Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early stage lung cancer. J Clin Oncol 2006 ; 24: 4833–9. doi: 10.1200/JCO.2006.07.5937 [PubMed] [Cross Ref]
51 . Song SY, , Choi W, , Shin SS, , Lee SW, , Ahn SD, , Kim JH., et al. . Fractionated stereotactic body radiation therapy for medically inoperable stage I lung cancer adjacent to central large bronchus. Lung Cancer 2009 ; 66: 89–93. doi: 10.1016/j.lungcan.2008.12.016 [PubMed] [Cross Ref]
52 . Corradetti MN, , Haas AR, , Rengan R.. Central-airway necrosis after stereotactic body-radiation therapy. N Engl J Med 2012 ; 366: 2327–9. doi: 10.1056/NEJMc1203770 [PubMed] [Cross Ref]
53 . Haasbeek CJ, , Lagerwaard FJ, , Slotman BJ, , Senan S.. Outcomes of stereotactic ablative radiotherapy for centrally located early stage lung cancer. J Thorac Oncol 2011 ; 6: 2036–43. doi: 10.1097/jto.0b013e31822e71d8 [PubMed] [Cross Ref]
54 . Howington JA, , Blum MG, , Chang AC, , Balekian AA, , Murthy SC.. Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 ; 143(Suppl. 5): e278S–313S. doi: 10.1378/chest.12-2359 [PubMed] [Cross Ref]
55 . Huang K, , Dahele M, , Senan S, , Guckenberger M, , Rodrigues GB, , Ward A., et al. . Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiother Oncol 2012 ; 102: 335–42. doi: 10.1016/j.radonc.2011.12.018 [PubMed] [Cross Ref]
56 . Radiation Therapy Oncology Group, RTOG0813. NCT00750269 [Updated 9 September 2009.] Available from: http://rpc.mdanderson.org/rpc/credentialing/files/0813-Master-2-9-11.pdf.
57 . Modh A, , Rimner A, , Williams E, , Foster A, , Shah M, , Shi W., et al. . Local control and toxicity in a large cohort of central lung tumors treated with stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2014 ; 90: 1168–76. doi: 10.1016/j.ijrobp.2014.08.008 [PMC free article] [PubMed] [Cross Ref]
58 . Radiation Therapy Oncology Group, RTOG0236. A Phase II trial of stereotactic body radiation therapy (SBRT) in the treatment of patients with medically inoperable stage I/II non-small cell lung cancer. NCT000874. [Updated 9 September 2009.] Available from: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study0236
59 . Fakiris AJ, , McGarry RC, , Yiannoutsos CT, , Papiez L, , Williams M, , Henderson MA., et al. . Stereotactic body radiation therapy for early stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 2009 ; 75: 677–82. doi: 10.1016/j.ijrobp.2008.11.042 [PubMed] [Cross Ref]
60 . Li Q, , Swanick CW, , Allen PK, , Gomez DR, , Welsh JW, , Liao Z., et al. . Stereotactic ablative radiotherapy (SABR) using 70 Gy in 10 fractions for non-small cell lung cancer: exploration of clinical indications. Radiother Oncol 2014 ; 112: 256–61. doi: 10.1016/j.radonc.2014.07.010 [PubMed] [Cross Ref]
61 . Nishimura S, , Takeda A, , Sanuki N, , Ishikura S, , Oku Y, , Aoki Y., et al. . Toxicities of organs at risk in the mediastinal and hilar regions following stereotactic body radiotherapy for centrally located lung tumors. J Thorac Oncol 2014 ; 9: 1370–6. doi: 10.1097/jto.0000000000000260 [PubMed] [Cross Ref]
62 . Milano MT, , Chen Y, , Katz AW, , Philip A, , Schell MC, , Okunieff P.. Central thoracic lesions treated with hypofractionated stereotactic body radiotherapy. Radiother Oncol 2009 ; 91: 301–6. doi: 10.1016/j.radonc.2009.03.005 [PubMed] [Cross Ref]
63 . Oshiro Y, , Aruga T, , Tsuboi K, , Marino K, , Hara R, , Sanayama Y., et al. . Stereotactic body radiotherapy for lung tumors at the pulmonary hilum. Strahlenther Onkol 2010 ; 186: 274–9. doi: 10.1007/s00066-010-2072-y [PubMed] [Cross Ref]
64 . Unger K, , Ju A, , Oermann E, , Suy S, , Yu X, , Vahdat S., et al. . CyberKnife for hilar lung tumors: report of clinical response and toxicity. J Hematol Oncol 2010 ; 3: 39. doi: 10.1186/1756-8722-3-39 [PMC free article] [PubMed] [Cross Ref]
65 . Cannon DM, , Mehta MP, , Adkison JB, , Khuntia D, , Traynor AM, , Tomé WA., et al. . Dose-limiting toxicity after hypofractionated dose-escalated radiotherapy in non-small-cell lung cancer. J Clin Oncol 2013 ; 31: 4343–8. doi: 10.1200/jco.2013.51.5353 [PMC free article] [PubMed] [Cross Ref]
66 . Timmerman R, , Heinzerling J, , Abdulrahman R, , Choy H, , Meyer JL.. Stereotactic body radiation therapy for thoracic cancers: recommendations for patient selection, setup and therapy. Front Radiat Ther Oncol 2011 ; 43: 395–411. doi: 10.1159/000322503 [PubMed] [Cross Ref]
67 . Nuyttens JJ, , van der Voort van Zyp NC, , Praag J, , Aluwini S, , van Klaveren RJ, , Verhoef C., et al. . Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors. Radiother Oncol 2012 ; 102: 383–7. doi: 10.1016/j.radonc.2011.12.023 [PubMed] [Cross Ref]
68 . Bonomo P, , Livi L, , Rampini A, , Meattini I, , Agresti B, , Simontacchi G., et al. . Stereotactic body radiotherapy for cardiac and paracardiac metastases: University of Florence experience. La Radiologia medica 2013 ; 118: 1055–65. doi: 10.1007/s11547-013-0932-0 [PubMed] [Cross Ref]
69 . Onimaru R, , Shirato H, , Shimizu S, , Kitamura K, , Xu B, , Fukumoto S., et al. . Tolerance of organs at risk in small-volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers. Int J Radiat Oncol Biol Phys 2003 ; 56: 126–35. doi: 10.1016/s0360-3016(03)00095-6 [PubMed] [Cross Ref]
70 . Stephans KL, , Djemil T, , Diaconu C, , Reddy CA, , Xia P, , Woody NM., et al. . Esophageal dose tolerance to hypofractionated stereotactic body radiation therapy: risk factors for late toxicity. Int J Radiat Oncol Biol Phys 2014 ; 90: 197–202. doi: 10.1016/j.ijrobp.2014.05.011 [PubMed] [Cross Ref]
71 . Kirkpatrick JP, , van der Kogel AJ, , Schultheiss TE.. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys 2010 ; 76(3 Suppl.): S42–9. doi: 10.1016/j.ijrobp.2009.04.095 [PubMed] [Cross Ref]
72 . Forquer JA, , Fakiris AJ, , Timmerman RD, , Lo SS, , Perkins SM, , McGarry RC., et al. . Brachial plexopathy from stereotactic body radiotherapy in early stage NSCLC: dose-limiting toxicity in apical tumor sites. Radiother Oncol 2009 ; 93: 408–13. doi: 10.1016/j.radonc.2009.04.018 [PubMed] [Cross Ref]
73 . Borst GR, , Ishikawa M, , Nijkamp J, , Hauptmann M, , Shirato H, , Onimaru R., et al. . Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy. Radiother Oncol 2009 ; 91: 307–13. doi: 10.1016/j.radonc.2009.02.003 [PubMed] [Cross Ref]
74 . Stanic S, , Paulus R, , Timmerman RD, , Michalski JM, , Barriger RB, , Bezjak A., et al. . No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early-stage peripheral non-small cell lung cancer: an analysis of RTOG 0236. Int J Radiat Oncol Biol Phys 2014 ; 88: 1092–9. doi: 10.1016/j.ijrobp.2013.12.050 [PMC free article] [PubMed] [Cross Ref]
75 . Taremi M, , Hope A, , Lindsay P, , Dahele M, , Fung S, , Purdie TG., et al. . Predictors of radiotherapy induced bone injury (RIBI) after stereotactic lung radiotherapy. Radiat Oncol 2012 ; 7: 159. doi: 10.1186/1748-717X-7-159 [PMC free article] [PubMed] [Cross Ref]
76 . Strigari L, , Benassi M, , Sarnelli A, , Polico R, , D'Andrea M.. A modified hypoxia-based TCP model to investigate the clinical outcome of stereotactic hypofractionated regimes for early stage non-small-cell lung cancer (NSCLC). Med Phys 2012 ; 39: 4502–14. doi: 10.1118/1.4730292 [PubMed] [Cross Ref]
77 . Guckenberger M, , Klement RJ, , Allgäuer M, , Appold S, , Dieckmann K, , Ernst I., et al. . Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer. Radiother Oncol 2013 ; 109: 13–20. doi: 10.1016/j.radonc.2013.09.005 [PubMed] [Cross Ref]
78 . Brown JM, , Carlson DJ, , Brenner DJ.. The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? Int J Radiat Oncol Biol Phys 2014 ; 88: 254–62. doi: 10.1016/j.ijrobp.2013.07.022 [PMC free article] [PubMed] [Cross Ref]
79 . Takeda A, , Kunieda E, , Takeda T, , Tanaka M, , Sanuki N, , Fujii H., et al. . Possible misinterpretation of demarcated solid patterns of radiation fibrosis on CT scans as tumor recurrence in patients receiving hypofractionated stereotactic radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 2008 ; 70: 1057–65. doi: 10.1016/j.ijrobp.2007.07.2383 [PubMed] [Cross Ref]
80 . Vahdat S, , Oermann EK, , Collins SP, , Yu X, , Abedalthagafi M, , Debrito P., et al. . CyberKnife radiosurgery for inoperable stage IA non-small cell lung cancer: 18F-fluorodeoxyglucose positron emission tomography/computed tomography serial tumor response assessment. J Hematol Oncol 2010 ; 3: 6. doi: 10.1186/1756-8722-3-6 [PMC free article] [PubMed] [Cross Ref]
82 . Melidis C, , Bosch WR, , Izewska J, , Fidarova E, , Zubizarreta E, , Ulin K., et al. . Global harmonization of quality assurance naming conventions in radiation therapy clinical trials. Int J Radiat Oncol Biol Phys 2014 ; 90: 1242–9. doi: 10.1016/j.ijrobp.2014.08.348 [PubMed] [Cross Ref]
83 . Fairchild A, , Aird E, , Fenton PA, , Gregoire V, , Gulyban A, , Lacombe D., et al. . EORTC Radiation Oncology Group quality assurance platform: establishment of a digital central review facility. Radiother Oncol 2012 ; 103: 279–86. doi: 10.1016/j.radonc.2012.04.015 [PubMed] [Cross Ref]

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