Review of Hypofractionated Small Volume Radiotherapy for Early-stage Non-small Cell Lung Cancer

Clinical Oncology (2008) 20: 666e676 doi:10.1016/j.clon.2008.06.005

Overview

Review of Hypofractionated Small Volume Radiotherapy for Early-stage Non-small Cell Lung Cancer J. Brock*, S. Ashleyy, J. Bedfordzx, E. Nioutsikouz, M. Partridgez, M. Brada*k *Academic Unit of Radiotherapy & Oncology, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK; yResearch and Development, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK; zJoint Department of Physics, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK; xRadiotherapy Physics, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK; kThe Institute of Cancer Research and Lung Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK

ABSTRACT: A review of the technical aspects of high-dose hypofractionated radiotherapy for localised non-small cell lung cancer was carried out to allow correlation with outcome measures and with a consensus view of the technique. A Pubmed search carried out between January 2001 and April 2007 identified 15 studies for inclusion. The clinical and technical aspects of treatment were extracted and their effect on survival, progression-free survival and toxicity were assessed using the summary statistic of weighted means. A comparison was made with the RTOG 0236 consensus study protocol. The range of variables in the studies precluded correlation of outcome with tumour parameters, dose fractionation and technical aspects such as immobilisation, techniques dealing with breathing motion, beam number and arrangement and organ at risk dose constraints. Robust data to justify a consensus view were not found, which suggests that further studies are required. They should focus on developing the treatment technique of stereotactic body radiation therapy for earlystage non-small cell lung cancer and correlating it with outcome to provide a rational basis for future randomised trials, comparing the technique with conformal radiotherapy and surgery, and the introduction of the technique into routine clinical practice. Brock, J. et al. (2008). Clinical Oncology 20, 666—676 ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Hypofractionation, non-small cell lung cancer, radiotherapy, stereotactic

Statement of Search Strategies Used and Sources of Information A Medline search was carried out between January 2001 and April 2007 for hypofractionated or stereotactic body radiation therapy (SBRT) of primary non-small cell lung cancer (search terms: hypofractionation, SBRT, EBRT, lung, NSCLC, radiotherapy). Technical details of planning and delivery were recorded, and where not available, requested from authors. Tumour stage and locations were also recorded. Outcome was assessed using local control, survival and toxicity data. Comparative actuarial outcome data were obtained either from the published text or graphs. The summary figures were expressed as a weighted mean, weighted for the initial number of patients in the study.

Introduction External beam radiotherapy is the treatment of choice for inoperable non-small cell lung cancer (NSCLC), although with standard techniques local disease control and survival are disappointing (5-year survival 21% for stage I disease [1]). Local control is an important determinant of survival 0936-6555/08/200666þ11 $35.00/0

and improvement in the delivery of effective radiotherapy is expected to improve long-term outcome. This may be achieved by dose escalation [2e6], with concomitant chemotherapy [7e10], by increasing the biological effective dose (BED) with acceleration, hyperfractionation [11] and by high-dose hypofractionation. The use of high-dose hypofractionation, defined here as R 3 Gy per fraction in fewer treatment sessions (usually maximum 15) in a shortened treatment time (!4 weeks), has been limited by toxicity of normal tissues, particularly lung, necessarily included in the target volume to account for microscopic tumour extension and tumour and patient movement. New techniques of treatment delivery combined with better imaging allow for high-dose hypofractionated radiotherapy for small lung tumours and this has become one of the available options for radical radiotherapy in NSCLC. The potential advantages of hypofractionation include a shorter overall treatment time, which minimises accelerated repopulation, potential dose escalation with a higher BED and patient convenience. It may also reduce demand on radiotherapy resources by using fewer fractions, although individual treatment sessions are longer. Hypofractionated radiotherapy has been reserved for the treatment of small tumours where only a limited volume of

ª 2008 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

HYPOFRACTIONATED SMALL VOLUME RADIOTHERAPY FOR NSCLC

normal lung is treated. The volume of normal lung included in the high-dose volume is reduced further by more accurate imaging and target registration and by techniques that minimise tumour and patient movement. Tumour movement with respiration can be reduced by a stereotactic body frame with abdominal compression [12,13], voluntary breathhold [14,15] or active breathing control (ABC) [16]. The effect of motion can also be minimised if treatment is gated to part of the respiratory cycle [17,18], the moving tumour is tracked [19], or the tumour is imaged with respiratorycorrelated computed tomography (four-dimensional computed tomography) with a high dose delivered only to the mean tumour position [20]. Image guidance, including cone beam computed tomography [21e24], in-room computed tomography carried out before each fraction [25,26] and three-dimensional tracking of fiducials during treatment [27] improve the accuracy of treatment by aiding patient set-up and confirming anatomical tumour location. Precise positioning and imaging for radiation delivery has been termed stereotactic body radiotherapy (SBRT). An ongoing phase II Radiation Therapy Oncology Group (RTOG) multicentre study (RTOG 0236) delivering 60 Gy in three fractions to T1eT3 peripheral lung tumours over 8e14 days uses a hypofractionated protocol based on a consensus view of an expert panel reviewing available evidence to date [28]. We carried out a review of the published studies of hypofractionated radiotherapy for NSCLC to summarise the techniques used, their rationale, and to try to identify the optimum technique based on outcome data. We also attempted to relate these results to the RTOG consensus view.

Materials and Methods A Medline search between January 2001 and April 2007 for high-dose hypofractionated radiation therapy of primary NSCLC (search terms: hypofractionation, SBRT, EBRT, lung, NSCLC, radiotherapy) yielded 17 published reports. Studies using heavy particle therapy and those using a single fraction of photon therapy were not included. In the case of multiple publications from one institution, only the most recent, largest series was included to avoid duplication of data, resulting in 15 publications (12 single or multi-centre phase I/II studies [29e40] and three retrospective reviews [41e43]) suitable for inclusion. No phase III randomised data were found. Technical details of planning and delivery were recorded, as were tumour stage and locations. Several investigators were contacted and provided further information on what organ at risk (OAR) constraints were applied. Outcome was assessed using local control, survival and toxicity data. Comparative actuarial outcome data were obtained either from the published text or graphs. The summary figures were expressed as a weighted mean, weighted for the initial number of patients in the study.

Results Fifteen publications of hypofractionated radiotherapy for early-stage NSCLC were reviewed, comprising 880 patients

667

with NSCLC. Aspects of treatment planning and delivery have been tabulated and categorised to allow for the assessment of outcome.

Tumour Parameters Tumour size and location The size, stage and location of tumours treated are shown in Table 1. In six of 11 studies where eligible tumour size was specified, the maximum tumour diameter treated was %6 cm; only one centre allowed larger (%7 cm) tumours and four studies only smaller (%5 cm) tumours. In the largest reported study, the median tumour diameter was 2.8 cm [36]. In only two of 15 studies central tumours were excluded (in three of 13 studies the prescribed dose for central tumours was lower than for peripheral tumours). In four studies nodal involvement was accepted, most probably if N1 nodes were close to the primary tumour mass [29].

Technical Aspects of Treatment Immobilisation and set-up The use of an immobilisation device was reported in 10 studies (Table 2). The most common was a stereotactic body frame comprising a rigid box with a vacuum pillow. The immobilisation method was not specified in five studies. Tumour motion and margin determination An assessment of tumour motion was reported in 11 of 15 publications (not specified in two and apparently not Table 1 e Eligibility criteria for patients with non-small cell lung cancer treated with hypofractionated radiotherapy in 15 published reports Tumour stage(s)

Reference

Maximum size (diameter)

[43] [31] [33] [35] [37] [36] [38]

I I I I I I T1e3N0M0

%5 cm %6 cm %4.5 cm %6 cm %7 cm %6 cm e

[32] [34] [42] [39] [30]

‘Limited stage’ I ‘Non-metastatic’ I and II I

e !4 cm e Most %5 cm %6 cm

[41]

I

%6 cm

[40] [29]

I T1e2N0e1M0

%6 cm e

Eligible tumour locations Any Any but dose adapted* Any Any but dose adapted* Any Any Central tumours excluded Not specified Any Any Any Central tumours excluded Any but mainly peripheral Any but dose adapted* Any

*Dose higher for peripheral than central tumours.

668

CLINICAL ONCOLOGY

Table 2 e Methods for immobilisation, assessing and intervening in respiratory motion and determining clinical target volumeeplanning target volume (CTVePTV) margin in 15 published reports of hypofractionated radiotherapy in early-stage non-small cell lung cancer Method of immobilisation Reference Body frame

Other

Assessing extent of motion

No

No

[31]

No

No

[33]

Yes

No

[35]

No

No

[37]

GTV ¼ CTV CTVePTV margin 5 mm axially and 10 mm cranio-caudally Yes in some Vacuum e Seven institutions used respiratory GTVeCTV ¼ 0e5 mm cases pillow gating or breath-hold. One used CTVePTV ¼ 2e10 mm fiducial markers for tracking Yes No Dynamic computed Diaphragm control template used GTVeCTV 2e3 mm tomography if breathing motion O5 mm CTVePTV 5 mm axially and 5e10 mm cranio-caudally Daily computed tomography verification Yes No Not specified Not specified Not specified Yes No Fluoroscopy If motion O8 mm cranio-caudally, ITVePTV 5 mm axially and diaphragm control used 8e10 mm cranio-caudally Yes No Not specified Not specified GTVePTV 5e10 mm No Vacuum Slow computed tomography If motion O1 cm, extra GTVePTV minimum 10 mm pillow and fluoroscopy margins added Not Not specified Four-dimensional computed Abdominal compression if ITV formed using maximum specified tomography motion O1 cm inhale and maximum exhale data sets; 5 mm margin added to form PTV Yes No Fluoroscopy Abdominal compression if CTVePTV margin 5e10 mm motion O5 mm axially and 10 mm cranio-caudally No Vacuum Sequential computed Not specified PTV individualised pillow tomography scans and orthogonal films taken to determine motion Not Not Fluoroscopy and/or e GTVePTV margin 10e15 mm specified specified on-treatment imaging in all directions

[36]

[38]

[32] [34] [42] [39] [30]

[41] [40]

[29]

No

Planning scan at neutral, inspiratory and expiratory phases e

If motion R1 cm, shallow breaths with oxygen mask  abdominal pressure belt e

Margin determination

[43]

Yes

Fluoroscopy Computed tomography guided Planning scan at neutral, inspiratory and expiratory phases Fluoroscopy

Intervention for motion

If O5 mm cranio-caudal motion, diaphragm control used e

Usually 5 mm around CTV (taking motion into account) PTV 10 mm around composite CTV

GTVeCTV 5 mm CTVePTV margin 5e10 mm cranio-caudally PTV margin 5 mm axially, but 10 mm cranio-caudally

Abdominal compression device only

GTV, gross tumour volume; CTV, clinical target volume; PTV, planning target volume; ITV, internal target volume.

carried out in a further two studies). Methods included fluoroscopy, slow computed tomography, deep inspiration and expiration computed tomography, multiple computed tomography scans with orthogonal films and four-dimensional computed tomography. In nine studies, intervention was described either to account for motion outside specified limits or to control it (Table 2). The most common intervention was abdominal compression (seven studies). The margin added to the clinical target volume (CTV) to generate the planning target volume (PTV), where specified, was %10 mm, except in one study where it was up to 15 mm.

Dose fractionation and radiation delivery The prescribed dose ranged from 18 to 90 Gy and the dose per fraction from 3 to 20 Gy, given in a total of one to 22 fractions (Table 3). The overall treatment time was 3e27 days. The most frequently prescribed regimens were in the ranges 30e48 Gy in three to four fractions or 48e60 Gy in five to 10 fractions. Where a dose was prescribed to the 100% isodose line, the most common prescriptions were 60 Gy in eight fractions for peripheral tumours and 48 Gy in eight fractions for central lesions. Studies utilising heterogeneity within the PTV prescribed to the periphery of the

HYPOFRACTIONATED SMALL VOLUME RADIOTHERAPY FOR NSCLC

PTV and the most frequent dose-fractionation regimes were 50 Gy in 10 fractions, 45 Gy in three fractions, 40 Gy in five fractions and 36 Gy in three fractions. The most commonly used beam arrangement was six to 10 non-coplanar beams, although up to 20 beams were used (Table 4). Several studies also used dynamic arcs and one used radiosurgery with a multi-headed 60Co unit (gamma knife) [39]. One publication reported an optimisation study of target volume dose distribution and normal tissue dose constraints [35].

Organ at risk dose constraints The applied dose constraints are shown in Table 5. Five studies did not report the application of OAR dose constraints. Dose limits for hypofractionated regimens were set using either the linear quadratic model with tolerances based on a 2 Gy/fraction regimen [35] or the OAR tolerances defined by the RTOG 0236 study [30]. For comparison, BED was calculated from the reported OAR constraints, using the equation BED ¼ nd(1 þ d/a/b), where n is the number of fractions, d is the dose per fraction and a/b was taken as 2 for the spinal cord and heart, 3 for the oesophagus and brachial plexus and 2 or 3 for other central structures. The calculated BED for reported constraints was 72.0e94.5 Gy for the spinal cord, 106.7e108.0 Gy for the oesophagus, 88e94 Gy for the brachial plexus and up to 180 Gy for other central structures, except in two studies, which chose lower limits for all OARs (BED 49e60 Gy for the spinal cord, 41.6e78.0 Gy for the oesophagus and 49 Gy for the heart). V20 was reported as the limiting parameter for the tolerance dose to normal lung in only two studies.

Table 3 e Dose-fractionation schedules used in 15 published reports of hypofractionated radiotherapy for early-stage nonsmall cell lung cancer Total Dose per Number of Overall treatment Reference dose (Gy) fraction (Gy) fractions time (days) [43] [31] [33] [35] [37] [36] [38] [32] [34] [42] [39] [30] [41] [40] [29]

50e60 48e60 30e40 48e60 24e60 18e75 30e37.5 45 48 30e90 50 45e60 30e48 24e40 52.5

5e12 6e7.5 10 6e7.5 8e20 3e18 10e12.5 15 12 Median 8 5 5e20 10e20 7e12.5 3.5

N/A, information not available.

5e10 8 3e4 8 3 1e22 3 3 4 Median 5 10 3e10 2e4 3e5 15

5e12 12 3e4 12 8e12 N/A Approximately 8 5e8 5e13 Median 27 12 N/A 3e12 3e10 19

669

Table 4 e Beam arrangement and number of beams to deliver hypofractionated radiotherapy in published reports of hypofractionated radiotherapy in early-stage non-small cell lung cancer Number of fixed beams Reference [43] [31] [33] [35] [37] [36] [38] [32] [34] [42] [39] [30] [41] [40] [29]

C e 8 C or N 4e8 C or N e e e e N/A e N/A Single or multiple e 5e9 Multiple 2e3

N

Number of arcs

6e15 e e 4e12 3e4 7 e 6e20 3e10 4e12 3e4 N/A N/A 6e10 e N/A N/A foci of beams with 60Co unit 7e10 e e e e Multiple e e e

C, coplanar; N, non-coplanar; N/A, information not available. A single type of beam arrangement (fixed beams or arcs) was generally used for each patient.

Clinical Outcome Local control, survival and toxicity Reported local control, survival and toxicity are summarised in Table 6. Weighted 2-year survival after hypofractionated radiotherapy was 65% and 2-year local progression-free survival 89%. One study reported a 5-year survival of 26% [41]. The weighted mean 2-year survival was not significantly different for those treated with R 10 Gy per fraction (n ¼ 262) vs !10 Gy per fraction (n ¼ 168) (70 and 66%, respectively) (Table 7). The incidence of symptomatic pneumonitis ( R grade 2) reported in the publications ranged from 0 to 29% with a weighted mean of 6.5%. Of the 12 prospective studies, nine reported radiation pneumonitis of R grade 2. Oesophagitis was usually transient and rare late toxicities were rib fracture, benign pleural effusion, soft tissue fibrosis and chest wall pain. Several studies reported cases of mild radiation-induced acute whole body reactions, including fever, chills, ache and nausea, which settled with supportive measures within a few hours of each treatment session. One patient died from a bleeding oesophageal ulcer after receiving 48 Gy in eight fractions for a central tumour.

Discussion We carried out a review of published studies on hypofractionated stereotactic radiotherapy (often termed SBRT) in patients with localised NSCLC. As with any new approach there is a considerable diversity of techniques used,

670 Table 5 e Dose constraints and the corresponding calculated biological effective dose (BED) (overall treatment time not taken into account) applied to thoracic organs in published studies of hypofractionated radiotherapy in early-stage non-small cell lung cancer and in the RTOG 0236 study Spinal cord Reference

Lung

Limit

BED

Limit

Oesophagus BED

Limit

Other BED

Limit

e e e 30 Gy/8 fractions %6 Gy/fraction e 21 Gy/3 fractions e e e 30 Gy/10 fractions

e e e 86.3 e 80 94.5 e e e 75

e e e e e e e e V20 minimised e V20 ! 20%

e e e e e e e e e e e

e e e 40 Gy/8 fractions e e e e e e e

e e e 106.7 e e e e e e e

e e e Brachial plexus 37 Gy/8 fractions e e e e e e Central structures 50 Gy/10 fractions

[30]

18 Gy/3 fractions

72

V20 ! 10%

e

27 Gy/3 fractions

108

Ipsilateral brachial plexus 24 Gy/3 fractions Heart, trachea and ipsilateral bronchus 30 Gy/3 fractions

[41] [40] [29] RTOG 0236* [5,37,57,69e77]

e 15 Gy/3 fractions or 20 Gy/5 fractions 26.25 Gy/15 fractions 18 Gy/3 fractions

e e 52.5 or 60 e

e e

49 72

e

*Consensus limits agreed by the study committee.

V20 ! 10%

e 21 Gy/3 fractions or 27.5 Gy/5 fractions 26.25 Gy/15 fractions 27 Gy/3 fractions

e 70 or 78

e e

41.6 Heart 26.25 Gy/15 fractions 108 (if a/b ¼ 3) Ipsilateral brachial plexus 24 Gy/3 fractions Heart, trachea and ipsilateral bronchus 30 Gy/3 fractions

e e e 94 (if a/b ¼ 3) e e e e e e 175 (if a/b ¼ 2) 133.3 (if a/b ¼ 3) 88 (if a/b ¼ 3) 180 (if a/b ¼ 2) 130 (if a/b ¼ 3) e e 49 (if a/b ¼ 2) 88 (if a/b ¼ 3) 180 (if a/b ¼ 2) 130 (if a/b ¼ 3)

CLINICAL ONCOLOGY

[43] [31] [33] [35] [37] [36] [38] [32] [34] [42] [39]

BED

HYPOFRACTIONATED SMALL VOLUME RADIOTHERAPY FOR NSCLC

671

Table 6 e Reported survival, local control and toxicity in 15 published reports of hypofractionated radiotherapy for early-stage non-small cell lung cancer

Reference

n

Median follow-up (months)

[43] [31] [33] [35] [37] [36] [38] [32] [34]

50 22 9 25 37 245 20 49 45

36 24 18 18 15 24 11 e 30

[42] [39] [30] [41] [40] [29] Weighted mean

75 43 22 138 68 32

17 27 8 33 17 21

Actuarial survival at 2 years 77% Estimated as 50% Not evaluable 47% Not evaluable Estimated as 70% 32% 47% 90% stage IA 72% stage IB 45% 78% Not evaluable Estimated as 65% 71% 56% 65%

although consensus has been reached for the purpose of a common study protocol [28]. The impetus for this review was to identify common methodology and to attempt an outcome analysis in relation to some of the technical parameters. The number of technical variables and the range of prognostic factors in patients with NSCLC (e.g. tumour size, location and stage and patient characteristics such as age and co-morbidities) make outcome analysis difficult. However, treatment guidelines should be based on objective technical evaluation and comparison of outcome data in terms of survival, tumour control or toxicity, although this may not be easily achievable.

Tumour Parameters Tumour size and location Most investigators set a maximum tumour diameter at 6 cm, with some advocating treatment of smaller (and very few larger) tumours. Tumour (gross tumour volume [GTV]) and PTV size determine the amount of normal tissue irradiated and will affect the risk of radiation pneumonitis, as is the case for conventional radiotherapy. There is insufficient clinical information available to relate tumour size to toxicity and such data are required from future studies. As with conventional radiotherapy [44e46], tumour size is one Table 7 e Weighted survival by dose per fraction ( R10Gy or !10Gy) Dose/fraction R 10 Gy !10 Gy

No. of patients

2-year survival

262 168

70% 66%

Local progression-free survival at 2 years

Toxicity (symptomatic pneumonitis R grade 2)

Not evaluable Not evaluable 90% Estimated as 85% Not evaluable 87% 92% 85% 97% stage IA 100% stage IB Not evaluable 95% Not evaluable Estimated as 91% 88% Not evaluable 89%

0 0 0 0 19% 7% 3% Not evaluable 4% Estimated as 3% 5% 5% 1% 29% 3% 6.5%

of the determinants of outcome. There were insufficient individual patient data available to carry out such an analysis. Nevertheless, one study of 75 patients treated with SBRT (to 8 Gy per fraction [median] in five fractions over 27 days) reported a median survival of 25.7 months in patients with a GTV ! 65 cm3 and 9.9 months for GTV O 65 cm3 (with respective 5-year survival of 24 and 0%) [42]. There are no clear restrictions on tumour location, but as with conventional radiotherapy, care needs to be taken with OAR doses, particularly when treating central lesions and those close to the spinal cord. The consensus for eligibility for RTOG 0236 is peripheral (only) tumours, T stage 1e3; the protocol does not offer the option to adapt the prescribed dose to doseevolume histograms for central OARs.

Technical Aspects of Treatment The RTOG consensus study describes the following methods of treatment planning and delivery: The three-dimensional coordinates of the tumour isocentre are determined with reference to fiducial markers in a body frame or tomographic images of the tumour in real time. Breathing motion is limited by various techniques, including abdominal compression, gating or ABC. The CTV is defined as the GTV, and a margin of 0.5 cm axially and 1 cm craniocaudally is applied to form the PTV. Treatment is delivered with multiple coplanar or non-coplanar static beams or arcs. If static beams are used, the requirement is for a minimum of seven non-opposing beams. For the purposes of dose planning and calculation of monitor units for actual treatment, correction for tissue heterogeneity is not applied, and all of the following criteria are required: normalisation to a point dose close to the centre of mass

672

CLINICAL ONCOLOGY

corresponding to 100%; 99% of the PTV must receive 90% of the prescription dose; the prescription isodose surface selected should be between 60 and 90% of the centre of mass dose; the cumulative volume of all tissue outside the PTV receiving R 105% of the prescription dose must be %15% of the volume of the PTV; PTV coverage conformality is judged by the ratio of the volume of the prescription isodose meeting the above criteria to the volume of the PTV, and it should ideally be !1.2. This review has compared techniques described for the different stages of treatment planning and delivery in the reviewed studies to determine if there is evidence to support the RTOG consensus study protocol.

Immobilisation and set-up Patient immobilisation is critical in achieving high accuracy of treatment delivery. Analysis of set-up errors using a stereotactic frame with a vacuum pillow combined with daily on-treatment imaging verification showed that correction was required in 25% (20/80) of patients. The mean error in 37 patients treated to 40e48 Gy in four fractions was 4.9 mm [12]. The accuracy of a frameless technique (using treatment room computed tomography, X-ray verification and an abdominal pressure belt if tumour movement exceeded 1 cm cranio-caudally during shallow breathing) of !5 mm [26,47] was comparable with the body frame. Hypofractionated radiotherapy is therefore feasible with patients in the standard treatment position if a local set-up accuracy protocol is followed. The RTOG consensus requires accuracy of set-up, using a body frame or real-time tumour imaging, consistent with most published studies. Patient comfort is also important, as treatment times are longer than for conventional fractionated treatments (20e30 min [48,49]).

Tumour motion and margin determination Tumour motion needs to be taken into account, to accurately target the tumour while keeping doses to adjacent OARs (usually lung) to a minimum. With the techniques in the reviewed studies there remains uncertainty about the actual tumour position during treatment. The integration of respiratory movements into treatment planning using fluoroscopy, slow computed tomography or multiple computed tomography scans was the most commonly used method of dealing with tumour motion; one study used four-dimensional computed tomography-defined mid-ventilatory tumour position [20], which can be used with or without respiratory gating [50]. Other methods for integrating respiratory movements into treatment planning, such as breath-hold techniques, respiratory gating, and tracking [51], may further improve targeting accuracy and allow additional treatment volume reduction. The RTOG consensus does require respiratory motion to be taken into account for treatment planning, and although the recommendation is that this be done with gating or ABC

breath-hold, the use of abdominal compression, now probably an out-dated technique, is permitted. Dose fractionation and radiation delivery The most common dose-fractionation schedules used are 10 Gy per fraction with a total of three fractions (prescribed to the PTV periphery) and 7.5 Gy per fraction with a total of eight fractions (prescribed to the 100% isodose). The RTOG consensus dose of three fractions of 20 Gy per fraction was used in only two studies. Optimum dose fractionation for the SBRT of localised NSCLC has not been defined, with a suggestion that five to 10 fractions may be appropriate in radiobiological terms [52]. In a retrospective review of 245 patients with stage I disease, local control and survival rates were better with a BED R 100 Gy (a/ b for tumour of 10) compared with !100 Gy (respective local recurrence rates 8.1% vs 26.4%, P ! 0.05, and 3-year survival 88.4% vs 69.4%, P ! 0.05) [36]. However, taking into account the duration of treatment and the potential tumour doubling time (Tpot ¼ 5) there was no survival advantage seen with higher BED [42]. We were not able to show a difference in outcome in patients treated with !10 Gy/fraction compared with R 10 Gy/fraction, although the apparent lack of difference may be confounded by different characteristics of the patient populations. Future studies defining the appropriate dose fractionation may be of value. There are limited objective data on the optimum number and arrangement of beams. Target and normal tissue dose distributions are not improved using nine equally spaced beams rather than five to seven beams with optimised angles and intensities for IMRT planning at various tumour sites [53e55]. A planning study using model spherical targets of 2e7 cm diameter in the lung suggested an improved dose gradient using up to 15 beams, and an improved normal tissue complication probability increasing the number of beams from five to nine, with both coplanar and non-coplanar configurations. Nine beams were suggested as the optimum arrangement for lung lesions O2 cm maximum diameter and up to 13 beams for smaller lesions [56]. Optimisation studies assessing the number of beams for SBRT at different sites show that non-coplanar arrangements with six to eight beams [57], 10 beams [58] or six arcs of 120 [35] give the optimum dose distributions. Our optimisation studies for small peripheral lung tumours suggest that five to seven non-coplanar beams may give optimum target coverage while minimising the dose to normal lung tissue (unpublished). Differences in recommended beam arrangement and number may be explained by varying tumour sites (abdominal vs lung malignancies), forward vs inverse planning and optimisation techniques. The RTOG consensus for lung SBRT is to use seven to 10 non-opposing non-coplanar beams. Increasing the number of beams tends to increase the volume of OARs irradiated to a low dose while reducing high-dose exposure and the risk of hot spots within the chest wall or skin. ‘Bathing’ tissues with low-dose radiotherapy may increase the risk of second malignancies [59,60], but this is of limited relevance to an

HYPOFRACTIONATED SMALL VOLUME RADIOTHERAPY FOR NSCLC

older population with poor prognosis disease. The use of a smaller number of optimised beams or arc therapy results in equivalent target coverage with shorter beam delivery times and improved patient comfort. Limiting toxicity to organs at risk OAR tolerance doses derived from 2 Gy per fraction schedules may not translate to altered fractionation schedules if they do not take into account the overall treatment time [61]. Although there are data on the tolerance of the spinal cord [62], the limits for other thoracic organs are less clear. With conventionally fractionated radiotherapy, the risk of pneumonitis correlates with V20 (the percentage of total lung volume exceeding 20 Gy) [63,64], V13, mean lung dose (MLD) and lung Veff (lung-effective volume) [4]. The parameter best predicting pneumonitis using large dose per fraction schedules is not known, although V20 may still be valid [65]. Planning in the RTOG 0236 study accepts marked PTV heterogeneity, with high central doses, in favour of reduced doses to OARs. Although the dose constraints set for the oesophagus and other central structures are consistent with those used in the reviewed studies, the constraints for lung tissue (V20 ! 10%) and spinal cord (BED 72) are more strict. The tolerances of thoracic organs to hypofractionated radiotherapy are important to ascertain. Only one treatment-related death was reported out of 880 patients treated. This was due to a bleeding oesophageal ulcer after treatment for a central tumour to 48 Gy in eight fractions [35]. All other studies reported acceptable toxicity, with no radiation myelitis recorded. As toxicity was assessed in some studies only retrospectively and survival of this cohort is limited, the information on the apparent safety of SBRT should be treated with caution.

Clinical Outcome Local control, survival and toxicity The principal hypothesis of SBRT in localised NSCLC is that combining more targeted delivery with effective dose escalation improves local tumour control and survival. This review of studies published to date suggests that the technique is safe and deliverable, but a direct comparison with surgery and conventionally fractionated threedimensional conformal radiotherapy is not available. The range of outcomes reported will probably reflect patient selection, with varying co-morbidity scores and differences in assessment of local control. The 2-year local control rate (weighted mean) of 89% and survival of 65% from the reported studies after SBRT seems better than the approximate 53% 2-year overall survival after conventional radiotherapy [1] and similar to the 5-year local control rate of 90% and survival of 50e75% after surgery of localised NSCLC [66e68]. Such comparisons are confounded by patient selection, with

673

better prognosis patients selected for more intensive and invasive treatments. Prospective randomised studies comparing SBRT with modern fractionated radiotherapy and with surgery to assess the true benefit of hypofractionation are underway. The reported toxicity in the studies of SBRT, where weighted mean incidence of pneumonitis R grade 2 was 6.5%, is consistent with published data for moderate late radiation pneumonitis after conventionally fractionated radiotherapy in stage I NSCLC (1.9e18%) [1]. Despite a review of the published data, the available information and the range of variables in the different studies make it impossible to correlate technical aspects of treatment with outcome.

Conclusion Small-volume hypofractionated radiotherapy results in favourable disease control and survival in selected patients with early-stage NSCLC and has been postulated to be comparable with surgery. To achieve local control requires tumoricidal doses to be delivered using the optimum method of radiation delivery to recognised normal tissue dose constraints. Although there is consensus on the technique of treatment for the purpose of a multicentre trial, a review of existing published studies suggests the need for more robust studies to define the optimum technical means of radiation delivery and dosefractionation parameters. Ideally technical studies should be supported by biologically and clinically relevant end points. Ultimately, randomised trials will be required to compare some of the undefined parameters, particularly focussing on dose fractionation using optimised techniques of delivery. Ideally, hypofractionated SBRT should be compared with surgery and best conventional radical radiotherapy using appropriate dose escalation, although this may be difficult to achieve. At present it is important to gather standardised clinical outcome data in well-defined patient populations from ongoing phase I/II studies to provide an objective basis for a rational selection of the optimum treatment techniques. Acknowledgements. This work was undertaken in The Royal Marsden NHS Foundation Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, The Royal Marsden NHS Foundation Trust and Cancer Research UK Section of Radiotherapy [CRUK] grant number C46/A2131. Author for correspondence: J. Brock, Academic Unit of Radiotherapy & Oncology, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: þ44-20-8661-3621; Fax: þ44-20-8661-9211; E-mail: [email protected] Received 19 February 2008; received in revised form 12 May 2008; accepted 12 June 2008

674

CLINICAL ONCOLOGY

References 1 Qiao X, Tullgren O, Lax I, Sirzen F, Lewensohn R. The role of radiotherapy in treatment of stage I non-small cell lung cancer. Lung Cancer 2003;41(1):1e11. 2 Narayan S, Henning GT, Ten Haken RK, Sullivan MA, Martel MK, Hayman JA. Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer. Lung Cancer 2004;44(1):79e88. 3 Belderbos JS, Heemsbergen WD, De Jaeger K, Baas P, Lebesque JV. Final results of a phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2006;66(1):126e134. 4 Kong FM, Hayman JA, Griffith KA, et al. Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys 2006;65(4):1075e1086. 5 Hayman JA, Martel MK, Ten Haken RK, et al. Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial. J Clin Oncol 2001; 19(1):127e136. 6 Bradley J, Graham MV, Winter K, et al. Toxicity and outcome results of RTOG 9311: a phase IeII dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 2005;61(2):318e328. 7 Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced nonsmall-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 2005;23(25):5883e5891. 8 Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d’Oncologie ThoraciqueGroupe Francais de Pneumo-Cancerologie NPC 95-01 study. J Clin Oncol 2005;23(25):5910e5917. 9 Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17(9): 2692e2699. 10 Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 2004;46(1):87e98. 11 Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 1997;350(9072):161e165. 12 Nagata Y, Negoro Y, Aoki T, et al. Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2002;52(4):1041e1046. 13 Wulf J, Hadinger U, Oppitz U, Thiele W, Ness-Dourdoumas R, Flentje M. Stereotactic radiotherapy of targets in the lung and liver. Strahlenther Onkol 2001;177(12):645e655. 14 Kim DJ, Murray BR, Halperin R, Roa WH. Held-breath self-gating technique for radiotherapy of non-small-cell lung cancer: a feasibility study. Int J Radiat Oncol Biol Phys 2001;49(1):43e49. 15 Onishi H, Kuriyama K, Komiyama T, et al. CT evaluation of patient deep inspiration self-breath-holding: how precisely can patients reproduce the tumor position in the absence of respiratory monitoring devices? Med Phys 2003;30(6): 1183e1187.

16 Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys 1999;44(4):911e919. 17 Ford EC, Mageras GS, Yorke E, Rosenzweig KE, Wagman R, Ling CC. Evaluation of respiratory movement during gated radiotherapy using film and electronic portal imaging. Int J Radiat Oncol Biol Phys 2002;52(2):522e531. 18 Giraud P, Yorke E, Ford EC, et al. Reduction of organ motion in lung tumors with respiratory gating. Lung Cancer 2006;51(1):41e51. 19 Brown WT, Wu X, Wen BC, et al. Early results of CyberKnife image-guided robotic stereotactic radiosurgery for treatment of lung tumors. Comput Aided Surg 2007;12(5):253e261. 20 Wolthaus JW, Schneider C, Sonke JJ, et al. Mid-ventilation CT scan construction from four-dimensional respiration-correlated CT scans for radiotherapy planning of lung cancer patients. Int J Radiat Oncol Biol Phys 2006;65(5):1560e1571. 21 Guckenberger M, Meyer J, Vordermark D, Baier K, Wilbert J, Flentje M. Magnitude and clinical relevance of translational and rotational patient setup errors: a cone-beam CT study. Int J Radiat Oncol Biol Phys 2006;65(3):934e942. 22 Oelfke U, Tucking T, Nill S, et al. Linac-integrated kV-cone beam CT: technical features and first applications. Med Dosim 2006;31(1):62e70. 23 Purdie TG, Moseley DJ, Bissonnette JP, et al. Respiration correlated cone-beam computed tomography and 4DCT for evaluating target motion in stereotactic lung radiation therapy. Acta Oncol 2006;45(7):915e922. 24 Sidhu K, Ford EC, Spirou S, et al. Optimization of conformal thoracic radiotherapy using cone-beam CT imaging for treatment verification. Int J Radiat Oncol Biol Phys 2003;55(3): 757e767. 25 Onishi H, Kuriyama K, Komiyama T, et al. A new irradiation system for lung cancer combining linear accelerator, computed tomography, patient self-breath-holding, and patient-directed beam-control without respiratory monitoring devices. Int J Radiat Oncol Biol Phys 2003;56(1):14e20. 26 Uematsu M, Shioda A, Suda A, et al. Intrafractional tumor position stability during computed tomography (CT)-guided frameless stereotactic radiation therapy for lung or liver cancers with a fusion of CT and linear accelerator (FOCAL) unit. Int J Radiat Oncol Biol Phys 2000;48(2):443e448. 27 Shirato H, Shimizu S, Kunieda T, et al. Physical aspects of a realtime tumor-tracking system for gated radiotherapy. Int J Radiat Oncol Biol Phys 2000;48(4):1187e1195. 28 Timmerman R, Galvin J, Michalski J, et al. Accreditation and quality assurance for Radiation Therapy Oncology Group: multicenter clinical trials using stereotactic body radiation therapy in lung cancer. Acta Oncol 2006;45(7):779e786. 29 Faria SL, Bezjak A, Purdie TG, et al. Absence of toxicity with hypofractionated 3-dimensional radiation therapy for inoperable, early stage non-small cell lung cancer. Radiat Oncol 2006;1:42. 30 Franks KN, Bezjak A, Purdie TG, et al. Early results of imageguided radiation therapy in lung stereotactic body radiotherapy (SBRT). Clin Oncol (R Coll Radiol) 2007;19(3):S10. 31 Fukumoto S, Shirato H, Shimzu S, et al. Small-volume imageguided radiotherapy using hypofractionated, coplanar, and noncoplanar multiple fields for patients with inoperable stage I nonsmall cell lung carcinomas. Cancer 2002;95(7): 1546e1553. 32 Hoyer M. Prospective study on stereotactic radiotherapy of limited stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2005;63(2S):S396. 33 Lee SW, Choi EK, Park HJ, et al. Stereotactic body frame based fractionated radiosurgery on consecutive days for primary or

HYPOFRACTIONATED SMALL VOLUME RADIOTHERAPY FOR NSCLC

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

metastatic tumors in the lung. Lung Cancer 2003;40(3): 309e315. Nagata Y, Takayama K, Matsuo Y, 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(5):1427e1431. Onimaru R, Shirato H, Shimizu 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(1):126e135. Onishi H, Araki T, Shirato H, 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(7):1623e1631. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 2003;124(5):1946e1955. Wulf J, Haedinger U, Oppitz U, Thiele W, Mueller G, Flentje M. Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients. Int J Radiat Oncol Biol Phys 2004; 60(1):186e196. Xia T, Li H, Sun Q, et al. Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable stage I/II nonsmall-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;66(1): 117e125. Zimmermann FB, Geinitz H, Schill S, et al. Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) nonsmall-cell lung cancer (NSCLC). Acta Oncol 2006;45(7):796e801. Baumann P, Nyman J, Lax I, et al. Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries. Acta Oncol 2006;45(7):787e795. Beitler JJ, Badine EA, El-Sayah D, et al. Stereotactic body radiation therapy for nonmetastatic lung cancer: an analysis of 75 patients treated over 5 years. Int J Radiat Oncol Biol Phys 2006;65(1):100e106. Uematsu M, Shioda A, Suda A, et al. Computed tomographyguided frameless stereotactic radiotherapy for stage I non-small cell lung cancer: a 5-year experience. Int J Radiat Oncol Biol Phys 2001;51(3):666e670. Fang LC, Komaki R, Allen P, Guerrero T, Mohan R, Cox JD. Comparison of outcomes for patients with medically inoperable stage I non-small-cell lung cancer treated with two-dimensional vs. three-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 2006;66(1):108e116. Martel MK, Strawderman M, Hazuka MB, Turrisi AT, Fraass BA, Lichter AS. Volume and dose parameters for survival of nonsmall cell lung cancer patients. Radiother Oncol 1997;44(1): 23e29. Gauden S, Ramsay J, Tripcony L. The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung. Chest 1995;108(5):1278e1282. Uematsu M, Sonderegger M, Shioda A, et al. Daily positioning accuracy of frameless stereotactic radiation therapy with a fusion of computed tomography and linear accelerator (focal) unit: evaluation of z-axis with a z-marker. Radiother Oncol 1999;50(3):337e339. Uematsu M, Shioda A, Tahara K, et al. Focal, high dose, and fractionated modified stereotactic radiation therapy for lung carcinoma patients: a preliminary experience. Cancer 1998; 82(6):1062e1070.

675

49 Nyman J, Johansson KA, Hulten U. Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancerdmature results for medically inoperable patients. Lung Cancer 2006; 51(1):97e103. 50 Underberg RW, Lagerwaard FJ, Slotman BJ, Cuijpers JP, Senan S. Benefit of respiration-gated stereotactic radiotherapy for stage I lung cancer: an analysis of 4dct datasets. Int J Radiat Oncol Biol Phys 2005;62(2):554e560. 51 Giraud P, Yorke E, Jiang S, Simon L, Rosenzweig K, Mageras G. Reduction of organ motion effects in IMRT and conformal 3D radiation delivery by using gating and tracking techniques. Cancer Radiother 2006;10(5):269e282. 52 Ruggieri R. Hypofractionation in non-small cell lung cancer (NSCLC): suggestions from modelling both acute and chronic hypoxia. Phys Med Biol 2004;49(20):4811e4823. 53 Bortfeld T, Schlegel W. Optimization of beam orientations in radiation therapy: some theoretical considerations. Phys Med Biol 1993;38(2):291e304. 54 Das S, Cullip T, Tracton G, et al. Beam orientation selection for intensity-modulated radiation therapy based on target equivalent uniform dose maximization. Int J Radiat Oncol Biol Phys 2003;55(1):215e224. 55 D’Souza WD, Meyer RR, Shi L. Selection of beam orientations in intensity-modulated radiation therapy using single-beam indices and integer programming. Phys Med Biol 2004;49(15): 3465e3481. 56 Liu R, Buatti JM, Howes TL, Dill J, Modrick JM, Meeks SL. Optimal number of beams for stereotactic body radiotherapy of lung and liver lesions. Int J Radiat Oncol Biol Phys 2006;66(3): 906e912. 57 Lax I, Blomgren H, Naslund I, Svanstrom R. Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol 1994;33(6):677e683. 58 de Pooter JA, Mendez Romero A, Jansen WP, et al. Computer optimization of noncoplanar beam setups improves stereotactic treatment of liver tumors. Int J Radiat Oncol Biol Phys 2006; 66(3):913e922. 59 Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56(1): 83e88. 60 Kry SF, Salehpour M, Followill DS, et al. The calculated risk of fatal secondary malignancies from intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2005;62(4): 1195e1203. 61 Guerrero M, Li XA. Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy. Phys Med Biol 2004;49(20):4825e4835. 62 Macbeth FR, Wheldon TE, Girling DJ, et al. Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol) 1996;8(3):176e181. 63 Graham MV, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1999;45(2):323e329. 64 Claude L, Perol D, Ginestet C, et al. A prospective study on radiation pneumonitis following conformal radiation therapy in non-small-cell lung cancer: clinical and dosimetric factors analysis. Radiother Oncol 2004;71(2):175e181. 65 Clenton SJ, Fisher PM, Conway J, Kirkbride P, Hatton MQ. The use of lung dose-volume histograms in predicting post-radiation pneumonitis after non-conventionally fractionated radiotherapy

676

66 67

68

69 70

71

CLINICAL ONCOLOGY

for thoracic carcinoma. Clin Oncol (R Coll Radiol) 2005;17(8): 599e603. Chang MY, Sugarbaker DJ. Surgery for early stage non-small cell lung cancer. Semin Surg Oncol 2003;21(2):74e84. Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109(1):120e129. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988;96(3):440e447. Blomgren H. Radiosurgery for tumors in the body: clinical experience using a new method. J Radiosurgery 1998;1(1):63e74. Blomgren H, Lax I, Naslund I, Svanstrom R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol 1995;34(6):861e870. Bradley JD, Graham MV, Winter K. Acute and late toxicity results of RTOG 9311: A dose escalation study using conformal radiation therapy in patients with inoperable non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2003;57(2 Suppl): S137eS138.

72 Cardenes H, Timmerman R, Papiez L. Extracranial stereotactic radioablation: Review of biological basis, technique and preliminary clinical experience. Oncologia 2002;23(4): 193e199. 73 Curran Jr WJ, Moldofsky PJ, Solin LJ. Analysis of the influence of elective nodal irradiation on postirradiation pulmonary function. Cancer 1990;65(11):2488e2493. 74 Krol AD, Aussems P, Noordijk EM, Hermans J, Leer JW. Local irradiation alone for peripheral stage I lung cancer: Could we omit the elective regional nodal irradiation? Int J Radiat Oncol Biol Phys 1996;34(2):297e302. 75 Robertson JM, Ten Haken RK, Hazuka MB, et al. Dose escalation for non-small cell lung cancer using conformal radiation therapy. Int J Radiat Oncol Biol Phys 1997;37(5):1079e1085. 76 Slotman BJ, Antonisse IE, Njo KH. Limited field irradiation in early stage (T1-2N0) non-small cell lung cancer. Radiother Oncol 1996;41(1):41e44. 77 Williams TE, Thomas Jr CR, Turrisi III AT. Counterpoint: better radiation treatment of non-small cell lung cancer using new techniques without elective nodal irradiation. Semin Radiat Oncol 2000;10(4):315e323.