Respiratory Gating Techniques for Optimization of Lung Cancer Radiotherapy

ORIGINAL ARTICLE

Respiratory Gating Techniques for Optimization of Lung Cancer Radiotherapy Philippe Giraud, MD, PhD,*† Esra Morvan, PhD,† Line Claude, MD,‡ Franc¸oise Mornex, MD, PhD,§ Ce´cile Le Pechoux, MD,储 Jean-Marc Bachaud, MD,¶ Pierre Boisselier, MD,# Ve´ronique Beckendorf, MD,** Magali Morelle, MD,†† Marie-Odile Carre`re, MD, PhD,†† and The STIC Study Centers

Purpose: The primary objective of the STIC 2003 project was to compare the clinical and economic aspects of respiratory-gated conformal radiotherapy (RGRT), an innovative technique proposed to limit the impact of respiratory movements during irradiation, versus conventional conformal radiotherapy, the reference radiation therapy for lung cancer. Methods and Materials: A comparative, nonrandomized, multicenter, and prospective cost toxicity analysis was performed in the context of this project between April 2004 and June 2008 in 20 French centers. Only the results of the clinical study are presented here, as the results of the economic assessment have been published previously. Results: The final results based on 401 evaluable patients confirm the feasibility and good reproducibility of the various RGRT systems. The results of this study demonstrated a marked reduction of dosimetric parameters predictive of pulmonary, cardiac and esophageal toxicity as a result of the various respiratory gating techniques. These dosimetric benefits were mainly observed with deep inspiration breath-hold (DIBH) techniques (ABC and SDX systems), which markedly increased the total lung volume compared with the inspiration-synchronized system based on tidal volume (Real-time Position Management). These theoretical dosimetric benefits were correlated clinically with a significant reduction of pulmonary acute toxicity, and the pulmonary, cardiac, and esophageal late toxicities, *Department of Radiation Oncology, Paris Descartes University, Sorbonne Paris Cité, Hoˆpital Europe´en Georges Pompidou, Paris, France; †Department of Radiation Oncology, Institut Curie, Paris, France; ‡Department of Radiation Oncology, Centre Le´on Be´rard, Lyon, France; §Department of Radiation Oncology, Hospices Civils de Lyon, Lyon, France; 储Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France; ¶Department of Radiation Oncology, Institut Claudius Regaud, Toulouse, France; #Department of Radiation Oncology, Centre Val D’Aurelle, Montpellier, France; **Department of Radiation Oncology, Centre Alexis Vautrin, Nancy, France; and ††GATE UMR CNRS 5824, Centre Le´on Be´rard, Lyon, France. Disclosure: The authors declare no conflicts of interest. Presented at the 52nd Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), San Diego, CA, October 31–November 4, 2010. Address for correspondence: Philippe Giraud, MD, PhD, Service d’Oncologie Radiothe´rapie, Hoˆpital Europe´en Georges Pompidou, 20, rue Leblanc, 75015 Paris. E-mail: [email protected] Copyright © 2011 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/11/0612-2058

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especially with DIBH techniques. Pulmonary function parameters, although more heterogeneous, especially DLCO, showed a tendency to reduction of pulmonary toxicity in the RGRT group. Conclusions: RGRT seems to be essential to reduce toxicities, especially the pulmonary, cardiac, and esophageal late toxicities with the DIBH methods. Key Words: Non-small cell lung cancer, Respiratory gating, Breath-hold techniques, Toxicities. (J Thorac Oncol. 2011;6: 2058–2068)

A

dapting radiotherapy to respiratory movements has always been a major concern in chest radiotherapy. The importance of this aspect has been further accentuated with the development of conformal radiotherapy (CRT), with and without intensity modulation, using reduced irradiation fields, and especially the growing interest in stereotactic hypofractionated radiotherapy.1 These new techniques were developed very rapidly in the 1990s as a result of progress in information technology, but the various uncertainties of treatment, especially related to respiratory movements, were not studied in detail. Radiotherapists rapidly had to make a number of choices. In the absence of precise data, they incorporated empirical safety margins of 1.5 to 2 cm derived from conventional radiotherapy.2– 4 Nevertheless, the development of these high-precision strategies, which potentially allow dose escalation to the lung tumor volume, consequently makes respiratory movements of the order of 1 cm unacceptable.4,5 The diffusion of respiratory gating (or breathing adapted) techniques therefore constitutes a priority to improve the quality and the results of radiotherapy.6 In 2003, a medicoeconomic assessment of the various breathing adapted radiotherapy methods for the treatment of lung cancers was conducted in the context of a project funded by the French Ministry of Health, entitled Programme de Soutien aux Innovations Diagnostiques et The´rapeutiques Couˆteuses (STIC) (Expensive Diagnostic and Therapeutic Innovation Support Program). Twenty radiotherapy departments from all over France, specialized in the treatment of lung cancer, participated in this joint project to guide decision makers and to provide precise data for or against the diffusion of this innovation by comparing it with standard treatment,

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Respiratory Gating Techniques for Lung Cancer

conventional CRT without respiratory gating. This study was initiated in April 2004 according to a nonrandomized design, but this does not constitute a limitation, as this study was based on a pragmatic approach. At the end of the recruitment phase, 401 patients were included: 218 patients in the respiratory-gated radiotherapy group (RGRT) and 183 in the reference group (CRT). This is the largest study to date evaluating the various breathing adapted radiotherapy techniques to optimize irradiation of lung cancers. This article presents the general methodology of the project, setting up of the study, and the results of the clinical study 48 months after starting recruitment; as the results of the economic study have already been published in a specialized journal.7,8

PATIENTS AND METHODS Patients This multicenter study was conducted in 13 French cancer centers, six teaching hospitals and one nonprofit private clinic. All patients were referred for non-small cell lung cancer (NSCLC). The medical chart review process was submitted to and approved by the ethical review board. Patient inclusion criteria were as follows: histologically documented NSCLC, with or without lung resection, requiring curative irradiation; no contraindication to thoracomediastinal irradiation; satisfactory performance status (WHO score ⱕ2); chemotherapy, especially concomitant chemotherapy, was authorized; age ⱖ18 years; forced expiratory volume in 1 second (FEV1) ⬎1 L (or 40% of predicted) on baseline pulmonary function tests (PFTs); absence of superior vena cava syndrome or major pericardial effusion; and satisfactory compliance with follow-up.

FIGURE 1. Patient in the treatment position with the SDX spirometric device and diagram of the breathing curve (red) visualized by the patient with the video glasses and by the operator. The patient visualizes the time course of lung volume (red) and the degree of breath-hold (green zone) determined during a training session. After three FB cycles, the patient is asked to achieve and maintain this DIBH level (plateau phase of the red curve). CT acquisition or irradiation is performed during this phase.

Materials and Methods Materials Three respiratory gating devices were tested: the Realtime Position Management system (RPM; Varian Medical Systems, Palo Alto); and two spirometric breath-holding devices, the ABC active breath-holding system (Active Breathing Control, Elekta, Stockholm, Sweden), and the SDX deep inspiration breath-hold (DIBH) system (Dyn’R, Toulouse, France; Fig. 1). The RPM system monitors the patient’s respiratory cycle by means of a small plastic block placed on the patient’s abdomen onto which two reflective markers are fixed. These reflective markers reflect the light of an infrared beam onto a charge-coupled device camera placed in a fixed position in relation to the patient and connected to a computer, in turn connected to the linear accelerator (Fig. 2). Movement of the reflectors during breathing is analyzed in real time by software that controls triggering of the accelerator according to a predefined gate.9,10,11 Spirometric breath-hold systems are based on a similar strategy and consist of blocking the patient’s breathing, usually in inspiration, during acquisition, or irradiation, either voluntarily (SDX) or by occlusion of a valve (ABC). These two techniques require a preparation phase to define the most comfortable degree of inspiration for the patient and the optimal breath-hold for treatment. This level usually corresponds to 70% or 80% of the patient’s maximum inspiration

FIGURE 2. The RPM system. An infrared camera illuminates a marker placed on the patient’s abdomen, onto which two reflectors are fixed.

with a safety margin of ⫾100 ml. These systems were the first to be used routinely, and the original method was initially proposed by the Memorial Sloan Kettering Cancer Center team.12–17

Methodology Three computed tomography (CT) acquisitions were performed in each patient: the first two CT acquisitions were performed with the DIBH device and the RPM system (4DCT) to quantify the interbreath-hold variability and therefore the reproducibility of the device, and a final acquisition

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was performed in free breathing (FB). An injection of contrast agent was performed during the FB acquisition to facilitate delineation of target volumes. Target volumes were defined according to International Commission on Radiation Units and Measurements recommendations.18 The clinical target volume (CTV) corresponded to the gross target volume ⫹ 8 mm (adenocarcinoma) or ⫹ 6 mm (squamous cell carcinoma) or ⫹ 5 mm (other histologies).19 The internal target volume (ITV) for the RGRT group corresponded to the CTV ⫹ intra-RGRT variability; the intra-RGRT variability was obtained after fusion of the two DIBH acquisitions by combining the two CTVs. The setup margin added a 2-mm safety margin to the ITV, resulting in the final planning target volume (PTV; Figure 3). The total dose to the PTV had to be situated between 65 and 70 Gy (1.8 and 2.2 Gy per fraction) with a homogeneity of ⫹7%/⫺5%. Dose constraints were as follows: maximum dose (Dmax) to the spinal cord: 45 Gy; volume of the two lungs minus PTV receiving a dose of at least 20 Gy (V20): less than 37% (V20⬍37%); and volume of esophagus receiving a dose of at least 50 Gy (V50): less than 35% (V50⬍35%). For the CRT group, ITV corresponded to CTV ⫹ 3 mm for an upper or middle lobe tumor and CTV ⫹ 8 mm for a lower lobe tumor, and the setup margin corresponded to ITV ⫹ 2 mm. The daily reproducibility was assessed by electronic portals acquisitions performed for all patients according to the following protocol: the first 3 days and then twice a week until the end of radiation. The tolerance limits were 3 mm in all planes. The anatomical lines of reference were as follows: The trachea and carina, the two clavicles, the two pulmonary apices, and the vertebral column for the anteroposterior images. The trachea, the two pulmonary apices, the vertebral column, and the posterior chest wall for the lateral images.

Common Quality Assurance Program The 20 participating institutions developed common procedures to standardize quality assurance and all quality

controls during the various steps of respiratory gating techniques.20

Endpoints The first step of this study consisted of verifying that the various RGRT devices were reliable and reproducible. For this purpose, data of the two acquisitions performed with one of the RGRT systems were compared. Analysis of CTV reflects reproducibility of the systems in terms of the tumor and would seem to be the most relevant, because it is directly related to the precision and reproducibility objectives of RGRT. Nevertheless, the results of this analysis are highly dependent on contouring uncertainties. Total lung volume (TLV), usually estimated by automatic lung contouring, was also tested, as it is probably more representative of the reproducibility of RGRT techniques. All patients were regularly evaluated according to objective and standardized criteria and methods of clinical evaluation. For all patients, the initial staging included a chest and upper abdomen CT scan, a CT scan and/or an magnetic resonance imaging of the brain, and a PET scan. In addition, the specific evaluation for this study consisted of physical examination, chest x-ray, PFT with plethysmography and determination of the diffusing capacity of the lung for carbon monoxide (DLCO), and chest CT scan at baseline and then at 3, 6, 12, 18, and 24 months. Safety was the major end point evaluated according to common parameters and scales in all 20 institutions: Radiation Therapy Oncology Group classification for evaluation of acute toxicity and Late effects of Normal Tissues (Subjective, Objective, Management, Analytic) classification for evaluation of late toxicity (esophagus, lung, and heart), PFT results, and the rate of grade ⬎2 radiation pneumonitis. Only the highest grade in each category of the Radiation Therapy Oncology Group and Late effects of Normal Tissues (Subjective, Objective, Management, Analytic) classifications was recorded at each evaluation for each organ analyzed.21,22 The other endpoints were as follows: Clinical endpoints: local control (RECIST criteria), recurrence-free survival, and overall survival. Dosimetric endpoints: mean dose (Dmean), minimum dose (Dmin), maximum dose (Dmax), dose to 95% and 5% of the volume (D95 and D05) in PTV; calculation of lung V20, V25, V37, and Dmean; cardiac Dmean, Dmax, and V40; and esophageal V50, EL50, EL60 (length of esophagus receiving a dose of 50 Gy and 60 Gy, respectively), Dmean and Dmax.

Statistical Analysis

FIGURE 3. Target volumes in axial (A), coronal (B), sagittal (C), and 3D views defined according to the protocol recommendations: GTV (red), CTV (blue), ITV (green), and set-up margin (yellow).

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Statistical analysis was performed by R software R.23 Descriptive data analysis was performed. Qualitative variables were described by sample sizes and corresponding percentages, and quantitative variables were described by their mean, median, and standard deviation. In bivariate analyses, qualitative variables were studied by ␹2 test or Fisher’s exact test, and quantitative variables were studied by Student t test or Kruskal-Wallis test, as appropriate. Quantitative variables for which two successive measures were available were analyzed by a concordance test. Survival

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curves were estimated by the Kaplan-Meier method and were compared by the log-rank test. PFT parameters (TLV, DLCO, and FEV1) were expressed as a percentage of the difference between the posttreatment value and the baseline value over the baseline value. Results were considered to be significant for p ⬍ 0.05.

RESULTS Four hundred one patients were included in the study. Table 1 shows patient characteristics in the two treatment groups. The median age was 65 years (range, 57– 87 years). The histology most frequently encountered was squamous cell carcinoma (49%) followed by adenocarcinoma (34%). Tumors were mostly located in the right lung (62%) and in the upper lobe (62%). In terms of TNM stage, most tumors were stage T2-T3 (63%) and N2 (44%). Neoadjuvant chemotherapy had been administered before radiotherapy in 69% of cases. Concomitant chemotherapy was proposed in 49% of cases. Three hundred eighty patients (94.7%) were smokers or ex-smokers before the diagnosis of lung cancer and 95% of smokers continued smoking during radiotherapy. The median follow-up was 25 months (range, 0 –39 months). Forty-five percent of patients were treated by CRT (183) and 55% were treated by RGRT (218). Among the various respiratory gating systems used, 78% of patients included in the RGRT group were treated with the SDX, 15% with the ABC, and 7% with the RPM systems. Fifty-five per cent of patients were treated with an arm support (arm above the head) and alpha cradle immobilization. The majority of patients (65%) were irradiated with a photon beam with a maximum energy greater than 18 MV. The median prescribed dose was 66 Gy (range, 6 –79 Gy) over a median duration of 50 days (range, 4 –79 days). The RGRT group comprised more patients with respiratory failure than the CRT group (68 versus 32%, p ⫽ 0.02). Nevertheless, no difference was observed in terms of FEV1 and VC. As this study was not randomized, the investigators naturally included patients with more severe respiratory failure in the RGRT group. Similarly, the RGRT group comprised significantly more patients with T1/T2 tumors than the CRT group (56% versus 40%, p ⫽ 0.006), resulting in a larger proportion of small tumors, potentially more mobile with breathing, in the RGRT group. No difference in terms of N stage was observed between the two groups. All the classic parameters such as T and N stage, previous history, smoking status, and especially tumor location (localization on lobe) have been tested and did not show up as significant factors for acute and late toxicities and efficacy.

Feasibility Compliance Eighty-eight percent of patients scheduled to receive RGRT were treated with this technique. Twenty-one patients initially scheduled to receive RGRT were finally treated with FB. These changes were because of an insufficient respiratory capacity to use a breath-hold system (ABC or SDX) in 12 patients, very poor performance status in two patients, and

TABLE 1.

Respiratory Gating Techniques for Lung Cancer

Patient Characteristics

Characteristics Age Median Range Gender Male Female Histology SCC ADC Other Affected side RUL RML RLL LUL LLL TNM stage T1 T2 T3 T4 Tx N0 N1 N2 N3 Smoking Ex-smokers Current smokers Respiratory insufficiency Yes Chemotherapy Neoadjuvant Concomitant Radiotherapy Type SDX ABC RPM WHO performance status 0 1 2

All

CRT

RGRT

p

65 57–87

67 42–86

64 33–87

NS

334 67

154 29

180 38

NS

198 138 65

90 60 33

108 78 32

NS

151 24 70 106 50

71 7 39 52 14

80 17 31 54 36

NS

46 143 103 85 24 111 24 184 82

12 59 55 44 13 45 9 88 41

34 84 48 41 11 66 15 96 41

0.006

380 361

174 166

206 195

NS

207

59

148

0.02

275 197

137 97

138 100

NS

401

183

218 171 32 15

190 168 43

82 68 33

108 100 10

NS

NS

NS, not significant; p, difference between RGRT and CRT.

poor understanding of the breath-hold technique in seven patients.

Analysis of the Reproducibility of Respiratory Gating Systems An excellent correlation was observed between the two respiratory-gated CT acquisitions for CTV and TLV. These results confirm theoretical studies conducted by the quality assurance group on various phantoms.24 This correlation between the two respiratory-gated CT acquisitions allowed

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FIGURE 4. Correlation curves between two consecutive respiratorygated CT acquisitions with (A) all respiratory gating devices and (B) for the three devices separately analyzed for CTV and TLV. TABLE 2.

Dosimetric Parameters

Volumes PTV Volume (cm3) Dmax (Gy) Dmean (Gy) D95 (Gy) D5 (Gy) Lungs Volume (cm3) V20 (%) V25 (%) V37 (%) Dmean (Gy) Heart Volume (cm3) V40 (%) Dmax (Gy) Dmean (Gy) Esophagus EL50 (cm) EL60 (cm) V50 (%) Dmax (Gy) Dmean (Gy)

CRT

RGRT

p

360 ⫾ 229 70.1 ⫾ 5.7 58.5 ⫾ 7.6 60.1 ⫾ 36.1 63.9 ⫾ 11.8

282 ⫾ 176 69.9 ⫾ 5.6 57.8 ⫾ 6.9 61.0 ⫾ 9.9 64.5 ⫾ 8.9

⬍0.00001 NS NS ⬍0.0001 ⬍0.001

3949 ⫾ 1272 26.5 ⫾ 12.5 23.2 ⫾ 10.8 15.1 ⫾ 8.1 15.6 ⫾ 7.7

5371 ⫾ 1485 22.8 ⫾ 9.6 18.8 ⫾ 8.2 11.8 ⫾ 5.7 12.8 ⫾ 5.1

⬍0.00001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001

697 ⫾ 190 11.5 ⫾ 13.7 55.3 ⫾ 21.8 13.1 ⫾ 10.3

638 ⫾ 171 8.1 ⫾ 10.6 51.5 ⫾ 23.5 10.9 ⫾ 9.2

⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001

7.1 ⫾ 4.7 5.8 ⫾ 4.4 25.5 ⫾ 20.4 59.1 ⫾ 17.4 24.4 ⫾ 12.2

6.6 ⫾ 4.6 5.4 ⫾ 5.2 22.6 ⫾ 18.3 58.4 ⫾ 18.1 22.5 ⫾ 11.3

⬍0.0001 ⬍0.001 ⬍0.0001 ⬍0.0001 ⬍0.0001

NS, not significant; p, difference between RGRT and CRT.

comparison of dosimetric parameters measured in CRT with the mean parameters measured during the two respiratorygated acquisitions. Individual analysis of the three devices used in this study showed a good concordance between the measured CTV values and TLV during two respiratory-gated acquisitions (Figure 4). Nevertheless, absolute values of the corre-

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lation coefficients for the two breath-hold systems (ABC and SDX) were better than for RPM, but this difference is difficult to interpret in view of the small number of patients treated by RPM.

Analysis of Dosimetric Data Tumor Target Volumes CTV were comparable in CRT and in RGRT. Nevertheless, as a result of the protocol, ITV and PTV were significantly smaller in the RGRT group. The difference in PTV between RGRT and CRT was 282 ⫾ 176 ml versus 360 ⫾ 232 ml, respectively (p ⬍ 0.00001). The dosimetric coverage of CTV and PTV tumor-target volumes was comparable with the two modes of radiotherapy. Nevertheless, differences in mean values of PTV D95 and D5 were significantly higher in the RGRT (Table 2).

Lungs TLV was significantly greater during DIBH acquisitions (mean of ⫹1421 ml, 5371 ⫾ 1485 ml versus 3949 ⫾ 1272 ml, p ⬍ 0.00001). This marked increase of healthy lung volume because of inflation by the various DIBH techniques resulted in a significant reduction of the following dosimetric parameters: V20 (22.8% versus 26.5%, p ⬍ 0.0001), V25 (18.8% versus 23.2%, p ⬍ 0.0001), V37 (11.8% versus 15.1%, p ⬍ 0.0001), Dmax (69 Gy versus 70 Gy, p ⫽ 0.04), and Dmean (12.8 Gy versus 15.6 Gy, p ⬍ 0.0001) between RGRT and CRT, respectively (Table 2, Figure 5).

Heart Total heart volume was significantly different according to the mode of irradiation: 638 ⫾ 171 ml versus 697 ⫾ 190 mL in RGRT and CRT, respectively (p ⬍ 0.0001). This reduction of heart volume observed in the RGRT group can be explained by relative compression of the heart by the two

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FIGURE 5. Comparison of TLV distribution and of the lung volume receiving a dose of at least 25 Gy (V25) according to the respiratory gating technique: with (RGRT) or without (CRT) respiratory gating.

FIGURE 6. Comparison of distributions of the Cardiac Dmax and V40 between a radiotherapy technique with (RGRT) or without (CRT) respiratory gating.

lungs in DIBH. Dmax, Dmean, and V40 were significantly lower in the RGRT group (Table 2, Figure 6).

Esophagus Dmax and Dmean were significantly higher in the CRT group than in the RGRT group: 59.1 ⫾ 17.4 Gy versus 58.4 ⫾ 18.1 Gy (p ⬍ 0.0001) and 24.4 ⫾ 12.2 Gy versus 22.5 ⫾ 11.3 Gy (p ⬍ 0.0001), respectively. The other dosimetric parameters measured were also lower in the RGRT group (Table 2).

Toxicity Acute Toxicity Overall, 74% of patients experienced at least one form of clinical toxicity, usually esophagitis (65%); 34% of patients experienced pulmonary toxicity, 26% experienced cutaneous toxicity, and 1.7% experienced cardiac toxicity. No significant difference was observed in terms of acute toxicity between the two groups except for pulmonary toxicity, which was more frequent in the CRT group than in the RGRT group (48% versus 36%, p ⫽ 0.02). No significant difference was observed in terms of grade. The other cutaneous, esophageal, and cardiac toxicities were identical in the two groups (Table 3).

Late Toxicity In the overall population, clinical pulmonary toxicity decreased regularly throughout follow-up with a peak incidence at the 3-month and 6-month assessments (Table 3). Overall, 61% of patients did not experience any pulmonary toxicity. PFTs performed after 24 months of follow-up showed a marked reduction of DLCO (median, ⫺37%) and a less marked reduction of FEV1 (median, ⫺12.5%) and TLV (median, ⫺10.4%) in the overall population. Cardiac and esophageal toxicity is described in detail in Table 3. At the 3-month assessment, the only significant between-group differences concerned the number of hospitalizations (CRT: 24% versus RGRT: 14%, p ⫽ 0.01) and the number of consultations (CRT: 67% versus RGRT: 56%, p ⫽ 0.04). From the 6th month onward, the incidence of grade ⱖ3 toxicity was higher in the CRT group than in the RGRT group (9% versus 6%, p ⫽ 0.03). A significant difference in the esophageal toxicity was also observed between the two groups with 2.7% in the RGRT group versus 7% in the CRT group. No significant difference in terms of toxicity was observed between the two groups at the following assessments. Analysis of PFT parameters did not reveal any significant difference between the two groups at the various as-

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TABLE 3.

Acute and Late Toxicities

Organs Lungs

Date Acute 6th mo 12th mo 24th mo

PFT (difference between pretests in %)

6th mo

12th mo

24th mo

Heart

Acute 6th mo 12th mo 24th mo

Esophagus

Acute 6th mo 12th mo 24th mo

Grades

CRT (%), n ⴝ 183

RGRT (%), n ⴝ 218

p

Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 FEV1 DLCO TLV FEV1 DLCO TLV FEV1 DLCO TLV Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4

85 (46) 3 (1.6) 43 (23) 17 (9) 30 (16) 7 (3.8) 15 (8) 5 (2.7) ⫺7.3 ⫾ 20.7 ⫺16.6 ⫾ 38.6 ⫺9.3 ⫾ 15.4 ⫺7.1 ⫾ 27.4 20.5 ⫾ 178.1 ⫺8.8 ⫾ 16.9 ⫺13.8 ⫾ 19.6 ⫺66.8 ⫾ 21.8 ⫺7.9 ⫾ 15.5 4 (2.1) 0 0 0 2 (1.1) 0 1 (0.5) 0 118 (64.5) 6 (3.2) 12 (5.5) 1 (0.5) 0 0 0 0

74 (34) 5 (2.2) 51 (23) 13 (6) 35 (16) 11 (5) 20 (9) 4 (1.8) 26.3 ⫾ 268.1 26.1 ⫾ 148.4 36.9 ⫾ 240.4 ⫺4.8 ⫾ 25.2 4.6 ⫾ 124.4 ⫺8.3 ⫾ 20.2 ⫺3.6 ⫾ 21.3 ⫺17.3 ⫾ 66.2 ⫺1.5 ⫾ 35.7 3 (1.3) 0 2 (0.9) 0 2 (0.9) 1 (0.4) 0 0 128 (58.7) 11 (5) 6 (3.2) 0 2 (0.9) 0 0 0

0.02 0.03 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.04 NS NS

NS, not significant; p, difference between RGRT and CRT.

sessments. Nevertheless, a tendency to deterioration of DLCO, FEV1, and TLV was observed at the 24th month in the CRT group (Table 3).

Efficacy After a median follow-up of 26 months (range, 1– 47 months), 169 patients were alive (43%), 14 had been lost to follow-up (4%), and 208 patients had died (53%). A total of 244 patients (64%) experienced disease progression after radiotherapy. One hundred fifty-eight (43%) of these patients developed metastatic disease and 34% developed local recurrence, in irradiation fields in 94 cases (88%) and outside of irradiation fields in 12% of cases. Twenty-seven percent of patients experienced synchronous metastatic and local progression. Among the causes of death, 159 patients (76%) died of lung cancer, 13% died of intercurrent infection, and 11% died of another cause or an unknown cause. The majority of cases of disease progression occurred during the first year (90%). Local recurrences predominantly occurred between the 3rd and 12th months with no difference in the distribution

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between recurrences inside and outside of irradiation fields. Metastatic disease progression was mainly observed during the first year (78%), especially during the first 6 months (62%). Figure 7 presents overall survival and specific survival curves, disease-free interval, and metastasis-free interval in the overall population treated for lung cancer. No significant difference of efficacy was observed between the two groups in terms of overall survival, specific survival, or disease-free interval.

Comparison of the Three Respiratory Gating Techniques The three groups were strictly comparable except in terms of tumor size, with significantly more T1/T2 tumors in the RPM group than in the SDX and ABC groups (73% versus 58.1% versus 25.4%, p ⫽ 0.02). Patients treated with one of the DIBH techniques had lower FEV1 and VC values than patients in the RPM group. These findings confirm the selective inclusion of patients with more severe respiratory

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FIGURE 7. Overall (A) and disease-free (B) survival (log-rank test) according to the radiotherapy technique with (RGRT) or without (FB) respiratory gating.

failure and more advanced tumors in the ABC and SDX DIBH groups.

techniques accentuated the differences observed between the various systems (Table 4).

Analysis of Dosimetric Data

For the lungs, a significant reduction of all dosimetric parameters predictive of pulmonary toxicity was observed with DIBH systems. For the heart, a significant difference was demonstrated in terms of potential cardiac toxicity. For the esophagus, the same tendency was confirmed and was statistically significant after combining the ABC and SDX groups, i.e., a reduction of Dmax, Dmean, and V50.

As expected, TLV was significantly greater on acquisitions using a DIBH system (ABC and SDX) than on acquisitions using the inspiration-synchronized system (RPM; mean, ⫹2400 mL; ABC: 5510 ⫾ 1064 mL versus SDX: 5540 ⫾ 1426 mL versus RPM: 3106 ⫾ 602 mL; p ⬍ 0.00001). This increase of TLV resulted in a significant reduction of V20 and V25 between the SDX and ABC systems versus the RPM system (Figure 8). A tendency to reduction of Dmean and V37 was also observed. No significant difference of dosimetric parameters was observed for the heart and esophagus (Table 4). Despite a different stage distribution between the three groups on inclusion, CTV and PTV were not significantly different between the groups. The dosimetric coverage of the CTV and PTV, evaluated in terms of Dmax, Dmean, D95, and D5, was similar with the various techniques. As the ABC and SDX systems are very similar in terms of their DIBH technique, they were considered together for subsequent comparisons with RPM. Grouping of these two

Acute Toxicity Overall, a higher hospitalization rate but fewer specialist consultations were observed during radiotherapy in the RPM group than in the other two groups. Nevertheless, esophageal, cardiac, and pulmonary toxicities were identical in the three groups. Identical results were observed after combining the two DIBH groups.

Late Toxicity No significant difference in terms of clinical toxicity or PFT was observed between the three groups at the subsequent assessments.

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FIGURE 8. Comparison of TLV distribution according to three devices (ABC, SDX, and RPM) separately analyzed.

Efficacy No significant difference of efficacy in terms of overall survival, specific survival, and disease-free interval was observed between the three groups. The local recurrence rate was 43.3% in the ABC group, 36.7% in the SDX group, and 13% in the RPM group. The distribution of local recurrences inside or outside of irradiation fields was as follows: ABC: 82% versus 18%; SDX: 88% versus 12%; RPM: 50% versus 50%. Identical results were observed after combining the two DIBH groups.

DISCUSSION The STIC project, based on a large number of patients with a long follow-up, confirms the preliminary results published on the various respiratory gating devices derived from smaller patient series.12,13,17,25–27 The primary objective of this study was to compare the clinical and economic aspects of respiratory-gated conformal radiotherapy (RGRT), an innovative technique proposed to limit the impact of respiratory movements during irradiation, versus conventional CRT, the reference radiation therapy for NSCLC. This study is not randomized but is the result of a pragmatic and free choice of the different teams according to the availability of these techniques in the 20 participating centers and on patientrelated (frail patient, respiratory insufficiency, but able to maintain apnea: PS0 or 1…) or tumor-related (small tumor size, middle or lower lobe, mobile with respiration …) criteria. In the end, the two groups differed only according to size (smaller and consequently more favorable to RGRT) and respiratory insufficiency (more severe in the RGRT group). The final results based on 401 evaluable patients confirm the feasibility and good reproducibility of the various respiratory gating systems, regardless of tumor site. The results of this

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study demonstrated a marked reduction of dosimetric parameters predictive of pulmonary, cardiac, and esophageal toxicity as a result of the various respiratory gating techniques. These dosimetric benefits were mainly observed with DIBH techniques (ABC and SDX systems), which markedly increased the TLV compared with the inspiration-synchronized system based on tidal volume (RPM); however, this difference must be interpreted in view of the small number of patients treated by RPM. With a median follow-up of 25 months, these theoretical dosimetric benefits were correlated clinically with a significant reduction of toxicity, pulmonary acute toxicity, and pulmonary, cardiac, and esophageal late toxicities. Pulmonary function parameters, especially DLCO, although more heterogeneous, showed a tendency to reduction of pulmonary toxicity in the RGRT group. The clinical results show that the treatment of lung cancer has a limited efficacy and is relatively toxic. The large number of local recurrences with irradiation fields associated with considerable pulmonary and esophageal toxicity confirm the need for very precise irradiation techniques to increase the dose delivered to the target volume, while ensuring optimal protection of adjacent healthy tissues. Published studies comparing the various respiratory gating methods show that they all provide a real clinical benefit and that each technique has its own specificities6,25,26,28 and indications in the various situations encountered in routine clinical practice. Nevertheless, DIBH techniques are more widely used throughout the world than synchronized techniques.12,13,17,25,27 Nevertheless, the use of RGRT requires additional resources in terms of patient preparation and teaching of DIBH techniques, and especially in terms of treatment sessions which are an average of several minutes longer than conventional techniques, resulting in increased demands on personnel and equipment.1,6,8,29,30 All respiratory gating methods also benefit from the contribution of image-guided radiotherapy.29,31 Just like bone alignment techniques, visualization of the real position of the target volume during breathing improves the overall quality of radiation therapy. Although the implementation of one or more respiratory gating techniques was initially motivated by the need to limit respiratory movements, these techniques now allow new modalities of irradiation, such as hypofractionated and intensity-modulated radiotherapy.5,27,32 Sophisticated and more or less dedicated apparatuses, such as Novalis TX (BrainLAB, Feldkirchen, Germany), Cyberknife (Accuray, Sunnyvale), or dynamic arc therapy, combined with an appropriate respiratory gating technique are already operational. Tomotherapy (Tomotherapy, Madison) should also be available in the near future.5,6

CONCLUSION Respiratory-gated radiotherapy seems to be essential to reduce acute and late toxicity, especially pulmonary acute toxicity, and pulmonary, cardiac, and esophageal late toxicities during chest irradiation. DIBH respiratory gating techniques seem to be more efficient than synchronized systems to reduce these various toxicities, at least in terms

Copyright © 2011 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology • Volume 6, Number 12, December 2011

TABLE 4.

Respiratory Gating Techniques for Lung Cancer

Dosimetric Data Between the Three Respiratory Gating Techniques

Volumes PTV Volume (ml) D95 (Gy) D5 (Gy) Lungs Volume (ml) V20 (%) V25 (%) V37 (%) Dmax (Gy) Dmean (Gy) Heart Volume (ml) V40 (%) Dmax (Gy) Dmean (Gy) Esophagus EL50 (cm) V50 (%) Dmax (Gy) Dmean (Gy)

ABCa

SDXa

ABC ⴙ SDX

RPMa

pa

303 ⫾ 132 60.8 ⫾ 9.3 70.3 ⫾ 5.5

308 ⫾ 209 57.8 ⫾ 12.0 63.3 ⫾ 12.1

307 ⫾ 199 58.8 ⫾ 9.2 65.2 ⫾ 6.7

253 ⫾ 141 61.8 ⫾ 4.1 66.9 ⫾ 3.2

NS NS NS

5510 ⫾ 1064 19.6 ⫾ 8.0 15.8 ⫾ 7.0 10.4 ⫾ 4.5 70.8 ⫾ 6.3 11.2 ⫾ 3.8

5540 ⫾ 1426 22.8 ⫾ 9.3 18.9 ⫾ 7.8 11.9 ⫾ 5.9 69.2 ⫾ 7.1 12.9 ⫾ 5.1

5532 ⫾ 1357 22.3 ⫾ 9.2 18.4 ⫾ 7.8 11.6 ⫾ 5.8 69.4 ⫾ 7.0 12.7 ⫾ 5.0

3106 ⫾ 602.4 27.9 ⫾ 10.9 23.9 ⫾ 9.7 14.2 ⫾ 4.7 66.9 ⫾ 4.1 14.3 ⫾ 4.3

⬍0.00001 0.02 0.007 NS 0.04 NS

623 ⫾ 141 6.6 ⫾ 6.9 54.5 ⫾ 21.8 9.3 ⫾ 7.9

636 ⫾ 182 8.2 ⫾ 11.8 50.5 ⫾ 24.0 11.0 ⫾ 9.6

630 ⫾ 152 7.9 ⫾ 11.2 51.1 ⫾ 23.7 10.8 ⫾ 9.4

660 ⫾ 139 11.6 ⫾ 10.8 57.5 ⫾ 15.8 14.3 ⫾ 8.1

NS NS NS NS

6.3 ⫾ 4.3 22.2 ⫾ 18.1 60.3 ⫾ 14.9 21.1 ⫾ 9.0

6.5 ⫾ 4.6 21.4 ⫾ 18.3 57.1 ⫾ 19.2 22.2 ⫾ 11.5

6.5 ⫾ 4.6 21.6 ⫾ 18.2 57.6 ⫾ 18.3 22.0 ⫾ 11.2

7.5 ⫾ 4.8 28.8 ⫾ 17.3 64.3 ⫾ 3.6 27.1 ⫾ 10.3

NS NS NS NS

Values in bold (ABC ⫹ SDX) are the significant difference with the RPM group. a p, comparison between the three devices. NS, no significant.

of dosimetric parameters. From the economic point of view, RGRT induces excess equipment and running costs, which must be taken into account in the fee structure to encourage the development and routine use of these techniques.

ACKNOWLEDGMENTS The authors thank all physicians, physicists, and therapists who helped in the success of this project. They also thank the French National Institute of Cancer (INCa) and the Ministry of Health (DHOS) for their support. The STIC Study Centers: Centres Franc¸ois Baclesse (Caen), Henri Becquerel (Rouen), Le´on Be´rard (Lyon), Rene´ Gauducheau (Nantes), Jean Godinot (Reims), Antoine Lacassagne (Nice), Oscar Lambret (Lille), Val d’Aurelle (Montpellier), Alexis Vautrin (Nancy); Instituts Bergonie´ (Bordeaux), Curie (Paris), Claudius Regaud (Toulouse), Gustave Roussy (Villejuif), Sainte Catherine (Avignon); Hospices Civiles (Lyon); CHU Jean Minjoz (Besanc¸on), Saint Andre´ (Bordeaux), Pitie´-Salpeˆtrie`re (Paris), Georges Pompidou (Paris), Saint Louis (Paris); CHG la Source (Orle´ans). REFERENCES 1. Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology report of AAPM Task Group 76. Med Phys 2006;33:3874 –3900. 2. Giraud P, De Rycke Y, Dubray B, et al. Conformal radiotherapy (CRT) planning for lung cancer: analysis of intrathoracic organ motion during extreme phases of breathing. Int J Radiat Oncol Biol Phys 2001;51: 1081–1092. 3. Goitein M. Organ and tumor motion: an overview. Semin Radiat Oncol 2004;14:2–9.

4. Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys 2001;50:265–278. 5. Giraud P, Yorke E, Jiang S, Simon L, et al. Reduction of organ motion effects in IMRT and conformal 3D radiation delivery by using gating and tracking techniques. Cancer Radiother 2006;10:269 –282. 6. Jiang SB, Wolfgang J, Mageras GS. Quality assurance challenges for motion-adaptive radiation therapy: gating, breath holding, and fourdimensional computed tomography. Int J Radiat Oncol Biol Phys 2008; 71:S103–S107. 7. Morelle M, Remonnay R, Giraud P, et al. Analyzing multiple learning effects in health care using multilevel modeling: application to radiotherapy at an early stage of innovation. Int J Technol Assess Health Care 2009;25:232–239. 8. Remonnay R, Morelle M, Giraud P, et al. The cost of respiration-gated radiotherapy in the framework of a clinical research programme “STIC”. Cancer Radiother 2009;13:281–290. 9. Keall P. 4-dimensional computed tomography imaging and treatment planning. Semin Radiat Oncol 2004;14:81–90. 10. Rietzel E, Pan T, Chen GT. Four-dimensional computed tomography: image formation and clinical protocol. Med Phys 2005;32: 874 – 889. 11. Sonke JJ, Lebesque J, van Herk M. Variabiliy of four-dimensional computed tomography patient models. Int J Radiat Oncol Biol Phys 2008;70:590 –598. 12. Rosenzweig KE, Hanley J, Mah D, et al. The deep inspiration breathhold technique in the treatment of inoperable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2000;48:81– 87. 13. Kim DJ, Murray BR, Halperin R, et al. Held-breath self-gating technique for radiotherapy of non-small-cell lung cancer: a feasibility study. Int J Radiat Oncol Biol Phys 2001;49:43– 49. 14. Kini VR, Vedam SS, Keall PJ, et al. Patient training in respiratory-gated radiotherapy. Med Dosim 2003;28:7–11. 15. Mah D, Hanley J, Rosenzweig KE, et al. Technical aspects of the deep inspiration breath-hold technique in the treatment of thoracic cancer. Int J Radiat Oncol Biol Phys 2000;48:1175–1185. 16. Hanley J, Debois MM, Mah D, et al. Deep inspiration breath-hold technique for lung tumors: the potential value of target immobilization

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2067

Giraud et al.

17.

18.

19.

20. 21. 22.

23.

24.

Journal of Thoracic Oncology • Volume 6, Number 12, December 2011

and reduced lung density in dose escalation. Int J Radiat Oncol Biol Phys 1999;45:603– 611. 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;44:911–919. International Commission on Radiation Units and Measurements. ICRU Report 62: Prescribing, Recording, and Reporting Photon Beam Therapy (Supplement to ICRU Report 50). Bethesda, MD: International Commission on Radiation Units and Measurements, 1999. Giraud Ph, Antoine M, Larrouy A, et al. Evaluation of microscopic tumor extension in non-small cell lung cancer (NSCLC) for threedimensional conformal radiotherapy (3DCRT) planning. Int J Radiat Oncol Biol Phys 2000;48:1015–1024. Simon L, Giraud Ph, Dumas JL, et al. Practical recommendations for breathing-adapted radiotherapy. Cancer Radiother 2007;11:214 –224. LENT/SOMA tables. Radiother Oncol 1995;35:17– 60. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–1346. R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0. Available at: http://www.R-project.org. Accessed July 8, 2011. Simon L, Giraud P, Servois V, et al. Lung volume assessment for a

2068

25. 26. 27.

28. 29. 30. 31. 32.

cross-comparison of two breathing adapted techniques in radiotherapy. Int J Radiat Oncol Biol Phys 2005;63:602– 609. Berson AM, Emery R, Rodriguez L, et al. Clinical experience using respiratory gated radiation therapy: Comparison of free-breathing and breath-hold techniques. Int J Radiat Oncol Biol Phys 2004;60:419 – 426. Chen QS, Weinhous MS, Deibel FC, et al. Fluoroscopic study of tumor motion due to breathing: facilitating precise radiation therapy for lung cancer patients. Med Phys 2001;28:1850 –1856. Remouchamps VM, Vicini FA, Sharpe MB, et al. Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation. Int J Radiat Oncol Biol Phys 2003;55:392– 406. Engelsman M, Damen EM, De Jaeger K, et al. The effect of breathing and set-up errors on the cumulative dose to a lung tumor. Radiother Oncol 2001;60:95–105. Korreman SS, Juhler-Nottrup T, Boyer AL. Respiratory gated beam delivery cannot facilitate margin reduction, unless combined with respiratory correlated image guidance. Radiother Oncol 2008;86:61– 68. Vedam SS, Keall PJ, Kini VR, et al. Determining parameters for respiration-gated radiotherapy. Med Phys 2001;28:2139 –2146. Yorke E, Rosenzweig KE, Wagman R, et al. Interfractional anatomic variation in patients treated with respiration-gated radiotherapy. J Appl Clin Med Phys 2005;6:19 –32. Duan J, Shen S, Fiveash JB, et al. Dosimetric effect of respiration-gated beam on IMRT delivery. Med Phys 2003;30:2241–2252.

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