Giraud, Philippe MD, PhD*†; Morvan, Esra PhD†; Claude, Line MD‡; Mornex, Françoise MD, PhD§; Le Pechoux, Cécile MD∥; Bachaud, Jean-Marc MD¶; Boisselier, Pierre MD#; Beckendorf, Véronique MD**; Morelle, Magali MD††; Carrère, Marie-Odile MD, PhD††; The STIC Study Centers
Adapting 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 Thérapeutiques Coûteuses (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, 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
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 ≤2); chemotherapy, especially concomitant chemotherapy, was authorized; age ≥18 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.
Materials and Methods
Three respiratory gating devices were tested: the Real-time 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 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
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 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
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 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 χ2 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 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.
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.
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 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 comparison of dosimetric parameters measured in CRT with the mean parameters measured during the two respiratory-gated 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 correlation 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).
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).
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 lungs in DIBH. Dmax, Dmean, and V40 were significantly lower in the RGRT group (Table 2, Figure 6).
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).
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).
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 ≥3 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 assessments. Nevertheless, a tendency to deterioration of DLCO, FEV1, and TLV was observed at the 24th month in the CRT group (Table 3).
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 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 failure and more advanced tumors in the ABC and SDX DIBH groups.
Analysis of Dosimetric Data
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 techniques accentuated the differences observed between the various systems (Table 4).
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.
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.
No significant difference in terms of clinical toxicity or PFT was observed between the three groups at the subsequent assessments.
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.
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 patient-related (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 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
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 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.
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 François Baclesse (Caen), Henri Becquerel (Rouen), Léon Bérard (Lyon), René Gauducheau (Nantes), Jean Godinot (Reims), Antoine Lacassagne (Nice), Oscar Lambret (Lille), Val d'Aurelle (Montpellier), Alexis Vautrin (Nancy); Instituts Bergonié (Bordeaux), Curie (Paris), Claudius Regaud (Toulouse), Gustave Roussy (Villejuif), Sainte Catherine (Avignon); Hospices Civiles (Lyon); CHU Jean Minjoz (Besançon), Saint André (Bordeaux), Pitié-Salpêtrière (Paris), Georges Pompidou (Paris), Saint Louis (Paris); CHG la Source (Orléans).
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