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Involved-Node and Involved-Field Volumetric Modulated Arc vs. Fixed Beam Intensity-Modulated Radiotherapy for Female Patients With Early-Stage Supra-Diaphragmatic Hodgkin Lymphoma: A Comparative Planning Study
Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 5, pp. 1578–1586, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2009.05.012
PHYSICS CONTRIBUTION
INVOLVED-NODE AND INVOLVED-FIELD VOLUMETRIC MODULATED ARC VS. FIXED BEAM INTENSITY-MODULATED RADIOTHERAPY FOR FEMALE PATIENTS WITH EARLY-STAGE SUPRA-DIAPHRAGMATIC HODGKIN LYMPHOMA: A COMPARATIVE PLANNING STUDY DAMIEN C. WEBER, M.D.,* NICOLAS PEGURET, M.D.,* GIOVANNA DIPASQUALE, M.SC.,* z AND LUCA COZZI, PH.D. * Department of Radiation Oncology, Geneva University Hospital, University of Geneva; and z Oncology Institute of Southern Switzerland, Medical Physics Unit, Bellinzona, Switzerland Purpose: A comparative treatment planning study was performed to compare volumetric-modulated arc (RA) to conventional intensity modulated (IMRT) for involved-field (IFRT) and involved-node (INRT) radiotherapy for Hodgkin lymphoma (HL). Methods and Materials: Plans for 10 early-stage HL female patients were computed for RA and IMRT. First, the planning target volume (PTV) coverage and organs at risk (OAR) dose deposition was assessed between the two modalities. Second, the OAR (lung, breast, heart, thyroid, and submandibular gland) dose–volume histograms were computed and compared for IFRT and INRT, respectively. Results: For IFRT and INRT, PTV coverage was equally homogeneous with both RA and IMRT. By and large, the OAR irradiation with IFRT planning was not significantly different between RA and IMRT. For INRT, doses computed for RA were, however, usually lower than those with IMRT, particularly so for the lung, breast, and thyroid. Regardless of RA and IMRT modalities, a significant 20–50% decrease of the OAR computed mean doses was observed with INRT when compared with IFRT (Breast DMean 1.5 ± 1.1 vs. 2.6 ± 1.7 Gy, p < 0.01 and 1.6 ± 1.1 vs. 2.9 ± 1.9 Gy, p < 0.01 for RA and IMRT, respectively). Conclusions: RA and IMRT results in similar level of dose homogeneity. With INRT but not IFRT planning, the computed doses to the PTV and OAR were usually higher and lower with RA when compared to IMRT. Regardless of the treatment modality, INRT when compared with IFRT planning led to a significant decrease in OAR doses, particularly so for the breast and heart. Ó 2009 Elsevier Inc. Volumetric modulated arc therapy, IMRT, Hodgkin lymphoma, Involved node radiotherapy, Involved field radiotherapy.
The overall prognosis of patients with early-stage Hodgkin lymphoma (HL) is excellent, with an overall 10-year survival of more than 75% (1). With the current multimodality treatment, most patients achieve a lifelong complete remission, but poor health status (2) and secondary cancers (SC) remain a serious late effect of treatment (3). More importantly, SC are currently the primary cause of mortality among these cured patients (4). Female HL survivors present an increased risk of breast cancer (5). Consequentially, it is of paramount importance to decrease the breast dose of radiotherapy (RT) delivered for HL. Mediastinal RT is also associated with cardiotoxicity, especially in HL patients receiving a substantial cumulative
amount of anthracyclines. As such, the dose delivered to the heart should be also as low as reasonably possible. Intensity-modulated RT (IMRT) has the potential to achieve substantial improvement in dose distribution, when compared with non-IMRT dose deposition. IMRT can be delivered with fixed beam (thereafter, IMRT) or with volumetric modulated arc therapy (thereafter, RapidArc [RA]). Shahidi et al. have reported on the site of relapse after chemotherapy alone in 61 Stage I and II HL patients (6). Most of the recurrences (>80%) occurred in the initial involved lymph nodes. As such, the European Organization for Research and Treatment of Cancer (EORTC)–Groupe d’Etude des Lymphome de l’Adulte (GELA) has recommended that involved node RT (INRT) and not involved field RT
Reprint requests to: PD Dr.med. Damien C. Weber, Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. Tel: (+41) 22 38 27 090; Fax: (+41) 22 38 27 117; E-mail: [email protected]
Conflict of interest: Dr. L. Cozzi acts as Scientific Advisor to Varian Medical Systems. Other authors have no conflict of interest. Received March 26, 2009, and in revised form May 8, 2009. Accepted for publication May 11, 2009.
INTRODUCTION
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(IFRT) should be administered to early-stage HL patients, providing that modern diagnostic and therapeutic modalities, not limited but including 18f-Fluorodeoxyglucose (FDC)positron emission tomodensitometry (PET) and accurate radiation technology, should be used (7). It remains to be demonstrated however if INRT significantly decreases the OAR in vicinity of the target volume and if this observed decremental dose deposition is clinically significant. The present study was undertaken to assess the treatment planning inter-comparison between the best available photon techniques, namely RA and IMRT, as applied to a total of 10 early-stage female supra-diaphragmatic HL patients. Additionally, the dose delivered to the organs at risk (OAR) with IFRT and INRT were compared for both treatment modalities. METHODS AND MATERIALS
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the mid-clavicular head, the xiphoid process, the sternum, and the anterior portion of the latissimus dorsi muscle, respectively. Submandibular glands (SG) and thyroids were easily defined on the CT scans after intravenous contrast injection. The heart was defined from the auricles to the tip of this organ. The non-target tissue was defined as the patient’s volume covered by the CT scan minus the planning target volume (PTV).
IFRT The PTVIFRT derived from the volume defined by the IFRT approach of the Ann Arbor Staging system. RT fields were defined according to the guidelines of Yahalom and Mauch (8). The PTVIFRT was the CTV, including the GTV, expanded with a generically isotropic three-dimensional margin of 19–25 (mean, 21.7 1.7) mm automatically generated to precisely match the IFRT conventional fields. As recommended by the EORTC-GELA Lymphoma group guidelines, the major blood vessels and heart were avoided when possible (7).
Patients
INRT
Ten young female patients (mean age, 27.3 11.9) with earlystage (I-II) supra-diaphragmatic HL and mediastinal tumor masses who had been treated with conventional IFRT (30 Gy) in our institution were selected for this study. All had undergone prechemotherapy FDG-PET computed tomography (CT) imaging, with intravenous iodine contrast injection, as part of an institutional ethics–approved RT simulation protocol. A set of three triangulation lasers identical to those used on the linear accelerators, as well as a flat table top, were used for patient accurate positioning during the PET CT data acquisition (Biograph 16; Siemens Medical Solutions, Erlangen, Germany). Of note, patients underwent a second PET CT after two cycles of chemotherapy to assess the metabolic response. Finally, these patients underwent a postchemotherapy planning CT with iodine intravenous contrast injection and 3-mm slice thickness for RT planning (Picker 2000, Cleveland, OH). The simulation PET CT and planning CT were performed with the same immobilization devices (thermo-plastic mask) and the exact same position verified by the sets of lasers, with the patient in the supine position and the arm along the body.
The PTVINRT was the CTV, including the GTV, with a generically isotropic three-dimensional margin of 10 mm automatically generated (7). As recommended by the EORTC-GELA Lymphoma group guidelines, the major blood vessels and heart were avoided when possible (7).
Target definition Contouring was performed with Eclipse, version 8.6.10 (Varian, Palo Alto, CA). The gross tumor volume (GTV) was the lymph node remnant(s) after chemotherapy observed on the postchemotherapy planning CT (7). The clinical tumor volume (CTV) was the initial volume of the morphologic PET-positive lymph node(s) before chemotherapy. CTV were contoured by one experienced radiation oncologists (D.C.W.) using the Leonardo platform (Siemens Medical Solutions/CTI, Knoxville, TN). This volume delineated on the prechemotherapy simulation PET CT datasets was transferred to the final postchemotherapy planning CT using the picture archiving communication system. The CTV was modified automatically using the Eclipse editing tool to exclude the CTV from the abutting OAR when appropriate. A generically isotropic three-dimensional margin of 1 mm was implemented in the CTV editing process.
OAR delineation The whole breast was delineated on the CT datasets using a standard window (0) and width (500) level. Breast glandular tissue was limited posteriorly, anteriorly, superiorly, inferiorly, medially, and laterally by the pectoralis muscle, the first 5 mm beneath the skin,
Treatment IFRT and INRT were planned to deliver 30 Gy to PET defined target volumes. The initial goal for all treatment plans was to obtain PTV dose homogeneity of –5% and +7%, as recommended by the International Commission on Radiation Units and Measurements Report No. 50 (9). The beam energy used for all treatment was 6 MV. The treatment plans were generated using nine-field IMRT and RA techniques, all computed on the Varian Eclipse treatment planning system (TPS, version 8.6) with 6-MV photon beams from a Varian Clinac equipped with a millennium multileaf collimator with 120 leaves. Plans for RA were optimized selecting a maximum DR of 600 MU/min and a fixed DR of 600 MU/min was selected for IMRT. RA uses continuous variation of the instantaneous dose rate, millennium multileaf collimator leaf positions, and gantry rotational speed to optimize the dose distribution. Details about RA optimization process have been published elsewhere (10). To minimize the contribution of tongue and groove effect during the arc rotation and to benefit from leaves trajectories noncoplanar with respect to patient’s axis, the collimator rotation in RA remains fixed to a value different from zero. In the present study collimator was rotated to 30 depending on the patient. RA plan consisted on a single arc 360 . For IMRT, plans were designed according to the dynamic sliding window method with nine fixed gantry equally spaced beams (gantry starting angle 0 ). One single isocenter was located at the target center of mass. All beams were coplanar with collimator angle set to 0 . The millennium multileaf collimator was used for the study. The Anisotropic Analytical Algorithm photon dose calculation algorithm was used for all cases (11). The dose calculation grid was set to 2.5 mm. The dose constraints to the OAR are listed in Table 1. Quantitative evaluation of plans was performed by means of cumulative dose–volume histograms (DVHs). For PTV, the values of D1% and D99% (dose received by the 1% and 99% of the volume, respectively) were defined as metrics for minimum and maximum doses
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Table 1. Radiotherapy dose constraints to OAR OAR
D1% (Gy)
D33% (Gy)
D50% (Gy)
Priority
Lung Heart Breast Thyroid SG PTV PTV
20* 30* 20 30 15 31.5 28.5
10 15 10 25 10 —
5 7.7 5 18 5 —
4 2 3 5 6 1 1
Abbreviations: OAR = organs at risk; PTV = planning target volume; SG = submandibular gland. * As a result of tumor coverage requirements, a waiver can be applied on these dose constraints.
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To visualize the global difference between treatment techniques and planning paradigms, average cumulative DVH for GTV and PTV, OAR and non-target tissue, were built from the individual DVHs. These DVHs were obtained by averaging the corresponding volumes over the whole patient’s cohort for each dose bin of 0.05 Gy.
Statistical analysis The Wilcoxon matched-paired signed-rank test was used to compare the results among the RA-IMRT and IFRT-INRT plans. The threshold for statistical significance was p # 0.05. All statistical tests were two-sided and were performed using the StatView Statistical Analysis System, version 5.0 (SAS Institute Inc., Cary, NC).
RESULTS and thereafter reported. To complement the appraisal of mean dose, V95% and V107% (the volume receiving at least 95% or at most 107% of the prescribed dose) were reported. The dose conformity (12) index was calculated: (volume included in the 95% isodose)/volume PTV (CI95%). Inhomogeneity coefficients within the PTV were computed as (D5% – D95%)/D Mean, where Dn% is the minimal dose delivered to the percentage of volume of the target volume. Additionally, the number of monitor units (MU) required to deliver 2 Gy fraction was calculated for each plan. For non-target tissue, the integral dose (DoseInt), is defined as the integral of the absorbed dose extended to over all voxels excluding those within the target volume (DoseInt dimensions are Gy*cm3*105). This was reported together with the observed mean dose and some representative Dn% and VnGy (volume receiving n Gy) values.
RA vs. IMRT analysis For IFRT, PTV coverage was optimal and equally homogeneous with both RA and IMRT (Fig. 1). The mean V107% was identical (Table 2). A statistical trend toward better tumor conformation (CI95%) for IFRT (p = 0.14) was observed with RA (Table 2). The mean D95% was 28.4 0.5 vs. 28.3 0.4 Gy (p = 0.17) for RA and IMRT, respectively. For INRT, PTV was equally homogeneous, but a statistical trend toward signification for optimized PTV coverage with RA was observed (CI95% 0.96 0.04 vs. 0.94 0.02; p = 0.07; Table 2). The mean D95% was 28.7 0.5 vs. 28.3 0.4 Gy (p = 0.07) for RA and IMRT, respectively.
Fig. 1. Color wash volumetric-modulated arc radiotherapy (RA) and conventional intensity-modulated radiotherapy (IMRT) for involved-field (IFRT) and involved-node (INRT) for 2 patients (A, B) with Hodgkin lymphoma Stage IIB.
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Table 2. Comparison of mean dosimetric parameters computed for RA and IMRT
Variable
IF
RT
IN
RT
Objectives
RA
IMRT
p
RA
IMRT
p
30.0 31.5 28.5 — 100 0.0 1.0 0.0
916 30.0 31.7 0.4 27.2 0.7 2.9 0.8 94.0 3.9 0.5 1.2 0.94 0.04 0.1 0.03
571 30.0 31.7 0.4 26.8 0.7 3.0 0.6 93.4 2.2 0.5 0.7 0.93 0.02 0.1 0.02
— 0.24 0.09 0.20 0.14 0.20 0.14 0.20
451 30.0 31.4 0.4 27.7 0.8 2.4 0.6 95.8 4.0 0.2 0.4 0.96 0.04 0.08 0.03
332 30.0 31.4 0.3 27.0 0.7 2.8 0.6 93.9 2.3 0.1 0.4 0.94 0.02 0.09 0.02
— 0.65 <0.01* 0.11 0.07 0.48 0.07 0.11
— 20.0y 10.0 5.0 —
8.2 1.5 28.5 1.2 9.4 1.7 5.5 1.5 30.9 6.2
8.4 1.5 28.4 1.4 10.2 1.5 6.0 1.9 33.8 6.6
0.09 0.51 0.03* 0.11 0.04*
6.4 1.5 26.2 2.2 7.2 1.8 3.8 1.9 23.2 7.4
6.7 1.4 26.2 2.1 8.4 1.4 4.1 2.2 26.1 6.9
0.04* 0.65 <0.01* 0.17 0.01*
— 30.0z 15.0 7.7 —
7.4 6.5 23.8 10.1 7.9 8.6 5.1 7.9 23.5 27.8
7.2 6.3 24.5 8.8 7.6 8.7 4.9 7.6 22.9 26.3
0.20 0.44 0.33 0.28 0.58
4.4 4.9 17.4 13.0 4.4 6.7 3.1 4.9 13.2 23.3
4.0 4.3 17.3 12.8 3.7 5.3 2.4 3.6 11.5 18.5
0.06 0.65 0.06 0.04* 0.35
— 20.0 10.0 5.0 -
2.6 1.7 13.7 8.1 2.4 1.9 1.3 0.9 6.7 6.8
2.9 1.9 15.2 7.9 2.6 2.1 1.2 0.9 9.4 8.9
0.01* 0.02* 0.17 0.51 0.01*
1.5 1.1 9.6 6.1 1.2 0.9 0.8 0.7 2.2 2.7
1.6 1.1 10.7 6.5 1.0 0.8 0.6 0.6 3.6 4.1
0.22 <0.01* 0.02* 0.05* 0.03*
— 30.0 25.0 18.0 —
23.3 9.0 28.2 8.0 25.4 9.2 23.9 9.8 85.8 31.7
23.7 9.0 28.5 7.5 25.4 9.5 24.2 9.7 88.2 31.3
0.14 0.24 0.89 0.56 0.03*
16.7 8.7 26.8 9.0 19.7 9.6 16.4 9.5 65.1 33.6
17.4 8.8 25.4 9.2 20.3 9.4 17.4 9.2 74.3 34.9
0.04* 0.24 0.39 0.11 0.01*
— 15.0 10.0 5.0 —
4.8 9.2 7.8 11.3 4.8 9.2 4.5 9.2 23.6 40.8
4.9 9.5 7.7 11.6 5.0 9.5 4.7 9.4 26.7 42.3
0.89 0.65 0.96 0.96 0.99
3.4 8.7 4.2 9.3 3.6 8.9 3.4 8.7 10.0 31.6
3.3 8.8 4.0 9.6 3.5 9.2 3.3 8.9 10.0 31.6
0.28 0.28 0.44 0.65 —
— — — —
6.7 1.9 23.1 7.2 1.1 0.5 376 84
7.1 1.8 26.3 7.5 1.2 0.5 1255 322
<0.01* <0.01* 0.04* <0.01*
5.1 1.8 16.8 6.8 0.9 0.4 367 99
5.3 1.7 18.7 7.8 0.9 0.5 1020 282
<0.01* <0.01* 0.06 <0.01*
3
PTV IFRT/INRT (cm ) DMean D1%(Gy) D99%(Gy) D5%–D95%(Gy) V95% (%) V107% (%) CI95% IC Lung DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Heart DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Breast DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Thyroid DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) SG DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V3 Gy(%) Non target tissue DMean(Gy) V10 Gy(%) DoseIntz Monitor units
Abbreviations: IF = involved field; IN = involved node; RA = volumetric modulated arc therapy; PTV = planning target volume; IMRT = intensity-modulated radiotherapy; RT = radiotherapy; CI95% = conformity index; DoseInt = integral dose. For CI95% see text. * Statistically significant; Wilcoxon matched-paired signed-rank test. y The OARs objectives could be waived to respect the target dose constraints. z Unit: Gy cm3 105.
Lung, IFRT. As a result of the planning dose constraints (Table 1), both techniques did not usually respect the planning objectives for D1% and D50%, whereas the objectives for D33% could be respected in a majority of patients (Table 2). Save for D1%, all lung dose–volume metrics were decreased with RA (Table 2). Compared with IMRT, the use of RA resulted in a significant decrease of lung irradiation in the mid-dose level (Table 2).
Lung, INRT. All but one planning dose constraints (D1%; Table 2) with both techniques were respected in a majority of patients, as a result of the smaller PTVs (Table 2). A significant decrease of lung dose–volume metrics was observed with RA in the mid-, but not the high-dose level (Table 2). Heart, IFRT. Planning dose constraints were met by all techniques in a majority of patients and no relevant difference was observed between RA and IMRT (Table 2).
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Table 3. Comparison of mean dosimetric OAR parameters computed for IFRT and INRT
Variable Lung DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Heart DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Breast DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Thyroid DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) SG DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V3 Gy(%) Non target tissue DMean(Gy) V10 Gy(%) y DoseInt
R
A
IM
RT
IFRT
INRT
p
IFRT
INRT
p
8.2 1.4 28.4 1.2 9.4 1.7 5.5 1.5 30.9 6.2
6.4 1.5 26.2 2.2 7.2 1.7 3.8 1.9 23.2 7.4
<0.01* <0.01* <0.01* <0.01* <0.01*
8.4 1.5 28.3 1.4 10.2 1.5 5.9 1.8 33.8 6.6
6.7 1.4 26.2 2.1 8.3 1.4 4.1 2.2 26.1 6.9
<0.01* <0.01* <0.01* <0.01* <0.01*
7.4 6.5 23.8 10.1 7.9 8.6 5.1 7.9 23.5 27.8
4.4 4.9 17.4 13.0 4.4 6.7 3.1 4.9 13.2 23.3
<0.01* <0.01* <0.01* <0.01* 0.01*
7.2 6.2 24.5 8.8 7.6 8.7 4.9 7.6 22.9 26.3
4.0 4.3 4.0 4.3 3.7 5.3 2.4 3.6 11.5 18.5
<0.01* <0.01* <0.01* <0.01* <0.01*
2.6 1.7 13.7 8.1 2.4 1.9 1.3 0.9 6.7 6.8
1.5 1.1 9.6 6.1 1.2 0.9 0.7 0.7 2.2 2.7
<0.01* <0.01* <0.01* <0.01* <0.01*
2.9 1.9 12.2 7.9 2.6 2.1 1.2 0.9 9.3 8.9
1.6 1.1 10.7 6.5 1.0 0.8 0.6 0.6 3.6 4.1
<0.01* <0.01* <0.01* <0.01* <0.01*
23.3 9.0 28.2 8.0 25.4 9.2 23.9 9.8 85.8 31.7
16.7 8.6 26.8 9.0 19.7 9.6 16.4 9.5 65.1 33.6
<0.01* 0.08* <0.01* <0.01* <0.01*
23.7 9.0 28.5 7.5 25.4 9.5 24.2 9.7 88.2 31.3
17.4 8.8 25.4 9.2 20.3 9.4 17.4 9.0 74.3 34.9
<0.01* <0.01* <0.01* <0.01* <0.01*
4.8 9.2 7.8 11.3 4.8 9.2 4.5 9.2 23.6 40.8
3.4 8.7 4.2 9.3 3.6 8.9 3.4 8.7 10.0 31.6
<0.01* <0.01* <0.01* <0.01* 0.07*
4.9 9.5 7.7 11.6 5.0 9.5 4.7 9.4 26.7 42.3
3.3 8.8 4.0 9.6 3.5 9.2 3.3 8.9 10.0 31.6
<0.01* <0.01* <0.01* <0.01* 0.11
6.7 1.9 23.1 7.2 1.1 0.5
5.1 1.8 16.8 6.8 0.9 0.4
<0.01* <0.01* <0.01*
7.1 1.8 26.3 7.5 1.2 0.5
5.3 1.7 18.7 7.8 0.9 0.5
<0.01* <0.01* <0.01*
Abbreviations: IF = involved field; IN = involved node; RA = volumetric modulated arc therapy; IMRT = intensity-modulated radiotherapy; RT = radiotherapy; DoseInt = integral dose. * Statistically significant; Wilcoxon matched-paired signed-rank test. y Unit: Gy cm3 105.
Heart, INRT. Planning dose constraints were met by all techniques in a majority of patients (Table 2). Save for D50%, all other dose–volume metrics were nonsignificantly decreased with IMRT when compared with RA (Table 2). Breast, IFRT. Planning dose constraints were met by all techniques (in a majority of patients for DMean; Table 2). A significant difference was observed in the breast high- and mid-dose level between RA and IMRT. Breast, INRT. Planning dose constraints were met by all techniques (Table 2). A significant decrease of breast irradiation at the Gy unit level was observed with IMRT. Conversely, RA planning allowed a significant reduction of the irradiation of the breast in the low- to mid-dose level (Table 2). Thyroid IFRT. Planning dose constraints were met by both techniques in a majority of patients except for D33% (Table 2). V10Gy was significantly decreased with RA. Thyroid INRT. Planning dose constraints were met by both techniques (Table 2). The dose in the mid-dose level
(DMean and V10Gy) was significantly decreased with RA when compared with IMRT. SG IFRT and INRT. Planning dose constraints were met by both techniques in a majority of patients and no relevant difference was observed between RA and IMRT (Table 2). Healthy tissue, IFRT, and INRT. No planning dose constraints were implemented. Dose–volume metrics were substantially decreased with RA when compared with IMRT (Table 2). More specifically, the DoseInt was significantly decreased with RA-IFRT and RA-INRT when compared with IMRT-IFRT and IMRT-IFRT planning, respectively (Table 2; Fig. 1). Monitor unit. The mean number of MU per fraction was significantly reduced by a factor of approximately three for RA, when compared with IMRT planning (Table 2). IFRT vs. INRT analysis Independently of RA or IMRT, INRT when compared with IFRT planning reduced substantially all computed doses to the OAR (Table 3; Fig. 2). For the lung, a mean
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Fig. 2. Mean dose–volume histograms for planning target volumes (PTVs) and organs at risk (OAR) for involved-field (IF) and for involved-node (IN) radiotherapy. IMRT = intensity-modulated radiotherapy; RA = volumetric-modulated arc radiotherapy.
decrease of 21.9 7.0% (p < 0.01) and 19.9 5.8% (p < 0.01) for DMean was calculated for RA and IMRT, respectively (Fig. 2). Likewise, the computed mean decrease of DMean for the heart and breast were 50.5 15.1% (p < 0.01) 44.8 16.3% (p < 0.01) and 42.3 13.2% (p < 0.01) 46.7 11.4% (p < 0.01) for RA and IMRT, respectively (Fig. 2). The computed mean decrease of DMean for
the thyroid and SG were 30.2 16.5% (p < 0.01) 30.2 16.9% (p < 0.01) and 40.4 21.9 (p < 0.01) 43.1 23.2% (p < 0.01) for RA and IMRT, respectively (Fig. 2). Finally, computed mean DosInt was decreased by one fourth with INRT when compared with IFRT planning (24.4 8.4%; p < 0.01 and 24.7 7.2%; p < 0.01 with RA and IMRT, respectively).
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DISCUSSION
with mantle or mini-mantle irradiation, substantially reduces the dose to these OAR by a factor of approximately 50 and 10, respectively, although these calculated IFRT breast doses may be somewhat underestimated (15). It is a fundamental principle in radiation oncology that, all things being equal, the probability of SC increases as the radiation dose to OAR is increased, with no safe cutoff value. Reports on atomic bomb survivors suggest an increased risk of breast cancer below the Gy unit. With have chosen to select only female HL patients for this study, as they are at risk for SC, with a reported incidence of 57 times that expected in the normal population (16). INRT planning decreased the breast dose significantly by a factor of approximately two with both RA and IMRT (Table 3). Among the SCs, breast cancer is the most common malignancy among female survivors (17, 18). In a case control study stemming from five population-based cancer registries, an increase in the absolute risk of secondary breast cancers with the thoracic radiation dose was observed for patients diagnosed at age 30 years or younger (5). Compared with that of the general population, the relative risk of breast SC was 1.7 (95% CI 0.6–5.2), 8.5 (95% CI 5.4–13.2), and 10.5 (95% CI 6.8–16.0) after 0, 20–39.9, and $40 Gy of mediastinal RT with no chemotherapy, respectively. Likewise, other reports suggest that the risk of breast cancer is dose related (19–21). As such, delivering radiation to smaller volumes, such with an INRT paradigm, could potentially decrease the substantial SC rate of HL’s survivors. This hypothesis was theoretically validated by the analysis from the Princess Margaret Hospital converting breast dose data to breast cancer risk using a quantitative model (22). Moving from mantle to IFRT would reduce breast SC risk by 65% and reducing the prescribed dose by 40% would reduce cancer risk by a further 40%. The predicted risk for SC of this cohort planned with IFRT and INRT will be fully assessed in a forthcoming publication. Late cardiac toxicity usually observed 5–10 years after treatment for HL is also a major concern for HL survivors (23, 24), especially for those with preexisting cardiovascular risk factors (25). Compared with the general population, the cardiac morbidity for HL survivors after doxorubicin and mediastinal RT is increased three- to five-fold, when adjusting for other cardiac competing risk factors (26, 27). Age <20 years at the time of irradiation, such as observed in half of our patient cohort, is a major risk factor for cardiac mortality (23, 27). Moreover, mediastinal dose was also a major risk factor for cardiac toxicity in the Stanford series (23). Damage to the vascular endothelium of the arteries is believed to be the main pathogenic process of radiation-induced heart disease in animal models (28) and humans (29). As such, decreasing the computed cardiac dose with INRT (Table 3) may substantially decrease the cardiac morbidity. The observed decrease for the breast dose with INRT is mostly relevant when nonconventional RT (i.e., RA or IMRT) is administered. Administering conventional mediastinal RT (30 Gy) delivers approximately a mean dose of 1 Gy (range, 0.1–5.8) to the breasts (data not shown). Administering intensity modulated RT, be it RA
The present study evaluated the conformal OAR sparing ability of both RA and IMRT. With INRT but not IFRT planning, dose–volume metrics were usually lower with RA, when compared with IMRT, particularly so for the lung, heart and thyroid (Table 2). As with IMRT, RA delivers radiation with a multileaf collimator, which changes the shape of the treatment field dynamically, but unlike the latter technique that delivers IMRT from a relatively small number of fixed gantry angles, the whole treatment is delivered with only one rotation and not with fixed fields, which is thus potentially faster. Treatment time is a paramount parameter when evaluating these two techniques. At one extreme, if this parameter is ignored, in concert with neglecting the dose rate continuous variation and the usage of non-zero collimator angles (putting more leaves couples in play to generate every pixel of modulation), these two modalities are theoretically alike: slowing down the gantry to infinitesimally small rotational speeds for RA enables one to fully exploit fluencemodulation at any given angle while using numerous gantry angles for IMRT delivers dose distributions that could be very similar to those obtained by simple conformal dynamic rotation of the gantry (13). Nonetheless, RA has two additional previously mentioned features, which increase the space and the modulation capability beyond limits recently suggested by Bortfeld and Webb (13). Taking into account the full range of optimization features (i.e., increasing the number of fields for IMRT and reducing the rotational speed, incorporating dose rate variation and non-zero collimation for RA), the observed advantage with RA for INRT planning may also result from the increased distance from the PTV and OAR, when compared with IFRT planning: RA exploits optimally all angles to conform dose deposition in three dimensions to the target and its so-called less advantageous fluence modulation capability, when compared with IMRT planning with its finite sampling of gantry angles but optimized per field intensity modulation ability, does not penalize the resulting treatment plans. Noteworthy, the optimization of the beam angles for IMRT may be a debatable parameter, which does not occur with RA. Additionally, RA for these HL patients could be considered more efficient, because the number of MU is significantly decreased with this modality (Table 2). This significant decrease in MU will translate in a treatment time reduction and consequential reduction in scatter and linear accelerator head leakage dose (14). Importantly, it remains to be demonstrated that the observed ‘‘advantage’’ of RA for certain OAR observed in this study will translate into a clinical benefit. To the best of our knowledge, the present study is the first series to compare formally the OAR doses computed with IFRT and INRT planning. Our results show that an overwhelming number of dose–volume metrics are significantly decreased with INRT when compared with IFRT planning (Table 3). These data are in line with a recent study, assessing breasts doses in an anthropomorphic phantom, which showed that IFRT delivered to the cervical region, when compared
RapidArc vs. IMRT for early-stage Hodgkin lymphoma d D. C. WEBER et al.
or IMRT, increases this mean dose by a factor of 2–3. We are left with the conundrum of how to capitalize the conformal ability of intensity modulated RT with its potential decrease in toxicity for structures within the treatment field (i.e., lung, heart) while avoiding any consequential increase of SC risk to the outfield OAR such as the breasts. With its intrinsic increase of integral dose, nonconventional RT may contra-productively nullify the potential advantage of this modality. As such, the potential benefit of a generally smaller RT volume, which can be validly inferred from Table 3, should be particularly desirable if IMRT is the chosen treatment modality for a given patient. As a result of our institutional protocol, all HL patients undergo PET CT simulation before chemotherapy. As recently discussed in the EORTC-GELA guidelines, PET data should be used for INRT planning purposes (30). A note of caution should be made however on the optimal feasibility of INRT planning for early HL which has never been tested in a prospective trial with appropriate quality insurance. First, the current threshold of involved lymph nodes is debated, with a usually accepted cutoff value of 1.5 cm (31). Second, cross-sectioned lymph nodes observed on CT axial slices can have various directions, making thus their precise measurements unreliable. Third, reporting lymph
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node’s sizes is plagued by interobserver variability, even among experienced radiologists (32). Fourth, small (<1 cm) PET-negative lymph nodes may enclose disease (30). Finally, the isotropic margins for INRT varies from one cooperative groups to another, with an advocated cutoff value of 1 cm for the EORTC-GELA group (7), 2–3 cm for the German Hodgkin Study Group (33), and $3 cm in Canada (34). The feasibility of INRT planning for patients included in prospective protocols has been recently assessed, highlighting some methodologic difficulties (30, 33). The interpretation of data stemming from dose comparison series may be limited by the different optimization algorithms, which was not a shortcoming in this study using the Anisotropic Analytical Algorithm. It has however several limitations. First, commercial TPSs do not assess all the components contributing to the scattered and leaked dose delivered to OAR located not directly in vicinity of the target volume. Doses detailed in Tables 2 and 3 may well be underestimated (15). Second, the accuracy of these estimated OAR doses may vary from one TPS to another. It remains to be demonstrated that these data apply to other commercially available planning systems. Last, these data may be only applicable to a limited sample (mediastinal mass, female individuals) of all early-stage HL patients.
REFERENCES 1. Specht L, Gray RG, Clarke MJ, et al. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin’s disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin’s Disease Collaborative Group. J Clin Oncol 1998;16: 830–843. 2. Ng AK, Li S, Recklitis C, et al. Health practice in long-term survivors of Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2008;71:468–476. 3. Franklin JG, Paus MD, Pluetschow A, et al. Chemotherapy, radiotherapy and combined modality for Hodgkin’s disease, with emphasis on second cancer risk. Cochrane Database Syst Rev 2005: CD003187. 4. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al. Long-term cause-specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol 2003;21:3431–3439. 5. Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 2005;97:1428–1437. 6. Shahidi M, Kamangari N, Ashley S, et al. Site of relapse after chemotherapy alone for stage I and II Hodgkin’s disease. Radiother Oncol 2006;78:1–5. 7. Girinsky T, van der Maazen R, Specht L, et al. Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: Concepts and guidelines. Radiother Oncol 2006;79: 270–277. 8. Yahalom J, Mauch P. The involved field is back: Issues in delineating the radiation field in Hodgkin’s disease. Ann Oncol 2002;13(Suppl. 1):79–83. 9. International Commission on Radiation Units and Measurements. Prescribing, recording and reporting photon beam therapy. Washington, DC: Report 50; 1993. 10. Fogliata A, Clivio A, Nicolini G, et al. Intensity modulation with photons for benign intracranial tumours: A planning comparison of volumetric single arc, helical arc and fixed gantry techniques. Radiother Oncol 2008;89:254–262.
11. Ulmer W, Pyyry J, Kaissl WA. 3D photon superposition/convolution algorithm and its foundation on results of Monte Carlo calculations. Phys Med Biol 2005;50:1767–1790. 12. Feuvret L, Noel G, Mazeron JJ, et al. Conformity index: A review. Int J Radiat Oncol Biol Phys 2006;64:333–342. 13. Bortfeld T, Webb S. Single-Arc IMRT? Phys Med Biol 2009; 54:N9–N20. 14. Shaffer R, Morris WJ, Moiseenko V, et al. Volumetric modulated arc therapy and conventional intensity-modulated radiotherapy for simultaneous maximal intraprostatic boost: a planning comparison study. Clinical Oncology 2009;21:401–407. 15. Wirth A, Kron T, Wittwer H, et al. Phantom measurements and computed estimates of breast dose with radiotherapy for Hodgkin’s lymphoma: Dose reduction with the use of the involved field. J Med Imaging Radiat Oncol 2008;52:394–402. 16. Tarbell NJ, Gelber RD, Weinstein HJ, et al. Sex differences in risk of second malignant tumours after Hodgkin’s disease in childhood. Lancet 1993;341:1428–1432. 17. Henry-Amar M. Second cancer after the treatment for Hodgkin’s disease: A report from the International Database on Hodgkin’s Disease. Ann Oncol 1992;3(Suppl 4):117–128. 18. Dores GM, Metayer C, Curtis RE, et al. Second malignant neoplasms among long-term survivors of Hodgkin’s disease: A population-based evaluation over 25 years. J Clin Oncol 2002;20:3484–3494. 19. Boice JD Jr. Radiation and breast carcinogenesis. Med Pediatr Oncol 2001;36:508–513. 20. van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst 2003;95: 971–980. 21. Basu SK, Schwartz C, Fisher SG, et al. Unilateral and bilateral breast cancer in women surviving pediatric Hodgkin’s disease. Int J Radiat Oncol Biol Phys 2008;72:34–40. 22. Koh ES, Tran TH, Heydarian M, et al. A comparison of mantle versus involved-field radiotherapy for Hodgkin’s lymphoma:
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Reduction in normal tissue dose and second cancer risk. Radiat Oncol 2007;2:13. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA 1993;270:1949–1955. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol 2002; 20:2101–2108. Glanzmann C, Kaufmann P, Jenni R, et al. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother Oncol 1998;46:51–62. Myrehaug S, Pintilie M, Tsang R, et al. Cardiac morbidity following modern treatment for Hodgkin lymphoma: Supra-additive cardiotoxicity of doxorubicin and radiation therapy. Leuk Lymphoma 2008;49:1486–1493. Aleman BMP, van den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 2007;109:1878–1886. Stewart FA, Heeneman S, Te Poele J, et al. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE-/- mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. Am J Pathol 2006;168:649–658.
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29. Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: A surgical and autopsy study of 27 cases. Hum Pathol 1996;27:766–773. 30. Girinsky T, Specht L, Ghalibafian M, et al. The conundrum of Hodgkin lymphoma nodes: To be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines. Radiother Oncol 2008;88: 202–210. 31. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 1989;7:1630–1636. 32. Fletcher BD, Glicksman AS, Gieser P. Interobserver variability in the detection of cervical-thoracic Hodgkin’s disease by computed tomography. J Clin Oncol 1999;17:2153–2159. 33. Eich HT, Muller RP, Engenhart-Cabillic R, et al. Involved-node radiotherapy in early-stage Hodgkin’s lymphoma. Definition and guidelines of the German Hodgkin Study Group (GHSG). Strahlenther Onkol 2008;184:406–410. 34. Campbell BA, Voss N, Pickles T, et al. Involved-nodal radiation therapy as a component of combination therapy for limited stage Hodgkin lymphoma: A question of field size. J Clin Oncol 2008;26:5170–5174.
doi:10.1016/j.ijrobp.2009.05.012
PHYSICS CONTRIBUTION
INVOLVED-NODE AND INVOLVED-FIELD VOLUMETRIC MODULATED ARC VS. FIXED BEAM INTENSITY-MODULATED RADIOTHERAPY FOR FEMALE PATIENTS WITH EARLY-STAGE SUPRA-DIAPHRAGMATIC HODGKIN LYMPHOMA: A COMPARATIVE PLANNING STUDY DAMIEN C. WEBER, M.D.,* NICOLAS PEGURET, M.D.,* GIOVANNA DIPASQUALE, M.SC.,* z AND LUCA COZZI, PH.D. * Department of Radiation Oncology, Geneva University Hospital, University of Geneva; and z Oncology Institute of Southern Switzerland, Medical Physics Unit, Bellinzona, Switzerland Purpose: A comparative treatment planning study was performed to compare volumetric-modulated arc (RA) to conventional intensity modulated (IMRT) for involved-field (IFRT) and involved-node (INRT) radiotherapy for Hodgkin lymphoma (HL). Methods and Materials: Plans for 10 early-stage HL female patients were computed for RA and IMRT. First, the planning target volume (PTV) coverage and organs at risk (OAR) dose deposition was assessed between the two modalities. Second, the OAR (lung, breast, heart, thyroid, and submandibular gland) dose–volume histograms were computed and compared for IFRT and INRT, respectively. Results: For IFRT and INRT, PTV coverage was equally homogeneous with both RA and IMRT. By and large, the OAR irradiation with IFRT planning was not significantly different between RA and IMRT. For INRT, doses computed for RA were, however, usually lower than those with IMRT, particularly so for the lung, breast, and thyroid. Regardless of RA and IMRT modalities, a significant 20–50% decrease of the OAR computed mean doses was observed with INRT when compared with IFRT (Breast DMean 1.5 ± 1.1 vs. 2.6 ± 1.7 Gy, p < 0.01 and 1.6 ± 1.1 vs. 2.9 ± 1.9 Gy, p < 0.01 for RA and IMRT, respectively). Conclusions: RA and IMRT results in similar level of dose homogeneity. With INRT but not IFRT planning, the computed doses to the PTV and OAR were usually higher and lower with RA when compared to IMRT. Regardless of the treatment modality, INRT when compared with IFRT planning led to a significant decrease in OAR doses, particularly so for the breast and heart. Ó 2009 Elsevier Inc. Volumetric modulated arc therapy, IMRT, Hodgkin lymphoma, Involved node radiotherapy, Involved field radiotherapy.
The overall prognosis of patients with early-stage Hodgkin lymphoma (HL) is excellent, with an overall 10-year survival of more than 75% (1). With the current multimodality treatment, most patients achieve a lifelong complete remission, but poor health status (2) and secondary cancers (SC) remain a serious late effect of treatment (3). More importantly, SC are currently the primary cause of mortality among these cured patients (4). Female HL survivors present an increased risk of breast cancer (5). Consequentially, it is of paramount importance to decrease the breast dose of radiotherapy (RT) delivered for HL. Mediastinal RT is also associated with cardiotoxicity, especially in HL patients receiving a substantial cumulative
amount of anthracyclines. As such, the dose delivered to the heart should be also as low as reasonably possible. Intensity-modulated RT (IMRT) has the potential to achieve substantial improvement in dose distribution, when compared with non-IMRT dose deposition. IMRT can be delivered with fixed beam (thereafter, IMRT) or with volumetric modulated arc therapy (thereafter, RapidArc [RA]). Shahidi et al. have reported on the site of relapse after chemotherapy alone in 61 Stage I and II HL patients (6). Most of the recurrences (>80%) occurred in the initial involved lymph nodes. As such, the European Organization for Research and Treatment of Cancer (EORTC)–Groupe d’Etude des Lymphome de l’Adulte (GELA) has recommended that involved node RT (INRT) and not involved field RT
Reprint requests to: PD Dr.med. Damien C. Weber, Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. Tel: (+41) 22 38 27 090; Fax: (+41) 22 38 27 117; E-mail: [email protected]
Conflict of interest: Dr. L. Cozzi acts as Scientific Advisor to Varian Medical Systems. Other authors have no conflict of interest. Received March 26, 2009, and in revised form May 8, 2009. Accepted for publication May 11, 2009.
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RapidArc vs. IMRT for early-stage Hodgkin lymphoma d D. C. WEBER et al.
(IFRT) should be administered to early-stage HL patients, providing that modern diagnostic and therapeutic modalities, not limited but including 18f-Fluorodeoxyglucose (FDC)positron emission tomodensitometry (PET) and accurate radiation technology, should be used (7). It remains to be demonstrated however if INRT significantly decreases the OAR in vicinity of the target volume and if this observed decremental dose deposition is clinically significant. The present study was undertaken to assess the treatment planning inter-comparison between the best available photon techniques, namely RA and IMRT, as applied to a total of 10 early-stage female supra-diaphragmatic HL patients. Additionally, the dose delivered to the organs at risk (OAR) with IFRT and INRT were compared for both treatment modalities. METHODS AND MATERIALS
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the mid-clavicular head, the xiphoid process, the sternum, and the anterior portion of the latissimus dorsi muscle, respectively. Submandibular glands (SG) and thyroids were easily defined on the CT scans after intravenous contrast injection. The heart was defined from the auricles to the tip of this organ. The non-target tissue was defined as the patient’s volume covered by the CT scan minus the planning target volume (PTV).
IFRT The PTVIFRT derived from the volume defined by the IFRT approach of the Ann Arbor Staging system. RT fields were defined according to the guidelines of Yahalom and Mauch (8). The PTVIFRT was the CTV, including the GTV, expanded with a generically isotropic three-dimensional margin of 19–25 (mean, 21.7 1.7) mm automatically generated to precisely match the IFRT conventional fields. As recommended by the EORTC-GELA Lymphoma group guidelines, the major blood vessels and heart were avoided when possible (7).
Patients
INRT
Ten young female patients (mean age, 27.3 11.9) with earlystage (I-II) supra-diaphragmatic HL and mediastinal tumor masses who had been treated with conventional IFRT (30 Gy) in our institution were selected for this study. All had undergone prechemotherapy FDG-PET computed tomography (CT) imaging, with intravenous iodine contrast injection, as part of an institutional ethics–approved RT simulation protocol. A set of three triangulation lasers identical to those used on the linear accelerators, as well as a flat table top, were used for patient accurate positioning during the PET CT data acquisition (Biograph 16; Siemens Medical Solutions, Erlangen, Germany). Of note, patients underwent a second PET CT after two cycles of chemotherapy to assess the metabolic response. Finally, these patients underwent a postchemotherapy planning CT with iodine intravenous contrast injection and 3-mm slice thickness for RT planning (Picker 2000, Cleveland, OH). The simulation PET CT and planning CT were performed with the same immobilization devices (thermo-plastic mask) and the exact same position verified by the sets of lasers, with the patient in the supine position and the arm along the body.
The PTVINRT was the CTV, including the GTV, with a generically isotropic three-dimensional margin of 10 mm automatically generated (7). As recommended by the EORTC-GELA Lymphoma group guidelines, the major blood vessels and heart were avoided when possible (7).
Target definition Contouring was performed with Eclipse, version 8.6.10 (Varian, Palo Alto, CA). The gross tumor volume (GTV) was the lymph node remnant(s) after chemotherapy observed on the postchemotherapy planning CT (7). The clinical tumor volume (CTV) was the initial volume of the morphologic PET-positive lymph node(s) before chemotherapy. CTV were contoured by one experienced radiation oncologists (D.C.W.) using the Leonardo platform (Siemens Medical Solutions/CTI, Knoxville, TN). This volume delineated on the prechemotherapy simulation PET CT datasets was transferred to the final postchemotherapy planning CT using the picture archiving communication system. The CTV was modified automatically using the Eclipse editing tool to exclude the CTV from the abutting OAR when appropriate. A generically isotropic three-dimensional margin of 1 mm was implemented in the CTV editing process.
OAR delineation The whole breast was delineated on the CT datasets using a standard window (0) and width (500) level. Breast glandular tissue was limited posteriorly, anteriorly, superiorly, inferiorly, medially, and laterally by the pectoralis muscle, the first 5 mm beneath the skin,
Treatment IFRT and INRT were planned to deliver 30 Gy to PET defined target volumes. The initial goal for all treatment plans was to obtain PTV dose homogeneity of –5% and +7%, as recommended by the International Commission on Radiation Units and Measurements Report No. 50 (9). The beam energy used for all treatment was 6 MV. The treatment plans were generated using nine-field IMRT and RA techniques, all computed on the Varian Eclipse treatment planning system (TPS, version 8.6) with 6-MV photon beams from a Varian Clinac equipped with a millennium multileaf collimator with 120 leaves. Plans for RA were optimized selecting a maximum DR of 600 MU/min and a fixed DR of 600 MU/min was selected for IMRT. RA uses continuous variation of the instantaneous dose rate, millennium multileaf collimator leaf positions, and gantry rotational speed to optimize the dose distribution. Details about RA optimization process have been published elsewhere (10). To minimize the contribution of tongue and groove effect during the arc rotation and to benefit from leaves trajectories noncoplanar with respect to patient’s axis, the collimator rotation in RA remains fixed to a value different from zero. In the present study collimator was rotated to 30 depending on the patient. RA plan consisted on a single arc 360 . For IMRT, plans were designed according to the dynamic sliding window method with nine fixed gantry equally spaced beams (gantry starting angle 0 ). One single isocenter was located at the target center of mass. All beams were coplanar with collimator angle set to 0 . The millennium multileaf collimator was used for the study. The Anisotropic Analytical Algorithm photon dose calculation algorithm was used for all cases (11). The dose calculation grid was set to 2.5 mm. The dose constraints to the OAR are listed in Table 1. Quantitative evaluation of plans was performed by means of cumulative dose–volume histograms (DVHs). For PTV, the values of D1% and D99% (dose received by the 1% and 99% of the volume, respectively) were defined as metrics for minimum and maximum doses
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Table 1. Radiotherapy dose constraints to OAR OAR
D1% (Gy)
D33% (Gy)
D50% (Gy)
Priority
Lung Heart Breast Thyroid SG PTV PTV
20* 30* 20 30 15 31.5 28.5
10 15 10 25 10 —
5 7.7 5 18 5 —
4 2 3 5 6 1 1
Abbreviations: OAR = organs at risk; PTV = planning target volume; SG = submandibular gland. * As a result of tumor coverage requirements, a waiver can be applied on these dose constraints.
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To visualize the global difference between treatment techniques and planning paradigms, average cumulative DVH for GTV and PTV, OAR and non-target tissue, were built from the individual DVHs. These DVHs were obtained by averaging the corresponding volumes over the whole patient’s cohort for each dose bin of 0.05 Gy.
Statistical analysis The Wilcoxon matched-paired signed-rank test was used to compare the results among the RA-IMRT and IFRT-INRT plans. The threshold for statistical significance was p # 0.05. All statistical tests were two-sided and were performed using the StatView Statistical Analysis System, version 5.0 (SAS Institute Inc., Cary, NC).
RESULTS and thereafter reported. To complement the appraisal of mean dose, V95% and V107% (the volume receiving at least 95% or at most 107% of the prescribed dose) were reported. The dose conformity (12) index was calculated: (volume included in the 95% isodose)/volume PTV (CI95%). Inhomogeneity coefficients within the PTV were computed as (D5% – D95%)/D Mean, where Dn% is the minimal dose delivered to the percentage of volume of the target volume. Additionally, the number of monitor units (MU) required to deliver 2 Gy fraction was calculated for each plan. For non-target tissue, the integral dose (DoseInt), is defined as the integral of the absorbed dose extended to over all voxels excluding those within the target volume (DoseInt dimensions are Gy*cm3*105). This was reported together with the observed mean dose and some representative Dn% and VnGy (volume receiving n Gy) values.
RA vs. IMRT analysis For IFRT, PTV coverage was optimal and equally homogeneous with both RA and IMRT (Fig. 1). The mean V107% was identical (Table 2). A statistical trend toward better tumor conformation (CI95%) for IFRT (p = 0.14) was observed with RA (Table 2). The mean D95% was 28.4 0.5 vs. 28.3 0.4 Gy (p = 0.17) for RA and IMRT, respectively. For INRT, PTV was equally homogeneous, but a statistical trend toward signification for optimized PTV coverage with RA was observed (CI95% 0.96 0.04 vs. 0.94 0.02; p = 0.07; Table 2). The mean D95% was 28.7 0.5 vs. 28.3 0.4 Gy (p = 0.07) for RA and IMRT, respectively.
Fig. 1. Color wash volumetric-modulated arc radiotherapy (RA) and conventional intensity-modulated radiotherapy (IMRT) for involved-field (IFRT) and involved-node (INRT) for 2 patients (A, B) with Hodgkin lymphoma Stage IIB.
RapidArc vs. IMRT for early-stage Hodgkin lymphoma d D. C. WEBER et al.
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Table 2. Comparison of mean dosimetric parameters computed for RA and IMRT
Variable
IF
RT
IN
RT
Objectives
RA
IMRT
p
RA
IMRT
p
30.0 31.5 28.5 — 100 0.0 1.0 0.0
916 30.0 31.7 0.4 27.2 0.7 2.9 0.8 94.0 3.9 0.5 1.2 0.94 0.04 0.1 0.03
571 30.0 31.7 0.4 26.8 0.7 3.0 0.6 93.4 2.2 0.5 0.7 0.93 0.02 0.1 0.02
— 0.24 0.09 0.20 0.14 0.20 0.14 0.20
451 30.0 31.4 0.4 27.7 0.8 2.4 0.6 95.8 4.0 0.2 0.4 0.96 0.04 0.08 0.03
332 30.0 31.4 0.3 27.0 0.7 2.8 0.6 93.9 2.3 0.1 0.4 0.94 0.02 0.09 0.02
— 0.65 <0.01* 0.11 0.07 0.48 0.07 0.11
— 20.0y 10.0 5.0 —
8.2 1.5 28.5 1.2 9.4 1.7 5.5 1.5 30.9 6.2
8.4 1.5 28.4 1.4 10.2 1.5 6.0 1.9 33.8 6.6
0.09 0.51 0.03* 0.11 0.04*
6.4 1.5 26.2 2.2 7.2 1.8 3.8 1.9 23.2 7.4
6.7 1.4 26.2 2.1 8.4 1.4 4.1 2.2 26.1 6.9
0.04* 0.65 <0.01* 0.17 0.01*
— 30.0z 15.0 7.7 —
7.4 6.5 23.8 10.1 7.9 8.6 5.1 7.9 23.5 27.8
7.2 6.3 24.5 8.8 7.6 8.7 4.9 7.6 22.9 26.3
0.20 0.44 0.33 0.28 0.58
4.4 4.9 17.4 13.0 4.4 6.7 3.1 4.9 13.2 23.3
4.0 4.3 17.3 12.8 3.7 5.3 2.4 3.6 11.5 18.5
0.06 0.65 0.06 0.04* 0.35
— 20.0 10.0 5.0 -
2.6 1.7 13.7 8.1 2.4 1.9 1.3 0.9 6.7 6.8
2.9 1.9 15.2 7.9 2.6 2.1 1.2 0.9 9.4 8.9
0.01* 0.02* 0.17 0.51 0.01*
1.5 1.1 9.6 6.1 1.2 0.9 0.8 0.7 2.2 2.7
1.6 1.1 10.7 6.5 1.0 0.8 0.6 0.6 3.6 4.1
0.22 <0.01* 0.02* 0.05* 0.03*
— 30.0 25.0 18.0 —
23.3 9.0 28.2 8.0 25.4 9.2 23.9 9.8 85.8 31.7
23.7 9.0 28.5 7.5 25.4 9.5 24.2 9.7 88.2 31.3
0.14 0.24 0.89 0.56 0.03*
16.7 8.7 26.8 9.0 19.7 9.6 16.4 9.5 65.1 33.6
17.4 8.8 25.4 9.2 20.3 9.4 17.4 9.2 74.3 34.9
0.04* 0.24 0.39 0.11 0.01*
— 15.0 10.0 5.0 —
4.8 9.2 7.8 11.3 4.8 9.2 4.5 9.2 23.6 40.8
4.9 9.5 7.7 11.6 5.0 9.5 4.7 9.4 26.7 42.3
0.89 0.65 0.96 0.96 0.99
3.4 8.7 4.2 9.3 3.6 8.9 3.4 8.7 10.0 31.6
3.3 8.8 4.0 9.6 3.5 9.2 3.3 8.9 10.0 31.6
0.28 0.28 0.44 0.65 —
— — — —
6.7 1.9 23.1 7.2 1.1 0.5 376 84
7.1 1.8 26.3 7.5 1.2 0.5 1255 322
<0.01* <0.01* 0.04* <0.01*
5.1 1.8 16.8 6.8 0.9 0.4 367 99
5.3 1.7 18.7 7.8 0.9 0.5 1020 282
<0.01* <0.01* 0.06 <0.01*
3
PTV IFRT/INRT (cm ) DMean D1%(Gy) D99%(Gy) D5%–D95%(Gy) V95% (%) V107% (%) CI95% IC Lung DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Heart DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Breast DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Thyroid DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) SG DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V3 Gy(%) Non target tissue DMean(Gy) V10 Gy(%) DoseIntz Monitor units
Abbreviations: IF = involved field; IN = involved node; RA = volumetric modulated arc therapy; PTV = planning target volume; IMRT = intensity-modulated radiotherapy; RT = radiotherapy; CI95% = conformity index; DoseInt = integral dose. For CI95% see text. * Statistically significant; Wilcoxon matched-paired signed-rank test. y The OARs objectives could be waived to respect the target dose constraints. z Unit: Gy cm3 105.
Lung, IFRT. As a result of the planning dose constraints (Table 1), both techniques did not usually respect the planning objectives for D1% and D50%, whereas the objectives for D33% could be respected in a majority of patients (Table 2). Save for D1%, all lung dose–volume metrics were decreased with RA (Table 2). Compared with IMRT, the use of RA resulted in a significant decrease of lung irradiation in the mid-dose level (Table 2).
Lung, INRT. All but one planning dose constraints (D1%; Table 2) with both techniques were respected in a majority of patients, as a result of the smaller PTVs (Table 2). A significant decrease of lung dose–volume metrics was observed with RA in the mid-, but not the high-dose level (Table 2). Heart, IFRT. Planning dose constraints were met by all techniques in a majority of patients and no relevant difference was observed between RA and IMRT (Table 2).
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Table 3. Comparison of mean dosimetric OAR parameters computed for IFRT and INRT
Variable Lung DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Heart DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Breast DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) Thyroid DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V10 Gy(%) SG DMean(Gy) D1%(Gy) D33%(Gy) D50%(Gy) V3 Gy(%) Non target tissue DMean(Gy) V10 Gy(%) y DoseInt
R
A
IM
RT
IFRT
INRT
p
IFRT
INRT
p
8.2 1.4 28.4 1.2 9.4 1.7 5.5 1.5 30.9 6.2
6.4 1.5 26.2 2.2 7.2 1.7 3.8 1.9 23.2 7.4
<0.01* <0.01* <0.01* <0.01* <0.01*
8.4 1.5 28.3 1.4 10.2 1.5 5.9 1.8 33.8 6.6
6.7 1.4 26.2 2.1 8.3 1.4 4.1 2.2 26.1 6.9
<0.01* <0.01* <0.01* <0.01* <0.01*
7.4 6.5 23.8 10.1 7.9 8.6 5.1 7.9 23.5 27.8
4.4 4.9 17.4 13.0 4.4 6.7 3.1 4.9 13.2 23.3
<0.01* <0.01* <0.01* <0.01* 0.01*
7.2 6.2 24.5 8.8 7.6 8.7 4.9 7.6 22.9 26.3
4.0 4.3 4.0 4.3 3.7 5.3 2.4 3.6 11.5 18.5
<0.01* <0.01* <0.01* <0.01* <0.01*
2.6 1.7 13.7 8.1 2.4 1.9 1.3 0.9 6.7 6.8
1.5 1.1 9.6 6.1 1.2 0.9 0.7 0.7 2.2 2.7
<0.01* <0.01* <0.01* <0.01* <0.01*
2.9 1.9 12.2 7.9 2.6 2.1 1.2 0.9 9.3 8.9
1.6 1.1 10.7 6.5 1.0 0.8 0.6 0.6 3.6 4.1
<0.01* <0.01* <0.01* <0.01* <0.01*
23.3 9.0 28.2 8.0 25.4 9.2 23.9 9.8 85.8 31.7
16.7 8.6 26.8 9.0 19.7 9.6 16.4 9.5 65.1 33.6
<0.01* 0.08* <0.01* <0.01* <0.01*
23.7 9.0 28.5 7.5 25.4 9.5 24.2 9.7 88.2 31.3
17.4 8.8 25.4 9.2 20.3 9.4 17.4 9.0 74.3 34.9
<0.01* <0.01* <0.01* <0.01* <0.01*
4.8 9.2 7.8 11.3 4.8 9.2 4.5 9.2 23.6 40.8
3.4 8.7 4.2 9.3 3.6 8.9 3.4 8.7 10.0 31.6
<0.01* <0.01* <0.01* <0.01* 0.07*
4.9 9.5 7.7 11.6 5.0 9.5 4.7 9.4 26.7 42.3
3.3 8.8 4.0 9.6 3.5 9.2 3.3 8.9 10.0 31.6
<0.01* <0.01* <0.01* <0.01* 0.11
6.7 1.9 23.1 7.2 1.1 0.5
5.1 1.8 16.8 6.8 0.9 0.4
<0.01* <0.01* <0.01*
7.1 1.8 26.3 7.5 1.2 0.5
5.3 1.7 18.7 7.8 0.9 0.5
<0.01* <0.01* <0.01*
Abbreviations: IF = involved field; IN = involved node; RA = volumetric modulated arc therapy; IMRT = intensity-modulated radiotherapy; RT = radiotherapy; DoseInt = integral dose. * Statistically significant; Wilcoxon matched-paired signed-rank test. y Unit: Gy cm3 105.
Heart, INRT. Planning dose constraints were met by all techniques in a majority of patients (Table 2). Save for D50%, all other dose–volume metrics were nonsignificantly decreased with IMRT when compared with RA (Table 2). Breast, IFRT. Planning dose constraints were met by all techniques (in a majority of patients for DMean; Table 2). A significant difference was observed in the breast high- and mid-dose level between RA and IMRT. Breast, INRT. Planning dose constraints were met by all techniques (Table 2). A significant decrease of breast irradiation at the Gy unit level was observed with IMRT. Conversely, RA planning allowed a significant reduction of the irradiation of the breast in the low- to mid-dose level (Table 2). Thyroid IFRT. Planning dose constraints were met by both techniques in a majority of patients except for D33% (Table 2). V10Gy was significantly decreased with RA. Thyroid INRT. Planning dose constraints were met by both techniques (Table 2). The dose in the mid-dose level
(DMean and V10Gy) was significantly decreased with RA when compared with IMRT. SG IFRT and INRT. Planning dose constraints were met by both techniques in a majority of patients and no relevant difference was observed between RA and IMRT (Table 2). Healthy tissue, IFRT, and INRT. No planning dose constraints were implemented. Dose–volume metrics were substantially decreased with RA when compared with IMRT (Table 2). More specifically, the DoseInt was significantly decreased with RA-IFRT and RA-INRT when compared with IMRT-IFRT and IMRT-IFRT planning, respectively (Table 2; Fig. 1). Monitor unit. The mean number of MU per fraction was significantly reduced by a factor of approximately three for RA, when compared with IMRT planning (Table 2). IFRT vs. INRT analysis Independently of RA or IMRT, INRT when compared with IFRT planning reduced substantially all computed doses to the OAR (Table 3; Fig. 2). For the lung, a mean
RapidArc vs. IMRT for early-stage Hodgkin lymphoma d D. C. WEBER et al.
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Fig. 2. Mean dose–volume histograms for planning target volumes (PTVs) and organs at risk (OAR) for involved-field (IF) and for involved-node (IN) radiotherapy. IMRT = intensity-modulated radiotherapy; RA = volumetric-modulated arc radiotherapy.
decrease of 21.9 7.0% (p < 0.01) and 19.9 5.8% (p < 0.01) for DMean was calculated for RA and IMRT, respectively (Fig. 2). Likewise, the computed mean decrease of DMean for the heart and breast were 50.5 15.1% (p < 0.01) 44.8 16.3% (p < 0.01) and 42.3 13.2% (p < 0.01) 46.7 11.4% (p < 0.01) for RA and IMRT, respectively (Fig. 2). The computed mean decrease of DMean for
the thyroid and SG were 30.2 16.5% (p < 0.01) 30.2 16.9% (p < 0.01) and 40.4 21.9 (p < 0.01) 43.1 23.2% (p < 0.01) for RA and IMRT, respectively (Fig. 2). Finally, computed mean DosInt was decreased by one fourth with INRT when compared with IFRT planning (24.4 8.4%; p < 0.01 and 24.7 7.2%; p < 0.01 with RA and IMRT, respectively).
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DISCUSSION
with mantle or mini-mantle irradiation, substantially reduces the dose to these OAR by a factor of approximately 50 and 10, respectively, although these calculated IFRT breast doses may be somewhat underestimated (15). It is a fundamental principle in radiation oncology that, all things being equal, the probability of SC increases as the radiation dose to OAR is increased, with no safe cutoff value. Reports on atomic bomb survivors suggest an increased risk of breast cancer below the Gy unit. With have chosen to select only female HL patients for this study, as they are at risk for SC, with a reported incidence of 57 times that expected in the normal population (16). INRT planning decreased the breast dose significantly by a factor of approximately two with both RA and IMRT (Table 3). Among the SCs, breast cancer is the most common malignancy among female survivors (17, 18). In a case control study stemming from five population-based cancer registries, an increase in the absolute risk of secondary breast cancers with the thoracic radiation dose was observed for patients diagnosed at age 30 years or younger (5). Compared with that of the general population, the relative risk of breast SC was 1.7 (95% CI 0.6–5.2), 8.5 (95% CI 5.4–13.2), and 10.5 (95% CI 6.8–16.0) after 0, 20–39.9, and $40 Gy of mediastinal RT with no chemotherapy, respectively. Likewise, other reports suggest that the risk of breast cancer is dose related (19–21). As such, delivering radiation to smaller volumes, such with an INRT paradigm, could potentially decrease the substantial SC rate of HL’s survivors. This hypothesis was theoretically validated by the analysis from the Princess Margaret Hospital converting breast dose data to breast cancer risk using a quantitative model (22). Moving from mantle to IFRT would reduce breast SC risk by 65% and reducing the prescribed dose by 40% would reduce cancer risk by a further 40%. The predicted risk for SC of this cohort planned with IFRT and INRT will be fully assessed in a forthcoming publication. Late cardiac toxicity usually observed 5–10 years after treatment for HL is also a major concern for HL survivors (23, 24), especially for those with preexisting cardiovascular risk factors (25). Compared with the general population, the cardiac morbidity for HL survivors after doxorubicin and mediastinal RT is increased three- to five-fold, when adjusting for other cardiac competing risk factors (26, 27). Age <20 years at the time of irradiation, such as observed in half of our patient cohort, is a major risk factor for cardiac mortality (23, 27). Moreover, mediastinal dose was also a major risk factor for cardiac toxicity in the Stanford series (23). Damage to the vascular endothelium of the arteries is believed to be the main pathogenic process of radiation-induced heart disease in animal models (28) and humans (29). As such, decreasing the computed cardiac dose with INRT (Table 3) may substantially decrease the cardiac morbidity. The observed decrease for the breast dose with INRT is mostly relevant when nonconventional RT (i.e., RA or IMRT) is administered. Administering conventional mediastinal RT (30 Gy) delivers approximately a mean dose of 1 Gy (range, 0.1–5.8) to the breasts (data not shown). Administering intensity modulated RT, be it RA
The present study evaluated the conformal OAR sparing ability of both RA and IMRT. With INRT but not IFRT planning, dose–volume metrics were usually lower with RA, when compared with IMRT, particularly so for the lung, heart and thyroid (Table 2). As with IMRT, RA delivers radiation with a multileaf collimator, which changes the shape of the treatment field dynamically, but unlike the latter technique that delivers IMRT from a relatively small number of fixed gantry angles, the whole treatment is delivered with only one rotation and not with fixed fields, which is thus potentially faster. Treatment time is a paramount parameter when evaluating these two techniques. At one extreme, if this parameter is ignored, in concert with neglecting the dose rate continuous variation and the usage of non-zero collimator angles (putting more leaves couples in play to generate every pixel of modulation), these two modalities are theoretically alike: slowing down the gantry to infinitesimally small rotational speeds for RA enables one to fully exploit fluencemodulation at any given angle while using numerous gantry angles for IMRT delivers dose distributions that could be very similar to those obtained by simple conformal dynamic rotation of the gantry (13). Nonetheless, RA has two additional previously mentioned features, which increase the space and the modulation capability beyond limits recently suggested by Bortfeld and Webb (13). Taking into account the full range of optimization features (i.e., increasing the number of fields for IMRT and reducing the rotational speed, incorporating dose rate variation and non-zero collimation for RA), the observed advantage with RA for INRT planning may also result from the increased distance from the PTV and OAR, when compared with IFRT planning: RA exploits optimally all angles to conform dose deposition in three dimensions to the target and its so-called less advantageous fluence modulation capability, when compared with IMRT planning with its finite sampling of gantry angles but optimized per field intensity modulation ability, does not penalize the resulting treatment plans. Noteworthy, the optimization of the beam angles for IMRT may be a debatable parameter, which does not occur with RA. Additionally, RA for these HL patients could be considered more efficient, because the number of MU is significantly decreased with this modality (Table 2). This significant decrease in MU will translate in a treatment time reduction and consequential reduction in scatter and linear accelerator head leakage dose (14). Importantly, it remains to be demonstrated that the observed ‘‘advantage’’ of RA for certain OAR observed in this study will translate into a clinical benefit. To the best of our knowledge, the present study is the first series to compare formally the OAR doses computed with IFRT and INRT planning. Our results show that an overwhelming number of dose–volume metrics are significantly decreased with INRT when compared with IFRT planning (Table 3). These data are in line with a recent study, assessing breasts doses in an anthropomorphic phantom, which showed that IFRT delivered to the cervical region, when compared
RapidArc vs. IMRT for early-stage Hodgkin lymphoma d D. C. WEBER et al.
or IMRT, increases this mean dose by a factor of 2–3. We are left with the conundrum of how to capitalize the conformal ability of intensity modulated RT with its potential decrease in toxicity for structures within the treatment field (i.e., lung, heart) while avoiding any consequential increase of SC risk to the outfield OAR such as the breasts. With its intrinsic increase of integral dose, nonconventional RT may contra-productively nullify the potential advantage of this modality. As such, the potential benefit of a generally smaller RT volume, which can be validly inferred from Table 3, should be particularly desirable if IMRT is the chosen treatment modality for a given patient. As a result of our institutional protocol, all HL patients undergo PET CT simulation before chemotherapy. As recently discussed in the EORTC-GELA guidelines, PET data should be used for INRT planning purposes (30). A note of caution should be made however on the optimal feasibility of INRT planning for early HL which has never been tested in a prospective trial with appropriate quality insurance. First, the current threshold of involved lymph nodes is debated, with a usually accepted cutoff value of 1.5 cm (31). Second, cross-sectioned lymph nodes observed on CT axial slices can have various directions, making thus their precise measurements unreliable. Third, reporting lymph
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node’s sizes is plagued by interobserver variability, even among experienced radiologists (32). Fourth, small (<1 cm) PET-negative lymph nodes may enclose disease (30). Finally, the isotropic margins for INRT varies from one cooperative groups to another, with an advocated cutoff value of 1 cm for the EORTC-GELA group (7), 2–3 cm for the German Hodgkin Study Group (33), and $3 cm in Canada (34). The feasibility of INRT planning for patients included in prospective protocols has been recently assessed, highlighting some methodologic difficulties (30, 33). The interpretation of data stemming from dose comparison series may be limited by the different optimization algorithms, which was not a shortcoming in this study using the Anisotropic Analytical Algorithm. It has however several limitations. First, commercial TPSs do not assess all the components contributing to the scattered and leaked dose delivered to OAR located not directly in vicinity of the target volume. Doses detailed in Tables 2 and 3 may well be underestimated (15). Second, the accuracy of these estimated OAR doses may vary from one TPS to another. It remains to be demonstrated that these data apply to other commercially available planning systems. Last, these data may be only applicable to a limited sample (mediastinal mass, female individuals) of all early-stage HL patients.
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