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First French experiences of total body irradiations using helical TomoTherapy®
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Original article
First French experiences of total body irradiations using helical ® TomoTherapy ®
Premières expériences franc¸aises d’irradiation corporelle totale par TomoTherapy R. Sun a , X. Cuenca a , R. Itti b , S. Nguyen Quoc c , J.-P. Vernant c , J.-J. Mazeron a , C. Jenny d , M. Chea d,∗ a
Department of radiation oncology, hôpital Pitié-Salpêtrière, 47–83, boulevard de l’Hôpital, 75651 Paris cedex 13, France Department of radiation oncology, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France c Department of hematology, hôpital Pitié-Salpêtrière, 47–83, boulevard de l’Hôpital, 75651 Paris cedex 13, France d Department of medical physics, hôpital Pitié-Salpêtrière, 47–83, boulevard de l’Hôpital, 75651 Paris cedex 13, France b
a r t i c l e
i n f o
Article history: Received 22 November 2016 Received in revised form 19 January 2017 Accepted 24 January 2017 Keywords: Radiotherapy Total body irradiation ® Helical TomoTherapy Junction method Bone marrow transplant
a b s t r a c t ®
Purpose. – Dynamic conformal radiotherapy with helical TomoTherapy (HT) offers a more quantitative paradigm for total body irradiation. Treatment planning, delivery, dose verification of the first French ® experiences of total body irradiation using helical TomoTherapy are presented. Materials and methods. – Patients planned for total body irradiation at our institution from February 2012 to May 2013 were reported. Total body irradiation consisted in a single fraction of 2 Gy. Planning target volume was divided in two due to the limited translation length of the table. Delivery quality assurance was performed with cylindrical phantom, ionization chamber and films. Thermoluminescent dosimeters and radiochromic films were used for in vivo dosimetry and junction region heterogeneity assessment. Results. – Six patients were included. One finally did not receive the treatment but dosimetric data were analyzed. Planned V95% was covered by D95% and V2% did not exceed D107% for five of the six patients. The mean relative difference between measured and calculated absolute dose of the Delivery quality assurance was always less than 2.5% (mean value ± SD: 1% ± 0.67%). Gamma index (3%; 3 mm) was less than 1 for at least 93% of the points (value ± SD: 97.4 ± 1.6% and 96.6 ± 2.5% for upper and lower part of treatment respectively). Difference between in vivo measured and calculated dose was above 5% for only two out of 15 points (maximum: 10.2%, mean: 0.73 ± 4.6%). Junction region heterogeneity was in average 5.8 ± 1%. The total treatment session of total body irradiation lasted 120 min, with a mean beam on time of 17.2 ± 0.6 and 11.2 ± 1.6 min for upper and lower part of the body respectively. ® Conclusion. – Total body irradiation using helical TomoTherapy guaranteed high dose homogeneity throughout the body and dose verification was achievable, showing small difference between planned and delivered doses. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2017 Societ rights reserved.
r é s u m é Mots clés : Radiothérapie Irradiation corporelle totale Tomothérapie hélicoïdale Méthode de jonction Transplantation de moelle osseuse
Objectif. – Les techniques non conformationnelles ne permettent pas un contrôle et une homogénéité de la dose dans les irradiations corporelles totales. Nous décrivons la planification, l’administration et la ® vérification de la dose des premières irradiations corporelles totales franc¸aises par TomoTherapy . Matériel et méthodes. – Les données des patients pour qui une irradiation corporelle totale par ® TomoTherapy a été planifiée dans notre centre entre février 2012 et mai 2013 sont rapportées. L’irradiation corporelle totale consistait en une séance unique de 2 Gy. Le volume cible prévisionnel a été divisé en deux à cause de la longueur limitée de traitement. L’assurance qualité a été effectuée dans
∗ Corresponding author. E-mail address: [email protected] (M. Chea). http://dx.doi.org/10.1016/j.canrad.2017.01.014 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2017 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
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un fantôme cylindrique avec des films et des chambres d’ionisation. La dosimétrie in vivo et l’évaluation de l’homogénéité de la dose dans la zone de jonction ont été réalisées par dosimètres thermoluminescents et films radiochromiques. Résultats. – Six patients ont été inclus. Un n’a finalement pas rec¸u de traitement, mais les données dosimétriques sont rapportées. Le volume recevant 95 % de la dose prescrite (V95 % ) était couverte par la D95 % et celui recevant 2 % (V2 % ) était inclus dans l’isodose 107 % (D107 % ) pour cinq patients sur six. Pour le contrôle qualité, la différence entre doses délivrée mesurée et théorique était toujours moins de 2,5 % (moyenne ± déviation standard : 1 % ± 0,67 %). Le gamma index (3 % ; 3 mm) était de moins de 1 pour au moins 93 % des points (97,4 ± 1,6 % et 96,6 ± 2,5 % respectivement pour les plans supérieurs et inférieurs). Une différence relative entre doses mesurée in vivo et attendue était de plus de 5 % pour deux parmi 15 mesures (0,73 ± 4,6 %). L’hétérogénéité dans la zone de jonction était en moyenne de 5,8 ± 1 %. La réalisation totale l’irradiation corporelle totale a demandé 120 min avec un temps de traitement de 17,2 ± 0 min et 11,2 ± 1,6 min pour respectivement les parties supérieure et inférieure. Conclusion. – La tomothérapie a permis une distribution homogène de la dose. Les différences entre doses mesurée et théorique étaient faibles. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2017 Societ ´ ´ droits reserv es.
1. Introduction Total body irradiation is widely used as a preparatory regime before bone marrow transplant to provide both immunosuppressive and cytotoxic effects. Nevertheless, current accepted techniques of total body irradiation are laborious, time-consuming and cumbersome, and lead to significant acute and late toxicity due to the non-conformity of beam-application with the inability to individually spare organs at risk [1–5]. In addition, dose prescription and verification is usually limited to single-point measurements. The advent of dynamic conformal radiotherapy in the form ® of helical TomoTherapy offers a new and more quantitative paradigm for total body irradiation dose planning and delivery. Different groups have investigated the feasibility of this technology in total body irradiation, total marrow- or total lymphoid irradia® tion and it seems that the use of helical TomoTherapy is feasible and could increase the homogeneity of dose distribution on target structures and decrease the dose to the organs at risk [6–13]. However, the length of planning target volume (PTV) is limited to 145 cm (due to the limited translation length of the table), so it is necessary to treat the patient in two parts with special management of the junction to ensure the quality of treatment. The purpose ® of this study was to establish the use of helical TomoTherapy for the conditioning regimen before bone marrow transplant at our institute. Treatment planning, delivery, dose verification of the six first French experiences of total body irradiation using helical ® TomoTherapy are here presented. We attempted to have good homogeneity coverage without over- or under-coverage. Because of the limited length of treatment ® with helical TomoTherapy , we used an original junction between upper and upper part of the patient.
Fig. 1. First French experiences of total body irradiation using helical ® TomoTherapy : immobilization and in vivo measurements. Patients were immobilized in a supine position using a whole body vacuum bag and a thermoplastic head mask. The junction region homogeneity was checked with at least one radiochromic films on each thigh. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : immobilisation et mesures in vivo. Le patient était immobilisé en décubitus dorsal par un matelas sous vide et un masque thermoformé. L’homogénéité de la dose dans la zone de jonction a été évaluée par au moins un film radiochromique sur chaque cuisse.
To check the tilt of the body, tattoo marks were also placed in the pelvic area. Two sets of planning kilovoltage CT images (Lightspeed RT 16, GE, USA) with a 5 mm slice thickness were acquired: one for the upper body HFS oriented (from vertex to knees) and one for the lower body FFS oriented (from feet to pelvis).
2. Methods
2.2. Contouring
2.1. Positioning/planning CT
The ISOgray treatment planning system was used for contouring (version 4.1.2.64L, Dosisoft, France). The target volume (PTV) was delineated with the external contours for lower and upper parts. The junction has been marked at mid-thighs: 15 cm above the knee on both thighs. We used five transition volumes of 2 cm each (Fig. 2). Some organs at risk were delineated and included lungs, brain, brainstem, spinal cord, eyes, crystalline lens, heart, liver and kidneys.
Patients were immobilized in a supine position using a wholebody vacuum bag (Elekta, Sweden) for body support and a customized thermoplastic head mask (three points) (Seemed© France) for head support on an adjustable combined board (Fig. 1). For localization purpose, tattoo marks were placed at least at the intersection of the mid-sagittal plane and the inter-nipple line and at the junction plane, which was defined by the mid-thighs plane.
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We prescribed 2 Gy delivered as a single dose to the planning target volume. The objectives to achieve were the coverage of 95% of the planning target volume by 95% of the prescribed dose, and the respect of a maximum of 107% of the prescribed dose, for the V2% (ICRU criteria [14,15]). The dose homogeneity index was defined as the ratio of the dose received by 90% of the planning target volume to the minimum dose received by the ‘hottest’ 10% of the planning target volume [16]. For the treatment planning, we chose a 5 cm field width, a pitch of 0.43 and a modulation factor of 1.8. 2.4. Positioning/image guidance, and treatment To avoid transferring the patient to another machine during treatment we divided the planning target volume of patients into two parts and the treatment was delivered in two consecutive times with different patient orientation: (I) head first from vertex to the junction plane and (II) after repositioning: feet first from toes to the junction plane. To control the dose gradient in the junction region, at midthighs, we used five transition volumes of 2 cm high for each volume, on which the upper and lower parts of the treatment are superimposed. For each treatment plan, the prescribed dose gradually decreased in the five transition volumes. In each transition volume, the sum dose prescribed of each plan (upper and lower) was 2 Gy. Positioning was verified prior to treatment using two megavoltage (MV)-CTs for the upper part on the craniocervical and the pelvic areas, and one MV CT for the lower part (on the knee area) [17]. For the upper part, the applied displacements in all directions were the average deviation between the 2 MV CT. If the deviation between the craniocervical and the pelvic MV CT requested displacements and the necessary displacements applied were less than 4 mm, the treatment started. Otherwise, the patient was clinically repositioned and MV CT were performed again. 2.5. Quality assurance
Fig. 2. First French experiences of total body irradiation using helical ® TomoTherapy : 3D view of the upper and the lower planning target volumes. Five transition volumes of 2 cm (colored planning target volumes) were created for the junction method. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : visualisation tridimensionnelle de la partie supérieur et inférieure du volume cible prévisionnel. Cinq volumes de transition de 2 cm de hauteur chacun (volume cible prévisionnel coloré) ont été construits pour la zone de jonction.
Three-dimensional data sets with contours were transferred ® ® to the TomoTherapy treatment planning system (TomoTherapy Inc., Madison, WI 53717–1954 USA) for planning. VoLOTM technology was available after the start of the study and was used to calculate and optimize the treatment plans of the last patient. 2.3. Conditioning regimen, dose prescription and fractionation The conditioning regimen consisted of total body irradiation the day before allograft (d1). Chemotherapy consisted of fludarabine 30 mg/m2 alone, from d4 to d2; or fludarabine 30 mg/m2 plus cyclosporine 14.5 mg/m2 from d6 to d2, depending on the decision of hematologists. Graft versus host disease was prevented by ® ciclosporin and mycophenolate mofetil (Cellcept ).
Each treatment plan was checked before the treatment by a qualified medical physicist to assure that the planning dose could be delivered with high accuracy. The delivery quality assurance was performed with cylindrical phantom (Cheese phantom, Med-Cal, USA), ionization chamber (Exradin A1SL, Standard imaging, USA) for absolute dose and films (EDR2, Carestream, Canada) for relative dose, and with at least: • two delivery quality assurance for the upper part: chest and junction; • one delivery quality assurance pour the lower part: junction. During the treatment session, in vivo dosimetry was performed with thermoluminescent dosimeters (GR200A, LiF) positioned on three different regions for each patient among sternum or axilla for the upper part, and the iliac fossae or between the legs at mid-thigh for the lower part. These regions had to be easily accessible without having to move the patient because thermoluminescent dosimeters were placed after the pretreatment MV CT. Positions of the thermoluminescent dosimeters were changed after the first treatments because the use of the iliac fossa region did not ensure electronic equilibrium. Conversely, the measurement point on the sternum was well suited. For this, the thermoluminescent dosimeters were placed 1.5 cm under the bolus to have enough dose build up. The bolus was considered during the treatment planning. There was a cluster of three to five thermoluminescent dosimeters for each measurement point. Measured doses were corrected to consider the daily calibration factor of the thermoluminescent dosimeters ®
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and a non-linearity dose response correction was applied. The relative difference between the corrected measured dose and calculated dose was defined as:
Age, sex, original disease of the patient, tolerance and adverse side effects were recorded. Characteristics of patients are resumed in Table 1.
Relative difference (%)
4. Results
mean corrected measured doses − calculated dose = × 100 calculated dose
From February 2012 to June 2013, six patients were planned for ® total body irradiation using helical TomoTherapy , but only five reached the treatment. We analyzed the treatment planning for all the six patients, as it has been fully performed for them all and we analyzed the quality assurance data for the five patients who were actually treated.
The junction region homogeneity was checked with at least one radiochromic films (EBT2, Ashland, USA) on each thigh. In the junction region, the dose heterogeneity was defined as: Dose heterogeneity (%) =
maximum dose − minimum dose × 100 maximum dose + minimum dose
4.1. Dosimetry
3. Patients
The average time between the start of delineation and the treatment planning validation was 11.5 days, ranging from 13 to 6 days. This reduction was permitted by the use of the VoLOTM technology. The time required to delineate was 4 h: 2 h for the target volume and the organs at risk and 2 h more for the five subvolumes of the junction region. For the upper part, the average volume (±SD) of the target covered by 95% of the prescribed dose (V95% ) was 95.6 ± 2.46%, and the average (±SD) volume exceeding 107% of the prescribed dose (V107% ) was 2.7 ± 1.85%. Only one of six patients presented an undercoverage with a V95% of 91.1%. V107% was less than 2% for three patients. In the other three patients, V107% was 6.4%, 2.3 and 2.1%. No patient presented undercoverage of the lower part of treatment, with a mean V95% of 98.0 ± 1.03%. Average V107% was 1.6 ± 1.00%, and exceeded 2% for two patients (2.2% and 3.3%). The average dose homogeneity index (±SD) (D90% /D10% ) was 0.93 ± 0.01 for the upper part (range: 0.91–0.94) and 0.94 ± 0.01 for the lower part (range 0.93–0.95) (Table 2, Fig. 3).
All patients whose total body irradiation using Helical ® TomoTherapy was planned at our institution were included. We analyzed all the available data, even if the patient had not actually received the treatment. From February 2012 to May 2013, six patients were included for conditioning before allogeneic bone marrow transplantation by ® total body irradiation using helical TomoTherapy . Three patients presented with chronic lymphocytic leukemia, of whom two were transformed into Richter’s syndrome, two with Hodgkin disease, and one with multiple myeloma. All patients presented with highrisk features such as non-response to chemotherapy, recurrence disease, and complex karyotype. Three patients were in complete or partial remission at time of the total body irradiation. Four patients have had prior autologous peripheral stem-cell transplantation, and two patients have had prior radiation therapy (30 Gy mediastinum, and 6 Gy total body irradiation).
Table 1 ® First French experiences of total body irradiation using helical TomoTherapy : patients’ characteristics. Three patients presented with chronic lymphocytic leukemia, of whom two were transformed into Richter’s syndrome, two with Hodgkin disease, and one with multiple myeloma. Four patients have had prior autologous peripheral stem cell transplantation, and two patients have had prior radiation therapy (30 Gy mediastinum, and 6 Gy total body irradiation). ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : caractéristique des patients. Trois patients étaient atteints d’une leucémie lymphoïde chronique, dont deux se sont transformées (syndrome de Richter). Deux patients avaient une maladie de Hodgkin, et un patient un myélome multiple. Quatre patients avaient rec¸u une autogreffe de cellules souches périphériques et deux avaient rec¸u une radiothérapie (une médiastinale et une corporelle totale). Patientno.
Sex and age
Diagnosis
In remission at time of total body irradiation?
Autologous-stem cell transplantation
Prior radiation treatment
Date of total body irradiation
1 2
Female, 66 years Male, 64 years
Richter 3rd recurrence Richter recurrence
– –
– –
13/03/2012 16/07/2012
3
Female, 65 years
May 2012
Female, 22 years
Yes
January 2012
5
Male, 59 years
February 2013
6
Female, 28 years
No, refractory to treatment No, refractory to treatment
Total body irradiation 6 Gy – May 2012 Mediastinum 30 Gy – April 2010 –
10/09/2012
4
Chronic lymphocytic leukemia 5th recurrence Hodgkin 3rd recurrence Myeloma 2nd recurrence Hodgkin non responsive 1st recurrence
Yes No, hyperlymphocytosis 42 G/l Yes
April 2012
–
18/10/2012 24/06/2013 Finally treated in another institution
Table 2 ® First French experiences of total body irradiation using helical TomoTherapy : dosimetric data for the treatment plans. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : données dosimétriques des plans de traitement. Patients (n = 6)
V95% (%)
V102% (%)
V107% (%)
Dmax (Gy)
D2% (Gy)
D98% (Gy)
Dmin (Gy)
Dose homogeneity index (D90% /D10% )
Upper part planning target volume Lower part planning target volume
95.63 (±2.46)
23.26 (±4.11)
2.69 (±1.85)
2.37 (±0.04)
2.15 (±0.03)
1.81 (±0.10)
0.93 (±0.16)
0.93 (±0.01)
97.95 (±1.03)
19.95 (2.09)
0.61 (1.00)
2,29 (±0.06)
2.14 (±0.02)
1.90 (±0.03)
1.90 (±0.03)
0.94 (±0.01)
Vx% : volume of the target covered by % of the prescribed dose; Dmax : maximum dose; Dmin : minimum dose.
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Fig. 3. First French experiences of total body irradiation using helical TomoTherapy : treatment plans of the first patient receiving a TomoTherapy in our institute. The delivered dose was homogenous for the upper, the lower part, and the junction plan. ® ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : plan de traitement du premier patient pris en charge par TomoTherapy dans notre centre. La dose délivrée était homogène pour les plans supérieurs, inférieurs et la zone de jonction.
There were no dose peaks above 123% of the prescribed dose. Actual average Dmean ± SD for lungs was 2.01 ± 0.02 Gy and 2.006 ± 0.018 Gy for right and left lung respectively. 4.2. Pretreatment verifications For the five patients analyzed, a total of 36 points were measured. The checking before the treatment showed a good correlation between planned and delivered absolute and relative dose. The average absolute dose relative difference (±SD) was 1 ± 1%, and for each delivery quality assurance, the relative difference between measured and calculated absolute dose was less than 2.5% (Table 3, Fig. 4). For the dose distribution comparison, gamma index (3%; 3 mm) was less than 1 for at least 93% of the points for all patients (mean value ± SD: 97.4 ± 1.6% and 96.6% ± 2.5% for upper and lower part of treatment respectively) (Table 3). 4.3. Treatment Three patients needed to be replaced for the upper part treatment, and two for the lower part treatment because of setup errors of more than 4 mm. The average (±SD) couch shifts were 1.0 (±2.3), –2.0 (±3.7) and 3.9 (±1.3) mm in the lateral, longitudinal and vertical directions
respectively for the upper part treatment. The mean difference between the treatment position and the expected position, according to the cranial and pelvic MV CT, was 0 mm in all directions with standard deviations of 1.1, 1.7, 1.6 mm in the lateral, longitudinal and vertical directions respectively. Regarding the lower part treatment, the average (±SD) couch shifts were 3.1 (±2.83), –5.05 (±1.06) and 3.80 (±1.27) mm in the lateral, longitudinal and vertical directions respectively. We needed three or four MV CT (mean 3.5) to replace the patient with accuracy. Beam-on-time ranged from 16.2 min to 17.8 min (average (±SD): 17.2 ± 0.55 min) for the upper plan and 8.7 min to 13 min (average (±SD): 11.2 ± 1.59 min) for the lower plan. Overall “in-room”-time exceeded beam-on-time, and was about 120 min per patient. 4.4. In vivo dosimetry Difference between in vivo measurements by thermoluminescent dosimeters and calculated dose was satisfactory, but among the 15 points (three points by patient), there was more than 5% difference between calculated and measured dose for two points: –7.6% on the right thigh in one patient, +10.2% on the left thigh in another patient (mean of the relative difference between measured and calculated dose (±SD): 1.19 ± 4.31%) There was no underdosing observed, and the measured dose stayed under 107% of the prescribed dose for each point, and upper 95% of the prescribed
Table 3 ® First French experiences of total body irradiation using helical TomoTherapy : pretreatment results (delivery quality assurance). Mean relative difference between measured and calculated dose (absolute dose and dose distribution). ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : résultats des contrôles qualités prétraitement. Différence relative moyenne entre dose mesurée et calculée (dose absolue et distribution de la dose).
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Mean (±SD)
Mean relative difference measured/calculated dose
Percentage of points with gamma index <1 (3%. 3 mm)
Upper part (%)
Lower part (%)
Upper part (%)
Lower part (%)
0.7 1.3 0.5 1.0 0.9 0.9 (±0.3)
1.3 1.8 0.8 0.8 1.1 1.2 (±0.4)
95.2 99.4 97.5 99.0 96.0 97.4 (±1.6)
95.4 95.5 99.0 100,0 93.2 96.6 (±2.5)
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Fig. 4. First French experiences of total body irradiation using helical TomoTherapy : example of the first patient’s upper part junction delivery quality assurance. The dose profiles showed that measured dose (in red) was consistent with calculated dose (in blue). ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : exemple de contrôle qualité réalisé pour la partie supérieur du plan de traitement du premier patient. Le profil de dose montre que la dose mesurée (en rouge) concorde avec la dose calculée (en bleu).
Table 4 ® First French experiences of total body irradiation using helical TomoTherapy : in vivo dosimetry. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : résultats de la dosimétrie in vivo. Thermoluminescent Mean measured dose (Gy) (±SD) dosimeters
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Calculated dose (Gy)
Relative difference between mean measured and calculated dose (%)
Junction heterogeneity
Cluster 1
Cluster 2
Cluster 3
Cluster 1
Cluster 2
Cluster 3
Cluster 1
Cluster 2
Cluster 3
Film 1 (%)
Film 2 (%)
Film 3 (%)
1.97 (0.02) 1.83 (0.04) 1.98 (0.03) 1.93 (0.02) 2.04 (0.02)
2.00 (0.72) 2.04 (0.02) 1.93 (0.05) 1.83 (0.09) 1.99 (0.03)
2.01 (0.01) 1.99 (0.01) 2.09 (0.04) 1.91 (0.01) 1.90 (0.08)
2.02 1.92 2.1 1.99 2.15
2.01 2.08 2.04 2.06 2.13
1.96 2.07 2.09 2.06 2.14
–3.25 1.86 3.54 0.78 4.10
–1.36 4.63 3.89 –7.60 2.79
1.63 2.80 10.16 –3.79 –2.33
±7.5 ±5.0 ±5.3 ±5.9 ±7.4
±4.5 ±4.7 ±6.0 ±5.2 ±7.7
±5.4 ±4.7 – – –
SD: standard deviation; Bold: relative differences higher than ± 5%.
dose. The average junction heterogeneity (±SD): was ±5.8% (±1%) (Table 4). 4.5. Patients One patient did not achieve the treatment because of a donor incident. He was finally treated in another centre. The median follow-up of the five other patients was 354 days (range: 153–615 days) with no death or relapse at the time of the analysis. Aplasia induced by the conditioning regimen lasted on average 14.6 days. Only one patient had difficulty to raise his platelets above Table 5 ® First French experiences of total body irradiation using helical TomoTherapy : hematological effects of the conditioning regimen. Aplasia induced by the conditioning regimen lasted on average 14.6 days. Two patients did not need transfusion of platelets or of packed red blood cells. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : effets hématologiques du protocole de conditionnement. L’aplasie induite durait en moyenne 14,6 jours. Deux patients n’ont pas nécessité de transfusion de plaquettes ni de culots globulaires. Patient No.
Times (days) until neutrophil count > 0.5 G/l
1 2 3 4 5
14 15 8 16 20
Times (days) until platelets count > 50 G/l 15 0 268 0 0
50 G/l. The use of a transfusion support was not necessary in the half of the patients. Overall acute morbidity of total body irradiation was low and corresponding to the aplasia: sepsis, which was controlled by antibiotics in all patients, but one patient had several episodes of infection and a prolonged aplasia which led to a prolonged hospitalization (137 days vs. 21 days on average for the other) (Table 5). Grade 4 side effects were not observed (Table 6). Two patients had acute graft versus host disease within the first hundred days. The gastrointestinal involvement was the most common presentation, and one patient had low intensity rectorrhagia, which responded to a medical treatment (Table 7). 5. Discussion We described the technical modalities used in our institute for ® the first French total body irradiation using helical TomoTherapy . Those modalities allowed a better control of the delivered dose and a good homogeneity in the dose distribution than nonconformational irradiation (lowest dose homogeneity index was 0.9). The dose homogeneity index obtained in our study, 0.93 ± 0.16 and 0.94 ± 0.01 respectively for the upper and the lower plan, are consistent with another published values [6,8]. For total body irradiation with organs at risk sparing, Hui et al. prescribed 13.2 Gy and observed a dose homogeneity index of 0.91, whereas Penagaricano et al. had a dose homogeneity index ranging from 0.91 to 0.95 for 12 Gy prescribed [6,8]. The in-homogeneity of the planned ®
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Table 6 ® First French experiences of total body irradiation using helical TomoTherapy : acute toxicity. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : toxicité aiguë. Patient No.
1 2 3 4 5
Toxicity
Duration of hospitalization (days)
Grade 1-2
Grade 3
Grade 4
Nausea, asthenia No No No No
Infection Febrile neutropenia, infection Repeated infections Infection No
No No No No No
dose is the consequence of the thread effect well known in the ® TomoTherapy treatments especially for large patients. To reduce the thread effect, the pitch has to be reduced but it will extend the treatment time [18]. We are satisfied with our compromise. In vivo dose verification of each individual treatment fraction is possible, and the difference between measured and calculated thermoluminescent dosimeters in our study was about 3 to 4% except for two patients were the difference were relatively high for one of their thighs. These results are consistent with previous clinical ® ˜ study [8]. studies on TomoTherapy , particularly Penagarícano’s The limited length of planning target volume (approximated 145 cm) due to the limited translation length of the table led to split the total body irradiation in two segments. Here we used an original junction method and the junction heterogeneity was consistent ® with data in the literature [19]: about ± 5% with TomoTherapy ® only, vs. ±17% with a linear accelerator and TomoTherapy . The treatment was achievable in a comfortable way for the patients. Overall “in-room” time was 120 min, mainly due to the clinical replacement time with 3 to 4 MV CT. With more experience, this time could be reduced to 90 min even for total marrow irradiation performed in our centre after the total body irradiation presented in this paper. The most important bias in the study is its retrospective nature, causing data gaps, especially in the monitoring of side effects of the total body irradiation, which prevents the accurate assessment of tolerance. However, the good tolerance of the total body irradiation in our institute was consistent with what has been described in literature [8,10,13]: only grade 1–2 digestive toxicity (nausea, mucositis) for one patient. It is also important to notice that the prescribed dose was low and corresponds to a reduced conditioning regimen, due to the selected patients of our cohort (elderly and/or relative contraindication to conventional hematopoietic cell transfusion with myeloablative conditioning regimen in younger patients). Indeed, these regimens appeared to allow donor engraftment with reduced risk of acute, life-threatening toxicity in this population [20,21]. ® Nevertheless, the experiment of TomoTherapy was successful, and the technical aspect of the treatment is reliable, especially the management of the junction. It was therefore quite conceivable to extrapolate this technique for irradiation of other volumes in our
Table 7 ® First French experiences of total body irradiation using helical TomoTherapy : graft versus host disease. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : réactions en rapport avec une maladie du greffon contre l’hôte. Patient No.
Graft versus host disease Acute (< 100 days)
Chronic (> 100 days)
1 2
Skin (grade 2), digestive (grade 3) Digestive (grade 3): bleeding
3 4 5
No No No
– Skin, digestive, lung (grade 4) – – –
21 22 137 19 22
Chemotherapy
Fludarabine Fludarabine Fludarabine + cyclophosphamide Fludarabine + cyclophosphamide Fludarabine
institute, such as total marrow irradiation, which is the subject of a French ongoing study (phase 1–2 study of total bone marrow ® irradiation with helicoidal TomoTherapy in first myeloma relapse (TOMMY), NCT01794572). Then, it will be necessary to develop studies to clearly assess the efficacy and safety compared to conventional radiation techniques. 6. Conclusion The good tolerance and better dose distribution encourage the ® use of TomoTherapy in total body irradiation, even in total marrow irradiation. Disclosure of interest The authors declare that they have no competing interest. References [1] Bölling T, Kreuziger DC, Ernst I, Elsayed H, Willich N. Retrospective, monocentric analysis of late effects after total body irradiation (TBI) in adults. Strahlenther Onkol 2011;187:311–5. [2] Linsenmeier C, Thoennessen D, Negretti L, Bourquin J-P, Streller T, Lütolf UM, et al. Total body irradiation (TBI) in pediatric patients. A single-center experience after 30 years of low-dose rate irradiation. Strahlenther Onkol 2010;186:614–20. [3] Gerstein J, Meyer A, Sykora K-W, Frühauf J, Karstens JH, Bremer M. Longterm renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT). Strahlenther Onkol 2009;185:751–5. [4] Ricardi U, Filippi AR, Biasin E, Ciammella P, Botticella A, Franco P, et al. Late toxicity in children undergoing hematopoietic stem cell transplantation with TBI-containing conditioning regimens for hematological malignancies. Strahlenther Onkol 2009;185:17–20. [5] Pommier P, Sunyach MP, Pasteuris C, Frappaz D, Carrie C. Second cancer after total-body irradiation (TBI) in childhood. Strahlenther Onkol 2009;185:13–6. [6] Hui SK, Kapatoes J, Fowler J, Henderson D, Olivera G, Manon RR, et al. Feasibility study of helical tomotherapy for total body or total marrow irradiation. Med Phys 2005;32:3214–24. [7] Zhuang AH, Liu A, Schultheiss TE, Wong JYC. Dosimetric study and verification of total body irradiation using helical tomotherapy and its comparison to extended SSD technique. Med Dosim 2010;35:243–9. ˜ [8] Penagarícano JA, Chao M, Van Rhee F, Moros EG, Corry PM, Ratanatharathorn V. Clinical feasibility of TBI with helical tomotherapy. Bone Marrow Transplant 2011;46:929–35. [9] Wong JYC, Liu A, Schultheiss T, Popplewell L, Stein A, Rosenthal J, et al. Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation. Biol Blood Marrow Transplant 2006;12:306–15. [10] Schultheiss TE, Wong J, Liu A, Olivera G, Somlo G. Image-guided total marrow and total lymphatic irradiation using helical tomotherapy. Int J Radiat Oncol Biol Phys 2007;67:1259–67. [11] Wong JYC, Rosenthal J, Liu A, Schultheiss T, Forman S, Somlo G. Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys 2009;73:273–9. [12] Shueng P-W, Lin S-C, Chong N-S, Lee H-Y, Tien H-J, Wu L-J, et al. Total marrow irradiation with helical tomotherapy for bone marrow transplantation of multiple myeloma: first experience in Asia. Technol Cancer Res Treat 2009;8:29–38. [13] Gruen A, Ebell W, Wlodarczyk W, Neumann O, Kuehl JS, Stromberger C, et al. Total body irradiation (TBI) using helical tomotherapy in children and young adults undergoing stem cell transplantation. Radiat Oncol 2013;8:92. [14] International Commission on Radiation Units Measurements (ICRU). Prescribing, recording and reporting photon beam therapy (Supplement to ICRU Report 50). In: ICRU Report 62. Oxford: Oxford University Press; 1999.
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[15] International Commission on Radiation Units Measurements (ICRU). Report 83: Prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy (IMRT). J ICRU 2010;10:1–106. [16] Mayo CS, Urie MM. A systematic benchmark method for analysis and comparison of IMRT treatment planning algorithms. Med Dosim 2003;28:235–42. [17] Hui SK, Lusczek E, DeFor T, Dusenbery K, Levitt S. Three-dimensional patient setup errors at different treatment sites measured by the Tomotherapy megavoltage CT. Strahlenther Onkol 2012;188:346–52. [18] Takahashi Y, Verneris MR, Dusenbery K, Wilke C, Storme G, Weisdorf DJ, et al. Peripheral dose heterogeneity due to the thread effect in total marrow irradiation with helical tomotherapy. Int J Radiat Oncol Biol Phys 2013;87:832–9.
[19] Zeverino M, Agostinelli S, Taccini G, Cavagnetto F, Garelli S, Gusinu M, et al. Advances in the implementation of helical tomotherapy-based total marrow irradiation with a novel field junction technique. Med Dosim 2012;37:314–20. [20] Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997;89:4531–6. [21] McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001;97:3390–400.
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Original article
First French experiences of total body irradiations using helical ® TomoTherapy ®
Premières expériences franc¸aises d’irradiation corporelle totale par TomoTherapy R. Sun a , X. Cuenca a , R. Itti b , S. Nguyen Quoc c , J.-P. Vernant c , J.-J. Mazeron a , C. Jenny d , M. Chea d,∗ a
Department of radiation oncology, hôpital Pitié-Salpêtrière, 47–83, boulevard de l’Hôpital, 75651 Paris cedex 13, France Department of radiation oncology, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France c Department of hematology, hôpital Pitié-Salpêtrière, 47–83, boulevard de l’Hôpital, 75651 Paris cedex 13, France d Department of medical physics, hôpital Pitié-Salpêtrière, 47–83, boulevard de l’Hôpital, 75651 Paris cedex 13, France b
a r t i c l e
i n f o
Article history: Received 22 November 2016 Received in revised form 19 January 2017 Accepted 24 January 2017 Keywords: Radiotherapy Total body irradiation ® Helical TomoTherapy Junction method Bone marrow transplant
a b s t r a c t ®
Purpose. – Dynamic conformal radiotherapy with helical TomoTherapy (HT) offers a more quantitative paradigm for total body irradiation. Treatment planning, delivery, dose verification of the first French ® experiences of total body irradiation using helical TomoTherapy are presented. Materials and methods. – Patients planned for total body irradiation at our institution from February 2012 to May 2013 were reported. Total body irradiation consisted in a single fraction of 2 Gy. Planning target volume was divided in two due to the limited translation length of the table. Delivery quality assurance was performed with cylindrical phantom, ionization chamber and films. Thermoluminescent dosimeters and radiochromic films were used for in vivo dosimetry and junction region heterogeneity assessment. Results. – Six patients were included. One finally did not receive the treatment but dosimetric data were analyzed. Planned V95% was covered by D95% and V2% did not exceed D107% for five of the six patients. The mean relative difference between measured and calculated absolute dose of the Delivery quality assurance was always less than 2.5% (mean value ± SD: 1% ± 0.67%). Gamma index (3%; 3 mm) was less than 1 for at least 93% of the points (value ± SD: 97.4 ± 1.6% and 96.6 ± 2.5% for upper and lower part of treatment respectively). Difference between in vivo measured and calculated dose was above 5% for only two out of 15 points (maximum: 10.2%, mean: 0.73 ± 4.6%). Junction region heterogeneity was in average 5.8 ± 1%. The total treatment session of total body irradiation lasted 120 min, with a mean beam on time of 17.2 ± 0.6 and 11.2 ± 1.6 min for upper and lower part of the body respectively. ® Conclusion. – Total body irradiation using helical TomoTherapy guaranteed high dose homogeneity throughout the body and dose verification was achievable, showing small difference between planned and delivered doses. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2017 Societ rights reserved.
r é s u m é Mots clés : Radiothérapie Irradiation corporelle totale Tomothérapie hélicoïdale Méthode de jonction Transplantation de moelle osseuse
Objectif. – Les techniques non conformationnelles ne permettent pas un contrôle et une homogénéité de la dose dans les irradiations corporelles totales. Nous décrivons la planification, l’administration et la ® vérification de la dose des premières irradiations corporelles totales franc¸aises par TomoTherapy . Matériel et méthodes. – Les données des patients pour qui une irradiation corporelle totale par ® TomoTherapy a été planifiée dans notre centre entre février 2012 et mai 2013 sont rapportées. L’irradiation corporelle totale consistait en une séance unique de 2 Gy. Le volume cible prévisionnel a été divisé en deux à cause de la longueur limitée de traitement. L’assurance qualité a été effectuée dans
∗ Corresponding author. E-mail address: [email protected] (M. Chea). http://dx.doi.org/10.1016/j.canrad.2017.01.014 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2017 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
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un fantôme cylindrique avec des films et des chambres d’ionisation. La dosimétrie in vivo et l’évaluation de l’homogénéité de la dose dans la zone de jonction ont été réalisées par dosimètres thermoluminescents et films radiochromiques. Résultats. – Six patients ont été inclus. Un n’a finalement pas rec¸u de traitement, mais les données dosimétriques sont rapportées. Le volume recevant 95 % de la dose prescrite (V95 % ) était couverte par la D95 % et celui recevant 2 % (V2 % ) était inclus dans l’isodose 107 % (D107 % ) pour cinq patients sur six. Pour le contrôle qualité, la différence entre doses délivrée mesurée et théorique était toujours moins de 2,5 % (moyenne ± déviation standard : 1 % ± 0,67 %). Le gamma index (3 % ; 3 mm) était de moins de 1 pour au moins 93 % des points (97,4 ± 1,6 % et 96,6 ± 2,5 % respectivement pour les plans supérieurs et inférieurs). Une différence relative entre doses mesurée in vivo et attendue était de plus de 5 % pour deux parmi 15 mesures (0,73 ± 4,6 %). L’hétérogénéité dans la zone de jonction était en moyenne de 5,8 ± 1 %. La réalisation totale l’irradiation corporelle totale a demandé 120 min avec un temps de traitement de 17,2 ± 0 min et 11,2 ± 1,6 min pour respectivement les parties supérieure et inférieure. Conclusion. – La tomothérapie a permis une distribution homogène de la dose. Les différences entre doses mesurée et théorique étaient faibles. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2017 Societ ´ ´ droits reserv es.
1. Introduction Total body irradiation is widely used as a preparatory regime before bone marrow transplant to provide both immunosuppressive and cytotoxic effects. Nevertheless, current accepted techniques of total body irradiation are laborious, time-consuming and cumbersome, and lead to significant acute and late toxicity due to the non-conformity of beam-application with the inability to individually spare organs at risk [1–5]. In addition, dose prescription and verification is usually limited to single-point measurements. The advent of dynamic conformal radiotherapy in the form ® of helical TomoTherapy offers a new and more quantitative paradigm for total body irradiation dose planning and delivery. Different groups have investigated the feasibility of this technology in total body irradiation, total marrow- or total lymphoid irradia® tion and it seems that the use of helical TomoTherapy is feasible and could increase the homogeneity of dose distribution on target structures and decrease the dose to the organs at risk [6–13]. However, the length of planning target volume (PTV) is limited to 145 cm (due to the limited translation length of the table), so it is necessary to treat the patient in two parts with special management of the junction to ensure the quality of treatment. The purpose ® of this study was to establish the use of helical TomoTherapy for the conditioning regimen before bone marrow transplant at our institute. Treatment planning, delivery, dose verification of the six first French experiences of total body irradiation using helical ® TomoTherapy are here presented. We attempted to have good homogeneity coverage without over- or under-coverage. Because of the limited length of treatment ® with helical TomoTherapy , we used an original junction between upper and upper part of the patient.
Fig. 1. First French experiences of total body irradiation using helical ® TomoTherapy : immobilization and in vivo measurements. Patients were immobilized in a supine position using a whole body vacuum bag and a thermoplastic head mask. The junction region homogeneity was checked with at least one radiochromic films on each thigh. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : immobilisation et mesures in vivo. Le patient était immobilisé en décubitus dorsal par un matelas sous vide et un masque thermoformé. L’homogénéité de la dose dans la zone de jonction a été évaluée par au moins un film radiochromique sur chaque cuisse.
To check the tilt of the body, tattoo marks were also placed in the pelvic area. Two sets of planning kilovoltage CT images (Lightspeed RT 16, GE, USA) with a 5 mm slice thickness were acquired: one for the upper body HFS oriented (from vertex to knees) and one for the lower body FFS oriented (from feet to pelvis).
2. Methods
2.2. Contouring
2.1. Positioning/planning CT
The ISOgray treatment planning system was used for contouring (version 4.1.2.64L, Dosisoft, France). The target volume (PTV) was delineated with the external contours for lower and upper parts. The junction has been marked at mid-thighs: 15 cm above the knee on both thighs. We used five transition volumes of 2 cm each (Fig. 2). Some organs at risk were delineated and included lungs, brain, brainstem, spinal cord, eyes, crystalline lens, heart, liver and kidneys.
Patients were immobilized in a supine position using a wholebody vacuum bag (Elekta, Sweden) for body support and a customized thermoplastic head mask (three points) (Seemed© France) for head support on an adjustable combined board (Fig. 1). For localization purpose, tattoo marks were placed at least at the intersection of the mid-sagittal plane and the inter-nipple line and at the junction plane, which was defined by the mid-thighs plane.
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We prescribed 2 Gy delivered as a single dose to the planning target volume. The objectives to achieve were the coverage of 95% of the planning target volume by 95% of the prescribed dose, and the respect of a maximum of 107% of the prescribed dose, for the V2% (ICRU criteria [14,15]). The dose homogeneity index was defined as the ratio of the dose received by 90% of the planning target volume to the minimum dose received by the ‘hottest’ 10% of the planning target volume [16]. For the treatment planning, we chose a 5 cm field width, a pitch of 0.43 and a modulation factor of 1.8. 2.4. Positioning/image guidance, and treatment To avoid transferring the patient to another machine during treatment we divided the planning target volume of patients into two parts and the treatment was delivered in two consecutive times with different patient orientation: (I) head first from vertex to the junction plane and (II) after repositioning: feet first from toes to the junction plane. To control the dose gradient in the junction region, at midthighs, we used five transition volumes of 2 cm high for each volume, on which the upper and lower parts of the treatment are superimposed. For each treatment plan, the prescribed dose gradually decreased in the five transition volumes. In each transition volume, the sum dose prescribed of each plan (upper and lower) was 2 Gy. Positioning was verified prior to treatment using two megavoltage (MV)-CTs for the upper part on the craniocervical and the pelvic areas, and one MV CT for the lower part (on the knee area) [17]. For the upper part, the applied displacements in all directions were the average deviation between the 2 MV CT. If the deviation between the craniocervical and the pelvic MV CT requested displacements and the necessary displacements applied were less than 4 mm, the treatment started. Otherwise, the patient was clinically repositioned and MV CT were performed again. 2.5. Quality assurance
Fig. 2. First French experiences of total body irradiation using helical ® TomoTherapy : 3D view of the upper and the lower planning target volumes. Five transition volumes of 2 cm (colored planning target volumes) were created for the junction method. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : visualisation tridimensionnelle de la partie supérieur et inférieure du volume cible prévisionnel. Cinq volumes de transition de 2 cm de hauteur chacun (volume cible prévisionnel coloré) ont été construits pour la zone de jonction.
Three-dimensional data sets with contours were transferred ® ® to the TomoTherapy treatment planning system (TomoTherapy Inc., Madison, WI 53717–1954 USA) for planning. VoLOTM technology was available after the start of the study and was used to calculate and optimize the treatment plans of the last patient. 2.3. Conditioning regimen, dose prescription and fractionation The conditioning regimen consisted of total body irradiation the day before allograft (d1). Chemotherapy consisted of fludarabine 30 mg/m2 alone, from d4 to d2; or fludarabine 30 mg/m2 plus cyclosporine 14.5 mg/m2 from d6 to d2, depending on the decision of hematologists. Graft versus host disease was prevented by ® ciclosporin and mycophenolate mofetil (Cellcept ).
Each treatment plan was checked before the treatment by a qualified medical physicist to assure that the planning dose could be delivered with high accuracy. The delivery quality assurance was performed with cylindrical phantom (Cheese phantom, Med-Cal, USA), ionization chamber (Exradin A1SL, Standard imaging, USA) for absolute dose and films (EDR2, Carestream, Canada) for relative dose, and with at least: • two delivery quality assurance for the upper part: chest and junction; • one delivery quality assurance pour the lower part: junction. During the treatment session, in vivo dosimetry was performed with thermoluminescent dosimeters (GR200A, LiF) positioned on three different regions for each patient among sternum or axilla for the upper part, and the iliac fossae or between the legs at mid-thigh for the lower part. These regions had to be easily accessible without having to move the patient because thermoluminescent dosimeters were placed after the pretreatment MV CT. Positions of the thermoluminescent dosimeters were changed after the first treatments because the use of the iliac fossa region did not ensure electronic equilibrium. Conversely, the measurement point on the sternum was well suited. For this, the thermoluminescent dosimeters were placed 1.5 cm under the bolus to have enough dose build up. The bolus was considered during the treatment planning. There was a cluster of three to five thermoluminescent dosimeters for each measurement point. Measured doses were corrected to consider the daily calibration factor of the thermoluminescent dosimeters ®
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and a non-linearity dose response correction was applied. The relative difference between the corrected measured dose and calculated dose was defined as:
Age, sex, original disease of the patient, tolerance and adverse side effects were recorded. Characteristics of patients are resumed in Table 1.
Relative difference (%)
4. Results
mean corrected measured doses − calculated dose = × 100 calculated dose
From February 2012 to June 2013, six patients were planned for ® total body irradiation using helical TomoTherapy , but only five reached the treatment. We analyzed the treatment planning for all the six patients, as it has been fully performed for them all and we analyzed the quality assurance data for the five patients who were actually treated.
The junction region homogeneity was checked with at least one radiochromic films (EBT2, Ashland, USA) on each thigh. In the junction region, the dose heterogeneity was defined as: Dose heterogeneity (%) =
maximum dose − minimum dose × 100 maximum dose + minimum dose
4.1. Dosimetry
3. Patients
The average time between the start of delineation and the treatment planning validation was 11.5 days, ranging from 13 to 6 days. This reduction was permitted by the use of the VoLOTM technology. The time required to delineate was 4 h: 2 h for the target volume and the organs at risk and 2 h more for the five subvolumes of the junction region. For the upper part, the average volume (±SD) of the target covered by 95% of the prescribed dose (V95% ) was 95.6 ± 2.46%, and the average (±SD) volume exceeding 107% of the prescribed dose (V107% ) was 2.7 ± 1.85%. Only one of six patients presented an undercoverage with a V95% of 91.1%. V107% was less than 2% for three patients. In the other three patients, V107% was 6.4%, 2.3 and 2.1%. No patient presented undercoverage of the lower part of treatment, with a mean V95% of 98.0 ± 1.03%. Average V107% was 1.6 ± 1.00%, and exceeded 2% for two patients (2.2% and 3.3%). The average dose homogeneity index (±SD) (D90% /D10% ) was 0.93 ± 0.01 for the upper part (range: 0.91–0.94) and 0.94 ± 0.01 for the lower part (range 0.93–0.95) (Table 2, Fig. 3).
All patients whose total body irradiation using Helical ® TomoTherapy was planned at our institution were included. We analyzed all the available data, even if the patient had not actually received the treatment. From February 2012 to May 2013, six patients were included for conditioning before allogeneic bone marrow transplantation by ® total body irradiation using helical TomoTherapy . Three patients presented with chronic lymphocytic leukemia, of whom two were transformed into Richter’s syndrome, two with Hodgkin disease, and one with multiple myeloma. All patients presented with highrisk features such as non-response to chemotherapy, recurrence disease, and complex karyotype. Three patients were in complete or partial remission at time of the total body irradiation. Four patients have had prior autologous peripheral stem-cell transplantation, and two patients have had prior radiation therapy (30 Gy mediastinum, and 6 Gy total body irradiation).
Table 1 ® First French experiences of total body irradiation using helical TomoTherapy : patients’ characteristics. Three patients presented with chronic lymphocytic leukemia, of whom two were transformed into Richter’s syndrome, two with Hodgkin disease, and one with multiple myeloma. Four patients have had prior autologous peripheral stem cell transplantation, and two patients have had prior radiation therapy (30 Gy mediastinum, and 6 Gy total body irradiation). ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : caractéristique des patients. Trois patients étaient atteints d’une leucémie lymphoïde chronique, dont deux se sont transformées (syndrome de Richter). Deux patients avaient une maladie de Hodgkin, et un patient un myélome multiple. Quatre patients avaient rec¸u une autogreffe de cellules souches périphériques et deux avaient rec¸u une radiothérapie (une médiastinale et une corporelle totale). Patientno.
Sex and age
Diagnosis
In remission at time of total body irradiation?
Autologous-stem cell transplantation
Prior radiation treatment
Date of total body irradiation
1 2
Female, 66 years Male, 64 years
Richter 3rd recurrence Richter recurrence
– –
– –
13/03/2012 16/07/2012
3
Female, 65 years
May 2012
Female, 22 years
Yes
January 2012
5
Male, 59 years
February 2013
6
Female, 28 years
No, refractory to treatment No, refractory to treatment
Total body irradiation 6 Gy – May 2012 Mediastinum 30 Gy – April 2010 –
10/09/2012
4
Chronic lymphocytic leukemia 5th recurrence Hodgkin 3rd recurrence Myeloma 2nd recurrence Hodgkin non responsive 1st recurrence
Yes No, hyperlymphocytosis 42 G/l Yes
April 2012
–
18/10/2012 24/06/2013 Finally treated in another institution
Table 2 ® First French experiences of total body irradiation using helical TomoTherapy : dosimetric data for the treatment plans. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : données dosimétriques des plans de traitement. Patients (n = 6)
V95% (%)
V102% (%)
V107% (%)
Dmax (Gy)
D2% (Gy)
D98% (Gy)
Dmin (Gy)
Dose homogeneity index (D90% /D10% )
Upper part planning target volume Lower part planning target volume
95.63 (±2.46)
23.26 (±4.11)
2.69 (±1.85)
2.37 (±0.04)
2.15 (±0.03)
1.81 (±0.10)
0.93 (±0.16)
0.93 (±0.01)
97.95 (±1.03)
19.95 (2.09)
0.61 (1.00)
2,29 (±0.06)
2.14 (±0.02)
1.90 (±0.03)
1.90 (±0.03)
0.94 (±0.01)
Vx% : volume of the target covered by % of the prescribed dose; Dmax : maximum dose; Dmin : minimum dose.
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Fig. 3. First French experiences of total body irradiation using helical TomoTherapy : treatment plans of the first patient receiving a TomoTherapy in our institute. The delivered dose was homogenous for the upper, the lower part, and the junction plan. ® ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : plan de traitement du premier patient pris en charge par TomoTherapy dans notre centre. La dose délivrée était homogène pour les plans supérieurs, inférieurs et la zone de jonction.
There were no dose peaks above 123% of the prescribed dose. Actual average Dmean ± SD for lungs was 2.01 ± 0.02 Gy and 2.006 ± 0.018 Gy for right and left lung respectively. 4.2. Pretreatment verifications For the five patients analyzed, a total of 36 points were measured. The checking before the treatment showed a good correlation between planned and delivered absolute and relative dose. The average absolute dose relative difference (±SD) was 1 ± 1%, and for each delivery quality assurance, the relative difference between measured and calculated absolute dose was less than 2.5% (Table 3, Fig. 4). For the dose distribution comparison, gamma index (3%; 3 mm) was less than 1 for at least 93% of the points for all patients (mean value ± SD: 97.4 ± 1.6% and 96.6% ± 2.5% for upper and lower part of treatment respectively) (Table 3). 4.3. Treatment Three patients needed to be replaced for the upper part treatment, and two for the lower part treatment because of setup errors of more than 4 mm. The average (±SD) couch shifts were 1.0 (±2.3), –2.0 (±3.7) and 3.9 (±1.3) mm in the lateral, longitudinal and vertical directions
respectively for the upper part treatment. The mean difference between the treatment position and the expected position, according to the cranial and pelvic MV CT, was 0 mm in all directions with standard deviations of 1.1, 1.7, 1.6 mm in the lateral, longitudinal and vertical directions respectively. Regarding the lower part treatment, the average (±SD) couch shifts were 3.1 (±2.83), –5.05 (±1.06) and 3.80 (±1.27) mm in the lateral, longitudinal and vertical directions respectively. We needed three or four MV CT (mean 3.5) to replace the patient with accuracy. Beam-on-time ranged from 16.2 min to 17.8 min (average (±SD): 17.2 ± 0.55 min) for the upper plan and 8.7 min to 13 min (average (±SD): 11.2 ± 1.59 min) for the lower plan. Overall “in-room”-time exceeded beam-on-time, and was about 120 min per patient. 4.4. In vivo dosimetry Difference between in vivo measurements by thermoluminescent dosimeters and calculated dose was satisfactory, but among the 15 points (three points by patient), there was more than 5% difference between calculated and measured dose for two points: –7.6% on the right thigh in one patient, +10.2% on the left thigh in another patient (mean of the relative difference between measured and calculated dose (±SD): 1.19 ± 4.31%) There was no underdosing observed, and the measured dose stayed under 107% of the prescribed dose for each point, and upper 95% of the prescribed
Table 3 ® First French experiences of total body irradiation using helical TomoTherapy : pretreatment results (delivery quality assurance). Mean relative difference between measured and calculated dose (absolute dose and dose distribution). ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : résultats des contrôles qualités prétraitement. Différence relative moyenne entre dose mesurée et calculée (dose absolue et distribution de la dose).
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Mean (±SD)
Mean relative difference measured/calculated dose
Percentage of points with gamma index <1 (3%. 3 mm)
Upper part (%)
Lower part (%)
Upper part (%)
Lower part (%)
0.7 1.3 0.5 1.0 0.9 0.9 (±0.3)
1.3 1.8 0.8 0.8 1.1 1.2 (±0.4)
95.2 99.4 97.5 99.0 96.0 97.4 (±1.6)
95.4 95.5 99.0 100,0 93.2 96.6 (±2.5)
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Fig. 4. First French experiences of total body irradiation using helical TomoTherapy : example of the first patient’s upper part junction delivery quality assurance. The dose profiles showed that measured dose (in red) was consistent with calculated dose (in blue). ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : exemple de contrôle qualité réalisé pour la partie supérieur du plan de traitement du premier patient. Le profil de dose montre que la dose mesurée (en rouge) concorde avec la dose calculée (en bleu).
Table 4 ® First French experiences of total body irradiation using helical TomoTherapy : in vivo dosimetry. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : résultats de la dosimétrie in vivo. Thermoluminescent Mean measured dose (Gy) (±SD) dosimeters
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Calculated dose (Gy)
Relative difference between mean measured and calculated dose (%)
Junction heterogeneity
Cluster 1
Cluster 2
Cluster 3
Cluster 1
Cluster 2
Cluster 3
Cluster 1
Cluster 2
Cluster 3
Film 1 (%)
Film 2 (%)
Film 3 (%)
1.97 (0.02) 1.83 (0.04) 1.98 (0.03) 1.93 (0.02) 2.04 (0.02)
2.00 (0.72) 2.04 (0.02) 1.93 (0.05) 1.83 (0.09) 1.99 (0.03)
2.01 (0.01) 1.99 (0.01) 2.09 (0.04) 1.91 (0.01) 1.90 (0.08)
2.02 1.92 2.1 1.99 2.15
2.01 2.08 2.04 2.06 2.13
1.96 2.07 2.09 2.06 2.14
–3.25 1.86 3.54 0.78 4.10
–1.36 4.63 3.89 –7.60 2.79
1.63 2.80 10.16 –3.79 –2.33
±7.5 ±5.0 ±5.3 ±5.9 ±7.4
±4.5 ±4.7 ±6.0 ±5.2 ±7.7
±5.4 ±4.7 – – –
SD: standard deviation; Bold: relative differences higher than ± 5%.
dose. The average junction heterogeneity (±SD): was ±5.8% (±1%) (Table 4). 4.5. Patients One patient did not achieve the treatment because of a donor incident. He was finally treated in another centre. The median follow-up of the five other patients was 354 days (range: 153–615 days) with no death or relapse at the time of the analysis. Aplasia induced by the conditioning regimen lasted on average 14.6 days. Only one patient had difficulty to raise his platelets above Table 5 ® First French experiences of total body irradiation using helical TomoTherapy : hematological effects of the conditioning regimen. Aplasia induced by the conditioning regimen lasted on average 14.6 days. Two patients did not need transfusion of platelets or of packed red blood cells. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : effets hématologiques du protocole de conditionnement. L’aplasie induite durait en moyenne 14,6 jours. Deux patients n’ont pas nécessité de transfusion de plaquettes ni de culots globulaires. Patient No.
Times (days) until neutrophil count > 0.5 G/l
1 2 3 4 5
14 15 8 16 20
Times (days) until platelets count > 50 G/l 15 0 268 0 0
50 G/l. The use of a transfusion support was not necessary in the half of the patients. Overall acute morbidity of total body irradiation was low and corresponding to the aplasia: sepsis, which was controlled by antibiotics in all patients, but one patient had several episodes of infection and a prolonged aplasia which led to a prolonged hospitalization (137 days vs. 21 days on average for the other) (Table 5). Grade 4 side effects were not observed (Table 6). Two patients had acute graft versus host disease within the first hundred days. The gastrointestinal involvement was the most common presentation, and one patient had low intensity rectorrhagia, which responded to a medical treatment (Table 7). 5. Discussion We described the technical modalities used in our institute for ® the first French total body irradiation using helical TomoTherapy . Those modalities allowed a better control of the delivered dose and a good homogeneity in the dose distribution than nonconformational irradiation (lowest dose homogeneity index was 0.9). The dose homogeneity index obtained in our study, 0.93 ± 0.16 and 0.94 ± 0.01 respectively for the upper and the lower plan, are consistent with another published values [6,8]. For total body irradiation with organs at risk sparing, Hui et al. prescribed 13.2 Gy and observed a dose homogeneity index of 0.91, whereas Penagaricano et al. had a dose homogeneity index ranging from 0.91 to 0.95 for 12 Gy prescribed [6,8]. The in-homogeneity of the planned ®
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Table 6 ® First French experiences of total body irradiation using helical TomoTherapy : acute toxicity. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : toxicité aiguë. Patient No.
1 2 3 4 5
Toxicity
Duration of hospitalization (days)
Grade 1-2
Grade 3
Grade 4
Nausea, asthenia No No No No
Infection Febrile neutropenia, infection Repeated infections Infection No
No No No No No
dose is the consequence of the thread effect well known in the ® TomoTherapy treatments especially for large patients. To reduce the thread effect, the pitch has to be reduced but it will extend the treatment time [18]. We are satisfied with our compromise. In vivo dose verification of each individual treatment fraction is possible, and the difference between measured and calculated thermoluminescent dosimeters in our study was about 3 to 4% except for two patients were the difference were relatively high for one of their thighs. These results are consistent with previous clinical ® ˜ study [8]. studies on TomoTherapy , particularly Penagarícano’s The limited length of planning target volume (approximated 145 cm) due to the limited translation length of the table led to split the total body irradiation in two segments. Here we used an original junction method and the junction heterogeneity was consistent ® with data in the literature [19]: about ± 5% with TomoTherapy ® only, vs. ±17% with a linear accelerator and TomoTherapy . The treatment was achievable in a comfortable way for the patients. Overall “in-room” time was 120 min, mainly due to the clinical replacement time with 3 to 4 MV CT. With more experience, this time could be reduced to 90 min even for total marrow irradiation performed in our centre after the total body irradiation presented in this paper. The most important bias in the study is its retrospective nature, causing data gaps, especially in the monitoring of side effects of the total body irradiation, which prevents the accurate assessment of tolerance. However, the good tolerance of the total body irradiation in our institute was consistent with what has been described in literature [8,10,13]: only grade 1–2 digestive toxicity (nausea, mucositis) for one patient. It is also important to notice that the prescribed dose was low and corresponds to a reduced conditioning regimen, due to the selected patients of our cohort (elderly and/or relative contraindication to conventional hematopoietic cell transfusion with myeloablative conditioning regimen in younger patients). Indeed, these regimens appeared to allow donor engraftment with reduced risk of acute, life-threatening toxicity in this population [20,21]. ® Nevertheless, the experiment of TomoTherapy was successful, and the technical aspect of the treatment is reliable, especially the management of the junction. It was therefore quite conceivable to extrapolate this technique for irradiation of other volumes in our
Table 7 ® First French experiences of total body irradiation using helical TomoTherapy : graft versus host disease. ® Premières irradiations corporelles totales franc¸aises par TomoTherapy : réactions en rapport avec une maladie du greffon contre l’hôte. Patient No.
Graft versus host disease Acute (< 100 days)
Chronic (> 100 days)
1 2
Skin (grade 2), digestive (grade 3) Digestive (grade 3): bleeding
3 4 5
No No No
– Skin, digestive, lung (grade 4) – – –
21 22 137 19 22
Chemotherapy
Fludarabine Fludarabine Fludarabine + cyclophosphamide Fludarabine + cyclophosphamide Fludarabine
institute, such as total marrow irradiation, which is the subject of a French ongoing study (phase 1–2 study of total bone marrow ® irradiation with helicoidal TomoTherapy in first myeloma relapse (TOMMY), NCT01794572). Then, it will be necessary to develop studies to clearly assess the efficacy and safety compared to conventional radiation techniques. 6. Conclusion The good tolerance and better dose distribution encourage the ® use of TomoTherapy in total body irradiation, even in total marrow irradiation. Disclosure of interest The authors declare that they have no competing interest. References [1] Bölling T, Kreuziger DC, Ernst I, Elsayed H, Willich N. Retrospective, monocentric analysis of late effects after total body irradiation (TBI) in adults. Strahlenther Onkol 2011;187:311–5. [2] Linsenmeier C, Thoennessen D, Negretti L, Bourquin J-P, Streller T, Lütolf UM, et al. Total body irradiation (TBI) in pediatric patients. A single-center experience after 30 years of low-dose rate irradiation. Strahlenther Onkol 2010;186:614–20. [3] Gerstein J, Meyer A, Sykora K-W, Frühauf J, Karstens JH, Bremer M. Longterm renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT). Strahlenther Onkol 2009;185:751–5. [4] Ricardi U, Filippi AR, Biasin E, Ciammella P, Botticella A, Franco P, et al. Late toxicity in children undergoing hematopoietic stem cell transplantation with TBI-containing conditioning regimens for hematological malignancies. Strahlenther Onkol 2009;185:17–20. [5] Pommier P, Sunyach MP, Pasteuris C, Frappaz D, Carrie C. Second cancer after total-body irradiation (TBI) in childhood. Strahlenther Onkol 2009;185:13–6. [6] Hui SK, Kapatoes J, Fowler J, Henderson D, Olivera G, Manon RR, et al. Feasibility study of helical tomotherapy for total body or total marrow irradiation. Med Phys 2005;32:3214–24. [7] Zhuang AH, Liu A, Schultheiss TE, Wong JYC. Dosimetric study and verification of total body irradiation using helical tomotherapy and its comparison to extended SSD technique. Med Dosim 2010;35:243–9. ˜ [8] Penagarícano JA, Chao M, Van Rhee F, Moros EG, Corry PM, Ratanatharathorn V. Clinical feasibility of TBI with helical tomotherapy. Bone Marrow Transplant 2011;46:929–35. [9] Wong JYC, Liu A, Schultheiss T, Popplewell L, Stein A, Rosenthal J, et al. Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation. Biol Blood Marrow Transplant 2006;12:306–15. [10] Schultheiss TE, Wong J, Liu A, Olivera G, Somlo G. Image-guided total marrow and total lymphatic irradiation using helical tomotherapy. Int J Radiat Oncol Biol Phys 2007;67:1259–67. [11] Wong JYC, Rosenthal J, Liu A, Schultheiss T, Forman S, Somlo G. Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys 2009;73:273–9. [12] Shueng P-W, Lin S-C, Chong N-S, Lee H-Y, Tien H-J, Wu L-J, et al. Total marrow irradiation with helical tomotherapy for bone marrow transplantation of multiple myeloma: first experience in Asia. Technol Cancer Res Treat 2009;8:29–38. [13] Gruen A, Ebell W, Wlodarczyk W, Neumann O, Kuehl JS, Stromberger C, et al. Total body irradiation (TBI) using helical tomotherapy in children and young adults undergoing stem cell transplantation. Radiat Oncol 2013;8:92. [14] International Commission on Radiation Units Measurements (ICRU). Prescribing, recording and reporting photon beam therapy (Supplement to ICRU Report 50). In: ICRU Report 62. Oxford: Oxford University Press; 1999.
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