Multicentre treatment planning inter-comparison in a national context: The liver stereotactic ablative radiotherapy case

Physica Medica 32 (2016) 277–283

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Technical Notes

Multicentre treatment planning inter-comparison in a national context: The liver stereotactic ablative radiotherapy case Marco Esposito a, Giulia Maggi b, Carmelo Marino c, Laura Bottalico d, Elisabetta Cagni e, Claudia Carbonini f, Michelina Casale g, Stefania Clemente h, Valentina D’Alesio d, David Fedele i, Francesca Romana Giglioli j, Valeria Landoni k, Anna Martinotti l, Roberta Nigro m, Lidia Strigari k,*, Elena Villaggi n, Pietro Mancosu b a

Azienda Sanitaria Firenze, Italy Humanitas Clinical and Research Center, Rozzano, Milano, Italy c Humanitas Catania, Catania, Italy d Malzoni Radiosurgery Center Salerno, Agropoli, Italy e Arciospedale S. Maria Nuova, Reggio Emilia, Italy f Niguarda Milano, Italy g Azienda Ospedaliera Santa Maria Terni, Terni, Italy h IRCCS CROB, Rionero in Vulture (PZ), Italy i Casa di cura San Rossore Pisa, Pisa, Italy j A.O.Città della Salute e della scienza di Torino, Italy k National Cancer Institute Regina Elena, Roma, Italy l CDI Milano, Italy m ASL Rieti, Italy n AUSL Piacenza, Italy b

A R T I C L E

I N F O

Article history: Received 4 March 2015 Received in revised form 27 August 2015 Accepted 12 September 2015 Available online 20 October 2015 Keywords: Stereotactic ablative radiotherapy (SABR) Stereotactic body radiation therapy (SBRT) Liver Multicentric clinical trial Dosimetry

A B S T R A C T

Purpose: To compare five liver metastasis stereotactic ablative radiotherapy (SABR) plans optimised in fourteen centres with 3D-Conformal-RT, IMRT, VMAT, CyberKnife and Tomotherapy and identify possible dosimetric differences. Methods: Dose prescription was 75 Gy in 3 fractions, normalised at 67%–95% isodose. Results: Excluding few cases, all institutions achieved the planning objectives. Differences up to 40% and 25% in mean dose to liver and PTV were found. No significant correlations between technological factors and DVH for target and OARs were observed; the optimisation strategies selected by the planners played a key role in the planning procedure. Conclusions: The human factor and the constraints imposed to the target volume have a greater dosimetric impact than treatment planning and radiation delivery technology in stereotactic treatment of liver metastases. Significant differences found both in terms of dosimetric target coverage and OAR sparing should be taken into consideration before starting a multi-institutional SARB clinical trial. © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Introduction Stereotactic Body Radiation Therapy (SBRT), or Stereotactic Ablative Radiotherapy (SABR) as it is commonly known nowadays, is a radiation therapy technique for treating small excranial tumours with high doses of radiation with a rapid dose fall off. The main features of SABR are the reduced number of fractions and large dosage per fraction. The efficacy of SABR was tested in several patient popu-

* Corresponding author. National Cancer Institute Regina Elena, Via E. Chianesi 53, 00144 Roma, Italy. Tel.: +39 06 52665602; fax: +39 06 52662740. E-mail address: [email protected] (L. Strigari).

lations with primary and metastatic limited tumours [1]. In particular, SABR may be appropriate for patients suffering from oligo-metastatic disease, defined as fewer than five lesions [2] or with organconfined limited volume primary tumours. The liver is a frequent metastasis location for most common solid tumours. In particular, in the event of an oligo-metastatic scenario, local therapy could increase overall survival. A non-invasive local approach using SABR was reported for both primary and secondary liver tumours, with local control rates higher than 90% and with limited toxicity in the setting of limited tumour burden [1,3–11]. However, the ideal dose to the target and the adequate dose constraints to liver and other organs at risk have not yet been standardised. Moreover, SABR efficacy has seldom been assessed in

http://dx.doi.org/10.1016/j.ejmp.2015.09.009 1120-1797/© 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

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large-scale randomised clinical trials. To our knowledge, the largest multi-institution study carried out on liver metastases involved 38 patients with 63 lesions from three participating institutions [10]. In 2012 the Italian Association of Medical Physics (Associazione Italiana di Fisica Medica – AIFM) established a working group dedicated to the dosimetric aspects of the SABR technique named “Dosimetry, physics, and radiobiology of image guided hypofractionated ablative radiotherapy” [12–14]. The aim of our study was to investigate whether a treatment protocol for SABR of liver metastasis could be reproduced in a modern national context, characterised by various radiation technologies, treatment planning systems (TPS) and planners with diverse experiences. For this purpose, we carried out a dosimetric comparison of the SABR metastatic liver plans performed in institutes with different technological characteristics.

Materials and methods Five series of images from a database of patients with single liver metastasis previously treated with SABR were randomly selected without limitations regarding target volume and location (minimum distance target-serial organs > 8 mm). The patients were placed in a supine position with their arms above their heads and were immobilised by means of a thermoplastic body mask with a Styrofoam block for abdominal compression to minimise internal organ motion. Contrast-free and three phases of contrast-enhanced planning computed tomography (CT) scans in free quiet breathing mode with a 3 mm slice thickness were acquired. Furthermore, in the event of lesions located in the VII or VIII hepatic segment or liver cupola shifts greater than 5 mm on the four simulation CTs, a four dimensional CT (4D-CT) was performed in order to better define the target margin [15]. The gross tumour volume (GTV) included macroscopic disease defined on multi-phase contrast-enhanced CT. The clinical target volume (CTV) was defined as equal to the GTV. The planning target volume (PTV) was generated by taking into account both the internal margin (IM) and the set-up margin (SM). The overall CTVPTV margin was defined as 8–12 mm in the cranial-caudal axis and 4–6 mm in the anterior-posterior and lateral axes depending on tumour location and patient compliance, allowing mainly for residual intra-fraction target motion as well as inaccuracies in CBCT image interpretation [5,15]. No markers were implanted. The organs at risk (OAR) considered were: healthy liver, spinal cord, kidneys, stomach, duodenum, heart, small bowel, oesophagus and ribs, according to the location of the lesion. The dose prescription was set to 75 Gy in three consecutive daily fractions of 25 Gy each. In accordance with the Ras Trial, the plans were normalised in order to cover the PTV with at least 67% of the prescribed dose (range 67–95%), with the aim of maximising it up to 95% [16]. Dose prescription downscaling up to 30% was allowed in case of difficulty in respecting OAR constraints. No specific constraint for maximum dose at PTV was considered. For the OARs, plans were required in order to meet the following constraints [7,17]:

• • • • • •

Liver volume receiving less than 15 Gy should be more than 700 cm3 (i.e. V15 Gy < (liver volume – 700 cm3)), D1 cm3 for spinal cord < 18 Gy (dose at 1 cm3 should be lower than 18 Gy), V15 Gy < 35% for both kidneys, D1 cm3 < 21 Gy for duodenum, small bowel, oesophagus, and stomach, D1 cm3 < 30 Gy for heart, D30 cm3 < 30 Gy for ribs was considered as a secondary constraint.

No specific objectives for mean OARs were requested. Planners were asked to use the ALARA (as low as reasonably achievable) philosophy to maximise the OAR sparing. Participants The AIFM SABR working group encouraged the group members to participate in the trial and 14 institutions from all over Italy accepted to take part in the inter-comparison. The institutions involved had different levels of experience in planning SABR in general and liver treatment in particular. Various RT technologies were used by the institutions participating in the inter-comparison: 2 Elekta VMAT/Monaco, 6 Varian VMAT/RapidArc, 2 IMRT (Elekta), 1 Dynamic Conformal Arc Therapy and 1 static field conformal RT, 1 Tomotherapy and 1 CyberKnife. Twelve institutions used inverse planning and two used forward planning techniques. Each participant received:

• • •

The five CT series with the corresponding DICOM-RT structures; The calibration curve of the CT for Hounsfield Unit conversion into relative electron densities; The constraints and the protocol described above. In accordance with the Ras Trial [16], no specific limits concerning the maximum dose and dose homogeneity on the PTV were specified.

The participants were asked to follow the plan using local equipment and to anonymously send back the dose volume histogram (DVH) and a file containing the relevant data. Data analysis The technical parameters of delivery were scored in terms of total number of monitor units (MU) and total beam on time (BOT). The dosimetric quality of the treatments was measured according to the DVH analysis and the global maximum dose to the body was reported in detail. Data were presented as mean values ± one standard deviation (SD). Dosimetric quality of treatments was measured based on DVH analysis, together with the global maximum dose to body. Concerning the targets, the mean dose and D95% were reported for PTV; V98% was considered for CTV. The dose homogeneity index (HI) was calculated as (D98%/D2%); Dose Spillage (DS) was calculated as (V50%/VolumePTV). Regarding the OARs, the mean dose, maximum dose (D1 cm3) and appropriate values of VxGy (volume receiving at least x Gy) were scored. A Matlab tool was developed in order to analyse the DVHs obtained from the 14 Institutes. In particular, each TPS has different DVH storage data sampling. However, all TPSs have at least one dose value every 0.1% of volume, therefore a uniform distribution was obtained by re-sampling the original data with Matlab. Pearson correlation coefficient was computed to establish the correlations between the DVH results (mean dose to PTV, mean dose to liver and spillage of 50% of dose) and technical parameters for: the irradiation technique (technological factor), the PTV volume (objective factor), and the optimisation strategies selected by the planners (human factor) evaluated using the HI. Statistical significance was established by means of the two tails t-Student test (p < 0.05). Results The participant’s characteristics are summarised in Table 1. In particular, the mean total MU averaged over the five plans and the 14 centres were 6489.5 ± 784.2 MU, ranging from 3923 MU for the 3D Conformal plan to 21,676 MU for Tomotherapy system. The mean values averaged over the 8 VMAT and the 2 IMRT were very similar (5940.6 MU vs. 6053.5 MU). Significant differences in BOT were

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Table 1 Centre characteristics with delivery technique, general experience in SABR (High: > 100 pz; Low: > 10 pz; No Experience: < 10 pz), mean total MU (with one standard deviation), and BOT. The last column reports the constraint/objective violations. Name

Experience in SABR

MU

BOT [min]

Constraint or objective violated

VMAT1 VMAT2 VMAT3 VMAT4 VMAT5 VMAT6 VMAT7 VMAT8 IMRT1 IMRT2 DCAT 3D-CONF Tomo Cyber

High High High High High High Low No experience Low Low High High High High

5935.4 ± 840.3 7044.2 ± 365.7 5208.6 ± 1059.6 7325.6 ± 266.3 5197.2 ± 862.2 6966.8 ± 714.1 4453.2 ± 391.9 5396.0 ± 804.7 5372.2 ± 909.9 6734.8 ± 1084.9 3922.6 ± 804.7 4940.2 ± 1304.3 21676.4 ± 2234.8 15007.0 ± 1981.3

2.4 ± 0.2 2.9 ± 0.2 3.4 ± 0.2 12.4 ± 0.9 8.6 ± 1.6 12.4 ± 1.1 8.4 ± 1.0 9.0 ± 1.3 11.6 ± 5.9 13 ± 4.6 22.0 ± 1.3 19.0 ± 4.2 25.1 ± 2.6 57 ± 2.3

None None Liver constraint violated in pz 1 None None None Duodenum constraint of maximum dose violated in pz 2 None None Liver constraint violated in pz 1 Liver constraint violated in pz 1 Minimum target coverage not achieved in pz 1 None None

Legend: 3D-CONF, 3D Conformal radiotherapy; Cyber, CyberKnife; DCAT, Dynamic Conformal Arc Therapy; IMRT, Intensity Modulated RadioTherapy; Tomo, Tomotherapy; VMAT, Volumetric Modulated Arc Therapy.

observed among the centres (mean value: 14.8 ± 13.9 min – range 2.4–57.0 min). The best results were obtained for VMAT using flattening filter free beams (VMAT1, VMAT2, VMAT3). Figure 1 shows the coronal representative view with planned isodoses for patient 1. Similar results were observed for other patients. The DVH results are reported in Table 2 for the 14 centres. The mean global maximum dose was 105.6 ± 3.3% (for all centres and patients: 78.3–149.6%). HI varied greatly from institution to institution, ranging from 1.07 to 1.53 due to different planning approaches (i.e. human factor). The mean dose to CTV and V98% were 100.8 ± 4.0% and 97.6 ± 4.5%, respectively, showing good target coverage; the mean dose to PTV and V95% were 99.7 ± 3.5% and 93.6 ± 4.4%, respectively. Many centres used dose down-scaling for patient number 1 in order to comply with the constraints on OARs. In one centre, with forward planning, the minimum dose coverage requirement (i.e. 67% of prescription dose) was not met for patient 1. Regarding the OARs, the dose volume constraints were respected in almost all cases and the maximum doses (i.e. D1 cm3) to duodenum, stomach, oesophagus, heart, and spinal cord were 14.5 ± 3.6 Gy (overall maximum: 21.3 Gy – in one case the constraint was not respected), 13.5 ± 20.0 Gy (max 19.9 Gy), 13.6 ± 10.5 Gy (max 21.0 Gy), 15.5 ± 7.0 Gy (max 29.5 Gy), and 11.5 ± 5.4 Gy (max 18.0 Gy). Mean liver volume receiving less than 15 Gy was 952 ± 139 cm3. Three institutions did not respect for patient 1 the dose volume limit for a healthy liver (i.e. 700 cm3 of liver should not receive more than 15 Gy). The Pearson coefficient for the most important dosimetric data (mean dose to liver and PTV and dose spilling) and the parameters influencing the planning in all patients are reported in Table 3. For the fourteen centres, the mean dose to PTV and the mean dose to liver in function of the PTV volume are reported in Fig. 2. Dose spillage, D98% and HI grouped for techniques for patient 1 are reported in Fig. 3. The significant difference of DVHs is mainly determined by the optimisation strategy selected by the planner rather than the technology used. Pearson correlation tests between dosimetric results and technique-related parameters are reported in supplementary material (Table S1). Discussion In this study we tested the possibility of introducing a SABR protocol for metastatic liver patients in a multi-institutional framework. To evaluate the dosimetric consistency among different hospitals and to identify possible criticisms in approaching multicentre SBRT study from the dosimetric/planning point of view, we simulated the

Ras Trial protocol application [16] for liver metastatic disease and used in other recent manuscripts [5,15,17,18,19]. This protocol adopted a large coverage condition (i.e. 67%–95%) in order to include centres with different TPS. We evaluated how planners with different experience and with different TPS understand the prescription and how they used in practice for producing an adequate local tumour control probability and minimising side effect for OARs. For the same reason we decided to evaluate the mean doses at OARs, even if they had no specific constraints. In fact, when the objectives are reached and the constraints are respected, the planner could decide if and how to perform a further optimisation of the treatment planning. The involved institutes represented the various RT technologies available at a national level. We tested if it was possible to reproduce stereotactic dose distributions with the same clinical intent using data from five representative patients. With the aim of avoiding more complex cases with multiple metastases, only single metastases were analysed. Despite the large differences in the irradiation techniques used, with the exception of a few cases, the main outcome was that all planners achieved the main objective of a SABR approach in all five patients, regarding both PTV dose coverage and OAR sparing. The huge PTV volume range (26.8 cm3– 180 cm3) could be explained as the patients were randomly extracted by a database without limitation on tumour volume. However, on ANOVA evaluation, the volume did not influence the analysis. The most complex case was patient number 1, mainly due to the lesion dimension limiting the dose to the target in order to spare a normal liver. In this case, one planner did not fulfil the minimum requirement of target coverage while the dose limit to the liver was not respected in three cases. The DVH comparison obtained with different technologies and/ or TPSs is the subject of an important scientific research study [20]. Each year new treatment tools (micro multi leaf collimators, rotational therapy, helical therapy, robotic therapy, radiobiological treatment planning) are put on the market with the aim of better conforming the dose to the target and reducing treatment time. In this regard, in our analysis the optimisation strategy selected by the planner played an important role in respect to the technology used. For example, as shown in Fig. 3, two planners using the same technology (linac Varian Flattering Filter Free beam with VMAT and TPS version Eclipse 10.0) produced two completely different types of DVHs: one preferred the dose to target (VMAT FF3) and the other favoured the liver sparing (VMAT FF1). Furthermore, dose homogeneity to target could play a strategic role in the optimisation process. The AAPM task group 101 on

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Figure 1. Coronal representative view with planned isodoses for patient 1. Colourwash ranging from 37.5 Gy to 71.25 Gy (i.e. 50%–95%) was used in all but two centres (in which the colourwash was not available).

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Table 2 Dose volume analysis for target and OAR of interests for each patient averaged over the 14 centres. The doses are expressed in percentages according to the prescription dose for target, in Gy for OAR. Organ

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

PTV D95% [%] PTV Dmean [%] CTV V98% [%] Body Max [Gy] Liver Dmean [Gy] Liver volume receiving <15 Gy [cm3] CTV [cm3] PTV [cm3] Liver [cm3] HI

86.8 ± 16.8 [60.2–108.2] 94.5 ± 13.9 [74.3–116.3] 91.1 ± 16.4 [73.0–114.0] 76.6 ± 9.7 [58.7–93.5] 25.2 ± 8.0 [22.7–28.9] 777.6 ± 110.5 [571.9–952.5]

93.3 ± 8.2 [80.9–100.0] 98.1 ± 6.3 [88.7–104.1] 95.6 ± 7.0 [86.0–102.2] 77.0 ± 3.7 [70.2–81.9] 19.8 ± 4.0 [18.6-21.7] 845 ± 148.7 [704.3–997.5]

97.5 ± 15.1 [77.5–129.6] 103.7 ± 13.1 [90.8–138.1] 102.9 ± 13.1 [90.9–135.3] 82.3 ± 11.0 [76.2–112.2] 17.9 ± 11.9 [15.0–23.6] 966.9 ± 80.0 [796.3–1083.3]

94.2 ± 8.0 [80.8–111.0] 101.5 ± 6.2 [93.5–117.6] 99.4 ± 5.5 [93.7–114.4] 81.5 ± 5.0 [76.1–95.2] 13.6 ± 1.9 [11.0–17.9] 1085 ± 152.3 [845.7–1215.9]

96.2 ± 6.6 [80.7–104.2] 100.4 ± 5.0 [88.7–107.5] 98.9 ± 4.5 [87.4–105.3] 78.4 ± 2.5 [76.4–84.3] 10.1 ± 1.4 [8.7–15.5] 1084.7 ± 112.7 [931–1230.7]

83.5 180.3 1516.3 1.24 ± 0.36 [1.11–1.57]

13.3 64.3 1372.3 1.15 ± 0.29 [1.05–1.39]

42.8 110.4 1557.7 1.14 ± 0.17 [1.05–1.24]

SBRT [21], in contrast with conventional RT, which requires uniform prescription dose to the target, suggests prescribing SBRT at a specific isodose (usually approximately 80%). However, the modern algorithms of inverse TPS intrinsically intend to obtain homogeneous dose to the PTV, because the systems were primarily designed for conventional fractionated RT treatment. Moreover, ICRU 83 suggests normalising to a mean value without specifically distinguishing between the standard RT and SABR approaches that may encourage a homogeneous dose distribution also for SBRT [22]. Although common practice in SABR emphasises high conformation and sharp dose fall-off over target dose homogeneity, there is no concrete evidence that improved target homogeneity would be detrimental for disease control as stated by Abacioglu [23]. An interesting and unintuitive correlation between homogeneity and gradient indexes and treatment related toxicity was observed and reported by

Table 3 The Pearson correlation between dosimetric results (mean dose to PTV, mean dose to liver and spilling of 50% of dose) and leaf dimensions or minimal collimator dimensions in column 2, irradiation techniques in column 3, Homogeneity Index in column 4 and dimension of PTV in cc in column 5. The correlations with p < 0.01 are shown.

18.3 63.3 1232.2 1.18 ± 0.33 [1.07–1.46]

4.8 26.8 1565.1 1.1 ± 0.19 [1.03–1.25]

Balagamwala et al. [24]. In that study, patients with gradient index (defined as volume of half/entire the prescription isodose) greater than 3.0 were associated with a lower incidence of motor or auditory deficits compared to patients treated with sharper dose distributions. The same study also correlated homogeneity with toxicity. Therefore, the observed spread in dose homogeneity across different centres could be attributed to different approaches. Moreover, a con-cause for the spread of the HIs over the different centres could be found in the lack of a maximum dose constraint to the target. We would like to emphasise that our study was focused on dose distribution comparison, without considering other essential aspects regarding target definition, dose delivery, on board imaging for which further evaluation is required. In this study, the target volumes were intentionally delineated prior to data distribution to eliminate inaccuracy and variability of the contouring process (CT scanning, image fusion, etc.) and enable comparison of DVHs and radiobiological parameters. Furthermore, lesions with different positions and volumes were considered and the data should be considered carefully. Finally, determining the optimal dose prescription scheduling to the target was not the objective of the study.

R Pearson

Leaf/coll. dim

Technique

HI

PTV dimension

Conclusions

Mean dose PTV Mean dose liver Dose spillage

−0.04 0.06 0.12

0.08 0.09 0.12

−0.48 (p < 0.01) 0.08 −0.39 (p < 0.01)

−0.75 (p < 0.01) 0.76 (p < 0.01) −0.21

Significant differences were observed both in terms of target coverage and OAR sparing. The human factor and the constraints imposed to the target volume have a greater dosimetric impact

Figure 2. Mean dose to PTV and mean dose to liver in function of PTV volume for the 14 centres.

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Figure 3. Average values of Dose spillage, D98% and HI for patient 1. Bars represent maximum and minimum values found in all patients.

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