Potential proton and photon dose degradation in advanced head and neck cancer patients by intratherapy changes

Abstract Purpose Evaluation of dose degradation by anatomic changes for head‐and‐neck cancer (HNC) intensity‐modulated proton therapy (IMPT) relative to intensity‐modulated photon therapy (IMRT) and identification of potential indicators for IMPT treatment plan adaptation. Methods For 31 advanced HNC datasets, IMPT and IMRT plans were recalculated on a computed tomography scan (CT) taken after about 4 weeks of therapy. Dose parameter changes were determined for the organs at risk (OARs) spinal cord, brain stem, parotid glands, brachial plexus, and mandible, for the clinical target volume (CTV) and the healthy tissue outside planning target volume (PTV). Correlation of dose degradation with target volume changes and quality of rigid CT matching was investigated. Results Recalculated IMPT dose distributions showed stronger degradation than the IMRT doses. OAR analysis revealed significant changes in parotid median dose (IMPT) and near maximum dose (D 1ml) of spinal cord (IMPT, IMRT) and mandible (IMPT). OAR dose parameters remained lower in IMPT cases. CTV coverage (V 95%) and overdose (V 107%) deteriorated for IMPT plans to (93.4 ± 5.4)% and (10.6 ± 12.5)%, while those for IMRT plans remained acceptable. Recalculated plans showed similarly decreased PTV conformity, but considerable hotspots, also outside the PTV, emerged in IMPT cases. Lower CT matching quality was significantly correlated with loss of PTV conformity (IMPT, IMRT), CTV homogeneity and coverage (IMPT). Target shrinkage correlated with increased dose in brachial plexus (IMRT, IMPT), hotspot generation outside the PTV (IMPT) and lower PTV conformity (IMRT). Conclusions The study underlines the necessity of precise positioning and monitoring of anatomy changes, especially in IMPT which might require adaptation more often. Since OAR doses remained typically below constraints, IMPT plan adaptation will be indicated by target dose degradations.


| INTRODUCTION
Tumor-conformal treatment plans with steep dose gradients are required for radiotherapeutic treatment of advanced head-and-neck cancer (HNC). The target volumes are surrounded by critical normal tissue structures and may comprise some hundred milliliters when including lymph nodes and/or lymphatic pathways. Conformal dose distributions are typically provided by advanced photon therapy techniques like intensity-modulated radiotherapy (IMRT). 1 While intensity-modulated proton therapy (IMPT) can more effectively reduce the dose to healthy tissue [2][3][4][5] and thus allow for further dose escalation, 6 proton beams are prone to range uncertainties if the penetrated tissue changes during therapy. Gradual intratherapy changes in HNC patient anatomy, mainly caused by weight loss, shrinkage of tumor, and shift of close-by structures can be assessed via imaging, e.g. by computed tomography (CT), and are of concern during radiotherapy treatment. 7,8 The dosimetric consequences of such changes, namely the potential underdose of target volumes and overdose in organs at risk (OARs), have been quantified in detail for IMRT plans. 9,10 Treatment plan adaptation can be used to prevent severe dose degradation throughout the fractionated treatment course 11 and is related with lower normal tissue complication probabilities. 12 For IMRT treatment, up to two adaptation steps was reported to be sufficient and is logistically feasible. [13][14][15][16] Adaptive IMRT has been shown to be associated with improved locoregional control, 17 especially for advanced tumor stages. 18 Similar detailed clinical data are not available for IMPT treatment.

2.A | Patient data
A cohort of advanced HNC patients with UICC stage III or higher received PET/CT imaging prior and during definite radiochemotherapy in our clinic. 23 For the presented retrospective planning study, CT images of the PET/CT scans taken before therapy (CT plan ) and after approximately 20 fractions (CT recalc ) were used from 31 patients without intubation and that were scanned both times with thermoplastic head-and-shoulder mask for a sufficiently large region in cranio-caudal direction. Both CTs were acquired with the same protocol and have the same voxel size of either (1.37 9 1.37 9 5) mm 3 or (0.98 9 0.98 9 3) mm 3 . Patient characteristics are summarized in Table 1. Patients gave their written consent and the local ethics committee approved the study.
Targets and OARs were delineated on CT plan as described earlier. 4 The gross tumor volume (GTV) included the primary tumor and involved lymph nodes. The clinical target volume (CTV) was created by a 5-10 mm isotropic GTV expansion corrected for noninfiltrated bone and air cavities, and a prophylactic volume for elective lymph nodes defined according to Gr egoire et al. 24 was added. The planning target volume (PTV) was defined by CTV margins of 5 mm in cranio-caudal direction and 4 mm in plane with a 3 mm distance to the external contour except for three patients with skin infiltration. A 10 mm build-up bolus was applied for those patients to achieve adequate dose coverage in IMRT plans. The isotropic PTV concept was used for IMRT and IMPT planning for better comparability of dose distributions outside target volumes and same intersection of OARs with PTV. Published guidelines were applied for parotid gland 25 and brachial plexus delineation 26,27 and internal guidelines for spinal cord, brain stem, and mandible delineation. Artifacts in soft tissue arising from metal implants were contoured and overwritten before dose calculation. Planning risk volumes with 3 mm margin for spinal cord, brain stem, and plexuses were included.
Contours were transferred from CT plan to CT recalc by deformable image registration and adjusted afterward. Workload of contour adjustment was split among two physicians. CTV sizes for both CT scans, and therefore a quantification of anatomical changes, are included in Table 1. Even though the CTs are taken from photon radiotherapy patients, the study assumes that anatomical changes induced by IMPT and IMRT are similar.

2.B | Dose prescription, treatment planning
All dose values will be stated in Gy and refer either to absolute absorbed photon dose or to absorbed proton dose weighted by a constant relative biological effectiveness of 1.1. The intended treatment course consists of two series with homogeneous dose prescription of 2 Gy per fraction to the respective PTV. A full-field series of 25 fractions (50 Gy) would be followed by a sequential boost series of 11 fractions (22 Gy; not evaluated in this study) to escalate the dose in the non-elective target volume to 72 Gy. The aim was to irradiate at least 95% of the PTV with more than 95% of the prescribed dose (V 95% > 95%), to avoid dose levels above 107% (V 107% = 0%) and to provide a PTV D mean close to prescription. OAR constraints for spinal cord (D max < 45 Gy), brain stem (D max < 54 Gy) and brachial plexus (D max < 72 Gy) had higher priority than target coverage.
Dose to parotid glands (D median < 26 Gy) and mandible (minimum dose received by 1 ml: D 1ml < 75 Gy) was minimized without compromising target dose. In cases where the contralateral/ipsilateral parotid gland could not be assigned a priori due to the bilateral target volume, they were distinguished after treatment planning according to the lower/higher D median value. Assuming equal dose contribution over 36 fractions, OAR constraints for the full-field series of 25 For each patient, an IMRT and an IMPT plan for the full-field series were calculated as described previously. 4 Step-and-shot IMRT plans were optimized using the treatment planning system (TPS) Pinnacle 3 (Philips Healthcare, Amsterdam, Netherlands) and consisted of seven almost equidistant but individually adjustable, coplanar 6 MV fields. Seven to nine fields are considered as optimal, 28

| RESULTS
Exemplary dose distributions from IMRT and IMPT plans on CT plan and CT recalc are shown in Fig. 2. Statistics of investigated fraction dose parameters in OARs, targets and healthy tissue are presented in Fig. 3 and Table 2.

3.B | Changes after 20 fractions
The contoured CTV on CT recalc was on average (37 AE 24) ml (mean AE standard deviation) smaller than on CT plan (

| DISCUSSION
We analyzed the potential dose degradation due to intra therapy changes for IMPT treatment plans in comparison to IMRT plans.  41 reported correlation between increased CTV V 107% and initial CTV size, which was low in our study containing more advanced HNC, but moderate correlation between PTV size/ shrinkage and formation of hotspots in healthy tissue was found here.
Besides indicating the importance of monitoring anatomic changes and performing plan adaptation, we have shown that reasonable effort is required for exact patient positioning, since loss of target coverage, homogeneity and conformity were significantly worse for less accurate CT matching for proton plans. Shoulder adjustment and verification of head tilt under the mask system is essential; repositioning by couch shift only is insufficient. We believe that the suboptimal CT matching in this study is realistic for current radiotherapy treatment. The standard image guidance for positioning in proton therapy is orthogonal X-ray 42  to the limitation of having only one control CT available. Thus, no conclusions could be drawn for impact of anatomical changes on biological endpoints like normal tissue complication and tumor control probability, and no investigations on optimal adaptation time points could be performed.

| CONCLUSION
IMPT plans provide superior dose distributions in advanced HNC but these are more prone to intra therapy changes. The study underlines that precise positioning and monitoring of anatomy changes are mandatory for reliable IMPT treatment. In consideration of the larger absolute changes, IMPT plans might require adaptation more often than IMRT plans. Since OAR doses remained typically below constraints, indications for adaptive IMPT should rather be derived from target dose degradation.

CONF LICT OF I NTEREST
The authors declare no conflict of interest.