Potential benefits of adaptive intensity-modulated proton therapy in nasopharyngeal carcinomas.

PURPOSE
To investigate potential advantages of adaptive intensity-modulated proton beam therapy (A-IMPT) by comparing it to adaptive intensity-modulated X-ray therapy (A-IMXT) for nasopharyngeal carcinomas (NPC).


METHODS
Ten patients with NPC treated with A-IMXT (step and shoot approach) and concomitant chemotherapy between 2014 and 2016 were selected. In the actual treatment, 46 Gy in 23 fractions (46Gy/23Fx.) was prescribed using the initial plan and 24Gy/12Fx was prescribed using an adapted plan thereafter. New treatment planning of A-IMPT was made for the same patients using equivalent dose fractionation schedule and dose constraints. The dose volume statistics based on deformable images and dose accumulation was used in the comparison of A-IMXT with A-IMPT.


RESULTS
The means of the Dmean of the right parotid gland (P < 0.001), right TM joint (P < 0.001), left TM joint (P < 0.001), oral cavity (P < 0.001), supraglottic larynx (P = 0.001), glottic larynx (P < 0.001), , middle PCM (P = 0.0371), interior PCM (P < 0.001), cricopharyngeal muscle (P = 0.03643), and thyroid gland (P = 0.00216), in A-IMPT are lower than those of A-IMXT, with statistical significance. The means of, D0.03cc , and Dmean of each sub portion of auditory apparatus and D30% for Eustachian tube and D0.5cc for mastoid volume in A-IMPT are significantly lower than those of A-IMXT. The mean doses to the oral cavity, supraglottic larynx, and glottic larynx were all reduced by more than 20 Gy (RBE = 1.1).


CONCLUSIONS
An adaptive approach is suggested to enhance the potential benefit of IMPT compared to IMXT to reduce adverse effects for patients with NPC.


| INTRODUCTION
The standard treatment for nasopharyngeal cancer (NPC) is radiotherapy and concomitant chemotherapy followed by adjuvant chemotherapy. 1 Intensity-modulated X-ray radiotherapy (IMXT) has been used widely and is accepted as the treatment of choice for NPC. 2,3 However, adverse effects of IMXT with concomitant chemotherapy are still serious in a majority of patients and further improvements in radiation technology are warranted. 4 In the IMXT of NPC, due to the changes in the body surface, weight loss, and the shrinkage of tumors during treatment, it is well known that tumor relapse and adverse-effect rates may be increased by reduced doses to the clinical target volume (CTV) and excessive doses to the organs at risk (OARs). [5][6][7][8] Adaptive radiotherapy, in which treatment parameters are adjusted to conform to changes in anatomy during the irradiation, has been suggested to overcome these problems. 9,10 After the initial radiotherapy administration of 30-40 Gy using the initial plan, an additional 30-40 Gy is administered using an adapted plan which reflects the changes in anatomy. Encouraging improvements in loco-regional control rates have been observed using adaptive radiotherapy, although advantages in overall survival were not obvious in a retrospective study. 10 After the introduction of scanning proton beam technology, the usefulness of intensity-modulated proton therapy (IMPT) has been shown to reduce the dose to various OARs for NPC and several dose comparative studies between IMXT and IMPT have been published. [11][12][13][14] Contrary to general expectations, Lewis et al. have pointed out that the superiority of IMPT to IMXT in reducing the dose to the OARs is not consistent among these studies. 14 Widesott et al. even found opposite results for the mandible and larynx. 12 IMPT with the adaptive approach (A-IMPT) has recently been shown to be a promising future technology to enhance the dosimetric advantages compared to IMXT with the adaptive approach (A-IMXT) for NPC. 15 The spot size in the scanning beam for IMPT is becoming shaper than before 16 and new technologies such as a short-range applicator for treating superficial tumors 17 are available with recent state-of-art apparatus. Treatment planning systems have been improved to make A-IMPT practical in daily practice. As far as we were able to survey, however, no dosimetric studies have been reported comparing A-IMXT with A-IMPT for NPC. Furthermore, recent treatment planning using precise imaging has made it possible to analyze detailed dose-volume factors associated with ear disorders following radiotherapy in NPC 18,19 We have compared detailed dose volumetric statistics of OARs between A-IMXT and A-IMPT for hearing disorders. In the study, we investigated whether there are dosimetric advantages of A-IMPT when compared to A-IMXT for NPC by using simulation planning of IMPT for actual data of patients who have been treated with adaptive IMXT in our institution.

2.A | Patient selection
Based on previous reports in the literature, 12,14 we assumed that the mean dose to the oral cavity in A-IMPT would be 10 Gy (RBE = 1.1) lower than A-IMXT with a standard deviation of 7 Gy (RBE = 1.1).
To determine the differences in the mean dose to the oral cavity, the number of patients required to assure 80% power to detect differences in a two-sided significance level of 1% was calculated by paired t-test. 20 The required sample size was calculated to be 10 by SAS® version9.4 (Cary, NC, USA).
There were 13 patients with NPC who were all treated with A-IMXT (step and shoot method) and concomitant chemotherapy between April 2014 and July 2016 at Hokkaido University Hospital.
Two patients were excluded because they received induction chemotherapy before IMXT with concomitant chemotherapy. One patient was excluded because of treatment by step and shoot IMXT in the initial part but by the volumetric arc therapy technique (VMAT) in the subsequent adaptive part. Finally, the remaining 10 patients were included in the dosimetric comparison. The characteristics of these 10 patients are shown in Table 1. The TNM classification and the clinical stage in Table 1 was according to the UICC TNM classification 7 th edition.

2.B | Target volume, OARs, and dose prescription
This was a prospective clinical study (JCOG1015) based on an original study by Nishimura et al. in Japan with IMXT. 9,21 That protocol was based on practical standard IMXT in Japan for nasopharyngeal carcinoma. Our IMPT study was designed to be compatible with that protocol.
| 175 (GTV node). These were contoured using fused images of computed tomography (CT) and magnetic resonance imaging (MRI). The CTV primary and CTV node were implemented by adding a 1.0-cm margin to the GTV and an additional margin for high-risk patients accounting for microscopic extensions to the GTV primary and GTV node, respectively. The clinical target volumes in the initial plan (CTV46) consisted of the CTV46 primary, the CTV46 node and the prophylactic regional lymph node. The prophylactic lymph nodes were contoured according to international consensus guidelines. 22 The planning target volume for the initial plan (PTV46) was imple-  A 3-mm planning organs at risk volume (PRV) margin was added to the brain stem, optic nerve, optic chiasm, and spinal cord. In the actual treatment, 46 Gy in 23 fractions (46Gy/23Fx) was prescribed using the initial plan and 24Gy/12Fx was prescribed using the adaptive plan. We created a plan to irradiate the PTV46 with 70Gy/35Fx on the initial CT (initial plan). The plan was created so that the dose regulation for the target and OARs would meet the criteria. Next, a plan to irradiate PTV70 with 70Gy/35Fx was created on the second CT (adaptive plan), and the dose regulation for the target/OARs was also created to meet the criteria. Finally, the dose in the initial plan was multiplied by 46/70 and the dose in the adaptive plan was multiplied by 24/70, and the sum was regarded as the dose to CTV and OARs. For the initial CT, a plan to irradiate 70 Gy (RBE = 1.1)/35Fx to CTV46 was developed (initial plan). The plan was created so that dose regulation for the target and OARs would meet the criteria.

2.D | A-IMPT planning
Next a plan to CTV70 with 70 Gy (RBE = 1.1)/35Fx was created on the second CT (adaptive plan), and the dose regulation for the target/OARs also meet the criteria. Finally the dose in the initial plan was multiplied by 46/70 and the doses in the adaptive plan was multiplied by 24/70, and the sum was regarded as the dose to the CTV and OARs.

2.E | Image registration, dose accumulation, and evaluation
We decided to deform the adaptive plan CT to the original plan according to a previous study by Gora et al. which described adaptive radiotherapy for head and neck cancers. 25 Our method of adaptive treatment planning and dose accumulation in A-IMXT and A-IMPT in this study was based on this method as is illustrated in Fig. 1. We used MIM version 6.92 (EuroMeditec, Tokyo) for the deformable image registration of the initial and adaptive plans. The CT images in the adaptive plan were deformed to be registered into the CT images in the initial plan. The CTV70 was deformed and registered into the CT used in the initial plan. The deformed CTV70 is denoted as CTV70'. Dose volume statistics were carried out by adding the dose in the initial plan to the dose in the adaptive plan on the CT images in the initial plan.

2.F | Statistical comparison
The conformation number (CN) published by van't Riet et al. was used for the comparison between IMXT and IMPT. 26 The CN is the product of a tumor coverage factor and a normal tissue over dosage factor. In this study, the CN is the product of CTV covered by the volume of 70 Gy divided by CTV, and CTV covered by the 70 Gy divided by the volume of the prescription isodose, that is, 70 Gy in the body.
The homogeneity index (HI) was obtained by dividing the dose administered by 5% of CTV70' (D 5% ) by the dose which was administered to 95% of CTV70' (D 95% ). Dose volume parameters were selected to be compatible with previous studies as far as possible.
Dose volume statistics for the OARs were all analyzed and a comparison of A-IMXT and A-IMPT was made. The paired t-test was used to compare the mean dose (D mean ), the D 0.03cc and the maximum dose level given to each OAR. The dose for 30% (D 30% ) of the Eustachian tube and dose for 0.5cc of mastoid air cells volume (D 0.5cc ) were also measured since these have been reported to be important dose volume parameters associated with ear disorders following IMXT. 19 3 | RESULTS between the prescriptions for A-IMXT and A-IMPT (Table 2). However, the mean V 70Gy (BODY) (P < 0.001) was significantly lower in A-IMPT than in A-IMXT.

3.A | Comparison of dose distribution
There was a significant difference in the mean of the CN of A-  lower than those with A-IMXT with statistical significance ( Table 3).  Table 4. D 30% for Eustachian tube, D 0.5cc and D 0.03cc for mastoid air cells volume were all significantly lower in A-IMPT comparing to A-IMXT in both ears.
The means of the V 60Gy (P = 0.00228), V 50Gy (P = 0.00164), V 40Gy (P < 0.001), V 30Gy (P < 0.001), V 20Gy (P < 0.001), V 10Gy (P < 0.001), and V 5Gy (P < 0.001) to the skin in A-IMPT are lower than those with A-IMXT with statistical significance as shown in Table 5.  19 We have  1.1)). The appropriate dose volume parameter for skin reaction was recently reported to be V 5Gy to V 60Gy by Kawamura et al. 24 We have found that A-IMPT can reduce any of these dose parameters in this study.

| DISCUSSION
These results imply that the adaptive approach enhances the potential benefit of IMPT over that of IMXT to reduce adverse effects significantly. Additionally, we found that the CN was significantly improved with A-IMPT as compared with A-IMXT for NPC in this study. Considering that the adaptive approach is generally effective to improve the CN of CTV for tumors which commonly change in shape of the CTV during radiotherapy, 28 A-IMPT has potential benefits to improve the therapeutic ratio for nasopharyngeal carcinomas.
The present study has several potential shortcomings: First, we have not compared the differences in normal tissue complication probabilities and tumor control probability for A-IMXT and A-IMPT.
However, the differences in the mean dose to OARs at low dose levels and hot spots in the CTV may not lead to meaningful differences in clinical outcomes. It will be important to investigate the actual differences in adverse effects for each OARs in clinical outcomes in prospective clinical research.
A second shortcoming is the absence of established ways to estimate the appropriateness of A-IMXT plans in our study in comparison to A-IMPT plans. However, since A-IMXT was used for the ten patients in our institution, there was no intention to make the A-T A B L E 3 Dose volume parameters for each OAR in A-IMXT and A-IMPT plans.
| 181 5% change in dose inside the critical organ or target volume was an indicator for re-planning. The problem of this individualized approach would be the reproducibility of the treatment protocol in the particular institution. Alternatively, we may use a 2-adaptation course rather than a 1-adaptation course with IMPT as an alternative approach to keep the robustness of the treatment protocol. In either case, we will be able to use the present study as the basic dose volume data for A-IMPT data to be compared.

CONF LICT OF I NTERESTS
The authors have no conflict of interests to declare.