Potential benefits of adaptive intensity modulated proton therapy in nasopharyngeal carcinomas: a planning comparison study

doi:10.21203/rs.3.rs-24923/v1

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Potential benefits of adaptive intensity modulated proton therapy in nasopharyngeal carcinomas: a planning comparison study

https://doi.org/10.21203/rs.3.rs-24923/v1

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published 01 Sep, 2019

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Background

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

Six patients with NPC treated with A-IMXT (step and shoot approach) and concomitant chemotherapy between 2015 and 2016 were selected. In the actual treatment, 46 Gy in 23fr fractions was prescribed using the initial plan and 24 Gy/12fr 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 mean doses to the right parotid gland (p = 0.004), left parotid gland (p = 0.012), the oral cavity (p < 0.001), the thyroid gland (p = 0.047), the supraglottic larynx (p < 0.001), the glottic larynx (p = 0.001), the superior pharyngeal constrictor muscle (PCM) (p < 0.001), the middle PCM (p = 0.002), the inferior PCM (p < 0.001), and the cricopharyngeal muscle (p = 0.031) in A-IMPT are statistically significantly lower than those of A-IMRT with the statistical significance. The mean dose to the oral cavity, supraglottic larynx, and glottic larynx were all reduced by more than 20 GyE.

Conclusion

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

Oncology

proton beam therapy

intensity modulated radiotherapy

adaptive radiotherapy

nasopharyngeal carcinoma

dosimetric comparative study

The standard treatment for nasopharyngeal cancer (NPC) is radiotherapy and concomitant chemotherapy followed by adjuvant chemotherapy¹. 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 the concomitant chemotherapy are still serious in a majority of patients and further improvements in radiation technology are warranted⁴.

In the IMXT of NPC, and due to the changes in the body surface, weight loss, and the shrinkage of tumors during treatment; it is well known that the tumor relapse and adverse effect rates may be increased by reduced doses to the clinical target volume (CTV) excessive doses to the organs at risk (OAR) ^5–8. Adaptive radiotherapy, in which treatment parameters are adjusted to conform with changes in anatomy during the irradiation, has been suggested to overcome these problems^{9, 10}. After the initial radiotherapy giving 30–40 Gy using an initial plan, an additional 30–40 Gy was given using an adapted plan which reflect the changes in anatomy during the initial irradiation. Encouraging improvements in loco-regional control rates were observed using the adaptive radiotherapy although advantages in overall survival ware not obvious in a retrospective study¹⁰.

Recently, the usefulness of intensity modulated proton therapy (IMPT) has been reported to reduce the dose to the OAR for NPC^11–14. Also, IMPT with the adaptive approach has been expected to be a promising future technology for NPC¹⁵. However, there has been no dosimetric comparative reports of IMPT for the adaptive approach used with NPC.

In this study, we have investigated whether there are dosimetric advantage of the adaptive IMPT comparing to the adaptive IMXT for NPC by using simulation planning of IMPT for actual data of patients who have been treated with the adaptive IMXT in our institution.

Patient selection

Based on previous reports in the literature^12,14, we assumed that the mean dose to the oral cavity would be 20 Gy lower with a standard deviation of 12 Gy in the adaptive IMPT (A-IMPT) compared to the adaptive IMXT (A-IMXT). To determine the differences in the mean dose to the oral cavity, the number of patients required to assure 80% power to detect the difference at a two-sided significance level of 5% was calculated by paired t test¹⁶. The sample size was calculated to be six by web tool and SAS®version9.4(Cary, NC).

There were nine patients with NPC who were all treated with A-IMXT (step and shoot approach) and concomitant chemotherapy between 2015 May and 2016 July at Hokkaido University Hospital. Two patients were excluded because they received induction chemotherapy before the 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 six patients were included in the dosimetric comparison. The characteristics of these six patients are shown in Table 1. The TNM classification and the clinical stage in Table 1 was according to the AJCC TNM classification 7th edition.

Table 1

Patient characteristics
Patient number	Age	Gender	T stage*	N stage*	M stage	Clinical stage
1	58	Male	T1	N2	M0	Ⅲ
2	66	Female	T1	N2	M0	Ⅲ
3	60	Male	T1	N1	M0	Ⅱ
4	67	Male	T3	N1	M0	Ⅲ
5	58	Male	T1	N2	M0	Ⅲ
6	69	Male	T3	N1	M0	Ⅲ

*UICC 7th edition

Target Volume, OAR, And Dose Prescription

In the initial plan, Gross tumor volume (GTV), consisted of both a primary lesion (GTV primary) and metastatic lymph nodes (GTV node). These were contoured using fusion images of computed tomography (CT) and magnetic resonance imaging (MRI). The CTV primary and CTV node were basically made 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. Clinical target volumes in the initial plan (CTV1) consisted of the CTV primary, the CTV node, and the prophylactic regional lymph node. The prophylactic lymph nodes were contoured according to the international consensus guideline¹⁷. Planning target volume for the initial plan, PTV1, was produced by adding an additional 3.0 mm as the set-up margin to the CTV1.

To make the adaptive plan, patients were rescanned by CT and MRI at the time when they were given 24 Gy/12fr-28Gy/14fr. The clinical target volume in the adaptive plan (CTV2) which consisted of the CTV2 primary and the CTV2 node was contoured using the rescanned CT. The planning target volume for the adaptive plan (PTV2) was produced by adding an additional 3.0 mm as the set-up margin to the CTV2.

The brain stem, optic nerve, optic chiasma, oral cavity, thyroid gland, and supraglottic larynx, glottis larynx and superior pharyngeal constrictor muscle, middle pharyngeal constrictor muscle, inferior constrictor muscle and cricopharyngeal muscle were contoured for OARs. Basically, a 3 mm Planning organ at risk volume (PRV) margin were added to the brain stem, optic nerve, optic chiasm, and spinal cord.

A-IMXT Planning

Pinnacle³ v9.0 (Phillips, Medical Systems, WI) was used in the inverse treatment planning of IMXT using 7 portals and step and shoot techniques.

In the actual treatment, 46 Gy in 23 fractions (46 Gy/23Fr) was prescribed using the initial plan and 24 Gy/12Fr was prescribed using the adaptive plan.

Dose constraints for OARs in the inverse planning are shown in Supplementary table S1 (Spinal cord PRV ≤ 50 Gy, Brainstem PRV ≤ 60 Gy, Optic nerves PRV ≤ 60 Gy, Optic chiasm PRV ≤ 60 Gy). The plans were optimized to ensure 100% of the prescription dose to cover 95% of the volume of PTV1 and PTV2.

Plans to irradiate 70 Gy to the PTV1 were made based on the initial CT (initial plan) and used in the plans to irradiate 70 Gy to PTV2 on the second CT (adaptive plan). The dose to the OARs and CTV in the initial plan was estimated by dividing the dose to the OARs and CTV multiplied by 46/70. The dose to the OARs and CTV in the adaptive plan was estimated by dividing the dose to the OARs and CTV multiplied 24/70.

A-IMPT Planning

The VQA version 3.077 (Hitachi co ltd., Tokyo) was used in the inverse treatment planning of the IMPT using 3 portals at 80, 160, and 200 degrees. The dose distribution was calculated using the beam profile of the spot scanning dedicated proton beam therapy system, PROBEAT-RT, (Hitachi, co ltd., Tokyo).

Relative biological effectiveness (RBE) was assumed to be 1.1 throughout the irradiated volume and we used 1GyE, which is the physical dose times 1.1, as the unit of absorbed dose in the treatment planning. In the actual treatment, 46GyE in 23 fractions (46GyE/23Fr) was prescribed using the initial plan and 24GyE/12Fr was prescribed using the adaptive plan.

Robust optimization was used to prescribe at least 70GyE at D_99% of CTV by shifting the CT images by 3 mm and assuming an uncertainty in the range of 3.5%.

The dose constraints for OARs in the inverse planning are shown in Table 2 (Spinal cord PRV ≤ 50GyE, Brainstem PRV ≤ 60GyE, Optic nerves PRV ≤ 60GyE, and Optic chiasm PRV ≤ 60GyE). Plans were optimized to ensure 100% of the prescription dose to cover 99% of the volume of CTV1and CTV2.

For the initial CT, plans to irradiate 70GyE to CTV1 were made (initial plan) and for the second CT, plans to irradiate 70GyE to CTV2 were made (adaptive plan).The dose to the OARs and CTV in the initial plan was estimated by dividing the dose to the OARs and CTV multiplied by 46/70. The dose to the OARs and CTV in the adaptive plan was estimated just by dividing the dose to the OARs and CTV multiplied by 24/70.

Table 2

Mean dosimetric parameters, Conformity index and Homogeneity index of the target of the A-IMRT and A-IMPT treatment plans
	A-IMRT (Mean ± SD)	A-IMPT (Mean ± SD)	p value
V70Gy (BODY)	412.2 ± 149.3	348.8 ± 149.4	0.0013
V70Gy (CTV70)	216.3 ± 85.2	218.2 ± 88.6	0.31
D5% (CTV70)	73.9 ± 0.62	73.5 ± 1.43	0.007
D95% (CTV70)	71.3 ± 0.64	71.6 ± 0.98	0.58
Conformity Index	1.94 ± 0.23	1.59 ± 0.12	0.0068
Homogeneity Index	1.04 ± 0.009	1.03 ± 0.008	0.073

Abbreviations: V70Gy, volume receiving 70 Gy; D5%, dose to the 5% of the volume; D95%, dose to the 95% of the volume.

Image Registration, Dose Accumulation, And Evaluation (Figure 1)

The way of adaptive treatment planning and dose accumulation in A-IMXT and A-IMPT has been based on the method previously described by Goras et al.¹⁸ and is illustrated in Fig. 1. We used the 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 CTV2 was deformed and registered into the CT used in the initial plan. The deformed CTV2 was denoted as CTV70. Dose volume statistics were carried out by adding the dose in the initial plan to the dose in adaptive plan on the CT images in the initial plan.

Statistical Comparison:

The conformity index (CI) was obtained by dividing the volume in the body which received 70 Gy or more by the volume in the CTV70 which received 70 Gy or more in A-IMXT and 70GyE or more in A-IMPT. The homogeneity index (HI) was obtained by dividing the dose which was received by 5% of CTV70, D5%, by the dose which was received by 95% of CTV70, D95%.

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 (Dmean) for the OARs. We contoured the oral cavity, pharyngeal constrictor muscle (PCM), and larynx according to the Charlotte et al. method¹⁹.

Comparison of Dose Distribution

Figure 2,3 show isodose distributions and Dose Volume Histogram (DVH) of A-IMXT and A-IMPT for the same NPC patient. Comparing the two dose distributions, it shows that the doses to the oral cavity and larynx in A-IMPT are significantly lower than those in A-IMXT. In A-IMPT, the anterior part of the oral cavity and a part of the larynx received no irradiation although a low but definite dose was given to the oral cavity and larynx in A-IMXT.

CI And HI Of CTV

The mean dosimetric parameters, CI of CTV70 and the HI of CTV70 are shown in Table 2. The mean CI of CTV70 in A-IMPT (1.60 ± 0.12) was statistically significantly lower than that of CTV70 in A-IMXT (1.94 ± 0.23) (p = 0.007).

The mean HI of CTV70 in A-IMPT (1.03 ± 0.08) was smaller than the mean HI of A-IMXT (1.04 ± 0.007) also statistically significant (p = 0.037).

Dose Volume Statistics For The OARs

Dose to the spinal cord, brain stem, optic nerve, and optic chiasm, were not significantly different (Table 3).

The mean dose to right parotid gland (p = 0.004), left parotid gland (p = 0.012), oral cavity (p < 0.001), thyroid gland (p = 0.047), supraglottic larynx (p < 0.001), glottic larynx (p = 0.001), superior PCM (p < 0.001), middle PCM (p = 0.002), interior PCM (p < 0.001), and cricopharyngeal muscle (p = 0.031) in A-IMPT are lower than those with A-IMXT with statistical significance (Table 3).

Table 3

Comparison of the mean maximum or mean doses to normal tissues of A-IMPT and A-IMPT.
		A-IMXT (Mean ± SD)	A-IMPT (Meaan ± SD)	p value
Right parotid gland	Dmean	30.1 ± 5.6	22.7 ± 8.4	0.00401
Left parotid gland	Dmean	34.5 ± 10.0	32.3 ± 10.7	0.0119
Oral cavity	Dmean	51.6 ± 4.7	23.2 ± 5.8	< 0.001
Thyroid gland	Dmean	47.4 ± 7.6	42.2 ± 6.1	0.047
Supraglottic larynx	Dmean	47 ± 9.1	26.8 ± 8.1	< 0.001
Glottic larynx	Dmean	38.8 ± 7.8	17.7 ± 4.3	0.00103
Superior PCM	Dmean	69.9 ± 1.9	66.8 ± 2.6	0.0004
Middle PCM	Dmean	56.8 ± 9.1	46.2 ± 13.1	0.00177
Inferior PCM	Dmean	44.6 ± 7.5	34.1 ± 7.1	< 0.001
Cricopharyngeal muscle	Dmean	39.2 ± 5.9	32.7 ± 5.7	0.031
Spinal cord	Dmax	47.5 ± 1.80	46.0 ± 4.10	0.243
Brain stem	Dmax	58.2 ± 1.50	55.5 ± 4.00	0.080
Left optic nerve	Dmax	35.3 ± 20.9	29.8 ± 15.1	0.270
Right optic nerve	Dmax	34.4 ± 20.2	27.0 ± 14.0	0.120
Chiasma	Dmax	24.4 ± 20.9	20.2 ± 16.1	0.230

abbreviations: PCM pharyngeal constrictor muscle.

Previous studies reporting comparisons between IMXT and IMPT for NPC are the following.

Taheri-Kadkhoda et al.²⁰ compared the IMPT and IMXT plans. They showed that IMPT improves the tumor coverage and conformation and reduces the average mean dose to several organs at risk. In that study, the average mean dose to the oral cavity in IMPT (mean: min -max, 38.1: 33.9–43.7) was significantly lower than with IMXT (44.0: 40.5–46.7). The average mean dose of to the larynx in IMPT (14.3: 8.6–18.5) was also significantly lower than with IMXT (30.6: 24.3–35.3).

Widesott et al.²¹ compared IMPT and IMXT plans of helical tomotherapy for nasopharyngeal cancer, and found that the IMPT plan showed lower average mean doses for the parotid glands and comparable average mean doses for the thyroid gland. They did not compare dose distributions of IMXT and IMPT to the oral cavity, but instead made a ROI of the ’mucosa outside PTV’ which includes the oral cavity and the pharynx, with a 0.5 cm margin added to the PTV. The average mean dose to the “mucosa outside PTV” of IMRT was 26.2 Gy ± 2.7 Gy and for IMPT it was 18.0 ± 1.6GyE. The mean dose for the pharyngeal constrictor muscle was not evaluated as an organ at risk. It was concluded that the IMPT allows a better sparing of most organs at risk at medium-to-low doses.

Lewis et al.¹⁴, in a study with 9 NPC patients, compared the IMXT and IMPT plans. They compared mean doses to 29 OARs. and reported that the IMPT plan could reduce 13 OARs mean doses significantly more than the IMXT plan. The mean dose to the oral cavity in IMPT (16.56 ± 7.67 Gy) was significantly lower than with IMXT (36.96 ± 7.90 Gy) in that study. The mean dose of the larynx in IMPT (29.56 ± 7.83GyE) was also significantly lower than with IMXT (42.75 ± 9.94GyE). The dose to the parotid glands were not significantly different. The dose to the thyroid gland and pharyngeal constrictor muscle were not evaluated.

None of these previous studies, have used adaptive approaches with either IMXT or IMPT.

The A-IMXT for head and neck cancer has been reviewed recently by Castelli et al.²² Here it was found that further randomized clinical trials are required to show more solid evidence. Previous studies suggest benefits of A-IMXT when comparing with IMXT in decreasing xerostomia, increasing quality of life, and increasing local control. Patients with the largest early anatomical and dose variations were suggested to be the best candidates for A-IMXT. The present study showed that the A-IMPT plan with A-IMXT would significantly increase the advantages of IMPT over IMXT for dose reductions to the OAR, while maintaining the tumor coverage.

We found that, compared with A-IMXT, A-IMPT reduces the mean dose to the oral cavity, larynx, and pharyngeal constrictor muscle, and to the parotid gland, while it maintains optimal tumor coverage for NPC significantly better. Notably, the differences in the mean dose to the oral cavity and larynx were much larger than the differences between IMXT and IMPT without the adaptive approach as reported in previous studies by Zahra et al.²⁰, Widesott et al. ²¹ and Lewis et al. ¹⁴. The mean dose to the oral cavity, supraglottic larynx, and glottic larynx were all reduced more than 20 GyE in this study as shown in Table 3 with none of the mean dose reductions to the OAR larger than 20 GyE in the previous studies. This would imply that the adaptive approach enhances the potential benefit of IMPT compared with IMXT to reduce adverse effects. Additionally, the CI of CTV was significantly improved with IMPT as compared with IMXT. Considering that the adaptive approach is generally effective to improve the CI of CTV for tumors which commonly change the shape of the CTV during radiotherapy²³, the adaptive 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 complications probability and tumor control probability between A-IMXT and A-IMPT. It is well known that 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 OAR 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, as in comparison to A-IMPT plans. However, since the A-IMXT has been used for the six patients in our institution, there was no intention to make the A-IMXT dose distribution suboptimal in this study. Thus, the superiority in the A-IMPT plan in this study can be interpreted with more confidence than in studies using A-IMXT plans which are made for virtual comparison but not used clinically.

Third, we conducted the A-IMXT planning using the step and shoot approach. Recently, however, the VMAT approach is more often used clinically. If the VMAT approach had been used instead of step and shoot, the difference for OARs between A-IMXT and A-IMPT may have been smaller. Ning²³ et al. compared 20 patient dosimetries with single arc VMAT, dual arc VMAT, and step and shoot IMRT. There the mean doses to the oral cavity were 40.35 ± 4.77 Gy, 36.99 ± 6.18 Gy, and 43.21 ± 5.60 Gy respectively. We cannot simply compare these results with ours, but assume that even if we make the IMXT plan with the VMAT technique, the dose to the oral cavity in A-IMPT plan would have been preferential to the adaptive VMAT plan. This is because low but definite doses are irradiated to the entire oral cavity in the VMAT plan in the Ning et al²⁴. study while the anterior part of the oral cavity was spared from any irradiation in the A-IMPT plan in all the patients in this study.

Compared with A-IMXT, A-IMPT presents significant benefits in the dose distribution and potential benefits in reducing clinical adverse effects on the oral cavity and larynx and with better conformity and equivalent dose homogeneity in the CTV of NPC. The adaptive approach is suggested to enhance the potential benefits of IMPT compared to IMXT by reducing adverse effects for patients with NPC.

IMXT: intensity modulated X-ray radiotherapy; IMPT: intensity modulated proton therapy; A-IMPT: adaptive intensity modulated proton beam therapy; A-IMXT: adaptive intensity modulated X-ray therapy; NPC: nasopharyngeal cancer; CTV: clinical target volume, OAR: organs at risk; VMAT: volumetric arc therapy technique; GTV: gross tumor volume ; CT: computed tomography; MRI: magnetic resonance imaging: PRV: planning organ at risk volume; CI: conformity index; HI: homogeneity index; Dmean: mean dose; PCM: pharyngeal constrictor muscle; DVH: Dose volume Histogram

Ethics approval and consent to participants: This study was approved by the ethics committee of Hokkaido University in January of 2019 (IRB no.018-0231).

Consent for publication: not applicable.

Availability of data and materials: The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: This study was supported by MEXT/JSPS KAKENHI Grants No.19K08088 and No.18H02758.

Authors contributions: HM, KY, YD and RO participated in patient date collection. HM, KY, ST, TM, TY, and RS participated in simulation planning. HM, KY, HS and IY participated in date analysis. HM, KY, TY, NF and HS drafted manuscript. SS and HA provided senior input throughout the study. All authors read and approved the final manuscript.

Acknowledgement: A part of this study has been presented in ASTRO 2019 in Chicago.

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Potential benefits of adaptive intensity modulated proton therapy in nasopharyngeal carcinomas: a planning comparison study

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Abstract

Background

Methods

Results

Conclusion

Figures

Background

Material And Methods

Patient selection

Target Volume, OAR, And Dose Prescription

A-IMXT Planning

A-IMPT Planning

Image Registration, Dose Accumulation, And Evaluation (Figure 1)

Statistical Comparison:

Results

Comparison of Dose Distribution

CI And HI Of CTV

Dose Volume Statistics For The OARs

Discussion

Conclusion

Abbreviations

Declarations

References

Supplementary Files

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