1 Early in vivo Radiation Damage Quantification for Pediatric Craniospinal Irradiation Using Longitudinal MRI for Intensity Modulated Proton Therapy

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Early in vivo Radiation Damage Quantification for Pediatric Craniospinal

Irradiation Using Longitudinal MRI for Intensity Modulated Proton Therapy

Chih-Wei Chang, PhD1, Matt Goette, PhD1, Nadja Kadom, MD2, Yinan Wang, MD1, Jacob Wynne, MD1,

Tonghe Wang, PhD3, Tian Liu, PhD4, Natia Esiashvili, MD1, Jun Zhou, PhD1,

Bree R. Eaton, MD1* and Xiaofeng Yang, PhD1*

1Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA 30308

2Department of Radiology and Imaging Sciences, Emory University and Children’s Healthcare of Atlanta, Atlanta,

GA 30308

3Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065

4Department of Radiation Oncology, Mount Sinai Medical Center, New York, NY 10029

Email: xiaofeng.yang@emory.edu and brupper@emory.edu

Running title: Quantification of in vivo proton damage for pediatric craniospinal irradiation

Manuscript Type: Original Research

arXiv: 2210.15557

Abstract

Purpose: Proton vertebral body sparing craniospinal irradiation (VBS CSI) treats the thecal sac while

avoiding the anterior vertebral bodies in effort to reduce myelosuppression and growth inhibition. However,

robust treatment planning needs to compensate proton range uncertainty, contributing unwanted doses

within the vertebral bodies. This work aims to develop an early in vivo radiation damage quantification

method using longitudinal magnetic resonance (MR) scans to quantify dose effect during fractionated CSI.

Materials and methods: Ten pediatric patients were enrolled in a prospective clinical trial of proton VBS

CSI receiving 23.4-36 Gy. Monte Carlo robust planning was used with spinal clinical target volumes

defined as the thecal sac and neural foramina. T1/T2-weighted MR scans were acquired before, during, and

after treatments to detect transition from hematopoietic to less metabolically active fatty marrow. MR signal

intensity histograms at each time point were analyzed and fitted by multi-Gaussian models to quantify

radiation damages.

Results: Fatty marrow filtration was observed on MR images as early as the fifth fraction of treatment.

Maximum radiation-induced marrow damage occurred 40-50 days from the treatment start, followed by

marrow regeneration. The mean damage ratios were 0.23, 0.41, 0.59, and 0.54 corresponding to 10, 20, 40,

and 60 days from the treatment start.

Conclusions: We demonstrated a non-invasive method to identify early vertebral marrow damage based

on radiation-induced fatty marrow replacement. The proposed method can be potentially used to quantify

the quality of CSI vertebral sparing to preserve metabolically active hematopoietic bone marrow.

arXiv: 2210.15557

1 Introduction

Craniospinal irradiation (CSI) is a curative treatment for several pediatric central nervous system

malignancies. The CSI target volume includes the entire brain and thecal sac as the clinical target volume

to minimize the risk of tumor dissemination throughout the neuroaxis [1]. Conventional photon CSI

treatment may induce various short- and long-term side effects, including odynophagia, anorexia, bone

marrow suppression causing lymphopenia, and secondary malignant neoplasms [2-5] in these young

patients with very favorable prognoses. Clinical evidence also has shown that growing children can further

develop spinal lordosis, kyphosis, or scoliosis when growth plates are asymmetrically irradiated [6-8].

Consequently, pediatric radiation oncologists have historically recommended treating vertebral bodies and

growth plates wholistically for growing children [9]. Even with this practice, Paulino et al. [10] reported

that 16.7% and 54.5% of patients developed scoliosis 15 years after their vertebral ossification centers

received CSI doses of 18 - 24 Gy and 34.2 - 40 Gy, respectively. Thus, a treatment technique with conformal

dose delivery and avoidance of the vertebral bodies is desired for CSI in children to reduce toxicity and

improve quality of life.

Intensity modulated proton therapy [11] is an attractive technique for the treatment of pediatric CNS

malignancies due to its superior dose conformality and reduced integral dose to surrounding healthy tissues.

Clinical evidence has shown that proton CSI can reduce radiation toxicity and achieve equivalent long-term

disease control relative to photon therapy [12-15]. Unlike photon beams, the integral depth dose curve of

proton beams exhibits a distal peak near the end of the proton range (Bragg peak) that enables dose

deposition without significant exit dose. Proton CSI has the potential to leverage this physical feature to

treat the entire thecal sac while sparing the spinal growth plate. However, current proton therapy treatment

planning usually includes a margin of 3.5% reserved for proton range uncertainty [16-18]. Such uncertainty

requires the inclusion of parts of the vertebral bodies during treatment planning to ensure that the target

volume receives adequate dose coverage, and the sparing of growth plates can be compromised.

Given this uncertainty in proton therapy, a method of quantifying the in vivo proton damage during

treatments would be valuable to verify the accuracy of treatments and to facilitate adaptive re-planning, if

necessary, when using a steep dose gradient for vertebral body sparing (VBS). After proton CSI, radiation-

induced fatty marrow infiltration can be observed in the spine following treatment using magnetic

resonance imaging (MRI) [19, 20]. Replacement of hematopoietic marrow provides physiologic evidence

to retrospectively investigate the potential in vivo proton range uncertainty [21, 22]. However, there remains

a paucity of data from which to deduce when marrow conversion happens and how to use this information

to protect vertebral growth plates.

Although fatty marrow replacement has been detected at the end of treatment [23, 24], whether fatty marrow

may be observed on MR images between earlier treatment fractions in children remains unknown. This

study aims to perform MRI at specified intervals during proton VBS CSI to detect how early radiographic

marrow changes become evident and to evaluate whether the planned radiation dose deposition in bone can

be correlated to proportional proton damage within vertebral marrow. These findings may potentially be

used to support real-time medical decision-making, for instance to determine if growth plates are

sufficiently spared or replanning is necessary to reduce excessively conservative proton range margins.

Quantification of uncertainty will be considered to demonstrate the reliability, applicability, and feasibility

of the proposed method for CSI intensity modulated proton therapy with vertebral body sparing.

arXiv: 2210.15557

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1EarlyinvivoRadiationDamageQuantificationforPediatricCraniospinalIrradiationUsingLongitudinalMRIforIntensityModulatedProtonTherapyChih-WeiChang,PhD1,MattGoette,PhD1,NadjaKadom,MD2,YinanWang,MD1,JacobWynne,MD1,TongheWang,PhD3,TianLiu,PhD4,NatiaEsiashvili,MD1,JunZhou,PhD1,BreeR.Eaton,MD1*andXiaofengYa...

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1 Early in vivo Radiation Damage Quantification for Pediatric Craniospinal Irradiation Using Longitudinal MRI for Intensity Modulated Proton Therapy

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