Quantitative Imaging Biomarkers of Treatment Response in Osteosarcoma and Ewing Sarcoma

Neoadjuvant chemotherapy (NAC) for osteosarcoma (OS) and Ewing sarcoma (ES) is associated
with significant immediate and long-term complications, particularly difficult to endure in
adolescent patients. Tumor response is assessed only at resection, often after the patient
has received months of potentially toxic and ineffective therapy. Surgical approaches in
this setting are extensive and life changing, with amputations not uncommon. Poor response
to NAC is the single most important prognostic indicator in localized OS/ES. Early
identification of those patients unlikely to benefit from the prescribed regimen could have
significant clinical implications and allow for earlier adjustments in the patient's
therapy. In patients with OS/ES there remains a compelling yet unmet need for more advanced
quantitative, noninvasive imaging methods that can be deployed early after the initiation of
treatment and which are capable of longitudinally measuring quantitative changes in relevant
physiological, metabolic and/or biophysical parameters that can serve as reliable
surrogates, or even predictors, of long-term tumor response to intervention, including
pathological response at surgery. In this pilot study we will use multi-parametric 3 Tesla
(3T) MRI, deployed before and after the first cycle of NAC, to correlate early changes in
imaging biomarkers with the patient's eventual histopathological response at surgical
resection. We will measure treatment-induced changes in: 1) protein content, measured via
the amide proton transfer asymmetry (APTasym) using chemical exchange saturation transfer
(CEST) MRI); 2) tumor fibrosis, measured via the magnetization transfer ratio (MTR) using
magnetization transfer (MT) MRI); 3) tumor cellularity, measured via the apparent diffusion
coefficient (ADC) using diffusion-weighted MRI); and 4) tumor perfusion, measured via the
volume transfer coefficient (Ktrans) using dynamic contrast-enhanced DCE-MRI. The relevance
and future clinical impact of each of these imaging biomarkers (alone or in combination) in
OS/ES is potentially very high.

Inclusion Criteria:

- Subjects must be 13 years of age or older.

- Subjects (or their parent or legal guardian) must have signed Internal Review Board
(IRB)-approved assent/informed consent documentation.

- Subjects must have histologically proven osteogenic sarcoma, malignant fibrous
histiocytoma (MFH), or Ewing sarcoma.

- Subjects must be planned for resection (this includes localized resectable disease or
patients with metastatic disease with planned palliative resection) and scheduled to
begin neoadjuvant chemotherapy

Exclusion Criteria:

- Subjects who are under 13 years of age.

- Subjects who have any type of bioimplant activated by mechanical, electronic, or
magnetic means (e.g., cochlear implants, pacemakers, neurostimulators,
biostimulators, electronic infusion pumps, etc), because such devices may be
displaced or malfunction.

- Subjects who have any type of ferromagnetic bioimplant that could potentially be
displaced.

- Subjects who have cerebral aneurysm clips.

- Subjects who may have shrapnel imbedded in their bodies (such as from war wounds),
metal workers and machinists (potential for metallic fragments in or near the eyes).

- Subjects with inadequate renal function (creatinine ≥1.5 times upper limit of normal)
or acute or chronic renal insufficiency (estimated glomerular filtration rate <30
mL/min).

- Subjects who are pregnant or breast feeding, because the effects of high field MRI on
fetuses are not yet known. Urine pregnancy test/or serum human chorionic gonadotropin
(HCG) will also be performed on women of child bearing potential.

- Subjects who have exhibited past allergic or other adverse reactions in response to
intravenous injection of Magnevist® (gadopentetate dimeglumine) or other
gadolinium-containing contrast agents.

- Subjects who exhibit noticeable anxiety and/or claustrophobia or who exhibit severe
vertigo when they are moved into the magnet bore.

- Subjects incapable of giving informed written consent, for the following reasons:

- Inability to adhere to the experimental protocols for any reason

- Inability to communicate with the research team

- Limited ability to give informed consent due to mental disability, altered
mental status, confusion, or psychiatric disorders

- Prisoners or other individuals deemed to be susceptible to coercion