Abscopal Radiation Effects on Bone

Post-radiotherapy fragility fractures are a frequent complication of orthopedic oncology care
of sarcoma patients, who often receive radiotherapy (XRT) as adjunctive treatment. Prediction
of these fractures is difficult as there has been no demonstrable relationship shown, to
date, between bone density and fracture risk for this population. Treatment for an impending
fracture due to radiotherapy does exist in the form of prophylactic operative stabilization
with an intramedullary nail to prevent the bone from breaking. Without the ability to predict
those patients at higher risk for fracture, clinical indications for prophylactic treatment
are difficult to develop.

Bone density has been investigated as a possible fracture prediction tool. Work by Dhakal et
al. suggested specifically that bone density, as measured by dual-energy x-ray absorptiometry
(DXA), of the irradiated limb is not decreased following therapeutic doses of radiotherapy
(50 Gy) administered for soft tissue sarcomas. However, their technique did not measure
pre-radiotherapy bone mineral density (BMD), but rather compared post-radiotherapy BMD of the
irradiated site to contralateral and ipsilateral non-irradiated long bones of the extremity.
While this technique accounted for disuse osteopenia (bone loss due to decreased use of the
afflicted limb), it did not account for any systemic effects of radiation therapy. This is
important, because largely based on their work, BMD has not been utilized as a predictor of
risk of fracture, and other measures have been sought for this particular clinical situation
without success. Others have also failed to show decreased BMD within the irradiated field.
However, these studies have either lacked power to show statistical significance or the
patient population was pediatric, a growing population in which age related accrual of bone
density was a potential confounder.

What Dhakal and others did not account for was the possibility of abscopal (systemic) effects
of radiotherapy that might also affect the contralateral and distant sites. Recent work in
this investigators laboratory and others using small animal models has suggested that
radiation to one limb has statistically significant effects on the contralateral limb in
terms of decreased bone mineral density and loss of bone strength. The importance and
clinical implications of such an abscopal effect is as of yet unclear. At the very least, its
presence calls into question the conclusion that bone density is not decreased at the site of
radiation, since differences may only be able to be shown when compared to non-irradiated
control subjects. Moreover, there may be an adverse effect on distant bones, further lowering
BMD and contributing to fragility fractures, particularly in post-menopausal women who are
already at some increased risk. There is mixed clinical data on this topic, with one series
of 45,662 prostate cancer patients showing a 76% increased risk of hip fracture (regional
bone) following pelvic radiation, but no increased risk of fractures outside the field of
radiation in three studies of patients with pelvic radiation for cervical and other female
cancers or prostate cancer.

The investigators of this study propose to determine whether human subjects undergoing
radiotherapy for soft tissue sarcomas exhibit for abscopal bone loss. Patients in the PI's
(Dr. Damron) practice obtain baseline-staging studies, including computerized tomography (CT)
of the chest/abdomen/pelvis prior to treatment. Post-treatment, patients then undergo
oncology surveillance utilizing routine repetitive computerized tomography of the chest and
sometimes of the abdomen/pelvis for a subset where the baseline abdomen/pelvis CT scans show
abnormalities that need to be followed. These CT scans, when combined with calibration
phantoms of known density, afford a prime opportunity to quantify bone mineral density based
on those scans at sites distant to the primary site of radiotherapy (typically in the
extremity).

This project will also evaluate a secondary aim, that of comparing effectiveness of
utilization of CT vs BMD as a tool to evaluate bone loss in short term with a potential for
long term fracture prediction in this patient population. In order to accomplish this aim,
simultaneously, in a subset of patients who give consent for non-standard of care DXA scans,
the investigators will evaluate the potential abscopal bone loss by assessing changes in BMD
as measured by DXA, a tool that is a gold standard for bone density evaluation and for
fracture prediction in routine clinical practice. The investigators will compare BMD pre- and
post-radiotherapy at the site of irradiation, and further compare this change to that of the
change in BMD at distant sites.

Inclusion Criteria:

- Patients of Dr. Damron's being treated for soft tissue sarcoma of an extremity, who
will undergone radiotherapy, and will follow with Dr. Damron for routine oncology
surveillance with routine CT scans of the chest at minimum.

- Must be at least 18 years of age and no older than 89 years of age.

Exclusion Criteria:

- Patients who are treated with radiotherapy but who do not have soft tissue sarcoma,
such as those with metastatic carcinoma,

- Patients who have soft tissue sarcoma who will not receive adjuvant radiotherapy, such
as those with atypical lipomatous tumors or other low grade soft tissue sarcomas

- Patients who will not be obtaining their follow up CT studies at Upstate Bone and
Joint Center-since the calibration phantom needs to be located in one central
location.

- Incarcerated patients

- Patients younger than 18 years of age