Proton Radiotherapy for Extremity Soft Tissue Sarcoma

This study will be performed in two phases. In the first phase, feasibility will be
established using the primary objectives set below. The second part will begin no earlier
than 30 days after the last patient in the initial phase has completed treatment and once
safety and feasibility has been verified.

The primary objective of this study is feasibility. The study will be deemed infeasible if
10% or more of patients experience one of the following:

1. Patient cannot be given treatment because anatomy is such that a dosimetrically
satisfactory treatment plan cannot be devised (95% of planning target volume covered by
95% of the dose).

2. Patient is unable to tolerate more than 25% of treatments (for any reasonable to set
patient up within acceptable limits of tolerance, patient unable to tolerate treatment
position or immobilization for duration of treatment) using proton radiotherapy. Note:
this end-point is proton-therapy specific, and indicates feasibility of proton as
opposed to photon radiotherapy. For example, if the proton-specific patient
immobilization/positioning is not well tolerated or extra time in the treatment
position is too long or uncomfortable, protons delivered per protocol would be deemed
not feasible compared to photons. Any treatments that cannot be delivered with protons
will be delivered using photons, so that the patient receives the prescribed tumor
dose.

3. Patient is unable to complete all of his/her treatments within 10 days of estimated
date of treatment completion or requires a treatment break greater than 5 days.
Additionally, no greater than 33% of patients experience a significant toxicity.

Primary Objectives for second phase of study are:

- The primary objective of Phase II in the pre-operative group will be to evaluate the
wound complication rate of pre-operative proton radiotherapy in patients with STS of
the lower extremity.

- The primary objective of Phase II in the post-operative group will be to evaluate the
functional outcome (e.g., fibrosis, joint stiffness, edema) at two years after
post-operative proton radiotherapy in patients with STS of the lower extremity.

Secondary Objectives for both phases of study are:

- To assess the local control rate, progression-free survival and overall survival of
proton radiotherapy for STS of the extremity.

- To determine the acute and late toxicities of proton radiotherapy to the extremities.

- To monitor for effects of proton treatment on tumor and normal tissues using
radiographic imaging (both cohorts) or ex-vivo analysis of tissue samples
(pre-operative cohort only).

- To examine the relationship between pre-treatment hypoxia as determined by F18-EF5
scanning and treatment outcome.

Inclusion Criteria:

- Patients with a histologic diagnosis of soft tissue sarcoma of the extremities are
eligible for this study.

- Patient must be 18 years of age.

- Patients must have evidence of disease limited to the extremities.

- For the pre-operative group, patients must be considered operable/resectable and a
candidate for pre-operative radiotherapy as judged by the attending surgeon and
radiation oncologist. The clinical evaluation of patients will include a work up as
per the standard of care. All patients in the pre-operative group will be evaluated
for this protocol PRIOR to the initiation of therapy.

- For the post-operative group, patients must be considered operable/resectable (if
evaluated prior to resection) and a candidate for post-operative radiotherapy by the
attending surgeon and radiation oncologist. The clinical evaluation of patients will
include a work up as per the standard of care. Patients in the post-operative group
may be evaluated PRIOR to the initiation of any therapy or may be referred for
evaluation after surgical resection.

- ECOG status of 0-2.

- Patients must sign a document that indicates that they are aware of the investigative
nature of the treatment of this protocol, and the potential benefits and risks.
Patients unwilling or unable to sign informed consent are excluded from the study.

- Women of child-bearing potential as long as she agrees to use a recognized method of
birth control (e.g. oral contraceptive, IUD, condoms or other barrier methods etc.).
Hysterectomy or menopause must be clinically documented.

- Negative urine pregnancy test for females of childbearing potential on the day of the
F18-EF5 PET scan prior to F18-EF5 injection

Exclusion Criteria:

- Pregnant women, women planning to become pregnant and women that are nursing.

- Patients who experience surgical complications that prevent radiation from starting
for 5 months or more, unless there is evidence of gross residual disease.