1. Successful treatment of pediatric desmoid tumors using hydroxyurea Naomi Balamuth, M.D. Richard Womer, M.D. November 13, 2008

2. Background : Pediatric Desmoid Tumors Primary treatment is aimed at local control Surgical excision, when feasible, is front-line Chemotherapy: (Skapek, et al., JCO, 2007) Vinblastine/Methotrexate (COG) 8/26 (30%) with a measurable response 10/26 (38%) with stable disease Toxicity: Myelosuppression, nausea, vomiting Radiation therapy: (Merchant et al., Int J Radiat Biol Phys, 2000) Median dose 50 Gy 10/13 patients (77%) with substantial morbidity (poor growth, endocrinopathies) Novel therapies with decreased short and long-term toxicities are needed

3. Rationale: Hydroxyurea has shown efficacy in other benign neoplasms Hydroxyurea has shown some efficacy in treatment of meningiomas Meningioma cells are sensitive to HU in vitro and in xenograft models (Shrell, et al. J Neurosurg, 1997) Adult meningioma patients treated with HU had a 15 - 65% tumor volume reduction (Loven, et al. J Neuro-oncol, 2004) Most groups report a majority of patients with stable disease (Newton, et al., J Neuro-oncol, 2000, Rosenthal, et al. J Clin Neurosci, 2002, Mason, et al. J Neurosurg, 2002) Desmoids, like meningiomas, are tumors of benign histology, but an aggressive phenotype

4. Rationale: Hydroxyurea Newton, Neurosurg Focus, 2007 75/135 with stable disease or better

5. Hydroxyurea is safe and well tolerated Urea analog, initially synthesized by Dresler and Stein in 1869 Inhibits ribonucleotide reductase Important in de novo DNA synthesis and DNA repair Orally bioavailable Well tolerated as a chronic medication in the sickle cell population (including pediatrics) Tumor responses described in CML, melanoma, ovarian carcinoma

6. Study Design Retrospective chart review of 15 pediatric patients treated with hydroxyurea at The Children’s Hospital of Philadelphia between 1998 and 2005 18 desmoid tumor 1 plexiform fibrohistiocytic tumor with lung metastases Primary Objective: To evaluate the best response over time in patients treated with hydroxyurea for desmoid tumors

7. Patient characteristics Tumor location 8 extremity 7 torso 4 head/neck Median age at initiation of therapy: 10.3 years (1.4 - 19.9 years) Median dose of hydroxyurea: 27 mg/kg (18 - 62 mg/kg) Wide range of prior therapies –VBL/MTX –Sulindac –Doxorubicin –Tamoxifen –Vincristine –Radiation –Surgery –None

8. Response Criteria Complete Response (CR): No clinical or radiographic evidence of tumor Partial Response (PR): At least a 50% reduction in the maximum product of two perpendicular dimensions Minor Response (MR): At least a 25% reduction in the maximum produce to two perpendicular dimensions Symptomatic Response (SR): Decrease in pain with no change in tumor dimensions

10. IRS Groups III and IV

11. Time to progression

12. Results Summary IRS Groups I/II: 4/4 patients (100%) with a complete/partial response IRS Groups III/IV: 4/14 patients (29%) with a complete/partial response 7/14 patients (50%) with stable disease 3/14 patients (21%) with progressive disease Median time from from initiation of HU therapy to progression was 1250 days (mean 493 days). Minimal to no toxicity

13. Future Directions Phase II trial in adult and pediatric patients soon to begin at CHOP & Penn Plan to enroll 30 patients Primary objective: To determine the response rate for patients taking hydroxyurea as treatment for desmoid tumors Secondary objectives: To determine the duration of response To determine effects on tumor-related pain Potential consideration of hydroxyurea in combination with other agents Explore biologic correlates of response

14. Thanks to Shantae Ockimey for chart abstraction and assistance with data analysis