Successful treatment of pediatric desmoid tumors using hydroxyurea

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 75/135 with stable disease or better Newton, Neurosurg Focus, 2007

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