Post on 08-Jul-2015
Successful treatment of pediatric desmoid tumors
using hydroxyurea
Naomi Balamuth, M.D.
Richard Womer, M.D.
November 13, 2008
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
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
Rationale: Hydroxyurea
Newton, Neurosurg Focus, 2007
75/135 with stable disease or better
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
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
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
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
IRS Groups III and IV
Time to progression
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
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
Thanks to Shantae Ockimey for chart abstractionand assistance with data analysis