Successful treatment of pediatric desmoid tumors using hydroxyurea

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