Chemotherapy for Desmoid Tumor in Children

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1 Chemotherapy for Desmoid Tumor in Children Stephen X. Skapek, MD Associate Professor Department of Pediatrics, Section of Hematology/Oncology The University of Chicago

2 Introduction to Desmoid Tumor in children aka Aggressive Fibromatosis, Infantile Fibromatosis, other names. Incidence: 2-4 cases per million per year Peak incidences: 6 to 15 years of age Puberty to age 40 years in women Typical symptoms: Tumor (78%) Pain (33%) Joint motility (11%) Skapek et al. JCO 2007

3 The Biology of Desmoid Tumor in Children Monoclonal fibroblastic proliferative disease Intermediate Grade neoplasm Locally-invasive growth Absence of metastatic potential

4 What causes Desmoid Tumor in children? Risk factors: APC mutation syndromes Gardner s, FAP High estrogen states (pregnancy) Prior surgical trauma

5 The Molecular Biology of Desmoid Tumor in children The APC β-catenin pathway Mutation in APC gene or β-catenin gene is associated with Desmoid Tumor APC Cell Growth β-catenin

6 The Molecular Biology of Desmoid Tumor in children The APC β-catenin pathway Mutation in APC gene or β-catenin gene is associated with Desmoid Tumor APC** Cell Growth β-catenin APC** Cell Growth β-catenin APC** APC** β-catenin Cell Growth Cell Growth β-catenin

7 Example of microscopic appearance of Desmoid Tumor

8 Why treat a child with Desmoid Tumor? Pain Deformity Functional impairment Death when vital organs involved

9 How do we treat children with Desmoid Tumor? First-line therapy Surgery Problem: disease recurrence Second-line therapy Radiation Problems: long term side-effects, lack of efficacy Chemotherapy Cytotoxic Non-cytotoxic Hormonal therapy Anti-inflammatory drugs

10 How do we make Desmoid Tumor treatment decisions in children? Symptomatic? Growing tumor? Dangerous location? Observe? Y N Easy to remove surgically? Amenable to radiation? Y N Radiation Y N Surgery Chemotherapy Recurrent tumor?

11 How does one decide which chemotherapy to use? Many stories of small number of patients treated with a medicine Very few systematic studies of a single therapy

12 How to systematically evaluate a single chemotherapy protocol A prospective clinical trial Adequate number of patients similarly treated to draw conclusions Patients treated at multiple centers to remove single-institution bias Collaborative pediatric oncology study groups Pediatric Oncology Group (POG) Before 1999 Children s Oncology Group (COG) After 1999

13 POG 9650 Phase II trial of Vinblastine and Methotrexate for DT in children Based on a single report of these medicines used in 8 patients Given by IV injection weekly for 6 months then every-other week for 6 months

14 POG 9650: Study Design A Phase II study Test the feasibility of doing this study across North America Explore whether the medicines have activity Eligibility Recurrent desmoid New tumor, not amenable to surgery or radiation 18 years of age

15 POG 9650: Results Enrollment August 1997 to February 2001 Successfully met enrollment goals ~1 patient/month

16 POG 9650: Results Patient characteristics Skapek et al JCO 2007

17 POG 9650: Results Skapek et al JCO 2007

18 POG 9650: Results Side effects of therapy Skapek et al JCO 2007

19 P9650: Conclusions VBL and MTX reasonably well tolerated Combination appears to promote tumor regression or block tumor growth in ~70% of children A national clinical trial of chemotherapy for children with Desmoid Tumor is possible!

20 What about targeted therapy for children with Desmoid Tumor? Long-standing connection between desmoid tumor and estrogen hormones Laboratory evidence that anti-inflammatory drugs may be useful in tumors with abnormalities of APC gene pathway

21 Children s Oncology Group Study ARST0321 Phase II evaluation of the combination of sulindac and tamoxifen Patients receive sulindac/tamoxifen combination for 4 weeks following the documentation of complete response, or Until time of progressive disease, or Until completion of 12 months of therapy.

22 ARST0321: Results Opened in COG February 2004 July 2009 Over 80 institutions participated across North America ~ 70 patients enrolled Results: Too early to say

23 Can we come up with better targeted therapy? APC** Cell Growth β-catenin New treatment?

24 mtor may also be deregulated in Desmoid Tumor mtor inhibitor mtor APC** Cell Growth β-catenin

25 Single case report. 7 year old male with tuberous sclerosis Recurrent chest wall fibromatosis Treated with sirolimus Significant tumor regression within 6 months Prolonged disease stabilization Pressey et al. PB&C 2010

26 Pediatric Desmoid Tumor Study #3 Pilot study to explore the use of mtor inhibitor (Sirolimus) in children and young adults Following completion of the Pilot Study, anticipate carrying out a Phase II study Considering a randomized design, potentially comparing to observation only for a subset of patients with no symptoms. Study proposal is being reviewed by the U Chicago Institutional Review Board now.

27 Acknowledgements Pediatric Oncology Group and Children s Oncology Group members Support from the Desmoid Tumor Research Foundation Patients and their families