Activity of medical therapy (Methotrexate + Vinblastine/Vinorelbine or Tamoxifen) in Desmoid Fibromatosis (DF): retrospective analysis from a 76-patient single-institution series Palma Dileo1,  Claudio Piovesan1,  Marianna Silletta2,  Elisa Puma1,  Roberta Sanfilippo1,  Elisabetta Pennacchioli1,  Marco Fiore1,  Alessandro Gronchi1,  Paolo Giovanni Casali1 1Istituto Nazionale Tumori, Milan, Italy;  2Campus Biomedico, Rome, Italy

Desmoid Fibromatosis (DF) Abdominal Extra-abdominal Intra-abdominal 3

Desmoid Fibromatosis (DF)

DF: treatment options Surgery Radiation therapy Medical therapy Observation 3

DF: medical options Anti-estrogens (e.g., TAM) Nonsteroidal anti-inflammatory drugs (NSAIDs) Chemotherapy MTX + VBL/VNB doxorubicin-based chemotherapy ….. Interferons Molecular therapy 3

DF: a stepwise approach Observation Surgery and/or Radiotherapy “Non aggressive” medical therapy Molecular therapy “Conventional” chemotherapy

MTX + VBL/VNB: published evidence Author # pts Duration of therapy Response RR (%) FU (months) Weiss et al. 1989 8 NR 2 CR, 4 PR, 1 MR 75 2-30 Skapek et al. 1998 10 52 weeks 3 CR, 2 PR, 3 SD, 2 PD 50 5-37 Weiss et al. 1999 13 60 < 12 Reich et al. 1999 5 2 CR, 1 PR, 1 MR, 1 SD 7-76 Azzarelli et al. 2001 27 27 weeks 4 OR, 19 SD 17 6-96 Skapek et al. 2007 28 1 CR, 4 PR, 3 MR, 10 SD 40

TAM: published evidence Author # pts Duration of therapy FAP Response Response duration (months) Kinzbrunner et al. 1983 1 NR Yes PR Rock et al. 1984 5 2 SD, 3 PD Procter et al. 1987 No SD 14 Thomas et al. 1990 CR 12 Sportiello et al. 1991 27 Wilken et al. 1991 96 Mukherjee et al. 1995 24 Chao et al. 2000 7 months 72 Gwynne et al. 2005 168 Ohashi et al. 2006 Morris et al. 2007

Patient Disposition Patients Treatment 76 pts diagnosed with DF were analyzed (Dataset of the Istituto Nazionale Tumori, Milan, from 1977 to 2004) 56/76 received first line medical treatment as follows 36 MTX + VBL/VNB 20 TAM At the time of analysis, data were available from all pts treated Treatment MTX @ 30 mg/m2 + VBL @ 6 mg/m2 or MTX @ 50 mg + VNB @ 30 mg/m2 (every 10 days) MTX+VBL/VNB was administered for a median of 27 courses TAM from 10 to 60 mg daily up to 2 years

Objectives and Endpoints evaluate the antitumor activity of MTX + VBL/VNB or TAM Endpoints Primary response rate Secondary progression-free survival

Patient Characteristics (56 pts) Sex Female 43 (76%) Male 13 (24%) Age Median (range) 29 (3-64) yrs Syndromic Sporadic 48 (86%) FAP/Gardner 8* (14%) Site Abdominal (non mesenteric) 18 (32%) Extra-abdominal 38 (68%) * extra-abdominal locations

Tumor response Best Response No. of pts (%) As of February 2008 MTX + VBL/VNB 11 (30%) PR 20 (55%) SD 4 (11%) PD TAM 3 (15%) CR + PR 11 (55%) 6 (30%)

MTX + VNB Baseline After 26 cycles

TAM Baseline After 1 year treatment

MTX+VBL/VNB: duration of response (months) Sex Age Primary Site # cycles Best response F 16 supraclavicular 52 PR 82 M 56 armpit 31 62 49 arm 38 209 23 abdominal wall 48 35 34 paravertebral 40 72 15 thigh 37 43 26 41 124 F* 24 pelvis 70 21 gluteal region & thigh 57 61 scapular girdle 88 29 28 84 Diagnosis during pregnancy

MTX+VBL/VNB: PFS 50 100 150 200 250 90 80 70 60 40 30 20 10 months 50 100 150 200 250 90 80 70 60 40 30 20 10 months PFS (%) Number at risk 36 24 12 7 4 1

TAM: duration of response (months) Sex Age Primary Site # cycles Best response F 58 neck 2 years CR 24 18 scapular girdle PR 20 M 45 thoracic wall 12

TAM: PFS 50 100 150 200 90 80 70 60 40 30 20 10 months PFS (%) Number at risk 9 6 2 1

MTX+VBL/VNB: tolerability issues Overall well tolerated Mild hepatic toxicity (elevated transaminases)  always regressed after dose decrease or treatment delay Mild nausea

TAM: tolerability issues Overall well tolerated Gynecomastia Libido decrease

Progression to TAM Response MTX + VNB Baseline PD to TAM MR to MTX + VNB Of note, 5/6 pts progressed on TAM responded to MTX + VNB

Conclusions As shown by a few published studies, in this single-institution retrospective analysis MTX + VBL/VNB was associated with an interesting response, and prolonged SD, rate Likewise, as suggested by anecdotal-only published evidence, TAM was able to give tumor responses, occasionally major, as well as prolonged SDs Both medical therapies are of interest in a non-metastasizing disease, marked by a prolonged, variable natural history Possibly in sequence, both are useful options within a conservative stepwise medical treatment of this disease

Acknowledgments We wish to thank the patients and their families the nurses, clinical staff, and radiologists, who have made this work possible 16

Istituto Nazionale Tumori Milan, Italy Fondazione IRCCS Istituto Nazionale Tumori Milan, Italy palma.dileo@istitutotumori.mi.it 3