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

Desmoid Fibromatosis (DF)

DF: treatment options

Surgery

Radiation therapy

Medical therapy

Observation

DF: medical options

Anti-estrogens (e.g., TAM)

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Chemotherapy • MTX + VBL/VNB

• doxorubicin-based chemotherapy

• …..

Interferons

Molecular therapy

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 NR NR 60 < 12

Reich et al. 1999 5 52 weeks 2 CR, 1 PR, 1 MR, 1 SD

60 7-76

Azzarelli et al. 2001 27 27 weeks 4 OR, 19 SD 17 6-96

Skapek et al. 2007 28 52 weeks 1 CR, 4 PR, 3 MR, 10 SD

40 NR

TAM:published evidence

Author # pts Duration of therapy

FAP Response Response duration (months)

Kinzbrunner et al. 1983 1 NR Yes PR NR

Rock et al. 1984 5 NR NR 2 SD, 3 PD NR

Procter et al. 1987 1 NR No SD 14

Thomas et al. 1990 1 NR No CR 12

Sportiello et al. 1991 1 NR No CR 27

Wilken et al. 1991 1 NR No PR 96

Mukherjee et al. 1995 1 NR NR PR 24

Chao et al. 2000 1 7 months No PR 72

Gwynne et al. 2005 1 NR No PR 168

Ohashi et al. 2006 1 NR No PR NR

Morris et al. 2007 1 NR No PR NR

Patient Disposition

Patients 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

Objectives 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

SyndromicSporadic 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 (%)MTX + VBL/VNB 11 (30%) PR

20 (55%) SD

4 (11%) PD

TAM 3 (15%) CR + PR

11 (55%) SD

6 (30%) PD

As of February 2008

MTX + VNB

After 26 cyclesBaseline

TAM

Baseline After 1 year treatment

MTX+VBL/VNB:duration of response

F 16 supraclavicular 52 PR 82

M 56 armpit 31 PR 62

F 49 arm 38 PR 209

F 23 abdominal wall 48 PR 35

M 34 paravertebral 40 PR 72

F 15 thigh 37 PR 43

M 26 supraclavicular 41 PR 124

F* 24 pelvis 52 PR 70

M 21 gluteal region & thigh 15 PR 57

F 61 scapular girdle 40 PR 88

F 29 supraclavicular 28 PR 84

Sex Age Primary Site # cycles Best response

Duration of Response(months)

Diagnosis during pregnancy

MTX+VBL/VNB:PFS

0 50 100 150 200 250

100

90

80

70

60

50

40

30

20

10

0

months

PF

S (

%)

Number at risk36 24 12 7 4 1

TAM:duration of response

F 58 neck 2 years CR 24

F 18 scapular girdle 2 years PR 20

M 45 thoracic wall 2 years PR 12

Sex Age Primary Site # cycles Best response

Duration of Response(months)

TAM:PFS

0 50 100 150 200

100

90

80

70

60

50

40

30

20

10

0

months

PF

S (

%)

Number at risk20 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 TAMResponse 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

Fondazione IRCCS Istituto Nazionale Tumori Milan, Italypalma.dileo@istitutotumori.mi.it