i tumori desmoidi: attualità terapeutiche · i tumori desmoidi: attualità terapeutiche verona, 23...

I tumori desmoidi: attualità terapeutiche

Verona, 23-24 Novembre 2010Verona, 23-24 Novembre 2010

Dott.ssa S. Stasolla, Dott.ssa D. Bocale, Dott.ssa M. T. Rotelli, Dott. A. Cavallini, Prof. D. Altomare

Sez. Chirurgia Generale e Trapianti di Fegato

D.E.T.O

Dir: Prof. Vincenzo Memeo

Università degli Studi di Bari

Desmoid tumor, also known as aggressive fibromatosi s, is a rare

disease

Desmoid tumors

Greek “Desmos” : aponeurosis, tendon

I tumori desmoidi: attualità terapeuticheVerona, 23-24 Novembre 2010

• Rare clonal proliferation of fibroblasts with an

abundant collagen matrix that may arise in deep soft

tissue

• DT are locally aggressive and characterized by

Desmoid tumors

infiltrative or expansive growth and high risk of local

recurrence

• They do not, however, have the capacity to

metastatize. Hence, desmoid tumors are considered

benign and not malignant


Desmoid tumors

• Desmoid tumors may occur sporadically, or in

association with familial adenomatous polyposis (FAP)

(Gardner’s syndrome)

• Desmoid tumors are the 2 nd leading cause of disease-

related mortality in patients with FAP (Clark et al. Br J Surg

1999)


Aetiology of Desmoids

� Gene mutation (APC and beta catenin)Lazar AJF et al. Specific mutations in the b-catenin gene (CTNNB1) correlate with local

recurrence in sporadic desmoid tumors. Am J Pathol.2008; 173:1518-27

� Hormonal effects

� Trauma


Desmoid tumors location

Gardner Syndrome (10-20% of FAPs)

mesentery 50%

abdominal wall/trunk 48%

multifocal 40%

extremities 2%extremities 2%

Sporadic Desmoids

extremities 60%

abdominal wall/trunk 35%

mesentery 5%


Treatment options of Desmoid tumors

• No treatment (wait & see)

• Conservative treatment

• Surgery

recurrence rate ranging 20%- 46%


SURGERY for Desmoid tumors

• Intrabdominal • Limbs

• Toraco/abdominal wall• Toraco/abdominal wall

Open questionDifferent risk of recurrence?


• Resection margins ?• Infiltrative vs capsulated desmoids ?• Re-recurrence ?

Risk factors for Desmoid recurrence

• Re-recurrence ?• Gender ?• Association with FAP ?• Genetic predisposition ?


SURGERY for Desmoid tumors

always feasible?


• N° Patients 234

• Females 143 (61%)• Desmoid site (sporadic)

– Upper extremities 96

SURGERY for Sporadic Desmoid tumors

– Upper extremities 96– Lower extremities 112– Abdominal wall and pelvis 26

• Total recurrence rate 17 %• Significantly higher risk of recurrence in females

Henry J. Mankin et al. Extra-Abdominal Desmoid Tumors: A report of 234 Cases. J Surg Oncol. 2009 Oct 29


Personal experience with Gardner’s

Desmoids

GARDNER'S SYNDROME (6-48 mths follow up)

Surgery Toremifenepatients location recurrent patients location response

DC. abdominal wall 2 DC. abdominal wall progressive disease

C. abdominal wall 1 V. intraabdominal complete response


C. abdominal wall 1 V. intraabdominal complete response

B. abdominal wall 3 C intraabdominal partial response

S. intraabdominal ? S. intraabdominal stable disease

R intraabdominal complete response

P. intraabdominal complete response

A. intraabdominal complete response

F. abdominal wall complete response

SPORADIC / Surgerypatients location recurrence treatment

M. intraabdominal no

De C. abdominal wall yes anti-estrogen therapy

Personal experience with sporadic

Desmoids

G. abdominal wall noProphylactic anti-estrogen therapy

N. abdominal wall no

C. pararectal no

G. pelvic no

B. abdominal wall no


• Medical therapy :

- Cytotoxic

Treatment options of Desmoid tumors

- Non cytotoxic


Non citotoxic treatment of Desmoid tumors

• Hormonal agentsAnti-estrogen receptors

Tamoxifene - Toremifene - Raloxifene

Progesterone, Medroxyprogesterone acetate, Prednizolone, Testolactone, Gosereline Gosereline

• Anti-inflammatory agentsSulindac (NSAID) , Celecoxib (COX-2 inhibitor)

• Other molecules Pirfenidone (antifibrotic agent)

Melatonin, Interferon alpha, Imatinib, (tyrosine kinase inhibitor)


Non citotoxic therapy of desmoids tumors

• Still based on empirical or anedoctical dataobtained by case reports or short caseseries where anti-hormonal, anti-inflammatory drugs, and so on.. have beeninflammatory drugs, and so on.. have beenused with alternate fortune

• Anti-estrogen therapy is the most widelyused medical treatment for DT


Why considering anti-estrogen therapy for desmoids?

• Female sex more frequently involved

• Often triggered by pregnancy• Often triggered by pregnancy

• Low incidence after menopause


Clinical response of Desmoids to anti-estrogens

Is unpredictable

Some of them respond remarkably to anti-estrogen therapies

Some desmoids non-responders to one anti-estrogen, respond

Partial regression or arrest of growth, or, the onset of a dru gresistance with tumor recurrence despite the ongoing anti- estrogentherapy

therapies some others not, for unknown reasons.

respond favorably to another one (sharing the same receptors).


Anti-estrogen therapy for desmoid tumorSystematic review

• PubMed search, Excerpta Medica Database(EMBASE) , Cochrane Library, Google

• Only patients treated by Toremifene, Tamoxifeneand Raloxifene alone or in association with otherand Raloxifene alone or in association with otherdrugs

• Patients with prophylactic antiestrogen therapywere excluded

• Patients included in papers with insufficientinformation about the treatment were excluded


N° patients: 168

Male

Female

69%31%

Systematic review (30 case report and 11 case series)

Age : 1 -70 years(median) : 30.5 years

Follow up: 3 - 168 mths(median) : 24 mths

Primary: 92

Recurrence: 34

Not reported: 42

Gardner : 96

Sporadic : 58

Not reported: 14

69%


Compound N ° pts Daily dosage

associated drug

Tamoxifen 38 Tam 20-160mg

Tamoxifen + NSAIDS 65 Tam 20-120mg NSAIDS 40-800 mg

Tamoxifen + Megace 1 Tam 20mg Megace 300 mg

Tamoxifen + Prednisolone 1 Tam 20mg Prednisol. 60 mg

Tamoxifen + chemotherapy 10 Tam 20mg Not reported

Anti–estrogens therapy for Desmoids

Tamoxifen + chemotherapy 10 Tam 20mg Not reported

Tamoxifen + Goserelin 1 Tam 30mg Goserelin

Toremifene 27 Tor 120-600 mg

Toremifene + Melatonin 4 Tor 60 mg Melatonin 10 mg

Toremifene + Interferon alfa 4 Tor 240 mg INFa-2b 3 m ilion UI

Raloxifene 13 Ra 120 mg

Raloxifene + Sulindac 3 Ra 80-120 mg Sulindac 300 mg



40%

50%

60% Gardner (pr.+rec.) vs Sporadic (pr.+rec.)

% o

f pat

ient

s

0%

10%

20%

30%

CR+PR SD PD

Gardner (pr.+rec.)

Sporadic (pr.+rec.)

% o

f pat

ient

s



50

60

70

80

THERAPYP<0.001

0

10

20

30

40

50

anti-estrogen alone anti-estrogen+NSAIDs

pts tot

CR + PR

f pat

ient

s


40%

50%

60%

Tam

Tam. vs Tam/NSAIDS

Anti–estrogens therapy for Desmoids. Review

% o

f pat

ient

s

P=0.043

0%

10%

20%

30%

CR + PR SD PD

Tam

Tam + NSAIDS

% o

f pat

ient

s


Anti–estrogens therapy for Desmoids. Review

40%

50%

60%Tamoxifen vs Toremifene

% o

f pat

ient

s

0%

10%

20%

30%

CR + PR SD PD

Tam

TOR

% o

f pat

ient

s


8 pts TAM failedToremifene 5 pts CR/PR = 62.5%

3 pts PD = 37.5%

Response to TOREMIFENE after TAMOXIFENE failure


A proposal for the management of

Desmoid tumors

Surgery AE therapy

AE therapy Surgery

Chemo radiotherapy Chemo radiotherapy

Surgery AE therapy

Recurrence

Recurrence Recurrence

Recurrence


CONCLUSIONS

Despite several bias can limit the reliabilityof the data reported in the literature, theuse of anti-oestrogen is fully justified as analternative to chemo or radiotherapy beforealternative to chemo or radiotherapy beforeor instead of surgery, particularly whensurgical removal is life-threatening orimpossible

(level of evidence III, grade of recommendation D)


Grazie per l’attenzione

i tumori desmoidi: attualità terapeutiche · i tumori desmoidi: attualità terapeutiche verona, 23...

Documents