EORTC : Phase II pilot study of moderate dose radiotherapy for inoperable desmoid-type fibromatosis Ronald B. Keus, Remi A. Nout, Jean-Yves Blay, Joseph M. de Jong, Frank Saran, Michael Sokal, Joerg T. Hartmann, Steve J. Gwyther, Pancras C. Hogendoorn, Monia Ouali, Anne Kirkpatrick, Wilfried Budach, Winette van der Graaf.

Nuyttens et al. Cancer

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Single arm phase II trial to determine the efficacy of moderate doses of radiotherapy for desmoid-type fibromatosis in patients with inoperable tumor or when mutilating surgery is needed. Radiation schedule tested  56 Gy in 28 fractions 2 Gy per fraction 5 fractions per week Primary objective: demonstrate that local control rate at 3 years > 50% Sample size: To exclude a 3-year local-control rate ≤50% with 1- sided  =10% and 90% power if the true local-control rate is 70%  40 patients needed (Fleming design) Study Objectives and Design 4

 Histologically confirmed desmoid-type fibromatosis arising in any site in one of the following categories: Primary, recurrent (after prior complete remission or complete resection) or progressive (after any prior treatment not including radiotherapy) disease, that is either inoperable, or requiring a major operation resulting in a large functional or cosmetic deficit or mutilation (confirmed by a surgeon) Incompletely resected tumor leaving gross residual disease not suitable for further surgery. (Surgery performed <3 m before entry)  Measurable disease according to RECIST 1.0  No concurrent endocrine or chemotherapy  No prior or concurrent limb perfusion with TNF  Age ≥ 16 years  Informed consent Study population 5

Accrual 6 InstitutionPrincipal InvestigatorNr (%) ARNHEM'S RADIOTHERAPT.I. (NL)Keus Ronald9 (20.5%) UNIVERSITY MEDICAL CENTER LEIDEN (NL)Noordijk E.M.7 (15.9%) CENTRE LEON BERARD (FR)Blay Jean Yves7 (15.9%) AZM/RTIL MAASTRICHT (NL)De Jong Joseph4 (9.1%) NOTTINGHAM GEN/CITY (GB)Sokal Michael4 (9.1%) UNIVERSITÄTS KLINIKUM TUEBINGEN (DE)Hartmann Jörg Thomas3 (6.8%) ROYAL MARSDEN LONDON (GB)Saran Frank3 (6.8%) M.S-K.C.CTR.WARSAW (PL)Ruka Wlodzimierz2 (4.5%) CHRISTIE’s MANCHESTER (GB)Wylie James2 (4.5%) CLIN. UNIV. ST. LUC (BE)Scalliet Pierre1 (2.3%) WESTON PK SHEFFIELD (GB)Robinson M.H.1 (2.3%) B. VERBEETEN INSTITUTE TILBURG (NL)Poortmans Philip1 (2.3%) Total44 44 patients recruited between13/11/ 2001 and 02/04/2008

All patients (N=44) N (%) Eligible yes 41 (93.2) no 3 (6.8) Reasons ineligibility: Sclerosing epithelioid fibrosarcoma (1) desmoplastic fibroblastoma (1) Treatment start before registration (1) Eligibility and analysis populations 7 Patient PopulationNumber of patients ITT44 Per-protocol41 Median follow-up:4.8 years

Patient characteristics 8 (N=44) N (%) Sex male 17 (38.6) female 27 (61.4) Age (years) Median39.5 Range Chronic disease2 (4.5) Disease category primary 17 (38.6) recurrent 17 (38.6) progressive 6 (13.6) Incomplete resection 4 (9.1)

Disease characteristics 9 Disease category Total (N=44) primary (N=17) recurrent (N=17) Prog. (N=6) Inc. resected (N=4) Tumor site Neck (2.3) Thoracic wall (22.7) Abdominal wall (11.4) Pelvis (2.3) Lower extremity (29.5) Upper extremity (31.8) Time since 1 st diagnosis Median (months)3.2 m18.7 m19.4 m2.9 m11.8 m Maximum2.2 yrs27.2 yrs6.2 yrs9.8 years 27.2 yrs

Prior therapy Total (N=44) N (%) Prior radiotherapy outside fields2 (4.5) Prior surgery complete15 (34.1) incomplete11 (25.0) Prior chemotherapy 5 (11.4) Endocrine therapy 4 (9.1) Prior treatments 10

Irradiation technique 11 Irradiation technique + Energy All patients (N=44) N (%) photons 40 (90.9) 4-10 mv36 >10 mv3 unspecified energy1 electrons 3 (6.8) 4-10 mv1 >10 mv2 mixed (>10 mv) 1 (2.3)

Radiation therapy 12 (N=44) N (%) Total number of fractions 25x 2 Gy 1 (2.3) 27x 2Gy 1 (2.3) 28 x 2 Gy 42 (95.5) Duration of treatment Median39d Range37d – 63d Total dose (56 Grays) Median56.0 Range Received at least 56 Gy: 42 (95.5) 4 patients interrupted irradiation: 3 for toxicity (epidermitis G3, erythema G2, skin blistering) and 1 due to an unrelated medical event.

Acute side efffects (CTC – AE 2.0) 13 All gradesGrade 2Grade 3 Fatigue19 (43.2%)5 (11.4%)0 Rash/Desquamation 28 (63.6%) 11 (20.5%) 3 (6.8%) Other dermatology/skin 13 (29.5%)8 (18.2%)1 (2.3%) Arthralgia 6 (13.6%) 3 (6.8%) 1 (2.3%) Myalgia 6 (13.6%) 1 (2.3%)0 Other pain 13 (29.5%) 10 (22.6%)0 Gastrointestinal 9 (20.5%) 1 (2.3%)

Late toxicity (RTOG-EORTC) 14 # of patientsGrading Skin18 (40.9%)grade 3: 1 patient grade 4: 1 patient Lymphedema 10 (22.6%) grade 1: 5 patients NA : 5 patients Pain 8 (18.6%)NA Joint stiffness 2 (4.5%) NA Loss of function 2 (4.5%)NA Atrophy 1 (2.3%)NA Induration/fibrosis 3 (6.8%) NA * NA = grading not indicated

Local control at 3 years: main analysis Time (years) 81.5% 3 80% CI: 74.0%-89.1% 95% CI: 71.8%-91.3% This is >50%  Success!

Objective response to therapy 16 Best overall response within 3 years after treatment All patients (N=44) N (%) CR 6 (13.6) PR 16 (36.4) SD 18 (40.9) PD 3 (6.8) Not assessable 1 (2.3) Objective response to therapy was evaluated on the basis of lesions included in the irradiation field. After 3 years the response further improved in 3 patients: PR => CR 1, SD =>CR 1 and SD => PR 1 patient. Five patients had new lesions, 1 was located in the RT fields.

Moderate dose of radiotherapy is an effective treatment for patients with desmoid-type fibromatosis resulting in 81.5% local control rate at 3 years. Response after radiation therapy is slow with continuous regression even after 3 yrs. Acute side effects are mild. Edema as late toxicity in patients with extremity lesions was seen frequently. Radiotherapy should be considered for patients with symptomatic and progressive desmoid-type fibromatosis. Conclusions 17

Statistical considerations: → A Fleming phase II one step design H0: 3-years local progression-free rate P0 = 50% H1: 3-years local progression-free rate P1 > 50% 1-sided Alpha=0.1 and Power=90%. 40 patients required Summary of the trial 18

accrual patients recruited between13/11/ 2001 and 02/04/2008

Literature comparison RT only results Size/response data 4 categories of disease  Primary,  Recurrent after complete resection, or CR on Chemo  Progressive after any treatment except RT  Gross residual disease after surgery <3 mths Question following the study Slides to be added 20

For the acute toxicity,  Grade 3 included skin reaction in 4 patients (9.1%), stomatitis in 1 patient (2.3%) and pain in 1 patient (2.4%).  No grade 4 acute side effects were reported For the late toxicity, 2 patients had G3/G4 skin RT morbidity. The other late but scored mild toxicities frequently encountered were edema (10 pts) and pain (8 patients). No Serious Adverse Event was reported Treatment safety 21