personalizing desmoid care – the pros and cons of therapeutic

Personalizing desmoid care – the pros and cons of therapeutic

intervention

Aimee M. Crago, M.D., Ph.D., FACS Assistant Attending Surgeon

Memorial Sloan Kettering Cancer Center

Desmoid Tumor Research Foundation Philadelphia, PA

October 17th, 2015

Desmoid fibromatosis • Locally aggressive tumor without metastatic potential. • Associated in >95% of patients with mutation in CTNNB1

gene, APC loss or rarely in context of Gardner’syndrome. • Historically treated with surgery though high rates of

local recurrence were reported (25-50%). • Radiation has been considered in the adjuvant setting,

but rarely used now. • Now have options of:

– Chemotherapeutics like sorafenib or Doxil – Observation – Cryoablation

Desmoid fibromatosis

Clinical questions in management of desmoid fibromatosis

• Five potential treatment modalities – Surgery, the historical gold standard – Radiation – Observation, proposed to be the new gold standard – Systemic therapies – Cryoablation

• How do we counsel patients regarding appropriate treatment?


Observation • PROS:

– No complications of treatment

• CONS: – Tumors may be symptomatic at presentation – Disease progression is not uncommon

87 patients

30 wait & see (including

COX2 inhibitor)

57 immediate

intervention

2-year PFS ~30%

34 to the OR

21 medical management


<45y.o

>=45y.o primary

recurrent p=0.48 p=0.55

<=5cm

>5cm, <=10cm

>10cm

chest

abdominal wall

extremity, GI, other

p=0.08 (GI vs. chest) p=0.04

Risks for progression Age

Size

Presentation status

Site


Surgery • PROS:

– Able to accurately predict risk of recurrence based on clinic factors and chose ideal candidates

– Potentially curative

• CONS: – Recurrence rates as high as 50%

in some series – Short and long-term morbidities

– Limb dysfunction – Short bowel syndrome


Crago, et al. (2013) Ann Surg. 258: 347-53.

Prognosis in desmoids – A nomogram to predict post-operative recurrence


Crago, et al. (2013) Ann Surg. 258: 347-53.

Radiation • PROS:

– Effective Local control rates 70% – Avoid surgical morbidities

• CONS: – Complications

• Fibrosis of joints • Fracture • Radiation enteritis • Secondary malignancy


Ballo et al. (1999) J. Clin. Oncol. 17:158-67.

Systemic therapy

• PROS: – Avoid significant morbidities historically associated

with surgical resection • Short bowel syndrome • Amputation

• CONS: – Side effects of chemotherapy

• Fatigue, anorexia, neutropenia, infection, hand-foot syndrome

– Thought to have limited efficacy but targeted therapies with improved outcomes (sorafenib, notch inhibitors)


• Retrospective review of: – 68 patients with advanced desmoid tumors, median follow-up 63 months – treated with 157 lines of systemic therapy – Best RECIST responses

Therapy administered Lines of treatment given

Partial response

Stable disease

Progressive disease Median PFS

Anthracycline-based 35 13 (37%) 18 (51%) 4 (11%) Not reached

Methotrexate (single agent) 12 4 (33%) 6 (50%) 2 (17%) 9.4

Hormonal therapy 26 6 (23%) 17 (65%) 3 (12%) 12

Vinca-containing combination 10 2 (20%) 6 (60%) 2 (20%) Not reached

DTIC or temazolamide 16 2 (13%) 12 (75%) 2 (13%) 14.3

Tyrosine kinase inhibitor 35 3 (9%) 25 (71%) 7 (20%) 26.8

Other cytotoxic agents 8 0 7 (88%) 1 (12%) 3.7

Total 142 31 (21%) 91 (64%) 30 (21%) 14.1

*Sorafenib now also an option based on NCCN guidelines, 70% clinical benefit, may be more effective in extremity versus intraabdominal tumors

De Carmargo, Maki et al (2010) Cancer 116:2258-65.


Sorafenib in desmoid fibromatosis 24 patients managed with sorafenib, effects delineated in retrospect


Gounder, Maki et al. (2011) Clin. Cancer Res. 17:4082-90.

Cryoablation

• PROS: – Avoid complex surgery and prolonged recovery – Minimal morbidity

• CONS: – Generally limited indications:

• Small size • Anatomic constraints (not near major neurovascular

bundle, bowel, skin, etc.) • Often abdominal and chest wall tumors


Modality Ideal patients

Observation • Small lesions • Abdominal wall lesions • Asymptomatic patients

Surgery • Small tumors • Abdominal wall lesions or mesenteric desmoids • Older patients • Known growth or symptoms

Systemic therapy • Known growth or symptoms • High risk of post-operative recurrence • Significant morbidity related to surgery

Cryoablation • Small tumors • Surrounded by soft tissue or bone

Radiation • Refractory to systemic therapies • Inoperable • Known growth or symptoms


2012 – 53yo with rapid recurrence of multifocal disease after resection of an 11cm desmoid of the calf in 2011, mild symptoms.

PROS CONS

Observation Avoid side effects Symptomatic

Surgery Potentially curative 30% chance of recurrence Significant risk of Achilles injury

Radiation Control disease Long-term risk of sarcoma Radiation to ankle and knee

Cryoablation Possibility to control disease Significant risk of injury to skin

Systemic therapy 70% disease control with sorafenib

Side effects of systemic therapy- fatigue, hand-foot syndrome


PRE-TX

POST-TX

• 2.5 years of sorafenib • Dose reduced due to mild hand-foot syndrome

• Reached maximal response, off drug for 6 months with no regrowth of tumor


Soft Tissue Sarcoma 47 y.o pharmacist with asymptomatic abdominal mass

Observation

13.1 cm 19.6 cm

PROS CONS

Observation Avoid side effects Potential to develop fistula, obstruction

Surgery Option to debulk Certain short bowel syndrome

Radiation N/A Radiation enteritis

Cryoablation N/A Too large

Systemic therapy 70% disease control Side effects of systemic therapy- fatigue, hand-foot syndrome

Started on Doxil, grade 1 fatigue and hand/foot syndrome

Started on Doxil, grade 1 fatigue and hand/foot syndrome

PROS CONS

Observation Avoid side effects Potential for regrowth

Surgery Potential to debulk Likely incomplete resection, risk of regrowth


Cryoablation N/A Too large

Systemic therapy Minimal additional response possible



PROS CONS

Observation Minimal chance of progression N/A

Surgery >90% chance of cure Long-term potential for hernia


Cryoablation Optimal size Minimal experience



• 37y.o. post-partum presents with asymptomatic rectus sheath mass

• Biopsy proved desmoid-type fibromatosis

Rectus sheath desmoid


PROS CONS

Observation Minimal chance of progression N/A

Surgery >90% chance of cure Long-term potential for hernia


Cryoablation Optimal size Minimal experience



• Return to clinic for follow-up in 3 months

• Increased pain

• Imaging with growth of desmoid

Rectus sheath desmoid


NED 4 years post-operatively, minimal residual discomfort related to mesh repair

29y.o. with fungating desmoid in the left axilla causing contracture of the shoulder

PROS CONS

Observation N/A Significant symptoms

Surgery Potential for cure, alleviate symptoms

50% chance of recurrence Adjacent to nerves of brachial plexus

Radiation N/A Fibrosis to joint

Cryoablation N/A Too big

Systemic therapy 70% rate of disease control, common improvement in symptoms


PROS CONS

Observation N/A Significant symptoms


50% chance of recurrence Adjacent to nerves of brachial plexus


Cryoablation N/A Too big

Systemic therapy N/A Failed systemic therapy

Unable to tolerate the drug due to side effects

Pathology: Desmoid-type fibromatosis. - The tumor measures 10.5 cm in greatest dimension. - The tumor extends to the inferior margin (R1 resection).


11 months post-operative - small 2cm recurrence by MRI

PROS CONS

Observation Small, asymptomatic Some residual compromise in function


50% chance of recurrence


Cryoablation Small, surrounded by soft tissue Minimal experience

Systemic therapy N/A Failed systemic therapy

NED now two year post-procedure with no evidence of neurovascular compromise, improved range of motion vs. preop


Conclusions • Multiple treatment options now exist for

patients presenting with desmoid-type fibromatosis.

• Each has specific indications as well as contraindications.

• Careful consideration of each treatment modality can lead to long term disease and symptom control with minimal morbidity.

• Choice is based on discussion of pros and cons between patient and disease specialist.


personalizing desmoid care – the pros and cons of therapeutic

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