Perspectives in GIST treatment

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Small round cell sarcomas in adults
Palma Dileo palma.dileo_at_istitutotumori.mi.it
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Small round cell sarcoma
EFT
RMS
DSRCT
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• 1921 - James Ewing described the case of a
  14-year-old girl with malignant bone tumor with
  distinguished features, which he called diffuse
  endothelioma
• ES is one of the entity included in the Ewings
  sarcoma family of tumors (ESFT) peripheral
  primitive neuroectodermal tumor (PNET),
  extraosseous Ewings sarcoma (EES), Askins tumor
  (ES of the chest wall)

CD99
Courtesy of dr. Parafioriti
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Ewing family tumors (EFTs) (pPNET Peripheral
primitive neuroectodermal tumors )

• Studies using
• immunohistochemical markers
• cytogenetics
• molecular genetics
• tissue culture
• indicate that these tumors are all derived from
  the same primordial stem cell

Delattre O, et al. N Engl J Med 331 (5) 294-9,
1994.
Denny CT. Cancer Invest 14 (1) 83-8, 1996. 
Llombart-Bosch A et al. Cancer 66 (12) 2589-601,
1990
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EFTs

• Prognostic factors are site (outcomes for
  extremity disease is much more favorable than
  pelvis primary disease), tumor volume, presence
  of metastases (approximately 25 of patients with
  Ewings sarcoma present with metastatic disease,
  most commonly to the lung or other bones)
• Almost 95 of the cases demonstrate chromosomal
  translocations between chromosomes 11 and 22 as
  well as variant forms and secondary chromosomal
  changes (e.g. trisomy 8)

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EFTs

• This family of tumors is common in children and
  young adults (peak incidence occurs in the second
  decade and is less common in children under 5 or
  in adults over 30 years old)
• EFTs are very aggressive and for this reason
  multiagent chemotherapy is vital to a curative
  management strategy, with the support of surgery
  and/or local radiation therapy to obtain local
  control

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EFTs - Treatment

• Large randomized clinical trial (NEJM 2003)
• Outcome was improved when the ifosfamide and
  etoposide combination was given in alternating
  courses with vincristine, doxorubicin (or
  dactinomycin), and cyclophosphamide
• Pts M at diagnosis
• No significative difference in EFS at 5 years
• Pts non M at diagnosis
• Better EFS in the experimental arm (693 vs
  544)
• Better OS in the experimental arm (723.4 vs
  613.6)

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Localized disease
Thus, standard treatment now alternates courses
of chemotherapy that include ifosfamide/etoposide
with appropriate supportive care for the
myelotoxicity caused by this regimen
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EFTs in adults

• In the adult population the most frequent
  presentation is extraosseus

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Extraskeletal Ewing sarcoma

• First described in 1969
• Tefft M et al. Radiology 1969 92 1501-9
• Angervall L et al. Cancer 1975 36 240-251

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Hum Pathol 2001 Oct 32(10)1109-15
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Extraskeletal Ewings sarcoma

• Most common sites
• trunk (32)
• extremity (26)
• Head and neck (18)
• retroperitoneum (16)
• other sites (8)
• Evenly distributed between genders
• Broader age range at the time of diagnosis
• Higher average age at presentation
• Few data available addressing optimal treatment

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Literature Review of Extraskeletal ES Clinical
Series
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Extraskeletal Ewings sarcoma in adults

• 16 pts (Dana-Farber Cancer Institute) from 1975
  to 1985
• 10 pts with extraskeletal (5) or pelvic primaries
  (5)
• Median DF 10 months
• Median OS 34 months
• No relapses after 18 months of DFS
• Treatment consisted of
• Chemotherapy (VAC or VACA)
• Radiation therapy (3.900-6.400 cGy)
• Surgery (when feasible)
• Extraskeletal and pelvic disease
• occurred in a disproportionately large segment of
  older population (range 17-50 median age 22
  years)
• Associated with a poor prognosis

Siegel RD et al. Am J Clin Oncol. 1988 Dec
11(6)614-7
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Extraskeletal Ewings sarcoma in adults

• 50 pts (Mayo Clinic) from 1935 to 1985
• 42 pts (23 females, 19 males) with soft tissue
  primaries
• Mean age of 22
• Treatment consisted of
• Chemotherapy (after 1970 similar to the IRS
  regimen)
• Radiation therapy (4.000-5.000 cGy)
• Surgery (when feasible)
• OS
• 2-years 54
• 5-years 38.5
• Increase survival at presentation since 1970 (48
  5-years survival compared with 28 before 1970)
• Decrease survival was noted
• Pelvic tumors, incomplete resections, presence of
  metastatic disease

Rud NP et al. Cancer 1989 Oct 1 64(7)1548-53
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Extraskeletal Ewings sarcoma in adults

• 24 pts (Indiana University, Indianapolis) from
  1977 to 1995
• 11 pts (5 females, 6 males) gt 16 years with
  extraskeletal primaries
• Mean age of 23 years
• Treatment consisted of
• Chemotherapy (Vincristin, Doxorubicin,
  Cyclophosphamide, Ifosfamide, Etoposide)
• Radiation therapy (2.500-6.000 cGy)
• Surgery (when feasible)
• OS
• 5-years 46
• DFS
• 27
• Favorable prognosis in extremity lesions

Ahmad R et al. Cancer 1999 Feb 1 85(3)725-31
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Extraskeletal Ewings sarcoma in adults

• 37 pts (Dana-Farber Cancer Institute) from 1979
  to 1996
• 18 pts with extraskeletal primaries
• Mean age of 26 years
• Treatment consisted of
• Chemotherapy (VAdC or MAID or VadCA/IE or VAC or
  VAdCA)
• Radiation therapy (4.000-6.450 cGy)
• Surgery (when feasible)
• OS
• 5-years 21 12
• Predictors for death on multivariate analysis
• Metastatic disease at presentation (HR 3.4,
  p0.01)
• Primary extraskeletal (HR 5.0, p0.005)
• Age 26(HR 3.7, p0.02)

Baldini EH et al. Ann Surg 1999 230, 1, 79-86
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Literature Review of EFTs in adults
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As for the metastatic disease...
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EURO-E.W.I.N.G. 99Combination CT with or without
PBSC Transplantation, RT, and/or Surgery in pts
with Ewings sarcoma

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HD-CT e EFTs

• 33 Pts enrolled
• 10 CTX, CBDCA and VP16
• 21 with regimen including iFX
• 2 other regimen
• HDCT
• 22 pts busulphan melphalan
• 7 pts melphalan etoposide
• 3 pts TBI
• 3 pts melphalan (2 TBI)
• 1 pts busulfan CTX
• RR in 17/19 pz ?52.9
• 7 pts CR e 2 PR
• 3 pts MR e 3 SD
• 2 pts PD
• 2 years EFS? 42.5 (95 CI, 2659)
• 5 years EFS? 38.2 (95 CI, 2155)

McTiernan A et al. Ann Onc.17 1301-1305, 2006
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HD-CT e EFTs

• 97 pts enrolled (M _at_ diagnosis)
• EFS ?37
• OS ?38
• 75 Pts HD-CT
• EFS ?47
• 44 pts lung M
• EFS?52
• 22 pts bone M (no BM invasion)
• EFS?36
• Multivariate analysis EFS and OS ? 3 prognostic
  factors indipendenti
• Age
• Fever _at_ diagnosis
• Bone Marrow invasion

Oberlin O et al. J Clin Oncol. 2006 Aug
2024(24)3997-4002.
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EFTs further lines

• 16 pts in PD during first line or relapsed
• 12 M _at_ diagnosis
• Treatament
• temozolomide 100 mg/m2/d (day 1-5) Irinotecan
  10-20 mg/m2/d (day 1-5 e 8-12) q21-28 days.
• 1 CR, 3 PR, and 3 MR
• Moderate hematological toxicity
• Diarrhea G 3-4
• 11 of cycles (due to irinotecan)

Wagner LM et al. Pediatr Blood Cancer. 2005 Nov
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Wagner LM et al.Clin Cancer Res. 2004 Feb
110(3)840-8
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EFTs further lines

• 54 pts PD during first line or relapsed
• Treatment
• Topotecan 0.75 mg/m2/d (day 1-5) e CTX 250
  mg/m2/d (day 1-5)
• 52 pz valutabili per risposta
• 19 CR, 5 PR, 2 SD, 26 PD
• After median follow-up of 23.1 mesi (range
  7.8-59.8)
• 25.9 pts responded (13 CR e 1 PR)

Hunold A et al. Pediatr Blood Cancer. 2006
Nov47(6)795-800.
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EFTs the news

• Overexpression of IGF1R seems to be implicated in
  many tumor models as playing a role in cell
  growth and tumorigenesis
• Blockade of the IGF-IR inhibits the growth of
  EFTss family of tumors cells
• Helmans lab has been a pioneer in studing
  whether the presence of the IGF-IR is required
  for transformation by the EWS/FLI-1 fusion
  protein
• Several IGF-1R antibody in clinic
• Roche (R1507)
• Pfizer (CP-751,871)
• Schering-Plough
• ImClone
• Amgen

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Controversy uncertainty

• Role of age at diagnosis remains to be rule out,
  with
• Some studies showing older age to be associated
  with poorer outcome (Ferrari et al.)
• Others showing no association between age and
  survival
• Presence of primary metastatic disease, larger
  tumor volume, pelvic/central primary site, and
  poor histological response to preoperative
  chemotherapy are known adverse prognostic factors
  in pediatric series likely to apply also in
  adults
• How best to manage adult patients with EFT
• By treating them following the lessons learned
  from the pediatric experience
• Euro Ewing will address the issue of the dose
  intensification in unfavorable presentations,
  although uncontrolled evidence of its
  effectiveness in the metastatic setting has been
  provided

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Summary

• Biological/Clinical behavior of extraskeletal
  Ewings sarcoma is similar to bone Ewings
  sarcoma (chemo/radiosensitivity)
• Extraskeletal Ewings sarcoma are more frequent
  in adult pts
• Peculiar sites of origin
• Paravertebral region
• Chest wall
• Lower extremities and rarely pelvic and hip
  regions
• Retroperitoneum
• Unusual sites (lung, uterus, ovary, urinary
  bladder, kidney)
• Treatment should follow the same guidelines as
  for bone Ewings sarcoma, but a stratified
  treatment should be worked out for different risk
  categories

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Summary

• There is room for a prospective study on
  extraskeletal ES of adults with the intent of
  studing the natural history of the disease, but
  also the opportunity to test therapeutic
  innovative hypotesis
• waiting for the IGF1R

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No man, even under torture, can say exactly what
a tumour is J. Ewing, 1916
Courtesy of dr. Parafioriti