Alessandra Fabi

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Brain Metastases current and future options
Alessandra Fabi
Roma, 16 Novembre 2006
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Improve drug delivery to brain tumours
Selective inhibition of MDR transporters P-glycop
rotein MDR-associated protein BC resistence
protein Highly expressed BBB Paclitaxel
valspodar (2nd generation P-glicoprotein pump)
1 Paclitaxel elacridar (3rd generation
P-glicoprotein pump) 2, 3
biricodar zosuquidar
1 Fellner, J Clin Invest, 2002 2 Kemper Clin
Cancer Res, 2003 3 Robert, J Med Chem, 2003
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Primary tumors with a frequent brain diffusion
and chemosensitive
GERM-CELL TUMOURS PEB regimen (Heinorm) SCLC PE
regimen (Italian Oncology Group) BREAST
CANCER (CMF, PE, Taxane-including regimen)
Can BBB not to be a cause of chemoresistence but
the biological characteristics of primary tumour ?
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Breast cancer and brain metastases

• Incidence
• 10 -16 (30 autopsies)
• prevalent site supratentorial
• 2-5 leptomeningeal metastases
• 2 metastasis sincron at diagnosis
• median PFS 34 months

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Breast cancer and brain metastases

• Risk Factors
• Age (Tsukada 2003)
• Hormonal Receptors (Samaan 1984)
• ER - vs ER 10 vs 4
• Overespression HER2 and Trastuzumab (Kallionemi
  1991, Burstain 2003)
• - predictor of site of first relapse 4.3 vs
  0.4
• - increase incidence of BM in HER2 T treated
  pts
• - higher incidence in trastuzumab (28-43)
• Adjuvant chemiotherapy vs no treatment (Carey
  BCRT 2001)
• 50 vs 26 (p0.012)

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Prognostic Factors
724 pz
3-yrs S 27 vs 44 5-yrs S 11 vs 28
Median Survival 87-93/ 94-00 28 mos vs 45
mos
HR
HR-
3-yrs S 14 vs16 5-yrs S 4 vs 8
3-yrs S 33 vs 60 5-yrs S 14 vs 38
Andre et al. JCO 2004
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SURGERY RADIOTHERAPY (WBRT, RS) CHEMOTHERAPY
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SURGERY
? Patchell 90 48 pts (10 breast
primary) Surgery alone vs Surgery
-gtWBRT functional independence 8 vs 38
weeks Recurrence 18 vs 70 Survival 15 vs
40 weeks ? Noordijk 94 63 pts (19 breast
primary) Surgery alone vs Surgery
-gtWBRT Survival 18 vs 36 weeks Benefit of
combined therapy seen only in pts with stable or
absent extracranial disease ? Mintz 96 Surgery
alone vs Surgery -gtWBRT Survival no difference
Surgical resection should be considered seriously
in pts with single metastases and stable or
absent extracranial disease
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Stereotactic Radiosurgery

• ? Single metastases
• Median Survival after brain diagnosis 15-18
  months
• Median Survival after SRS 7-13 months
• ? Retrospective analysis (SRS vs Surgery) (15
  breast primary)
• Conflicting results for single metastases
• ? RTOG 95-08 02 333 pts (1-3 metastases)
• SRS WBRT vs WBRT alone
• Survival no difference
• Improvement KPS 43 vs 27 (p0.03)
• Local tumor control (1 yr) 82 vs 71 (p0.01)

In most cases seem resonable to limit SRS to with
1 to 3 brain metastases and who have controlled
extracranial disease and adequate performance
status
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Therapeutical Possibility
Chemotherapy alone Chemotherapy concurrently
with WBRT Radiosensitizing Agents Target
Therapy
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CHEMOTHERAPY AND BC
? Bloob-brain barrier and small, lipid-soluble
molecules ? P-glicoprotein expressed by brain
capillary endothelium and mediates efflux of
anthracyclines, taxanes and vinca alkaloids
Lin et al. JCO 2004
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Capecitabine, breast cancer and brain metastases
response
Fabi et al., Anticancer Research 2006
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Rosner et al. 100 pts ( Rr 50 - median duration
7 months) Boogerd et al 22 pts (Rr 59)
WBRT /-TMZ Rr 96 vs 67 (p0.017)
Rr 38 - 55
Durable remission in leptomenigeal metastases
CHEMOTHERAPY, BREAST CANCER AND BRAIN METASTASES
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Chemotherapy alone and activity on BM

Langer et Metha, JCO 2005
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Chemotherapy concurrently with WBRT
Langer et Metha, JCO 2005
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NEW RADIOSENSITIZING AGENTS
RTOG 7916, 1991 Phase III WBRT (30Gy
vs 50 Gy) ns S, risk of death, WBRT
misonidazole
PS RTOG 8905, 1995 Phase III WBRT
bromodeoxyuridine S 0.904 RTOG
BR0119 Phase III RPA II WBRT
melatonin S ns
morning or evening RTOG BR0118
Phase III RPA II WBRT thalidomide
ongoing
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Management of Brain Metastasis from BC Primary
Therapy

• Lesion number Diagnostic uncertainty Surgery or
  
• and asymptomatic observation If grows,
  surgery or SRS WBRT
• lt 1 cm
• 1 Convincing metastasis
• gt 1 cm Single KPSgt70 and controlled
  primary Surgery or SRS
• (gt3 cm) WBRT
• KPS lt 70 and uncontrolled primary WBRT
  (surgery if tumor causes mass effect)
• Solitary Surgery WBRT or SRS (lt 3 cm)
  WBRT for non surgical candidate
• (if gt 3 cm, WBRT only)
• 2-3 WBRT SRS for KPS gt 70 and controlled
  primary
• or
• Surgery (if highly symptomatic or mass effect)
  WBRT
• or
• WBRT for KPS lt 70 or uncontrolled primary
• gt 3 WBRT (surgery to lesions causing mass
  effect)

Chang et al, The Oncologist 2003
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BRAIN METASTASES FROM DIFFERENT TUMOR TYPES A
SURVEY ANALISYS FROM A MULTIDISCIPLINARY
EXPERIENCE

• A.Fabi, A.Felici, A.Mirri, I.Sperduti, E.Bria,
  F.Serraino, G.Lanzetta, G.Mansueto, L.Moscetti,
  A.Pace, S.Telera,
• and CM.Carapella
• (the Latium Neuro-Oncology Group)

Varese, AINO 2004 Edimburgo, EANO 2005
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END-POINTS

• Primary
• To define a multidisciplinary approach based on
  the primary tumor stage, prognostic class and
  chemo and/or radio-sensitivity
• To clarify the commonly employed therapeutic
  strategies and to indicate the most effective
  approach arising from a multidisciplinary
  experience

Fabi et al, EANO 2005
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PRIMARY SITE ()
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N of Lesions ()
41.1
39.1
19.8
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BM TREATMENT 1st LINE

• 253 pts
• WBRT 116 (45.9)
• CHEMOTHERAPY 54 (21.3)
• SURGERY 52 (20.6)
• RADIOSURGERY 24 (9.5)
• NIHIL 7 (2.8)

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BM TREATMENT 2nd LINE

• 134 pts
• CHEMOTHERAPY 72 (53.7)
• WBRT 47 (35)
• SURGERY 10 (7.4)
• RADIOSURGERY 5 (3.7)

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3- yrs Overall Survival
Median OS 13 months ( 95 C.I. 10-16 )
50.9

28.1
12
Months
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1-yr Overall Survival
51.4

56.0
29.1
p 0.03
13.4
months
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2-yrs Overall Survival

40.3
29.0
15.0
p lt.0001
months
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2-yrs Overall Survival
Mediana S (mos) SRS/Surgery 19 (16-22) WBRT
10 (7-13) CT
9 (7-10)

38.6
26.4
11.9
p .001
Months
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BRAIN METASTASES FROM BREAST CANCER
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Breast Cancer and Brain Metastases 2-yrs Overall
Survival
Median OS 17 months ( 95 C.I. 6-29 )
56.0

43.0
Months
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Breast Cancer and Brain Metastases 2-yrs Overall
Survival
90.0
58.3

15.9
p .007
months
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Breast Cancer and Brain Metastases 2-yrs Overall
Survival
58.3

40.0
37.5
Months
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New target therapy
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LAPATINIB
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• Increasing of incidence because increasing of
  survival
• Higher survival because more therapeutic
  approches
• Early diagnosis allows an improvement of
  survival for the possibility to a local therapy
• The need for more effective CNS-directed
  treatments may become more pressing becouse
  improvements in systemic treatment for breast
  cancer could lead to a greater incidence of BM
• Radiation therapy remains the mainstay of
  treatment for BM
• ? SRS and surgery can benefit patients with
  limited metastatic brain disease and good KPS

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• ? Chemotherapy could be a first therapeutical
  option in case of multiple lesions and
  uncontrolled extracranial disease or failure to
  local treatment
• ? The patient with brain metastases can now be
  treated
• ? Future areas of research
• - Characterization of risk factors and molecular
  mechanism
• Evaluation of radiologic screening strategies
• More optimization of indication for timing of
  surgery, WBRT and SRS
• Development of novel chemotherapeutic and
  biological targeted approaches

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Grazie