Alessandra FabiAlessandra Fabi

Brain Metastases: current and future options

Brain Metastases: current and future options

Roma, 16 Novembre 2006Roma, 16 Novembre 2006

Improve drug delivery to brain tumoursImprove drug delivery to brain tumours

Selective inhibition of MDR transporters

P-glycoprotein 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

Selective inhibition of MDR transporters

P-glycoprotein 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

Primary tumors with a frequent brain diffusion and

chemosensitiveGERM-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 ?

Incidence

10 -16 % (30% autopsies)

prevalent site: supratentorial

2-5 % leptomeningeal metastases

2% metastasis sincron at diagnosis

median PFS 34 months

Incidence

10 -16 % (30% autopsies)

prevalent site: supratentorial

2-5 % leptomeningeal metastases

2% metastasis sincron at diagnosis

median PFS 34 months

Breast cancer and brain metastasesBreast 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% (p=0.012)

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% (p=0.012)

Breast cancer and brain metastasesBreast cancer and brain metastases

Prognostic FactorsPrognostic Factors724 pz724 pz

3-yrs S: 27% vs 44%5-yrs S: 11% vs 28%3-yrs S: 27% vs 44%5-yrs S: 11% vs 28%

HR+ HR-

3-yrs S: 33% vs 60%5-yrs S: 14% vs 38%

3-yrs S: 14% vs16%5-yrs S: 4% vs 8%

Andre et al.

JCO 2004

Andre et al.

JCO 2004

Median Survival ’87-’93/ ’94-’00= 28 mos vs 45 mos

Median Survival ’87-’93/ ’94-’00= 28 mos vs 45 mos

SURGERY

RADIOTHERAPY (WBRT, RS)

CHEMOTHERAPY

SURGERY

RADIOTHERAPY (WBRT, RS)

CHEMOTHERAPY

SURGERYSURGERY

Patchell ’90 48 pts (10% breast primary)

Surgery alone vs Surgery ->WBRT

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 ->WBRT

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 ->WBRT

Survival no difference

Patchell ’90 48 pts (10% breast primary)

Surgery alone vs Surgery ->WBRT

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 ->WBRT

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 ->WBRT

Survival no difference

Surgical resection should be considered seriously in pts with single metastases

and stable or absent extracranial disease

Surgical resection should be considered seriously in pts with single metastases

and stable or absent extracranial disease

Stereotactic RadiosurgeryStereotactic 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% (p=0.03)

Local tumor control (1 yr) 82% vs 71% (p=0.01)

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% (p=0.03)

Local tumor control (1 yr) 82% vs 71% (p=0.01)

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

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

Therapeutical Possibility

Chemotherapy alone

Chemotherapy concurrently with WBRT

Radiosensitizing Agents

Target Therapy

Chemotherapy alone

Chemotherapy concurrently with WBRT

Radiosensitizing Agents

Target Therapy

CHEMOTHERAPY AND BCCHEMOTHERAPY 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

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 2004Lin et al. JCO 2004

Capecitabine, breast cancer and brain metastases response

Fabi et al., Anticancer Research 2006

Rosner et al.

100 pts ( Rr 50% - median duration 7 months)

Boogerd et al

22 pts (Rr 59%)

Rosner et al.

100 pts ( Rr 50% - median duration 7 months)

Boogerd et al

22 pts (Rr 59%)

WBRT +/-TMZ

Rr 96% vs 67% (p=0.017)

WBRT +/-TMZ

Rr 96% vs 67% (p=0.017)

Durable remission in leptomenigeal metastasesDurable remission in leptomenigeal metastases

Rr 38% - 55%

CHEMOTHERAPY, BREAST CANCER AND BRAIN METASTASES

Chemotherapy alone and activity on BM Chemotherapy alone and activity on BM

Langer et Metha, JCO 2005Langer et Metha, JCO 2005

Chemotherapy concurrently with WBRT

Langer et Metha, JCO 2005Langer et Metha, JCO 2005

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

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

NEW RADIOSENSITIZING AGENTS

Lesion number Diagnostic uncertainty Surgery or

and asymptomatic observation If grows, surgery or SRS +WBRT

< 1 cm

1 Convincing metastasis

> 1 cm Single KPS>70 and controlled primary Surgery or SRS

(>3 cm)+ WBRT

KPS < 70 and uncontrolled primary WBRT (surgery if tumor causes mass effect)

Solitary Surgery + WBRT or SRS (< 3 cm) + WBRT for non surgical candidate

(if > 3 cm, WBRT only)

2-3 WBRT + SRS for KPS > 70 and controlled primary

or

Surgery (if highly symptomatic or mass effect) + WBRT

or

WBRT for KPS < 70 or uncontrolled primary

> 3 WBRT (surgery to lesions causing mass effect)

Management of Brain Metastasis from BC – Primary Therapy Management of Brain Metastasis from BC – Primary Therapy

Chang et al, The Oncologist 2003Chang et al, The Oncologist 2003

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)

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

Varese, AINO 2004

Edimburgo, EANO 2005

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

PRIMARY SITE (%)

0

10

20

30

40

50

N° of Lesions (%)

1

2 3

> = 4

39.1%

19.8%

41.1%

253 pts: WBRT : 116 (45.9%)

CHEMOTHERAPY: 54 (21.3%)

SURGERY: 52 (20.6%)

RADIOSURGERY: 24 (9.5%)

NIHIL: 7 (2.8%)

BM TREATMENT – 1st LINE

134 pts: CHEMOTHERAPY: 72 (53.7%)

WBRT: 47 (35%)

SURGERY: 10 (7.4%)

RADIOSURGERY: 5 (3.7%)

BM TREATMENT – 2nd LINE

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36

12 %12 %

3- yrs Overall Survival3- yrs Overall Survival

Median OS = 13 months

( 95% C.I. 10-16 )

Months

%50.9 %50.9 %

28.1 %28.1 %

0

20

40

60

80

100

0 2 4 6 8 10 12 colon- rectumbreastmelanomalung

29.1 %29.1 %

1-yr Overall Survival1-yr Overall Survival

months

%

13.4 %13.4 %

51.4 %51.4 %

56.0 %56.0 %

p =0.03

0

20

40

60

80

100

0 4 8 12 16 20 24 1 lesion2-3 lesions>=4 lesions

15.0 %15.0 %

2-yrs Overall Survival2-yrs Overall Survival

months

%

29.0 %29.0 %

40.3 %40.3 %

p <.0001

0

20

40

60

80

100

0 4 8 12 16 20 24 SRS- SWBRTCT

11.9 %11.9 %

2-yrs Overall Survival2-yrs Overall Survival

Months

%

26.4 %26.4 %

38.6 %38.6 %

p =.001

Mediana S (mos)

SRS/Surgery : 19 (16-22)

WBRT : 10 (7-13)

CT : 9 (7-10)

BRAIN METASTASES FROM BREAST CANCER

BRAIN METASTASES FROM BREAST CANCER

0

20

40

60

80

100

0 4 8 12 16 20 24

0

20

40

60

80

100

0 4 8 12 16 20 24

43.0 %43.0 %

Breast Cancer and Brain Metastases 2-yrs Overall Survival

Breast Cancer and Brain Metastases 2-yrs Overall Survival

Median OS = 17 months

( 95% C.I. 6-29 )

Months

%56.0 %56.0 %

0

20

40

60

80

100

0 4 8 12 16 20 24 1 lesion2-3 lesions>=4 lesions

15.9 %15.9 %

Breast Cancer and Brain Metastases

2-yrs Overall Survival

Breast Cancer and Brain Metastases

2-yrs Overall Survival

months

%58.3 %58.3 %

90.0 %90.0 %

p =.007

0

20

40

60

80

100

0 4 8 12 16 20 24 SRS- SRT WBCT

37.5 %37.5 %

Breast Cancer and Brain Metastases2-yrs Overall Survival

Breast Cancer and Brain Metastases2-yrs Overall Survival

Months

%58.3 %58.3 %

40.0 %40.0 %

LAPATINIB

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

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

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

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