Mediterranean School of Oncology I Tumori Cerebrali Metastasi Cerebrali Chemioterapia

1
Mediterranean School of
Oncology I Tumori CerebraliMetastasi
CerebraliChemioterapia

• Massimo Rinaldi

Roma, 6-7 luglio 2006
2
Brain Metastases

• The annual incidence of BM in USA exceeds 170.000
  cases
• At autopsy, one quarter of pts dying from cancer
  have BM
• The peak age group is 55 to 65 years.
• 20-35 of the pts with solid tumors
• 12/100.000 subjects/ year

3
METASTASI CEREBRALI

• Il 25 dei pazienti con tumore maligno sviluppa
  metastasi cerebrali
• Di queste il 50 è singola
• il 20 è duplice
• il 30 delle volte gt 3
• L80 delle localizzazioni é sovratentoriale
• Nel 30 dei casi sono sincrone

4
Brain Metastases
Frequency Rate Lung 35 -
60 Breast 15 - 25 Unknown 10 -
15 Melanoma 5 - 20 Colon
5 Kidney Prostate Testis lt 5 Ovary
Sarcoma
(Johnson JD et al Neurosurg Clin N Am, 1998)
5
Metastasi cerebrali
La maggior parte delle mestastasi cerebrali
coinvolgono il tessuto cerebrale, meno spesso la
dura madre, aracnoide e la pia madre
(leptomeninge), la base cranica e i nervi cranici
6
The mechanism of brain spreading

• The molecular mechanism is largely unknown
• BM seem to be the result of multiple genetic
  gains and losses
• Recent researches indicate that the development
  of melanoma cells capable of metastasing to the
  brain requires the expression of specific
  neurotrophic factors, neurotrophic factor
  receptors, and the overexpression of heparanases,
  enzymes required for degradation of the
  extracellular proteoglycan matrix.

7
Brain Metastases

• Increasing rate for
• Higher sensitivity of diagnostic imaging
• Prolonged patients survival

8
Steroids improve neurological dysfunction and
prolong survival to approx. 2 months
WBRT alone improves neurological dysfunction and
prolongs survival to approx 3-5 months
WBRT and radiosurgery or neurosurgical
resection improve neurological dysfunction and
prolong survival to approx. 8-11 months
Chemotherapy?
A Zabel Lung Cancer 2004
9
Chemotherapy

• ? Generally considered disappointing due to the
  Blood Brain Barrier
• The Integrity of the BBB excludes hydrophylic or
  heigh molecular weight agents
• The Sanctuary
• BM from chemosensitive tumors respond to CT
  breast, SCLC, testicular cancers
• Difficult to make definitive conclusions due to
  the lack of adequate randomized trials

10
LA BARRIERA EMATOENCEFALICA
Lendotelio dei vasi cerebrali ha caratteristiche
morfologiche e funzionali che permettono la
realizzazione della barriera ematoencefalica che
impedisce lingresso nel liquido interstiziale di
qualunque sostanza incapace di diffondere
liberamente attraverso le membrane
11
LA BARRIERA EMATOENCEFALICA

• Nel SNC possono quindi penetrare solamente
• farmaci con un adeguato coefficiente di
  distribuzione (direttamente dipendente dal
  coefficiente di ripartizione)
• farmaci capaci di utilizzare i sistemi di
  trasporto presenti a livello della barriera
  ematoencefalica

Lo stato di impermeabilità è ridotto a livello
dei plessi coroidei e di altre regioni
periventricolari, dove hanno normalmente luogo i
processi di filtrazione e secrezione. Inoltre,
limpermeabilità della barriera è ridotta in
corso di infiammazione e infezione (meningite).
12
The role of the blood-brain barrier
Hydrophylic drugs transport is limited by the
presence of tight junctions between the brain
endothelial cells
13
The role of the blood-brain barrier
The transport rate of hydrophobic drugs by
passive diffusion cannot be sufficiently
predicted by lipophilicity, suggesting the
existance of carrier type system affecting net
brain uptake (Pgp)
14
The role of the blood-brain barrier

• Before the development of brain metastases, an
  intact blood-brain barrier may prevent dependable
  dispersion of chemotherapy into the brain
  parenchyma.
• Drug entry into the brain depends on molecular
  weight, lipid solubility, degree of ionization,
  protein or tissue binding, and local cerebral
  blood flow.

No preventive effect
15
The role of the blood-brain barrier

• Tsukada  suggested that the blood-brain barrier
  may increase the incidence of brain metastases
  after systemic chemotherapy by inducing a
  relative pharmacologic sanctuary within the
  central nervous system.
• Anatomic barriers play a role, but the
  blood-brain barrier usually is disrupted at the
  site of brain metastases and after cranial
  radiation, and other factors must play a role in
  the relative chemoresistance found within the
  brain.

16
The role of the blood-brain barrier

• Whether the BBB is functional when BM are
  present is not so evident
• The discrepance between blood and CSF
  concentration of drugs is not indicative of BBB
  penetrance
• The protective role of BBB is limited to normal
  brain tissue and not to metastatic tumor tissue
• The strongest argument against BBB is that very
  often there is no differential response of
  metastases at extra and intra-cerebral sites

17
The role of the blood-brain barrier
In conclusion the role of the BBB in explaining
failure of chemotherapy for BM is unclair at
least in certain tumors it may well play a role
but probably one which is limited to normal brain
and micro-metastatic disease and which may have
represented as more important than it actually is.
18
Chemotherapy in BM

• Role to be defined
• Chemoresistance of metastatic clones
• High priority in chemosensitive tumors
• (SCLC, Breast, Ovary)
• Higher RR in chemonaïve patients than in 2nd and
  third lines

19
Brain metastases chemotherapy? or Metastatic
disease (including BM) chemotherapy?
20
A prospective study has assessed the activity of
a CDDP/VP16 regimen in pts with BM ORR of 38,
30, and 0 in breast cancer, NSCLC and melanoma
pts, similar to those of systemic diseases.
V Franciosi et Al Cancer , 1999
21
BM in Breast Cancer

• Non randomized studies RR 50, MS 5.5-14 momths,
  1yS 31
• GOIRC in 56 pts treated with PE, RR 38, 1yS 31
• Integration with RT ?

22
BM in testicular cancer

• BM at initial diagnosis have a high RR to DDP-CT,
  with a 5-year survival rate of 45
• BM after CT have a lower RR, with a 5-year
  survival rate of 12 however, survival is
  effectively increased with surgery and RT if
  single metastasis

23
BM chemotherapy has been largely employed in Lung
Cancer
24
Factors conditioning the treatment of BM in Lung
Cancer
Whether a patient with BM of lung cancer will be
treated with the aim of reducing the number/size
of BM depends on several factors performance
status, life expectancy, neurological function,
previous anti-tumor therapy, number of BM and
status of extra-cranial tumor
PE Postmus, Ann Oncol 1999
25
Brain metastases in SCLC

• At the time of diagnosis 10 of pts present with
  BM
• BM rise to 20 during therapy and to 50 at
  autopsy
• The actuarial probability of developing BM
  increases with prolonged survival from 50 to 80
  at two years from diagnosis

Nugent JL
26
CT in BM from SCLC at diagnosis
Patients (n)
ORR ()
27
Systemic CT of BM in SCLC
Adequate evidence seems to suggest that brain
metastases from SCLC at initial diagnosis respond
as well to systemic CT as does extracranial
disease, which indicates that first-line RT is
not necessary, even though it has not been
documented in randomized setting
C Kristensen, JCO 1992
28
CT for pts with relapse in the brain from SCLC
Patients (n)
ORR ()
29
Treating BM with CT in SCLC

• Treating pts with BM after the initial CT
  encounters the same problems as II line CT in pts
  recurring at other sites
• The efficacy of CT against BM is probably more or
  less comparable to that of WBRT
• WBRTCT is better than CT alone?
• EORTC random study with WBRT Teniposide vs
  Teniposide RR in brain 57 vs 22 (plt0.001),
  longer TTP in brain (p0.005), RR out brain 67
  vs 55 (plt0.09), OS 3.5 vs 3.2 m

30
Response of asymptomatic BM from SCLC to systemic
first-line CT

• 181 pts, treated with CDE
• Synchronous asymptomatic BM in 24 pts
• RR of BM 27
• Systemic RR 73
• BM RR evidently lower than systemic RR

T Scute et Al. JCO, 2006 May
31
Brain metastases in NSCLC

• The incidence of clinically relevant BM is
  estimated to be 20
• Up to 40 of pts have brain lesions identifiable
  at autopsy
• The incidence is rising as a result of advances
  in neuroimaging, routine staging and improvement
  in systemic therapy

Sorensen JB
32
Prognostic factors in NSCLC pts with BM
231 pts with BM analyzed for prognostic factors
or survival determinants of poor outcome
were sex, age, gender, PS, serum sodium level
and the presence of neurological symptoms and
high serum NSE
W Jacot, Br J Cancer, 2001
33
Factors affecting the risk of BM after CT-RT in
LA-NSCLC
150 pts with stage II/III treated with DDP/TAX
and RT Crude and 2-year actuarial rates of BM
19, 30 Stage IIIB associated with higher risk
of BM Crude and 2-year act. risk of BM for CT
RT 27, 39 and 15 and 20 for CTRT
(plt0.05) On multivariate analysis, timing of CT
(plt0.01) and stage IIIA vs IIIB (plt0.01) remained
significant
TJ Robnett, JCO 2001
34
Retrospective SWOG review time from treatment to
subsequent BM

• 422 pts in stage IIIA/B NSCLC
• 20 BM only
• 6.5 BM not only
• 46.5 developed BM within 16 weeks

LE Gaspar ASCO 2003
35
Treating BM with CT in NSCLC
The efficacy is comparable to that of pts with a
tumor for which there is no so effective CT In
general the efficacy is not different from the
overall activity in pts with stage IV NSCLC The
way to improve the results is to identify more
active chemotherapy To exclude BM from clinical
studies is questionable
PE Postmus, Ann Oncol, 1999
36
CT in NSCLC-BM

• A Japanese Randomized Trial of WBRT alone vs
  WBRTChloroetylnitrosoreas or WBRTdichloroetylnit
  rosoureastegafur higher RR (up to 74) but
  similar S in 100 pts
• GOIRC treated 43 pts with PE RR 30, MTTP 4
  months, MS 8 months, 1yS 25

37
Phase III study of early vs delayed WBRT with
concurrent DDP/VNR in BM of NSCLC
171 pts 86 in Arm A (delayed), 85 in Arm B
(early)
G Robinet, Ann Oncol 2001
38
RT and concomitant Carboplatin in BM-NSCLC
Phase III study

• 42 pts
• WBRT alone (20Gy x 5) /- CARBO 70 mg/sm x 5 days
• MS 4.4 mo in RT alone arm and 3.7 in RTC arm
  (p0.64)
• ORR 10 in the RT arm and 29 in the RTC arm
  (p0.24)
• The trial was closed early because of poor accrual

Guerrieri M Lung Cancer 2004
39
Systemic CT as a primary treatment of BM in pts
with NSCLC
31 pts treated with Carbo/TAX ORR at extracranial
sites 23.3 ORR in the brain 36.7 MS
estimated 34 wk

JS Lee, IASLC 2000
40
BM of primary NSCLC treated with CT
36 pts treated with DDP/VP16 17 single BM,
19 multiple BM ORR in brain 12 (33.3) CR in
brain 3 (8.4) PR in brain 9 (25) MS 22 wk,
R 43 wk
DM Jovanovic, IASLC, 2000
41
CT as primary treatment
42
ILCP Study Design
ITALIAN LUNG CANCER PROJECT
R A N D O M I Z E
Cisplatin 75 mg/m2, d 2
Q3wks Gemcitabine 1250 mg/m2, d 1 8
Stratification STAGE (IIIb vs. IV) PS (0-1 vs.
2) CENTER
Carboplatin AUC 6, d. 1
Q3wks Paclitaxel 225 mg/m2, d 1
Cisplatin 100 mg/m2, d1 Q4wks
Vinorelbine 25 mg/m2 wkly x 12 then every
other week
43
ILCP Study Demographics
ITALIAN LUNG CANCER PROJECT
44
ITALIAN LUNG CANCER PROJECT
ILCP Study Response Rate
Cisplatin/ Gemcitabine
Cisplatin/ Vinorelbine
Carboplatin/ Paclitaxel
No. of patients C.R. P.R. S.D. P.D. Unevaluable OR
R
205 0 62 81 36 26 (13) 30
201 1 60 62 34 44 (22) 30
201 1 63 75 37 25 (12) 32
Plt.002 Chi-square test
45
ITALIAN LUNG CANCER PROJECT
ILCP Response of BM to CT
Cisplatin/ Gemcitabine
Cisplatin/ Vinorelbine
Carboplatin/ Paclitaxel
Patients C.R. P.R. S.D. P.D. Not Evaluated
31 4 6 7 5 9
24 5 1 6 2 10
27 7 7 10 0 3
ORR in Brain Metastases 37
46
Chemotherapy, by its terapeutic and prognostic
value, may be considered as the cornerstone of
the combined medical and surgical sequence
whereby brain metastasectomy is followed by
chemotherapy and further focal treatmet of the
primary lung tumor in responders to
chemotherapy.Response to pre-operative CT
before focal treatment was the main favorable
prognostic factor (p0.023), and further
identified pts who had benefit from resection of
the lung tumor, with a significantly better
outcome.
Chemotherapy is the cornerstone of the combined
surgical treatment of lung cancer with
synchronous BM
GN Cottin, Lung Cancer May 2006
47
Gefitinib in BM-NSCLC

• 41 pts treated with 250 mg/d
• ODCR 27 (PR 10, SD 17)
• MDR 13.5 m, MPFS 3 m
• DCR higher in WBRT pretreatd pts (p 0.05) and ADC
  (p 0.08)

Ceresoli Ann Oncol 2004
48
Gefitinib in BM-NSCLC
K Hotta Lung Cancer 2004 14 pts 1CR, 5PR,
8SD Y Namba Clin Lung Cancer 2004 15 pts 60
ORR, MTTR 26 days, MDR 8.7 m, MOS 8.3 m DH Lee
Clin Cancer Res 2005 10 pts 7 OR 1 SD, 1yS
73 S Shimato Neuro-Oncol 2006 8 pts 3 R.
All responders had EGFR mutations
14 pts 6 OR (1CR, 5PR, 8 SD)
Hisamoto A Lung Cancer 2004
21 pts OR 33.3
CH Chiu Lung Cancer 2005
49
1/3 of women with HER2 MBC develop CNS
metastasesBBB prevent Trastuzumab to reach
adequate concentrations in CSFLapatinib (oral
inhibitor of EGFR and HER2) can penetrate the CNS
Breast Cancer
ASCO 2006
50
Central nervous system metastases of a
malignancy are equally sensitive to chemotherapy
as its metastases elsewhere in the body. This
is due to the fact that the blood-brain barrier
is disrupted in contrast enhancing brain
metastases, and does not limit the response to
chemotherapy. Up-front chemotherapeutic
treatment instead of radiotherapy of brain
metastases should therefore be based on the
chemosensitivity of the primary tumor to the used
regimen, and not on the question whether the used
agent penetrates an intact blood-brain barrier.
Eur J Cancer 2003
51
First-line chemotherapy for brain metastases or
with only minor neurological signs and symptoms,
and who have an indication for systematic
chemotherapy for metastases elsewhere in the
body. In contrast, central nervous system
micrometastases may hide behind an intact
barrier, and this may be clinically relevant in
patients that can be cured with chemotherapy
Cytochrome P450 3A4 inducing anti-epileptic
drugs like phenytoin, carbamazepine and
phenobarbital may significantly increase the
metabolism of many chemotherapeutic agents like
CPT11 and paclitaxel (but also of newer
biological agents like many tyrosine kinase
inhibitors).
Eur J Cancer 2003
52
and in resistant or recurrent BM after first
line chemotherapy?
53
CHEMIOTERAPIA DELLE METASTASI CEREBRALILA
BARRIERA EMATOENCEFALICA

• FARMACO IDEALE
• non ciclo specifico
• altamente liposolubile
• basso grado di ionizzazione
• basso peso molecolare

54
Temozolamide in BM
Temozolamide is an oral, second-generation
alkylating agent rapidly absorbed in oral
administration with a spontaneous conversion at
physiologic pH to the active metabolite
imidazole-carboxamide in the tissues. Temozolamide
has a demonstrated ability to cross the BBB,
reaching CSF concentrations 30-40 of plasma
concentrations
55
Temozolamide in BM
Three scenarios

• TMZ alone for recurrent/progressive disease
• TMZ alone for newly diagnosed BM
• TMZ in combination with WBRT for newly diagnosed
  lesions

56
Temozolamide in BM
57
Phase II study of Temozolamide in heavily
pretreated cancer pts with BM
28 pts (12 NSCLC, 5 SCLC) treated with
T 150 mg/sm/day x 5 days every 4
weeks 1 PR (NSCLC) (4), 4 SD (2 SCLC) (17) MS
4.5 months, mTTP 3 months Gr 3 headache in 3 pts,
Gr 3 nausea in 4 pts, Grade 3 vomiting in 4 pts,
all other adverse events were Gr 1-2
C Christodoulou, Ann Oncol 2001
58
A phase II study of Temozolamide for recurrent BM
36 pts (lung cancer 56) treated with T 150
mg/m2/day x 5 days every 4 weeks
Gr 3 thrombocytop. in 2 pts, Gr 3-4 lymphopenia
in 4 pts
2 PR (8), 9 SD (35)
LE Abrey, ASCO 2000
59
Concurrent TMZ and RT followed by adjuvant TMZ
TMZ 60 mg/sm/d x 2 w WBRT 30 Gy and a 6-9 Gy
boost, followed by TMZ 200 mg/sm x 5 dd/4w x 6
cycles
RR 55 after 6 cycles (86 in 11 lung cancer)
Dardoufas, PASCO 2001
60
Random Phase II study with TMZ and RT
TMZ and WBRT vs WBRT
RR 66
RR 96
P0.0017
48 LC MS 7.3 m
27.5 LC MS 4 m
P0.031
Antonadou D, IASLC 2003
61
Phase II TMZ WBRT in BM-NSCLC S Dawood
OR 13/17 MS 9 mTMZ WBRT in BM
from solid tumors R Addeo 5 CR in BC
and NSCLC 21 PR 11/BC 9/NSCLC
3/others 1yS 59
ASCO 2006
62
Fotemustine
La sintesi chimica di fotemustina ha avuto come
obiettivo di migliorare luptake cellulare, in
particolare nelle cellule tumorali il passaggio
attraverso la barriera emato-encefalica.
Deloffre P. Cancer Comm., 1990
63
FOTEMUSTINA
MECCANISMO DAZIONE

• Alchilazione delle basi azotate
• Formazione di ponti intracatenari e intercatenari
• Rottura dei filamenti
• Impossibilità di una corretta lettura del DNA
• Fase S (preferenzialmente), G2 e M

Tapeiro H. Anticancer Res. 1989
64
Velocità di passaggio
Concentrazione (mcg/mL)

100
50
40
30

20
Muphoran
10
2
4
3
5
7
6
8
9
10
1
Tempo (min)
65
Fotemustine in Malignant Melanoma

66
(No Transcript)
67
(No Transcript)
68
Fotemustine in NSCLC

• R Rudd 1994 Untreated Pts PR 13.5
• JL Pujol 1994 Poor Prognosis OR 17 BM 2/12
• DDP A Reviere 1994 PR 23 BM 37.5
• DDP C Cotto 1996 PR 20 BM 28

69
FTM - Toxicity
Pujol J.L. et al. Br. J Cancer, 69,
1136-1140,1994
70
FTM/DDP Results
Partial Response
40
37,5 N3
30
20
Patients ()
10
0
Brain Metastases
Riviere A. et al. Eur. J Cancer, 30A,
587-590,1994
71
FTM/DDP Toxicity
Neurotoxicity (G1-2 in 3 pts) Nephrotoxicity (G1
in 2 pts)
Riviere A. et al. Eur. J Cancer, 30A,
587-590,1994
72
BM FTM/DDP Results
BM Responses
30
28 7/25
25
20
Patients ()
15
10
5
0
Tot
Cotto C et al. Eur. J Cancer, 32A, 69-71,1996
73
BM PERSPECTIVES

• ICRF-187 is a new drug which rescues TOPO II but
  does not pass BBB therefore enables
  dose-escalation of VP16/VM26
• RMP-7 is a bradykinin B2 receptor agonist when
  co-administered with hydrophilic drugs such as
  DDP or DDP-analogues, temporarely increases the
  permeability of BBB relaxing the thight junctions
• Cyclosporin A and its analogue PSC 833 can
  modulate BBB improving the delivery of CT

74
CONCLUSIONS

• In chemosensitive tumors and in some partially
  chemosensitive tumors, BM do not behave
  differently from other metastatic sites in
  response to CT the only way to improve the
  results is to identify more active CT
• In lung cancer, it is questionable whether a
  distinction needs to be made between pts with or
  whitout BM for inclusion in phase II and III
  studies
• In chemosensitive tumors, chemotherapy is a
  valid therapeutic alternative
• TMZ , Fotemustine and targeted therapy in CT
  resistant patients