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  1. Brain Metastases: current and future options Alessandra Fabi Roma, 16 Novembre 2006

  2. Improve 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 1 Fellner, J Clin Invest, 2002 2 Kemper Clin Cancer Res, 2003 3 Robert, J Med Chem, 2003

  3. 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 ?

  4. 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

  5. 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% (p=0.012)

  6. 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

  7. SURGERY RADIOTHERAPY (WBRT, RS) CHEMOTHERAPY

  8. SURGERY 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

  9. 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% (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

  10. Therapeutical Possibility Chemotherapy alone Chemotherapy concurrently with WBRT Radiosensitizing Agents Target Therapy

  11. 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

  12. Capecitabine, breast cancer and brain metastases response Fabi et al., Anticancer Research 2006

  13. 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) Rr 38% - 55% Durable remission in leptomenigeal metastases CHEMOTHERAPY, BREAST CANCER AND BRAIN METASTASES

  14. Chemotherapy alone and activity on BM Langer et Metha, JCO 2005

  15. Chemotherapy concurrently with WBRT Langer et Metha, JCO 2005

  16. 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

  17. Management of Brain Metastasis from BC – Primary Therapy 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) Chang et al, The Oncologist 2003

  18. 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

  19. 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

  20. PRIMARY SITE (%)

  21. N° of Lesions (%) 41.1% 39.1% 19.8%

  22. 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%)

  23. BM TREATMENT – 2nd LINE 134 pts: • CHEMOTHERAPY: 72 (53.7%) • WBRT: 47 (35%) • SURGERY: 10 (7.4%) • RADIOSURGERY: 5 (3.7%)

  24. 3- yrs Overall Survival Median OS = 13 months ( 95% C.I. 10-16 ) 50.9 % % 28.1 % 12 % Months

  25. 1-yr Overall Survival 51.4 % % 56.0 % 29.1 % p =0.03 13.4 % months

  26. 2-yrs Overall Survival % 40.3 % 29.0 % 15.0 % p <.0001 months

  27. 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

  28. BRAIN METASTASES FROM BREAST CANCER

  29. Breast Cancer and Brain Metastases 2-yrs Overall Survival Median OS = 17 months ( 95% C.I. 6-29 ) 56.0 % % 43.0 % Months

  30. Breast Cancer and BrainMetastases 2-yrs Overall Survival 90.0 % 58.3 % % 15.9 % p =.007 months

  31. Breast Cancer and BrainMetastases 2-yrs Overall Survival 58.3 % % 40.0 % 37.5 % Months

  32. New target therapy

  33. LAPATINIB

  34. 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

  35. 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

  36. Grazie