Brain metastases and meningitis carcinomatosa: Prof. Rafal Dziadziuszko Medical University of Gdańsk, Poland

Transcription

1 Brain metastases and meningitis carcinomatosa: a palliative situation? Prof. Rafal Dziadziuszko Medical University of Gdańsk, Poland SAMO, Lucerne, February 1-2, 2013

2 Treatment options for NSCLC patients with brain metastases Whole brain radiotherapy (WBRT) Stereotactic radiotherapy Surgery Chemotherapy Targeted therapies Best supportive care

3 Stratification of cancer patients with brain metastases KPS 70 Age<65 and Controlled primary site and No mets outside CNS KPS 70 Primary site active and/or Mets outside CNS present Age 65 KPS< 70 Median OS 7.1 months 4.2 months 2.3 months Gaspar IJROBP 1997;37:

4 Stratification of cancer patients with brain metastases Gaspar IJROBP 1997;37:

5 Stratification of cancer patients with brain metastases: Graded Prognostic Assessment (GPA) Score Sperduto JCO 2012;30:

6 Stratification of NSCLC patients with brain metastases: Graded Prognostic Assessment (GPA) Score Sperduto JCO 2012;30:

7 Stratification of NSCLC patients with brain metastases: Graded Prognostic Assessment (GPA) Score Median OS according to treatment of NSCLC patients with brain metastases (months) WBRT SRS WBRT+SRS S+SRS S+WBRT S+WBRT+SRS 3,53 9,86 12,72 11,86 11,66 12,06 Sperduto JCO 2012;30:

8 NSCLC Patients with 1-3 metastases: Indications for surgery vs. SRS Surgery Single lesions Larger lesions w/mass effect Outside vulnerable surgical areas No contraindications to surgery SRS Smaller lesions Multiple lesions (1 3?) All locations in the brain, including brain stem Patients who are not surgical candidates

9 Key evidence: WBRT vs. SRS + WBRT RTOG 9509 trial (N=331) 1-3 metastases, < 40 mm WBRT 37,5 Gy/15 fx Local control 71% vs 82%; p<0,05 Overall survival 6,5 vs 5,7 months; NS Subset of pts with single metastasis: OS 4,9 vs 6,5 months; p<0,05 6-month KPS improvement and steroid intake favors SRS Andrews DW Lancet 2004

10 Key evidence: Surgery / SRS with or without WBRT EORTC trial (N=359) 1-3 brain metastases <30 mm Disease control outside CNS WHO PS 0-2 Randomizations after surgery or SRS: WBRT vs observation WBRT 30 Gy/10 fr Kocher M JCO 2011

11 Key evidence: Surgery / SRS with or without WBRT EORTC trial (N=359) Kocher M JCO 2011

12 Key evidence: Surgery / SRS with or without WBRT EORTC trial (N=359) Kocher M JCO 2011

13 WBRT: Cognitive function deficit Chang Lancet 2009

14 Surgery and SRS: Summary Should be considered in selected good prognosis patients with 1 3 brain metastases SRS improves survival when added to WBRT in patients with single metastasis WBRT improves local control but not survival when added to surgery or SRS WBRT associated with moderate cognitive disfunction

15 Brain metastases: response rates to chemotherapy Van den Bent Eur J Cancer 2003;39:

16 Brain metastases: response rates to chemotherapy In fit patients, intracranial lesion response rates similar to extracranial response rates in NSCLC chemonaive patients treated on 3rd generation chemotherapy trials with cisplatin, paclitaxel, gemcitabine or vinorelbine Cortes J. i wsp. Oncology 2003;64:28-35 Bernardo G. i wsp. Cancer Invest.2002; 20:

17 Does targeted therapy change the brain mets landscape in NSCLC?

18 Case for discussion 44 year old female with stage IV lung adenocarcinoma who failed 2 lines of chemotherapy (platinum/vinorelbine, docetaxel) and experimental erlotinib + R1507 (anti IGF1R antibody) Molecular testing: EGFR(-), KRAS (-), ALK (+) by FISH Asymptomatic brain metastases found on CT scan (~5 lesions)

19 Case for discussion Should we start with crizotinib or WBRT or both?

20 Case for discussion 6-weeks on treatment with crizotinib

21 Case for discussion 6-weeks on treatment with crizotinib

22 Case for discussion At 4 months, patient experienced symptomatic brain progression with continued systemic disease control She then received WBRT with 30Gy/10fx; crizotinib stopped during RT and then restarted She continued to have intra- and extracranial response for 2 years after WBRT then experienced intrathoracic relapse

23 Pharmacokinetic brain relapse ALK+ NSCLC has propensity for early brain dissemination (~30% of pts participating in PROFILE 07 trial) Crizotinib penetration to CSF <1% Many progressions occur exclusively in the CNS With continued systemic control, serial CNS imaging is warranted while on crizotinib to institute WBRT and SRS early, possibly disrupt BBB and prevent neurologic symptoms Novel ALK inhibitors better CNS penetration

24 Efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with brain metastases Gefitinib exposure in CSF Gefitinib exposure in CSF = 2.4% of plasma (Xu JTO 2011) 6 patients treated concomitantly with WBRT

25 Blood brain barrier (BBB)

26 Efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with brain metastases Jamal-Hanjani M. CCR 2011; 18:938

27 EGFR TKIs for tx of brain metastases in patients w/ EGFR mutated tumors 28 NSCLC patients with NSCLC and brain mets Phase II study with either gefitinib or erlotinib RR = 83%, median PFS = 6.6 months, median OS = 15.9 months Park SJ et al., Lung Cancer 2012

28 Pharmacokinetics of EGFR inhibitors in NSCLC 15 patients w/egfr mutant tumors and brain metastases Mean concentration Gefitinib 3.7ng/mL 1.13% Erlotinib 28.7ng/mL 2.77% CSF penetration Togashi Y et al., Cancer Chemother Pharmacol 2012

29 Progression to EGFR inhibitors in brain metastases or meningitis carcinomatosa Mechanism could be pharmacokinetic In a gefitinib treated patient, consider switch to erlotinib to achieve higher CSF concentrations Several retrospective series demonstrate some efficacy of erlotinib pulse-dosing, e.g. erlotinib 300mg every other day or erlotinib 600mg every 4 days

30 Can I treat brain metastases in NSCLC EGFR mut patient with WBRT and concurrent erlotinib/gefitinib? Most retrospective data indicate no significant toxicity of concurrent tx; some suggest increased efficacy However few case reports with significant toxicity are published Comparative clinical trial is ongoing Before the results of the trial become available, I use WBRT and temporalily stop erlotinib or gefitinib

31 Take-home messages Stratification of BM patients according to prognostic models is important WBRT remains standard of care in most patients Surgery or SBRT should be considered in selected good prognosis patients with 1 3 brain metastases; RT clinical trials are ongoing in this population Targeted therapies completely change this landscape in biologically defined subsets of pts Beware of brain pharmacokinetic issues!

32 Thank you for your attention!