Optimal Management of Isolated HER2+ve Brain Metastases

Transcription

1 Optimal Management of Isolated HER2+ve Brain Metastases Eliot Sims November 2013

2 Background Her2+ve patients 15% of all breast cancer Even with adjuvant trastuzumab 10-15% relapse Trastuzumab does not cross intact BBB High incidence of brain metastases Patients have a better prognosis

3 Management of Patients with Her2+ve Brain metastases Patients should be closely followed up Management depends on number & size of mets Important to control both systemic & brain disease Management of patients must be multidisciplinary Case studies

4 Presentation of Patients with Her2+ve Brain metastases Presentation at diagnosis with brain metastases +/- systemic disease No evidence of systemic disease and develop CNS disease (only) in follow up On treatment for systemic metastases and develop brain metastases with systemic disease either controlled or progressing

5 Classification of patient Number of metastases Size of metastases Location within brain Control of extracranial disease

6 Understand Prognosis

7 Priestman TJ et al. Final results of the RCR trial comparing two different radiotherapy schedules in the treatment of cerebral metastases. Clin Oncol 1996,8: patients were eligible for analysis: Median survival was 77 days with two fractions (95% CI 68-89) and 84 days for the longer schedule (95% CI ). overall responses were seen in 39% of those given two fractions and 44% of patients receiving ten fractions.

8 RPA RTOG RPA scores (recursive partitioning analysis) Class Definition Median Survival controlled primary RPA 1 age<65 no extracranial mets 7.1 months RPA 2 neither RPA 1 or RPA months RPA 3 KPS< months RED 1997;37: RED 2008;70:

9 Proportion surviving Overall survival by independent assessment Median OS, mos No. events Hazard ratio 95% CI Log-rank P value 1.0 lap + Xeloda (n=70) Kadcyla (n=67) P< % % 64.7% % 0.2 No. at risk lap+ Xeloda Kadcyla 0 Time (months)

10 Breast GPA graded prognostic assessment Basal ER - Her 2 - Luminal A ER + Her 2- Her2 ER - Her2 + Luminal B ER + Her2 + Sperduto Red Journal (5)

11 Multiple Brain Metastases

12 Isolated brain metastases Post whole brain radiotherapy Good response Poor response Observe closely Consider xeloda Monitor need for Radiosurgery

13 The blood brain barrier EGF showed a lower incidence of 1st progression at CNS sites in the lap+cap arm 2 Exploratory results from EAP. lap+cap demonstrated an overall response rate of 18% in the CNS 3. In EGF105084, 241 patients were given lapatinib only. The CNS response rate was 6% (16/241). Addition of capecitabine to lapatinib in 49 patients with CNS disease progression on lapatinib alone. CNS responses occurred in 20% Geyer CE et al. NEJM 2006;355: Cameron D, et al. Breast Cancer Res Treat 2008; 112: Boccardo et al.. JCO 2008; 26: 64s (Abstr 1094). 4.Lin NU, et al..j Clin Oncol (Meeting Abstracts) 2007; 25: 35s (Abstr 1012).

14 Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: RCT Hopkins Verbal Learning Test used to measure decline in learning and memory The primary endpoint was cognitive decline in learning and memory. Pts randomized to SRS+WBRT had twice the risk of cognitive decline compared to SRS pts (52% versus 24%). 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone Trial stopped by data monitoring committee because of excess memory decline Chang EL. Lancet Oncol 2009;10(11):

15 WBRT - Side effects and concerns Neurological QOL /SE not just due to WBRT Systemic therapy e.g. chemo Previous surgery Drugs e.g. Steroids Anticonvulsants Opioids Systemic disease Review of effects of WBRT 1 Neurocognitive decline maximal at 4 months Insufficiently assessed in long term survivors Partially resolves over time Generally not severe Dependent on brain metastases control 1. Neurocognitive function impairment after WBRT for brain mets:, Radiation Oncology 2012, 7:77

16 Oligometastases

17 Alternative local treatment for 1-3 mets Stereotactic Radiotherapy Gammaknife Cyberknife Linac based NCB draft guidance all platforms are acceptable (need centre to be competent at delivery of these techniques)

18 NEED MDT SRS/SBRT Boost after WBRT RTOG 9508 (Lancet 2004;363: ) SRS instead of WBRT (Aoyama JAMA 2006;295: ) Most now feel SRS and surgery are equal Surgery better for some & SRS for others Attraction: avoid WBRT side effects

19 NHSCB/D5/1 guidance on SRS/SRBT MDT; local, neuro, stereotactic PS KPS>70 Diagnosis of cancer established and absent or controllable primary disease No pressure symptoms (or surgery) Pre treatment scans vol <20cc (<3cm)** Life expectancy from extracranial disease >6months Treat new lesions - >3months and above Retreat lesions - >6 months and above

20 EORTC JCO (2) Phase 3 to define role of adj WBRT after local therapy (surgery or RS) Hypothesis: WBRT can increase duration of functional independence Stable systemic CA 1-3 brain mets <3cm WHO PS 0-2 Randomize WBRT vs Observation 1 o survival with independence measured by time to WHO PS >2 2 o intracranial relapse, PFS, OS, late toxicity and QOL Breast cancer 11% of the 359 pts entered (?HER2)

21 QOL Results Not dedicated neurocog function but use QOL (EORTC QLQ-C30 and QLQ BN20) Overall, pts better QOL in observation arm Stat significant for; global health at 9 months Physical functioning at 8 wks Cognitive function at 12 months Fatigue at 8 wks Conclusion WBRT has negative impact therefore observation with close MRI FU better approach JCO (1) 65-72

22 WBRT Observation PFS (Months) Neurol Death (%) Initial lesion 2yr RR after surgery (%) Initial lesion 2yr RR after radiosurgery (%) New site 2yr RR after surgery (%) New site 2yr RR after radiosurgery (%) Time to PS>2 (months) Death Intracranial progression (%) Median OS (months) % randomised to observation avoided WBRT completely Salvage therapy more frequent in the observation arm

23 Neurocognitive Sparing Strategies Use memantine to prevent radiation damage Hippocampal shielding techniques for WBRT Irradiate surgical tumour beds with radiosurgery Use low dose per fraction 40Gy in 20 fractions?

24 CASES

25 Case presentation 1 LR at diagnosis. CA Lt Brst. Lt WLE +ANC June 2005 T1(18) N0 G3 ER+ HER2+ Nov10: Liver lung Ophthalmic and Bone mets. Feb 12 : Brain mets-widespread. Given WBRT Apr 12: 4cm mediastinal mass. Pamidronate xeloda lapatinib.

26 Case presentation 1 Aug 12: Scanning PR mediastinum and brain. Oct 12: Chemo break due to side effects Feb 13: Progressive liver mets. Stable brain mets. TDM-1 trial Oct 13: CR liver and excellent PR brain.

27 13/2/12 diagnosis 14/4/12 post WBRT 14/8/12 4/12 X+L 1/10/12 Chemo break 18/2/13 Start TDM-1

28 Feb 2013 Oct 2013

29 Case presentation 2 KS at diagnosis CA Rt Brst. Masty +ANC Nov 2010 T2 N3 G3 ER+ HER2+ Apr 12: Headaches oligomets. No visceral mets. Excision Rt cerebellar met. WBRT 30Gy/10fractions-PR Options gamma knife or alternative systemic therapy. Xel + lap given to shrink mets. Sept 12 PR. Nov 12: increased Lt frontal & parietal lesions. Gamma knife

30

31 4/4/12 23/5/12 28/8/12 21/11/12 4/2/13 diagnosis Post WBRT 3/12 X+L 6/12 X+L Post ɣ knife

32 Case presentation 2 April 13 progression left frontal lobe metastasis & new right cerebellar lesion Excision left frontal metastasis May 2013 Gamma knife cerebellar lesion June 2013 MRI Sept 2013 no progression. No visceral mets.

33 4/2/13 Post ɣ knife 23/4/13 progression 12/9/13 post excision & ɣ knife

34 Summary Concern of systemic control vs. other solid tumours Prognosis of Her2+ve brain mets Management of brain mets requires MDT approach Surgery SRS WBRT & Chemotherapy all have a role

35 Optimal Management of Isolated HER2+ve Brain Metastases Eliot Sims November 2013