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ESMO-ESTRO Joint Symposium:
Innovative approaches to the treatment
of brain metastases
120IN HOW NEW INSIGHTS IN THE BIOLOGY OF BRAIN
METASTASES MAY LEAD TO THE IDENTIFICATION OF NEW
EFFECTIVE MEDICAL THERAPIES
B. Gril
Women’s Cancer Section, Laboratory of Molecular Pharmacology, National
Cancer Institute, National Institutes of Health, Bethesda, MD, UNITED STATES
OF AMERICA
Brain metastases are a devastating event in the progression of cancer and are
expected to increase in incidence as chemotherapies improve and lead to better
systemic disease control. The brain offers unique environment as it is protected by
the blood–brain barrier, which strongly limits the penetration of drugs. Using a
quantitative model system for experimental breast cancer brain metastasis, vascular
permeability was heterogeneous in brain metastases, with only 10% of lesions
exhibiting sufficient permeability to mount an apoptotic response to taxol, suggesting
that inadequate chemotherapeutic drug distribution accounts for a lack of efficacy.
We have tested 18 compounds, both traditional chemotherapeutics and small
molecule inhibitors, for efficacy in an experimental brain metastasis model.
Prevention of the development of brain metastases was observed using vorinostat,
lapatinib, pazopanib, TPI-287, gemcitabine and irinotecan. No drug effectively
shrunk already established metastases. Our work strongly suggests that preventive
approaches for the development of brain metastases constitutes a feasible clinical
goal. We advocate the use of “secondary brain metastasis prevention” trials, in which
patients with limited, treated brain metastases (without whole brain radiotherapy) are
randomized to a preventive or placebo, with time to the development of a new
metastasis as an endpoint. Close collaboration between researchers and medical
oncologists will be needed to address these challenges brought on by this growing
and incurable disease.
Disclosure: B. Gril: Dr. Patricia Steeg received research founding from Glaxo Smith
Kline (for lapatinib, pazopanib and PLK inhibitor) and from Millennium
Pharmaceuticals (for TAK-285).
121IN PUTTING DRUGS AT WORK AGAINST BRAIN METASTASES
IN HER2 POSITIVE BC: RESULTS OF THE LANDSCAPE TRIAL
T. Bachelot 1 , G. Romieu 2 , C. Cropet 3 , M. Campone 4 , V. Diéras 5 , M. Jimenez 6 ,
F. Dalenc 7 , E. Le Rhun 8 , C. Labbe-Devilliers 4
1 Département De Cancérologie Médicale, Centre Léon Bérard, Lyon, FRANCE,
2 Oncologie Médicale, Centre Val d’Aurelle, Montpellier, FRANCE, 3 Unité De
Biostatistique Et D’evaluation Des Thérapeutiques, Centre Léon Bérard, Lyon,
FRANCE, 4 Medical Oncology, Centre René Gauducheau (ICO) Institut de
Cancerologie de l’Ouest, St Herblain, FRANCE, 5 Department of Medical
Oncology, Clinical Trial Unit, Institut Curie, Paris, FRANCE, 6 R&d, Unicancer,
Paris, FRANCE, 7 Oncologie Médicale, Centre Claudius Regaud, Toulouse,
FRANCE, 8 Département De Sénologie, Centre Oscar LAMBRET, Lille, FRANCE
Background: Brain metastases (BM) occur in 30 to 50% of metastatic breast cancers
(MBC) overexpressing HER2. In case of diffuse BM, current treatment is primarily
based on whole brain radiotherapy (WBRT). Few systemic options are available.
Lapatinib (L) has shown some activity in association with capecitabine (C) after
previous WBRT. The LANDSCAPE study assessed the efficacy of the association
before any local treatment.
Methods: Eligible pts had HER2+ MBC with BM not previously treated with WBRT,
C or L. They received lapatinib 1,250 mg once daily and oral capecitabine 2,000 mg/
m 2 from day 1 to day 14, every 21 days. The primary endpoint was the rate of central
nervous system objective responses (CNS-OR) defined as a ≥50% volumetric
reduction of CNS lesions in the absence of all the following: increasing steroid use,
progressive neurologic symptoms, or progressive extra-CNS disease. Secondary
endpoints included time to progression (TTP), time to WBRT, and toxicity.
Findings: From April 2009 to August 2010, forty-five patients were included in the
study. 44 patients were evaluable for efficacy, with a median follow-up of 21.2
months (range 2.2-27.6).The CNS-OR rate was 67.4% (95% CI: 51.5%-80.9%).
Thirty-seven patients (86%) exhibited a reduction in tumor volume. Median time to
progression was 5.5 months (95% CI: 4.3-6). At the time of analysis, 81.8% of
patients had received brain radiotherapy, median time to radiotherapy was 8.3
months (95% CI: 5.4-9.1). Most adverse events (AE) were grade 1-2 as already
reported for this association, 22 patients (49%) experienced grade 3 or 4 treatment
related toxicity and 14 patients presented at least one SAE; treatment was
discontinued due to toxicity in 4 pts
Interpretation: The association of L and C is effective in the treatment of BM of
HER2 positive BC. Our data suggest that this regimen might be used right away at
diagnosis of BM. This approach might change the management of selected patients
with BM, allowing a delayed WBRT. This strategy deserves further evaluation to
confirm the clinical benefits for patients in terms of survival, cognitive functions and
quality of life. We are currently planning such a randomized clinical trial.
Disclosure: T. Bachelot: GSK: Board member Travel accommodation Reaserch grant,
M. Campone: GSK: Board Member, V. Diéras: GSK: Board Member. All other
authors have declared no conflicts of interest.
122IN DOES IMRT, IMAT, TOMOTHERAPY REDUCE THE
NEUROTOXICITY OF WHOLE BRAIN RADIOTHERAPY?
No abstract submitted at time of going to press.
Annals of Oncology 23 (Supplement 9): ix62, 2012
doi:10.1093/annonc/mds486
123IN THE BIOLOGICAL RATIONALE AND POTENTIAL ROLE OF
RADIATION DOSE ESCALATION IN PATIENTS WITH BRAIN
METASTASES
F.J. Lagerwaard
Radiation Oncology, Vrije University Medical Centre (VUMC), Amsterdam,
NETHERLANDS
The majority of patients with BM from solid tumors have a prognosis of only a few
months based on extracranial tumor activity and performance status. The standard of
care for these patients consists of palliative treatment with steroids, and, if
appropriate, a short course of whole brain radiotherapy (WBRT). Several prognostic
classification systems such as the RPA classification [Gaspar 1997] or the DS-GPA
[Sperduto 2008] enable identifying a subset of patients that may have long-term
survival, provided that the BM are treated aggressively.
Although neurosurgery is the traditional treatment for single BM at an accessible
location, radiosurgery (RS) has been established as a non-invasive alternative. RS
involves high-precision delivery of a single fraction of approximately 20 Gy directed
to the lesion, resulting in local control rates of 60-90%, dependent on the size and
aspect (poorer control for necrotic lesions). The survival benefit of RS has only been
confirmed for a single BM in a randomized study [Andrews 2004], but improved
functional autonomy was observed in all groups with 1-3 BM. The question whether
WBRT should be added to RS has been a long-standing unresolved issue with
proponents highlighting the better intracranial control, and opponents pointing out
the neurocognitive toxicity of WBRT and available salvage options. As the risk of
developing new BM following RS alone is not only dependent on extracranial tumor
activity (reseeding) but also on the number of initially treated BM (misdiagnosis of
occult BM), a more differentiated approach may be better suited.
A well selected patient group with multiple BM in good performance status and
absent progressive extracranial disease may be candidates for recently developed
advanced radiation planning and delivery. Techniques such as volumetric
intensity-modulated arc therapy (VMAT, RapidArc) or Tomotherapy have enabled
fast and accurate delivery of fractionated stereotactic integrated boosts to multiple BM
in combination with WBRT. The integrated approach of this technique allows steep
dose gradients outside the BM, thereby minimizing toxicity. Early experiences with
this technique have reported relatively high intracranial control rates.
Disclosure: F.J. Lagerwaard: The Department of Radiation Oncology has research
agreements with Varian medical systems and BrainLAB AG. The author has received
honoraria for presentations from Varian medical systems and BrainLAB AG
ix62 | Abstracts Volume 23 | Supplement 9 | September 2012