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28 กรกฏาคม 2552 15:58:06
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Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA1 mutation carrier

New response evaluation criteria in solid tumours:

Revised RECIST guideline (version 1.1)

E.A. Eisenhauera,*, P. Therasseb, J. Bogaertsc, L.H. Schwartzd, D. Sargente, R. Fordf,
J. Danceyg, S. Arbuckh, S. Gwytheri, M. Mooneyg, L. Rubinsteing, L. Shankarg, L. Doddg,
R. Kaplanj, D. Lacombec, J. Verweijk
aNational Cancer Institute of Canada – Clinical Trials Group, 10 Stuart Street, Queen’s University, Kingston, ON, Canada
bGlaxoSmithKline Biologicals, Rixensart, Belgium
cEuropean Organisation for Research and Treatment of Cancer, Data Centre, Brussels, Belgium
dMemorial Sloan Kettering Cancer Center, New York, NY, USA
eMayo Clinic, Rochester, MN, USA
fRadPharm, Princeton, NJ, USA
gDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
hSchering-Plough, Kenilworth, NJ, USA
iEast Surrey Hospital, Redhill, Surrey, UK
jNational Cancer Research Network, Leeds, UK
kErasmus University Medical Center, Rotterdam, The Netherlands
Article history:
Received 17 October 2008
Accepted 29 October 2008
Response criteria Solid tumours Guidelines
Background: Assessment of the change in tumour burden is an important feature of the
clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response)
and disease progression are useful endpoints in clinical trials. Since RECISTwas published
in 2000, many investigators, cooperative groups, industry and government authorities have
adopted these criteria in the assessment of treatment outcomes. However, a number of
questions and issues have arisen which have led to the development of a revised RECIST
guideline (version 1.1). Evidence for changes, summarised in separate papers in this special
issue, has come from assessment of a large data warehouse (>6500 patients), simulation
studies and literature reviews.
Highlights of revised RECIST 1.1: Major changes include: Number of lesions to be assessed: based
on evidence from numerous trial databases merged into a data warehouse for analysis purposes,
the number of lesions required to assess tumour burden for response determination
has been reduced from a maximum of 10 to a maximum of five total (and from five to two
per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes
with a short axis of P15 mm are considered measurable and assessable as target lesions.
The short axis measurement should be included in the sum of lesions in calculation of
tumour response. Nodes that shrink to <10 mm short axis are considered normal. Confirmation
of response is required for trials with response primary endpoint but is no longer
required in randomised studies since the control arm serves as appropriate means of interpretation
of data. Disease progression is clarified in several aspects: in addition to the previous
definition of progression in target disease of 20% increase in sum, a 5 mm absolute
increase is now required as well to guard against over calling PD when the total sum is very
0959-8049/$ - see front matter  2008 Elsevier Ltd. All rights reserved.
* Corresponding author: Tel.: +1 613 533 6430; fax: +1 613 533 2411.
E-mail address: eeisenhauer@ctg.queensu.ca This e-mail address is being protected from spambots. You need JavaScript enabled to view it (E.A. Eisenhauer).
EUROPEAN JOURNAL OF CANCER 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
available at www.sciencedirect.com
journal homepage: www.ejconline.com

Inhibition of Poly(ADP-Ribose) Polymerase in Tumors

from BRCA Mutation Carriers

Peter C. Fong, M.D., David S. Boss, M.Sc., Timothy A. Yap, M.D., Andrew Tutt, M.D., Ph.D., Peijun Wu, Ph.D.,

Marja Mergui-Roelvink, M.D., Peter Mortimer, Ph.D., Helen Swaisland, B.Sc., Alan Lau, Ph.D.,

Mark J. O’Connor, Ph.D., Alan Ashworth, Ph.D., James Carmichael, M.D., Stan B. Kaye, M.D.,

Jan H.M. Schellens, M.D., Ph.D., and Johann S. de Bono, M.D., Ph.D.

This article (10.1056/NEJMoa0900212) was

published on June 24, 2009, at NEJM.org.

N Engl J Med 2009;361:123-34.

Copyright © 2009 Massachusetts Medical Society




The inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) is

a potential synthetic lethal therapeutic strategy for the treatment of cancers with

specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2

mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281),

a novel, potent, orally active PARP inhibitor.


This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic

characteristics of olaparib. Selection was aimed at having a study population

enriched in carriers of a BRCA1 or BRCA2 mutation.


We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation
and 1 had a strong family history of BRCA-associated cancer but declined to undergo

mutational testing. The olaparib dose and schedule were increased from 10 mg daily

for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting

toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood

alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade

4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort,

consisting only of carriers of a
BRCA1 or BRCA2 mutation, to receive olaparib at a

dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal

symptoms. There was no obvious increase in adverse effects seen in the mutation

carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic

studies confirmed PARP inhibition in surrogate samples (of peripheral-

blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue.

Objective antitumor activity was reported only in mutation carriers, all of whom had

ovarian, breast, or prostate cancer and had received multiple treatment regimens.


Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP,

and has antitumor activity in cancer associated with the
BRCA1 or BRCA2 mutation.

(ClinicalTrials.gov number, NCT00516373.)


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