In Two Different Cancers,
Success with Drugs New and Old
by David W. Sharp
Medicine
Top Ten Papers
Rank
Papers
Cites
Mar-Apr 08
Rank
Jan-Feb 08
1
S.E. Nissen, K. Wolski,
"Effect of rosiglitazone on the
risk of myocardial infarction and
death from cardiovascular causes,"
New Engl. J. Med.,
356(24): 2457-71, 14 June 2007.
[Cleveland Clinic, OH]
*178DR
78
2
2
R. Sladek, et al.,
"A genome-wide association study
identifies novel risk loci for type
2 diabetes," Nature,
445(7130): 881-5, 22 February 2007.
[14 institutions worldwide]
*138CR
52
†
3
B. Escudier, et al.,
"Sorafenib in advanced clear-cell
renal-cell carcinoma," New
Engl. J. Med., 356(2): 125-34,
11 January 2007. [15 institutions
worldwide] *124NE
59
4
4
R.J. Motzer, et al.,
"Sunitinib versus interferon alfa
in metastatic renal-cell
carcinoma," New Engl. J.
Med., 356(2): 115-24, 11
January 2007. [10 institutions
worldwide] *124NE
56
5
5
L.J. Scott, et al.,
"A genome-wide association study of
type 2 diabetes in Finns detects
multiple susceptibility variants,"
Science, 316(5829):
1341-5, 1 June 2007. [12 U.S. and
Finland institutions] *173PS
50
†
6
G.J. Moran, et al.,
"Methicillin-resistant S.
Aureus infections among
patients in the emergency
department," New Engl. J.
Med., 355(7): 666-74, 17
August 2006. [U. Calif., Los
Angeles; Ctrs. Disease Control
& Prevent., Atlanta, GA]
*074AN
48
8
7
E. Zeggini, et al.,
"Replication of genome-wide
association signals in UK samples
reveals risk loci for type 2
diabetes," Science,
316(5829): 1336-41, 1 June 2007.
[10 U.K. institutions]
*173PS
45
†
8
M. Talpaz, et al.,
"Dasatinib in imatinib-resistant
Philadelphia chromosome-positive
leukemias," New Engl. J.
Med., 354(24): 2531-41, 15
June 2006. [M.D. Anderson Cancer
Ctr., Houston, TX; U. Calif., Los
Angeles; Bristol-Myers Squibb,
Wallingford, CT; Howard Hughes Med.
Inst., Chevy Chase, MD]
*052KU
43
†
9
D. Cunningham, et
al., "Perioperative
chemotherapy versus surgery alone
for resectable gastroesophageal
cancer," New Engl. J.
Med., 355(1): 11-20, 6 July
2006. [9 U.K. and Netherlands
institutions] *060DT
39
†
10
C.E. Geyer, et al.,
"Lapatinib plus capecitabine for
HER-2 positive advanced breast
cancer," New Engl. J.
Med., 355(26): 2733-43, 28
December 2006. [15 institutions
worldwide] *120UA
No fewer than five papers in the current Top Ten relate to
malignant disease, so let us focus for the moment on just two of the
newcomers. Papers #8 and #9 are very different, and not just because of
the different diagnoses.
The treatment options for patients with chronic myeloid leukemia (CML)
have been revolutionized by the arrival of the drug imatinib. This
illness is caused by a chromosomal abnormality that results in an
abnormally active form of the enzyme tyrosine kinase, and imatinib is
an inhibitor specifically aimed at this target. As with any drug,
imatinib is not always tolerated. Also, despite the impressive clinical
improvements achieved by patients taking this drug, a few leukemia
cells stay behind and are prone to further mutation in the relevant
gene (known as BCR-ABL) so that relapses are possible. In a
commentary on paper #8, Dr. Brian J. Druker (New Engl. J.
Med., 354[24]: 2594-6, 2006; see also his interview in Science
Watch, March/April 2003) wonders why pharmaceutical companies
would want to plow research-and-development funding into what might
ordinarily be thought of as a small market, for CML is "a disease that
affects fewer than 5000 patients per year in the United States." One
reason, he argues, is that drugs that arrive via genomic or molecular
medicine (i.e., drugs engineered to go for specific targets identified
via detailed basic research at a subcellular level) can be tested on
patients most likely to benefit, so that drug development times might
be shortened. Imatinib and the related agent dasatinib that is the
focus of #8 (and also nilotinib, the subject of a companion paper to #8
[see H. Kantarjian, et al., New Engl. J. Med., 354
(24): 2542-51, 2006; 31 cites this period]) are early successful
examples of the new approach to pharmaceutical research that has been
nicely described for the more general reader by, for example, Dr. Allen
D. Roses (Lancet, 355[9212]: 1358-61, 2000).
As reported in #8, the patients with CML (a small number had a specific
type of acute leukemia) were resistant to or intolerant of imatinib. A
complete hematologic response was achieved in all but 3 of the 40
patients who were in chronic-phase CML, and at a median follow-up of 12
months this response had been maintained in 95%. Major responses were
seen in the 31 of the other 44 leukemia patients. This phase I trial
included studies of BCR-ABL mutations. One mutation (T3151)
remains a problem because this genotype does not respond to either
dasatinib or nilotinib. Newer agents in the pipeline may resolve this
difficulty in time.
If #8 helps with treatment choices in CML, #9 certainly does so for
gastric cancer, a much more common disease. In an accompanying
editorial, Dr. John S. Macdonald (New Engl. J. Med., 355
[1]:76-77, 2006) sees this "well designed and well executed" phase III
trial as one providing "solid evidence that perioperative therapy with
a regimen of ECF [epirubicin, cisplatin, and fluorouracil] improves the
outcome for patients with respectable gastric cancer identified before
gastrectomy." Imatinib, dasatinib, and nilotinib are relatively new
drugs. The ECF combination is not, having been devised two decades ago,
long before genomic medicine took off. And one of the problems that
clinicians and their patients face with stomach cancer is an old one,
too. Surgical techniques pioneered in Japan have not been successfully
translated into western medicine. This trial, an international one but
supported by the U.K.’s Medical Research Council, looked at the
effects of giving ECF before and after surgery (perioperative). The
results are impressive. For example, the 5-year survival rate was 36%
in the group given perioperative ECF compared with 23% in the
surgery-only group. In this trial the first patient was randomized in
July, 1994, and both the paper and the attendant editorial note that
newer drugs are now available (e.g., capecitabine and oxaliplatin). For
both chronic myeloid leukemia and gastric cancer there is more to be
done.
A former deputy editor of The Lancet, Mr. David W.
Sharp, M.A. (Cambridge), is a freelance writer living in
Minchinhampton, Gloucestershire, U.K.
Keywords: chronic myeloid leukemia, CML, imatinib, imatinib-resistant,
dasatinib, Brian J. Druker, gastric cancer, ECF, epirubicin, cisplatin,
fluorouracil, stomach cancer..