Investigating Angiogenesis Inhibitors and
Other Drugs in Kidney Cancer
by David W. Sharp
Medicine Top Ten
Papers
Rank
Papers
Citations This Period
(Sep-Oct 07)
Rank Last Period (Jul-Aug
07)
1
C.L. Ogden, et al., "Prevalence of
overweight and obesity in the United States,
1999-2004,"JAMA, 295(13): 1549-55, 5
April 2006. [Ctrs. for Disease Control, Atlanta, GA]
*028RG
118
1
2
The DREAM Trial Investigators (H.C. Gerstein, et
al.), "Effect of rosiglitazone on the
frequency of diabetes in patients with impaired
glucose tolerance or impaired fasting glucose: a
randomised controlled trial,"Lancet,
368(9541): 1096-1105, 23 September 2006. [Correspond.
address: Population Health Res. Inst., Hamilton, Ont.,
Canada] *089IC
52
†
3
T. Sjöblom, et al., "The consensus
coding sequences of human
breast and colorectal
cancers,"Science, 314(5797): 268-74,
13 October 2006. [11 U.S. institutions] *093TV
52
†
4
P.J. Rosenfeld, et al., "Ranibizumab for
neovascular age-related macular degeneration,"New Engl. J. Med., 355(14): 1419-31, 5 October
2006. [5 U.S. institutions] *090UA
52
†
5
R.J. Motzer, et al., "Activity of SU11248,
a multitargeted inhibitor of vascular endothelial growth
factor receptor and platelet-derived growth factor
receptor, in patients with metastatic renal cell
carcinoma,"J. Clin. Oncol., 24(1):
16-24, 1 January 2006. [8 U.S. institutions] *998QS
48
†
6
R.H. Duerr, et al., "A genome-wide
association study identifies IL23R as an
inflammatory bowel disease gene,"Science, 314(5804): 1461-3, 1 December 2006. [18
U.S. and Canadian institutions] *110UF
44
†
7
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
44
†
8
The Heart Outcomes Prevention Evaluation (HOPE) 2
Investigators (E. Lonn, et al.),
"Homocysteine lowering with folic acid and B
vitamins in vascular disease,"New Engl. J.
Med., 354(15): 1567-77, 13 April 2006. [Writing Group:
9 institutions worldwide] *031WW
43
†
9
The FIELD Study Investigators (A. Keech, et al.),
"Effects of long-term fenofibrate therapy on
cardiovascular events in 9795 people with type 2 diabetes
mellitus (the FIELD study): Randomised controlled
trial,"Lancet, 366(9500): 1849-61,
Nov-Dec 2005. [Correspond. address: U. Sydney, Australia]
*988ZR
42
†
10
A. Sandler, et al.,
"Paclitaxel-carboplatin alone or with bevacizumab
for non-small-cell lung cancer,"New Engl. J.
Med., 355(24): 2542-50, 14 December 2006. [7 U.S.
institutions] *116BZ
Most cases of kidney cancer are of the type known as renal-cell carcinoma.
This is by no means the most common cancer, perhaps with no more than
40,000 new cases being diagnosed in the United States every year. However,
once surgical management has done all it can, treatment options have been
few and the results of them far from brilliant.
For metastatic renal-cell carcinoma, cytokine therapy with interleukin-2 or
interferon alfa may be tried. Among newer drugs attracting attention are
sunitinib (Sutent, SU11248) and sorafenib (Nevaxar, BAY-43-9006), and both
are attaining citation prominence, the first drug being the subject of two
clinical studies in the Top Ten (#5, #7) while the other one is waiting in
the wings at #15 (B. Escudier, et al., New Engl. J. Med.,
356[2], 125-34, 2007; latest bimonthly count 38).
Dr. Robert J. Motzer and colleagues (#5) summarize the biological rationale
for trying tyrosine kinase inhibitors, and preclinical studies had
suggested that sunitinib might have activity against both new vessel growth
(angiogenesis) and tumor-cell proliferation. Theirs was a phase II
(uncontrolled) clinical study in 63 patients with metastatic cancer in whom
cytokine treatment had not been successful.
Encouragingly, 25 patients had a partial response to sunitinib and 17
others experienced stabilization of their disease. Toxicity, principally
fatigue, was "manageable," though four patients did experience a decline in
cardiac ejection fraction.
Almost exactly a year later in publication terms, Motzer et al.
moved the sunitinib story on significantly. Paper #7 reports a phase III,
randomized controlled trial comparing the new drug with interferon alfa in
750 cases, but this time the patients had not previously been given
systemic therapy.
Progression-free survival was significantly longer in the sunitinib group
than in the patients given interferon (median 11 months vs. 5 months).
Declines in ejection fraction of any severity were recorded in 10 out of
375 patients in the sunitinib group and in 3 of 360 controls, but there
were no clinical consequences of this.
The third paper (#15) is about sorafenib, which is a "multikinase inhibitor
of tumor-cell proliferation and angiogenesis." In this randomized,
placebo-controlled trial in 903 patients whose renal-cell carcinoma was
resistant to standard therapy, the active drug was associated with
increased progression-free survival.
Other drugs being explored in such patients and whose mode of action has a
well-founded molecular basis include bevacizumab (recently shown in a phase
III trial, again by Escudier and colleagues [Lancet, 370(9605):
2103-11, 2007] to significantly improve progression-free survival in
comparison with interferon alfa-2a), axitinib, and temsirolimus.
One can certainly see why Dr. Nicholas J. Vogelzang, in his January, 2006,
editorial linked to #5 (J. Clin. Oncol., 24[1]: 1-3, 2006),
described the treatment options for metastatic renal carcinoma as "an
embarrassment of riches." The field of runners will be trimmed down in time
on the basis of comparative efficacy in head-to-head trials and of other
factors such as cost and toxicity. One current concern with sunitinib is
cardiac toxicity (T.F. Chu, et al., Lancet, 370[9604]:
2011-19, 2007; H. Joensuu, Lancet, 370[9604]: 1978-80), and
patients given this drug may need regular checks on their cardiac function
(e.g., by measurement of left-ventricular ejection
fraction)."
A former deputy editor of The Lancet, Mr. David W. Sharp,
M.A. (Cambridge), is a freelance writer living in Minchinhampton,
U.K.