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Renal
Cell Cancer: Background
What
is RCC?
There has been a steady increase in the incidence of renal
cell carcinoma (RCC) - kidney cancer - since the 1970s
that is not accountable by the increased use of diagnostic
imaging procedures and technology. In addition, during
the last two decades, there has been a steady increase
in mortality rates from RCC, and these two trends - rising
incidence and rising mortality - make RCC a major oncological
therapeutic challenge.
As of 2006, RCC accounts for approximately 2% of all cancers
in the United States, with an incidence of 38,890 new
cases/year estimated, according to the latest ACS statistics
(Jemal et al., CA Cancer J Clin (2006): Cancer
Statistics, 2006); also: PDF
Version), and with a 3:2 prevalence of RCC in women
over men, and for men RCC is the third most common genitourinary
cancer (after prostate and bladder cancer). In the US,
Dr Wong-Ho Chow at the Division of Cancer Epidemiology
and Genetics and colleagues at the Division of Cancer
Control and Population Sciences at the NCI have demonstrated
that the age-adjusted incidence of RCC has been rising
for the past 60+ years at a annual rate of approximately
2% - 3% (Chow et al., JAMA (1999):
Rising Incidence of Renal Cell Cancer in the United
States). However, in terms of the EU nations,
although mortality rates from kidney cancer increased
throughout Europe up until the late 1980s or early 1990s,
in the late 1990s, a greater than three-fold difference
in kidney cancer mortality was observed between the countries
with the highest rates, the Czech Republic, the Baltic
Republics and Hungary, and those with the lowest rates,
Romania, Portugal and Greece (Levi et al., Ann Oncol (2004):
Declining
mortality from kidney cancer in Europe).
Although the prognosis for patients with RCC, especially
advanced disease, remains relatively disappointing, and
RCC is the sixth leading cause of cancer deaths in developed
nations, nonetheless the 5-year survival rates for RCC
have been improving significantly, from 52% in 1974-1976,
to 56% in 1983-1985, up to 66% during 1995-2003. As to
mortality, every year, approximately 13,000 people die
from RCC, not only from complications associated with
advanced disease, but also unfortunately due in part to
paucity of effective treatments. The 5-year survival proportion
for patients who present with stage IV disease is less
than 10% (Moltzer et al., New Eng J Med (1996): Renal-Cell
Carcinoma).
RCC is more common in persons of northern European ancestry
than
ancestry compared to African or Asian descent, and is
diagnosed at a median age of 60 years. Although the exact
etiology of sporadic RCC has not been fully
determined, smoking, obesity, and renal dialysis have
all been associated
with increased incidence. When RCC is diagnosed, typically
as much as 30% of patients will present with metastatic
disease at initial diagnosis.
Renal cell carcinomas (RCCs) constitute about 80 - 85%
of all primary renal neoplasms. There are five distinct
types of renal neoplasms: (1) clear cell renal carcinomas,
(2) papillary or chromophilic (15%), (3) chromophobic
(5%), (4) oncocytic (less than 1%) and (5) collecting
duct carcinomas (extremely rare).
RCC, alternatively known as clear-cell cancer or renal
adenocarcinoma, originates from the proximal tubal epithelium,
and is characterized by a distinct clear or granular cell
appearance visible by light microscopy, If detected at
an early stage, RCC can frequently be treated successfully
by radical nephrectomy with nephron-sparing surgery, but
as many as 20% to 30% of patients may develop metastatic
disease following this procedure, primarily due to non-recognized
having characteristic (but non-specific symptoms) such
as fatigue, weight loss, malaise, fever and/or night sweats.
Because most patients with early-stage disease are asymptomatic,
RCC is most often diagnosed at later stages; indeed, about
one-third to one-half of RCC patients present with locally
advanced or stage IV disease. The most common symptoms
at presentation are hematuria, flank pain, or a palpable
mass in the flank or abdomen, but affected individuals
may also experience fatigue and malaise, weight loss,
fever, hypertension,or electrolyte abnormalities.
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New
and Emerging Directions in RCC Treatment
The
Classical Era: Surgery + Cytokine-based Immunotherapy
Surgery
Although nephrectomy originated as an extensive
resection of a tumor-bearing kidney, perirenal fat,
regional lymph nodes, and ipsilateral adrenal gland,
it has evolved to include partial nephrectomy, useful
for patients presenting with smaller tumors, and various
specialized forms of resection. Nephrectomy has now
become standard as cytoreductive surgery prior to systemic
treatment based primarily on the results of the RCTs
conducted in the early 2000s by Flanigan et al. (N Eng
J Med (2001): Nephrectomy
Followed by Interferon Alfa-2b Compared with Interferon
Alfa-2b Alone for Metastatic Renal-Cell Cancer)
which demonstrated that among patient with metastatic
RCC nephrectomy followed by interferon therapy yields
longer survival than interferon monotherapy, and by
Mickisch et al. (Lancer (2001): Radical
nephrectomy plus interferon-alfa-based immunotherapy
compared with interferon alfa alone in metastatic renal-cell
carcinoma: a randomised trial) which refined
these findings in the same RCC populations (metastatic
RCC with good performance status), demonstrating that
radical nephrectomy before interferon-based immunotherapy
substantially delayed TTP (time to progression) and
improved survival.
However, two points must be noted: (1) in both of these
RCTs the survival benefit was limited to, and strongly
dependent on, overall performance score/status, and
(2) The timing of immunotherapy, either as neoadjuvant
(prior to nephrectomy) or adjuvant treatment (following
nephrectomy) in the multimodality approach of synchronous
metastatic RCC remains controversial in the absence
of dispositive findings (Bex et al., Technol Cancer
Res Treat (20030: The
Timing of Immunotherapy and Nephrectomy in Multimodality
Treatment of Metastatic Renal Cell Carcinoma
[pdf]).
BRM (Biological Response Modifiers)
/ Immunotherapy
In contrast to many other cancers, RCC is generally
resistant to both chemotherapy and hormone therapy (Molzer
et al., J Clin Oncol (2000): Effect
of Cytokine Therapy on Survival for Patients With Advanced
Renal Cell Carcinoma) and so until recently
treatment options for RCC has been limited until the
non-specific biological response modifiers were introduced
in the 1980, with immunotherapy using single-agent interleukin-2
(IL-2) and interferon (IFN), yielding a significant
advance in total response rates (complete + partial)
of between 10% to 20%, a modest response level nonetheless
superior to that priorly obtainable via chemotherapy
(RJ Amato, Ann Oncol (2005):
Renal cell carcinoma: review of novel single-agent
therapeutics and combination regimens). Note
that IL-2 (proleukin), a pleotropic cytokine with no
intrinsic antitumor activity of its own but with ability
to activate antitumor cytotoxic T cells and several
other cytokinesis, is currently the only FDA approved
(1992) immunotherapy for the treatment of metastatic
RCC, and while interferon, as interferon alfa-2a (Roferon-A),
is widely used in Europe for the treatment of metastatic
RCC in Europe, it continues to lack FDA approval in
the US. To improve upon these findings and exploit combination
IL-2 plus IFN- trials were later conducted in an effort
to exploit significant synergy as seen in vitro models,
response rates nonetheless rarely exceeded 20% to 30%
(see RJ Amato, cited above).
Another issue in cytokine immunotherapy is the relative
value of high- versus low-dose therapies. To address
this question, David McDermott and coresearchers (McDermott
et al., J Clin Oncol (2005): Randomized
Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous
Interleukin-2 and Interferon in Patients With Metastatic
Renal Cell Carcinoma) conducted a randomized
phase III study to compare the relative value of HD
IL-2 (high-dose IL-2) and low-dose IL-2 and IFN, finding
that HD IL-2 was significantly superior to both lower
doses of IL-2 or IL-2 and IFN in terms of response rates
and response quality, with the response quality, as
reflected by the CR rate, durable CR rate, and response
duration also favoring HD IL-2, although only durable
CR rate was statistically significant. And despite the
fact that HD IL-2 did not have a significant impact
on median progression-free survival (PFS) or median
overall survival (OS) since it was not anticiapated
that there would be any significant differences in these
survival end points, gven that IL-2–based therapy
for metastatic RCC benefits a minority of patients (and
note that patients with any performance status above
1, with their primary tumor in place, or with liver
or bone metastases are less likely to respond to IL-2–based
therapy), nonetheless, as Ramsey and Aitchison (cited
above) observed, although such responses are only seen
in a small number of patients, IL-2 is still the only
treatment that is consistently associated with a durable
and complete response that can be considered "curative"
in any sense.
In addition, HD IL-2 treatment is associated with very
serious and e toxicities that represent significant
management challenges, and for this reason typically
must be administered at a small number of specialized
institutions, (in the US, fewer than 80 such institutions).
One of the most significant IL-2 toxicities is CLS (capillary
leak syndrome), associated with serious cardiovascular
(such as severe hypotension), central nervous system
(semicoma potential), and pulmonary adverse events,
so that to qualify for this demanding therapy patients
need to meet certain criteria - such as, favorable cardiac
stress and pulmonary function tests results, good PS,
low creatinine, and no anemia (see Robin Green, Renal
Cell Carcinoma: Today’s Targeted Therapies Improving
Tomorrow’s Outcomes [Meniscus Newsletter] (2006):
Current and Emerging Treatments for Renal Cell Carcinoma
[pdf]).
However, recent results from the Percy Quattro study
reported at ASCO 2005 (Negrier et al., Journal of Clinical
Oncology, 2005 ASCO Annual Meeting Proceedings (2005):
Do cytokines improve survival in patients with metastatic
renal cell carcinoma (MRCC) of intermediate prognosis?
Results of the prospective randomized PERCY Quattro
trial) has raised some serious questions concerning
the role of IL-2 and IFN in the intermediate prognostic
group which failed to demonstrate any survival benefit
of IL-2 or IFN, the a combination of the two cytokines
over patients not receiving any cytokine therapy, queswtioning
the therapeutic rationale for continuing to deploy cytokine
therapay in in metastatic RCC patients with intermediate
prognosis on other than a case-by-case basis, especially
important given that tt is estimated that only 20% of
patients with metastatic renal cancer are categorized
as good risk and consequently as suitable candidates
for cytokine therapy (Ramsey & Aitchison, Nat Clin
Pract Urol (2006): Treatment
for Renal Cancer: Are We Beyond the Cytokine Era?).
As to interferon/IFN (deployed in about 30% of RCC patients),
it exhibits immunomodulation, direct antiproliferative
action, enhancement of leucocyte-mediated cytotoxicity,
and antiangiogenic activity, and improves median survival
and is usually given not as montherapy but in combination
with IL-2 and/or chemotherapy, with an overall response
rate
of 10% to 15%, including some complete responses (CRs),
although for many patients the common treatment-related
adverse effects of fatigue and flu-like symptoms may
be intolerable. The Cochrane Review meta-analysis (Coppin
et al. Cochrane Database Syst Rev (2006: Immunotherapy
for advanced renal cell cancer) of 4 trials
comparing IFN with control found that patients in the
IFN treatment group had a higher RR (response rate)
as well as improved 1-year survival; and while noting
the need for more effective specific therapy, the reviewers
concluded that for fit patients with metatases at diagnosis
and minimal symptoms, nephrectomy followed by interferon-alfa
gives the best survival strategy for fully validated
therapies.
More recently, in an effort to sustain higher response
with IFN therapy, European investigators have explored
the potential additive or synergistic value of adding
a retinoid to IFN therapy: Nina Aass and coresearchers
in the EORTC 30951 Trial (Aass et al., J Clin Oncol
(2006): Randomized
Phase II/III Trial of Interferon Alfa-2a With and Without
13-cis-Retinoic Acid in Patients With Progressive Metastatic
Renal Cell Carcinoma: The European Organisation for
Research and Treatment of Cancer Genito-Urinary Tract
Cancer Group (EORTC 30951)) found that patients
with progressive metastatic RCC treated with IFN--2a
plus the retinoid 13-cis-retinoic acid (13-CRA) had
significantly longer PFS (progression-free survival)
as well as OS (overall survival) compared with patients
on IFN-Alfa-2a alone, although the result is only marginally
significant in favor of the combination therapy, and
there was a relatively high degree of limiting toxicity
associated with the combination regimen, and given this
the authors soberly note that the small prolongation
in survival must be balanced against an increased frequency
and grade of treatment adverse effects, though not of
serious character. And German researchers Jens Atzpodien
and Martina Reitz (Atzpodien & Reitz, Cancer Biother
Radiopharm (2006): Long-Term
Maintenance Therapy in Interferon-a2a/Interleukin-2-Pretreated
Advanced Renal-Cell Carcinoma Patients) have
subsequently reported their own results in using prolonged
maintenance treatment consisting of intermittent IFN-Alfa-2a
and IL-2, combined with long-term daily peroral 13-cis-retinoic
acid (13-CRA), again finding prolongation of PFS and
OS, with the maintenance therapy being well or moderately
tolerated.
All told, median survival with IFN monotherapy is generally
less than 12 months, in contrast to long-term survival
on IL-2 of almost 20% for 5-year, not 1-year, survival
rates (on IL-2 survival issues, see Sylvie Négrier's
thoughtful editorial, J Clin Oncol (2004): Better
Survival With Interleukin-2-Based Regimens? Possibly
Only in Highly Selected Patients).
The Biological Era:
However, recent research advances have clarified and
deepened our understanding of the molecular biological
mechanisms underlying both RCC and also oncogenesis
- for example, dysfunction of immune regulation, activation
of signal transduction pathways, and tumor angiogenesis
in particular - and also identified several pathways
involved in the pathophysiology of the most common RCC
histologic form, fostering a new era of extensive exploration
of new more finely targeted molecular therapies (see
the thoughtful reflections of Ramaprasad Srinivasan
and W. Marston Linehan at the Urologic Oncology Branch
of the Center for Cancer Research at NCI (J Clin Oncol
(2005): Targeted
for Destruction: The Molecular Basis for Development
of Novel Therapeutic Strategies in Renal Cell Cancer);
and the overviews by Jean-Jacques Patard and colleagues
at the Rennes University Hospital (European Urol (2006):
Understanding the Importance of Smart Drugs in Renal
Cell Carcinoma); Brian Rini at UCSF (Oncologist
(2005): VEGF-Targeted
Therapy in Metastatic Renal Cell Carcinoma);
A Erdem Canda and Ziya Kirkali (Urol J (2006): Current
Management of Renal Cell Carcinoma and Targeted Therapy),
and finally the sober commentary of Nicholas Vogelzang
of the University of Nevada School of Medicine and the
Nevada Cancer Institute (J Clin Oncol (2006): Treatment
Options in Metastatic Renal Carcinoma: An Embarrassment
of Riches)).
Sorafenib
Sorafenib (Nexavar), formerly BAY 43-9006, is
an oral small-molecule TKI tyrosine kinase inhibitor
(TKI) of:
- cRAF
cRaf (also known as Raf1) is one of three members
of the Raf family of serine/threonine specific kinases
(along with aRaf and bRaf) that play a critical role
in regulating cell growth and differentiation, and
couple growth factor receptor stimulation to nuclear
transcription factors via the Ras/mitogen activated
protein kinase (MAPK) pathway. cRaf is involved in
the transduction of mitogenic signals from the cell
membrane to the nucleus, and is part of the Ras dependent
signaling pathway from receptors to the nucleus. The
Raf family of kinases is itself part of the Ras-Raf-MEK-ERK
(ERK) pathway, which has become a logical therapeutic
target of oncotherapeutics because it represents a
common downstream pathway for several key growth factor
tyrosine kinase receptors often mutated or overexpressed
in human cancers, and hence plays a critical role
in many aspects of tumorigenesis.
- VEGF (vascular
endothelial growth factor) receptor (VEGFR)-2, VEGFR-3)
- PDGFR-β;
(platelet-derived growth factor) receptor-β;
receptor
- Flt-3, and
- Kit
Sorafenib has demonstrated
anti-angiogenic activity and the ability to inhibit
the growth of human RCC, melanoma, colon, breast, ovarian,
and NSCLC non-small cell lung cancer, and received FDA
approval in December 2005 for the treatment of patients
with advanced RCC. Two critical sorafenib studies led
to this approval. In the first, a randomized phase II
trial conducted by Mark Ratain and coresearchers (Ratain
et al., J Clin Oncol (2006): Phase
II Placebo-Controlled Randomized Discontinuation Trial
of Sorafenib in Patients With Metastatic Renal Cell
Carcinoma) it was found that sorafenib exhibited
significant disease-stabilizing activity in metastatic
RCC: significantly more patients in the sorafenib group
were progression free compared with the placebo group,
with in addition an improvement in median PFS (progression-free
survival), and good tolerability on chronic daily oral
therapy; note that this trial - like several others
- suggest that the achievement of durable stable disease
(durable-SD) is an increasingly important and recognized
treatment goal of RCC. Finally, Renal
Cancer Watch notes that the discontinuation
design of the raises some methodological issues, and
on this see the commentary by Guru Sonpavde and associates
with US Oncology Research (Sonpavde et al., J Clin Oncol
(2006): Problems
With the Randomized Discontinuation Design),
and Mark Ratain's defense: J Clin Oncol (2006): In
Reply).
The second study was the phase III trial called TARGET
(Treatment Approaches in Renal Cancer Global Evaluation
Trial) conducted by B. Escudier and coresearchers (Escudier
et al., J Clin Oncol, 2005 ASCO Annual Meeting Proceedings
(2005): Randomized
phase III trial of the Raf kinase and VEGFR inhibitor
sorafenib (BAY 43–9006) in patients with advanced
renal cell carcinoma (RCC)) where patients with
unresectable or metastatic RCC who had failed 1 prior
therapy within the previous 8 months and whose ECOG
performance status was 0 or 1 with no brain metastases,
were randomized to sorafenib or placebo. At a planned
interim of median PFS (the secondary end point, with
OS (overall survival being the primary end point) patients
in the sorafenib group achieved a 24-week median PFS
that compared favorably with the 12-week PFS achieved
in the placebo group, and because of the improved PFS,
the trial was modified in April 2005 to permit cross
over from placebo to sorafenib. At the 2006 ASCO annual
meeting, this investigators presented an interim survival
analysis (Eisen et al, J Clin Oncol, 2006 ASCO Annual
Meeting Proceedings (2006): Randomized
phase III trial of sorafenib in advanced renal cell
carcinoma (RCC): Impact of crossover on survival )
6 months after crossover, with a a 19.3-month OS for
the sorafenib arm compared to 15.9-month OS for the
placebo arm, a favorable trend in OS but not yet reaching
statistical significance; the final analysis of OS is
ongoing. From these trials and others, it has been learned
that in terms of quality of response, sunitinib malate
can induce responses at multiple sites, with even patients
with liver metastases and bulky disease responding to
sorafenib therapy, unlike narrower response seen with
other agents restricted to patients with small-volume
tumors and pulmonary involvement.
The evidence to date suggests that sorafenib is well
tolerated, with manageable side effects: hand-foot
skin reaction (26%), diarrhea (30%), alopecia (23%),
fatigue (18%), nausea (14%), and hypertension (8%) (patel
et al., Br J Cancer (2006): Targeted
therapy for metastatic renal cell carcinoma).
Sunitinib
Another small-molecule TKI is sunitinib (Sutent),
inhibiting the tyrosine kinase activity of:
- all VEGF receptors;
- PDGF-α
and PDGF-β, receptors involved
in angiogenesis;
- Kit, RET,
and Flt-3, receptors involved in cellular proliferation.
received
FDA approval in January 2006 for the treatment of GIST
(gastrointestinal stromal tumor), and for advanced RCC,
the latter based on on partial response (PR) rates and
duration of response from two nonrandomized phase II
trials, both conducted by Robert Motzer of MSKCC and
coresearchers. In the first study, a multicenter phase
II trial (Motzer et al., J Clin Oncol (2006): 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),
the antitumor activity of sunitinib in metastatic RCC
as second-line therapy was demonstarted, a setting with
no effective systemic therapy prior to that point; 40%
partial responses and 27%stable disease were seen, and
with generally tolerated dosing and manageable toxicities.
Tthe second trial was an open-label, single-arm, multicenter
clinical trial (Motzer et al., JAMA (2006): Sunitinib
in Patients With Metastatic Renal Cell Carcinoma)
achieved an objective response rate of 34% and a median
PFS (progression-free survival) of 8.3 monthswith the
most common adverse events being fatigue (28%) and diarrhea
(20%), and with neutropenia (42%), elevation of lipase
(28%), and anemia (26%) the most common observed laboratory
abnormalities.
Robert Motzer and coresearchers are conducting a phase
III trial comparing sunitinib with IFN-α
as first-line therapy in patients with metastatic RCC,
and the results of a planned interim analysis were recently
presented at ASCO 2006 (Motzer et al, J Clin Oncol (2006):
Phase
III randomized trial of sunitinib malate (SU11248) versus
interferon-alfa (IFN-) as first-line systemic therapy
for patients with metastatic renal cell carcinoma (mRCC)),
were it was reported that in terms of PFS (the primary
end point), this was significantly longer in the sunitinib
treatment arm (11 months) compared with the IFN-α
arm (5 months), and with 31% partial response in the
sunitinib arm compared to 6% in the IFN-α
arm, and with similar rates of stable disease (sunitinib
48%; IFN-α 49%); OS has not yet been reached.
Bevacizumab
The humanized monoclonal anti-VEGF antibody bevacizumab
(Avastin) binds and neutralizes all biologically active
forms of VEGF and inhibits angiogenesis; although FDA
approved in February 2005 for the treatment of metastatic
CRC (colorectal cancer), some studies have demonstrated
potential efficacy in RCC. James Yang and colleagues
at NCI conducted a randomized, double-blind phase II
trial (Yang et al., N Engl J Med (2003): A
Randomized Trial of Bevacizumab, an Anti–Vascular
Endothelial Growth Factor Antibody, for Metastatic Renal
Cancer) of bevacizumab (3 mg/kg or 10 mg/kg)
vesrus placebo in 116 metastatic RCC patients, finding
a significant prolongation of time to disease progression
in the high-dose bevacizumab group compared with the
placebo group, yeilding at 4 months, a 64% probability
of being progression free for patients who received
the high-dose bevacizumab compared with 39% for the
low-dose group, and 20% for the placebo group.
John Hainsworth of the Sarah Cannon Research Institute
conducted a t trial (Hainswoth et al, J Clin Oncol (2005):
Treatment of Metastatic Renal Cell Carcinoma With
a Combination of Bevacizumab and Erlotinib)
of bevacizumab in combination with the TKI erlotinib
(Traceva) (used in NSCLC and pancreatic cancer), reporting
objective responses of 25% stable disease in 61%of 59
evaluable patients with metastatic RCC, and with median
PFS was 11 months and1-year PFS of 43%; the bevacizumab/erlotinib
combination was well tolerated. And although the efficacy
of bevacizumab/erlotinib treatment appears to be superior
when to results with either agent used alone compared
retrospectively, the phase II design of this trial disallows
a definitive conclusion.
(new) RCC and Diet
/ Nutrition / Lifestyle Factors
Although an early international study (Alicja Wolk et
al, Int J Cancer (1998): International
renal cell cancer study. VII. role of diet)
failed to find protein and fat as risk factors independent
of energy, the latter studies of Handa & Kreiger,
of Hu et al, among many others have found a consistent
adverse association (see our discussion below). However
this same international study did find that fried meats
in particular were associated with increased RCC risk
(also observed for fried and sauteed meats, and for
poultry previously by P Lindblad et al (Cancer Epidemiol
Biomarkers Prev (1997): Diet
and risk of renal cell cancer: a population-based case-control
study)), while vegetables and fruits were protective.
A significant inverse association with RCC was observed
with increasing total consumption of vegetables and
vegetable juices for males and females combined, and
for dark-green vegetables and cruciferous vegetables
for females, and an increased risk was observed (for
males and females combined) with increased consumption
of hamburger, sausage, beef, pork, lamb and processed
meats; as to vitamins and minerals, significant inverse
associations were observed for females taking vitamin
E or calcium supplements, and for males vitamin E or
iron for more than 5 years (Jinfu Hu et al, Cancer Causes
Control (2003): Diet
and vitamin or mineral supplements and risk of renal
cell carcinoma in Canada); yet Jung Lee and
colleagues (Cancer Epidemiol Biomarkers Prev (2006):
Intakes of Fruits, Vegetables, Vitamins A, C, and
E, and Carotenoids and Risk of Renal Cell Cancer)
observed an association of fruits and vegetable consumption
with a decreased risk of renal cell cancer for men,
but not for women.
The Canadian review of Kiren Handa and Nancy Kreiger
found that high-fat and high-protein diets might be
risk factors for renal cell carcinoma. The data also
suggest an increased risk associated with juice intake,
a finding not previously reported, more specifically
an increased risk associated with a high intake of fruit
juices in males, in addition to an increased risk of
fluid intake, per se. The most consistent results show
increased risks associated with the consumption of foods
such as meat, eggs and dairy products and reduced risk
for fruits and vegetables. Studies have shown a higher
risk associated with protein and fat and potential decreased
risks associated with vitamin C and vitamin E, fruits
and cruciferous and orange/green vegetable, although
the recent prospective study of Jung Lee and colleagues
(Cancer Epidemiol Biomarkers Prev (2006):
Intakes of Fruits, Vegetables, Vitamins A, C, and
E, and Carotenoids and Risk of Renal Cell Cancer)
failed to find any association of Vitamin E and RCC
risk, and the association of fruits and vegetable consumption
with decreased RCC risk was observed only in men, but
in for women. The benefit of Vitamin E and to a lesser
extent, Vitamin c, was recently confirmed in the Italian
case-control study of Christina Bosetti and her colleagues
(Int J Cancer (2007): Micronutrients
and the risk of renal cell cancer: A case-control study
from Italy).
In addition there appears to be a positive role of both
sunlight exposure via solar ultraviolet B (UV-B) radiation
and Vitamin D in renal cell cancer risk reduction: WB
Grant (Recent Results Cancer Res (2003): Ecologic
studies of solar UV-B radiation and cancer mortality
rates) assessed the protective role of UV-B
radiation and dietary factors in an multi-country ecologic
study of cancer mortality rates in Europe, finding an
inverse correlation of UV-B radiation with a number
of cancers, including renal cancer, as well as bladder,
breast, endometrial, ovarian, and prostate, with the
strogest correlastions between UV-B and multiple myeloma,
and NHL (on the inverse association of UV-B and Vitamin
D, and RCC risk, see also WB Grant: Anticancer Res (2006):
The likely role of vitamin D from solar ultraviolet-B
irradiance in increasing cancer survival) using
latitude as an index of solar UVB irradiance, and finding
that five-year survival rates south of 50 degrees N
were 20%-50% higher than those near 55 degrees latitude),
and the adverse association between obesity and enhanced
RCC risk may itself be at least partly mediated by Vitamin
D and UV-B, as obese individuals may also have lower
serum levels of vitamin D (MA Moyad, Semin Urol Oncol
(2001): Obesity,
interrelated mechanisms, and exposures and kidney cancer);
note of course that obesity and excess energy intake
are known etiologic risk factors for both renal cell
and non–renal cell cancer (Sai Yi Pan et al, Obesity,
Cancer Epidemiol Biomarkers Res (2006): High
Energy Intake, Lack of Physical Activity, and the Risk
of Kidney Cancer).
As to lifestyle factors, obesity is an established risk
factor of renal cell carcinoma, (K Handa & N Kreiger,
Public Health Nutr (2002): Diet
patterns and the risk of renal cell carcinoma),
and both obesity and cigarette smoking are the most
consistently established causal risk factors, accounting
for more than 20% and 30% of renal cell cancers, respectively
as found by Joseph McLaughlin and colleagues, International
Epidemiology Institute, Semin Oncol (2006): Epidemiologic
Aspects of Renal Cell Carcinoma), who furthermore
concluded that hypertension, rather than antihypertensive
drugs, appears to influence renal cell cancer development
and hence heighten risk, while they did not find convincing
the link between analgesics and renal cell cancer risk.
The adverse association of increased meat and protein
consumption with RCC is consonant with the fact that
a chronic high-protein intake is associated with a range
of functional and morphological changes: increased urinary
nitrogen excretion, increased vasopressin plasma levels,
increased creatinine clearance, increased GFR (glomerular
filtration rate), and increased renal hypertrophy and
hemodynamics, as well as eicosanoid production in renal
tubules, and the fact that patients with moderate renal
insufficiency benefit from a low-protein diet by slowing
the deterioration of renal functions (Cornelia Metges
and Christian Barth with the German Institute of Human
Nutrition, J Nutr (2000): Metabolic
Consequences of a High Dietary-Protein Intake in Adulthood:
Assessment of the Available Evidence).
In addition, there appears to be a molecular/genetic
connection mediating the dietary/nutritional associations
with RCC, through the von Hipple-Lindau (VHL) gene,
the tumor suppressor gene predisposing to both sporadic
renal cell carcinoma (RCC) and von Hippel-Lindau disease:
it appears that consumption of vegetables and citrus
fruit decreases the frequency of VHL mutations among
smokers, with citrus fruit decreases this VHL mutations
among all patients, while selenium protects against
multiple VHL mutations, and these effects are via the
mechansims that vegetables, citrus fruits, and selenium
protect the the renal VHL gene from mutational insults
that may be endogenous or common in a population (as
found by the Karolinska Institute study of Kari Hemminki
and colleagues, Carcinogenesis (2002); Molecular
epidemiology of VHL gene mutations in renal cell carcinoma
patients: relation to dietary and other factors)
Note that against these relatively consistent associations
cited above, in the first prospective study - called
the Swedish Mammography Cohort (SMC) and also
from the Karolinska Institute (J Nutr (2005): Major
Dietary Patterns and Risk of Renal Cell Carcinoma in
a Prospective Cohort of Swedish Women) - to
examine dietary patterns in relation to RCC risk, by
identifying a "Drinker" dietary pattern, defined
by high consumption of wine, hard liquor, beer, and
snacks, a "Healthy" pattern of high consumption
of fruits and vegetables, and a "Western"
pattern of high consumption of sweets, processed meat
and meats in general, high-fat dairy products and margarine/butter,
fried potato, refined grains, and soft drinks, this
study quite surprisingly failed to find an adverse association
of the Western diet pattern with increased RCC risk,
or of the Healthy diet pattern with decreased RCC risk,
against the balance of the other evidence, yet even
more surprisingly found an inverse - that is protective
- association between Drinker pattern and the risk of
RCC. Weighed against the strong evidence of the other
studies contradicting these conclusions, Renal Cancer
Watch does not find the results of this SMC prospective
cohort compelling, possibly due as the authors themselves
speculate to the low power imposed by the relatively
small number of RCC cases, reflected in wide confidence
intervals (CI): although the study appears quite large,
with a cohort of 46,572 women, there were only 93 incident
cases of RCC identified, being just .002% of the total
sudied population and this suggests that the study was
statistically underpowered to draw any convincing conclusions
concerning associations in the small RCC subgroup. On
one parameter of the Drinker pattern, however, there
is some external confirmation, namely of an inverse
(protective) association between alcohol intake and
risk of renal cell cancer (Jung lee et al, Cancer Epidemiol
Biomarkers Prev (2006): Total
Fluid Intake and Use of Individual Beverages and Risk
of Renal Cell Cancer in Two Large Cohorts; Sondat
Mahabir et al, Epidemiol Biomarkers Prev (2005): Prospective
Study of Alcohol Drinking and Renal Cell Cancer Risk
in a Cohort of Finnish Male Smokers).
Further data from the same above-cited Swedish Mammography
Cohort (SMC), recently reported by Alicja Wolk and
her colleagues at the National Institute of Environmental
Medicine, Karolinska Institute (Wolk et al., JAMA (2006):
Long-term Fatty Fish Consumption and Renal Cell Carcinoma
Incidence in Women), has shown that a diet rich
in fatty fish (such as salmon, herring, and mackerel)
is associated with lower RCC risk in women: the study
found that women who ate fatty fish at least once weekly
were 44% less likely to develop renal cancer over a
15 year follow-up than women who ate no fatty fish,
but there was no association with reduced RCC risk for
other types of fish or seafood (including lean fish
types like cod and tuna), and the risk reduction was
even more dramatic at 74% for consistent and long term
consumption (10 years or more) of fatty fish. even after
adjustment for an extensive set of potentially confounding
factors such as age, education, body mass index, other
aspects of diet, smoking, alcohol intake, hypertension,
and diabetes.
Emerging
Therapies
In our next coverage (December 2006), we will critically
review a number of emerging oncotherapies for RCC:
- Capecitabine (Xelod
- Axitinib (AG-013736)
- Temsirolimus
(CCI-779)
- Everolimus RAD001
- Rencarex (cG250)
- Pazopanib
(GW 786034)
- Lapatinib (Tykerb)
- Volociximab
(M200)
- Bortezomib (Velcade)
(PS-341)
- ABX-EGF
- Cetuximab (Erbitux)
- PTK/ZK
- BAY 59-8862
- Epothilone EP0906
- HSPPC-96 Vaccine
among several others.
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