Patients who received CN have also been reported to
have better IMDC prognostic profiles for OS; patients
with <4 IMDC prognostic factors were found likely to
benefit from CN.17 A number have found significantly
longer OS associated with previous CN.18-22 Despite these
results, a countervailing trend has emerged in the literature
with regard to the probability that CN will be performed
in the targeted therapy era. Psutka et al filled in
some gaps in the literature by analyzing trends in national
practice patterns in their study regarding the uptake
of targeted therapies and their impact on CN rates at
a time when these associations were poorly described.
One of the areas sparsely covered concerns the use of different
targeted therapies in conjunction with CN among
younger, pre-Medicare-aged patients. This is the group
that could benefit the most from multimodal treatment
.17
Characterizing trends observed between 2004 to 2010,
when the annual rate of targeted therapy utilization increased
markedly from 10% to 98.2%, Psutka et al found
a considerable decline in the utilization of CN. Among
the key findings:
56 Kidney Cancer Journal
• Lower rates of CN were observed in women.
• Increasing age was inversely related to receipt of CN,
even among the cohort of younger patients.
Intuitively, the authors suggest that physicians perceive
targeted therapy as less morbid than CN and thus
are less likely to recommend surgery. Despite retrospective
data on the relative safety of performing CN after
neoadjuvant targeted therapy, more study is needed to
generate compelling data in this regard for the targeted
therapy era. Nevertheless, there already are data from the
clinical trials that led to the approval of the targeted
agents.
The benefit of these therapies was demonstrated in patients
who, overwhelmingly, had undergone prior CN.7
Subsequently, and much further into the experience with
targeted therapies, observational data from two large European
studies suggest that CN is independently associated
with improved survival in mRCC patients undergoing
treatment with targeted therapy—and this was after
an adjustment for prognostic factors.(12,23) Delineating
strategies to include the use of established drugs and po-
Drilling Down into the CARMENA Trial:
Let’s Reassess Its Methodology and
Preserve the ‘Window of Opportunity’
for Cytoreductive Nephrectomy
An analysis by Michael L. Blute, Sr., MD
The development of targeted, non-surgical cancer therapies
has led some physicians to question cytoreductive nephrectomy—
surgery to remove the primary tumor—as the standard
of care for metastatic renal cell carcinoma patients. Since
the advent of targeted cancer therapies in the mid-2000s,
there has been a 50% reduction in the number of cytoreductive
nephrectomies. A review of the NCCDB showed that currently
only three out of ten patients with metastatic kidney
cancer undergo cytoreductive nephrectomy.
Improved systemic effectiveness and markedly increased
tolerability compared to cytokine therapy has resulted in targeted
therapy as front line therapy; however, it clouds the role
of cytoreductive nephrectomy in patients with metastasis.
The standard of care has shifted away from cytoreductive
nephrectomy in the absence of level 1 evidence for its cancer
survival benefit in the targeted therapy era. Abandoning cytoreductive
nephrectomy as a standard of care should be
viewed with concern.
Even with the advent of new agents, studies continue to
suggest that a combination of surgery and targeted therapy
produces the best outcome for patients. Two preliminary reports
in 20111,2 suggested a benefit from cytoreductive
nephrectomy before the initiation of targeted therapy. The
first report showed that median survival was 21.6 months for
patients undergoing cytoreductive nephrectomy and targeted
therapy (sunitinib or sorafenib), vs. 13.9 months for patients
undergoing targeted therapy alone. However, the differences
were not statistically significant due to small sample
size. The second report, with larger sample size, showed that
median survival was 19.8 months for the group undergoing
cytoreductive nephrectomy combined with targeted therapy
and 9.4 months for patients treated with targeted therapy
(sunitinib, sorafenib, or bevacizumab) alone.
Although targeted therapies are effective (Figure 2) and
usually well-tolerated by patients, they are not a cure. Another
concern is that many tumors eventually develop resistance
to targeted therapies. Theoretically, surgically removing the
primary tumor reduces the tumor burden, diminishes the primary
tumor’s suppression of the immune system and can
delay disease progression by removing growth promoters
and angiogenic factors. If you treat with targeted therapy
alone and the disease progresses, you may put patients out of
the window of opportunity where the surgery has a great impact.
The major concern is to identify patients who will not
benefit with cytoreductive nephrectomy as up to 17-20% of
patients with metastatic disease will rapidly progress. Improved
understanding of risk factors, surgical indication and
overall health of patients will improve patient selection. Ultimately,
molecular signals may help personalize options for
these patients.
Sunitinib Alone or After Nephrectomy
in Metastatic Renal-Cell Carcinoma?
The results of the 450-patient CARMENA Trial were reported
by Méjean et al.3 This trial demonstrates that sunitinib alone
was not inferior to the addition of surgery in patients who
present with stage IV disease. This was an intention to treat
analysis wherein not all patients received the assigned treat