Short Communication
Cytoreductive Nephrectomy Would Not Be Required In Intermediate and Poor Risk Patients with Metastatic Renal Cell Carcinoma Cancer
Ilya Tsimafeyeu*
Department of Cancer, Kidney Cancer Research Bureau, Russia
*Corresponding author: Ilya Tsimafeyeu, Department of Cancer, Kidney Cancer Research Bureau, Russia
Published: 18 Jul, 2018
Cite this article as: Tsimafeyeu I. Cytoreductive
Nephrectomy Would Not Be Required
In Intermediate and Poor Risk Patients
with Metastatic Renal Cell Carcinoma
Cancer. Clin Oncol. 2018; 3: 1502.
Short Communication
To date, cytoreductive nephrectomy before systemic therapy is generally recommended in patients with a potentially surgically resectable primary Renal Cell Carcinoma (RCC) and multiple metastases. Targeted therapy with tyrosine kinase inhibitors is widely used in the first-line treatment of metastatic renal cell carcinoma. The objective of CARMENA study was to determine whether cytoreductive surgery before the initiation of the targeted therapy in patients with metastatic Renal Cell Carcinoma (mRCC) is required.
20-Year-Old Standard
During the past 20 years it was believed that primary tumor resection in patients without a history of nephrectomy significantly improves the results of subsequent systemic therapy. This mainstay of therapy was adopted in the cytokine's era after the publication of the results of two studies that confirmed the need of cytoreductive nephrectomy before interferon treatment [1,2]. Therefore, inclusion criteria of the most studies of targeted agents traditionally contained cytoreductive nephrectomy or history of nephrectomy. Large meta-analyses and retrospective studies that included thousands of patients have unanimously found that primary tumor resection before targeted treatment is essential. Doubts expressed by certain groups and in a few studies [3- 5], in particular those concerning the inexpediency of nephrectomy in poor risk patients, were ignored, and the recommendations, such as those by NCCN [6], remained unchanged. And now the CARMENA study is performed [7] that have set the things straight.
The CARMENA Study
The intermediate and poor risk patients, according to the MSKCC criteria, were randomized
into a cytoreductive nephrectomy group with further sunitinib treatment (N=226) or a sunitinib
alone group without a primary tumor resection. The study had a noninferiority design, thus its
objective was to prove a similar efficacy of both approaches. The hazard ratio of the risk of death in
the groups was not to exceed 1.2, and the conclusion of similar efficacy could be made only in this
case.
The median values for primary tumor size and total tumor mass, including metastases, were
8.8/8.6 cm and 14/14.4 cm in nephrectomy+sunitinib / sunitinib alone groups, respectively. The
most common sites of metastases were lungs (>70%), lymph nodes (35-39%), and bones (36-37%).
In 6.7% of the patients randomized in the combined treatment group, cytoreductive treatment
could not be performed; 17.7% of the patients could not receive sunitinib. In the second group,
4.9% of the patients did not receive sunitinib and nephrectomy was performed in 17%. In case of
disease progression in both groups, the further treatment was performed in half of the patients and
it was similar (everolimus or axitinib).
With a median follow-up time of 50.9 months, the hazard ratio of the risks of death in the
groups was 0.89, thus the HR did not exceed the predetermined value of 1.2, signifying the equal life
span of patients with or without cytoreductive nephrectomy. The median overall survival was even
better in patients receiving sunitinib alone, 18.4 month versus 13.9 months in nephrectomy with
further sunitinib treatment group. The trend was observed in both the intermediate risk group (23.4
months versus 19 months, HR = 0.92) and the poor risk group (13.3 months versus 10.2 months,
HR = 0.86).
The median progression-free survival was 8.3 months in the sunitinib alone group and 7.2
months in the nephrectomy group (HR = 0.82). Objective response
rate was nearly similar - 29.1% and 27.4%, respectively. Disease
control (the sum of complete responses, partial responses and stable
disease) for 12 weeks and longer was significantly better in the
group without surgical treatment - 47.9% versus 36.6% (P = 0.02).
Moreover, the patients, in whom the primary tumor was not resected,
have received sunitinib for a longer period (8.5 months) as compared
to post-nephrectomy patients (6.7 months, P = 0.04). The incidence
of grade 3-4 adverse events was higher in the sunitinib alone group,
in which it was 42.7%; 32.8% of patients had grade 3-4 toxicity in
nephrectomy plus sunitinib group (P = 0.04).
How would the Study Results Influence the Routine Practice?
Of course, the results of the CARMENA study may be considered
positive: the primary endpoint of no differences in survival was
achieved. Thus, cytoreductive nephrectomy before sunitinib
initiation would not necessarily be beneficial in intermediate or poor
risk mRCC patients. The study shows that therapy with sunitinib in
mRCC patients should be started as early as possible, as a delay may
lead to a lower disease control and make the duration of sunitinib
treatment shorter. In the nearest future we may expect changes in
the practical guidelines. Intensive discussion of the study behind
the scenes showed that some urological oncologists would not be
ready to immediately abandon the tactics accepted earlier and would
continue to perform nephrectomy before systemic treatment. They
could be right in some circumstances. For example, in patients with
macrohematuria, pain, uncontrolled hypertension and paraneoplastic
syndrome nephrectomy will remain meaningful. Nephrectomy
would be palliative in these cases. It is unclear whether in favorable
risk patient's surgical treatment is required. Dr. Daniel George of
Duke University, who commented on the study at 2018 ASCO
Annual Meeting [8], has proposed that CARMENA results may be
extrapolated at the total patient population. However, if evidencebased
medicine principles are to be followed strictly, the effect of not
performing cytoreduction in the favorable risk group was not proved.
What is to be done with patients with non-clear cell carcinoma in
whom first-line sunitinib is also the drug of choice for intermediate
risk? Several month ago the results of another large retrospective
IMDC analysis were presented at GU ASCO Meeting [9], which
showed that cytoreductive nephrectomy in metastatic papillary renal
cancer increases overall survival by a factor of 2 from 8.6 to 16.3
months (HR=0.62, P<0.0001) with a restriction of worse results in
the poor risk group.
Of interest is the question of whether nephrectomy is needed
before treatment with other agents: temsirolimus (first-line treatment
standard in poor risk group with clear-cell and non-clear-cell mRCC
[10]), combination of nivolumab and ipilimumab (recently approved
in the US as a first-line treatment in intermediate and poor risk patients
[11]), cabozantinib (first-line treatment option in intermediate and
poor risk patients based on the results of CABOSUN study [12]). In
general, how would the study results influence the choice of the firstline
treatment? Would sunitinib, which demonstrated better results in
poor risk patients, be prescribed more frequently than temsirolimus
[13]? If the patient presents with a non-resected primary tumor and
intermediate/poor risk, what will the physician choose: immediate
sunitinib treatment or one-month interval for the patient to perform
a cytoreductive surgery and checkpoint inhibitors treatment after one
month? Should a different approach be considered when the primary
tumor in patient remains after the first-line sunitinib treatment:
should one consider cytoreductive nephrectomy before the secondline
treatment with nivolumab, axinitinib or lenvatinib combined
with everolimus? All these medications were studied mainly in
patients after a nephrectomy [14-16].
We have suddenly encountered a change of the treatment
standard of mRCC and many questions have arisen. However, after
the CARMENA study results were presented, there is no doubt that
cytoreductive nephrectomy is not required in intermediate/poor risk
patients mRCC. Cytoreductive nephrecromy does not increase the
overall survival or progression-free survival or response to further
targeted therapy and, moreover, is associated with possible surgical
complications and additional costs. Nevertheless, trial results are
not relevant to the patients with a poor performance status, lung
metastasis only, and minimal volumes of metastatic disease, because
population of these patients was not representative in CARMENA
study.
References
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