Download Review of guidelines on the treatment of metastatic renal cell

Review of guidelines on the treatment of
metastatic renal cell carcinoma
Denis Soulières, MD, MSc, FRCPC
Hematologist and Medical Oncologist
Centre Hospitalier de l’Université de Montréal
Department of Medicine, Service of Hematology and Medical Oncology
1560 Sherbrooke East, Montreal, Canada, H2L 4M1
[email protected]
Tel: 514-890-8000 ext 25381
Fax: 514-412-7803
No grant or affiliation to declare regarding this paper
Running title: Guidelines in metastatic RCC
Review of guidelines on the treatment of metastatic renal cell carcinoma
INTRODUCTION:
Principles that apply or should apply to the development of practice guidelines vary from one
professional group to the next, based on their interpretation of the literature as well as regional
particularities that relate more to access to therapy that its applicability or true racial
differences. Therefore, a review of guidelines is per se an impossible endeavour as it implies
applying judgement on an ensemble of processes that lead to best proposal based on available
data, information and conditions.
Another impediment to a review of guidelines is the rapidity at which the information is evolving
regarding a particular pathology. A magnitude of data with the potential to modify the practice
of physicians caring for patients suffering from metastatic renal cell carcinoma has emerged
over the last few years, including data on several studies stopped prematurely at interim
analysis based on positive results. The interpretation of data is therefore dependant on the
premises that final results will be concordant with early analysis and on the statistical strength
of the analysis not only of the primary endpoint, but also of secondary endpoints that should
corroborate the primary endpoint. This is based on the Prentice’s principle that states that a
result has a higher probability of being truly positive if other related endpoints are also positive.
(1) An advantage in progression-free survival has more chance of being true if a statistically
significant advantage is also present for other aspects of efficacy like response rate, time to
treatment failure and survival if this data is available.
Remembering this principle, it will therefore be the prerogative of the editorial nature of this
paper to determine that recommendations that are present in more than one guideline have
probably more reason to be ones that have the potential to impact practice. This paper will also
try to comment on the reasons for the selection of treatment options and whether or not
previous recommendations based on older data still apply in view of the treatment options that
have so drastically modified the prognosis and survival of patients with metastatic RCC.
TEXT:
Recognising the role of VHL and its value as a tumour target in RCC has made this disease one of
specific interest and an area where controversy on which agent to use and when to use it. (2)
Going from basically no efficacious therapy to several options also puts a strain on deciders who
have the responsibility to finance these new therapies with the best possible impact on the
whole population of patients with RCC. The guidelines should therefore be as strong as possible
and reflect possibilities that have an impact not just on a selected trial population, but also on a
population scale. For example, the study conducted in British Columbia on all patients treated
for RCC demonstrated that the introduction of sunitinib therapy for RCC resulted in a doubling
of overall survival compared with interferon therapy based on historical resulted. (3) This data
reinforces the validity of guidelines proposing the use of sunitinib for metastatic RCC patients in
first line of therapy.
Internationally recognised guidelines that were evaluated for the purpose of this paper include
those produced by the European Urology Association, the National Comprehensive Cancer
Network and the Canadian Urology Association (Canadian Kidney Cancer Forum). (4-6) The EUA
publication dates from 2007, whereas NCCN guidelines were reviewed in 2009. The published
guidelines of CUA were published in 2008, but a revision is completed and its major elements
will be reported here.
On surgery:
All guidelines refer to data on the positive impact of nephrectomy on survival of patients with
metastatic disease. Although recommended by all guidelines, some only propose it for patients
for which interferon therapy is scheduled or intended. Therefore, even though data pertaining
to this therapy is based on randomised trials, the comparator arm used a systemic therapy that
is not a standard that applies in 2009. (7,8) It is therefore adequate to either restrain its
applicability or question its validity or relevance for all patients. The limited data on patients
who have not undergone a nephrectomy before initiating a systemic targeted therapy does not
seem to indicate that there was a survival disadvantage. The data on the use of nephrectomy, a
procedure with a potential for severe complications, should therefore be put in context and
more fully studied, which is currently being addressed in a study conducted by a French
collaborative group.
On prognostic factors:
Most trials on investigational agents in the last few years have been done using a stratification
based on prognostic factors developed by Motzer established from a population of patients
starting therapy with interferon. (9) The impact of prognostic factors is extremely dependant on
the time of their measurement. Only in post-hoc analysis can we determine if the prognostic
value of these factors still applies. Although the validation of prognostic factors based on data
from recent trials does not seem to support the fact that they retain as much prognostic value,
they have been used as a therapy selection criteria in all guidelines. (10) Moreover, prognostic
factors used for patient selection or stratification varied from one study to another. This renders
treatment selection based on biologic parameters and review of data more difficult, not to say a
simple element of confusion. Although data seems to indicate a variation in survival between
poor risk and other patients, the difference is not as significant as was initially reported by
Motzer on the Memorial Sloan-Kettering experience on interferon patients. In view of this fact,
the Canadian guidelines have recently been modified partly to account for this realisation, at
least for first-line therapy. As stated before, if guidelines are followed adequately, they should
lead to a change in population based statistics, as those reported by Kollmannsberger. (3)
Incoherence on patient definition, as the one created by the addition of information on factors
which relevance, in the era of targeted therapy, makes evaluation of impact on whole
population difficult and possibly impossible since full and complete databases are not kept on all
patients with RCC or other types of cancer. Definition of cancer subgroups should therefore be
based on tumour characteristics that should be sought after if prospective data demonstrates an
impact on efficacy of new therapies (not unlike the development of trastuzumab in HER2
positive breast cancer). This principle is therefore moving away from prognostic factors that
should be independant of treatment and identify predictive factors of response to therapy.
Another option to design and tailor therapy is to use nomograms, but their use in daily practice
is not fully recognized and validation based on population studies like the one performed by
Kollmannsberger has not yet been reported. (11)
On anti-angiogenic therapy:
All guidelines state that sunitinib should be considered standard therapy in the first-line setting
for metastatic RCC. The Canadian guidelines recently modified their statement to include all
comers, without regard for risk factors since all subgroups analysed demonstrated a benefit in
terms of response and progression-free survival. One element that strikes in the analysis of
guidelines and that probably lead to these conclusions is the fact that sunitinib is the only
VEGFR-TKI to be proposed in the first-line setting. Trying to demonstrate differences between
this agent and sorafinib, the revision of the preferred surrogate markers of efficacy (response
rate) leads us to conclude that Prentice’s principle applies well to targeted therapy as well.
Sunitinib demonstrated higher response rates in all studies, and one can only assume that this is
correlated with an advantage in PFS, and ultimately in survival, as evidenced by multiple analysis
of the phase III trial as well as the Kollmannsberger paper. (3)
TKIs are not the only anti-angiogenic therapy that has proven active in metastatic RCC. A
combination of bevacizumab and interferon is also accepted in the guidelines as an option
based on 2 trials that were reported prematurely with an advantage on progression free
survival. However, the primary endpoint of the trials is overall survival, and a significant
advantage has not been reported as of now. It therefore seems rather difficult to propose it as a
standard in the first-line setting without formal evidence on the primary endpoint of the study.
Moreover, important questions remain on the validity of this combination compared to the use
of bevacizumab alone compared to interferon. The paucity of preclinical data leads most
clinicians to believe that this would probably cause more side effects than benefit. In fact, in
AVOREN, the combination was less well tolerated than interferon, whereas VEGFR-TKIs were
generally better tolerated than interferon. Since all guidelines list this treatment as an option, it
should be regarded as such, especially for patients for whom it is expected that therapy with
sunitinib might be a cause of significant grade 3 and 4 side effects.
Nonetheless, anti-angiogenic therapy is now first and foremost in the initial management of
metastatic RCC. The development of several new therapeutic options that are related to this
mechanism of action are still under development, and NCCN guidelines still list, and acceptably
so, the inclusion of patients in clinical trial, especially if they permit comparison with the new
standards of therapy.
It is also worth saying that several groups have published proposed guidelines on the
management of side effects that are so specifically related to VEGFR-TKIs, more specifically
hypothyroidism, fatigue, palmo-plantar erythema and hypertension. (12-13)
On m-TOR inhibitors
VHL mutations happening on both alleles provide an adequate explanation for the development
of a targeted therapy based on a clonal anomaly that leads to an “oncogenic addiction”.
However, other molecules involved in critical pathways of signal transduction seem to be
particularly important in cell proliferation in RCC. mTOR is a molecule that is closely related,
among other things, to pathways related to angiogenesis via the VHL complex. (12) Two
molecules have been the object of trials and analysis in the context of guideline development:
temsirolimus and everolimus. Unfortunately, it is difficult to establish differences between the
two molecules since the trial designs studied very different patient populations in terms of
patient characteristics and line of therapy. All guidelines propose the use of temsirolimus in
first-line for poor risk patients. But the poor risk defined in this population was different than for
the stratification factors used in trials evaluating anti-angiogenic agents. Moreover, as indicated
before, the Canadian guidelines left the stratification for VEGFR-TKIs, but kept temsirolimus as
an option for poor risk patients.
Everolimus is the latest drug to be added to the list of RCC drugs. First-line therapy has not been
the object of a trial, and in fact, most patients treated in further lines of therapy were in 3 rd, 4th
and 5th line at least one VEGFR-TKI. The study was initiated when sunitinib was not accepted as a
first-line standard. A true trial evaluating the efficacy of everolimus or another drug in the
second-line setting after a VEGFR-TKI has not yet been performed. The revised Canadian
guidelines recommend everolimus therapy as the standard after failure of a VEGFR-TKI.
However, this does not specifically imply therapy immediately after failure of this agent. It is
noteworthy that NCCN does not list everolimus specifically, even though a clinical trial is listed
as a consideration for patients with progression on a VEGFR-TKI.
On the periodic review of guidelines:
The discovery that RCC is, in fact, contrarily to previous data, a sensitive disease to targeted
therapy has made it a site of intense research activity that is ongoing. It is expected that new
results will be presented at important oncology conferences in the coming years. Regarding
existing guidelines, the review process is variable from one group to another. It should be
expected that the intensification of research and the availability of data will bring new and more
effective therapies and that guidelines will and should help the medical community differentiate
their value for the community of patients suffering of metastatic RCC.
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