Review Article
Sunitinib in Special Situations in their Daily Practice
Molina Díaz A1*, Afonso Afonso FJ2, Anido Herranz U3, Lázaro Quintela M4, Vázquez Estévez S5, Santomé Couto L6, Fernández Calvo O7, Asensio Sampedro U8 and Antón Aparicio LM1*
1Complejo Hospitalario Universitary de A Coruña, Spain
2Complejo Hospitalario Universitary de Ferrol, Spain
3Complejo Hospitalario Universitary de Santiago, Santiago de Compostela, Spain
4Complejo Hospitalario Universitary de Vigo, Spain
5Hospital Universitaio Lucus Augusti, Lugo, Spain
6Hospital POVISA, Spain
7Complejo Hospitalario Universitary de Orense, Spain
8Departamento Médico de Pfizer España
*Corresponding author: Antón Aparicio LM, Medical Oncology
Department, La Coruña University
Hospital (CHUAC), Servicio Galego de
Saúde (SERGAS), As Xubias, 84 PC
15006, La Coruña, Spain
Aurea Molina Díaz, Medical Oncology
Unit, Complexo Hospitalario
Universitario de A Coruña, C/As
Xubias sn 15006 A Coruña, Spain
Published: 07 Sep, 2016
Cite this article as: Molina Díaz A, Afonso Afonso FJ,
Anido Herranz U, Lázaro Quintela M,
Vázquez Estévez S, Santomé Couto L,
et al. Sunitinib in Special Situations in
their Daily Practice. Clin Oncol. 2016;
1: 1073.
Abstract
In the last decade, we have witnessed a change in the therapeutic management of patients with advanced kidney cancer. Systemic treatment of advanced Renal Cell Cancer (RCC) has been revolutionized by targeted therapy with drugs that block angiogenesis unfortunately; these studies are not always the reality of the practice of medical oncology at the inquiry reflected everyday and see how many subgroups of patients are not represented appropriately. Many patients with RCC do not meet inclusion criteria. For instance, more than 40% of patients with metastatic RCC are in special situations, i.e. elderly patients, bone metastases, hepatic impairment, type 1 and 2 diabetes, renal insufficiency and end-stage renal disease , haemodialysis , brain metastases, and unresectable surgery. These patients are poorly represented in trials. Little is known about the activity of targeted therapies, such of sunitinib, in these subsets of patients. It could be a benefit of sunitinib treatment for these patients, with good tolerance, by personalizing treatment in each situation. In this article, we review the use of sunitinib in these real practice patients and its specials situations.
Introduction
Systemic treatment of advanced RCC has been revolutionized by targeted therapy with drugs
that block angiogenesis. Vascular endothelial growth factor receptors and their ligands play
important roles in tumour growth and angiogenesis.
Sunitinib, an oral multitargeted tyrosine kinase inhibitor with an antiangiogenic and anti
-tumor properties, inhibits VEGFR, PDGFR, FLT3, KIT and RET was approved for the treatment of
advanced renal cell carcinoma since 2006.
A commonly asked question is whether patients with metastatic RCC (mRCC) in clinical trials
are representative of the general population for this disease. Many patients with mRCC do not meet
inclusion criteria, particularly those with a poorer prognosis. For instance, more than 40% of patients
with mRCC are in special situations, i.e. elderly patients, bone metastases, hepatic impairment, type
1 and 2 diabetes, renal insufficiency and end-stage renal disease , haemodialysis , brain metastases,
and unresectable surgery. These patients can have an extremely short life expectancy, and are poorly
represented in trials and they are often excluded from clinical TKIs therapy. This little is known
about the activity of targeted therapies, such of sunitinib, in these subsets of patients.
There have shown the efficacy of sunitinib in a broad mRCC population, particularly in
subgroups who might be predicted to tolerate therapy less well than patients in well-defined,
selected populations in the clinical phase II and III trials. Furthermore, there have shown that the
safety profile of sunitinib is very similar for these poor-prognosis groups to that reported in welldefined
patients populations [1-191].
Elderly Patients
Generally, elderly patients are no well represented in clinical trials, but in the case of sunitinib
phase III trial, 250 patients of 750, were 65 years old or older; and the benefit achieved was similar
to those younger [1].
At the expanded access program trial were included 1418 (32% of
the total) patients over 65 years old. In this subgroup, a response rate
of 17% was achieved (it should be noted that in this study the response
evaluation was not mandatory, which may explain the low percentage
of responses), progression-free survival (PFS) of 11.3 months (95%
CI 10.7-12.3) and an overall survival (OS) of 18.2 months (95% CI
16.6-19.8), which were similar to those of the overall study population
(PFS 10.9 months, OS 18.4 months) [2].
Despite the usual limitations, retrospective study in unselected
patients treated with sunitinib, indicate that patients ≥70 years of age
considered fit for the standards regimen by their medical oncologist
had a poorer safety and efficacy profile compared with younger
patients such as those enrolled in clinical trials [3,4]. However,
patients who were given an adapted regimen because of their delicacy
health experienced a better tolerance leading to a similar rate of
early discontinuation because of therapy-related adverse events [3].
The response rates, Os and PFS did not differ significantly between
the standard regimen (sunitinib 50 mg/day for 4 weeks on/2weeks
off) and the adapted regimen (sunitinib 37.5 mg/day for 4 weeks
on/2weeks off) groups [3,4].
Other smaller studies have also shown similar efficacy between
patients younger and older than 70 years. In a recent study published
by Hutson et al. [5] data from 1059 patients enrolled in 6 clinical trials
were analyzed, and the data of PFS and OS were compared using logrank
test in the population less than 70 years (n=857 ) vs. 70 years or
older (n=202). In the overall population trend it was found to better
PFS in the group of older patients (10.9 vs. 9 months; HR 0.85, 95%
CI 0.70-1.02, p=0.0830), data that are similar to a study with sorafenib
[6], raising the possibility that elderly patients with RCC may be more
responsive to anti-angiogenic therapy. In patients who were treated
with sunitinib in first line (n=783, 74%) PFS was comparable between
the 2 subgroups of patients, 9.9 vs. 11 months, respectively (HR 0.89;
95% CI 0.73-1.09; p=0.2629) and OS 23.6 vs. 25.6 (HR 0.93, 95%
CI 0.74-1.18, p=0.3350), and the same happened in the context of
cytokines after treatment.
A recent RCC tumor biopsy study revealed age-related differences
in tumor vasculature, in which clear cell RCC tumors from patients
aged ≥65 years had significantly higher micro vascular density than
those from patients aged <65 years, and markers of angiogenic
activity also differed [7].
Khambati et al. [8] published retrospective data from over 1300
patients treated with anti-VEGF therapies mRCC in the International
Database Consortium, finding a 10.4% of patients 75 years or older
(n = 144), of which 98 had received sunitinib as first-line. It did not
show significant differences in OS in both groups. Furthermore, when
adjusted by known poor prognostic factors [9], the hazard ratio for
age 75 years and older was not found to be associated with poorer OS
or shorter treatment duration.
In the other hand, data of Surveillance, Epidemiology, and End
Results (SEER) suggest that survival in patients >75 years is inferior
to the younger and do not have a better survival in the era of targeted
therapies (2005-2009) regarding the age of cytokines (1992-2004)
[10]. But, in this study comorbidity or the type of treatment used is
not contemplated, which could influence the results.
With respect to toxicity in this patient group, Hutson et al. [5]
found that some side effects were less frequent in younger patients,
including fatigue (60 vs. 69%), cough (20 vs. 29%), edema (17 vs.
27%), anemia (18 vs. 25%), decreased appetite (13 vs. 29%) and
thrombocytopenia (16 vs. 25%) [5]. Younger patients were more
likely to have a highest grade adverse effects of grade 1 or 2, and
older patients more likely to have a highest grade adverse effects
of grade 3, possibly due to more comorbidities in this population
[11,12]. Recently Jang et al. [13] published the results of an analysis of
cardiovascular toxicity after antiangiogenic therapy in patients older
than 65 years with renal cell carcinoma at the SEER database trial; 670
patients who received sunitinib or sorafenib were identified and they
found a risk for stroke with a hazard ratio (HR) of 2.28 for sunitinib
(1-5.22) and 5.30 for sorafenib (1.8-15.6).
There are data suggesting that older adults may be more prone
to discontinue therapy as a consequence of toxicity as opposed to
disease progression [14].
In the retrospective study of De Giorgi et al. [3] data of 185
patients were analyzed founding that there was a greater need for
dose reduction or schema’s changing in the group of patients of >70
years, but this did not affect PFS (11 months) or OS (25.5 months).
The efficacy profile of sunitinib appears comparable in older and
younger patients with advanced RCC, with some limited differences
in the safety profiles, that require lower doses more often without a
reduce in effectiveness.
Brain Metastases
The management of brain metastases from mRCC has not been
defined and must be do it on individual basis. Patient selection, and
the type of treatment chosen, has been shown to greatly influence
outcome in patients, when undergoing single fraction-radiosurgery
or multiple fractions-fractionated stereotactic radiosurgery (SRS) of
brain metastases.
In 1997, Gaspar et al. [15] reviewed patient characteristics and
treatment variables of three Radiation Oncology Treatment Group
Trials. A total of 1200 patients, were evaluable, and three prognostic
groups were identified (Table 1), using the recursive partitioning
analysis (RPA). Considering these factors, the usual therapeutic
approach of brain metastases is local treatment, surgery or SRS with
or without whole brain irradiation (WBRT).
Surgical management of brain metastases from RCC has been
investigated in three retrospective studies with a median survival
ranging from 14.5 to 23 months (16-18).
SRS has emerged as an alternative option, combining the potential
for definitive local control with a favorable adverse effect profile and
could be repeated in case of progression [19]. OS patients undergoing
monotherapy with SRS stratified by RPA class has been: 18-24, 8.5-
9.2, and 5.3-7.5 months for classes 1,2 and 3 respectively, with a local
control rate of 94% [20-22].
RCC has traditionally been considered a radioresistant tumor.
Because of the modest response of RCC BM to WBRT alone and the
low benefit in survival it is usually not an option for these patients
[23,24].
Studies in animals have shown that brain penetration of sunitinib
may reach 31%, a significantly higher penetration than that achieved
with other TKI, which ranges from 1 to 10% [25]. However, Dudek
et al. [26] have shown that transportation of sorafenib and sunitinib
across the intact blood-brain barrier was restricted, although the
incidence of brain metastases per unit time is decreased in patients
on TKI era in comparison to the cytokine era.
Patients with BM are usually excluded from all phase III
randomized clinical trials, and clinical data on the effectiveness of
TKIs against RCC BM are limited [27]. The efficacy of sunitinib for
the treatment of BM, same of other factors of poor prognosis, remain
unknown until results from the open-label, Expanded Access Program
(EAP) were published by Gore et al. [2]. In this EAP, of 321 patients
with BM included, 213 were evaluable for tumour response. No data
was given regarding prior Central nervous system (CNS) irradiation.
Patients received a median of 3 cycles of treatment compared to 6
cycles in the overall population. Rates of dose modification and
discontinuation of therapy were also similar. The safety profile of
sunitinib in the BM subgroup was similar to the overall population,
although the incidence of treatment-related AEs was lower; this
may be due to a shorter drug exposure. The most common AEs
were diarrhea (34%), fatigue (32%), nausea (29%), and mucosal
inflamation (27%). The most common grade 3/4 AEs were fatigue
and asthenia (both 7%), thrombocytopenia (6%), neutropenia (5%),
anemia (4%), and hand-foot syndrome (4%), and only one patient
developed a cerebral hemorrhage. The efficacy analysis of sunitinib
in this subgroup of patients found that 111 patients (52%) reported
stable disease (SD) for 3 months, 1 patient had a complete response
(CR), and 25 patients (12%) had a partial response (PR). Median PFS
and OS in patients with BM was 5.6 months (95% CI: 5.2-6.1), and 9.2
months (95% CI: 7.8-10.9), respectively, whereas median PFS and OS
for the overall population was 10.9 months (95% CI: 10.3-11.2) and
18.4 months (95% CI: 17.4-19.2) respectively (Table 2).
Several case reports [28-31] and retrospective series [32-34] of
RCC with BM have been published reporting the efficacy of sunitinib
in this setting and include cases with durable CR. Of these, highlight
the study published by Verma et al. [34]. They compared the outcome
in 41 patients from the pre-TKI era with 40 patients who received
TKI; their results suggest that TKIs are associated with a trend of
improvement in OS, but no significant improvement in local control
(LC) of BM.
The results from a phase II trial of sunitinib in patients with
RCC and untreated BM have been recently published [35]. The
primary end point was objective response rate in BM after 2 cycles of
treatment. In terms of efficacy, the outcome was not encouraging and
stabilization disease was the best response achieved, it was seen in 5
patients (31%). Median time to progression was 2.3 months (95% CI:
1.2-5.4); and median OS was 6.3 months (95% CI: 2.1-7.9). Sunitinib
appears to have an acceptable toxicity profile in patients with
untreated BM from RCC. The authors suggest that sunitinib might be
less present in brain than previously thought; a poor penetration or
an increased drug metabolism because of the effect of inducers, such
as glucocorticoids, might be part of the explanation.
Optimal treatment for brain metastasis remains a significant
unmet therapeutic need. Data for the use of targeted therapies in
patients with BM is limited because of the exclusion of these patients
from large trials, due to the perceiving risk of intracranial bleed and
the desire of including only patients with a better life expectancy.
However, clinical experience suggest that sunitinib may be a good
treatment option for patients with BM from RCC and its safety profile
is comparable to that of the overall population of patients with RCC.
Table 1
Table 1
Prognostic classes and associated survival in patients undergoing local
treatment for brain metastases.
Table 2
Bone Metastases
Approximately 1/3 of patients with mRCC have bone metastases
[36], the skeleton is a common metastatic site, after the lung, with
estimates of frequency ranging from 24% to 51% [37-39] , and
these patients are at risk of skeletal-related events, including pain,
pathologic fractures, spinal cord compression, surgery to bone, and
occasionally hypercalcemia [40].
In a recent analysis the presence of baseline bone metastases
was 28% [41], which is consistent with rates previously described
[42,43]. The rate of skeletal-related events in patients with bone
metastases was 6.4%, which is lower than previously reported rates.
In the cytokine era, when therapies for mRCC were limited, rates of
skeletal-related events in patients with bone metastases were >74%
[44]. The skeletal-related events rate in patients with bone metastases
secondary to mRCC in the targeted era is largely unknown.
Bone metastases are often associated with disseminated disease,
most frequently affecting the axial skeleton with osteolytic lesions
where bone resorption dominates over new bone formation [45].
In screened records of more than 1800 patients who died from
RCC, 22% had bone metastases. They showed that the majority of
patients with bone metastases at the time of RCC diagnosis were
classified as poor risk according to MSKCC criteria, while most of
good and intermediate risk patients developed bone metastases after
respectively, 24 and 5 months. Almost 70% of RCC patients with bone
metastases experience at least one skeletal-related event [46]. The
probability to develop bone metastases in RCC patients parallels with
increased survival related to the introduction of biological therapies.
As mentioned before, several studies suggest that the presence
of bone metastases is associated with poor prognosis even worse
than the prognosis of patients with liver metastases [47,48]. Bone
metastases are usually related to a more aggressive subtype of disease
as suggested by the higher percentage of patients with metastases
or Fuhrman grade 4 at the initial diagnosis, the shorter median
time between nephrectomy and diagnosis of metastatic disease
and the greater number of metastatic sites at the diagnosis [49].
However, long survival in patients with bone metastases from RCC
is not a rare event. This may be partially explained by data on tumor
biological heterogeneity [50], although other factors may affect the
natural history of bone metastases in RCC population. Some authors
suggest that bone metastases may have also a predictive significance,
particularly with anti- VEGF-targeted therapy [51-53].
The presence of bone metastases was associated with shorter OS
(13.2 vs. 20.2 mo) and shorter PFS (5.1 vs. 6.7 mo) when compared
with patients without bone metastases [41] and was an independent
factor for worse OS in patients treated with targeted therapy; a similar,
but less pronounced, trend was observed for PFS [54].
The number of bone metastases was associated neither with
the number of skeletal-related events nor with OS. No significant
differences in terms of OS were found when comparing patients
presenting with visceral metastases as first metastatic sites with those
with bone metastases as first metastatic site.
Outcomes of patients with mRCC have improved dramatically
since 2005, when agents targeting the vascular endothelial growth
factor and mammalian target of rapamycin pathways were introduced
[47].
Bone metastases from renal cell carcinoma are difficult to manage.
They tend to be large, highly destructive, and hyper vascular tumors.
They tend to be more resistant to systemic therapies than other
metastases. In a performed a retrospective review of bone metastases
of renal cell carcinoma to the extremities and pelvis; in patients
who had all undergone surgery [55], local control is an important
issue for patients with the potential for a long period of survival.
Wide resection of bone metastases was an independent predictor of
survival in patients with renal cell carcinoma [56]. Several authors
reported that spinal metastasis was defined as a significant risk factor
in patient survival [57,58] and one reason for the poorer prognosis
was the difficulty of wide resection of the vertebral lesions [59].
Although the management of patients with bone metastases
has been markedly improved by the introduction of bone-directed
targeted therapies, their prognosis is still dismal, with a mean survival
of 12 months [60,61]. The lower rate of skeletal-related events
documented in this era could be explained by the improved efficacy
of targeted agents. There are demonstrated that sunitinib prevented
the growth of renal cell carcinoma cells in a bone metastatic mouse
model and caused significant declines in bone turnover markers in
patients treated with sunitinib [62].
In the era of targeted therapy an overall comparison between two
TKI (including both first- and second-line treatment), sunitinib was
associated with a longer mean time to progression of pre-existing
metastatic bone lesions, which was close to reaching significance.
With respect to new metastatic bone lesions (including both first- and
second-line treatment), sunitinib was found to significantly prolong
mean time to occurrence.
In patients receiving first-line treatment, new metastatic lesions
occurred in similar number of patients treated with sunitinib and,
although not statistically significant, sunitinib appeared to prolong
the mean time to occurrence of new lesions. Similar results were
observed in patients with preexisting lesions. Although statistically
not significant, both sunitinib and sorafenib prolonged mean time to
progression of pre-existing bone metastases. Similarly, combining a
targeted agent such as sunitinib with radiation therapy may result in
radio sensitisation or increase sensitivity to the inhibitory effects of
the targeted agent [63-65].
In the pivotal Phase III study of sunitinib versus interferon -
alpha (IFN - α), 30 % of patients in each arm had bone metastases
[1]. In the baseline OS analysis, a greater benefit of sunitinib on IFN
- α was shown, regardless of the location of metastases (bone, lung
and liver) and the number of metastatic sites (1 vs. ≥2). Additionally,
the presence of bone metastases is a prognostic factor with sunitinib
OS (HR=1.462; 95% CI: 1077-1968; p=0.015 HR <1 risk reduction in
favor of the absence of bone metastases.) and INF - α (HR=1.632 95%
CI: 1198-2225; p=0.002) [66].
In a retrospective analysis of prognostic factors in mRCC, data
from 1059 patients treated with sunitinib in first (74%) and second
line (26%) at six clinical trials were analyzed. 29% of patients had
bone metastases. The presence of bone metastases was associated,
in multivariate analysis, with worse OS (16.1 vs. 27.8 months; HR
1.535, 95% CI: 1250-1886; p <0.0001), and in a subset of 215 patients
(long-responders sunitinib with median OS of at least 30 months),
the presence of bone metastases was independent prognostic factor
associated with a lower overall survival (42.7 vs. 54.5 months; HR
2.337, 95% CI: 1275-4285; p = 0.0061). Additionally, in a retrospective
study in which 223 patients treated with sunitinib in 4 centers are
analyzed, the presence of bone metastases was associated again with
a worse PFS (median 8.2 vs. 19.1 months, p <0.0001) and worse OS
(median 19.5 vs. 38.5 months; p <0.0001) compared with the absence
of these [47].
Bone metastases are a frequent problem in the patient with renal
cancer and several studies, point to make it a poor prognostic factor.
Treatment with sunitinib was found to reduce the incidence of new
metastatic bone lesions and significantly to prolong the mean time to
occurrence of new lesions.
Hemodialysis
There are currently few published data available on the use of
TKIs in patients receiving hemodialysis (HD) [67-76]. Owing to the
very limited number of cases reported in the literature, it is impossible
to make any definitive conclusions regarding the tolerability and
efficacy of TKIs in patients with mRCC receiving HD. Nevertheless,
the activity of sunitinib and sorafenib that we have observed in this
cohort of patients, is similar to that observed in patients with normal
renal function in phase III trials (disease control: sunitinib 75% vs.
79%) [1].
It is well known that the prevalence of RCC in dialysis patients
is much higher than in the general population. RCC patients may
undergo hemodialysis owing to decreased renal function due
to chronic kidney disease other than RCC. In addition, it is not
uncommon for RCC patients to undergo nephrectomy; this results
in a number of patients being dialyzed [77,78]. Although there
is a close connection between RCC and dialysis, clinical trials that
demonstrated the efficacy of the new drugs did not include patients
with renal failure. Consequently, a consensus or clinical guidelines
have not yet been established for sunitinib administration in dialyzed
patients.
Long term dialysis is a risk factor for renal cell carcinoma (RCC)
since the prevalence of RCC in hemodialysis or renal transplant
patients is 40 to 100 times higher than that of the general population.
The kidney and urinary tract organs are susceptible to systemic
carcinogenic effects extending from biochemical and immunologic
changes that occur with renal pathologies, resulting in loss of proper
renal function [77,79,80].
Although a high interpatient variability have been observed in
sunitinib concentrations and clearance, the plasma concentration
of sunitinib is not significantly modified by hemodialysis, and the
values of the extraction coefficient (E%) and hemodialysis clearance
(CHHD, mL/min) are all 0% and 0 ml/min in patients, which reflects
that PK are not altered by hemodialysis; therefore, sunitinib can be
administered at any time regardless of the timing of hemodialysis.
Case reports have shown the feasibility of using sunitinib in
patients with severe renal impairment [81] (defined as an eGFR <30
mL/min/1.73 m2) or on hemodialysis [67,76] but the pharmacokinetic
data for sunitinib in patients on hemodialysis is inconsistent [82].
Investigated the steady-state pharmacokinetics of sunitinib in two
patients treated with 50 mg sunitinib daily, for 4 out of every 6 weeks
while on hemodialysis. They concluded that hemodialysis did not
significantly modify the plasma concentrations of sunitinib or its
active metabolite SU12662, based on their comparable arterial and
venous concentrations 2h after the start of hemodialysis. However,
the pharmacokinetic parameters, including the area under the plasma
concentration-time curve and maximum plasma concentration,
showed a 10-fold difference between the two patients, and were not
in the range reported for patients with normal renal function [83].
Recently published a phase I open-label study evaluating the effects
of severe renal impairment (creatinine clearance <30 mL/min) and
hemodialysis on the pharmacokinetics and safety of a single 50 mg
dose of sunitinib. They also concluded that the clearance of sunitinib
and its active metabolite SU12662 was similar in patients with
severely impaired renal function or on hemodialysis, when compared
with patients with normal renal function, although plasma exposure
to sunitinib and SU12662 was significantly lower in subjects requiring
hemodialysis compared with those with normal renal function.
The pivotal phase III study that led to the approval of sunitinib
in advanced RCC excluded patients with a serum creatinine
concentration ≥1.5 times the upper limit of normal, and the
expanded-access trial of sunitinib excluded patients with a serum
creatinine concentration >2.0 times the upper limit of normal [2];
therefore, data regarding the efficacy and tolerability of sunitinib
in patients with renal impairment are limited. Recently, a phase I
open-label study evaluating the effects of severe renal impairment
(creatinine clearance <30 mL/min) and HD on the pharmacokinetics
and safety of a single 50 mg dose of sunitinib has been published.
The clearance of sunitinib and SU12662 was similar in patients
with severely impaired renal function, or undergoing HD, to that in
patients with normal renal function, although plasma exposure to
sunitinib and SU12662 was significantly lower in subjects requiring
HD than in those with normal renal function [84].
Published data suggest that patients with severe renal impairment
or end-stage renal disease on hemodialysis can be safely treated with
sunitinib at doses of 25-50 mg daily for 4 weeks followed by a 2-week
break. The observed efficacy and toxicity of therapy is similar to that
reported in patients with normal renal function.
Table 3
Pharmacokinetics
A recent phase I open-label parallel-group study, which included
eight patients receiving HD, found that plasma exposure to sunitinib
and its active metabolite was lower in patients receiving HD than
in those with normal renal function [85]. Arterial and venous
pharmacokinetic concentration data in that study indicated that
sunitinib was not eliminated via HD. The study showed that a single
dose of sunitinib was well tolerated in patients on HD without serious
toxic effects.
There are no significant differences in the pharmacokinetics
of sunitinib or its primary active metabolite (Su12662) between
single and repeated administration or between healthy individuals
and cancer patients. Previous studies have shown that plasma
concentrations reach their maximum between 6 and 12 hours after
a single oral dose of sunitinib, and bioavailability is unaffected by
food [86]. The area under the plasma concentration-time curve
(AUC) and maximum plasma concentration (Cmax) increase doseproportionately
in the dosing. With repeated administration, steadystate
concentrations of sunitinib and SU12662 are achieves in 10 to
14 days. Sunitinib accumulates 3 to 4 fold and SU12662 accumulates
7 to 10 fold.
Both sunitinib and SU12662 are metabolized primarily by
cytochrome P4503A4 (CYP3A4), with SU12662 comprising 23% to
37% of the total drug exposure. Elimination is primarily via the fecal
route with 61% of the administered dose; 16% of the administered
dose is eliminated through the urine [87]. The terminal half-lives of
sunitinib and SU12662 are approximately 40 to 60 hours and 80 to
110 hours, respectively.
Renal insufficiency is common in patients with solid tumors
and occurs in more than 50% of all cases studied [88]. Because
renal elimination plays a minor role in clearing sunitinib, renal
impairment would not be expected to have a significant effect
on its pharmacokinetics. A population pharmacokinetic analysis
indicated a lack of effect of sunitinib or Su12662 pharmacokinetics
in patients with mild to moderate renal impairment with calculated
creatinine clearance (CLcr) values in the range of 32 to 347 mL/min
[28,29]. However, data were unavailable for patients with severe renal
impairment (CLcr< 30 mL/min) or patients on hemodialysis.
Thus, based on the pharmacokinetic data, the currently approved
starting dose of sunitinib 50mg on Schedule 4/2 is likely appropriate
for patients with severe renal impairment. These findings may be
relevant to clinical practice, especially for RCC patients who have
undergone nephrectomy, for patient groups such as the elderly, or
for those with comorbid conditions such as diabetes who often report
coexisting renal insufficiency [88-90].
Comparing the outcome data of the patients on hemodialysis
with the non-hemodialysis-dependent patients, partial responses
were achieved in three patients undergoing hemodialysis and in three
non-hemodialysis-dependent patients. Stable disease was observed
in an additional six patients undergoing hemodialysis compared
with three non-hemodialysis-dependent patients, and one dialysis
patient developed progressive disease in comparison with two nonhemodialysis
patients.
The pharmacokinetic analyses of sunitinib and its main
metabolite in patients on hemodialysis must be considered further
[82,84]. Outcomes in some series of patients, in terms of median PFS
and 12-month OS, were similar to those observed in patients with
normal renal function treated with TKIs. Moreover, there were no
significant differences in outcomes (PFS and OS) among patients who
started TKIs on reduced doses and those who received full doses.
The sunitinib dose was 50 mg daily irrespective of hemodialysis in
Park’s report [77]. In contrast, Zastrow [68] started with a sunitinib
dose of 25 mg daily, irrespective of hemodialysis, and increased to 37.5
mg and 50 mg according to the patients' tolerance. Overall responses
were complete response (CR) by the patient in Park’s report, and
CR by one patient and stable disease by the other patient in Zastrow
et al.’s report. However, the dose intensity in these two reports was
similar to that used with non- ESRD patients and it seemed that
higher cumulative doses of the sunitinib resulted in better responses.
Comorbid Associated Conditions
Diabetes mellitus
Diabetes mellitus (DM) is an extremely complex disorder involving
insulin resistance and β-cell dysfunction. Insulin receptors and IG1
receptors activate a number of post-receptor cascades including Irs,
Sgk or Akt-2 protein kinases inducing protein synthesis, antilipolysis
and cell survival [91]. TKIs influence glucose metabolism, with both
elevated and decreased blood glucose levels that have been attributed
to TKI treatment. The molecular mechanism by which TKI controls
glucose homeostasis remains unknown. More disturbing is the
observation that the same TKI (for instance, imatinib or sunitinib)
can be associated either with hyperglycemic or TKIs seem to have
limited effect on lipids. Hyperglycemia has been reported with
sunitinib in 15% of patients with metastatic RCC [1], while it was
not reported in phases III trials of patients with advanced P-NETs or
GIST. In contrast, some patients treated by imatinib or sunitinib also
presented hypoglycemia and/or regression of long-standing diabetes
[92-97].
Recent reports suggest that sunitinib may affect glucose
metabolism in both diabetic and non-diabetic individuals [98,99].
Interestingly, sunitinib use has been associated with improvements
of glycemic control in diabetic patients [96,97]. Moreover, sunitinib
has resulted in reversal of type 1 diabetes in experimental animals
[100] and there are two recent reports of patients with established
type 1 diabetes who were able to discontinue insulin for several
months, whilst being on sunitinib treatment for a PNET and for renal
cell carcinoma, respectively [101,102]. In 2006 have been reported
similar observations in mice models using AG-013736, which is also a
tyrosine kinase inhibitor of VEGFR-1, -2 and -3. In this animal model,
a 21-day pre-treatment with AG-013736 improved blood glucose
handling [103]. According to the authors, this phenomenon could be
partially related to significant quantitative and qualitative capillary
regression in pancreatic islets. Interestingly, this VEGF-dependant
phenomenon was reversible after cessation of the treatment. Second,
IGF-1 regulates VEGF expression through HIF1-α [104].
The exact mechanism through which sunitinib lowers plasma
glucose levels is currently unclear. Several potential explanations have
been proposed, mainly based on the effects of imatinib, another TKI, on
carbohydrate metabolism. Most likely via a protective, antiapoptotic
effect on β-cells mediated by nuclear factor-κB; sunitinib have an
impact on insulin resistance by interfering with the IGF-1 pathway
[96]. The platelet- derived growth factor signaling pathway, through
which sunitinib works, was recently shown to control age-dependent
β-cell proliferation in mouse and human pancreatic islets [105]. The
phosphorylation of these proteins is crucial in insulin signaling and in
controlling the activity of cellular insulin effectors, such as enzymes.
Inhibition of phosphorylation by imatinib may result in better
signaling, better functioning of effectors, or both, with improvement
in insulin sensitivity. TKIs may also inhibit phosphorylation
processes involved in impaired insulin secretion. It is important to
emphasize that inflammation and oxidant stress, which seem to play a
crucial role in the pathogenesis of type 2 diabetes mellitus [106], share
several mechanisms with aberrations in cell differentiation, growth,
and proliferation.
There are reported an interesting clinical case of remission of type
I diabetes after sunitinib treatment [102].
A decrease of glucose uptake in a context of concomitant
gastrointestinal toxicity cannot be excluded, and oral glucose uptake
could consequently be reduced. In addition, direct intestinal toxicity
of sunitinib has been reported, and this could induce vitamin
malabsorption [107]. However, the hypothesis of altered glucose
transport is not confirmed, as glucose handling was not modified in
the animal model after an intravenous compared with an oral glucose
challenge after treatment [103]. Finally, drug-drug interaction
(between sunitinib and blood glucose-lowering drugs) could be
advanced as an additional basis for our findings. From a clinical
perspective, it is important that glucose levels of patients treated with
sunitinib are monitored on a regular basis.
Because treatment with TKI may be associated with hypoor
hyperglycemia, it is recommend measuring FPG and HbA1c
before initiating the TKI treatment. FPG will be checked every two
weeks during the first month then once every month. HbA1c will
be measured every three months. In a patient with known diabetes,
SMBG will be reinforced.
Renal insufficiency
Chronic kidney disease, defined as a glomerular filtration rate of
<60 mL/min/1.73 m2 [108], is commonly seen in patients with RCC,
occurring in 37% in one case series [109]. In a retrospective cohort
study of 10 886 patients with RCC, 16.4% and 21.8% of patients
progressed to dialysis or renal transplantation after partial and radical
nephrectomy, respectively [110]. In addition, RCC is a complication of
chronic kidney disease [111]. Recently reported a correlation between
the risk of cancer in men and chronic kidney disease, beginning when
the estimated glomerular filtration rate (eGFR) falls below 55 mL/
min/1.73 m2. When the eGFR is <40 mL/min/1.73 m2 the increased
risk of cancer was found to be site-specific for bladder, renal and lung
cancers. In addition [112] found that in the 5 years leading to renal
replacement therapy, the observed number of cases of renal cancer
was 193, compared with an expected 14 according to corresponding
population cancer incidence rates.
The prevalence of RCC is higher among patients with end-stage
renal disease and recipients of kidney transplants than in the general
population, and these patients have distinct clinical and pathological
RCC features [113-115]. The incidence of RCC is also higher in
patients with chronic kidney disease than in the general population,
and a significant number of these patients show progression to endstage
renal disease, with or without nephrectomy [88,90,113].
The sunitinib-related adverse effects in patients with renal
insufficiency were very similar to those in patients in previous phase
III studies that excluded patients with renal insufficiency. In a metaanalysis,
there are describe the elevation of serum creatinine of any
grade in 65% of patients treated with sunitinib with a risk ratio of 13.5
[116]. Deterioration of renal function is a well-recognised adverse
effect of treatment with sunitinib. In the study by Billemont et al. [96],
renal toxicity occurred in 37.5% of patients, but this adverse event
was associated with better overall survival and response rate.
The safety of sunitinib in a small population of patients with
severe renal impairment or on haemodialysis, is supported by
the observation that the overall incidence of dose modifications,
discontinuations and AEs in this cohort is similar to that seen within
the pivotal phase III trial and the expanded-access trial.
In a posterior study, in patients with mRCC with renal
insufficiency treated with sunitinib, the median PFS was 12.2 months
and the median OS was 26.3 months [117]. In the expanded-access
trial assessing the safety of sunitinib in patients with mRCC, the
median PFS was 10.9 months and the median OS was 18.4 months,
which are considerably shorter than those seen in the current study
[2].
Clearly showed that plasma exposure to sunitinib and SU12662
was significantly lower in patients requiring haemodialysis compared
with those with normal renal function [84]. They attributed this to
decreased drug absorption and consequently a lower bioavailability
in patients with end-stage renal disease. A risk for under-dosage of
sunitinib in those patients, even when administered at its usual dose,
is therefore implicated.
Sunitinib and its active metabolite SU12662 are primarily
excreted in the faces, but 15-20% is eliminated really [118]. The
pharmacokinetics of sunitinib indicated that renal function would
not be majorly affected.
Although, previous reports indicated that, following treatment
with sunitinib patients with mRCC with renal insufficiency
experienced deterioration of renal function [85], however, these
patients did not display differences in the efficacy or toxicities of
sunitinib. Several cases concerning dialysis-dependent mRCC
patients treated with sunitinib have been reported [77,82,119].
No significant difference in the rates of severe toxicity were
observed between the cohorts, with 4 (18.2%), 34 (14.5%) and 73
(13.7%) and patients with a toxicity event in the severe RI, moderate
RI and mild RI/normal GFR groups, respectively. The retrospective
analysis based on a large registry-based patient cohort indicates that
sunitinib is effective in patients with reduced glomerular filtration,
including patients with GFR below 30ml/min/1.73m2 as well as GFR
between 30 and 60ml/min/1.73m2 [120].
Hepatic impairment
Sunitinib is metabolized mainly by cytochrome P4503A4
(CYP3A4) to form the active metabolite, SU12662; SU12662 is also
metabolized by CYP3A4 6 [90]. SU12662 comprises 23-37% of the
total exposure [121]. Sunitinib and SU12662 are the major drugrelated
compounds that have been identified in plasma, urine, and
feces (representing 91.5, 86.4 and 73.8% of radioactivity in pooled
samples, respectively); minor metabolites have been identified in
urine and feces, but are generally not found in plasma. In a mass
balance study, 61% of the administered sunitinib dose was eliminated
in feces, with renal elimination accounting for 16% [87,122].
In a population pharmacokinetic analysis, no relationship was
observed between liver enzyme levels (evaluated using baseline
alanine aminotransferase [ALT] values [0-35 U/l, n=175; 36-69 U/l,
n=23; 70-140 U/l, n=6; >140 U/l, n=1]) and sunitinib or SU12662
pharmacokinetics [86].
The pharmacokinetics of sunitinib, SU12662, and total drug
were similar in subjects with mild or moderate hepatic impairment
as compared to subjects with normal liver function so its apparent
oral clearance was not significantly different in subjects with
hepatic impairment compared to normal subjects. The percentages
of unbound sunitinib and SU12662 were slightly smaller in the
subjects with hepatic impairment compared with the normal group.
Unbound sunitinib exposure (AUC0-∞,u, AUC0-last,u, and Cmax,u)
was not significantly changed in subjects with mild and moderate
hepatic impairment. The results demonstrated that mild or moderate
hepatic impairment, defined using the CP classification, and did not
significantly alter sunitinib systematic exposure (AUC0-∞, AUC0-last,
and Cmax) after a single dose. The half-life of sunitinib while consistent
with previous reports [86,87] was longer in both groups with hepatic
impairment compared with the normal group (mild: 79.5h; moderate:
79.2h; normal: 63.8h).
It is possible that the longer half-life of sunitinib in subjects
with hepatic impairment may be explained by a larger volume
of distribution in these subjects, resulting from an increase in
extracellular fluid (e.g., ascites, peripheral edema), as has been
reported [121,123-125]. Protein binding of sunitinib was similar
between groups, although slightly less in the normal group compared
with the groups with hepatic impairment. Significant differences
between the groups could not be concluded as the variability in the
protein-binding assay could not be quantified.
Sunitinib is metabolized mainly by cytochrome P4503A4
(CYP3A4). However, in population pharmacokinetic analysis, it
has been observed that the pharmacokinetics of sunitinib and its
metabolite were similar in subjects with mild or moderate hepatic
impairment as compared to subjects with normal liver function so
its apparent oral clearance was not significantly different in subjects
with hepatic impairment compared to normal subjects, although
it was noted a longer half-life of the drug in subjects with hepatic
impairment, probably by a larger volume of distribution.
Integrating Surgery
Surgical intervention is the primary treatment for early- stage
RCC; however, surgery alone has limited benefit in patients with
metastatic disease, except for palliative reasons [109]. For advanced or
metastatic disease, nephrectomy may only be curative if all metastatic
deposits are excised [125]. Therefore, a combination of surgery and
targeted therapy is increasingly being used for locally advanced and
mRCC in an attempt to improve patient outcomes.
The role of surgical intervention in patients with metastatic
renal cancer is twofold: to render a patient clinically free of all
sites of primary disease and metastases, termed nephrectomy /
metastasectomy, or to resects the primary tumor in the face of
unresectable metastatic disease prior to the initiation of systemic
therapy, termed cytoreductive nephrectomy [113].
In advanced RCC, surgery has undergone a transformation over
the past several decades. Historical indications for nephrectomy have
included palliation of pain, intractable hematuria, and paraneoplastic
symptoms [126]. However, angioinfarction may serve as a less
invasive alternative to palliative nephrectomy at present.
Debulking nephrectomy has become the standard of care in
appropriately selected patients with mRCC, based on an overall
survival advantage reported in two randomized prospective phase III
trials [127,128] and a combined meta-analysis [129]. Several other
retrospective series have shown a relationship between the percentages
of tumour removed and improved outcome [130]. Initially proposed
removing the primary tumour if its bulk was greater than that of the
metastasis. Later [131], it was identified that patients with >75% of the
tumour removed at the time of nephrectomy as most likely to benefit
from subsequent interleukin-2 immunotherapy. Most recently [132],
showed that >90% of the tumour burden removed at nephrectomy
was associated with longer overall survival. However, this last study
included a large percentage of patients who also underwent distant
metastasectomy.
In patients undergoing radical nephrectomy for RCC at the Mayo
Clinic who had either distant metastases at the time of diagnosis or
subsequently developed metastases, many factors as constitutional
symptoms at nephrectomy, metastases to the bone or liver,
metastases in multiple simultaneous sites, metastases at nephrectomy
or within 2 years after nephrectomy, tumor thrombus, nuclear grade
4, and coagulative tumor necrosis were predictors of poor survival. In
contrast, complete resection of all metastatic sites was associated with
improved survival. These authors recommend an aggressive surgical
approach to metastatic RCC, including debulking nephrectomy and
metastasectomy, when feasible [133].
It has been demonstrated in other series that lymph node status is
associated with poor outcome after cytoreductive nephrectomy and
immunotherapy [134,135].
The spontaneous regression of metastatic disease occurs almost
exclusively in the lung and only after removal of the primary tumour,
many authors have speculated that the primary tumor possesses
immunosuppressive properties [136]. One potential mechanism is
that the tumor acts as an immunological ‘sink,’ drawing and trapping
antibodies and circulating immune cells so that they cannot exert an
effect on metastatic sites [130,136,137]. Tumor cells may also impair
the activity of circulating immune cells by causing dysfunction of
T-cell receptors [138] and by interfering with signal transduction
mechanisms, [139-141] antigen processing, [142] and expression
of major histocompatibility complex antigens [143]. There is also
evidence that RCC may induce apoptosis of tumor-infiltrating
lymphocytes [144,145]. In addition, renal cancer cells have been
shown to produce inhibitory cytokines that may actively suppress
immunological responses [146,147]. In this section we review the
main studies that integrate anti target therapies to surgery.
Cytoreductive nephrectomy
There are several theoretical advantages to cytoreductive
nephrectomy (CN) prior to the initiation of systemic therapy. Several
authors cite the palliation of symptoms related to the primary tumor
such as pain, hematuria, and paraneoplastic syndromes. Also, some
patients may experience an improvement in its performance status
(PS) following debulking nephrectomy. There are published data
among 32 patients treated at Indiana University, 72% had a PS equal
to or better than their pre-operative status, including four patients
with a PS of 2 who improved to 0 or 1 postoperatively [148]. Another
potential advantage of CN is the concept of debulking: by removing
the primary tumor, fewer cancer cells are available to contribute to
the metastatic process.
Another theory regarding the effect of CN is related to the
angiogenic properties of the tumor [149]. Increased levels of serum
VEGF [150-152] as well as multiple other angiogenic growth factors
have been demonstrated in patients with RCC [153,154]. Removal
of the primary tumor along with reduction of circulating angiogenic
factors would thus allow stabilization of metastatic growth rates and
potentially enhanced immune defenses against metastatic sites.
The adoption of CN as a valid step in the treatment of metastatic
RCC comes from 2 randomized phase III trials and their combined
meta-analysis, evaluating the role of cytoreductive nephrectomy in
the immunotherapy era. Both studies used the same study design,
patient eligibility criteria, and treatments. In both trials a significant
improvement in overall survival (OS) was seen in patients randomized
to nephrectomy prior to IFN-a therapy [127-129].
Although CN was largely accepted as a necessary step in the
treatment of mRCC, this concept is now challenged with the use of
targeted therapy. Many believe we should abandon cytoreductive
nephrectomy and adopt a pure systemic treatment approach.
To present, there are no data to directly show the benefit of CN
in the targeted therapy era. In a published MD Anderson experience
[155], results obtained from 188 consecutive patients who received
targeted therapy and never underwent cytoreductive nephrectomy
were reported. The median survival for this group was 10.4 months,
very different from that observed in the phase III trials of sunitinib,
bevacizumab, or pazopanib, which range from 22 to 26 months.
Other trial [156] included 314 patients treated with targeted
therapy, and compared 201 patients who underwent cytoreductive
nephrectomy with 113 patients who did not. In the multivariable
analysis, CN was associated with improved overall survival in the
general cohort (19.8 months in patients who underwent nephrectomy
vs. 9.4 months in those who did not, hazard ratio 0.68), but on sub
analysis it was noted that patients with poor risk features derived
marginal benefit from surgery.
Two prospective, single arm phase II studies, investigating 2 cycles
or 3 cycles of sunitinib prior to nephrectomy in mCRC were evaluated
centrally with the objective of evaluate prospectively the safety and
efficacy of upfront sunitinib in this patients. With the exception of
the number of cycles of sunitinib given, both studies had identical
design and entry criteria. Authors reported that no patients became
inoperable due to local progression of disease, but 20% developed
progression of systemic disease prior to surgery. Nephrectomy was
possible in 71% of patients, the median progression free survival was
9 months (95% CI: 5-15 months) and no significant differences was
observed between of 2 vs. 3 cycles of sunitinib prior to nephrectomy
[157].
Actually, two ongoing trials are being conducted to address
the question about the role of the TKI in the CN. Both studies
were designed as prospective trials using sunitinib. The French
trial CARMENA (NCT00930033) is a randomized, non inferiority,
phase III trial evaluating the importance of nephrectomy in patients
presenting with mRCC treated with sunitinib and aims to enroll
576 patients. It was designed to compare OS (primary endpoint) in
patients treated with sunitinib alone versus treated with CN followed
by sunitinib. The other trial was designed by EORTC (NCT01099423)
to investigate the optimal timing of CN, comparing PFS in patients
treated with cytoreductive nephrectomy followed by sunitinib versus
sunitinib followed by surgery. The primary outcome will be the PFS.
We must await the results of these studies to determine if the role of
cytoreductive nephrectomy with sunitinib is similar (or not) to that
it has with cytokines.
Neoadjuvant therapy
There is a rationale for presurgical targeted therapy and
investigation of pretreated primary tumor tissue [158]. Neoadjuvant
therapy (NT) should refer to the administration of targeted therapy
in RCC to improve surgical resection of otherwise resectable/no
metastatic disease. Several potential clinical benefits of a neoadjuvant
or presurgical approach with targeted therapy can be envisaged that
may translate into a prolongation of PFS or OS.
NT may result in down staging of the primary tumor, which may,
in turn, facilitate surgical resection [159]. In particular, patients with
technically unresectable primary tumors, bulky regional lymph node
metastases, or caval thrombi, in whom complete resection may be
achieved after pretreatment, may potentially benefit most from this
approach. Some authors have included patients with a large distant
metastatic disease burden in the definition of unresectable disease
[160].
Initial reports suggested that TKIs, can induce some downsizing
at the level of the primary tumor. In patients treated with sunitinib
for advanced RCC who had not had prior nephrectomy, one study
showed tumor volume reduction of 31%, which was associated with
an increase in the volume of necrosis (39%) [161]. There is additional
evidence from several case reports where TKIs were used to downsize
caval thrombi and retroperitoneal lymph node metastasis followed
by a successful resection of the lesions [162-164]. However, unlike
downsizing, down staging or complete histologic remission are rare
events and only a few cases have been described [165].
Several presurgical phase 2 trials and retrospective series had
showed that the median downsizing of the longest diameter of the
primary tumor with various targeted agents ranged between 6% and
14.5%, while Response Evaluation Criteria In Solid Tumors (RECIST)
partial response of the primary tumor ranged between 3.3-6%.
There are small and retrospective series showing that preoperative
targeted therapy can be administered without an increased risk of
morbidity. The limited experience to date suggests that the shorter
half-lives of sunitinib allow discontinuation of this agent just a few
days prior to surgery [166].
One trial [167] assessed the activity of neoadjuvant sunitinib on
primary renal tumors in patients with advanced renal cell carcinoma
as well as the feasibility and safety of subsequent surgical resection. A
total of 19 patients with advanced RCC deemed unsuitable for initial
nephrectomy due to locally advanced disease or extensive metastatic
burden were treated with 50 mg sunitinib daily for 4 weeks on followed
by 2 weeks off. Tumor response was assessed by Response Evaluation
Criteria in Solid Tumors every 2 cycles and the rate of conversion
to resectable status was estimated. Partial responses of the primary
tumor were noted in 16%, 37% had stable disease and 47% had disease
progression in the primary tumor. Overall tumor response included
2 patients with partial response, 7 with stable disease and 10 with
disease progression. At a median follow-up of 6 months, 4 patients
(21%) had undergone nephrectomy and 5 died of disease progression.
No unexpected surgical morbidity was encountered. Viable tumor
was present in all 4 specimens. Sunitinib was associated with grade
3–4 toxicity in 7 patients (37%) and treatment was discontinued in 1
due to toxicity.
These studies allow us to conclude that administration of sunitinib
in patients with advanced renal cell carcinoma, with the primary
tumor in place, is feasible, safe and can lead to a reduction of tumor
burden, although the absence of results from prospective studies with
good design does not allow us to make recommendations at this time.
Postsurgical therapy
Patients without metastases usually are treated with a radical
surgical approach. Also, some patients with metastatic disease
are treated with surgery of their primary tumor and additional
metastasectomy. Although the absolute curative impact of
metastasectomy remains uncertain, operative intervention can also
provide effective palliation for symptomatic metastatic disease to
sites such as bone, brain, and adrenal gland [168]. In both scenarios,
a percentage of patients will have recurrence and eventually die
because of the disease. Therefore, appropriate adjuvant treatment for
reduction of relapse risk, could be very useful in patients at a higher
risk of relapse. At present, several therapies (immune, hormonal and
targeted therapies) has been proven, but no one has show be useful in
this setting [169].
A meta-analysis of adjuvant therapies (chemotherapy, immune
therapies, and hormonal treatments) for locally advanced RCC was
published in 2011 [170] and it concluded that, because there was no
evidence of any benefit and it caused substantial toxicity, there was
no support for using systemic therapy in the adjuvant setting, In this
analysis, no targeted therapy were included because no trial with this
treatment was completed at that time.
Targeted therapies are subject of current research in this subset of
patients, but so far have shown some benefit. We have recently known
the initial results from ASSURE (E2805), a phase III trial comparing
sunitinib and sorafenib in adjuvant setting in patients with resected
primary disease at high risk. These preliminary results indicate that it
is a negative study as their primary objective, DFS, is not met: median
time to disease recurrence did not differ between those who received
sorafenib or sunitinib after surgery (median 5.8 years) and those
treated with placebo (median 6 years) [171].
Several other trials are ongoing, testing the role of targeted therapy
in this scenario. One of this trials is the Sunitinib Treatment of Renal
Adjuvant Cancer Trial (NCT00375674), a phase III randomized,
double-blind, placebo-controlled trial, with 500 patients included
fulfilling high-risk criteria (UISS) and testing sunitinib for 1 year as
adjuvant therapy. Results about it primary end point, disease-free
survival, are expected through 2017.
The encouraging response data, both in primary tumors as in
metastases, suggest a probable role of targeted therapies integrating
with surgery as a rational step in the evolution of RCC treatment.
Presently, we do not have definitive evidence supporting changes
in the current treatment paradigms. In the absence of prospective
randomized data, CN remains a part of the treatment algorithm
for patients with metastatic disease and good PS with a resectable
tumor. By contrast, patients with poor overall health, large tumor
burden beyond the kidney, or highly aggressive disease are unlikely
to benefit from nephrectomy, and should receive systemic therapy
first. The hypothesis of the published analysis was that in the era
of VEGF-targeted therapy, a greater percentage of tumour volume
removed with debulking nephrectomy would be associated with an
improved PFS. The neoadjuvant use of sunitinib administration in
patients with advanced renal cell carcinoma appears to be feasible,
safe and can lead to a reduction of tumor burden. We must await the
final conclusions of ongoing studies evaluating the role of sunitinib
in patients at high risk of recurrence after surgery as primary therapy
for their malignancy.
Individualized Sunitinib Therapy
The data in the literature seem to give a prominent role to sunitinib
malate, a specific inhibitor of the tyrosine- kinase receptors, VEGFR
and PDGFR, as first-line treatment of mRCC. At the same time, as
one of the most significant aspects of targeted molecular therapies is
the need to continue the treatment until progression of the disease,
special attention must be addressed to monitoring any drug-related
side-effects, while at the same time under- standing the mechanisms
that give rise to them and their control in order to maintain adequate
dose intensity of the drug given.
Animal studies have revealed that total drug plasma concentration
(Sunitinib plus its active metabolite) in the range of 50–100ng/mL
was capable of inhibiting VEGFR-2 and PDGFR-α phosphorylation.
Toxicological evaluation of animal models revealed bone marrow
depletion and toxic effects in rats and monkeys, as well as adrenal
micro hemorrhages in rats. To minimize potential bone marrow and
adrenal toxicities in clinical evaluation, health authorities requested
an intermittent dosing schedule. Sunitinib was thus studied in cancer
patients using various schedules, including a 3-week cycle comprised
of treatment for 2 weeks followed by a 1-week rest period (schedule
2/1), a 4-week cycle comprising treatment for 2 weeks followed by a
2-week rest period (schedule 2/2), or a 6-week cycle comprised of a
4-week treatment followed by a 2-week rest period (schedule 4/2).
The longer-term impact of Sunitinib-associated toxicities is
also recognized to be increasingly important as patients are living
longer [172]. The high incidence of dose reduction, treatmentdiscontinuation
and AEs associated to sunitinib treatment lead
scientist to investigate alternative schedules of sunitinib in phase I-II
trials and retrospective analyses, aimed at optimizing the sunitinib
dosing schedule. In addition, pharmacokinetic analysis of data from
studies in healthy volunteers and patients with cancer demonstrated
high inter-patient variability in pharmacokinetics with a coefficient
of variation in the range of 40-60%. These observations support a
reversal of the desired pharmacodynamic effect during the 2 weeks
in which patients were off the drug and highlight the importance of
maintaining sunitinib drug levels, but do not address which dose/
schedule achieves this more optimally in patients with RCC.
The most common toxic reactions requiring dose reduction or
treatment interruption were grade 3 hand-foot syndromes (HFS),
grade 3 diarrhea, grade 3 thrombocytopenia and grade 3 neutropenia.
The most commonly used sunitinib treatment schedule is 50 mg daily
for 4 weeks followed by a 2-week interval off treatment (schedule 4/2).
Although previous reports have suggested that a maximal dose and
area under the serum concentration-time curve (AUC) may intensify
the therapeutic response [173], a phase III clinical trial showed that
more than 50% of patients required modification of the sunitinib
dosage or interruption of treatment owing to drug toxicity [1]. The
larger the dosage, the better the effect, but also the greater the toxicity.
Inability to deliver adequate sunitinib dose is relevant. In real
world clinical practice, maintenance of the dose intensity of sunitinib
is frequently challenging as a result of treatment-related adverse events
(AEs), such as fatigue, hypertension, HFS and thrombocytopenia,
resulting in the necessity of dose reduction or interruption in a large
proportion of patients receiving Sunitinib [174], whereas analyzed
pharmacologic data from six clinical trials, and reported that patients
with high-level drug exposure (AUC) showed longer overall survival,
prolonged time to progression and increased reduction of the tumor
burden [175]. Minimizing the time without therapy may be important
as tumor progression occurs during treatment interruption [38,176].
Thus, the substantial proportion of patients who may require dose
reduction/interruption with sunitinib could lead to lower plasma
levels and reduced clinical benefit. Alternative schedules of sunitinib
have been explored with the goal of improving drug tolerance and
maintaining dose intensity.
Classic-traditional schedule
The standard dosing schedule of sunitinib (schedule 4/2) was
based on preclinical data that the target plasma level of 50 ng/mL of
sunitinib and its primary metabolite, (SU12662), was maintained for
at least half of the daily dosing interval at this dose and schedule [118].
Preclinical pharmacokinetic and pharmacodynamic data showed that
target plasma concentrations of Sunitinib and their metabolite in the
range of 50–100 ng/mL were capable of inhibiting phosphorylation
of PDGFR-b and VEGFR-2, suggesting that this was the clinically
significant range. While initial studies planned to provide continuous
administration, schedule 4/2 was used to allow patients to recover
from potential bone marrow and adrenal micro hemorrhage observed
in animal models [118]. Dose-limiting toxicities (DLTs) included
fatigue, hypertension, and bullous skin toxicity [118].
Based on these findings, several subsequent clinical trials
examined schedule 4/2, and this regimen was approved due to its
excellent antitumor activity and manageable safety profile [1,177].
Continuous daily dose
One trial investigated the safety, tolerability and pharmacokinetics
of Sunitinib 50 mg 2/1 schedule [178]. Twelve patients with advanced
refractory malignancies were treated with sunitinib in this way.
Pharmacokinetic studies revealed no significant accumulation of
Sunitinib or SU12662. This schedule was tolerable, and no significant
drug accumulation was demonstrated, being the safety profile
consistent with the standard one.
In a phase II randomized study, EFFECT study [173], the
Sunitinib standard schedule was compared with a continuous daily
dose schedule (CDD) of 37.5 mg in a total of 146 naive patients with
clear cell mRCC. Median time to tumor progression, the primary end
point, was 9.9 months for 4/2 schedule and 7.1 months for the CDD
schedule (HR 0.77; 95% CI, 0.57 to 1.04; p=0.090) with no difference
observed in overall survival (23.1 vs. 23.5 months; p=0.615),
commonly reported adverse events, or patient-reported kidney
cancer symptoms. Schedule 4/2 was statistically superior to CDD
in time to deterioration, progression and disease related symptoms
(p=0.34). The rate of patients who discontinuities sunitinib because
of adverse events was 11% for 4/2 schedule vs. 15 % for CDD, drug
interruptions were 65% (4/2) vs. 62 % (CDD) and dose reductions
(4/2 vs. CDD; 36% vs. 43%). The authors concluded that no benefit in
efficacy or safety for CDD was demonstrated.
Three other non-randomized phase II studies on continuous
sunitinib dosing have been published, including more than three
hundred patients in total [179-181]. The ORR varied from 20 to 35%,
median PFS from 8.2 to 13 months and median OS from 19.8 to 25
months, all comparable to the study of Motzer et al. [2] 2012 and also
to the pivotal phase 3 trial. Phase II studies with CDD [180-182] had
percentage of dose reductions and treatment discontinuations due to
AEs which were comparable to the Motzer study [179].
Alternative schedule: biweekly schedule
The initial clinical trials with sunitinib employed intermittent
dosing schedules with a 2-week off-drug period. This early schedule
was selected based on the preclinical toxicology data available at
the time clinical investigation was initiated. However, preclinical
experiments have demonstrated tumor growth during the off-dosing
period [183], suggesting that sunitinib may be most effective with
more continuous dosing. These findings suggest that schedule 2/1
could be the optimal dosing schedule of sunitinib against mRCC that
balances efficacy and toxicity, since treatment on schedule 2/1 resulted
in a markedly improved QOL compared with that on schedule 4/2 by
relieving the profile of sunitinib related AEs.
Rainbow study [184] is a retrospective, multicentre study that
included 276 patients. 3 different treatment arms were: A (208
patients), who initiated at standard dose and continue to 2/1 schedule
due to toxicity; group B (41 patients), with initial treatment 2/1
because of poor performance status and group C, 27 patients, who
were treated on 4/2 (Control arm). A total of 211 consecutive patients
treated with the 4/2 schedule in another institution served as external
controls. Safety was the primary endpoint. Treatment duration
(TD), progression-free-survival (PFS) and overall survival were also
analyzed. There were clinical and histologic differences between
treatment arms, as median age (62 and 61 years), percentage of clear
cell carcinomas (94% and 87%) and good risk prognostic factors, 47%
and 36% in group A and B. In group C median age was 59, 96 % had
clear cell carcinoma and 22% were in good prognostic factor group.
Median treatment duration was 28.2 months in the 4/2-2/1 group
(total time spend with both schedules), 7.8 months in the 2/1 group
and 9.7 months in external controls. Median PFS were 30.2, 10.4
and 9.7 months with median OS not reached, 23.2 and 27.8 months
respectively.
Individualized treatment strategies to maximize dose and
minimize time without therapy are important. A single-center
retrospective review (Bjarnason G, 2014) was conducted on patients
with metastatic renal cell cancer. Dose/schedule modifications
(DSM) were done to keep toxicity (hematological, fatigue, skin and
gastrointestinal) at grade ≤2. DSM was 50 mg 14 days on/7 days off
with individualized increases in days of treatment. DSM-2 was 50 mg,
7 days on/7 days off with individualized increase in days on treatment.
DSM-3 was 37.5 mg with individualized 7-days break. DSM-4 was
25 mg with individualized 7 day breaks. Multivariable analysis
was performed for outcome as a function of patient and treatment
variables. A total of 172 patients were included in the analysis, most of
them had clear cell histology (79.1%) with sunitinib given in the first
line therapy in 59%.The DSM-1 and 2 and DSM-3 and 4 groups had a
progression-free survival (PFS) (10.9-11.9) and overall survival (OS)
(23.4-24.5) that were significantly better than the PFS (5.3 months;
p<0.001) and OS (14.4 months; p=0.03 and 0.003) for the standard
schedule (50 mg, 28/14).
The study in Japanese population shows the comparable
therapeutic efficacy of sunitinib delivered of the 2/1 schedule
compared to 4/2 in the treatment of patients with mRCC [184]. The
incidence of all AEs did not differ between the two dosing schedules,
but HFS and diarrhea occurred at significantly lower incidence with
Schedule 2/1. Dose interruptions were more likely in Schedule 4/2
than in the Schedule 2/1 group. In terms of efficacy, the objective
response rate tended to be higher in 4/2 schedule than in 2/1 (50%
vs. 32%), and median progression-free survival was longer in patients
on 2/1 compared to 4/2 schedule (18.4 versus 9.1 months). These
differences, did not reach statistical difference (p=0.14; p=0.13).
Najjar and colleagues [185] published a single center,
retrospective experience, in 30 patients who changed from 4/2 to
2/1 after toxicity. 97% of patients on 4/2 had grade 3 or 4 toxicities
that led to schedule 2/1. No grade 4 toxicities were reported and 27%
had grade 3 (p=0.0001) on 2/1 schedule, being fatigue and hand-foot
syndrome more significantly less frequent on 2/1 than 4/2 (p=0.0003;
p=0.0004, respectively).
Some studies [186,187] have reported better quality of life with
2/1 compared to 4/2 regimen. The Restore study is the only that
compares directly standard versus alternative 2/1 regimen [188]. 76
Asiatic patients were enrolled (38 to 4/2 schedule and 38 to alternative
schedule). The primary endpoint was failure-free survival (FFS)
at 6 months. 18 patients (ORR, 47%) in the schedule 2/1 achieved
a partial response (PR) while one patient had a complete response
and 11 patients had a PR (ORR 36%, 95% CI) in the schedule 4/2.
With a median follow-up duration of 47 months, the medium timeto.
Progression was 15.1 months in the schedule 2/1 and 10.1 months
in the schedule 4/2 (HR 0.69, 95% CI, 0.39-1.20). FFS at 6 months was
44% in schedule 4/2 and 63 % in schedule 2/1. Patients in 2/1 were
treated for a median of 7.7 months (95%, 3-12.3) of initial assigned
schedule while patients with 4/2 were treated for a median of 5.7
months (95% CI, 5-6.5) (HR 0.54, 95% CI, 0.32-0.91, p=0.021). 7
patients in the 4/2 crossed over to the 2/1 schedule, while none in the
2/1 crossover to 4/2 regimen (p=0.004).
Neutropenia (all grade 61% vs. 37%; grade 3-4, 28% vs. 11%;
p=0.0368) and fatigue (all grade 83% vs. 58%, p=0.0167) were most
frequently observed with 4/2. There is a strong tendency of lower
incidence of mucositis (all grade, 86% vs. 71%; p=0.116), and hand
foot syndrome (grade 3-4 33% vs. 18%; p=0.143) and rash (all grade,
56% vs. 34 %; p=0.0648) with schedule 2/1. Much less patients in the
2/1 schedule required dose reduction; 32 % and 68% of patients had at
least one dose reduction (p=0.021), in the 2/1 and 4/2 schedule arms
respectively.
Sunitinib-free interval regimen
There are different smaller studies that support sunitinib free
interval strategies. A small retrospective study reported the effects
of stopping sunitinib therapy in patients who had experienced a
complete response, with or without surgical metastectomy following
response to sunitinib [182]. At median follow up of 8.5 months,
disease had recurred in 5 patients, but in all cases re-introduction of
sunitinib was effective in regaining disease control.
At the ASCO Annual Meeting 2013, has been presented their
preliminary results on a prospective phase II trial of intermittent
sunitinib in previously untreated patients with mRCC [189]. Toxicity
was completely resolved during treatment stops, suggesting that
this intermittent dosing sunitinib may be better tolerated without
compromising sunitinib efficacy.
A randomized, multi-stage phase II/III study of sunitinib was
published comparing temporary cessation with allowing continuation,
at the time of maximal response, in the first-line treatment of locally
advanced/mRCC (the STAR trial) [190].
Other schedules
In a retrospective analysis, patients who had at least a grade
2 toxicity during sunitinib therapy were switched to a modified
schedule maintaining the same dose-intensity of 4/2 regimen: starting
on Monday, 1 tablet/day for 5 consecutive days a week (days 6 and 7
off therapy) for 5 weeks and 1 tablet/day on days 1, 3 and 5 in the sixth
week (days 2, 4, 6 and 7 off therapy) until disease progression [191].
The choice of an ideal schedule for single individual patient seems
still so far, due to the lack of biological insights that may guide the
decision-making process. Data on the efficacy and tolerability of
sunitinib continuously daily dose schedule seems to be less effective
and similarly tolerated than 4/2 standard schedule, and should not be
suggested for mRCC patients. Although supported by retrospective
and single studies, the 2/1 regimen seems to be effective and show
better toxicity profile, compliance to treatment, and dose intensity
compared to standard régimen and showed a lower incidence of
dose interruption and a similar oncological outcome compared with
the standard dosing schedule of 4-weeks-on and 2-weeks-off. The
decision to switch to schedule 2/1 versus attempting dose reduction
should be made at the discretion of the treating physician on the
basis of the patient’s subjective and objective toxicity, considering the
timing and type of toxicity for each patient.
Conclusions
In the last decade, we have witnessed a change in the therapeutic
management of patients with advanced RCC. The pivotal and
expanded access, with TKIs and inhibitors of the mTOR pathway,
studies has shown the ability to change the prognosis for these
patients. Unfortunately, these studies are not always the reality of
the practice of medical oncology at the inquiry reflected everyday
and see how many subgroups of patients are not represented
appropriately. Sunitinib was the first of these agents to be approved
by the health authorities by making it the most experienced agent
use, with publications and collection of experiences that allow some
recommendations in the subsets of patients none included in the
phase III studies.
In our real life practice, there are patients in special situations
like elderly patients, bone metastases, hepatic impairment, type
1 and 2 diabetes, renal insufficiency and end-stage renal disease,
haemodialysis, brain metastases, and unresectable surgery. Little is
known about the activity of targeted therapies, such of sunitinib, in
these subsets of patients. It could be a benefit of sunitinib treatment
for these patients, with good tolerance, by personalizing treatment in
each situation, even if that means changing the treatment schedule
without losing effectiveness [1-191].
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