SCIENTIFIC REPORT 2010 - 2011 - IOV

and experimental research. Several workers at IOV are now
deeply involved in the treatment of this disease, aiming at buiding
a multidisciplinary approach which has proven crucial for the
progress of research in other more common cancers.
a. CirCulaTiNG TumOr CEllS (CTC) iN paTiENTS TrEaTED wiTh
firST-liNE SuNiTiNib
CTC have a strong prognostic significange in breast,
colorectal and prostate cancer, but their value in patients with
advanced kidney cancer is sill poorly documented. A pilot study
evaluating CTC counts in advanced RCC patients treated with
first-line sunitinib has been carried out in cooperation with the
Immunology and Molecular Oncology Unit of IOV, and other
Oncological Units. More than 50 patients have been accrued so
far, and about two thirds of them had one or more CTC in the
blood. Total counts of CTC did not appear to correlate with the
number of metastatic sites, and response or progression during
sunitinib. However, when a count of apoptotic CTC was carried
out, we found that an increase in these biologically inactive cells
correlated with prolonged disease control. Based on these findings,
we plan to extend the accrual to this study in order to prove the
prognostic role of apoptotic CTC in advanced RCC.
b. SuNiTiNib iN vON hippEl-liNDau SyNDrOmE
Loss of function of the von Hippel-Lindau (VHL) gene located
on chromosome 3 is the cause of this rare syndrome, but is also
a key pathogenetic step in the development of sporadic clear cell
RCC, with ensuing over-expression of VEGF-R, Platelet-Derived
Growth Factor Receptor (PDGFR) and their ligands by the tumor
and surrounding endothelial cells. In cooperation with the Unit
for Hereditary Cancer of the IOV we started collecting data on
VHL syndrome patients with advanced or recurrent RCC seen at
our Institution. They were all treated with the TKI sunitinib as a
first line regimen. Preliminary results have been presented at the
ASCO Genitourinary Congress on February 2011.
C. SuNiTiNib iN ElDErly paTiENTS
Since the activity and tolerability of sunitinib in unselected
elderly patients ≥ 70 years are still poorly documented, we
performed a retrospective analysis on feasibility and outcome
of first or second-line sunitinib in 67 elderly patients with renal
carcinoma followed in six oncological centers (IOV, Verona,
Vicenza, Rovigo, Udine, Lucca). We found that dose reductions
THE DEPARTMENTS - DEPARTMENT OF CLINICAL ONCOLOGY
42
(up-front or after a few cycles) are frequently needed, but median
PFS of about 13 months compares favourably with published data,
with only three cases of cardiotoxicity. Results were presented at
the ECCO Conference in October 2009. In cooperation with
IRST-Meldola we are currently conducting a larger analysis in
elderly patients receiving sunitinib as a first-line treatment for
advanced cancer.
D. pharmaCOkiNETiCS Of Oral DruGS aND COrrElaTiON wiTh
rESpONSE aND TOxiCiTy
Both sunitinib and everolimus (an inhibitor of m-TOR
complex) are administered at fixed oral doses with no modifications
according to age or body surface. Yet, recent data show that
plasma drug levels may be different among patients due to dose
reductions and heterogeneity in pharmacokinetics (mainly due
to polymorphisms of Cytochrome P450 family proteins and/or
concomitant medications). Different blood concentrations may
translate into different toxicity rates as well as reduced tumor
control. In cooperation with the Pharmacology Unit of CRO-
Aviano and IRST-Meldola we plan to conduct a study evaluating
the blood levels of sunitinib and everolimus administered to
young and elderly RCC patients. Our aims are to assess agerelated
differences, to clarify situations of unexpected toxicity and
to elaborate predictive models in which daily dose modifications
of sunitinib and everolimus might be driven by pharmacogenomic
polymorphisms (Cytochrome 3A4 or other proteins), actual
blood concentrations of native drug and its active metabolites as
well as co-administration of other drugs interfering with hepatic
drug metabolism.
E. CarDiOTOxiCiTy Of Oral Tki
Since hypertension, decrease in Left Ventricular Ejection
Fraction (LVEF), clinically symptomatic congestive heart failure,
myocardial hyschemia and rhythm alterations have been described
in patients treated with sunitinib and sorafenib, all patients
with RCC treated at IOV undergo cardiologic monitoring in
cooperation with the Cardiology Unit. Over the years 2006-2010,
around 70 patients were followed with clinical examination,
electrocardiogram and echocardiography performed at 4 to 6
months intervals. Several cardiac events were registered, mainly
grade 1 or 2 according to CTCAE and reversible after appropriate
treatments, allowing the majority of patients to resume treatment.
A retrospective evaluation of type, treatment and outcome of these