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patients were admitted to the oncology day care unit for 8 hours in order to facilitate
repeated blood testing. Blood samples were obtained before the injection of LMWH
and 1, 2, 3, 4, 6 and 8 hours after LMWH subcutaneous administration, and tested
for anti Xa activity as a surrogate marker of bioavailable LMWH levels. The trial was
approved by the ethics committee of Shaare Zedek Medical Center. ClinicalTrials.gov
Identifier: NCT00716898. Study funding: Israel Cancer Association.
Results: Eleven patients were enrolled; one was excluded from analysis due to
complete remission at time of VTE diagnosis. Peak anti Xa activity was achieved
after 2, 3, 4, 6, and 8 hours in 2, 3, 2, 2, and 1 patient respectively. 60% of the
patients (n = 6) did not reach the therapeutic anti Xa activity target (0.6 -1.0 IU/ml)
at 4 hours after subcutaneous administration of LMWH. Average anti Xa activity at 4
hours was 0.62 ± 0.29 IU/ml as opposed to 1.1 IU/ml in historical controls of
non-oncology patients.
Conclusions: Our results show that a substantial number of cancer patients suffering
from VTE and treated with standard dose enoxoparin do not reach therapeutic target
anti Xa activity. If confirmed in a larger study, our results suggests that cancer
patients suffering from VTE should be tested for anti Xa activity and LMWH dose
should be titrated accordingly in order to achieve effective anticoagulation.
Disclosure: All authors have declared no conflicts of interest.
1617 EDMONTON SYMPTOM ASSESSMENT SCALE (ESAS) FOR
ROUTINE SYMPTOM ASSESSMENT OF NON-ADVANCED
PATIENTS WITH SOLID OR HAEMATOLOGICAL
MALIGNANCIES ON ONCOLOGICAL THERAPIES
C.I. Ripamonti1 , S. Boldini2 , L. Buonaccorso3 , E. Bandieri4 , A. Maruelli5 ,M.
A. Pessi6 and G. Miccinesi7 1
Supportive Care in Cancer Unit, Fondazione IRCCS - Istituto Nazionale dei
Tumori, Milano, ITALY, 2 Supportive Care in Cancer, Fondazione IRCCS, Istituto
Nazionale dei Tumori Milano, Milano, ITALY, 3 Psychology, AMO Association of
Oncological Patients from nine towns and villages in the Northen Area of
Modena, Mirandola, ITALY, 4 Oncological Unit, Azienda USL Modena CeVEAS
Modena, Mirandola Modena, ITALY, 5 Psychology Unit, LILT and Centre for
Oncological Rehabilitation CERION of Florence, Firenze, ITALY, 6 Supportive Care
in Cancer, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, ITALY,
7
Epidemiology, Cancer Prevention and Research Institute ISPO Florence,
Florence, ITALY
The Edmonton Symptom Assessment Scale (ESAS) was developed for use in daily
symptom assessment of palliative care patients. We used the ESAS validated version in
Italian Language to assess the presence and intensity of symptoms (not at all = 0; mild
1-4, not controlled ≥5) in 108 patients with solid and 86 with haematologic malignancies
and no metastases, on active oncological treatments (156 patients) or during follow-up.
In haematologic group, dyspnoea was ≥ 5 in 12% of the patients in respect to 3% of solid
tumour group (chi2 test, p = 0.002). Not controlled fatigue, drowsiness and dyspnoea
were significantly more frequent in patients on cure (p = 0.041; p = 0.026; p = 0.010
respectively). The intensity of all the symptoms was higher in patients with a KPS of
70-90 in respect to those with KPS > 90, and in patients above the clinical HADS cutoff
(10/11) in respect to those below. The intensity of psychological suffering was higher for
patients who requested psychological support. The correlation (rho of Pearson) between
the anxiety and depression items of ESAS with HADs was >.5, whereas the feeling of
well- being in ESAS inversely strongly correlated with all the other ESAS symptoms (rho
> .4); anorexia with nausea and drowsiness; drowsiness with fatigue; and anxiety with
depression. As the ESAS assesses the most frequent symptoms referred to by the patients
during oncological treatments, its administration to the patients in the routine practice
before each visit with the oncologist can give him/her the information on the presence
and intensity of physical and emotional symptoms.
Disclosure: All authors have declared no conflicts of interest.
1618 IN VITRO DRUG-DRUG INTERACTION STUDIES WITH THE
ANTIEMETIC DRUG NETUPITANT AND ITS MAJOR
METABOLITES M1 AND M2, INVOLVING SEVERAL HUMAN
CYTOCHROME P450 ISOENZYMES
C. Giuliano 1 ,E.Lovati 1 , C. Funk 2 , M. Potthast 2 and C. Pietra 1
1 Preclinical R&D, Helsinn Healthcare SA, Lugano, SWITZERLAND, 2 Non-clinical
Drug Safety, Hoffmann La-Roche Ltd., Basel, SWITZERLAND
Introduction: Nausea and emesis are significant adverse events of chemotherapy.
Substance P plays a major role in the emetic process especially in the delayed emesis
occurring 24h after treatment and beyond. Antagonism of substance P effect at the
neurokinin 1 (NK1) receptor level is a validated target in showing a broad antiemetic
activity in animal models of emesis and also in humans. Within the new NK1
antagonists in clinical trials, Netupitant (Netu) has been characterized as an
antiemetic in vitro and in vivo in various pharmacological experiments against
emesis induced by chemotherapeutics. In vitro studies have shown that the CYP3A4
isoenzyme is the major enzyme involved in the oxidative metabolism of Netu.
Methods: The in vitro inhibition potential of Netu and its major metabolites M1 and
M2 has been studied for the human cytochrome P450 isoenzymes CYP1A2, 2C9,
2C19, 2D6 and 3A4 utilizing human liver microsomes and isoform selective
substrates.
Results: Netu inhibited the CYP3A4-dependent metabolism of the two isoform
selective probe-substrates midazolam and testosterone with estimated IC 50 (±S.E.)
values of 5.9 ± 1 and 1.7 ± 0.2 µM, respectively. For the hydroxylation of diclofenac,
catalyzed by CYP2C9, IC50 (±S.E.) of 18.0 ± 6 and 22.6 ± 3 µM were calculated in two
different experiments, utilizing both the free base, and the Netu hydrochloride as
inhibitors. Netu showed no significant inhibition potential for CYP1A2, 2C19 and
2D6 (IC 50s >100 µM).
Conclusions: Significant metabolic drug-drug interactions in human are not
anticipated for compounds metabolized mainly by CYP1A2, 2C19 and 2D6 and are
very unlikely for CYP2C9 metabolized drugs based on the expected human plasma
concentration of Netu in the low μmolar range. However, metabolic drug-drug
interactions are possible for co-medicated drugs metabolized mainly by CYP3A4,
based on the high in vitro affinity of Netu for this isoenzyme, as tested with
testosterone and midazolam (app Ki ∼ 1.1 to 2.2 µM) and for the inhibition potential
of the metabolites M1 and M2 similar to the parent compound. The in vivo CYP3A4
interaction has been studied in appropriate designed clinical interaction studies.
Disclosure: C. Giuliano: Helsinn healthcare employee, E. Lovati: Helsinn Healthcare
employee, C. Funk: Roche employee, M. Potthast: Roche employee, C. Pietra: Helsinn
employee.
1619 CILASTATIN ATTENUATES CISPLATIN-INDUCED
NEPHROTOXICITY WITHOUT COMPROMISING
ANTITUMORAL ACTIVITY
Annals of Oncology
B. Humanes1 , M. Blanco Codesido2 , A. Lázaro1 , S. Camaño1 and A. Tejedor1 1
Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, SPAIN,
2
Servicio de Oncología Médica, Hospital General Univ. Gregorio Marañon,
Madrid, SPAIN
Introduction: Cisplatin (CDDP) is a very effective and common treatment in solid
malignancies used mostly in breast, ovarian, bladder, esophageal, gastric, head and
neck cancer and germ cell tumors. One of the most important side effects of CDDP
is the nephrotoxicity, especially with CDDP doses higher than 60 mg/m2, affecting as
much as 30% of the patients. Nephrotoxicity is a limitating side effect on treatment
with CDDP, preventing patients with limit kidney function of receiving the drug and
stopping treatment once kidney function has worsened. Cilastatin (Cls) is a specific
inhibitor of renal dedydrodipeptidase I (DHP-I) which prevents hydrolysis of
imipenem and its accumulation in the proximal tubule. In this work we hypothesized
that Cls acts as a nephroprotector against CDDP-induced damage without
compromising antitumor activity.
Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different
malignancies (colon, breast, ovarian, bladder) were cultured with different
concentrations of CDDP (1, 10 and 30 µM) in the presence or absence of Cls. Cell
viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium
bromide) assay. Raft staining was measured with toxine B
choleric and FasL by confocal microscopy.
Results: Cls interfered with CDDP-induced FasL signalling at raft level on PTCs
brush border. Concomitant treatment with Cls reduced CDDP-induced changes.
Several tumoral cell lines were tested with CDDP and Cls together. Cls did not
increase or decreased tumor growth alone or in combination with CDDP. CDDP
sensitivity was not affected by Cls.
Conclusion: By binding a DHP-I, Cls blocks CDDP-induced PTCs apoptosis but it
does not affect the CDDP antitumoral activity. Our findings suggest that the affinity
of Cls for renal DHP-I makes this effect specific for proximal tubular cells and may
be related to a reduction in intracellular drug accumulation. Cls administration might
represent a novel strategy in the prevention of CDDP-induced acute renal injury. Cls
treatment could potentially increase the number of patients undergoing CDDP
treatment or maintaining treatment. Further clinical trials for renal function
preservation in cancer patients are on development.
Disclosure: All authors have declared no conflicts of interest.
1620 WEIGHT LOSS DESPITE ORAL GLUTAMINE
SUPPLEMENTATION PREDICTS POOR PROGNOSIS IN
LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER
PATIENTS TREATED WITH CONCURRENT
CHEMORADIOTHERAPY
C. Parlak 1 , S. Topuk 1 , O. Ozyilkan 2 and E. Topkan 1
1 Department of Radiation Oncology, Baskent University Adana Medical Faculty,
Adana, TURKEY, 2 Medical Oncology, Baskent University Faculty of
MedicineAdana Uygulama Ve Arastirma Mer., Adana, TURKEY
Background: In this retrospective study, we investigated potential impact of weight
change according to oral glutamine supplementation (GLT) on survival in patients
with stage IIIB non-small cell lung cancer (NSCLC) treated with concurrent
chemoradiotherapy.
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