SCIENTIFIC REPORT 2010 - 2011 - IOV

Major Ongoing Research Projects
NEw ThErapEuTiC STraTEGiES iN ThE TrEaTmENT Of
GaSTrO-iNTESTiNal (Gi) TumOrS
Principal Investigators: Sara Lonardi, Davide Pastorelli, Vittorina
Zagonel
The management of GI tract cancers (both colorectal and
non-colorectal) has widely changed over the last years, switching
from a “tumor” perspective to a “patient’s tailored” approach.
Identification of prognostic and predictive markers, optimization
of multidisciplinary strategies, and new targeted drug development
are some of the major points of interest for clinical and experimental
research. Several trials are currently ongoing at our Institution in
collaboration with multidisciplinary groups of Padua and others
Oncology Units and national groups.
A. prOGNOSTiC aND prEDiCTivE faCTOrS
The identification of patients characterized by a worse
prognosis or by a higher probability of response to certain
treatments is crucial to select the “better population” for the
“better therapeutic strategy”, and it is one of the main areas of
research at our Institution.
Molecular factors predictive of response to pre-operative
chemo-radiation in locally advanced rectal cancer.
Pre-operative chemo-radiotherapy (pCRT) approach for
locally advanced rectal cancer is worldwide accepted as a standard
treatment. The prediction of response to CRT has the potential
to spare unnecessary toxic treatments for non-responders and,
in selected cases, to allow a conservative surgery (local excision).
Multiple patient- and tumor-related factors have been evaluated
as potential predictors of response, but few studies take the tumor
biology into account. Patients with rectal cancer, candidate to
receive the same schedule of pCRT will be prospectively evaluated
to assess the correlation of carcinoembryonic antigen (CEA),
cell-free circulating DNA (cfDNA), levels of telomerase reverse
transcriptase (h-TERT) and circulating tumor cells (CTC) with
pathological response after pCRT and disease recurrence.
Pharmacogenetic profiling and clinical outcome of patients
with high-risk stage II and III colon cancer treated with adjuvant
FOLFOX-4/XELOX chemotherapy and bevacizumab.
Oxaliplatin plus a fluoropyrimidine (FOLFOX/XELOX) is
THE DEPARTMENTS - DEPARTMENT OF CLINICAL ONCOLOGY
39
the worldwide standard adjuvant therapy for high-risk stage II
and III colorectal cancer, but the optimal duration of therapy and
the management of toxicities remain to be resolved. Hopefully,
it would be useful to find predictive/prognostic markers that
could allow future adjuvant strategies to be optimized and
individualized. Genomic polymorphisms in drug target genes,
genes encoding DNA-repair enzymes and detoxification pathways
may influence the activity of 5-Fluorouracil/capecitabine and
Oxaliplatin, and their identification may improve the tailoring of
chemotherapy and the choice of the optimal treatment strategy.
In the present multicenter study, a panel of 17 polymorphisms
within eleven genes in patients with radically resected high-risk
stage II and III colon cancer undergoing adjuvant FOLFOX-4/
XELOX chemotherapy and bevacizumab within a prospective
phase III randomized clinical trial will be evaluated.
Prospective evaluation of -1498 C/T VEGF polymorphism
in the prediction of benefit from first-line FOLFIRI plus
bevacizumab in metastatic colorectal cancer patients.
Many studies have demonstrated that specific VEGF single
nucleotide polymorphisms (SNPs) may affect gene transcription
with a consequent variable production of VEGF and a probable
indirect effect on pathogenesis and evolution of several disorders
in which angiogenesis may be critical. Patients bearing -1498
T/T genotype had significantly shorter progression-free survival
(PFS) and worse, but not statistically significant, overall
survival (OS) compared to patients carrying at least one C
allele. On this basis we planned to prospectively evaluate the
potential predictive role of -1498 C/T VEGF polymorphism in
CRC patients treated with first-line FOLFIRI plus Bevacirumab.
Primary objective is to evaluate the correlation between -1498
C/T VEGF allelic variants and first-line PFS, while the secondary
objectives is to evaluate the correlation with response rate, overall
survival and toxicities attributable to Bevacizumab.
B. OpTimizaTiON Of ThE TimiNG Of aDiuvaNT ChEmOThErapy
Gastric and pancreatic cancers are a major cause of mortality
worldwide. Prognosis is poor unless the cancer is diagnosed at
a very early stage. Therapeutic options for patients with stage
I-III gastric and pancreatic cancer include surgery plus adjuvant
chemotherapy with or without radiotherapy, but the optimal