Annual Meeting Proceedings Part 1 - American Society of Clinical ...

3629 General Poster Session (Board #38B), Mon, 8:00 AM-12:00 PM
Phase II trial evaluating a 12-week regimen of interdigitating FOLFOX
chemotherapy plus pelvic chemoradiation for the simultaneous treatment
of primary and metastatic rectal cancer. Presenting Author: Michael
Michael, Peter MacCallum Cancer Centre, Melbourne, Australia
Background: Current chemotherapy regimens used during chemoradiation
(CRT) are adequate for radiosensitization but suboptimal for systemic
control. The aim of this study was to assess tolerability, and local/systemic
benefits of new regimen delivering intensive chemotherapy and radical
radiotherapy in an interdigitating manner. Methods: Phase II prospective
study for patients (pts) with untreated simultaneous symptomatic primary
and metastatic rectal cancer. The treatment regimen: 12 weeks long.
FOLFOX chemotherapy (oxaliplatin 100mg/m2, leucovorin 200mg/m2,
5-FU 400mg/m2 bolus, all day 1, and 5FU continuous infusion [CI] 2.4
g/m2/46 hours) was given in weeks 1, 6, and 11. Pelvic CRT: 25.2 Gy in 3
weeks, 1.8 Gy/fr, with concurrent oxaliplatin 85mg/m2 day 1 and 5-FU CI
200mg/m2/day given in weeks 3-5, and 8-10. Pts received, in 12 weeks, 3
courses of FOLFOX and pelvic radiation 50.4 Gy with concurrent oxaliplatin/
5-FU. All pt were staged with CT, MRI and FDG-PET before and posttreatment.
Results: 26 pts treated. The mean age was 61 years, 69% male.
Rectal primary MRI stage was T2 4%, T3 81% and T4 15%. Liver and lung
metastases were present in 81%, and 35% of pts, respectively: 38% of
patients had more than one site of metastatic disease. 24 pts (92%)
completed the 12-week treatment regimen. All pts received the planned
radiation dose. 65% of pts received the planned number of oxaliplatin
courses with 88% of pts receiving at least 75% of the protocol oxaliplatin
dose. In this 12-week period, grade 3 toxicities were neutropenia 23%,
diarrhoea 15%, and radiation perineal skin reaction 12%. Only grade 4
toxicity was neutropenia: 15%. PET metabolic response (CR�PR) rate for
rectal primary was 96%. Overall PET metabolic response rate for metastatic
disease was 60% (CR rate 16%). Conclusions: It is thus feasible to
deliver intensive chemotherapy and radical radiotherapy in an interdigitating
manner to treat both primary and metastatic rectal cancer simultaneously.
High completion and response rates are encouraging. This regimen is
the subject of a current phase II neoadjuvant trial for resectable rectal
cancer (TROG 09.01).
3631 General Poster Session (Board #38D), Mon, 8:00 AM-12:00 PM
A phase I dose-escalation study of TAS-102 in patients (pts) with refractory
metastatic colorectal cancer (mCRC). Presenting Author: Manish Patel,
Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL
Background: TAS-102 is an oral combination of a novel antimetabolite
5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI)
that prevents degradation of FTD. In preclinical studies, TAS-102 is
effective against human colorectal tumors with innate and acquired
resistance to 5FU. A Japanese randomized phase 2 study demonstrated a
significant survival improvement of TAS-102 over placebo in refractory
mCRC (HR�0.56 p�0.0011, EMCC2011). The present study was conducted
to determine the MTD of TAS-102 in Western pts with refractory
mCRC. Methods: Pts with mCRC who had received at least 2 lines of
chemotherapy including a fluoropyrimidine, irinotecan and oxaliplatin were
enrolled at an initial dose level of 30 mg/m2 BID days 1- 5 and days 8-12
every 4wks using a standard 3�3 design. A second dose level of 35 mg/m2 ,
which was the MTD for Japanese pts, was the maximal targeted dose in this
study. Results: 12 pts received TAS-102 (30/35 mg/m2�3/9, M/F�7/5,
Age 44-75, PS0/1�8/4). Pts received a median of 3 prior regimens for
metastatic disease. No DLT was observed in the initial dose level (0/3) and
one DLT (grade 3 febrile neutropenia) was observed at 35mg/m2 (1/9).
Other drug-related � grade 3 toxicities observed in cycle 1 included
neutropenia at 58% (7/12). To date, a median number of treatment cycles
at the MTD has not been reached as 5 pts are still receiving therapy (range
1-3� cycles). Conclusions: Western patients with refractory mCRC showed
the same MTD as Japanese pts (35 mg/m2 BID, days 1- 5 and days 8-12
every 4wks) and the safety profile was consistent between the populations.
The trial has entered an expansion phase to assess further safety and
preliminary efficacy. A phase 3 trial is being planned.
Gastrointestinal (Colorectal) Cancer
235s
3630 General Poster Session (Board #38C), Mon, 8:00 AM-12:00 PM
Evaluation of the prognostic utility of miRNA and multiple genetic markers
in stage IIA colon cancer. Presenting Author: Elizabeth Mambo, Asuragen
Inc., Austin, TX
Background: The variable prognoses of stage II colon cancer subjects have
provoked a therapeutic dilemma of who should receive adjuvant therapy.
Presently, prognosis is evaluated on often subjective histopathological
features. Reliable, objective markers that can accurately predict recurrence
risk are needed. Using retrospectively collected tumor samples with known
clinical outcome, we evaluated the prognostic utility of miRNA together
with clinicopathological features and molecular markers with suggestive
prognostic value. Methods: We evaluated the expression of miRNA in 118
stage IIA FFPE tumors (73 non-recurrent, NR; 45 recurrent, R) using the
Affymetrix Gene Chip V1.0 microarray, and performed RT-qPCR to verify
select miRNAs. We also sequenced KRAS codons 12/13, and BRAF codon
600, and assessed MSI status using a fluorescent PCR-based assay. MMR
protein expression was determined by IHC. An empirical approach was
applied to screen miRNA using combinatorial criteria of microarray 2-way
ANOVA analysis, Kaplan-Meier curve logrank, and single and multivariate
Cox-regression. miRNA was the most significant predictor among all
histopathological and molecular features (FDR�0.05). A miRNA classifier
was built with nested two-layer cross-validation. Results: The top miRNA
model was selected based on AUC estimates and Cox-regression p-value.
This model included 30 miRNAs; 25 of these were common with the
empirical approach, confirming the robustness of candidate selection. The
miRNA classifier distinguished R from NR cases with an AUC of ~0.74.
Among all histopathological and molecular features evaluated, grade was
significantly associated with disease-free survival (logrank p�0.05). Both
single variate and multivariate Cox analysis revealed that grade and PMS2
status were strongly associated with recurrence (p�0.05). Lastly, lack of
expression of PMS2 and MLH1, BRAF V600E and MSI was highly
correlated (� coefficient � 0.6), and associated with non-recurrent
disease. Conclusions: These data provide strong support for miRNAs as
independent prognostic biomarkers for stage IIA colon cancer.Validation
work is ongoing to demonstrate the potential utility of these miRNAs in
patient stratification.
3632 General Poster Session (Board #38E), Mon, 8:00 AM-12:00 PM
Surgical resection and peri-operative chemotherapy for colorectal cancer
(CRC) liver metastases in routine clinical practice: A population-based
outcomes study. Presenting Author: Christopher M. Booth, Queen’s University
Cancer Research Institute, Kingston, ON, Canada
Background: Resection of liver metastases combined with peri-operative
chemotherapy is an important treatment option for patients with advanced
CRC. Most of the literature describes outcomes achieved in highly selected
patients treated at a few high volume institutions. Here we report the
results of a population-based study of the management and outcome of all
patients who underwent resection of CRC liver metastases in Ontario,
Canada. Methods: All cases of CRC in Ontario who underwent surgical
resection of liver metastases in 1994-2009 were identified using the
population-based Ontario Cancer Registry (OCR). The OCR captures
diagnostic and demographic information on ~98% of all incident cancer
cases in Ontario. We linked electronic records of treatment to the OCR to
identify surgery, neoadjuvant (NACT) and adjuvant chemotherapy (ACT).
We describe time trends in treatment and survival using 3 study periods:
1994-1999, 2000-2004, 2005-2009. Results: During 1994-2009, 2717
patients underwent resection of CRC liver metastases in Ontario; mean age
was 65 years and 61% were male. From 1994-2009 there was a 103%
increase in the number of patients undergoing resection of liver metastases
(117/year to 237/year) while incident cases of CRC during this time
increased by 31% (5285/year to 6956/year). Use of NACT increased over
the study period: 94-99, 11% (78/700); 00-04, 15% (124/830); 05-09,
36%; (424/1187), (p�0.001). Use of ACT also increased: 94-99, 38%
(263/700); 00-04, 40% (335/830); 05-09, 45% (532/1187), (p�0.006).
In 2005-2009 there was substantial variation across geographic regions in
use of NACT (range 19% to 46%, p�0.029) and ACT (range 31% to 56%,
p�0.015). Five year overall survival during the 3 study periods was 36%
(95%CI 32-39%), 40% (95%CI 36-43%), and 47% (95%CI 43-51%)
(p�0.001). Conclusions: Resection of CRC liver metastases in routine
practice in the general population of Ontario is associated with survival
outcomes that are comparable to those reported in case series from leading
comprehensive cancer centres. Survival improved over the study period
despite a greater proportion of patients with CRC undergoing liver resection.
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