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

226s Gastrointestinal (Colorectal) Cancer
3593 General Poster Session (Board #33F), Mon, 8:00 AM-12:00 PM
Phase II trial of combined chemotherapy with irinotecan, S-1, and
bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer:
Update analysis—Hokkaido Gastrointestinal Cancer Study Group (HGCSG)
trial. Presenting Author: Satoshi Yuki, Department of Gastroenterology,
Hokkaido University Hospital, Sapporo, Japan
Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853–
860) previously demonstrated the non-inferiority of Irinotecan plus S-1(IRIS)
to FOLFIRI for metastatic colorectal cancer(mCRC), with progression-free
survival (PFS) as the primary endpoint. We previously reported that IRIS
plus bevacizumab(IRIS/bev) is very effective as first-line treatment (Komatsu
Y et al. ESMO 2010). We now report the updated results of this study.
Methods: Eligible patients had to have mCRC with a confirmed diagnosis of
adenocarcinoma, an age of �20 years, ECOG performance status (PS) of
0-1, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o.
was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5
mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The primary
endpoint was safety. The secondary endpoints included overall response
(OR), progression-free survival (PFS), and overall survival (OS). Results: The
target number of 53 patients was enrolled as of March 2009. The results
are reported for 52 patients with evaluable lesions. The clinical characteristics
of the patients were as follows. The median age was 63.5 years (range,
48 to 82). The male:female ratio was 3:2. The performance status on the
Eastern Cooperative Oncology Group scale was 0. In January 2012, on
safety analysis, the incidence of grade 3 or 4 neutropenia was 27%. The
incidences of other grade 3 or 4 adverse reactions were as follows: diarrhea,
17%; anorexia, 4%; stomatitis, 2%; hypertension, 21%; and gastrointestinal
perforation, 0%. The overall response rate was 63.5%. Three patients
had complete response. Thirty patients had partial response, 16 had stable
disease, none had progressive disease, and 3 were not evaluable. Median
progression-free survival was 17.0 months and median survival time was
39.6 months. Conclusions: IRIS/Bev is a remarkably active and generally
well-tolerated first-line treatment for patients with mCRC. Randomized
control trial comparing this regimen with oxaliplatin containing regimen(X-
ELOX or mFOLFOX6 plus bevacizumab) is being planned.
3595 General Poster Session (Board #33H), Mon, 8:00 AM-12:00 PM
Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and
sorafenib (Sor) in patients with locally advanced, K-ras-mutated rectal
cancer (LARC): A phase I/II trial (SAKK 41/08). Presenting Author: Roger
Von Moos, Kantonsspital Graubünden, Chur, Switzerland
Background: 40% of patients (pts) with LARC present with K-ras mutation.
Sor is an inhibitor of ras/raf and of VEGFR. Furthermore Sor has radiosensitizing
effects. These facts build a strong rationale to use Sor in combination
with preoperative RT and Cape in pts with K-ras mutant tumors. Methods:
Pts with K-ras mutated mrT3-4 and / or mrN�, M0 disease were recruited
in cohorts of 7 pts per dose level (DL). Dose limiting toxicity (DLT) was
defined as any G3 or higher non hematological toxicity (tox) or haematological
tox during � 7 days, which are possibly, probably or definitely related to
trial treatment occurring during and up to 4 weeks after last administration.
If � 2 out of 7 pts experienced a DLT, then the next cohort was treated at a
higher dose level. If � 2 out of 7 pts suffered from a DLT, this DL would be
considered too toxic and a dose level below would be tested in the next
cohort. The highest dose level with � 2 out of 7 pts experienced a DLT
would be recommended for the phase II part. In all dose levels RT was given
in 25 fractions at 1.8Gy (45Gy). Results: In 8 centers in Switzerland a total
of 21 pts in 3 cohorts have been treated in the phase 1 study. After
observing severe skin toxicity and diarrhea (2 pt with skin toxicity G3, one
patient (pt) with diarrhea G3 plus hand-foot syndrome (HFS) (G3)) an
amendment was implemented to reduce the Sor dose from 400mg BID to
once daily. In DL 1 after the amendment, 2 pts experienced a DLT (enteritis
G3, dermatitis G3). Two pts in DL 2 suffered from a DLT (cystitis G3 plus
HFS G3, cardiac ischemia G3). Further non dose-limiting G3 toxicities
after the amendment were lymphopenia (G3) (1pt, DL 2) and hypocalcaemia
(G3) (1 pt, DL 2). No Grade 4 toxicity was seen. DL 2 is the
recommended dose for phase II. Conclusions: After reducing the Sor dose to
400mg once daily, neoadjuvant treatment with Sor in combination with full
dose Cape and RT was tolerable and the toxicities manageable.
Dose level
(each with 7 pts)
Capecitabine (mg/m 2 )
per day during 5 weeks
Sorafenib (mg)
per day during 5 weeks
DL 1 before amendment 2 x 600 2 x 400
DL 1 after amendment 2 x 600 1 x 400
DL 2 after amendment 2 x 825 1 x 400
3594 General Poster Session (Board #33G), Mon, 8:00 AM-12:00 PM
Functional SNPs in vascular endothelial growth factor (VEGF-A) and overall
survival (OS) in bevacizumab-treated patients with metastatic colorectal
cancer (mCRC). Presenting Author: Janet E. Murphy, Massachusetts
General Hospital Cancer Center, Boston, MA
Background: Functional SNPs in VEGF-A are prognostic for OS in several
malignancies, but not described definitively in mCRC. In bevacizumabtreated
patients with advanced breast cancer, VEGF -2578AA and -1154A
were predictive of OS—the latter SNP reported in a recent mCRC series as
well. We examined the association between five functional VEGF-A SNPs
and OS in a large cohort of bevacizumab-treated patients with mCRC.
Methods: 403 patients with mCRC treated from 2004-2010 were included
in a retrospective analysis. DNA extraction, genotyping, and SNP evaluation
were performed according to standard protocols. Survival was calculated
from the time of Stage IV diagnosis until death. Data were censored as
of 12/31/2010. Results: There were 279 deaths in this group of 403
patients (69%). Median age was 55.7 (24-86 y), and 54% of patients were
male. Age, sex, race, tumor grade, chemotherapies, and curative surgery
(metastatectomy to negative margins) were considered. Significant clinical
predictors of OS in univariate Cox modeling were cetuximab treatment
[HR�1.46; 95% CI 1.13-1.88; p�0.0014], irinotecan treatment
[HR�2.10; 1.32-3.35; p�0.001], and curative surgery [HR�0.36; 0.25-
0.75; p�0.001]. Significant negative interaction was found between both
cetuximab and irinotecan and curative surgery, and in modeling that
included this interaction, only surgery remained predictive. In multivariate
analysis, no association was found between VEGF-A and OS (Table).
Conclusions: There was no association between five functional VEGF-A
SNPs and OS in this large bevacizumab-treated mCRC cohort.
SNP Allelic pairs HR [95% CI] Allelic pairs HR [95% CI]
VEGF-2578 C/A vs C/C 1.10 [0.82-1.46] A/A vs C/C 1.06 [0.77-1.46]
VEGF-1154 A/G vs A/A 1.14 [0.89-1.47] G/G vs A/A 0.93 [0.63-1.37]
VEGF-460 C/T vs T/T 1.02 [0.76-1.36] C/C vs T/T 0.95 [0.69-1.30]
VEGF�405 C/G vs G/G 1.13 [0.87-1.47] C/C vs G/G 0.94 [0.67-1.32]
VEGF�936 C/T vs C/C 1.14 [0.87-1.49] T/T vs C/C 0.90 [0.37-2.17]
3596 General Poster Session (Board #34A), Mon, 8:00 AM-12:00 PM
Treating patients with colorectal liver metastasis: A national decisionmaking
analysis to understand choice of therapy. Presenting Author:
Timothy M. Pawlik, Johns Hopkins Hospital, Baltimore, MD
Background: Criteria for resectability of colon cancer liver metastases (CLM)
are evolving, yet little is known about how physicians choose a therapeutic
strategy for potentially resectable CLM. Methods: Physicians completed a
national web-based survey that consisted of varied CLM case scenarios.
Respondents choose among 3 treatment strategies: immediate liver resection(LR),
preoperative chemotherapy followed by surgery(C¡LR), or palliative
chemotherapy (PC). Data were analyzed using multinomial logistic
regression, yielding relative risk ratios (RRR). Results: Of 219 respondents,
79% practiced at academic centers and 63% were in practice �10 years.
Median number of cases evaluated was 4/month. Surgical training varied:
51% surgical oncology (SO), 44% hepatobiliary/transplant (HB/LT), 5% no
fellowship. While each factor impacted choice of CLM therapy, the relative
impact differed (p�0.01). Synchronous CLM presentation increased the
choice of C¡LR (OR 4.27) and PC (OR 3.10) versus LR (p�0.001). For
patients with more extensive intrahepatic disease (i.e., 5 tumors, both
lobes) respondents strongly favored C¡LR (OR 5.12) and PC (OR 9.60)
versus LR (p�0.001). The presence of hilar lymph-node disease was
associated with a strong aversion to LR with surgeons more likely to choose
C¡LR (OR 8.92) or PC (OR 49.9) (p�0.001). Interestingly, even the
presence of a resectable solitary lung metastasis strongly deterred choice of
LR with respondents favoring C¡LR (OR 4.43) or PC (OR 6.97) (p�0.001).
While other factors such as patient age, tumor size, and extent of resection
impacted choice of therapy, the relative size of these effects was modest.
After controlling for clinical factors, surgeons with more years in practice
were more likely to choose LR (RRR 1.4). SO-trained surgeons were more
likely than HB/LT-trained surgeons to choose C¡LR (RRR 2.5) or PC (RRR
4.15)(p�0.001). Conclusions: This is the first study to define the relative
impact of key clinical factors on choice of therapy for CLM. While clinical
factors influence choice of therapy, surgical subspeciality and physician
experience are also important determinants of care.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.