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plus intravenous Bev(7.5mg/kg q 21d) for 12/12. This abstract overviews the final
toxicity data (15/12 minimum follow up per patient) from the Q2 trial.
Results: 1952 patients were consented and randomised and, after excluding patients
who did not receive at least one cycle of treatment, 963 patients receiving Cape alone
and 959 patients receiving Cape plus Bev were analysed. Baseline characteristics
(gender / age / stage of disease) were balanced across the 2 arms. See frequency of
selected toxicities, as % patients, in table below.
Discussion: As expected, the rates of hypertension (all grade or high grade) and
proteinuria and wound healing (all grade) were significantly higher among patients
receiving Bev. Although the addition of Bev did not increase diarrhoea rates, the
frequency and severity of HFS was increased. This is not well recognised. Although
cardiac chest pain was not increased by the addition of Bev, both arterial and venous
thrombo-embolism (ATE/VTE) rates were increased although the difference only
reached significance for VTE in this study. This is in contrast to most results in the
advanced disease setting and may be a result of an interaction between post-operative
risk of VTE and pro-thrombotic potential of Bev. Of note, an excess of ‘possibly
treatment-related’ deaths was found in patients receiving Bev (1.9% vs 0.8%:RR2.3:CI
1.0-5.2) and this just reached significance (p = 0.05). All results will be expanded in
detail in the presentation / poster.
Cape/ Bev Cape RR/CI/p
Hypertension (all grades) 33.4 7.8 4.3/3.4-5.4/p < 0.001
Hypertension (g3/4) 3.8 0.6 6.0/2.6-14.2/p < 0.001
Proteinuria (all grades) 20.5 5.1 4.0/3.0-5.4/p < 0.001
Poor wound healing (all grades) 3.1 1.8 1.8/1.0-3.2/p = 0.05
Diarrhoea (g3/4) 10.8 10.6 1.0/0.8-1.3/p = 0.9
Hand-foot syndrome (g3/4) 26.8 20.9 1.3/1.1-1.5/p = 0.002
Cardiac chest pain SAE 2.7 2.6 1.0/0.6-1.8/p = 0.9
Arterial Thromboembolism SAE 1.1 0.6 1.8/0.7-5.0/p = 0.2
Venous Thromboembolism SAE 4.3 2.3 1.9/1.1-3.1/p = 0.01
Disclosure: R.S. Midgley: Auther has received no strings attached educational
unrestricted grant for clinical research and has sat on advisory boards for Roche.
V. Potter: Auther has received a travel grant and has sat on an advisory board for
ROche. E. Segelov: Author has sat on an advisory board for Roche Autralia.
D.R. Ferry: Auther has received travel grants, research grants and has sat on advisory
boards for Roche. S. Grumett: Auther has received traval grants and has sat on
advisory boards for Roche. D.J. Kerr: Auther has received no strings attached
educational unrestricted grant for clinical research and has sat on Advisory Boards
for ROche. All other authors have declared no conflicts of interest.
531P SHOULD PALLIATIVE RESECTION OF PRIMARY TUMOR BE
PERFORMED IN PATIENTS WITH ADVANCED COLORECTAL
CANCER? A SYSTEMATIC REVIEW & META-ANALYSIS
S. Ahmed 1 , R.K. Shahid 2 , A. Leis 3 , K. Haider 1 , P. Pahwa 3
1 Medical Oncology, Saskatoon Cancer Centre University of Saskatchewan,
Saskatoon, SK, CANADA, 2 Medicine, University of Saskatchewan, Saskatoon,
SK, CANADA, 3 Community Health & Epidemiology, University of Saskatchewan,
Saskatoon, SK, CANADA
Background: Colorectal cancer (CRC) is a leading cause of cancer death. Surgical
resection of the primary tumor in patients with advanced CRC remains controversial.
Limited data is available regarding potential benefits and risk of primary tumor
resection in such patients.
Objectives: To compare survival of patients with advanced CRC who underwent
surgical resection of primary tumor with patients without resection. The review also
aims to determine post-operative mortality & non-fatal complications rates, primary
tumor complications rate (PTCR), non-resection surgical procedures rate (NSPR)
and quality of life (QOL).
Methods: A literature search was conducted by using CENTRAL (2012), Medline
(1946-2012), and EMBASE (1947-2012). Selection Criteria: Studies involving patients
with advanced colorectal adenocarcinoma who underwent primary tumor resection
were selected using pre-specified eligibility criteria with restriction to publication
dates from 1980, English language and human studies. Data Collection and analysis:
Screening, evaluation of relevant articles and data abstraction was done in
duplication and agreement was assessed. Articles that met the inclusion criteria were
assessed for quality by using Ottawa-Newcastle score. Data was collected and
synthesized as per protocol.
Results: Of total of 3379 reports, 15 retrospective observational studies were selected
with patients population of 12456. Among 12456 patients, 8620 (69%) underwent
surgery with a median overall survival of the 15.2 months (range: 10-30.7) compared
with 11.4 months (range: 3-22) of the non-resection group. Hazard ratio (HR) for
survival was 1.44 (95% CI: 1.26-1.64) favoring surgical intervention. Mean 30 days
post-operative mortality and non-fatal complications rates were 4.9% (95% CI: 0-9.7)
& 25.9% (95%CI: 20.1-31.6) respectively. Mean PTCR & NSPR in the control group
were 29.7% (95%CI: 18.5-41.0) and 27.6% (95 CI: 15.4-39.9) respectively. No study
provided QOL data. Sub-group analysis that were defined a priori revealed HR of
1.46 (95% CI: 1.20-1.78) favoring surgical intervention in patients treated with
modern chemotherapy.
Conclusions: The retrospective data favors primary tumors resection in advanced
CRC. Future prospective randomized trials are warranted to confirm the findings.
Disclosure: All authors have declared no conflicts of interest.
532P PTEN AND ADVANCED COLORECTAL CANCER (CRC):
ANALYSIS FROM THE PHASE III AGITG MAX TRIAL OF
CAPECITABINE ALONE OR IN COMBINATION WITH
BEVACIZUMAB +/- MITOMYCIN C
T. Price 1 , J. Hardingham 1 , C. Lee 2 , A. Townsend 1 , J. Wrin 1 , K. Wilson 2 ,
A. Weickhardt 3 , R.J. Simes 2 , C. Munroe 3 , N. Tebbutt 4
1 Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville
South, SA, AUSTRALIA, 2 CTC, University of Sydney, Sydney, NSW,
AUSTRALIA, 3 Oncology, Ludwig Institute, Melbourne, VIC, AUSTRALIA,
4 Medical Oncology, Austin Hospital, Heidelberg, VIC, AUSTRALIA
Background: The tumour suppressor gene PTEN may have a role as a biomarker for
anti-EGFR therapy in CRC. As PTEN expression also has a relationship with VEGF
expression via HIF-1 alpha, and the PI3K/mTOR pathways, we have explored the
potential that PTEN loss may be predictive of outcome with an anti-VEGF agent. We
also assess the prognostic value of PTEN as this remains controversial.
Methods: Patients enrolled in the Phase III MAX trial of capecitabine (C) +/bevacizumab
(B) (+/- mitomycin C (M)) with available tissues were analysed for
PTEN expression (loss v no loss) as assessed using a Taqman® copy number assay to
measure copy number variation at the PTEN locus. The predictive value of PTEN
status for bevacizumab efficacy was examined. PTEN status was also correlated with
progression-free survival (PFS) and overall survival (OS) outcomes, and a second sub
analysis grouping PTEN by KRAS/BRAF status was also performed.
Results: Of the original 471 patients enrolled in the trial, tissues from 302 (64.1%)
patients were analysed. Baseline characteristics of those with and without tissues were
comparable. PTEN loss was observed in 38.7% of patients. There was no relationship
between PTEN loss and KRAS or BRAF mutation (KRAS/BRAF MT v WT with
PTEN loss; 34%/37% v 41%/39% respectively). PTEN loss was associated with rectal
primary (p = 0.01) and lower rates of lung metastasis (p = 0.03). By using the
comparison of C v CB + CBM, PTEN status was not significantly predictive of the
effectiveness of B for PFS or OS (Table). PTEN status is also not prognostic for PFS
or OS in multivariate analyses adjusting for other baseline factors (Loss v No Loss
PFS HR 0.9 (0.7-1.16), OS HR 1.04 (0.79-1.38)). PTEN was also not prognostic when
assessed by KRAS and BRAF status.
Conclusions: PTEN status did not significantly predict different benefit with
anti-VEGF therapy. PTEN status was not prognostic for survival in advanced
colorectal cancer.
C vs CB + CBM Loss No loss P value (for interaction)
PFS HR 0.51 0.33 - 0.79 HR 0.72 0.52-0.98 P = .26
OS HR 0.75 0.47-1.19 HR 1.00 0.70-1.43 P = .35
Disclosure: T. Price: Uncompensated Advisory board Merck, AMGEN and Roche.
Travel grants Merck and AMGEN. N. Tebbutt: Uncompensated Ad board Roche. All
other authors have declared no conflicts of interest.
533P SOMATIC K-RAS MUTATION IS PREDICTIVE IN COLORECTAL
CANCER, BUT IS IT PROGNOSTIC? A SYSTEMATIC REVIEW
AND META-ANALYSIS
I.B. Tan, T. Seah, S.L. Koo, S. Choo, C.K. Tham, D. Chong
Medical Oncology, National Cancer Centre, Singapore, SINGAPORE
Annals of Oncology
Background: Consistent data from retrospective molecular analysis performed in
multiple phase 3 Randomized controlled trials (RCTs) have established that somatic
KRAS mutation (K-RAS-mt) is a strong predictor of non-response to anti-epidermal
growth factor receptor antibody (anti-EGFR) therapy in colorectal cancer. However,
K-RAS’s role as a prognostic marker remains undefined. We performed a systematic
review and meta-analysis to determine the prognostic significance of somatic K-RAS
mutation.
Methods: We searched MEDLINE, EMBASE, and CENTRAL databases, ESMO and
ASCO meeting proceedings for Phase 3 RCTs in colorectal cancer for which
retrospective molecular analysis of K-RAS mutation was performed on archival
patient samples. Studies were pooled according to setting of treatment (adjuvant, 1 st
line metastatic, refractory). Meta-analysis was performed using random-effects model.
The outcomes of interest were disease-free survival in the adjuvant setting and
overall survival (OS) for advanced disease.
Results: 14 Phase 3 trials which enrolled 18,991 patients were identified, of whom
13,143 had K-RAS status ascertained (69.2% range: 48%-100%) In pooled data of
ix182 | Abstracts Volume 23 | Supplement 9 | September 2012