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

220s Gastrointestinal (Colorectal) Cancer
3569 General Poster Session (Board #30A), Mon, 8:00 AM-12:00 PM
Short-term clinical outcomes from a randomized controlled trial to evaluate
laparoscopic versus open complete mesocolic excision for stage II,III
colorectal cancer (CRC): Japan Clinical Oncology Group study JCOG0404
(NCT00147134). Presenting Author: Yusuke Nishizawa, National Cancer
Center Hospital East, Kashiwa, Japan
Background: The benefits of laparoscopic surgery (LAP) in comparison with
open surgery (OP) have been suggested; however, the long-term survival of
LAP for advanced CRC requiring complete mesocolic excision is still
unclear. We conducted a study to confirm the non-inferiority of LAP to OP
in terms of overall survival (OS)with less frequent post-operative morbidity.
Short-term outcomes including post-operative complications are presented
here. Methods: Only accredited surgeons from 30 Japanese institutions
participated. Eligibility criteria included histologically proven CRC; tumor
located in the cecum, ascending, sigmoid or rectosigmoid colon; T3 or
deeper lesion without involvement of other organs; N0–2 and M0; tumor
size ��8 cm; patient age 20-75 years. Patients were randomized
preoperatively.Patients with pathological stage III received adjuvant chemotherapy
with fluorouracil plus leucovorin. The primary endpoint is OS. and
the planned sample size was 1050. Results: A total of 1057 patients were
randomized (OP: 528, LAP: 529) between October 2004 and March 2009.
Conversion to OP was needed for 29 (5.4%) patients in LAP arm (technical
conversion; 2.3%, indicated conversion; 2.8%, complicated conversion;
0.4%). Patients assigned to LAP had less blood loss compared with those
assigned to OP (median 30 ml vs 85 ml, p�0.001), although LAP lasted
52 minutes longer than did OP (p�0.001). Radicality of resection as
assessed by number of resected lymph nodes did not differ between two
groups. LAP was associated with earlier recovery of bowel function
(p�0.001), and with a shorter hospital stay (p�0.001) compared with OP.
Morbidity and mortality untill discharge did not differ between two groups,
except for less wound-related complications in LAP (p�0.007). Conclusions:
Laparoscopic complete mesocolic excision for stage II,III colorectal cancer
can be performed safely and short-term clinical benefits was demonstrated.
If the non-inferiority of LAP in OS is demonstrated in the primary analysis
planned in 2014 , LAP will be the new standard procedure for CRC.
3571 General Poster Session (Board #30C), Mon, 8:00 AM-12:00 PM
A randomized phase II study of capecitabine-based chemoradiation with or
without bevacizumab in resectable locally advanced rectal cancer. Presenting
Author: Mercedes Martinez Villacampa, Instituto Catalán de Oncología,
Hospital Durans i Reynals, Hospitalet de Llobregat, Spain
Background: The addition of bevacizumab (BEV) to capecitabine (CAP)based
chemoradiation (CRT) has shown encouraging efficacy in locally
advanced rectal cancer (LARC), in nonrandomized studies. This randomized
phase II study investigated the effect of adding BEV to preoperative
CAP-based CRT in patients (pts), with LARC. Methods: The primary end
point was pathologic complete response (pCR). A two-stage design was
used. Assuming a minimum pCR rate of at least 15% in one of the arms, a
difference between the two arms of 10%, and accepting a probability of
correct selection of 87%, 41 pts per arm were needed. Patients with LARC
(Stages II-III assessed by MRI) and ECOG PS �2 were randomized to
concurrent radiotherapy 45Gy/25f/5 weeks � CAP (825mg/m²/bid) � BEV
every 2 weeks (5 mg/kg for 3 doses) (arm A) or the same schedule without
BEV (arm B). Surgery was scheduled 6-8 weeks after completing CRT.
Results: 90 pts were randomized (arm A/B: 44/46). Patient’s characteristics
were well balanced between both arms: male 61%, median age 62
years, median distance from anal verge 7 cm, T3 79%, N� 87%. 40
(91%)/43 (93%) of pts (arm A/B) finalized the planned CRT � surgery
treatment. Overall grade 3-4 toxicity rates were 18 % and 13% (arm A/B,
p�0.50); no grade 3-4 hematological toxicity was reported. Postoperative
complications were 19(43%)/17(37%)(arm A/B). Efficacy data on patients
who actually underwent surgery are reported in the table. Conclusions: The
addition of BEV to CAP-based preoperative CRT has shown to be feasible
and safe in the local control of LARC. No differences in pCR were observed
and longer follow-up is needed to assess the impact on survival endpoints.
Arm A: RT�CAP�BVZ Arm B: RT�CAP
Surgery performed 43 (98%) 46 (100%) p:0.49
pCR (ypT0N0) 7 (16%) 5 (11%) p: 0.54
R0 resection rates 42 (95.45%) 44 (96%) p:1.0
Downstaging (lower
26 (59%) 18 (39%) p: 0.0429
pT compared with
the pretreatment cT)
Sphincter saving surgery 27 (61%) 31 (67%) p: 0.66
3570 General Poster Session (Board #30B), Mon, 8:00 AM-12:00 PM
Phase II study of dacarbazine for metastatic colorectal cancer with
determined MGMT status. Presenting Author: Alessio Amatu, Ospedale
Niguarda Ca’ Granda, Milan, Italy
Background: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA
repair protein that removes mutagenic and cytotoxic adducts from O6- guanine in DNA. Roughly 40% of colorectal cancers (CRCs) display MGMT
deficiency due to promoter hypermethylation leading to silencing of the
gene. Alkylating agents exert their antitumor activity by DNA methylation at
the O6 –guanine site, inducing base pair mismatch; therefore, activity of
these compounds may be enhanced in CRCs lacking MGMT (Esteller,
2004; Pegg, 1990). Despite anecdotal reports about activity of dacarbazine
in CRC (Shacham-Shmueli, 2011) no clinical trials assessed monotherapy
with dacarbazine for metastatic CRC. Methods: We conducted a
phase II study of dacarbazine in CRCs who had failed standard therapies
(oxaliplatin, irinotecan, fluoropyrimidines and cetuximab or panitumumab
if KRAS WT), PS�0-1, with adequate organ function, and measurable
disease as per RECIST criteria assessed by CT scans at baseline and every 8
weeks. All patients had tumor tissue assessed for MGMT as promoter
hypermethylation. Patients received dacarbazine 250 mg/m2 i.v. d1-4,
q21 until PD or untolerable toxicity (with a maximum of 6 cycles in case of
SD). We employed a Simon, two-stage design to determinate if the ORR of
dacarbazine treatment would be � 10%. Secondary endpoints were
association of response/resistance with loss of expression of MGMT, PFS
and disease control rate. Results: In the first stage, from June 2011 to
November 2011 we enrolled 40 pts (male 68%, median age 67 y [range
29-81], PS�0 50%, KRAS mut 55%). Pts received a median of 3 cycles
[range 1-11]. Toxicities included (All Grades/Grade 3-4 %): fatigue (58/5),
constipation (38/0), nausea/vomiting (35/0), anemia (20/2.5), platelet
count decrease (10/5). 36 pts were evaluable for objective response.
Overall, 2 pts (5%) achieved PR and 5 pts (12.5%) had SD. All pts with PR
had tumors with MGMT promoter hypermethylation. Conclusions: Having
exceeded the boundaries of futility (at least 2 objective responses in the
first stage), the trial proceeds to the second stage, enrolling 28 more
patients. Analysis of MGMT promoter hypermethylation and association
with sensitivity/resistance is performed at the end of the second stage.
3572 General Poster Session (Board #31A), Mon, 8:00 AM-12:00 PM
Analysis of plasma biomarkers potentially associated with antiangiogenic
resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of
cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in
patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic
colorectal carcinoma (mCRC). Presenting Author: Jeremy David
Shapiro, Cabrini Hospital and Monash University, Melbourne, Australia
Background: In the CO.20 trial, the addition of BRIV, a tyrosine kinase
inhibitor targeting vascular endothelial and fibroblast growth factor receptors
(VEGFR2,3 and FGFR 1,2,3), to CET, increased objective response
rate and progression free survival, but did not significantly increase overall
survival. Previous clinical studies demonstrated modulation of circulating
angiogenic factors (CAF) in CRC which occur on therapy or upon progression
(Kopetz JCO 2010). Methods: CO.20 pts were randomized 1:1 to CET
plus either BRIV (Arm A) or placebo (ARM B) in a double-blind design. Pts
may have had 1 prior anti-VEGF based therapy, but no prior anti-EGFR
therapy. Primary endpoint was overall survival (OS). Baseline pre-treatment
plasma samples were analyzed using commercial Multi-Analyte ELISAs to
measure CAF, immunologic, and growth factors, with an initial discovery
and subsequent validation data set. Results: 750 pts were randomized (376
in Arm A and 374 in Arm B). Median OS in the intent-to-treat population
was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio
(HR)�0.88; 95%CI�0.74-1.03; p�0.12. In an exploratory subgroup
analysis, there is a statistically non-significant trend favoring the effect of
brivanib on OS among the 41% pts who received prior anti-VEGF therapy
versus those who did not.Baseline plasma samples were collected from
96% of pts, and analysis is ongoing. Results of the largest circulating
biomarker analysis will be presented. CAF results will be compared with
response and survival data to look for potential patient subgroups that may
benefit more from the combination treatment. Conclusions: This large scale
analysis will provide insights on the potential use of CAF or CAF profiles as
predictive markers in CRC.
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