The 2012 Gastrointestinal Cancers Symposium, held in
January in San Francisco, featured several important presentations related to
esophageal and gastric cancers.
Topics included the evolution and potential
chemopreventive treatment of Barrett’s esophagus, as well as important
updates about adjuvant therapy and advanced disease trials in gastric cancer.
David H. Ilson
Janusz Jankowski, MD, MBBS, a professor at Barts
and The London School of Medicine and Dentistry, presented an overview of the
use of aspirin as a potential primary and secondary preventive agent in
Data accrued largely from cardiovascular trials
employing aspirin therapy indicate a primary preventive benefit for many
cancers, ranging from a 10% to 20% reduction in the risk for cancer-related
Aspirin appeared to meet the criteria as a candidate
preventive therapy because of its added potential cardiovascular risk
reduction, its low cost and the fact that severe adverse events —
including bleeding — occur in an overall relatively low 2% of patients.
Because the duration of aspirin therapy required to
achieve a meaningful clinical benefit exceeds 5 to 10 years — and may take
as long as 20 years — and because the risk for gastrointestinal adverse
events escalates in age increments in patients aged older than 60 or 70 years,
patients aged older than 75 years may not be candidates for consideration for
such chemopreventive therapy.
Data for the secondary prevention of esophageal cancer,
reflecting patients with established premalignant Barrett’s esophagus
taking aspirin to reduce the risk of progression to cancer, await maturation of
the Aspirin Esomeprazole Chemoprevention Trial (ASPECT).
Jankowski presented preliminary safety data from this
trial involving more than 2,500 patients with Barrett’s esophagus.
Patients were randomly assigned to low-dose 20 mg or high-dose 80 mg
esomeprazole (Nexium, AstraZeneca), and to treatment with or without 300 mg of
daily aspirin. Aspirin intolerance was identified in 5% of patients, and the
rate of severe adverse events was 0.5% per year.
Efficacy data, including rates of progression to cancer
and effect on cardiovascular events, await further follow-up.
Jankowski concluded that the use of aspirin preventive
therapy should be reserved for patients with primary risk factors, including
patients with known cardiovascular disease, those with a history of colonic
polyps or treated colorectal cancer, and patients who carry the gene for
hereditary nonpolyposis colorectal cancer.
Because most patients are unlikely to attain any benefit
from aspirin therapy, routine daily use of aspirin is not recommended.
Predictive and prognostic biomarkers to demonstrate benefit for aspirin therapy
use must be identified.
Yoon-Koo Kang, MD, of the department of oncology
at Asan Medical Center at the University of Ulsan College of Medicine in South
Korea, presented updated data from the AMC 0101 trial.
This trial of adjuvant therapy in patients found to have
serosa-involved gastric cancer at surgery compared two approaches:
postoperative mitomycin combined with 3 months of oral doxifluridine after D2
gastrectomy for gastric cancer vs. an experimental arm administering one dose
of intraoperative intraperitoneal cisplatin followed by immediate postoperative
mitomycin, and then extended doxifluridine for 12 months given with 6 months of
Updated results included data on 521 patients, with a
median follow-up of 6.6 years.
Most patients (80%-84%) had distal gastric cancer,
whereas 49% to 50% had stage IIIA or stage IIIB disease, and more than 80% had
World Health Organization classification tubular adenocarcinoma.
Recurrence-free survival at 5 years improved on the experimental arm from 46.3%
to 53.9% (HR=0.73; 95% CI, 0.57-0.93), and 5-year OS improved from 50.3% to
59.2% (HR=0.77; 95% CI, 0.60-0.98).
Although the data suggest a potential benefit for the
strategy of postoperative intraperitoneal cisplatin, the experimental arm
included the added variables of immediate postoperative mitomycin, the
extension of oral chemotherapy from 3 months to 12 months, and the inclusion in
therapy of 6 months of cisplatin. A randomized trial in which the only variable
is the addition of intraperitoneal therapy to adjuvant systemic chemotherapy is
In advanced gastric cancer, Eric Van Cutsem, MD,
PhD, head of digestive oncology and professor of medicine with the
University Hospital Gasthuisberg in Leuven, Belgium, and colleagues presented
results from the GRANITE Trial.
This global study evaluated the use of the mammalian
target of rapamycin (mTOR) inhibitor everolimus (Afinitor, Novartis) 10 mg
daily vs. placebo in patients progressing on one or two lines of prior
chemotherapy for advanced disease. The primary endpoint was to improve OS.
Nearly 700 patients were randomly assigned in a 2:1
design to receive everolimus or placebo. The median age was 62 years.
Randomization was stratified by region, with 55% of the patients enrolled in
Asia and 45% enrolled in the rest of the world. Most (52.3%) had received two
prior lines of chemotherapy.
Median OS was 5.39 months in the everolimus group vs.
4.34 months in the placebo group (HR=0.9; 95% CI, 0.75-1.08).
Median PFS was 1.68 months in the everolimus group vs.
1.41 months in the placebo group (HR=0.66; 95% CI, 0.56-0.78).
Disease control — defined as complete response,
partial response or stable disease — was greater in the everolimus arm
(43.3% vs. 22%). Grade 3/4 adverse events were more common in the everolimus
arm (70.9% vs. 53.5%), and they included anorexia (11%), fatigue (7.8%) and
Overall, the trial failed to achieve its primary
endpoint, but the suggestion of improved response and PFS indicate that a small
subset of patients may benefit from the use of everolimus. The study of
biomarkers to potentially identify which patients may have had a therapy
benefit on this trial is ongoing.
Shah and colleagues presented data from a subset
analysis of the AVAGAST trial, which involved 750 patients with gastric cancer.
Patients received capecitabine (Xeloda, Hoffmann-La
Roche) plus cisplatin with or without bevacizumab (Avastin, Genentech).
Overall, the trial failed to meet the primary endpoint of improved OS with the
use of bevacizumab vs. placebo (median OS, 12.1 months vs. 10.1 months;
HR=0.87; P=.1002), despite improvements in antitumor response rate
(37.4% to 46%) and PFS (5.3 months to 6.7 months).
The researchers performed an unplanned and exploratory
subset analysis of outcome by tumor subtype (intestinal, diffuse or
proximal/gastroesophageal junction) and geographic region of therapy, and they
assessed potential plasma biomarkers.
In patients treated in Europe and the Americas, OS
trended inferior in patients with gastric cancer and diffuse histology. This
subgroup, however, seemed to benefit with improved median and OS with the
addition of bevacizumab to chemotherapy.
VEGF-A and neuropilin-1 plasma levels varied dependent
on the tumor histology and location, with lower VEGF-A and higher neuropilin-1
levels seen in the diffuse subtype. Lower VEGF-A and higher neuropilin-1 levels
also appeared to correlate with improved OS with bevacizumab. This exploratory
analysis is hypothesis-generating and indicates there may have been a
differential effect of bevacizumab by tumor histology and by candidate
anti-angiogenesis biomarkers. Further study of any putative biomarkers will
require validation in other studies.
Adjuvant therapy is now accepted as standard practice as
part of the surgical management for gastric cancer. Accepted adjuvant treatment
approaches now include the use of preoperative and postoperative chemotherapy
with combination epirubicin (Ellence, Pfizer), cisplatin and 5-FU;
postoperative chemotherapy alone after D2 resection with 6 months to 1 year of
5-FU–based chemotherapy; and postoperative 5-FU combined with radiotherapy
after less than a D1-2 resection.
The potential role of intraperitoneal chemotherapy will
require additional validation in other studies. For advanced gastric cancer,
the only proven beneficial targeted agent is trastuzumab (Herceptin,
Genentech), approved for use in combination chemotherapy in HER-2–positive
esophagogastric cancers. The identification of potential biomarkers to direct
anti-angiogenic therapy remains a work in progress.
- The following were presented at the 2012 Gastrointestinal Cancers
Symposium; Jan. 19-21, 2012; San Francisco:
- Jankowski JAZ. Chemoprevention of Barrett’s and esophageal
adenocarcinoma: State of the art in the year 2012. General Session I.
- Kang YK. Abstract #4.
- Shah MA. Abstract #5.
- Van Cutsem E. Abstract #LBA3.
For more information:
- David H. Ilson, MD, PhD, is a medical oncologist at Memorial
Sloan-Kettering Cancer Center. He also is HemOnc Today’s
gastrointestinal cancer section editor. Dr. Ilson reports no relevant financial