Hematology/Oncology

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

Aspirin as preventive agent

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 esophageal cancer.

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 death.

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.

AMC 0101 trial

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 cisplatin.

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 required.

GRANITE trial

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 stomatitis (4.6%).

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.

AVAGAST trial

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.

Conclusion

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.

References:

• 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 disclosures.