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This month we will be focusing on data from the recent 2009 Gastrointestinal Cancers Symposium. This multidisciplinary meeting was held in San Francisco in mid-January. The program included a number of didactic presentations as well as 563 abstracts, both oral, poster and published. Nearly 3000 attendees were present at this year’s meeting, including a large international contingent of attendees.
In this issue:
Esophagogastric Carcinomas and Pancreatic Cancers
Abstract 39: A phase II study of cetuximab with cisplatin and capecitabine as first-line treatment in advanced gastric cancer
An interesting phase II study was a poster presentation at this year’s Gastrointestinal Cancers Symposium. Dr Zhang from China discussed a phase II study of 54 patients with advanced gastric cancer who received the combination of cisplatin 80 mg/m2 and capecitabine 2000 mg/m2 every 3 weeks plus cetuximab weekly. Among 47 evaluable patients there were 24 partial responses (PR), 1 complete response (CR), and 15 stable disease (SD) responses for an ORR of 48%. The time-to-progression (TTP) was 5.23 months. Correlative studies demonstrated no K-ras mutations. But EGFR amplification was seen in a number of patients. Serum transforming growth factor alpha (TGFα) was much higher in those patients who achieved PR or CR. Transforming growth factor alpha correlated with TTP, but EGF and vascular endothelial growth factor (VEGF) expression did not. Treatment was said to be well tolerated. Further analysis is ongoing.
Abstract 4: Cetuximab-based neoadjuvant chemoradiation and surgical resection in patients with locally-advanced esophageal and gastric cancer
Dr Harold J Wanebo from Brown University presented phase II data regarding 54 evaluable patients with locally advanced GE carcinomas who were treated with the combination of paclitaxel, carboplatin and cetuximab with concurrent radiation therapy to 50.4 Gy. Forty-two of the 54 evaluable patients underwent surgical resection. The remaining 12 had restaging with endoscopy only. Of those resected, 25% achieved a pathologic CR and another 18% had only T1 microscopic residual disease. Twenty-three percent achieved a PR with T1-2 residual disease. The median disease-free survival (DFS) was 24 months, and the median OS was 29 months for those who underwent resection. The median OS was 14 months for those who underwent only endoscopic restaging without surgery. Of those who achieved a pCR at surgery, the 20-month DFS was 80% compared to 40% for those achieving PR. For those patients who went to surgery, but were found to have unresectable disease, the median OS was only 9 months. The authors concluded that neoadjuvant chemoradiation is tolerable and leads to significant down-staging of locally advanced esophageal and gastric cancers.
Abstract 5: Phase III trial of adjuvant capecitabine/cisplatin compared with capecitabine/cisplatin/RT in resected gastric cancer with D2 nodal dissection (ARTIST trial): Safety analysis
Since publication of the Intergroup 0116 trial several years ago, the combination of 5-FU/leucovorin/radiation has become a standard postoperative adjuvant regimen for resected gastric cancer. Some experts have criticized this trial because of the limited extent of nodal dissection with 54% of patients having less than a D1 resection. It has been said this could have led to a higher relapse rate in the surgery only group. Dr Jeeyun Lee presented the initial safety analysis of an ongoing Korean trial of 458 patients who underwent D2 resections followed by randomization to capecitabine/cisplatin (XP) for 6 cycles versus XP for 2 cycles followed by concurrent capecitabine + 50 Gy radiation followed by XP for an additional 2 cycles. Fifty-eight percent of the patients were either stage Ib or stage II. Approximately 80% underwent total gastrectomy. Seventy-five percent of patients in the XP arm completed all 6 cycles of adjuvant chemotherapy. Eighty-two percent of patients in the XP/RT arm completed the entire regimen. The primary endpoint is DFS, and results are expected to be available in 2011.
Novel Targeted Therapies in Esophageal and Gastric Cancer presentation by A. Craig Lockhart, MD
Some of the most interesting aspects of the symposium were presentations of data concerning emerging novel agents. Dr Craig Lockhart from Washington University in St. Louis presented an interesting discussion of novel targets and investigational agents with potential therapeutic applications in gastric and esophageal carcinomas. This included a discussion of ongoing trials with anti-epidermal growth factor receptor (EGFR) and anti-VEGF/vascular endothelial growth factor receptor (VEGFR) therapies. However, the presentation primarily focused on novel targets and agents including aurora kinases that are frequently over-expressed in esophageal cancer, sonic hedgehog mutations and over-expression. Dr Lockhart also focused on heat shock protein 90, commonly over-expressed in these cancers, m-TOR inhibitors with several trials underway in gastric cancer, and PI3 kinase, where inhibitors of this important signaling pathway are being evaluated. Undoubtedly there will be an increasing amount of data regarding these targets and novel agents in the next few years.
Now let’s move on to Pancreatic Cancer.
Abstract 114: Correlation of expression of S100A2 calcium-binding protein with response to pancreatectomy for pancreatic cancer
Dr Andrew Biankin, a surgeon from Sydney, Australia, reported a very interesting retrospective correlation of biomarkers with disease specific survival in pancreatic cancer. They evaluated 25-30 biomarkers known or suspected to be aberrantly expressed in pancreatic cancer by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 162 pancreatic cancer specimens including 72 resections. Only S100A2 proved to be an independent predictor of survival. Patients with high expression of S100A2 had a much poorer OS and did not benefit from pancreatectomy. Whereas patients with S100A2 negative tumors derived significant survival benefit from pancreatectomy, even in the presence of involved surgical margins or lymph node metastases. The median survival for patients with S100A2 negative tumors was 18.2 months versus 6.9 months for those with S100A2 over-expressing tumors. The S100 genes are clustered on chromosome 1q21. They have a tumor suppressor function and are important in cell cycle regulation and progression. S100A2 is a calcium binding protein and has been implicated in development of metastases, and its expression has also been correlated with poor prognosis in non-small cell lung cancer (NSCLC). It is worth noting that this was a retrospective study. Future studies with prospective measurement of S100A2 expression will be necessary to confirm these findings.
Abstract 120: A phase II trial of cationic liposomal paclitaxel in combination with gemcitabine in patients with unresectable pancreatic cancer
Dr M Löhr presented the results of an international randomized phase II study of EndoTAG-1, a novel cationic liposomal formulation of paclitaxel, with gemcitabine for unresectable pancreatic cancer. Many novel agents have been combined with and compared to gemcitabine alone in pancreatic cancer. All of these studies have been statistically negative except for the gemcitabine-erlotinib combination. These investigators compared gemcitabine alone with gemcitabine plus 3 different doses of EndoTAG-1 in 200 patients with locally advanced or metastatic pancreatic cancer. Response rates did not differ significantly and ranged from 13% to 16%, but PFS was significantly higher in the gemcitabine-EndoTAG-1 arms (4.2-4.6 months versus 2.7 months) and in OS (8.7-9.4 months versus 7.2 months for gemcitabine alone). Results were better with the intermediate and higher doses of EndoTAG-1 in combination with gemcitabine. EndoTAG-1 added no significant toxicity to that of gemcitabine alone with only grade 1-2 infusion reactions being more common. The authors concluded that further studies of this combination are warranted. There have been previous reports combining taxanes with gemcitabine in pancreatic cancer. You may recall that at the 2008 American Association for Cancer Research (AACR) meeting, phase I trial data was presented showing an objective response rate of approximately 70% in a small study of 20 patients with pancreatic cancer treated with the combination of gemcitabine and nab-paclitaxel. Further data regarding this trial is awaited.
Abstract 121: Placebo controlled, double blind, prospective, randomized study of the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A Report from the PROMID study group
Dr Arnold from Marburg, Germany presented interim results for the PROMID study group. This study randomized 162 previously untreated patients with low-grade neuroendocrine midgut tumors to octreotide LAR versus placebo. This report included the first 85 patients in the study. Patients had to have inoperable or metastatic disease that was measureable. Forty percent of patients had symptoms of the carcinoid syndrome, and 65% to70% had undergone resection of the primary tumor. Chromogranin A was elevated in 62% to 70%. Progression-free survival was 14.3 months for the octreotide LAR group compared to 6.0 months for the placebo group. Patients with less than 10% hepatic tumor load and a resected primary derived the most benefit from octreotide LAR. Whether the tumor was functioning or non-functioning did not affect response. This study continues, and further results including median survival will be presented in the future.
Abstract 122: A phase II trial of daily oral RAD001 (everolimus) in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy
Dr J C Yao from M. D. Anderson Cancer Center presented the data from an international trial of the novel, oral m-TOR inhibitor, everolimus, in patients with metastatic pancreatic neuroendocrine tumors who had progressed following cytotoxic chemotherapy. Patients were stratified according to prior and ongoing use of depot octreotide therapy. In this trial, 160 patients with low to intermediate grade pancreatic neuroendocrine tumors were enrolled. Prior studies of similar patient groups had reported 6-month PFS of 28%. In this trial with everolimus the PFS at 6 months by central radiology review was 65% to 70%. Median PFS in patients treated with everolimus alone was 9.3 months and for those who also received octreotide the PFS was 12.9 months. Chromogranin A response was approximately 50%. The most frequent adverse events were rash, diarrhea, fatigue, nausea and headache.
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