Onco’Zine reports about current research and development in hematology and oncology and includes comments on peer-reviewed reports and congress reports from international medical meetings.
The 11th World Congress on Gastrointestinal Cancer, organized by ESMO, the European Society for Medical Oncology, opens today in Barcelona, Spain, with a substantial increase in registered attendees over previous years.
The conference is expected to provide important practice updates and promising new research into the numerous types of cancers that affect the gastrointestinal tract.
“Ongoing study and changing standards in the treatment of gastrointestinal cancers have made it mandatory for clinicians to continually update their knowledge to keep up with advances in the field,” says Congress co-chair Dr. Eric Van Cutsem. “The World Congress on Gastrointestinal Cancer addresses the immediate practice implications of these changes.”
Researchers will present studies indicating prolonged progression-free survival and focusing on the importance of personalized cancer care.
Gastrointestinal cancers include anal cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, liver cancer (hepatoma), pancreatic cancer, and small intestine cancers. The most prevalent of these is colorectal cancer in the Western world and gastric cancer in Eastern World.
Colorectal cancer is a major public health problem in Western countries, with the highest incidence rates in North America, Western Europe, Australia and New Zealand. It is the third most common cancer in both men and women, and the third most common cause of cancer death in both sexes. About 630,000 deaths from colorectal cancer are expected this year worldwide, accounting for 8% of all cancer deaths. Gastric is the second most frequent cause of cancer related mortality, accounting for nearly 800,000 deaths each year worldwide.
Over 400 studies will be presented at the world’s largest GI cancer conference and published in the Annals of Oncology, the official journal of the European Society for Medical Oncology (ESMO), outlining research taking place across the globe. Some of the most important work in the field outlines improved patient outcomes through novel drug therapies including combination therapies and new applications of existing therapies.
Six abstracts have been selected by the congress chairs as “top abstracts”. A common thread of these recognized papers is prolonged progression-free survival, enabling patients to live longer with the disease and with a better quality of life. Moreover, the experts will discuss the changing paradigm in gastrointestinal cancer toward a more personalized treatment approach for patients with gastrointestinal cancers.
Also being recognized at the congress are researchers from developing nations who received grants based on the scientific merit of their submitted work.
The ESMO Conference: 11th World Congress on Gastrointestinal Cancer, developed and managed by Imedex, will be held from 24-27 June at the CCIB convention center in Barcelona. The internationally recognized faculty will include 72 experts, chaired by Mario Dicato, MD of the Luxembourg Medical Center in Luxembourg and Eric Van Cutsem, MD, PhD of the University Hospital Gasthuisberg in Leuven, Belgium. 3,500 people from nearly 100 countries are expected to attend.
Designed to promote a multidisciplinary approach to treatment, the scientific agenda offers targeted sessions for oncology surgeons and nurses as well as a comprehensive range of topics for researchers, gastroenterologists, as well as medical and radiation oncologists.
The conference has received endorsements from leading professional societies and organizations, solidifying the reputation of the Congress as the premier platform for specialists in cancer research, leading oncologists and practicing clinicians to review the state-of-the-art advances in gastrointestinal cancer and share the latest information on its multidisciplinary management. Specialized sessions for nurses, surgeons and young medical oncologists provide enhanced educational opportunities.
The 11th World Congress on Gastrointestinal Cancer Congress is endorsed by:
The Cholangiocarcinoma Foundation
ENETS (European Neuroendocrine Tumor Society)
EONS (European Oncology Nursing Society)
EORTC (European Organisation for Research and Treatment of Cancer) – GI Tumor Group
The U.S. Food and Drug Administration, in late December 2008, approved imatinib mesylate (Glivec®, Novartis AG, Lichtstrasse 35, 4056 Basel, Switzerland and Gleevec®, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, NJ) forthe post-surgery treatment of adult patients following complete surgical removal of KIT (CD117)-positive gastrointestinal stromal tumors (GIST).
The tyrosine kinase inhibitorimatinib mesylate is now the only post-surgery treatment indicated to delay the return of this highly aggressive cancer, filling a major need for GIST patients in the United States. The filing received FDA priority review status in August 2008, with regulatory reviews currently underway in other regions, including the European Union (EMEA) and Switzerland.
Soft Tissue Sarcoma While most cancers are carcinomas, gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas. These cancers grow from cells of the body’s connective or supportive tissues such as bone, cartilage, tendons, nerves, fat, muscle, synovial tissue, or blood vessels.
A life-threatening disease GIST is a life-threatening cancer of the GI tract affecting the digestive tract or nearby structures within the abdomen. It is the most common mesenchymal tumor of the gastrointestinal tract originating from cells found in the stomach and small intestine, Interstitial Cells of Cajal (ICCs) or from less differentiated stem cells or precursor cells, known as mesenchymal precurser cells, in the gut wall, which can develop into ICCs.
These Interstitial Cells of Cajal or ICCs are part of the autonomic nervous system , and generally found in the myenteric plexus and nearby areas between the circular and longitudinal layers of the gastrointestinal tract. Their function is to regulate gastrointestinal motility, or peristalsis, which is the autonomic movement of the GI tract to propel food and liquid through the digestive tract through the stomach and intestines.
Incidence Data concerning the worldwide prevalence of GIST is lacking. But some population based studies estimate the annual incidence to be 4,500 - 6,000 new cases per year in the United Sates (15-20 cases per million population), of which more than 90% are KIT-positive.
Genetics KIT - also known as CD117 - is a protein that, when mutated, has been identified as one of the major causes of GIST. These mutations result in spontaneous activation of tyrosine kinase domains, providing a constant growth stimulus to the tumor cells.
Many GIST contain mutations in exon 11 and, to a lesser degree, in exons 9, 13 or 16, of the c-kit (KIT) protooncogene coding for C-KIT (CD117). Imatinib mesylate inhibits the activity of several proteins such as KIT.
Some GISTs have a mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. Furthermore, a snall number of GISTs, aproximately 5-15%, have no detectable KIT or gene mutation. This includes most pediatric GISTs and GISTs arising in patients with an inactivation of the neurofibromatosis gene (NF1).
Like most cancers, GIST affects older people. The average age at presentation is 50 to 60 years of age. Children are rarely affected, while familial GIST develops in younger or middle-aged adults.
Difficult to diagnose Most patients, especially those with smaller tumors, are asymptomatic. Asymptomatic GISTs can be discovered incidentally during endoscopy or laparoscopy as well as during computed tomography (CT). Biopsy and endoscopic ultrasound are generally used for staging. However, because tumors are slow growing and symptoms of GIST are generally not different than other GI complaints such as nausea, vomiting, bleeding, dyspepsia and obstruction, earely detection of the cancer is rather dificult.
Approximately 60% of these tumors occur in the muscular wall of the stomach. However tumors may also develop in the small intestine, colon, rectum, esophagus and other intra-abdominal locations. The likelihood of malignant behavior is dependent on the size of the tumor and its rate of growth. Metastases usually occur within the abdominal cavity and/or the liver.
Treatment options Early gastrointestinal stromal tumors, or GIST that has not yet metastasized, is often treated initially with surgery to remove the cancer. Unfortunately, the risk of recurrence is high, and GIST remains relatively resistant to chemotherapy and/or radiation therapy. Targeted drugs that inhibit the KIT, such as imatinib mesylate, offer an important approach to treating these cancers. These drug are intended to be given to patients following surgery to help prevent recurrence.
However, in some cases patients with gastrointestinal stromal tumors (GIST) whose disease has progressed or who are unable to tolerate treatment with imatinib mesylate require alternative treatment. Researchers found that sunitinib malate (Sutent®, Pfizer Oncology, Pfizer Inc, 235 East 42nd Street, New York, NY 10017), an orally-available small-molecule multiple receptor tyrosine kinase inhibitor, delayed the time it takes for tumors or new lesions to grow in patients with this tare type of cancer. Specifically, the median time-to-tumor progression (TTP) for patients treated with sunitinib malate was 27 weeks compared to 6 weeks for patients who were not treated.
Established efficacy The efficacy of imatinib mesylate was established in a clinical trial in which patients received either imatinib mesylate or a placebo for one year after surgical removal of the tumor. The optimal treatment duration is not known.
There were significantly fewer recurrences of GIST in patients receiving imatinib mesylate than in patients who did not. The most frequently reported adverse reactions were diarrhea, fatigue, nausea, swelling of the feet, decreased red blood cell counts, rash, vomiting and abdominal pain.
Recurrence After initial removal, GIST tumors can return in as many as one of two patients. Recurrent GISTs are often more aggressive than primary tumors, with relapses associated with lower survival rates.
'After surgery, my doctor told me there was a high likelihood that my gastrointestinal tumors would come back. I immediately searched for a possible solution and found the Glivec clinical trial, which aimed to help patients like me,' said Roslyn Fuller, a GIST patient. 'This FDA approval is good news for me and other GIST patients who will now have the option to start treatment with Glivec earlier to help prevent recurrence.'
Phase II study The approval for this new indication is based on data from an international Phase III trial sponsored by the National Cancer Institute. The study showed a dramatic reduction in the return of GIST after surgery in patients treated for about one year with imatinib mesylate versus placebo.
The FDA regulatory filing for the adjuvant GIST indication was based on data from a Phase III, double-blind, randomized, multicenter, international study of more than 700 GIST patients who had undergone surgery to remove their tumors. The efficacy endpoint of the study was recurrence-free survival (RFS), defined as the time from the date of randomization to the date of recurrence or death from any cause. Participants were randomized to receive either imatinib mesylate 400 mg/day or a matching placebo for one year.
Based on a 14-month median follow up, 91.6% of patients receiving imatinib mesylate remained cancer-free compared with 80.2% of those taking placebo. (30 RFS events out of 359 patients in the imatinib mesylate arm (8.4%) compared to 70 RFS events out of 354 patients in the placebo arm (19.8%) (hazard ratio=0.398 [95% CI: 0.259, 0.610], p<0.0001).'Approval of Gleevec offers health care professionals and patients an important new therapeutic option for patients with this uncommon gastrointestinal disease,' said Richard Pazdur, M.D., director, Office of Oncology Drug Products, Center for Drug Evaluation and Research, FDA. 'It illustrates how the continued study of a once novel drug throughout its product lifecycle can yield new and important uses.'
Revolution in the making Imatinib mesylate was first approved by the FDA in 2001. It is one of the first drugs in a class of agents that block cellular communications that result in tumor growth. Soon after the introduction of effective molecularly targeted therapies such as imatinib mesylate and sunitinib malate the standard of practice for GIST rapidly changed.
'When Glivec was first approved for the treatment of inoperable and/or metastasized KIT-positive GIST six years ago, it revolutionized the treatment of this life-threatening cancer,' said David Epstein, President and CEO, Novartis Oncology. 'This atest FDA approval means patients can benefit from Glivec earlier in the course of their disease.'
Multiple indications The drug is now approved for nine indications, including the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML), Kit (CD117)-positive gastrointestinal stromal tumors which cannot be surgically removed and/or have already spread to other parts of the body (metastasized) and five other rare diseases.
Mode of Action The effectiveness of imatinib mesylate is based on overall hematological and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on hematological response rates in SM, HES/CEL, on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence free survival in adjuvant GIST, and on objective response rates in DFSP. Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML and GIST.
Z9001: A Phase III Randomized Double-blind Study of Adjuvant STI571 (Glivec®) Versus Placebo in Patients Following the Resection of Primary Gastrointestinal Stromal Tumor (GIST). Accessed January 2009.
American Cancer Society. Cancer Reference Information. Detailed Guide for Gastrointestinal Stromal Tumors. Key Statistics. Accessed January 2009.
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The conference is expected to provide important practice updates and promising new research into the numerous types of cancers that affect the gastrointestinal tract.
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