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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Advances in Therapy in Colorectal And Gastric Cancer


GOAL
To provide oncology and hematology healthcare practitioners with up-to-date information on the treatment and management of patients with colorectal or gastric cancer.

TARGET AUDIENCE
This activity is designed for oncology and hematology healthcare practitioners who manage and treat colorectal and gastric cancer. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing take responsibility for the content, quality, and scientific integrity of this CE activity. At the conclusion of this activity, the participant should be able to:
  • Facilitate gastrointestinal (GI) cancer research and education globally.
  • Promote the timely exchange and dissemination of new GI oncology-related knowledge and discovery.
  • Promote excellence in GI cancer care globally.
  • Reduce the social burden of GI cancers.
  • Develop an authoritative forum that builds international and regional consensus on therapy and research in GI oncology.
  • Inspire young investigators to engage in GI oncology research.
ACCREDITATION STATEMENT
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses' Credentialing Center's Commission on Accreditation.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

This 2.4 contact hour Educational Activity (Provider Directed/Learner Paced) is provided by The Institute for Johns Hopkins Nursing (50 minutes of content = 1 contact hour). Claim only those contact hours actually spent in the activity.

The estimated time to complete this educational activity: 2 hours.

Release date: February 15, 2007. Expiration date: February 15, 2009.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing names implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Sanofi-Aventis.Full Disclosure Policy Affecting CE Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. Johns Hopkins Office of Continuing Medical Education has identified and resolved all faculty conflicts of interest regarding this educational activity. The Program Director, Nursing Guest Editor, and Participating Faculty reported the following:

PROGRAM DIRECTOR
Michael A. Choti, MD, MBA, FACS
Professor of Surgery and Oncology
Johns Hopkins University School of Medicine
The Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins Hospital
Baltimore, Maryland
Dr Choti reports receiving honoraria from and serving on the speakers' bureau for Genentech, Inc and Sanofi-Aventis.

NURSING GUEST EDITOR
Keith McIntyre, CRNP
Nurse Practitioner
The Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins Hospital
Baltimore, Maryland
Mr McIntyre reports having no financial or advisory relationships with corporate organizations.

PARTICIPATING FACULTY
Jaffer A. Ajani, MD
Professor
Department of Gastrointestinal Medical Oncology
University of Texas MD Anderson Cancer Center
Houston, Texas
Dr Ajani reports receiving grants/research support from Amgen Inc, Bristol-Myers  Squibb, Daiichi, Enzon Pharmaceuticals, Pfizer, Inc, Sanofi-Aventis, and Taiho Pharmaceutical Co, Ltd; and serving on the speakers' bureau for Amgen Inc, Bristol-Myers Squibb, Daiichi, Enzon Pharmaceuticals, NMCR, Pfizer, Inc, Sanofi-Aventis, and Taiho Pharmaceutical Co, Ltd.
Richard M. Goldberg, MD
Director of Oncology Services
Associate Director of UNC Lineberger Comprehensive Cancer Center
University of North Carolina
Chapel Hill, North Carolina
Dr Goldberg reports receiving grants/research support from Pfizer, Inc and Sanofi-Aventis; serving as a consultant for Amgen Inc, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Inc, ImClone Systems Incorporated, Pfizer, Inc, and Sanofi-Aventis; and receiving honoraria from Genentech, Inc, Pfizer, Inc, and Sanofi-Aventis.

Daniel G. Haller, MD
Associate Chief
Clinical Affairs, Hematology-Oncology Division
Professor of Medicine
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Dr Haller reports receiving grants/research support from Amgen Inc, Bristol-Myers Squibb, Genentech, Inc, Novartis, Pfizer, Inc, Roche Pharmaceuticals, and Sanofi-Aventis; serving as a consultant for Genentech, Inc, Novartis, Pfizer, Inc, Roche Pharmaceuticals, and Sanofi-Aventis; receiving honoraria from Genentech, Inc, Roche Pharmaceuticals, and Sanofi-Aventis; and serving on the speakers' bureau for Genentech, Inc and Sanofi-Aventis.

John L. Marshall, MD
Associate Professor
Lombardi Comprehensive Cancer Center
Washington, DC
Dr Marshall reports receiving grants/research support/honoraria from and serving on the speakers' bureau for Amgen Inc, Bristol-Myers Squibb, Genentech, Inc, Pfizer, Inc, and Sanofi-Aventis; and serving as a consultant for Amgen Inc, Genentech, Inc, and Sanofi-Aventis.

Edith P. Mitchell, MD, FACP
Clinical Professor of Medicine and Medical Oncology
Director of Diversity and Minority Programs
Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, Pennsylvania
Dr Mitchell reports receiving grants/research support from Amgen Inc and Pfizer, Inc; serving as a consultant and on the speakers' bureau for Amgen Inc, Genentech, Inc, Pfizer, Inc, and Sanofi-Aventis; and receiving honoraria from Amgen Inc, Genentech, Inc, and Pfizer, Inc.

Notice: The audience is advised that articles in this CE activity contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Goldberg—bevacizumab, cetuximab, irinotecan, oxaliplatin, and panitumumab.
Dr Haller—capecitabine, cetuximab, and oxaliplatin.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.Advances in Therapy in Colorectal And Gastric Cancer
Michael A. Choti, MD, MBA, FACS,* and Keith McIntyre, CRNP

Gastrointestinal (GI) malignancies are a major source of cancer deaths throughout the world. Estimated new cases of colorectal cancer (CRC) in the United States amount to 148 610 (50 per 100 000) with deaths estimated at 55 170.1 Gastric cancer incidence in the United States is estimated at 10 per 100 000. In Japan the incidence of gastric cancer is much higher at 80 per 100 000, and worldwide deaths as a result of gastric cancer are estimated at 600 000. This makes gastric cancer the second leading cause of cancer death worldwide.

Colorectal cancers have genetic and environmental components. Conditions, such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), are examples of inheritable CRCs. However, it is believed that germ-line mutations in genes associated with these diseases render colonic tissues susceptible to malignant transformation and environmental factors then lead to the additional mutations that drive transformation.2 CRC begins as an adenomatous polyp, which gradually transforms into an invasive cancer. Some of the mutations associated with this transformation have been identified. Inactivation of both alleles of the adenomatous polyposis coli (APC) gene is one of the earliest events in this process.3 Germ-line loss of one allele of APC is also the initiating event for FAP. Mutations leading to the activation of K-ras also occur early in this process. Somewhat later, a cell within the adenoma loses heterozygosity in chromosome 18q, which causes loss of several tumor suppressor genes, such as DCC, DPC4, and MADR2, and begins to drive the adenoma towards carcinoma. Loss of heterozygosity of 18q and microsatellite instability have become useful prognostic risk assessment tools.4 In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p occurs late in the process. Mutations which lead to loss of function of DNA mismatch repair genes, such as hMLH1, hPMS1, or hPMS2, are the basis for HNPCC and are associated with a better prognosis.5

Environmental components affecting CRCs are often associated with diet. High dietary fat consumption along with low dietary fiber consumption was long thought to contribute to increased risk of disease; however, newer studies suggest only a modest effect.6 In contrast, alcohol consumption along with obesity are becoming better appreciated as risk factors. Additionally, selenium intake may be inversely related to risk in GI cancers.

Whereas current advances in medicine over the past 5 years have resulted in a 2-fold increase in survival for patients with CRC, the prognosis for gastric cancer is still poor. Gastric cancers have been associated with helicobacter pylori infection and acid reflux; however, as approximately 50% of the world population is estimated to be infected, the relative increase in risk is small.7 The progression to gastric cancer is believed to begin as chronic atrophic gastritis in the corpus or gastric body.8 Changes in gastric acid secretion lead to imbalances in proliferation and apoptosis of gastric epithelial cells, ultimately leading to foci of dysplasia and cancer. Smoking is associated with increased risk of gastric cancer; however, alcohol consumption is not.9

Treatment of GI cancers requires a multidisciplinary approach. This issue of Johns Hopkins Advanced Studies in Medicine provides complete coverage of a satellite symposium held in conjunction with the 2006  International Society of Gastrointestinal Oncology Conference in Arlington, Virginia, on September 22, 2006. The goal of this symposium was to provide the latest information concerning advances in the treatment of GI cancers. Recently concluded and ongoing clinical trials were reviewed throughout the symposium to establish critical concepts.

John L. Marshall, MD, began the symposium with a discussion of staging and adjuvant therapy associated with CRC. He first covered techniques commonly used in diagnosing and staging CRC and pointed out the particular importance of adequate lymph node evaluation. The development of the current FOLFOX (5-fluorouracil [5-FU], leucovorin, and oxaliplatin) regimen was then covered. A central theme in his talk involved the number of patients who will actually benefit from chemotherapy. It is of critical importance to develop prognostic tools that can distinguish among different patient populations. Of the various genetic markers currently being considered, loss of heterozygosity in chromosome 18q seems to be the best marker predicting a need for adjuvant chemotherapy in patients with stage II CRC. Finally, Dr Marshall covered several new trials that are considering the role of the newer targeted biologic agents in the adjuvant setting.

Daniel G. Haller, MD, then discussed the issues associated with managing cases of advanced CRC. Most importantly, he outlined which of the many available regimens is best suited for any one patient. He described the results of clinical trials introducing irinotecan- and oxaliplatin-containing regimens to the chemotherapeutic armament of the clinician and the issues surrounding bolus versus infusional 5-FU administration. Dr Haller also showed how treatment holidays can decrease toxicities and contain costs while pointing out the critical questions of how to manage the holiday period. Finally, the use of predictive markers was revisited in the context of assessing appropriate treatment regimens for specific patient populations. Dr Haller ended his talk with the important observation that the new regimens are transforming unresectable metastatic CRCs into resectable cases, thus extending the point at which a cure for this disease is possible.

Next, Jaffer A. Ajani, MD, brought the discussion to the topic of advanced gastric cancer. Here, given the poor prognosis of the patient, the question of simple survival is giving way to a more integrated assessment of total quality of life (QOL). Objective measures of QOL have been developed, allowing clinicians to use this as an endpoint in clinical trials. Interestingly, in all clinical trials to date, all increases in QOL were accompanied by an increase in efficacy. Dr Ajani introduced docetaxel to the discussion as the example of a recent change that has increased efficacy and QOL in the treatment of gastric cancer.

Edith P. Mitchell, MD, FACP, then summarized and integrated the information provided by the previous speakers. She then went on to describe what the near future holds in terms of recent advances in prognostic markers, chemotherapeutic targets, and novel imaging techniques.

In addition, this monograph includes 2 case studies. The first case study, which was presented by Dr Ajani, discusses the treatment of a female with gastric cancer and multiple liver metastases who enrolled in the phase I/II study of docetaxel, oxaliplatin, and 5-FU. Richard M. Goldberg, MD, co-chair of the meeting, then shares a case study about a female with advanced CRC and the role of surgery in her treatment. The meeting concluded with a lively panel discussion, which provided additional data and information on relevant clinical trials. It is clear that the treatment of GI cancers is rapidly evolving, and we are striving to provide the timely information necessary for your practice.

REFERENCES

1.    Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2006;56:106-130.
2.    Bresalier RS. Malignant and premalignant lesions of the colon. In: Friedman SL, McQuaid KR, Grendell JH, eds. Current Diagnosis and Treatment in Gastroenterology. New York, NY: Lange Medical Books/McGraw-Hill; 2003:403-435.
3.    Bodmer WF. Cancer genetics: colorectal cancer as a model. J Hum Genet. 2006;51:391-396.
4.    Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med. 1994;331:213-221.
5.    Andre T, Sargent D, Tabernero J, et al. Current issues in adjuvant treatment of stage II colon cancer. Ann Surg Oncol. 2006;13:887-898.
6.    van den Brandt PA, Goldbohm RA. Nutrition in the prevention of gastrointestinal cancer. Best Pract Res Clin Gastroenterol. 2006;20:589-603.
7.    Leung WK. Helicobacter pylori and gastric neoplasia. Contrib Microbiol. 2006;13:66-80.
8.    Ho SB. Tumors of the stomach and small intestine. In: Friedman SL, McQuaid KR, Grendell JH, eds. Current Diagnosis and Treatment in Gastroenterology. New York, NY: Lange Medical Books/McGraw-Hill; 2003:389 - 402.
9.    Shin VY, Cho CH. Nicotine and gastric cancer. Alcohol. 2005;35:259-264.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his/her article and all its contents.

*Professor of Surgery and Oncology, Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland.
Nurse Practitioner, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland.
Address correspondence to: Michael A. Choti, MD, MBA, FACS, Professor of Surgery and Oncology, The Johns Hopkins Hospital, Department of Surgery, Halstead 614, 600 North Wolfe Street, Baltimore, MD 21287-4606. E-mail: mchoti@jhmi.edu.



Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.