Philip A Pizzo, MD of National Cancer Institute
In spite of the enormous progress made in the treatment of childhood cancer, infectious complications, arising as a consequence of cyotoxic and immunosuppressive therapy, remains a major source for morbidity in children undergoing cancer therapy and can be an impediment to the delivery of cancer treatment. The Forum will focus on the practical issues that arise in the management of infectious complications, including the selection and use of antibiotic therapy. Because the cancer patient is immunosuppressed, infection with unusual organisms, commonly referred to as opportunists, can be a serious problem. Thus, the focus will also consider the advances and appropriate utilization of antifungal, antiviral and antiparasitic therapies.
In addition to considering ways to manage the microbes causing infection, recent developments in molecular biology and immunology now offer the prospect for improving or restoring the very immune system that cancer treatment can abrogate. The application of these new tools, referred to as biological response modifiers or cytokines, will also be considered in detail. The goal of the Forum will be to consider how advances in antimicrobial therapy and in the development of biologicals can be integrated to reduce the risk for infection and to improve the outcome of those infections which do occur.
Infectious complications remain a major cause of morbidity in children with cancer. This is a consequence of the abnormalities in the host defense system that result from both the cancer itself as well as the treatments used to control it. Unfortunately, the risk for such infections can limit the ability to deliver potentially beneficial cancer therapy. Thus, strategies to both treat these infectious disease complications as well as to prevent them are integral to the practice of pediatric oncology.
Accordingly, during the 1989 Forbeck Forum, clinicians and scientists from around the world gathered to develop a blueprint for the important research questions that will need to be addressed to improve the management and prevention of the infectious complications that are associated with cancer and its treatment. The initial discussion focused on the ways in which developments in antibiotic research influence clinical practice both now and in the future. Arthur Brown from Memorial Sloan- Kettering Hospital in New York and Ben di Pauw from the University of Nijmegen in the Netherlands considered the array of new antibiotics that became available during the 1980’s and considered the ways in which these agents should be used to optimize therapy. Importantly, the group focused on the methodology that is essential in conducting state-of-the-art clinical research. The relevance of these considerations to the deliberations of the Immunocompromised Host Society’s Consensus Panel that was chaired by Phil Pizzo in June of 1988 and to the Infectious Disease Society of America’s Consensus Report coordinated by Walter Hughes were considered. It was recognized that appropriate therapy really required an improvement in the ability to define which patients were at the highest risk for prolonged immunosuppression. This would not only help in the considerations regarding the initial management of patients who become febrile while they were neutropenic (i.e. low blood counts), but also in the appropriate modifications of this therapy should neutropenia and fever persist. This aspect of the discussion was led by Gerry Donowitz of the University of Virginia and Mary Ann Jackson from the University of Kansas. One of the major problems in patients with persistent neutropenia is fungal infections. Some of the advances in the diagnosis and treatment of these invasive fungal infections were discussed by Tom Walsch of the NCI and Gabriel Lopez-Berenstein of the MD Anderson Hospital. Some of the newer anti-fungal drugs offer particular benefit to cancer patients and strategies to study them were discussed.
In addition to infections caused by bacteria and fungi, viruses and protozoal infections can also be problematic for cancer patients. The major viral infections were discussed along with some recent advances in their treatment. Joel Meyers of The Fred Hutchinson Cancer Center led this discussion and the group agreed that cooperative studies to evaluate antiviral agents in children with or at risk for chickenpox (varicella) should be undertaken. In addition, Walter Hughes of the St. Jude Children’s Research Hospital led a discussion on new developments in the diagnosis and treatment of pneumocysistis infections. These are problems not only for children with cancer but also for those with AIDS. Plans for cooperative trials were discussed.
During the last decade, many new devices have been introduced to simplify the management of cancer patients. Foremost among these are surgically implanted indwelling intravenous devices. These make the administration of medications simpler and pain-free, improving the quality of life for children. At the same time, these devices are associated with infections and can pose a challenge to the oncologist. Claudio Viscoli from Italy discussed the problems with the diagnosis and management of these devices. In addition, Leigh Donowitz from the University of Virginia broadened the discussion to consider other strategies to prevent infectious complications in cancer patients.
One of the most exciting areas of development is the emerging field of biologicals. The revolution in molecular biology has led to the synthesis of molecules that can boost the immune system or accelerate the recovery of the bone marrow following chemotherapy. The role of antibody replacement in improving host defense was considered by Donna Ambrosino from Harvard and was coupled with discussions of lymphokines and cytokines (molecules that stimulate immune cells or bone marrow cells) by Art Ammann from Genentech. The prospect that these new biological agents could be used to bolster the immune system and improve the treatment and prevention of infections was discussed with considerable excitement and interest. Indeed, if these new molecules fulfill their promise, they can contribute to revitalized ways to improve the treatment of childhood cancer as well. Plans to study these agents were discussed and shared among the Forbeck Panel.
Quotes from Participants
“We are back in our respective busy lives where there is so little time to review and ponder the questions and the potential answers to the care and treatment of cancer patients. This past weekend was a rare and wonderful opportunity to do just that. Many thoughts and challenges came out of those meetings which I hope will come to productive research focus over the next year. One of the most important immediate benefits is having met or truly got to know people interested in these issues from all over the world.” -- Leigh G. Donowitz, MD, University of Virginia, Charlottesville, VA
Several projects have been developing … the role of herpes simplex as a co-pathogen will be investigated as suggested by Dr. Ben de Pauw’s experience in the Netherlands … the affirmation of our experience by investigators such as Dr. DePauw and Dr. Walter Hughes … directly related to my participation on the 1989 Forum, the Children’s Mercy Hospital will be cooperating with a study utilizing an orally administered antifungal agent in pediatric cancer patients with fever and neutropenia. Dr. Tom Walsh from the National Cancer Institute is the senior investigator in this study and through our meeting at the Forum; the Children’s Mercy Hospital will be cooperating with a study utilizing an orally administered antifungal agent in pediatric cancer patients with fever and neutropenia. Dr. Tom Walsh from the National Cancer Institute is the senior investigator in this study and through our meeting at the Forum; the Children’s Mercy Hospital has become involved.” -- Mary Anne Jackson, MD, Children’s Mercy Hospital, Kansas City, MO
“I feel that the meeting at Moss Creek was a scientifically and personally rewarding activity … the atmosphere was absolutely conducive toward collegial interactions.” -- Gabriel Lopez-Berestein, MD, MD Anderson, Houston, TX
“As I now have less patient contact … conferences such as the past one, especially when they are outgrowths of individuals who have experiences the consequences of illness, are reminders of what our goals should be.” -- Arthur J. Amman, MD, Genentech, Inc., San Francisco, CA
“I want to thank you for your kind hospitality and outstanding organization of the 1989 Forbeck Forum. The meeting provided a platform for the development of critical concepts on management of infections in cancer patients. It also led to plans for meaningful research collaborations among the participants.” -- Thomas J. Walsh, MD, National Cancer Institute, Bethesda, MD
This was an intense but thoroughly enjoyable opportunity to review the ongoing problems of infections in the compromised host and share ideas with many of the national and international leaders in this area. I certainly was honored to have been included and have come away with research ideas that we may put into effect over the next year.” -- Gerald R. Donowitz, MD, University of Virginia, Charlottesville, VA
Donna Ambrosino, MD
Dana-Farber Cancer Institute
Arthur Amman, MD
Arthur E. Brown
Memorial Sloan Kettering Cancer Center
Stephen J. Chanock, MD
National Cancer Institute
Ben de Pauw, MD
University Hospital Nijmegen
Gerald R. Donowitz, MD
University of Virginia
Leigh Donowitz, MD
University of Virginia
Walter Hughes, MD
St. Jude Children's Research Hospital
Mary Anne Jackson, MD
Children's Mercy Kansas City
Gabriel Lopez-Bernstein, MD
MD Anderson Cancer Center
Joel Meyers, MD
Fred Hutchinson Cancer Research Center
Philip A. Pizzo, MD
National Cancer Institute
Marc Rubin, MD
National Cancer Institute
Claude Viscoli, MD
Gaslini Children's Hospital
Thomas J. Walsh, MD
National Cancer Institute