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Dose Intensification in Pediatric Embryonal Malignancies

November 7–10, 1991

Chaired By

 Bruce Chabner, MD of National Cancer Institute

Meeting Description

Sessions:

  1. Pharmacological and Biological Basis for Dose Escalation
  2. Clinical Strategies for Dose Escalation
  3. Overcoming Drug Resistance in Pediatric Tumors
  4. Infectious Complications of Dose-Intensive Therapies

Meeting Summary

The seventh Forbeck Forum addressed the rationale and potential strategies for increasing dose of drug administered per unit time in treating pediatric patients. Evidence accumulating from an analysis of trials in adults, and to a lesser extent children, suggests that greater success is achieved by using the maximum tolerated dose intensity of chemotherapy. There now exists unprecedented opportunities for increasing dose intensity through the use of bone marrow protection or rescue strategies. The challenge facing the pediatric oncologist is to develop the optimal high-dose regimens, factoring in considerations of patient tolerance, optimally effective combinations of agents, and the schedule of drug administration. In order to consider this subject, experts on all phases of dose intensification were assembled, representing the best research in cancer drug testing, bone marrow rescue, treatment of infectious complications of chemotherapy, and the design of regimens that overcome drug resistance.

Speakers discussed the scientific rationale for increasing drug dose intensity as a strategy for improving outcome. Dr. Hryniuk discussed the overwhelming evidence from trials in adult solid tumors that dose intensity correlates with response rates for patients with breast, colon, and ovarian cancer. In pediatric tumors, analysis indicated that results are mixed.

Clinical strategies were discussed in the second session. Dr. Ungerleider stressed the need for studies of the benefit of dose intensification focusing on specific agents. The small number of patients in pediatric trials makes it difficult to answer questions in a timely manner, except in cooperative trials. Dr. Miller emphasized that new proteins capable of modifying bone marrow toxicity will allow dose escalation. Such strategies should allow more rapid reconstruction of bone marrow elements, should lead to decreased dependence on reinfusion of a patient’s own bone marrow, and permit expansion of human bone marrow in culture allowing possible genetic alteration of these cells to make them drug resistant. Dr. Ramsay discussed the current status of bone marrow transplantation. With few exceptions, transplantation has not earned a well-defined role in treating pediatric malignancy. However, it was pointed out that there has been little work to date on the development of high-dose regimens that utilize some newer drugs.

Dr. Chan introduced the issue of drug resistance in pediatric tumors. It is a frequent scenario for pediatric sarcomas to initially respond to chemotherapy and then to progress relentlessly after relapse. The Toronto group has found compelling evidence that. In at least three types of pediatric malignancies, a very specific form of drug resistance, mediated by the mdr gene and its p-glycoprotein, is associated with early relapse and death. Strategies for overcoming drug resistance were proposed and results with certain reversal strategies were presented by Dr. Chabner and Dr. Dalton. The group agreed that in mdr- positive tumors, new strategies should be implemented as initial treatment. Dr. Dalton presented results showing that in multiple myeloma and lymphoma, the development of mdr-type resistance is closely related to the total dose of vincristine and adriamycin received. Mitoxantrone induced a different form of resistance and might be useful in combination with vincristine. Dr. Kamen emphasized the importance of changing schedules of drug administration in the use of methotrexate in pediatric leukemia, not just total dose administered. D. Evans discussed the importance of drug level monitoring during dose – escalation with antimetabolites, alkylating agents, and etoposide.

Drs. Hathorn, Pizzo and Walsh reassured the group that the bacterial infectious complications of high-dose therapy are being diagnosed and treated effectively, although the therapy of fungal infections remains a significant problem.

As a result of the meeting, the attendees were charged with examining pediatric solid tumor protocols in their home institution and addressing the considerations raised. In particular, are doses optional? Are drug resistance considerations addressed? And are the optimal rescue strategies being employed to ameliorate toxicity?

At the National Cancer Institute, a new multidrug infusion protocol was begum in patients with pediatric sarcomas, modeled after a protocol outlined by the conference participants. The proposed study will be brought to the attention of the cooperative group study committees. A meeting report was published in the Journal of the National Cancer Institute (December, 1991).

Quotes from Participants
"Though progress may seem slow, the scientific connections made as a result of the Foundation present the opportunity for benefits which may seem intangible in the present, but will have consequential import for the future." -- Langdon Miller, MD, National Cancer Institute, Bethesda, MD

“I found it a unique and stimulating experience. It was a very positive event to be able to interact with others from around the country.” -- Norma Ramsay, Ph.D., University of Minnesota, Minneapolis, MN

“The caliber of presentations and discussion matched completely, I believe, the goals of the Foundation. While the problems remaining are still vast, efforts such as yours cannot but hasten the arrival at answers. The experience was enlightening and inspiring for me …”. -- David Fisher, MD, Ph.D., Massachusetts Institute of Technology, Cambridge, MA

“I felt that the meeting went very well and that, in the end, some very important issues were crystallized. Indeed, some will be followed up by our program at the NCI. I also was pleased with the discussions at the Scientific Advisory Board meeting and felt the directions discussed will enable the Foundation to continue to meet its very important goals and objectives.” -- Philip Pizzo, MD, National Cancer Institute, Bethesda, MD

“… format of selecting a beautiful area and creating a round-table atmosphere for investigators to discuss their research is excellent.” -- William Dalton, MD, Ph.D., University of Arizona, Tucson, AZ

“The chance to interact with the caliber of people that your group organized in an informal way, away from phones and other distractions is terrific. Scientifically, new thoughts appeared and solidification of older concepts occurred.” -- Barton Kamen, MD, Ph.D., University of Texas, Dallas, TX

The conference “contributed greatly to my possibilities to be adequately oriented in the field of neuroblastoma tumor biology research. It is my belief that [the Foundation] has taken on a pertinent task in supporting exchange of ideas in the scientific community, and also the creation of a common language on a worldwide basis in the field of clinical management of neuroblastoma.” -- Frank Hedborg, MD, Uppsala University, Sweden

Forum Participants

G. Peter Beardsley, MD, PhD
Yale School of Medicine

Joseph Bertino, MD
Memorial Sloan Kettering Cancer Center

Bruce Chabner, MD
National Cancer Institute

Helen Chan
The Hospital for Sick Children

William Dalton, MD, PhD
University of Arizona

William Evans, PharmD
St. Jude Children's Research Hospital

David Fisher, MD, PhD
Massachusetts General Hospital
 Forbeck Scholar

James Hathorn, MD
Duke University

William Hryniuk, MD, FRCPC
Ontario Cancer Foundation

Barton Kamen, MD, PhD
University of Texas Health Science Center

Langdon Miller, MD
National Cancer Institute

Philip Pizzo, MD
National Cancer Institute

Norma Ramsay, MD
University of Minnesota

Richard Ungerleider, MD
National Cancer Institute

Thomas Walsh, MD
National Cancer Institute