Annual Forum 1991 – Dose Intensification in Pediatric Malignancies

Bruce A. Chabner, MD, National Cancer Institute, Bethesda, MD

Dr. G. Peter Beardsley, Yale University School of Medicine, New Haven, CT
Dr. Joseph Bertino, Memorial Sloan-Kettering Cancer Center, NY, NY
Dr. Bruce Chabner, National Cancer Institute, Bethesda, MD
Dr. Helen Chan, The Hospital for Sick Children, Toronto, Ontario
Dr. William Dalton, University of Arizona, Tucson, AZ
Dr. William Evans, St. Jude Children’s Research Hospital, Memphis, TN
Dr. James Hathorn, Duke University Medical Center, Durham, NC
Dr. William Hryniuk, Ontario Cancer Foundation, Hamilton, Ontario
Dr. Barton Kamen, University of Texas Health Science Center, Dallas, TX
Dr. Langdon Miller, National Cancer Institute, Bethesda, MD
Dr. Philip Pizzo, National Cancer Institute, Bethesda, MD
Dr. Norma Ramsay, University of Minnesota Hospital, Minneapolis, MN
Dr. Richard Ungerleider, National Cancer Institute, Bethesda, MD
Dr. Thomas Walsh, National Cancer Institute, Bethesda, MD

Layout and Goals

  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

Outcome Report
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).