Dose Intensification in Pediatric Embryonal Malignancies

Forum Chairs

Bruce
Chabner
,
MD
Massachusetts General Hosp Cancer Center

Forum 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

Forum 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

Venue & Travel Information

Hilton Head Island

Travel Forms

TRAVEL FORMS DUE:
October 7, 1991
submit travel form

Travel Policy

Please familiarize yourself with our policies and procedures for travel. We truly appreciate you taking the time to participate in this meeting. As you make your plans, please remember that we are a nonprofit organization dependent on donations and volunteers. We do NOT pay for upgrades, change fees, incurred costs resulting from a flight change, transportation to or from your local (home side) airport, meals or other incidentals.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.
  • Spouses are welcome to come with you at their own cost but are not allowed to attend the meeting. Please no children.

What the Foundation Pays

Accommodations and meals are provided by the foundation during the meeting. Airfare will be covered only if booked through our travel agent. The Foundation will also cover airport transportation on the meeting side at the designated shuttle times. You can select not to utilize Foundation arranged transportation at your own expense when completing the travel form. Once your travel form is received your accommodations and airport transfer will be confirmed. Please let us know of any food allergies or other information we should be aware of on the travel forms.

  • If you would like your airfare covered by the Foundation, you must book with our travel agent. Note we do not cover upgrades, changes, late bookings, etc.
  • Flights must be booked at least 30 days prior to the meeting to confirm your accommodations and airport transfer.
  • As a nonprofit we utilize volunteers and other methods to maximize our efforts (or our donor support) when making accommodations and arranging ground transportation. Ground transportation will be provided upon your arrival either by a foundation volunteer or arranged shuttle. You will be provided airport transportation information the week of the meeting. We do not reimburse for home side airport transfer or incidentals while traveling.

Abstracts

Abstracts are due 30 days prior to the start of the meeting to allow enough time to prepare the meeting book.

The abstracts should be only one or two paragraphs outlining the theme of your presentation and should reflect the objective and spirit of the meeting (see above). Abstracts will be circulated about one week before the meeting. The meeting organizer will start requesting them a month before the meeting.

abstracts DUE:
October 7, 1991
submit abstract

Meeting Structure

The meeting structure has been developed over years of experience.

  • Participants have approximately 45 minutes, depending on the number of participants, for their presentation and discussion. The presentation is meant as a conversation start and should last about twenty minutes briefly covering background information and areas that are new or need further input. This should be structured in such a way as to lead to a lively discussion. Participants are encouraged to interrupt to ask questions or start discussions.
  • A MAXIMUM of 5 slide equivalents per presentation is allowed (Power point slides should not contain more than one graph or gel per slide and no more than 5 bullet points to stress the points being made by the presenter.) We appreciate cooperation with the spirit of this guideline. Handouts are welcome but should be distributed before sessions.
  • Everyone is expected to actively participate in every session and discussions.
  • The time spent at the meeting is relatively short, so please be familiar with papers received prior to the meeting.
  • It is very important that you commit to all sessions of the 2 days of meetings.

Forbeck Scholars Participation

Scholars are selected for each Forbeck Forum. These are outstanding junior clinical or post-doctoral fellows selected based on the quality and relevance of science.

  • Scholars present for 30-45 minutes, depending on the number of participants
  • The same presentation rules apply for scholars
  • After the Forum you are selected to attend, you will attend three years of Scholar Retreats held in Lake Geneva, WI. If you attend a Fall Forum, you will attend the Spring Retreat. If you attend a Spring Forum you will attend a Fall Retreat.
  • Scholars are selected by the Foundation Scientific Advisory Board and peer reviewers selected from past Forbeck Scholars.

General Program

The outline below illustrates a typical program schedule. You will receive a complete schedule, including speaking times, the Thursday the meeting starts.

Arrival Day
1:00 PM Arrivals
6:00 PM Cocktails (opt'l)
7:00 PM Dinner
Meeting Day 1
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Meeting Day 2
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Departure Day
7:00 AM Breakfast
8:00 AM Departures

Frequently Asked Questions

Below are some of our most Frequently Asked Questions. If you have something new to ask, please feel free to contact us.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • Frequently airport transfer is provided by volunteers. Please be patient on receiving this information. Airport transfer will be sent out prior to arrival.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.

Forum Participants

G. Peter
Beardsley
,
MD, PhD
Yale School of Medicine
Joseph
Bertino
,
MD
Memorial Sloan Kettering Cancer Center
Helen
Chan
,
The Hospital for Sick Children
William
Dalton
,
MD, PhD
University of Arizona
William
Evans
,
PharmD
St. Jude Children's Research Hospital
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 A.
Pizzo
,
MD
National Cancer Institute
Norma K.
Ramsay
,
MD
University of Minnesota
Richard
Ungerleider
,
MD
National Cancer Institute
Thomas J.
Walsh
,
MD
National Cancer Institute

Forum Scholars

David Fisher, MD, PhD
Massachusetts General Hospital