Second Malignancies

Carlo M.
Croce
,
MD
Jefferson Cancer Center

Forum Description

Sessions:

  1. Mechanisms
  2. Acute Leukemias
  3. Oncogenes and Tumor Suppressor Genes

Some of the drugs we use to treat cancers can cause so much damage to normal cells that secondary cancers can result later in life. We are gaining insights into which drugs are the “bad actors” and protocols are being developed to attempt to reduce the use of these agents. However, the problem is not this simple. Why does the problem only occur in some patients; who is at risk and why? What type of damage do the drugs do to cells and how does this lead to the development of new cancers? Are there options to reduce the problem and if so can they be introduced rapidly into the clinic?

One of the most distressing and frequent long-term complications of cancer treatment in children and adults, is the occurrence of acute leukemia caused by the drugs and irradiation used in treating the primary tumor. Alkylating agents such as cytoxan and melphalan have long been known to cause leukemia, presumably by damaging the DNA of normal hematopoietic precursor cells in the bone marrow. A second class of drugs, those that bind to topoisomerase II, including doxorubicin and etoposide, have been associated with increasing numbers of cases of acute leukemia. The leukemia has unusual and distinctive clinical and genetic features, and is associated with a break in chromosome 11 at a gene called the mixed lineage leukemia gene (MLL). The function of that gene, the reasons for its susceptibility to damage by these particular drugs, and measures that could be taken to identify patients at high risk of leukemia and to prevent its occurrence, is the subject of this conference.

Forum Summary

The 13th Forbeck Research Foundation Forum focused on the observation that secondary cancers can occur in patients, after they have been treated for their original malignancy. This effect is particularly marked following the administration of particular combinations of cytotoxic drugs. Most second malignancies are leukemias, and one of the groups of drugs known to cause these cancers is called ‘topoisomerase II inhibitors’. While the toxicity of these drugs is well recognized, they often form essential components of drug regimens used for the successful treatment of cancer.

The first part of the conference concentrated on how the topoisomerase II inhibitors function to prevent both cancer cells and others from functioning. It is known that these drugs and another group called topoisomerase I inhibitors act by blocking the action of particular proteins in the cells which are involved in the process of the division of DNA which occurs when cells divide. Part of the discussions revolved around the mechanisms by which cells die as a consequence of being exposed to these groups of cytotoxic drugs. More pertinent to the problem of second malignancies is what happens to cells which are damaged by the drugs but survive and ultimately become cancerous.

As indicated above, many of the secondary cancers that arise as a result of drug treatment are leukemias. The mechanism by which these occur is not clear. We can identify the cytotoxic drugs which are known to be causative agents in the development of secondary malignancies, and we know that these are capable of inducing breaks in DNA, but how this translates into cells becoming cancerous is not understood. What is clear is that large pieces of DNA can move from one chromosome to another (a process called translocation) and this occurs in a non-random fashion. The phenomenon of specific chromosomal translocations occurring in selected leukemias was discussed in detail. It is clear that the translocations observed in primary leukemias are also those which are observed in cancers arising as a result of drug treatment. One translocation which is particularly prevalent in drug induced leukemias involves chromosome 11 at position q23. A gene (a DNA sequence coding for a particular protein in the cell) intimately involved in this translocation had been identified and given the name MLL (ALL1, Htrx, or HRX). The function of this gene is not well understood but it codes for a very large protein which may interact with DNA. Studies are underway to attempt to define further the function of the gene. Unfortunately, no further insights are forthcoming as to how the action of drugs causing DNA strand breaks translates into specific translocations in leukemic cells.

Studies were also presented on the epidemiology of secondary malignancies. This means the study of populations of patients receiving chemotherapy to attempt to define those at particular risk of contracting a secondary cancer. The complexity of the problem was outlined and interesting data reviewed to try to address the problem.

The Forum resulted in an extremely lively interchange between the participants. The attendees welcomed the opportunity to discuss all aspects of studies into secondary malignancies (leukemias), the topics ranging from molecular pharmacology, genetics, protein chemistry, hematology and oncology. A consensus was agreed that where feasible, the use of high concentrations of topoisomerase II inhibitors should be avoided in cancer therapy. However, from a clinical viewpoint this is not necessarily an option until better combinations of drugs can be identified for the treatment of many different cancer types.

Quotes from Participants
“I was most impressed with the unique format of the Forum. I have never before been to a meeting that inspired (and demanded) such a vigorous and stimulating interchange between participants. I liked the format so much that I plan to institute a similar format at an MIH-sponsored meeting on the chemistry of anti-cancer drugs that I am helping to organize for next spring.” -- Neil Osheroff, Ph.D., Vanderbilt University Medical Center, Nashville, TN

"It has been a remarkable privilege and pleasure to have been part of the William Guy Forbeck Research Foundation since its inception. I have learned a tremendous amount from attending the Forums and by interacting with so many wonderful people … all of whom have made remarkable contributions to children and to improving knowledge to help our future generations.” -- Philip A. Pizzo, MD, Children’s Hospital, Boston, MA

Venue & Travel Information

Hilton Head Island

Travel Forms

TRAVEL FORMS DUE:
October 6, 1997
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 forum. 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 forum. 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 forum 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 forum.
  • Speaker agenda is not sent out prior to the forum. It will be provided upon arrival in the forum 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 forum. Please no children.

What the Foundation Pays

Accommodations and meals are provided by the foundation during the forum. Airfare will be covered only if booked through our travel agent. The Foundation will also cover airport transportation on the forum 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 forum 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 forum. 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 6, 1997
submit abstract

Forum Structure

The structure of the forum 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 forum is relatively short, so please be familiar with papers received prior to arrival.
  • It is very important that you commit to all sessions of the 2 days of the forum.

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 forum starts.

Arrival Day
1:00 PM Arrivals
6:00 PM Cocktails (opt'l)
7:00 PM Dinner
Forum 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
Forum 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 forum. 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 forum.
  • 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.
  • 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

Peter
Aplan
,
MD
Jefferson Cancer Center
Mary Ann
Bjornisti
,
PhD
Thomas Jefferson University
Richard
Fishel
,
PhD
Kimmel Cancer Center
John H.
Kersey
,
MD
University of Minnesota Cancer Center
Leroy
Liu
,
PhD
RW Johnson Medical School
Neil
Osheroff
,
PhD
Vanderbilt University Medical Center
Yves
Pommier
,
MD, PhD
National Cancer Institute
Les
Robinson
,
PhD, MPH
University of Minnesota
Janet
Rowley
,
MD
University of Chicago

Forum Scholars

Fotis Asimakopoulos
University of Wisconsin
David Crawford, MD, PhD
Oklahoma University