DR. BOLLARD: I thank you very much for your detailed response. My next question is actually to Dr. Gross, who is currently chairing the international study for upfront diffuse large B-cell lymphoma and Burkitt lymphoma in pediatric young adults. I would like you to speak to a couple of issues, and you can put it in the context of the current randomized trial, looking at rituximab vs no rituximab for this disease. I think firstly it would be useful for you to speak to the implications of this new classification system as we go forward with choosing new therapeutic strategies for these patients, and in particular I'd like to focus on the newly diagnosed diffuse large B-cell lymphoma patients who are in that adolescent/young adult range.
I would also be interested in your opinion regarding how you would manage a patient who is 17 years old but is going to turn 18 tomorrow, and he comes to you with newly diagnosed diffuse large B-cell lymphoma. As you know, the adult oncologists treat diffuse large B-cell lymphoma different to Burkitt lymphoma, and in pediatrics we generally treat these diseases the same. Do you tell this patient that you will treat him today on a pediatric regimen, or do you tell him to go tomorrow, when he's 18, to be treated by an adult oncologist? I would like you to justify your answer please.
DR. GROSS: First to discuss the implications of the new staging as it applies to the current international trial. As Dr. Cairo pointed out, this was developed through a literature review and evidence based analyses, but like any new staging system, the value of staging is to provide us with information that can try to help us to identify patients to improve their outcome. Essentially, staging is to help direct therapy or provide prognosis for outcome, and the only way to do that is to test new systems or classifications in a prospective fashion. Indeed, that is what we are trying to do with this international effort.
This international effort, just as an aside, illustrates one of the challenges of all rare cancers, but particularly pediatrics. In pediatric mature B-cell NHL, both large-cell and Burkitt, we are now at a cure rate of about 90%. To make advances, we don't have enough patients seen in North America and Australia, and it requires international collaboration. This trial, to get 600 patients randomized, it will take 7 years with 14 countries participating—that is one of the challenges, certainly, we have with pediatric NHL. Also, we want to try to gain as much information as possible, not just to the effect of rituximab as Dr. Bollard said, but also to test other questions such as the role or the value in validating this new staging system.
To talk about the controversy of treatment, certainly we know that there is a very different approach in pediatrics. For many years, we have treated diffuse large B-cell lymphoma just like Burkitt. This is a very important delineation when you're seen by a medical oncologist because the treatment for diffuse large B-cell lymphoma is outpatient therapy, ie rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Treatment for Burkitt is inpatient with high doses of methotrexate, but other higher doses of the same agents used to treat diffuse large B-cell lymphoma. The question is, do we really need to treat all the pediatric diffuse large B-cell lymphoma with these aggressive Burkitt regimens? I think one of the things that is encouraging to me as a pediatric oncologist is that we are beginning to learn that the biology is very different. Though the disease looks the same under the microscope or by flow cytometry, when you look at it genetically it's quite different. We know now that the younger the patient is with diffuse large B-cell lymphoma, even though it looks for all intents and purposes like the same disease as seen in adults, when you look at the genetics, many times, as high as 30% of the time, it will be genetically the same as a Burkitt lymphoma. I think when you're talking about young patients we can easily justify treating them both the same because the biology would suggest that a good number of patients would need Burkitt therapy to be cured.
Now, that changes over time, so that it appears that sometime in young adulthood, maybe somewhere between 25 and 35 years of age, you don't see the genetic disease that looks like diffuse large B-cell lymphoma, but is genetically Burkitt lymphoma. As for the 18-year-old patient that Dr. Bollard was posing to me, I've had several patients like this. I go through the pluses and minuses of the therapy, inpatient vs outpatient, but also the potential long-term side effects. The outpatient therapy has potentially more long-term side effects as far as potential infertility and potential heart damage. Every time I have given the choice to the family and the patient, the teenager has always chosen the outpatient therapy that you would get as an adult, and the parents always say they would rather have the inpatient therapy, and that spending a couple of days in the hospital to try to reduce the chance of long-term damage is their choice. It's a very interesting dynamic and I think sometimes the issues that go into choice of treatment are quite variable. My personal opinion is that hopefully in the future we will be able to have a better understanding of biology, so that when we see these patients, be they 18 or 25 years old, we're not looking at what it looks like under the microscope or who they see, and what they're used to giving, but the biology will determine which therapy is more likely to cure them. Right now we don't have that ability in most of the patients.