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New Treatments for Hodgkin’s Disease 

Hodgkin’s disease is uncommon but not rare. It is a disease with a low incidence; about 3:100,000 per year. What that means in all of North America and Europe is that there will be about 20,000 new cases per year. That’s important to contrast with the number of deaths per year in that same region, which is only about 1:2,000, indicating the dramatic success that we have when treating the disease. That translates into an interesting figure because if most of these patients are cured of their disease or they don’t die from lymphoma, then there is a substantial Hodgkins disease.

You saw Reed-Sternberg cells. I put up this one because it’s a rather famous one and tells us where the story began. This section was made from one of the original cases described by Thomas Hodgkin in 1830, kept at Guy’s hospital, eventually re-sectioned and made into this preparation and reminds us that the disease was accurately diagnosed a better part of 170 years ago, and has given us ample time to gather quite a bit of information about the natural history of the illness. As you heard, until recently there has been some difficulty deciding upon the specific cell of origin of the disease with conflicting information arising from cell antigens, cell surface antigen studies. Some indicating that this seemed to be a T-cell, some a B-cell.

There wasn’t any consistent translocation to guide us and it was difficult to decide just what sort of cell might be giving rise to the disease. The issue has been settled fairly well by a series of elegant experiments which initially demonstrated, based on single cell isolation techniques and PCR analysis, that there was an identical clonal P53 gene abnormality or mutation in the single cells when taken from multiple sites in the same cases, demonstrating a clonal etiology. Clonal immunoglobulin gene rearrangements were then demonstrated strongly.

I think, finishing up an elegantly conducted detective story and demonstrating unequivocally that the cell of origin for Hodgkin’s disease is a B lymphocyte. So we should change the name, as Peter said, to Hodgkin’s lymphoma and treat it as one of the B-cell types of lymphoma.

A couple of comments about epidemiology. This is an older slide taken from the 1950’s through early 70’s showing the classical so-called bi-modal distribution with an early peak here in the 20’s to 30’s, and then a later rise in older age patients. I think that this in fact is a bit of an exaggeration of what’s going on, however on any kind of an examination you should still remember that this is thought to be an accurate portrayal of the epidemiology of the disease and remember that this bi-modal distribution leads to a absolute number of patients being much greater in these younger ages because of course there are so many more younger patients.

Once the disease has been identified we need to embark on an orderly evaluation of the patient to determine the extent, the process that we usually refer to as staging. The steps that are necessary, both for Hodgkin’s lymphoma and non-Hodgkin’s lymphoma, I think are accomplishable in a relatively brief period of time and rely on a small set of quite standardized evaluations. It begins of course with a hematopathology review. One does need to be quite certain that you are dealing with Hodgkin’s lymphoma and that no mistake is made.

My job is to talk about the treatment, where we stand today and how we got there. So I’m going to do that by dividing the patient population into two groups; patients with early stage or limited stage Hodgkin’s disease or lymphoma, and patients with advanced stage disease. I need to make sure that you know what I’m talking about when I say early or limited stage, and now I’m referring to geographically localized disease and either stage I or II. So this is on one side of the diaphragm in nodal sites. For reasons that I’ll outline in a second, I’m excluding patients who

I want to walk through the issues that surround the use of laparotomy. Not because I think that very many of you in the future will recommend staging laparotomy for patients with Hodgkin’s disease, but to emphasize the insights that came from the use of the technique and how we can translate those insights into a treatment strategy, or an evaluation and treatment strategy, that omits this highly invasive staging maneuver. So first to remind you of what it actually included. It

If you do undertake to build your treatment paradigm on the basis of a staging laparotomy, you’ll assign the patients with pathologic stage Ia and IIa disease to extended field of radiation and achieve excellent results like this. With relapse-free survivals that tend to plateau at around 80%, with most of the relapses occurring in the first 5-10 years at the most, after diagnosis. And this large number of patients with longer follow-up very likely cured of their disease. That’s very

Are we home free? Well, no. The difficulty with early stage Hodgkin’s disease is not overcoming the challenge of curing the disease. I’ve been through our records in British Columbia and in the past 20 years, with well over 250 patients managed, we haven’t had but a single death from Hodgkin’s disease in all of those 250 patients. It’s very unlikely that a patient with early stage Hodgkin’s disease managed anywhere in North America or Europe any longer will die of

The real risk to these patients is that they die from something else, and that’s why their survival curve doesn’t come anywhere near paralleling an age-matched curve. So the challenge with these patients is to figure out what it is that they are dying from and to eliminate that as a risk for them. We look at our results and the sole single cause of the excess mortality is entirely second solid tumors. So the challenge in the future is to eliminate whatever it is that we are doing to these patients that is leading to their increased risk of developing solid tumors which eventually prove to be fatal. The best hint that we have is that this may be the radiation treatment so

Let’s split our focus now off to advanced stage disease. Just to remind you, I am now going to be talking about stage III or stage IV, by the Ann Arbor scheme, or patients with bulky disease at any site defined as I said before, or patients with B symptoms, or some combination of those findings. Here the story reaches back into the 1960’s when investigators described the combination chemotherapy regimen that we’ve all eventually come to refer to as MOPP chemotherapy; which included an alkylating agent, a vinc alkaloid, an oral antineoplastic agent - procarbazine and another - a corticosteroid - prednisone. A four drug regimen given in a