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GREG BERK, MD:  Welcome to Conversations with the Experts, a program geared toward informing you about the latest developments in lymphoma diagnosis, treatment and management.  I'm Dr. Greg Berk, an Attending physician at the New York Hospital Cornell Medical Center and Clinical System Professor of Medicine at Cornell Medical College.  Today I'll be discussing Hodgkin's disease with Dr. Joseph Connors who is a medical oncologist at the British Columbia Cancer Agency and Chairman of the Lymphoma Tumor Group for the Province of British Columbia.  Dr. Connors, welcome to the program.
 

JOSEPH CONNORS, MD:  I'm happy to be here.
 

GREG BERK, MD:  Dr. Connors, I'd like to discuss some of the new developments in the pathologic origins of Hodgkin's disease in specific relation to our recent findings that it's a B cell malignancy.  Could I ask you to talk about that?
 

JOSEPH CONNORS, MD:  Sure.  I think that this is an interesting scientific development and it represents the culmination of decades of intensive scientific investigation trying to pin down which type of cell the Hodgkin's disease malignant cells are derived from.  And as our audience knows, the lymphocytes in the body can be divided broadly into B and T cell types.  And the confusing thing has been that when one examines the malignant cells in Hodgkin's disease, some of the characteristics of the cells suggest a B cell origin, some a T cell origin and some perhaps even a macrophage origin.  But recently, it has been possible to show that the malignant cells in Hodgkin's disease have what's called a clonal immunoglobulin gene rearrangement.  And this means that unequivocally they are derived from the B cell lineage.  The series of experiments were quite elegant, but the technique that made the biggest difference was the ability to pluck out individual malignant cells and study the genomic characteristics of those individual cells.

By selecting multiple malignant cells from within the same biopsy and in a few cases in serial biopsies from the same patient, it's been possible to show that the malignant cells are all derived from the same clone of cells.  They all have a stable genetic abnormality of the immunoglobulin gene and its rearrangement.  And as I said, [it's been] unequivocally established that these are B cell in origin.

It's an academic achievement without any obvious direct therapeutic implications, but it settles an issue that has been long outstanding and puts Hodgkin's disease into the same area as the other malignancies where, of the lymphoid system, where similar kinds of definitive testing have been able to assign a specific cell lineage.
 

GREG BERK, MD:  Thank you, Dr. Connors.  The cells that you are referring to are those actually the Reed-Sternberg cells or is the Reed-Sternberg cell a different cell?
 

JOSEPH CONNORS, MD:  No.  The Reed-Sternberg cell is thought to represent the malignant cell.  However, there are other types of cells often visible within the biopsy that don't fulfill the criteria for Reed-Sternberg cells and are referred to sometimes as Hodgkin's cells.
 

GREG BERK, MD:  Correct.
 

JOSEPH CONNORS, MD:  And these cells are likewise thought to be part of the malignant clone.  And in fact, the work I was just referring to has helped to cement this by demonstrating that these actually have a clonally stable immunoglobulin gene rearrangement abnormality shared across these cells and indicating that they're all derived from the same clone.
 

GREG BERK, MD:  Dr. Connors, I want to shift gears a little bit.  I know you're not a radiologist, but we hear about new imaging techniques all the time in the field of oncology.  And I'm wondering if some of these new technologies such as MRI and PET scanning, are they playing a role at all in the initial diagnostic evaluation of patients with Hodgkin's disease, or in follow-up of patients with Hodgkin's disease.
 

JOSEPH CONNORS, MD:  Well, I think the most exciting development there has to do with PET scanning.  And I'll come back to that in a moment.  With regard, though, to the standard initial evaluation for a patient with Hodgkin's disease, I think that the tried and true techniques of chest radiography and CT-scanning of the chest, abdomen and pelvis have become the clearly established gold standard to provide to each patient.  And with the information from those tests sometimes supplemented by nuclear medicine scannings, such as gallium or bone scanning, an adequate picture emerges to plan treatment.  And that hasn't changed.

But the exciting thing recently has been the apparent ability of PET scanning which is a metabolically dynamic form of scanning to distinguish between the kind of residual masses that are left after treatment which are due to scar tissue, to distinguish those from active disease.  That potential may prove to be very real and to have therapeutic implications.

And there is a growing body of evidence indicating that at least under some circumstances, that PET scan can be used to distinguish between residual scar tissue and residual viable tumor.  And if that can be verified in bigger studies with better follow-up, then this will become, I think, one of the standard tools for making therapeutic decisions in the follow-up of patients with Hodgkin's disease.
 

GREG BERK, MD:  I know that's an area that we've done gallium scans on in the past, primarily patients with large mediastinal disease with residual – you know – masses.  Is there any emerging data on the sensitivity and specificity of PET scanning compared to gallium scanning?
 

JOSEPH CONNORS, MD:  I think it's just beginning to emerge now.  But what data I've had the opportunity to see would indicate that PET scan may be another step better in terms of both specificity and sensitivity.  And probably the most important of those two is the specificity because, as you know, these residual masses can be very difficult to figure out.  And even the gallium scan is not a perfect predictor.  And it may be possible that we will be putting together a complex of findings that take into consideration CT, gallium and PET scanning.  And from that complex have a more accurate ability to determine whether residual abnormalities are viable disease or just scar tissue.
 

GREG BERK, MD:   Dr. Connors, I'd like to get right into therapy and specifically chemotherapy of patients with advanced Hodgkin's disease.  There are some new data that's emerged over the past year from Europe.  I believe there's  a large German study which has received a lot of press using a combination regimen which is not typically used on this side of the ocean, but with very impressive results.  Can you comment on that?
 

JOSEPH CONNORS, MD:  Sure.  I'll begin by saying that one of the more important steps forward in the management of Hodgkin's disease established over the past decade has been the clear-cut superiority of a standard regimen that most of us use called ABVD which shows currently the best combination of efficacy against the disease and holding to a minimum the long-term complications that we don't want to see visited on our patients.  And I would say that internationally still the standard of therapy is right now ABVD when one is treating advanced Hodgkin's disease.

The Germans have formed a large and very important study group linking together many hundreds of German centers under the leadership of Dr. Diehl.  And they have been attempting to improve on the achievements of our standard chemotherapy regimen from the past.  And have put together a combination which is usually referred to by the initials of the drugs and it's called BEACOPP.  This is a regimen that adds to the fairly standard drugs like cyclophosphamide, vincristine, procarbazine and prednisone, the MOPP type drugs that we're used to using.  Adds some bleomycin but the most important thing is that it also adds etoposide and Adriamycin and it increases the dosing of the etoposide and the Adriamycin and the cyclophosphamide, considerably higher than we've used in the past.  The patients are assisted in receiving this treatment by the use of growth factors, specifically filgrastim or G-CSF to increase the neutrophil counts.  And this intensified form of chemotherapy, usually referred to as escalated BEACOPP, has been tested in an elegant, large set of trials.  And the preliminary results do indicate that this may be a step forward in terms of a regimen that is clearly more effective at eradicating or curing the Hodgkin's disease.

The problem that will emerge is that the escalation of these drugs and the inclusion of agents like cyclophosphamide and procarbazine mean that some of the less desirable, long-term toxicity of treatment will be retained by this regimen.  And those specific problems are the risk of inducing leukemia or other secondary malignancies and the risk of causing infertility in men or infertility and premature menopause in women.

And the difficulty we'll have sorting out clinically here is that there is going to be a trade-off.  A modest improvement in the likelihood of curing the disease to be weighed up against a guaranteed visiting of the infertility and premature menopause issues and the possibility of increasing the risk of leukemia on patients.  And I think it's going to be necessary to assess the likelihood of cure with a standard regimen like ABVD,  and if that likelihood is relatively high, sticking with the standard and low-toxicity treatment.  And only embarking on these newer and more intensified protocols when the increased toxicity can be clearly justified by the lower likelihood or ABVD or other standard regimens will be able to control the disease.
 

GREG BERK, MD:  Thank you.  You know, since the treatment-related leukemias that have been seen in Hodgkin's tend to occur usually within the first five years in contrast to the solid tumors, is there any information from the German trial yet -- or is it still too soon -- regarding the incidence of leukemia?
 

JOSEPH CONNORS, MD:  It's still awfully early.  The last update that was presented by Dr. Diehl on behalf of the German Hodgkin's Study Group, the median length of follow-up was still less than two years.  And so, we haven't a large cohort of patients followed out beyond the five-year, towards the ten-year mark that you need to make an assessment of leukemia.
But we know that the risk of leukemia is most closely linked to the use of an alkylating agent such as cyclophosphamide and the incorporation of procarbazine.  That's from our long experience with MOPP chemotherapy.
 

GREG BERK, MD:  Right.
 

JOSEPH CONNORS, MD:  And similar regimens.  So there is absolutely no reason to expect that this regimen will have a lower incidence of leukemia than those regimens.  But the question really revolves around whether it might have a higher one because of the potential additional contribution to leukemia of the etoposide that's added.  And another aspect that I didn't emphasize adequately earlier, and that is, that this regimen is always followed by irradiation to areas of nodal disease which was either bulky on presentation or remains still present after the chemotherapy -- such that 70% of patients are also receiving at least involved-field and sometimes wide-field radiotherapy.  So this is really combined modality therapy.

When you put together alkylators like cyclophosphamide, procarbazine and wide-field radiation, we know that you're going to move into a realm where there will be an incidence of 3% to 5% or higher of secondary leukemias.
 

GREG BERK, MD:  Right.  Do you see any added risk of adding the etoposide because that's a drug which has also been associated with leukemia?

JOSEPH CONNORS, MD: Well, I think that there is, if you like, a calculated risk,  if the increased risk from the etoposide is modest and the gain is substantial.  That is, if more patients are cured of Hodgkin's disease, then it is worth incorporating [it] into the recipe.  But that's the kind of issue that can only be settled with longer follow-up and more mature results.  And we'll have our chance to see because the trial that I'm referring to, eventually enrolled over a thousand patients.  And the data from it will be interesting and unfold over the next five to ten years.
 

GREG BERK, MD:  I have one final question, Dr. Connors, related to treatment-related complications and that's in regards to the problem long-term and long-term survivors with secondary solid tumors.  In our own practice we've seen a number of long-term Hodgkin's survivors who now have breast cancer.  And you know, how are the radiation therapists handling this issue as far as the fields involved, the doses of radiation being given?
 

JOSEPH CONNORS, MD:  Well, it's important to remember that the observations that we're making now about second malignancies, second solid tumors in Hodgkin's disease patients are based on secondary cancers that are showing up in patients who are cured of their Hodgkin's disease 10, 20 and sometimes even more years ago.  And this means that we're seeing now a reflection of the effects of irradiation as given two decades ago.
 

GREG BERK, MD:  Right.
 

JOSEPH CONNORS, MD:  The techniques of delivering radiation treatment have evolved just as the rest of oncology and the refinements have included such things as better and more
widespread use of simulation.  Better and more widespread use of megavoltage irradiation so that fields are tighter with more crisply defined edges.  A better understanding of how to adapt the radiation in combined modality therapy so that the size of fields can be smaller.  A tendency to move to a somewhat lower dose of irradiation so that I think fewer patients are being treated up at the 4500 or 5000 centigray level or higher and more in the 3500 to 4000 centigray range.  And so the simple way to summarize it is that the radiotherapy that we're using today, in terms of fields and dose is different and I hope better than what we were using 10 and 20 years ago and which we're now seeing having an impact on our patients.

So I think the radiotherapy community has incorporated all of the improvements in the technique for delivering their modality that they could reasonably do over the years.  And that already will weigh in and benefit our patients.

The other thing that's important as a development is that the more widespread use of combined modality therapy to capitalize on chemotherapies reached throughout the body to go after disease wherever it might be, complemented by radiation's ability to deal with the localized disease has meant that we're seeing patients now treated with some chemotherapy, and then follow it by radiation treatment that can be to a smaller field and to a lower dose.  And that should reduce some of the risk of secondary neoplasms from the radiation.

And finally, the best way to avoid a lot of risk for our patients is to cure their Hodgkin's disease first time around so that they don't have to have secondary treatments which often include more chemotherapy or added radiation treatment.  And as our treatment protocols have become even more effective at maintaining first remissions, we're going to be reducing the risk of secondary malignancies by eliminating the need for secondary treatments, salvage treatments given later on in the course of treatment.
 

GREG BERK, MD:  Dr. Connors, I want to thank you very much for being with us to share your expertise.  I also want to thank the audience as well and I encourage everyone to keep abreast of the latest developments in lymphoma by listening to our other Conversations with the Experts.  I'm Dr. Greg Berk.  And once again, Dr. Connors, thank you very much.
 

JOSEPH CONNORS, MD:  Thank you.