Role of radiation in Hodgkin’s lymphoma treatment remains controversial

In February, a study published in The New England Journal of Medicine compared chemotherapy alone with a chemotherapy-radiation combination regimen in patients with Hodgkin’s lymphoma.

The researchers hypothesized that chemotherapy alone may improve survival because it is associated with fewer late treatment-related deaths.

The study included 405 patients with previously untreated stage IA or IIA nonbulky disease.

At 12 years, OS was 94% among patients assigned to treatment with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) alone, compared with 87% among patients who received subtotal nodal radiation therapy. The improved survival rate among patients assigned to ABVD alone was due to a lower rate of death from causes other than lymphoma or toxic effects from treatment, researchers wrote.

Joseph R. Bertino, MD, Associate Medical Editor of HemOnc Today, led a round table discussion with HemOnc Today section editors in which participants discussed the study results, ideal chemotherapy dosing schedules and the role of PET scans in determining treatment plans.

The round table discussion follows.

Bertino: For many years, only subtotal radiation was used to treat early-stage Hodgkin’s disease. We were doing splenectomies on patients with clinical stage I and II disease to determine if the spleen was involved and to avoid radiating the spleen, which was part of the subtotal radiation program.

When chemotherapy was found to be effective, and when we realized that radiation therapy was the major culprit in causing secondary malignancies several years later, and when ABVD came along — which was relatively innocuous in terms of secondary malignancy — chemotherapy plus limited involved-field radiation therapy without splenectomy became the standard for limited-stage Hodgkin’s disease.

As ABVD was curative in 50% to 60% of patients with advanced disease, investigators tested the concept that chemotherapy alone could cure as many patients with limited disease with less of a risk for secondary malignancy. The evolution of that was to use chemotherapy alone in early-stage Hodgkin’s disease and try to avoid radiation alone.

The recent cooperative group study published in The New England Journal of Medicine has caused a lot of controversy. It included 405 patients with stage IA or IIA, nonbulky Hodgkin’s disease. Some were treated with ABVD alone, and others were treated with subnodal radiation therapy with or without ABVD therapy.

Patients in the ABVD-only group, both those with favorable and unfavorable risk profiles, received four to six cycles of ABVD. In the group assigned to subtotal nodal radiation therapy, those with a favorable risk profile received subtotal nodal radiation therapy alone, and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy.

The researchers compared all patients who had radiation therapy with those who underwent ABVD alone. Both groups did well, and the beauty of this paper is a long follow-up. The median length was 11.3 years. At 12 years, OS was 94% among those who received ABVD alone compared with 87% for those who received subtotal nodal radiation therapy, either alone or with ABVD. Deaths occurred more frequently among patients who had radiation therapy, but they were unrelated to Hodgkin’s disease.

The criticism of this paper from [Joachim Yahalom, MD, FACR, vice chair for academic programs in the department of radiation oncology at Memorial-Sloan Kettering Cancer Center] was that the researchers used subtotal radiation therapy, not involved-field radiation therapy. In a German study of patients with early-stage disease, researchers used two cycles of ABVD plus involved-field radiation therapy. It yielded about a 95% cure rate, but follow-up was only a couple years.

So, if you talk to some medical oncologists, they say, “Well, we don’t need radiation therapy.” If you talk to radiation therapists, they say, “We can’t abandon radiation therapy because currently a smaller dose — only 2,000 Gy or 2,500 Gy — is used and only to involved fields, and the cure rate is very high, likely without much in the way of long-term side effects.”

Morton Coleman, MD: The paper is interesting in that it tells us that 4,000 rads is absolutely no good and is associated with a lot of side effects. You get breast cancer. You get sarcomas. You get lung cancer. You get pericarditis. You get valvular disease. You get coronary disease. So no one in today’s world would ever consider this dose.

The big issue is: Are two cycles of chemotherapy plus 2,500 rads less toxic than six cycles or four cycles of chemotherapy? What’s really changed the equation is the PET scan. If you have a negative PET scan, if you take all comers with Hodgkin’s disease — or, for that matter, even large cell lymphoma — and your PET scan turns negative after one or two cycles, there’s only about a 10% chance — or, in the case of large cell lymphoma, a 15% chance — that you’re going to relapse.

In those patients who have a negative PET scan, I’m perfectly comfortable giving chemotherapy and stopping after four cycles. In fact, a few years ago, researchers from Argentina reported at ASH that they did PET scans after three cycles of chemotherapy for all comers with Hodgkin’s disease, and if the PET scans were negative, they stopped. Their data looked as good as any data they’ve had before.

I personally don’t give my patients any radiation, nor do most of my colleagues.

Bertino: You would not use radiation therapy?

Coleman: I don’t. And if not, how many cycles [of chemotherapy] do we want to give?

Bertino: Well, there is some controversy about whether a negative PET scan after two cycles is absolutely 
definitive.

Coleman: The controversy isn’t so much on the negatives. The controversy is the positives. If you have a true negative PET scan after one or two cycles, your chances of relapse are really quite small, especially in Hodgkin’s disease. If you look at the data across the board, the relapse rate is 10% or less.

Munir Ghesani, MD: You’re absolutely right. When we look at the negative scans and we follow them, we are so much more reassured that the treatment is effective and we don’t see the recurrences in that setting. With the positive scans, there is clearly a controversy. We find it is much easier to read the PET scans of patients who have only received chemotherapy because, in that category, the false-positive rate is much lower. It’s when you have added radiation that causes the second macrophage activation. Those macrophages that are activated in the field take up as much glucose as the cancer cells do, and that mixes up the picture. We are much more comfortable reading pure post-chemotherapy PETs as opposed to a combination of radiation and chemotherapy.

Coleman: I don’t want to get into the PET scan business, but you’re quite right. If you have a PET scan where the drop in the [standardized uptake value] score is very small, the chances that the patient is going to get cured by chemotherapy is relatively small. So I use the PET scan early on to direct my therapy in terms of Hodgkin’s disease and, if it’s negative after one or two cycles, I’ll stop after four in those very good risk patients. If it’s positive, I’m more inclined to use radiation.

Harry S. Jacob, MD, FRCPath(Hon): So a study has not been done to compare two cycles of chemotherapy with involved-field radiation vs. four to six cycles of ABVD?

Coleman: Correct, but it needs to be done.

Laurence Boxer, MD: In pediatrics, we’ve been driven to try to eliminate radiation therapy in several studies to document that limited chemotherapy has proven as effective in most patients compared to the combination of chemotherapy plus radiation therapy. There have been studies in the Children’s Oncology Group that have supported that. One of the issues for adolescent girls that we pointed out a number of years ago was to try to avoid mediastinal radiation because of the increased risk of breast cancer.

Coleman: The younger you are, the greater your chances of getting breast cancer, so it’s a problem.

Boxer: Interestingly enough, I remember reading about 35 years ago in Africa where they didn’t have fancy radiation therapy machines. They were giving chemotherapy alone, and I remember a publication in The Lancet in which they got dramatic responses.

Joseph Aisner, MD: So, Joe, what would you do at our place? What are you suggesting for stage I and stage II Hodgkin’s disease?

Bertino: I guess it’s a question of who sees them first.

Aisner: I think the data are pretty strong that chemotherapy alone will do as well as radiation. The question then becomes, what are the long-term side effects, which is the handicap for the 4,000 Gy or 4,500 Gy experience. The issue has been that it takes decades to play out the real long-term side effects. The counterpoint, of course, in youngsters is the reproductive issues. Nevertheless, I think that there is now sufficient international experience that suggests that chemotherapy does as well in early disease as combined modality. Then the question becomes one of resource use. In Third World countries, where the radiation equipment gets 100 or so treatments a day, this could be a real big problem, and shifting to chemotherapy alone could be a real advantage.

Jacob: Why are you still using bleomycin as part of the ABVD when there really seems to be a significant amount of toxicity in terms of pulmonary disease that doesn’t get picked up in time, and no one even really knows if you pick it up right away whether it makes much of a difference?

Also, there’s a significant increase, with any kind of chest radiation, of atherosclerotic premature coronary artery disease. It seems to me that’s another reason to steer away from radiation, and I’m all for that based on what I’ve heard from you experts, but I wonder why you’re not steering away from bleomycin and adding something different to that so we don’t have a pulmonary problem.

Bertino: Yes, that is a real problem. We have a curative regimen that, if you use two cycles of ABVD plus 2,000 Gy, you cure 97% of Hodgkin’s disease.

Jacob: Without pulmonary disease with only two cycles?

Bertino: Yes. Well, once in a while you get a patient who is allergic to bleomycin the first dose. I’ve seen that. Dr. Yahalom says that 2,000 rads is very safe and it probably will not have the long-term effects, but we just don’t know.

Coleman: Yes, we really don’t know what 2,000 rads does. As far as bleomycin is concerned, researchers in Germany are looking at whether you need it. In the past, they looked at three drugs vs. four, and four was better than three.

You don’t usually see the bleomycin lung toxicity before the fourth cycle, so if you’re careful to ask the patient about whether he or she has a cough or any kind of pulmonary symptom and follow the pulmonary function, you’ll do alright. The younger the patient, the better they’re able to tolerate bleomycin lung toxicity. As you get over age 60, apparently there’s something called bleomycin aldolase, which really falls dramatically in the elderly. If you get bleomycin lung and you’re elderly, chances are you’ll probably die. But you usually don’t see it before the fourth cycle.

Bertino: With the new CD-30 antibody conjugate, I wonder if we could come up with a regimen that doesn’t have bleomycin?

Coleman: That’s actually under investigation right now.

Bertino: That would be a great step forward. We wouldn’t have this argument anymore.

Coleman: In fact, they are looking at combining the new antibody with chemotherapy, but I think — bottom line — most of us are avoiding radiation in these patients.

Ghesani: Regarding the bleomycin toxicity, most centers now have PET/CT. When you see them on the follow-up, knowing the history, you can pick up bleomycin toxicity at a very early stage. What do you do even if you pick it up early, and does it make a difference — that’s another story. But there are ways to suspect and pick that up early in the stage so you can alert the oncologist that this is already happening so they can switch gears in terms of treatment.

Coleman: One of the side effects of radiating children was they would have stunted growth. When they would get 4,000 rads, they would have a normal head but a shortened trunk. Does 2,000 rads stunt the growth of bones?

Boxer: No, it does not.

Coleman: That’s very interesting. Also, ABVD in children doesn’t usually create sterility. The younger you are the less impact you have from ABVD on sterility.

Aisner: The other aspect about bleomycin is that you can follow it physiologically. If there is a drop in 20% of the CO diffusion, it’s time to stop the bleomycin. It’s much cheaper than a PET scan and just as fast.

Coleman: My custom is, after the third cycle, prior to the fourth cycle, fifth cycle and sixth cycle, I do pulmonary functions with diffusion lung capacity for carbon monoxide [DLCO]. If you ask about any kind of pulmonary symptom and you stop, you don’t get into trouble.

Bertino: So, we’ll be seeing Hodgkin’s patients treated both ways in the future, I think, whether you’re a radiation therapist or you’re a medical oncologist.

Ghesani: You talked about the PET scan costs. Just to put things into perspective, PET scans now get reimbursed at one-third of what they started off with 7 or 8 years ago.

Coleman: Everyone thinks that if you do a PET with low penetration CAT, which is the customary way to do it, that it’s more radiation than a CAT scan. It turns out that the PET is less radiation than the CAT, but it’s a lot more expensive still.

Ghesani: Yes, it still is compared to a CT scan, but a combination of PET/CT — compared with how it used to be reimbursed — now it’s really 30%.

Aisner: I’d like to ask Dr. Coleman about the current SWOG study looking at the PET trigger.

Coleman: Since I’m not in SWOG, I can’t fully comment, but in [chronic lymphocytic leukemia], everyone is looking at the role of intermediary PET vs. a PET scan at the end. The going dictum right now is the PET scan at the end is the way you should go, and the data are not fully secure in terms of interim PET scans.

Aisner: Right, there’s no Level I evidence for this.

Coleman: All I can tell you is that, if you turn negative after one or two, don’t bother to do the one after six because it’s going to be negative. To me, it’s a no-brainer to do it after one or two cycles.

Ghesani: There is a study in Blood that only had a 2-year follow-up, but they found that if it was negative early on in a 2-year follow-up, there was hardly ever any residual or recurrent disease at that stage. So there are some studies showing it.

Aisner: But that’s much too early because all the PET may be reflecting is the reduction of the volume in the number of cells, and it may have taken it below critical threshold. I don’t doubt it. I’m just saying that Level I evidence isn’t there yet.

Coleman: I think your question is valid, but if you look at data that’s generated — particularly with large-cell lymphoma — if you’re going to relapse, it usually occurs within the first 2 or 3 years. You can relapse 5 years down the pike and 10 years down the pike, but it’s single digits. If you get out at 3 years, chances are you’re probably home free. With Hodgkin’s, it’s a little different. They can come back a little bit later.

References:

Eich HT. J Clin Oncol. 2010;28:4199-4206.

Hutchings M. Blood. 2006;107:52-59.

Meyer RM. N Engl J Med. 2012;366:399-408.

Pavlovsky S. Abstract #1772. Presented at: American Society of Hematology 52nd Annual Meeting; Dec. 7-10, 2010; Orlando, Fla.

For more information:

Joseph Aisner, MD, can be reached at The Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08901-1914; email: aisnerjo@umdnj.edu.

Joseph R. Bertino, MD, can be reached at The Cancer Institute of New Jersey, 195 Little Albany St., Room 3034, New Brunswick, NJ 08901-1914; email: bertinoj@umdnj.edu.

Laurence Boxer, MD, can be reached at University of Michigan Health System, 1500 E. Medical Center Drive, #B1, Ann Arbor, MI 48109; email: laboxer@med.umich.edu.

Morton Coleman, MD, can be reached New York Presbyterian/Weill Cornell Center for Lymphoma and Myeloma, 1300 York Ave., New York, NY 10065.

Munir Ghesani, MD, can be reached at Department of Radiology, Beth Israel Medical Center, First Avenue at 16th Street, New York, NY 10003; email: mghesani@chpnet.org.

Harry S. Jacob, MD, FRCPath(Hon), can be reached at Hematology, Oncology and Transplantation Office, MMC 480 Mayo, 420 Delaware St., Minneapolis, MN 55455; email: jacob002@umn.edu.

Disclosure: Aisner, Bertino, Boxer, Coleman, Ghesani and Jacob report no relevant financial disclosures.