Bruce D. Cheson, MD; John A. Radford, MD


January 07, 2013

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Bruce D. Cheson, MD: Hello. I am Bruce Cheson, Deputy Chief of Hematology Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2012 annual meeting of the American Society of Hematology in Atlanta. Joining me today is my good friend John Radford, Professor of Medical Oncology at the Institute of Cancer Sciences of the University of Manchester and Christie Hospital in Manchester, United Kingdom. Welcome, John, and thank you for coming.

Less Treatment for Better Results?

As you are one of the world's experts in Hodgkin's lymphoma, I don't need to tell you that it has certainly been one of the success stories of oncology. It has been amazing how many patients we have been able to cure since the old days. Now, we seem to be at a point where we are poised to tailor our therapies.

John A. Radford, MD: Yes.

Dr. Cheson: For patients with high-risk disease, doing something different might be preferable to doing something more intensive (the subject of another conversation). For limited-stage disease, the early-stage patients, perhaps limiting the amount of therapy might minimize the long-term consequences. At this meeting, you are presenting the results of an eagerly awaited study, the RAPID trial,[1] which looked at radiotherapy and limited-stage Hodgkin's disease. Could you tell us how you designed the study, what you expected to find, and what you actually found?

Dr. Radford: The point was that in early-stage Hodgkin's lymphoma, the best long-term results are likely to occur if we give the right amount of treatment to effect a cure, but not more than is actually required. A very high proportion of people will be cured of their disease by a combination of chemotherapy and radiation. It may be that some of those people, or even most, could be cured by chemotherapy alone, and if that is the case, then that eliminates the long-term risks associated with radiotherapy in that population. The question then arises: How do we actually identify the patients who could be cured by chemotherapy alone? That was the background to RAPID.

Who Can Be Cured by Chemo Alone?

We said we wanted to test the ability of FDG-PET to identify the patients who could be cured by chemotherapy alone. We designed a study in which patients with stage IA or IIA Hodgkin's lymphoma, with no mediastinal bulk, had 3 cycles of standard ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine] chemotherapy. After that time, they had a PET scan, and if the PET scan was positive, we inferred that they had residual disease and they needed a further cycle of chemotherapy and radiation. For the patients who were negative, however, we instigated a randomization between no further treatment and involved-field radiotherapy to 30 Gy. The study effectively asked the question: Is it possible for a negative PET scan to identify the patients who can be treated by chemotherapy alone?

Dr. Cheson: Only 3 cycles of chemotherapy.

Dr. Radford: Only 3 cycles. The first assumption of the design was that the involved-field radiotherapy group would have a 3-year progression-free survival of 95%, and some loss of disease control in the no-further-treatment group would be acceptable, given the presumed benefits of not irradiating everybody. We set a noninferiority margin of -7%; in other words, we wanted to see a progression-free survival of 3 years in the no-further-treatment arm of at least 88%. The study started in 2003 and finished recruitment in 2010, with 602 patients registered across the United Kingdom. This study was part of the National Institute for Health Research portfolio of priority studies.

IDMC: Report the Data

The results have just been analyzed, and the Independent Data Monitoring Committee (IDMC) directed us to present the results because they thought they were meaningful. The reason I mention that is that the statistics were based on acquiring 46 events. We actually acquired 36 events, but the IDMC thought the results were very important and that we should get them out there.

All scans were centrally reviewed in London by Sally Barrington and Mike O'Doherty, and the negative PET scan was identified on the basis of a PET score of 1-2. On a 5-point scale, this means that there is a very low risk associated with that score of residual disease. A score of 1 is negative, and 2 is almost certainly negative but not so that we can say that with complete certainty.

Dr. Cheson: It could be more than mediastinal but is less than liver.

Dr. Radford: Exactly. The PET images were acquired at various sites around the country and sent down to London electronically. They were reviewed at the core lab of St. Thomas' Hospital in London, and then the score was assigned by those central reviewers. On the basis of this score, patients either went on to have additional therapy if they were PET positive or to be randomly assigned to either no further treatment or involved-field radiotherapy if they had a score of 1 or 2.

Negative PET; Forego RT?

Dr. Cheson: You had these done in real time?

Dr. Radford: They were done in real time, and the criteria were very tight. It wasn't just done on the basis of a local report. It was a central review of the PET images. Of the 602 patients, 75% were PET negative after 3 cycles of ABVD, and 420 of the PET-negative patients were randomly assigned to either no further treatment or involved-field radiotherapy. With a median of 48.6 months of follow-up, we have some outcomes that show that the progression-free survival for the no-further-treatment group is 90.8%. For the involved-field group, it is 94%. So, having radiotherapy does have an impact on progression-free survival, but the slight reduction in disease control with no further treatment is well within the noninferiority margin that we set up at the beginning. This means that we potentially have a method for identifying the patients who can be treated with 3 cycles of chemotherapy alone and have an excellent outcome.

What is really interesting is that the patients in the no-further-treatment arm who experienced a recurrence were salvaged successfully, in the main, by radiotherapy alone or radiotherapy plus chemotherapy -- the 2 main options. Only 4 of the 20 patients who relapsed went to transplant, so the incidence of transplantation was very low. That gives us confidence to start thinking about how we can use these data in future clinical trials and evaluation of this group of patients.

Two Studies Yield Differing Results

Dr. Cheson: The North American Intergroup Ralph Meyer-led study[2] used subtotal nodal irradiation (which has been criticized, but that is what was used back then) and had findings similar to yours -- a slightly inferior event-free or progression-free survival but with longer follow-up. In fact, they showed a superior overall survival because of the toxicities of radiation, so it will be very interesting to see what happens with your study. Your study is being presented in the context of the H10 trial from Raemaekers and coworkers, the Intergroup study.[3]Could you tell us a little bit about that? It has been a controversial study.

Dr. Radford: I am looking forward to seeing the results that are presented, but my understanding is that they have to close one of their arms because they were concerned about the rate of recurrence in their no-further-treatment arm. If we look at some of the data that have already been presented, there are some very striking differences between their study and ours in terms of design.

Dr. Cheson: What was their design?

Dr. Radford: Their PET scans were reviewed by several different individuals, to my understanding. We had just 2 individuals based in London review all the PET results. Their PET-positive rate was only 14%, and ours was 25%. In other words, there were some differences in the way this group of patients was evaluated by PET. It may well have been a very similar population to begin with, but after the initial therapy, those who were called PET negative and PET positive may have differed between the H10 study and the RAPID trial. This will be an interesting area of conversation between our groups, and we have plans to try and look at the data in that way.

Dr. Cheson: It will be interesting to hear the back-and-forth. How do you think people will criticize your study?

Dr. Radford: At 602 patients, it is not a very large study. Second, follow-up is still quite short. Third, the number of events that we required in the statistical modeling at the beginning has not yet been met. The reason we have reported now is under the direction of the IDMC. We have to be absolutely clear that this is just some additional information in this area that experts in the field can consider and integrate with other information from other studies and use it to move forward. We also need to do some further analysis after 5, 10, and 20 years. This is the nature of the beast in early-stage Hodgkin's lymphoma. We have to have prolonged follow-up so that we can see the real impact of those therapies downstream, because the attrition comes from the late effects of the treatments that we give up front. That is where people will have some comments, and I am perfectly accepting of those.

Quality of PET Review Affects Results

Dr. Cheson: You say that this is where trialists will be able to interpret the data, but what about a patient who walks into a private practitioner today, in December 2012, with early-stage disease that would fit your study? How should that patient be treated out there in the community?

Dr. Radford: The point here is that we can end the RAPID trial. We have been able to show that it is possible to identify, using PET, a group of patients who can have just 3 cycles of ABVD and do extremely well. However, that is predicated on an extremely tight, quality-controlled image acquisition of the PET scans and central review of the PET scans, so that we get absolute clarity about what the results means. We are doing that in a way that may not be possible everywhere, and so we have to bear that very much in mind when we start to think about how we should treat an individual patient. If that degree of quality control cannot be ensured, then it is safer, at this time, to give abbreviated chemotherapy plus involved-field radiation. We have to be sure that the quality of the tests that we apply is the same everywhere that they are being used.

Dr. Cheson: It is critically important for patients that we give them as little therapy as possible so that they can have a long life without being worried about the cardiac, pulmonary, and particularly the secondary malignancy complications of the treatments that we give them. We look forward to hearing the full presentation and hearing what are likely to be pointed questions, and the lively discussions that will ensue when everybody tries to make sense of the differences between your trial and the H10 trial. We are trying to get the best outcomes we can for our patients with Hodgkin's lymphoma, the longest survival with the least amount of treatment-related morbidity and mortality. Thank you for your courageous study, for joining us for this edition of Medscape Oncology Insights. This is Bruce Cheson from ASH 2012, and thank you for your attention.