The standard treatment for certain types of Hodgkin lymphoma is combined modality therapy – consisting of chemotherapy followed by radiation therapy. Recently, there has been an increasing trend toward treating patients with chemotherapy alone, omitting the radiation therapy entirely. Should this approach be adopted more widely, or should we still be using radiotherapy in the treatment of certain types of Hodgkin lymphoma?
In this edition of Drawing First Blood, ASH Clinical News invited Joseph M. Connors, MD, and Joachim Yahalom, MD, to debate this topic, with Dr. Connors arguing that chemotherapy alone is the optimal approach for treating Hodgkin lymphoma, and Dr. Yahalom arguing that radiotherapy is a necessary component of treatment.
Joseph M. Connors, MD: Before we start debating how to treat Hodgkin lymphoma, it might be best to discuss the areas where we agree. The chemotherapy of choice for adults with Hodgkin lymphoma of all stages is ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine). Despite more than two decades of attempts and many thousands of patients studied in prospective clinical trials, no alternative primary treatment regimen has ever been identified that results in a statistically significant better eventual overall survival than ABVD.
Joachim Yahalom, MD: Right, ABVD combined with radiation therapy is the most effective treatment for early favorable and unfavorable disease. Adding a low dose of 20 Gy in favorable patients with very limited disease allows us to restrict the amount of ABVD to two cycles. In less-favorable patients with bulky disease, B symptoms, or multiple involved sites, four ABVD cycles supplemented with 30 Gy to only the involved sites is the standard approach. This recommendation is based on results from the German Hodgkin Study Group (GHSG), which prospectively studied thousands of patients and determined that both disease control and overall survival were above 90 percent and no interim positron emission tomography (PET) scan was required during treatment course with this approach. Most guidelines in the United States and Europe regard this as the standard treatment, and it is hard to imagine how we can do better than that.
Dr. Connors: We are in agreement with each other and with experts worldwide in saying that the initial treatment of limited-stage (low bulk stage IA or IIA) Hodgkin lymphoma should start with two cycles of ABVD. Obviously, the number of cycles of ABVD needed to maximize effectiveness is more extensive for advanced-stage disease (typically six cycles). Fortunately, exposure to six cycles of ABVD maximizes its effectiveness, while minimizing late toxicity. At this level, it does not threaten fertility, nor is it associated with demonstrable increase in the risk of second malignancies such as leukemia. When we focus on what to do for limited-stage disease after two cycles of ABVD – whether it is a modest additional amount of chemotherapy or radiation – though, we disagree.
Dr. Yahalom: Obviously, in each stage, we treat differently. But, if a patient has an unfavorable profile despite being in the early stages of disease – meaning disease is limited to a single lymphatic site or to the upper part of the body – then I think almost everyone would agree that radiation therapy should be added, at least to the site of the bulk.
Dr. Connors: Not quite, and we need to be quite precise here because stage matters. With advanced-stage disease, a full course of six cycles of ABVD largely exhausts the usefulness of the ABVD. At that point, any definite residual lymphoma requires potentially non–cross-resistant treatment. This is best assessed with functional imaging, a PET scan and, if the PET scan is positive and involved field radiation therapy (IFRT) is feasible, radiation is the obvious choice at this point. When we focus on the decision point for limited-stage Hodgkin lymphoma after two cycles of ABVD, the relevant question when we consider removing radiation therapy from the equation becomes, “What marginal overall toxicity is added by two more cycles of ABVD, compared with the potential long-term toxicity of adding radiation?” Currently, there is no credible evidence that just two more cycles of ABVD makes any meaningful addition to the risks of late or long-term toxicity. In my opinion, one should choose radiation over completing treatment with two final cycles of chemotherapy if – and only if – there is compelling justification, such as an inadequate response to the initial two cycles of ABVD.
Fortunately, that type of failure of the two cycles of ABVD to induce a complete remission occurs in less than 20 percent of patients, but, when it does occur radiation should be strongly considered. When the optimal stage-appropriate use of ABVD is employed, the majority of patients with Hodgkin lymphoma do not require the use of radiotherapy.
Dr. Yahalom: But don’t you find it worrisome that almost all of the studies questioning the utility of radiation therapy have substituted the radiation therapy with more chemotherapy? For instance, the very well-publicized Canadian HD6 trial randomized early-stage Hodgkin lymphoma patients to radiotherapy alone, ABVD alone, or ABVD followed by extended field radiation therapy.1 This form of radical radiation therapy is now obsolete and was stopped in the 1980s; at that time, radiation was given through the whole body, from the ears to the pelvis and in full doses to every patient, even for very small and localized tumors.
In HD6, patients received four cycles of ABVD, with restaging of the disease through CT scanning after two and four cycles of therapy. If a patient’s CT scan showed response after two cycles, they received only two additional cycles of ABVD (four total); if the CT scan did not show response after two cycles, patients received the full six cycles of ABVD. The combined modality (two cycles of ABVD followed by radiation therapy) demonstrated significantly better disease control than the ABVD-alone group – who received double and, often, triple the amount of chemotherapy.
Additionally, we have to weigh the risks of the potential long-term toxicity of radiation therapy against the 10 to 15 percent risk of treatment failure without radiation – and the subsequent need for salvage therapy with high-dose chemotherapy, radiation, and stem cell transplantation. Salvage is a very traumatic event for patients – in terms of future health risks and the impact on quality of life. When a patient with relapsed disease has to drop out of college and think about freezing her eggs because of salvage therapy’s effects on fertility, I know this could have been avoided.
Dr. Connors: As I mentioned, a very helpful method of deciding who might benefit from radiation therapy is with the use of functional imaging with fluorodeoxyglucose (FDG)-PET. Patients with advanced-stage disease and a residual mass after six cycles of ABVD but a negative PET scan have a complete response and require no radiation. Those with a positive PET scan may benefit from IFRT, and it should definitely be provided if the field of treatment could be kept small enough to minimize toxicity.
About one-quarter of patients with a residual mass after ABVD will have a positive PET scan and require such radiation. For limited-stage disease, PET performed after two cycles of ABVD (PET2) is powerfully prognostic. The approximately 80 percent of patients with a negative PET2 have a 5 to 7 percent risk of eventually relapsing if treatment is completed with two more cycles of ABVD.
Choosing radiation instead of chemotherapy does reduce the risk of relapse, but only cuts it in half, to approximately 3 percent. That means that more than 30 patients need to receive radiation to benefit just one patient. That “benefit” is just avoidance of relapse – a questionable benefit when you consider that relapse can usually be cured. Thus, for the 30 patients not given radiation, we may risk two instead of just one patient relapsing — but 29 patients will have avoided radiation. In advanced-stage Hodgkin lymphoma, PET performed after six cycles of ABVD (PET6) is very useful in identifying patients with residual mass who do not need radiation. We already know that patients reaching a complete response assessed with CT scanning after six cycles of ABVD gain nothing from radiation.
With strategic use of PET, we can identify the three-quarters of patients who have a residual mass seen on CT but whose PET6 scan is negative and will not require radiation.
Dr. Yahalom: I understand that chemotherapy- only advocates may want to use the PET scan as a tool to tell if the patient can spare the radiation, but that tool is not working that well. Of course, PET scanning does give you more confidence when selecting patients for additional ABVD. As we have seen in the European H10 study, though, disease control is inferior when radiation is removed – not to a great degree, but still inferior.2
The H10 study randomized PET-negative patients after two cycles of ABVD to an additional cycle of ABVD followed by radiation therapy (the standard treatment) or to two additional cycles of ABVD (experimental treatment). After enrolling 1,137 patients, the investigators decided to terminate the no-radiation therapy arms due to an excessive number of failures in that arm. Researchers concluded that they would never be able to prove non-inferiority.
When a patient is PET-negative and does not receive radiation therapy, their disease control will be inferior.2 The UK RAPID trial also used PET scans to rule out radiation, using a very simple design: Patients with early-stage Hodgkin lymphoma received three cycles of ABVD, and, if the PET scan was negative, they were randomized to receive either 30 Gy of IFRT or no further treatment.3
This is the only study I know of where the patients who are not receiving radiation are not being compensated with more chemotherapy. However, my concern is that investigators need a larger number of patients – and a larger number of events – to come to any definitive conclusions, and the information so far is premature and their statistics can be interpreted in different ways.
Dr. Connors: I believe integrating a strategy using PET2 for limited-stage and PET6 for advanced-stage Hodgkin lymphoma into standard practice maintains very high cure rates while markedly reducing use of radiation therapy. The main reason the chemotherapy-alone approach has become strongly favored is simply that it avoids unnecessary treatment. No matter how much safer one makes radiation by decreasing dose and/or field size, it cannot be made perfectly safe. With careful use of PET scanning, we are able confine the use of radiation to a small minority with a demonstrated need for it.
Avoidance of unnecessary treatment always improves convenience and reduces cost. That is what makes omitting radiation when it is unnecessary so attractive. The management of secondary neoplasms adds inconvenience, cost, and, potentially, loss of life. So, why would we not avoid radiation therapy – a treatment technique that contributes to the induction of second malignancies? The large majority of patients with Hodgkin lymphoma can be cured, so we should employ a strategy that eliminates a component of treatment (radiation) when it is unnecessary but strongly endorses its use when there is a compelling reason to employ it (a positive PET scan). This approach actually enhances both quantity and quality of survival years gained.
Dr. Yahalom: If we can avoid any treatment, obviously that would be optimal, but I believe people who favor eliminating radiation have lingering fears about outdated methods, when radiation therapy was used without any chemotherapy and given in much stronger doses, over much larger areas, and without protection.
Now, though, this fear has been propagated to a degree that it detracts from the level of care. There were concerns about increasing the risk of other cancers – particularly breast cancer in female patients who received radiation therapy before the age of 30. Now, people are applying this information to a man in his 60s!
I understand the concerns with radiation therapy, but we have to remember that removing radiation does not only mean less toxicity, it also means more chemotherapy-related toxicity. Even if the results with chemotherapy-only approaches had proven equal to the results with the combined modality approach, patients would still end up with double or triple the amount of chemotherapy. My philosophy has been to do very little of each modality, to the point that neither modality is toxic – rather than treating with full doses of either modality.
New data from SEER and the National Cancer Data Base of more than 40,000 patients with early-stage Hodgkin lymphoma are showing a significant decrease in the use of radiation over the last 15 years – as well as a decrease in survival. This statistically significant decrease in survival was independent of other factors associated with avoiding radiotherapy.4 Since the 1950s, we have been continuously improving outcomes with this disease, so it is troubling to me that this trend could reverse direction because of unjustified fear of radiotherapy.4
Dr. Connors: We should be careful in interpreting evidence reported in an abstract. The National Cancer Data Base data seem strange. For example, genuine limited-stage Hodgkin lymphoma (low bulk stages IA and IIA) is found in only about 30 to 35 percent of patients, but this study included 54 percent of all cases; therefore, the data must have included many patients with bulky, symptomatic, or inadequately staged disease. Also, 10-year overall survival was only 80 percent; at my center, and I strongly suspect at your center, 10-year survival for patients with genuine limited-stage disease (low bulk stages IA and IIA) exceeds 95 percent.
This last exchange of views can return us to a common ground: We can agree that treatment decisions should be based on evidence that is gathered carefully, described precisely, and interpreted cautiously. This will result in the best possible outcomes for our patients.
- Meyer RM, Gospodarowicz MK, Connors JM, et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012;366:399-408.
- Raemaekers JM, Andre MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32:1188- 94.
- Radford J, Barrington S, Counsell N, et al. Involved field radiotherapy versus no further treatment in patients with clinical stages IA and IIA Hodgkin lymphoma and a ‘negative’ PET scan after 3 cycles ABVD. Results of the UK NCRI RAPID Trial [abstract]. Blood (ASH Annual Meeting Abstracts). 2012;120:547.
- Parikh RR, Yahalom J, Talcott JA, et al. Early-stage Hodgkin’s disease: the utilization of radiation therapy and its impact on overall survival. Int J Rado Onc. (ASTRO 2014 Annual Meeting Abstracts). CT-08.