I just finished attending the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland. This conference is held every other year. As the name implies, it is a conference focused on reviewing and presenting the very latest data on lymphomas. In this article I will address some of the burning questions in Hodgkin lymphoma we face today and provide some of the latest insights from Lugano.
There are at least 4 big questions in Hodgkin lymphoma these days, and I will address them separately here:
- Can radiation therapy be omitted in all early-stage patients?
- If no, then can a negative PET/CT scan after 2 cycles be used to select the patients in whom to omit radiation therapy?
- If an interim PET/CT scan after 2 cycles of ABVD is negative for residual disease, is it safe to omit the bleomycin in subsequent cycles?
- If an interim PET/CT scan after 2 cycles of ABVD is positive for residual disease, then is it helpful to change the ABVD to the more aggressive “escalated BEACOPP” regimen for the remaining 4 cycles?
Can radiation therapy be omitted in all early-stage patients?
NCIC HD6 Trial
One trial that has attempted to answer this question was the NCIC HD6 trial, published by Meyer and colleagues in the New England Journal of Medicine in 2012. The trial design was complicated and used subtotal nodal irradiation, which is almost certainly overtreatment with radiation therapy and is never used any more.
The results of the study were that, even though the rate of relapse was a little bit lower in the patients receiving radiation therapy, the overall survival rate was better in the patients that did NOT receive radiation therapy, probably due to that fact that toxicities from radiation therapy contributed to some deaths.
Other smaller studies have been conducted, but none was large enough to answer the question definitively.
So, at the present time, the question of whether radiation therapy is routinely necessary after several cycles of ABVD has been poorly studied. 2015 NCCN Guidelines state, “Combined modality therapy [meaning chemotherapy plus radiation therapy]…is the preferred treatment for patients with stage I-II favorable disease,” but also list ABVD alone as an option for selected patients. In patients with early-stage, unfavorable disease, NCCN Guidelines clearly favor an interim PET/CT strategy, though not all experts agree with that strategy.
If radiation therapy cannot be omitted in all early-stage patients, then can a negative PET/CT scan after 2 cycles be used to select the patients in whom to omit radiation therapy?
The RAPID trial, published by Radford and colleagues in the New England Journal of Medicine in April 2015, was one that attempted to answer this question. The trial was conducted in the United Kingdom. Patients were eligible only if they had favorable stage I-IIA disease, meaning that patients with bulky mediastinal masses and B symptoms were not eligible. A baseline PET/CT scan was generally not performed, but an interim PET scan was performed after 3 cycles of ABVD chemotherapy. If the PET scan was negative, then patients were randomly assigned to receive 30 Gy of involved-field radiotherapy vs. no therapy. If the PET was positive, then patients were given a fourth cycle of ABVD followed by involved-field radiotherapy.
After 3 cycles of ABVD, 75% of patients had a negative PET and 25% had a positive PET. In the PET-negative patients that were randomized (not all of these received the assigned therapy), the 3-year progression-free survival was 95% in the radiotherapy group and 91% in the observation group; the difference was statistically significant. In the patients that were actually treated according to the protocol, the 3-year PFS numbers were 97% in the radiotherapy group and 91% in the no-therapy group, again a statistically significant difference. So far, there is no significant difference in overall survival.
From the results, one cannot conclude that omitting involved-field radiotherapy results in a “non-inferior” PFS; however, the authors feel that “the results suggest that radiotherapy can be avoided for patients with negative PET findings.” Longer follow up is going to be necessary to determine whether a survival difference emerges between the groups.
EORTC H10 Trial
A second trial that addresses the same question is the EORTC H10 trial, published by Raemakers and colleagues in the Journal of Clinical Oncology in 2014. All patients had early-stage (stage I-II) disease and were classified as either favorable or unfavorable – unfavorable meaning they had one of the following risk factors: age over 50 years, more than 3 areas of nodal involvement, or bulky mediastinal disease. Favorable patients with a negative interim PET scan received either 3 cycles of ABVD followed by INRT or 4 cycles of ABVD without INRT. Unfavorable patients with a negative interim PET scan would get either 4 cycles of ABVD followed by INRT or 6 cycles of ABVD without INRT.
The preliminary results in the favorable PET-negative group are these:
Treatment Group Number of Patients 1-year PFS Results Significant?
ABVD x 3 + INRT 188 100% Yes
ABVD x 4, no INRT 193 95% Yes
The preliminary results in the unfavorable, PET-negative group are these:
Treatment Group Number of Patients 1-year PFS Results Significant?
ABVD x 4 + INRT 251 97% Yes
ABVD x 6, no INRT 268 95% Yes
The conclusion of the H10 trial was that, in early-stage HL, leaving out radiation therapy (and adding additional cycles of ABVD instead – 1 for favorable and 2 for unfavorable) significantly increases the risk of relapse. However, even in patients who omit radiation therapy, the results are still excellent, and the risk of relapse is low. Many relapsing patients may still be salvaged by additional chemotherapy and autologous transplant.
Two ongoing German studies – the HD16 and the HD17 trials – are both evaluating the role of interim PET scans in selecting patients to omit radiation therapy.
All these results take us to where we are now. What we do know is this: early-stage patients who receive radiotherapy seem to have a slightly lower risk of recurrence of their Hodgkin lymphoma. What we do NOT know, however, is whether such a reduction in the risk of recurrence translates into a higher chance of survival, which is what we really care about. What the NCIC HD.6 trial taught us is that sometimes the added radiation therapy, while reducing the risk of recurrence, worsens survival due to late toxicities from radiation therapy. Whether that result will be seen again in the trials using involved-field, as opposed to the larger-field subtotal nodal irradiation, is unknown at this time. In 2015 it is the responsibility of the patients and their oncologists to make these decisions as a team after a thorough discussion of what we know and what we don’t.
If an interim PET/CT scan after 2 cycles of ABVD is negative for residual disease, is it safe to omit the bleomycin in subsequent cycles?
This question was one of the two main questions addressed by the Response-Adapted Therapy Based on PET in Hodgkin Lymphoma (RATHL) trial, presented in Lugano by Dr. Johnson from the UK. In the study, patients with advanced stage (stage IIB-IV) Hodgkin lymphoma were treated with 2 cycles of ABVD and then underwent an interim PET/CT scan. If the PET/CT scan was negative, then patients were randomized to receive 4 cycles of either ABVD or AVD (i.e. ABVD without the bleomycin). Patients with a negative PET scan were discouraged from receiving radiation therapy, and few received it. If the PET/CT scan was positive, then patients were treated with escalated BEACOPP. Since there was no randomization between ABVD and escalated BEACOPP, the trial cannot be expected to determine whether patients with a positive interim PET/CT scan would fare better if they get escalated BEACOPP compared with ABVD.
The results of the trial in the interim PET-negative group can be summarized as follows:
- Dropping the bleomycin reduced the rate of infections and pulmonary toxicity.
- Dropping the bleomycin did not affect the 3-year progression-free survival (84-85% in both arms).
- Dropping the bleomycin did not affect the 3-year overall survival (97% in both arms).
The conclusion of the trial was that, in patients with advanced stage HL whose interim PET/CT after 2 cycles of ABVD is negative, dropping the bleomycin for the remaining 4 cycles slightly reduces toxicity without compromising efficacy. So, the answer to the question seems to be yes. Of note, this trial did NOT include early-stage patients, so in theory it could be risky to extrapolate the results to that group.
If an interim PET/CT scan after 2 cycles of ABVD is positive for residual disease, then is it helpful to change the ABVD to the more aggressive “escalated BEACOPP” regimen for the remaining 4 cycles?
EORTC H10 Trial
The same EORTC H10 trial discussed above also evaluated different regimens in patients with positive interim PET/CT scans. All patients received 2 cycles of ABVD and then underwent an interim PET/CT scan. Patients with a positive interim PET received either 2 cycles of ABVD or 2 cycles of escalated BEACOPP. All patients with positive interim PET scans received involved-nodal radiation, which narrows the radiation fields even further compared with involved-field radiation, after the completion of chemotherapy. The results of the trial in interim PET-negative patients were previously published in 2014 by Raemakers and collagues in the Journal of Clinical Oncology and were reviewed above. The results in the interim PET-positive patients were presented in Lugano.
The median follow up on this trial was 4.5 years, and all patients have been followed for at least 3 years. In the PET-positive patients, those assigned to escalated BEACOPP had improved 5-year progression-free survival compared with those treated with ABVD (91% vs. 77%). There was also a trend toward improved 5-year overall survival, though that did not reach statistical significance (96% vs. 89%). Toxicity was significantly higher in the escalated BEACOPP group, with neutropenic fever (24% vs. 1%) and infections occurring at a significantly higher rate.
From these results, the authors concluded that patients with positive interim PET/CT scans after 2 cycles of ABVD seem to benefit from changing chemotherapy regimens to escalated BEACOPP; there is a proven benefit in progression-free survival, though not a statistically significant benefit in overall survival, and there is increased toxicity from escalated BEACOPP. The discussant at the meeting, Dr. Engert, pointed out that the toxicity of this regimen would prevent some patients from being able to tolerate it. I would also point out that potential long-term risks of the more toxic escalated BEACOPP regimen, such as development of leukemia, could abrogate the relatively early benefits being reported at this time, so the real answer to this question may need to wait several years for longer follow up.
I would summarize my opinions on the answers to these questions as follows:
- Can radiation therapy be omitted in all early stage patients? I still feel like the answer is not really known. The NCIC HD6 trial clearly demonstrated that subtotal nodal radiation can be omitted, but subtotal nodal radiation is outdated and involves larger fields than involved-field or involved-nodal radiation therapy.
- Can a negative PET/CT scan after 2 cycles (interim PET) be used to select the patients in whom to omit radiation therapy? My answer is maybe. Patients with a negative interim PET who omit radiation therapy have a slightly higher risk of relapse. However, patients who relapse are often saved by additional chemotherapy, autologous stem cell transplant, and/or radiation therapy. It is possible that the higher risk of relapse will translate to one of the following:
- Lower overall survival due to deaths from relapsed Hodgkin lymphoma.
- Equal or improved overall survival due to effective salvage therapy and less radiation-related toxicity.
At the present time, we just do not know which of these outcomes will occur with long-term follow up of these patients, so we are going to have to be patient and make decisions with some degree of uncertainty.
- If an interim PET/CT scan after 2 cycles of ABVD is negative for residual disease, is it safe to omit the bleomycin in subsequent cycles? The answer is probably yes, in advanced-stage patients, but I would like to see how other professionals in the community view the RATHL results, and it would be safer to see the results in a peer-reviewed journal first.
- If an interim PET/CT scan after 2 cycles of ABVD is positive for residual disease, then is it helpful to change the ABVD to the more aggressive “escalated BEACOPP” regimen for the remaining 4 cycles? I think the jury is still out on this one. Other studies are ongoing to answer this question, and longer follow up would be useful to determine the late toxicities of the more intensive escalated BEACOPP regimen. However, I would not argue if patients and their physicians elected to make a switch from ABVD to escalated BEACOPP in this situation.