NEW YORK—The late effects of radiotherapy, including second cancers, heart disease, and lung disease, are of special concern in Hodgkin lymphoma (HL) because it is mainly a disease of young adults and long-term survival is possible in many patients. But in major randomized trials radiotherapy has been associated with better local control, so it appears that longer progression-free survival needs to be weighed against the possibility of inferior overall survival, a topic that was debated here at the International Congress on Hematologic Malignancies.
“One of the things we struggle with as clinicians is optimum management of our patients with Hodgkin lymphoma because we know the late consequences sometimes outweigh the risk of the disease,” said the meeting's Program Director, Andrew D. Zelenetz, MD, Vice Chair for Medical Informatics at Memorial Sloan Kettering Cancer Center. “But unless we cure the patient upfront, there is no worry about the late consequences.”
He then introduced the two experts who would be debating the question—specifically: “Early-Stage Hodgkin Lymphoma: Can Radiation Be Eliminated?”
- No, said Joachim Yahalom, MD, Attending Radiation Oncologist and Member of MSKCC, and Professor of Radiation Oncology at Weill Cornell Medical College.
- Yes, said John Radford, MD, Professor of Medical Oncology at the University of Manchester and the Christie NHS Foundation Trust in Manchester, U.K.
Redefining the Question
Yahalom launched into his topic with gusto, suggesting that the title of the session be changed from “Can Radiation Be Eliminated in Early-Stage HL?” to “Replacing Radiotherapy with More Chemotherapy While Accepting a Higher Risk of Relapse,” which got a laugh from the audience.
“Is it worth the price to eliminate radiation?” He set out to prove that it is not—first with data on approximately 42,000 patients from the National Cancer Data Base for 1998–2011. In that time period, 96 percent of patients with adult classical HL stages I-II received chemotherapy. Only 49 percent received radiotherapy—primarily because it was not part of the planned initial treatment strategy.
Ten-year overall survival for the entire cohort was 80.8 percent.
But 10-year overall survival for those receiving radiotherapy was 84.4 percent, versus 76.4 percent for those not receiving radiotherapy.
Still, overall survival in HL is a challenge to assess in a clinical trial, Yahalom admitted, because survival with disease is often very long, there are curative and temporizing salvage options, and one trial arm could be more effective but toxic, which is often not demonstrated.
A meta-analysis might be a better method, he said, citing a study from the Cochrane Haematological Malignancies Group (Herbst et al: Haematologica 2010;95:494-500). That analysis of five clinical trials showed that adding radiotherapy to chemotherapy increases both tumor control and overall survival in patients with early-stage HL.
Yahalom also addressed, but actually refuted, results from the Canadian-led NCIC ECOG HD-6 trial (Meyer et al: NEJM 2012;366:399-408). The trial compared ABVD chemotherapy alone vs. a chemoradiotherapy regimen, and concluded that chemotherapy alone may extend survival because it is associated with fewer late deaths. The trial gained considerable attention and was thought by some to be the definitive answer to the chemotherapy vs. chemoradiotherapy debate.
But Yahalom said HD-6 had significant shortcomings: it excluded “unfavorable” patients; the regimen used a sub-total nodal irradiation (STNI) approach that has long been abandoned as excessively toxic; and the 23 deaths reported as “other” for the chemoradiotherapy arm included a suicide, a drowning, a patient who died of Alzheimer's disease, and one cause unknown.
“Remove these [unusual events] and there is no p value,” Yahalom said.
More appropriate to cite, he said, is the German Hodgkin Study Group (GHSG) HD-10 trial (Engert et al: NEJM 2010;363:640-652), which achieved an overall survival rate of 97 percent with only two cycles of ABVD and the more modern modality of involved-field radiotherapy (IFRT).
PET Directs Therapy
Yahalom found support for chemoradiotherapy even in the UK NCRI RAPID trial of 602 newly diagnosed HL patients led by his opponent in the debate and reported at the 2012 American Society of Hematology Annual Meeting (Radford et al: ASH 2012, Abstract 547).
In that trial, FDG-PET was used after initial three cycles of initial ABVD chemotherapy to assign patients to treatment groups: PET-positive patients continued on ABVD, while PET-negative patients (75 percent of all patients) were randomly selected to receive either IFRT or no further therapy.
Three-year progression-free survival was higher in the PET-negative patients receiving IFRT vs. no further treatment (93.8% vs. 90.7%); nevertheless, the RAPID authors concluded that radiotherapy is unnecessary in patients who become PET negative after three cycles of ABVD.
Yahalom concluded that combined-modality therapy with limited chemotherapy and reduced-dose “smart-volume” radiotherapy is the safest and most effective approach for the majority of patients.
“Chemotherapy alone allows acceptable results, but not without a price—more chemotherapy complications, more relapse, and more need for salvage,” he said. “And the 10 percent of patients who fail due to omission of radiotherapy face a life-changing experience of salvage therapy with fertility concerns and other serious toxicity.”
‘Some of My Best Friends...’
When it was his turn, Radford said he agreed with Yahalom on many points, that he was not interested in eliminating radiotherapy entirely from treatment of early-stage HL, and that “some of my best friends are radiation oncologists.”
Rather, he said, “this is about learning how to use this important treatment in the best possible way.”
And radiotherapy is not the only treatment associated with late effects, he said, as chemotherapy has that potential to cause secondary AML/MDS, pulmonary fibrosis, infertility, or cardiac disease.
The question is how to use the mix of treatments in the best way, Radford said.
He also cited the NCIC ECOG HD-6 trial, and said he accepted that the trial was by no means perfect.
But Radford pointed out that the radiotherapy arm did have more than twice as many second malignancies (nine vs. four) as the chemotherapy arm.
Next, using many of the same slides as Yahalom, Radford reviewed the RAPID trial. Local control was better among the PET-negative patients who received radiotherapy after randomization, he admitted—92.8 percent progression-free survival at 48.6 months versus 90 percent for the no-further-treatment group.
That gain, however, was at the expense of irradiating all the patients in that treatment arm with the risk of late toxicity, he said.
And the message from the HD-10 study is the same as from RAPID, Radford said: that late effects of treatment are a major consideration in patients for whom long-term survival is likely, and therefore there is a balance to be struck between maximum initial disease control and the impact of late treatment toxicity.
Radford said he believed it is possible to use PET to identify patients with stages IA and IIA disease who will have a good outcome after chemotherapy alone, but that longer follow-up is required to confirm the hoped-for benefits of a PET-directed approach on 10- and 20-year survival and cause of death.
“It is possible using PET to individualize the use of radiotherapy in patients with early-stage HL and reduce the overall number exposed to the risk of radiation-induced second cancers and cardiovascular disease,” he said, “but PET-directed therapy requires quality-controlled image acquisition and reporting, and careful discussion of every patient.”
So, can irradiation be eliminated in early-stage HL?
Radford concluded that it can, in patients who are PET-negative after chemotherapy.
“In others, the addition of radiotherapy to chemotherapy is appropriate—in those who are PET-positive after chemotherapy, or those who are PET-negative but for whom recurrent disease presents more of a threat than late toxicity of radiotherapy, such as the older or comorbid patient.”