Less Is More in Early Hodgkin's Lymphoma

Janis C. Kelly

August 13, 2010

August 13, 2010 — Hodgkin's lymphoma patients are being diagnosed earlier and survive longer, and pressure is building to reduce early treatment intensity in an attempt to limit the secondary malignancies, cardiotoxicity, and other problems that occur years later and can be fatal.

German researchers have added weight to that argument with data showing that 2 cycles of chemotherapy followed by 20 Gy of involved-field radiation therapy are as effective as, and less toxic than, more intensive regimens in patients with good-prognosis stage I or II Hodgkin's lymphoma. Their study is published in the August 12 issue of the New England Journal of Medicine.

Lead author Andreas Engert, MD, chair of the German Hodgkin Study Group and professor of internal medicine, hematology, and oncology at the University Hospital of Cologne in Germany, told Medscape Medical News that the large multicenter study establishes proof of principle that patients with early-stage Hodgkin's lymphoma can safely be treated with 2 cycles of ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) followed by 20 Gy of radiation.

"In Europe, 2 [cycles of] ABVD plus 20 Gy will become standard. I guess the major question for US centers is whether radiotherapy can be omitted. Currently, they usually use 6 cycles of ABVD, which is certainly more toxic," Dr. Engert said.

Failure-Free Survival Rates Comparable

The researchers randomly assigned 1270 patients with newly diagnosed Hodgkin's lymphoma and a favorable prognosis to 1 of 4 treatment groups: either 4 or 2 cycles of ABVD followed by either 30 or 20 Gy of involved-field radiation therapy (Table 1).

Table 1: Reduced Treatment Intensity in Early Hodgkin's Lymphoma

Treatment Group 1 Group 2 Group 3 Group 4
ABVD (cycles) 4 4 2 2
Radiation dose (Gy) 30 20 30 20
ABVD doses: 25 mg/m2 ofdoxorubicin, 10 mg/m2 of bleomycin, 6 mg/m2 of vinblastine, and 375 mg/m2 of dacarbazine

The researchers report that all 4 regimens produced similar freedom from treatment failure and overall survival. At 5 years, failure-free survival rates were 93% with 4 cycles of ABVD and 91.1% with 2 cycles. There were no significant differences in freedom from treatment failure or overall survival between the 30 Gy and 20 Gy radiation doses.

As expected, patients who had 4 cycles of ABVD had more adverse events and acute treatment-related toxicity than those who had 2 cycles (grade 3 or 4 toxicity: 51.7% vs 33.2%).

The authors conclude that "in patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with 2 cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, 4 cycles of ABVD followed by 30 Gy of involved-field radiation therapy."

However, they caution that "given that many of the late, fatal complications of radiation therapy do not emerge until the second decade after treatment, our data cannot speak to the effect of treatment on overall survival."

"The next question is whether radiotherapy can be omitted after 2 or 3 cycles of ABVD in patients who are [positron emission tomography]-negative. We and the [European Organization for Research on Cancer Treatment] are running large clinical trials to answer this question," Dr. Engert said.

Balancing Risks

The question of how to balance the risk for a recurrence of Hodgkin's lymphoma with the risk for treatment-related complications was highlighted in an accompanying review by James O. Armitage, MD.

Dr. Armitage, who is from the Division of Oncology/Hematology at the University of Nebraska Medical Center in Omaha, noted that the 5-year survival rate is 90% for patients with early-stage Hodgkin's lymphoma, and that among good-prognosis patients with long follow-up, more die from treatment-related complications than from lymphoma.

The most important treatment complications are second malignancy, recurrent lymphoma, and cardiovascular events. Second malignancies occur at 1% per year for at least 30 years after treatment, and are particularly serious for women treated for early-stage Hodgkin's lymphoma.

"The risk is particularly high among women younger than 30 years of age who receive thoracic therapy; breast cancer develops in 30% to 40% of these patients in the 25 years after treatment," said Dr. Armitage.

"It seems intuitively obvious that reducing the radiation dose and field size would be likely to decrease the rate at which second malignant conditions occur, and case–control studies suggest this might be true," he added.

Dr. Armitage warned that enthusiasm for reducing treatment intensity should be accompanied by careful monitoring to detect the point at which deaths from recurrent Hodgkin's lymphoma begin to rise, signaling that the regimen is inadequate.

Experts Chime In

George P. Canellos, MD, from Harvard's Dana-Farber Cancer Institute in Boston, Massachusetts, agreed with Dr. Engert's support for less-intensive treatment of early-stage Hodgkin's lymphoma.

"In fact," Dr. Canellos told Medscape Medical News, "we don't radiate young patients with favorable presentation of early-stage disease. The real question should be: How can you justify placing the 75% of early Hodgkin's patients who do fine with chemotherapy alone at risk for later toxicities, which include not only a huge increase in breast cancer risk for young women but serious cardiotoxicity, sometimes requiring valve replacement?"

Dr. Canellos said that the most urgent needs are for biological assays (such as the CD68 marker) to identify patients likely to be chemotherapy-resistant, and for work on salvage regimens for the minority of early-stage patients whose Hodgkin's lymphoma will recur despite treatment. "This is early work, but we have had good outcomes with just repeating chemotherapy on some of these patients," he said.

Julie M. Vose, MD, who is chief of the Division of Hematology/Oncology at the University of Nebraska, was more cautious.

"I think this is an excellent study with a good design and good balanced randomization. I think the biggest issue is that this is specifically for very-good-prognosis patients and it would not be appropriate to use this on patients with any other characteristics than those in the study," she told Medscape Medical News.

"I think it may be appropriate to consider the 2 cycles vs 4 cycles. Some radiation oncologists are still concerned about the 20 Gy vs 30 Gy issue, and this part may need to be repeated. It was also positive with respect to less toxicity, so I think this is an advantage for the patients as well," said Dr. Vose, who also serves on the National Comprehensive Cancer Network lymphoma guidelines panel.

David J. Straus, MD, who is an attending physician on the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News that he was "surprised and disappointed" that the criteria for inclusion were not supplied in the published report, but provided only in a supplement that was difficult to access on the journal's Web site.

"Many of us have been eliminating radiation therapy entirely from treatment in early-stage [Hodgkin's lymphoma] because of the toxicity of radiation therapy that is usually delayed beyond 10 years," he said.

"At their median follow-up of 7 years, they are already seeing second malignancies and cardiovascular events — the major toxicities with radiation therapy — in all 4 arms of the trial. They have shown that in a favorable subgroup of patients, excellent results can be achieved with 2 cycles of chemotherapy and relatively low-dose radiation therapy, but I am not certain that this finding will have an impact on late morbidity and mortality among survivors due to late effects of treatment as long as the treatment includes radiation therapy," Dr. Straus said.

Dr. Engert, Dr. Armitage, Dr. Canellos, Dr. Vose, and Dr. Straus have disclosed no relevant financial relationships.

N Engl J Med. 2010;363:640-652, 653-662.


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