Modern treatment for early stage Hodgkin's lymphoma is highly effective, leaving most patients with no evidence of cancer. However, experts differ on the best approach: Is chemotherapy enough or does adding radiation therapy improve the outcome?
A systematic review comparing the two approaches found a clear advantage to combined therapy, at least in the short term. Those who received both chemotherapy and radiation were less likely to die or to have recurrences of their disease, within the next few years, than those who just had chemotherapy.
In view of the apparent superiority of combined treatment, "the available evidence suggests not to avoid additional radiotherapy," wrote review co-author Andreas Engert, M.D, in an email. He is a professor of internal medicine, hematology and oncology at the University Hospital of Cologne in Germany.
Richard Little, M.D., a senior oncologist at the National Cancer Institute, disagreed with that conclusion. "This is an unsettled treatment issue that goes back 40 years and more," he said. "It comes down to the question of late-term side effects associated with radiation," an area that the review did not address.
The reviewers analyzed data from five randomized controlled trials involving 1,245 patients with early stage Hodgkin's lymphoma. The studies took place between the 1970s and 2004, and used a variety of chemotherapy agents as well as diverse doses and types of radiation therapy.
The review appears in the latest issue of The Cochrane Library, a publication of the Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.
Analysis of the four studies that reported initial responses to treatment found that chemotherapy and combined therapy were equally effective in eliminating the malignancy in large part or entirely.
Still, differences appeared when researchers followed patients for periods that averaged between two and 11.4 years. Patients who received radiation therapy in addition to six cycles of chemotherapy were 40 percent as likely to die as those who had chemotherapy alone.
Similarly, among the four studies that included this data, the chances that the tumor would recur or progress among patients who had combined therapy was 41 percent of what it was for those who had chemotherapy alone.
It was not possible to track differences in survival or disease recurrence in subgroups defined by age, sex or the size and location of tumors when treatment began. "This was not a limitation of the meta-analysis, but of the trials themselves, which did not report information on these subgroups," Engert wrote.
The studies included in the meta-analysis took place over a 30-year span, and the chemotherapy agents used in the earlier ones were less effective than are those used today. Although this could weaken review findings, Engert wrote, he added that the relative effectiveness of chemotherapy and combined therapy was similar in early and later trials.
Analysis of all five studies showed that patients who also received radiation were no more likely to experience adverse effects than those who just had chemotherapy, and these side effects — infections, nausea and vomiting, and hair loss — were generally related to chemotherapy.
"Probably, the addition of radiotherapy does increases the long-term adverse event rate, but the studies weren't long enough to detect these events or didn't report them," Engert wrote.
Little said the missing information particularly was critical because most patients who develop Hodgkin's lymphoma are quite young, in their teens and twenties, and will recover.
"Complications due to radiotherapy are more likely to be seen 15, 20 or 30 years later," he said.
Second malignancies such as breast or lung cancer are a principal concern, but cardiovascular disease, thyroid disease and non-malignant lung disease develop as well. "Thirty years after radiation therapy, up to 30 percent of patients have been affected by these serious medical problems," he said.
"What's missing are data on real overall survival that would include patients who have radiation, develop a second cancer and die from it," Little said of the review.
The fact that radiotherapy appears to reduce early recurrences of Hodgkin's lymphoma "clearly tells us that some people benefit from it," Little said. Yet, by the reviewers' own analysis, at least 11 people must be treated to save one. "The real challenge, I think, is to identify those who need radiotherapy, so we can more selectively administer it," he said.
Ongoing clinical trials might reveal whether positron emission tomography or PET, an imaging test that aims to distinguish malignant from healthy tissue, can help doctors meet this challenge. "I'd advise patients to ask their doctors about these trials, or at least have a long, frank discussion about the risks of radiation," before deciding on treatment, Little said.
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