February 16, 2011 — Chemotherapy followed by localized radiation therapy continues to be the standard of care for patients with early-stage Hodgkin's lymphoma. However, because of concerns about the long-term adverse effects of radiation, such as secondary malignancies and cardiotoxicity, the role of radiotherapy has been questioned, and some experts argue for the use of chemotherapy alone.
This debate will be reignited with a new meta-analysis that shows an advantage to using both therapies. It was published in the February issue of the Cochrane Database of Systematic Reviews.
The meta-analysis shows that adding radiotherapy to chemotherapy improves both tumor control and overall survival at 5 years, compared with chemotherapy alone. However, the rates of complete responses were similar between patients who received both therapies and those who received chemotherapy alone.
The researchers evaluated 5 randomized controlled trials, with a total cohort of 1245 patients. The hazard ratio was 0.41 (95% confidence interval [CI], 0.25 to 0.66) for tumor control and 0.40 (95% CI, 0.27 to 0.61) for overall survival among patients who received both therapies, compared with those who received chemotherapy alone.
In a news release, coauthor Andreas Engert, MD, professor of internal medicine, hematology, and oncology at the University Hospital of Cologne, Germany, noted that "the available evidence suggests not to avoid additional radiotherapy."
However, other experts say that longer-term data are needed.
Balancing the Risks
Treatment of Hodgkin's lymphoma has improved during the past few decades, but controversy remains over the role of radiotherapy. Opponents have argued that it adds risk without clear benefit and that chemotherapy should be used alone. Proponents have argued that, compared with chemotherapy alone, outcomes are superior when both treatments are used. They also point out that the current use of lower doses and minifields of radiation are less damaging than the older radiotherapy schedules.
For example, Dr. Engert, who is also chair of the German Hodgkin Study Group, recently reported that 2 cycles of chemotherapy followed by 20 Gy of involved-field radiation therapy are as effective as more intensive regimens in patients with good-prognosis stage 1 or 2 Hodgkin's lymphoma, with less toxicity (N Engl J Med. 2010;363:640-652).
But the underlying question, as James O. Armitage, MD, points out in an editorial accompanying the 2010 study by Dr. Engert and colleagues, is how to balance the risk for a disease recurrence with the risk for treatment-related complications.
Dr. Armitage, who is from the University of Nebraska Medical Center in Omaha, explains that 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," he writes.
He also notes that given the trend toward less intensive treatment, "it will be important to watch for a point at which treatment becomes inadequate and the number of deaths from Hodgkin's lymphoma begin to increase."
Still an Unsettled Issue
In the new meta-analysis, Dr. Engert and colleagues demonstrate that the addition of radiotherapy to commonly used chemotherapy regimens increased 5-year overall survival and tumor control in patients with early-stage Hodgkin's lymphoma.
However, this is still an "unsettled treatment issue that goes back 40 years or more," said Richard Little, MD, a senior oncologist at the National Cancer Institute. "It comes down to the question of late-term side effects associated with radiation," which is an area that the meta-analysis did not address, he pointed out in a statement released by the Health Behavior News Service.
The follow-up period ranged from 2.0 to 11.4 years, and in all 5 studies, patients who received radiation therapy were no more likely to experience adverse events than those who received chemotherapy alone. Most adverse events were similar in both patient groups and were typical of those seen with chemotherapy.
The authors do note that long-term effects, such as secondary malignancies or cardiac disease, can occur after the reported observation times of trials. The addition of radiotherapy might increase the long-term adverse-event rate, but the studies didn't last long enough to identify these events or they didn't report them, said Dr. Engert.
Dr. Little points out that these missing data are critical, because most Hodgkin's lymphoma patients are quite young and will recover from their disease. Complications associated with radiotherapy are more likely to be observed decades later. According to Dr. Little, up to 30% of patients will be affected by serious medical problems 30 years after their initial treatment.
What is missing from this analysis is real data on overall survival, he explained, such as information on patients who received radiation therapy, developed a secondary malignancy, and died from it.
Longer-Term Follow-Up Needed
For their analysis, Dr. Engert and colleagues conducted a systematic review of randomized controlled trials that compared chemotherapy alone with chemotherapy plus radiation in patients with early-stage Hodgkin's lymphoma. Their end points were response rate, progression-free survival (or tumor control), and overall survival.
All 5 trials analyzed overall survival, but none reported progression-free survival data. Four of the trials reported some type of progression outcome and 4 reported response rate.
Although the chemotherapy regimens varied across studies, the summary hazard ratios in the subgroup analyses by chemotherapy regimen were very similar, the authors note. There was no observed difference in tumor control or overall survival among trials that examined the addition of involved-field or extended-field radiotherapy.
When looking at 5-year tumor control, they found that the number needed to treat with chemotherapy plus radiotherapy to prevent 1 additional relapse or progression was approximately 5. For 5-year survival, from 11 to 55 patients required treatment with additional radiotherapy to prevent a single death.
The authors conclude that because of the risk for serious late complications, follow-ups of more than 15 years would be helpful. They note that clear definitions of outcomes that examine tumor control would be useful in reducing heterogeneity in future studies, and they recommend the use of progression-free survival as an outcome measure.
The study was funded internally by "Köln Fortune", Medical Faculty University of Cologne, and externally by a grant from the Federal Ministry of Education and Research in Germany. The researchers have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2011;2:CD007110.
This debate will be reignited with a new meta-analysis that shows an advantage to using both therapies. It was published in the February issue of the Cochrane Database of Systematic Reviews.
The meta-analysis shows that adding radiotherapy to chemotherapy improves both tumor control and overall survival at 5 years, compared with chemotherapy alone. However, the rates of complete responses were similar between patients who received both therapies and those who received chemotherapy alone.
The researchers evaluated 5 randomized controlled trials, with a total cohort of 1245 patients. The hazard ratio was 0.41 (95% confidence interval [CI], 0.25 to 0.66) for tumor control and 0.40 (95% CI, 0.27 to 0.61) for overall survival among patients who received both therapies, compared with those who received chemotherapy alone.
In a news release, coauthor Andreas Engert, MD, professor of internal medicine, hematology, and oncology at the University Hospital of Cologne, Germany, noted that "the available evidence suggests not to avoid additional radiotherapy."
However, other experts say that longer-term data are needed.
Balancing the Risks
Treatment of Hodgkin's lymphoma has improved during the past few decades, but controversy remains over the role of radiotherapy. Opponents have argued that it adds risk without clear benefit and that chemotherapy should be used alone. Proponents have argued that, compared with chemotherapy alone, outcomes are superior when both treatments are used. They also point out that the current use of lower doses and minifields of radiation are less damaging than the older radiotherapy schedules.
For example, Dr. Engert, who is also chair of the German Hodgkin Study Group, recently reported that 2 cycles of chemotherapy followed by 20 Gy of involved-field radiation therapy are as effective as more intensive regimens in patients with good-prognosis stage 1 or 2 Hodgkin's lymphoma, with less toxicity (N Engl J Med. 2010;363:640-652).
But the underlying question, as James O. Armitage, MD, points out in an editorial accompanying the 2010 study by Dr. Engert and colleagues, is how to balance the risk for a disease recurrence with the risk for treatment-related complications.
Dr. Armitage, who is from the University of Nebraska Medical Center in Omaha, explains that 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," he writes.
He also notes that given the trend toward less intensive treatment, "it will be important to watch for a point at which treatment becomes inadequate and the number of deaths from Hodgkin's lymphoma begin to increase."
Still an Unsettled Issue
In the new meta-analysis, Dr. Engert and colleagues demonstrate that the addition of radiotherapy to commonly used chemotherapy regimens increased 5-year overall survival and tumor control in patients with early-stage Hodgkin's lymphoma.
However, this is still an "unsettled treatment issue that goes back 40 years or more," said Richard Little, MD, a senior oncologist at the National Cancer Institute. "It comes down to the question of late-term side effects associated with radiation," which is an area that the meta-analysis did not address, he pointed out in a statement released by the Health Behavior News Service.
The follow-up period ranged from 2.0 to 11.4 years, and in all 5 studies, patients who received radiation therapy were no more likely to experience adverse events than those who received chemotherapy alone. Most adverse events were similar in both patient groups and were typical of those seen with chemotherapy.
The authors do note that long-term effects, such as secondary malignancies or cardiac disease, can occur after the reported observation times of trials. The addition of radiotherapy might increase the long-term adverse-event rate, but the studies didn't last long enough to identify these events or they didn't report them, said Dr. Engert.
Dr. Little points out that these missing data are critical, because most Hodgkin's lymphoma patients are quite young and will recover from their disease. Complications associated with radiotherapy are more likely to be observed decades later. According to Dr. Little, up to 30% of patients will be affected by serious medical problems 30 years after their initial treatment.
What is missing from this analysis is real data on overall survival, he explained, such as information on patients who received radiation therapy, developed a secondary malignancy, and died from it.
Longer-Term Follow-Up Needed
For their analysis, Dr. Engert and colleagues conducted a systematic review of randomized controlled trials that compared chemotherapy alone with chemotherapy plus radiation in patients with early-stage Hodgkin's lymphoma. Their end points were response rate, progression-free survival (or tumor control), and overall survival.
All 5 trials analyzed overall survival, but none reported progression-free survival data. Four of the trials reported some type of progression outcome and 4 reported response rate.
Although the chemotherapy regimens varied across studies, the summary hazard ratios in the subgroup analyses by chemotherapy regimen were very similar, the authors note. There was no observed difference in tumor control or overall survival among trials that examined the addition of involved-field or extended-field radiotherapy.
When looking at 5-year tumor control, they found that the number needed to treat with chemotherapy plus radiotherapy to prevent 1 additional relapse or progression was approximately 5. For 5-year survival, from 11 to 55 patients required treatment with additional radiotherapy to prevent a single death.
The authors conclude that because of the risk for serious late complications, follow-ups of more than 15 years would be helpful. They note that clear definitions of outcomes that examine tumor control would be useful in reducing heterogeneity in future studies, and they recommend the use of progression-free survival as an outcome measure.
The study was funded internally by "Köln Fortune", Medical Faculty University of Cologne, and externally by a grant from the Federal Ministry of Education and Research in Germany. The researchers have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2011;2:CD007110.
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