Reducing Treatment Intensity Doesn't Compromise Results in Early-Stage Hodgkin Lymphoma
Response and cure rates are very high in patients with early-stage, low-risk Hodgkin lymphoma, but both acute and late adverse effects of treatment are common. A large randomized phase III trial in Europe found that reducing the dose of chemotherapy and radiotherapy did not compromise treatment efficacy but led to fewer side effects.
New England Journal of Medicine, August 12, 2010 (see the journal abstract).
Hodgkin lymphoma (HL) is a rare cancer that develops in the lymphatic system, the tissues and organs that produce, store, and carry white blood cells. About 30 percent of HL patients are diagnosed with early-stage, low-risk disease. In the past, such patients were typically treated with radiotherapy alone. Although this treatment cured many people, it also had severe long-term adverse effects, including cardiac problems, infertility, and second cancers.
Because HL often strikes people in their 30s, the toxic effects of treatment can affect the health and quality of life of patients for many years. In patients with a favorable prognosis, who have a long life expectancy, it is especially important to limit treatment toxicity. In the United States, most patients with early-stage, low-risk disease are now treated with combination chemotherapy alone or with chemotherapy and involved-field radiation therapy (IFRT), in which radiation is targeted to the lymph node regions that are known to be cancerous. However, researchers continue to look for ways to refine treatment regimens to lower the risk of long-term adverse effects while ensuring the best chance of long-term survival.
Researchers in Europe designed this study (dubbed HD10) to see whether it is possible to reduce the intensity of treatment for early-stage, low-risk HL without compromising its efficacy. Between 1998 and 2003, they recruited 1,370 previously untreated patients from 329 hospitals and outpatient practices in five countries. The patients’ median age was 36; 61 percent were male.
A total of 1,190 patients were confirmed as having stage I or II disease and no additional risk factors; they were therefore considered to have low-risk disease. These patients were randomly assigned to one of four treatment groups:
- Group 1 received the most intensive treatment: four cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by a total of 30 Gy of IFRT.
- Group 2 received the same amount and duration of ABVD chemotherapy but only 20 Gy of radiation.
- Group 3 received two cycles of ABVD chemotherapy followed by 30 Gy of radiotherapy.
- Group 4 received two cycles of ABVD chemotherapy followed by 20 Gy of radiotherapy.
Researchers followed the patients for a median of 7.5 years. The primary study outcome was freedom from treatment failure; the researchers also assessed overall survival, progression-free survival, and complete remission rate. Patients were also monitored for acute and long-term toxic effects of treatment, including the development of second cancers. For most analyses, the authors pooled pairs of treatment groups so that they could compare outcomes in people who received the high versus low chemotherapy doses and in people who received the high versus low radiation doses. That is, they compared groups 1 and 2, which received four cycles of ABVD chemotherapy, with groups 3 and 4, which received two cycles. And they compared groups 1 and 3, which received 30 Gy of radiation, with groups 2 and 4, which received 20 Gy.
The HD10 trial was conducted by the German Hodgkin Study Group; the principal investigator was Andreas Engert, M.D., of the University Hospital of Cologne in Cologne, Germany.
All of the treatments were highly effective, with 1,150 patients (97 percent) having a complete remission. In the chemotherapy comparison, the rates of freedom from treatment failure were not statistically significantly lower in the groups that received two ABVD cycles than in the groups that received four cycles. There were also no statistically significant differences in the other endpoints. Similarly, the radiation therapy comparison showed that a lower dose of radiation did not lead to worse outcomes. The authors also compared freedom from treatment failure in group 1 (the most intensive regimen) with that in group 4 (the least intensive regimen) and again found no statistically significant differences.
The treatment groups did, however, differ in the occurrence of acute toxic effects, such as infections, blood cell problems, and hair loss. Half of patients who received four cycles of chemotherapy had at least one severe toxic effect, compared with only one-third of those who received two cycles. Six of the seven patients who died after treatment had received four cycles. Only 16 (2.9 percent) of the patients who had received the reduced amount of radiation had at least one severe toxic effect, compared with 46 (8.7 percent) of the patients who had received 30 Gy. A total of 55 patients developed second cancers during the 7.5 year follow-up, with there were no statistically significant differences between the groups.
Because the use of radiation therapy leads to the development of secondary solid tumors, many experts feel that it should be avoided entirely if possible. “Radiotherapy is not necessary for all patients, and it is far and away the major source of late-term health problems after curing Hodgkin lymphoma,” said Richard Little, M.D., Senior Investigator in the Clinical Investigations Branch of NCI’s Division of Cancer Treatment and Diagnosis. Because so many patients are in their 20s and 30s at diagnosis, the late treatment effects that occur 20-plus years after primary treatment are affecting people 40 to 50 years old, “creating substantial disruption and curtailing some of the most productive and happy periods of their lives.”
In addition, the high survival rate observed in the trial—95 percent of patients were still alive at 8 years—suggests that some patients may have received more treatment than they actually needed. However, the authors point out that established clinical risk factors cannot be used to identify patients who can be cured with less treatment. Dr. Little agreed, adding that studies are underway “to redefine the use of fluorodeoxyglucose-positron emission tomography as a biomarker that can determine, very early in treatment, which patients can omit more intensive therapy, including radiotherapy, without compromising curative potential. Also, this strategy may identify patients whose Hodgkin lymphoma is likely to require more intensive treatment, including radiation therapy.” He added, “This line of work may change the paradigm for treating this cancer.”
Although the study showed that reducing the dose of chemotherapy and radiotherapy does not reduce effectiveness for most patients with early-stage disease, there was “no recognition in the study design for the curative potential of chemotherapy alone,” said Dr. Little. Any use of radiation therapy increases the risk of late radiation complications, and he noted that longer follow-up will be needed to obtain good information about the longer-term adverse effects associated with the treatments used in the study.
In an accompanying review article, James O. Armitage, M.D., of the University of Nebraska Medical Center in Omaha wrote that although “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...the relatively brief follow-up period in most studies and the lack of certainty regarding the relationship between radiation dose and cancer incidence make it impossible to draw definite conclusions.”
In addition, even though there were no statistically significant differences in treatment efficacy, the authors note that because of the study design, “a potential difference of 6.3 percentage points in favor of the more intensive treatment cannot be excluded.” However, any such advantage “must be weighed against the reductions in acute and late toxicity, lower costs of treatment, and better quality of life associated with shorter and less intense treatment,” they wrote.