High Risk of Second Cancers After Hodgkin's Lymphoma

Alexander M. Castellino, PhD

December 23, 2015

For patients with Hodgkin's lymphoma, long-term survival and cure comes at a price — and a significant one at that. Earlier this year, researchers from the Netherlands Cancer Institute, Amsterdam, reported that long-term survivors of Hodgkin's lymphoma have an increased cardiovascular risk. Now a study from the same group published December 24 in the New England Journal of Medicine reports a cumulative incidence of a second cancer is 48.5% after 40 years of surviving Hodgkin's lymphoma.

"With changes made in the 1990s for the treatment of Hodgkin's lymphoma, we expected to see a decrease in the occurrence of second malignancies in long-term survivors. Unfortunately, that is not what we observed," first author Michael Schaapveld, PhD, from the department of epidemiology at the National Cancer Institute in Amsterdam, told Medscape Medical News.

"The take-home message from these data is clear — radiation therapy and alkylating-agent–containing chemotherapy come at a long-term cost of second cancers," write John Radford, MD, from the University of Manchester and Dan L. Longo, MD, from the Dana-Farber Cancer Institute in an accompanying editorial.

Retrospective Data From the Netherlands

For the analysis of second cancers, the researchers included 3905 individuals in the Netherlands who had been treated for Hodgkin's lymphoma between 1965 and 2000. Patients were between 15 and 50 years of age at diagnosis and had survived at least 5 years after being treated.

Information for second cancers was extracted from medical records, which included dates of diagnoses, morphologic features, and treatment; in addition, information was also gleaned from questionnaires sent to general practitioners and by record linkage with the Netherlands Cancer Registry.

Of 2207 males and 1698 females who survived Hodgkin's lymphoma, almost half were treated in 1989–2000; approximately 30% were treated in 1977–1988, and 20% in 1965–1976.

Treatment varied: 27% received only radiation therapy; 12% received chemotherapy; and 61% received radiation therapy and chemotherapy. Median age at treatment initiation was 28.6 years; median follow-up was 19.1 years, with 27.5% of survivors being followed for at least 25 years.

During follow-up, 1055 second cancers were diagnosed in 908 survivors and corresponded to a risk of 4.6 times as high as the occurrence of cancer in the general population.

The cumulative incidence of a second cancer was 33.2% at 30 years compared with 9.6% in the general population and 48.5% at 40 years compared with 19.0% in the general population.

Breast cancer was the most common second cancer reported, followed by lung and gastrointestinal cancers. Thirty-year cumulative incidence was 16.6% for breast cancer, 7.1% for lower respiratory-tract cancers, 7.0% for gastrointestinal cancers, and 3.7% for non-Hodgkin's lymphomas.

The risk of solid cancer after treatment for Hodgkin's lymphoma was not lower among more recently treated patients than among those who were treated in earlier time periods, despite changes in treatment.

Breast cancer accounted for 20.4% of the total excess number of second cancers that were observed among all Hodgkin's lymphoma patients — male and female, but among females alone breast cancer accounted for 40.5% of the total excess number of second cancers.

In the supplementary appendix, the researchers showed that the cumulative incidence of second cancers did not differ significantly among the three date periods that were studied — that is, between 1965–1976, 1977–1988, and 1989–2000.

"Even 40 years after treatment for Hodgkin's lymphoma, survivors remain at increased risk for second cancers. The risk of solid cancer after treatment for Hodgkin's lymphoma was not lower among more recently treated patients than among those who were treated in earlier time periods, despite changes in treatment," Dr Schaapveld and colleagues conclude.

Improvements in Treatment, but Risk Remains

Dr Schaapveld explained the changes in treatment in an interview with Medscape Medical News. "From the mid-1980s to the early 1990s patients received large radiation fields and many received radiation below the diaphragm. In the mid-1990s, we shrank the radiation field and irradiated only the lymph-node areas involved." But this did not translate to benefits for long-term survivors. Patients who received irradiation above the diaphragm were at a 6.3 times higher risk of second cancers in the same region compared with incidence of cancer in the general population; patients were also at a 2.1 times higher risk of similar cancers when they did not receive irradiation above the diaphragm. Similar observations were reported for patients receiving irradiation below the diaphragm.

However, there were some hopeful signs, Dr Schaapveld indicated. Patients treated with smaller radiation fields (eg, supradiaphragmatic field radiotherapy not including the axilla) were at a 27% lower risk of second cancers compared with patients receiving complete mantle-field radiotherapy. Similarly, patients were at a 63% lower risk of breast cancer as a second malignancy if they received more limited supradiaphragmatic field radiotherapy vs complete mantle-field radiotherapy.

Unfortunately, the risk of second malignancy as breast cancer in the 1990s was no lower than the risk from the earlier 2 decades. Dr Schaapveld explained that this is probably due to an incomplete adoption of the more modern radiotherapy techniques and may even be explained on the basis of a change in the chemotherapy regimens used in the 1990s.

"Because many women were experiencing early menopause, we lowered the dose of alkylating agents to preserve fertility," he told Medscape Medical News.

However, ovarian suppression resulting from the alkylating regimens was likely responsible for decreasing the breast cancer incidence, he added. "With the lower doses of the alkylating agents, this protection was taken away," he said.

"These explanations are entirely plausible, but another possibility is that even the smaller fields and doses of therapeutic radiation are associated with a risk of second cancer, and the data for assessing this risk in populations treated with the most modern radiotherapy techniques now become even more critical," the editorialists write.

Significance for Clinical Practice

How should these observations be integrated into the clinical management of long-term survivors of Hodgkin's lymphoma?

"In the Netherlands, we have set up survivor clinics to screen for second cancers," Dr Schaapveld told Medscape Medical News.

"In addition, when we see a new patient, we need to balance the risk of recurrence by evaluating whether the patient will benefit from radiation or not," he pointed out.

"First, we need to minimize the risk of recurrence of Hodgkin's lymphoma. Subsequent to that we need to weigh the amount of treatment needed to minimize the risk of second cancers," Dr Schaapveld said.

The editorialists agree. "For current survivors of Hodgkin's lymphoma, information about risk should be provided, relevant screening made available, and any emerging symptoms investigated without delay in order to rule out second-cancer diagnosis," they state.

The second-cancer menace that undermines the long-term quality of life and survival after treatment for Hodgkin's lymphoma will continue to stalk our patients.

"For future patients, there is an urgent need to design, evaluate, and implement individualized treatment strategies that confine the exposure of the most toxic interventions to the patients with the worst disease prognosis — the group most likely to benefit from the more intensive treatment," they add.

"The onus lies with the entire oncologic community to achieve these aims — because unless we do, the second-cancer menace that undermines the long-term quality of life and survival after treatment for Hodgkin's lymphoma will continue to stalk our patients," the editorialists conclude.

Dr Schaapveld is hopeful that the advances made in radiation therapy after 2005 will change the picture. "From involved field radiation, we are now providing radiation to only the involved nodes. Radiation is also being provided in smaller doses," he said. However, these benefits may be evaluated only 15 to 20 years later, he indicated.

The authors and editorialists declared relevant financial relationships.

N Engl J Med. 2015;373:2499-511. Article, Editorial


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