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Second malignancy rates remain high among Hodgkin’s lymphoma survivors
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The risk for a second solid cancer among survivors of Hodgkin’s lymphoma did not improve among patients treated in the 1990s compared with those treated in earlier periods, according to study results published in The New England Journal of Medicine.
Further, survivors of Hodgkin’s lymphoma appeared to remain at risk for developing second solid cancers up to 40 years after treatment with curative intent.
Although survivors of Hodgkin’s lymphoma are known to be at increased risk for treatment-related subsequent neoplasms, researchers hypothesized that less-toxic treatments introduced in the late 1980s would mitigate that risk among patients treated between 1989 and 2000.
“On the basis of increased knowledge of late effects, the treatment of Hodgkin’s lymphoma has changed, with a trend toward the use of smaller radiation target volumes, lower radiation doses, and more effective, generally less toxic chemotherapy schemes,” Flora E. van Leeuwen, PhD, professor and division head of psychosocial research and epidemiology at Netherlands Cancer Institute in Amsterdam, and colleagues wrote. “However, the effect of these changes on the risk of a second cancer is still unknown.”
The researchers conducted an observational study of 3,905 Dutch patients (median age at treatment initiation, 28.6 years; 56.5% male) treated between 1965 and 2000 for Hodgkin’s lymphoma. All patients included in the analysis survived at least 5 years after treatment initiation, and 48.7% of the cohort (n = 1,902) received treatment between 1989 and 2000. Radiation therapy plus chemotherapy served as the most common treatment (60.5%; n = 2,364); other treatment options included radiation therapy only (27.3%; n = 1,068) and chemotherapy only (12.1%; n = 473).
According to the researchers, patients treated in the most recent treatment period (1989-2000) received smaller radiation target volumes, anthracycline-containing chemotherapy, lower doses of alkylating agents and less frequent infradiaphragmatic irradiation than those treated during earlier periods (1965-1976 and 1977-1988).
The researchers compared the risk for second cancers among patients with Hodgkin’s lymphoma with the expected risk based on cancer incidence in the general public.
After a median follow-up of 19.1 years (range, 5-47.2; median age at end of follow-up, 50.4 years), the researchers observed 1,055 second cancers in 908 patients. Overall, the risk for a second cancer appeared higher in survivors of Hodgkin’s lymphoma than in the general public (standardized incidence ratio [SIR] = 4.6; 95% CI, 4.3-4.9).
The risks for a second cancer were more than 10-fold greater in the survivors than general public for thyroid cancer, soft-tissue sarcoma, mesothelial and non-Hodgkin’s lymphoma. The SIRs were 5 to 10 times as high among survivors for cancers of the esophagus, stomach, pancreas and lung, as well as for leukemia.
Breast cancer contributed most to the overall absolute excess risk (20.4% excess risk of any second cancer), followed by lung cancer (20.2%), gastrointestinal tract cancer (19.7%) and non-Hodgkin’s lymphoma (13.1%).
The risk for a second cancer remained elevated in survivors compared with the general population for 35 years or more following treatment (SIR = 3.9; 95% CI, 2.8-5.4). The cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4-51.5).
The cumulative incidence of second cancers did not differ among patients treated from 1965 to 1976, 1977 to 1988, or 1989 to 2000.
Researchers noted that although patients treated with supradiaphragmatic-field radiotherapy not including the axilla appeared at a lower risk for developing breast cancer than patients exposed to mantle-field irradiation (HR = 0.37; 95% CI, 0.19-0.72), the risk for breast cancer did not improve in the most recent study period compared with the earlier periods.
Further, a cumulative procarbazine (Matulane, Sigma Tau) dose of 4.3 g or greater per square meter of body-surface area — which has been associated with early menopause — vs. no chemotherapy appeared associated with a significant reduction in breast cancer risk (HR = 0.57; 95% CI, 0.39-0.84). However, this treatment increased risk for gastrointestinal cancers (HR = 2.7; 95% CI, 1.69-4.3).
“For patients with newly diagnosed Hodgkin’s lymphoma, the risks for both radiation-related and chemotherapy-related late toxic effects must be carefully balanced against the risk of failing to control the primary disease,” van Leeuwen and colleagues wrote. “Awareness of the increased risk for subsequent malignant neoplasm remains of great importance for survivors of Hodgkin’s lymphoma and for their physicians.” – by Cameron Kelsall
Disclosure: Van Leeuwen reports grant support from the Dutch Cancer Society during the conduct of the study. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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John Kuruvilla
David C. Hodgson
Schaapveld and colleagues report the results of 3,905 patients enrolled in a database in the Netherlands who had survived for at least 5 years after the initiation of lymphoma treatment given between 1965 and 2000. The goal of the study was to evaluate the risks for a second cancer among these patients and compare them to the cancer incidence in the general population.
This is a very large dataset with lengthy follow-up, but the data are challenging to interpret given the evolution of treatment over time, as well as other potential confounders such as changes in cancer screening and lifestyle factors. The data have been presented by treatment period (1965-1976, 1977-1988 or 1989-2000), which makes interpretation of the cancer risk following specific therapeutic strategies very difficult. As treating clinicians, we would like to understand risk based on the treatment plan proposed for the patient more so than treatment era.
We would like to highlight several points from the paper. Omitting radiation from the axilla significantly lowered the risk for breast cancer (HR = 0.37), a finding that provides some reassurance that contemporary radiotherapy delivery per se should produce lower risks for breast cancer compared with mantle radiotherapy commonly used until at least the mid-1990s. However, although this change in radiation practice has been largely adopted, the breast cancer risk did not change over time, an observation that warrants consideration of factors other than radiotherapy.
Certainly, one key factor not accounted for in the study analysis is the adoption of breast cancer screening among survivors. Since 1965, when the first patients on the study were treated, there has been widespread recognition of the breast cancer risk among Hodgkin lymphoma survivors, as well as the implementation of a Dutch national breast screening program. As the researchers note, before 2001 “29.7% of breast cancers were detected by … screening …. [and] the rate is 60.8% since 2001.” Data are not presented about breast cancer stage over time, and screening is not formally accounted for in the analysis. But, it would be reasonable to infer that a doubling in the screening rate could stabilize the apparent incidence of breast cancer over time despite an actual reduction in the underlying biologic risk. And, paradoxically, this would be good news, not bad.
On the therapy side of this equation, the reduced use of procarbazine (Matulane, Sigma Tau) — an alkylating chemotherapy that can potentially reduce the risk for breast cancer due to ovarian suppression — also may be contributing to an increased rate of breast cancer. Similar confounding may be a concern for the rates of lung cancer and gastrointestinal cancers, for which lifestyle factors, such as smoking and screening, have evolved over time. The impact of these factors has not been well studied.
As Radford and Longo state in their editorial, one take-home message is clear: “Radiation therapy and alkylating agent-containing chemotherapy come at a long-term cost of second cancers.” Although this paper reports this risk based on older treatment strategies in the context of evolving strategies for cancer screening and lifestyle modification, it does not provide the answer to the question that patients and clinicians want today: What are the long-term risks of current therapy (ABVD–based treatment that may include modern radiation therapy strategies), and how can we better optimize the balance between cure and treatment toxicity?
Further studies are clearly needed in the field to help guide decisions for clinicians and patients.
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