Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy

Department of Pediatrics , Stanford University, Palo Alto, California, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2010; 28(7):1232-9. DOI: 10.1200/JCO.2009.24.8062
Source: PubMed


Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.
Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.
One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.
Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.

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    • "The 10-year overall survival of patients in our series was similar to most other series in the literature. Patients with classical Hodgkin’s lymphoma are known to have an increased risk of developing second malignancies [13,14,15,16]. We examined this second malignancy risk in the NLPHL cohort and found a 10-year freedom from second malignancy of 89%. "
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    ABSTRACT: Radiation therapy (RT) is commonly used as definitive treatment for early-stage nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL). We evaluated the cause-specific survival (CSS), overall survival (OS), and second malignancy (SM) rates in patients with early-stage NLPHL treated with RT. Patients with stage I-II NLPHL between 1988 and 2009 who underwent RT were selected from the Surveillance, Epidemiology and End Results database. Univariate analysis (UVA) for CSS and Os was performed using the Kaplan-Meier method and included age, gender, involved site, year of diagnosis, presence of B-symptoms, and extranodal involvement (ENI). Multivariable analysis (MVA) was performed using Cox Proportional Hazards modeling and included the above clinical variables. SM were classified as RT-related or non-RT-related. Freedom from SM and freedom from RT-related SM were determined using the Kaplan-Meier method. The study cohort included 469 patients. Median age was 37 years. The most common involved sites were the head and neck (36%), axilla/arm (26%), and multiple lymph node regions (18%). Sixty-eight percent had stage I disease, 70% were male, 4% had ENI, and 7% had B-symptoms. Median follow-up was 6 years. Ten-year CSS and Os were 98% and 88%, respectively. On UVA, none of the covariates was associated with CSS. Increasing age (p<0.01) and female gender (p<0.01) were associated with worse Os. On MVA, older age (p<0.01), female gender (p=0.04), multiple regions of involvement (p=0.03), stage I disease (p=0.02), and presence of B-symptoms (p=0.02) were associated with worse Os. Ten-year freedom from SM and freedom from RT-related SM were 89% and 99%, respectively. This is the largest series to evaluate the outcomes of stage I-II NLPHL patients treated with RT and found that this patient population has an excellent long-term prognosis and a low rate of RT-related second malignancies.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "However, in order to decrease the risk of subsequent SMN, there has been a greater emphasis on utilizing lower doses of radiation and smaller treatment fields (involved field radiation therapy), especially in younger patients [63]. However, this risk seems to still exist even when lower doses of radiation have been used in pediatric patients [58]. "
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    ABSTRACT: More than half of all cancer patients receive radiotherapy as a part of their treatment. With the increasing number of long-term cancer survivors, there is a growing concern about the risk of radiation induced second malignant neoplasm [SMN]. This risk appears to be highest for survivors of childhood cancers. The exact mechanism and dose-response relationship for radiation induced malignancy is not well understood, however, there have been growing efforts to develop strategies for the prevention and mitigation of radiation induced cancers. This review article focuses on the incidence, etiology, and risk factors for SMN in various organs after radiotherapy.
    Full-text · Article · Dec 2012 · International Journal of Environmental Research and Public Health
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    • "Among the 77 patients who were diagnosed with HL under the age of 21 years and underwent CMT, the SIRs for breast and thyroid cancers were significantly elevated at 25·8 (95% CI: 3·1–93·2) and 33·6 (95% CI: 4·1–122), respectively, and the 30-year incidence of non-haematological SMNs was 20%. These findings are comparable to those recently reported by a study of paediatric HL patients treated at Stanford University (O'Brien et al, 2010). Together, the results suggest that the paediatric population may have higher risks for SMNs even with low dose involved field radiation, despite other findings that a reduction in radiation dose does lower this risk (Constine, 2008; Castellino et al, 2011). "
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    ABSTRACT: To evaluate the impact of reduced radiation and combined modality therapy (CMT) in the treatment of Hodgkin lymphoma, we assessed the risk of second malignant neoplasms (SMNs) in patients who received extended-field radiotherapy only and patients who underwent CMT. Among 404 patients treated at Yale during 1970-2004, the risk of solid SMNs was elevated in the radiotherapy only group (n = 198, median follow-up = 21·1 years) compared to the general population, with a standardized incidence ratio (SIR) of 1·85 [95% confidence interval (CI): 1·17-2·78]. No increase was observed in the CMT group (n = 206, median follow-up = 14·3 years), although potential differences in SMN risk were indicated across the age spectrum in subgroup analysis. Patients who received mustard-containing regimens had increased risks for haematological SMNs (SIR = 8·74) and all SMNs (SIR = 1·85). When the analysis was stratified by age at diagnosis, children (0-20 years) had a significantly higher risk of SMNs (SIR = 5·24, 95% CI: 2·26-10·33), regardless of the treatment received. These findings suggest that recent treatment options utilizing lower dose radiation and less intense alkylator chemotherapy might be associated with lower incidences of SMNs among adults but not necessarily children.
    Preview · Article · Jul 2012 · British Journal of Haematology
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