Late Effects Study Group Research Articles

Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-Identification of high-risk populations to guide surveillance: A report from the Late Effects Study Group.

Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations. The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years. In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk. Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.

Risk Of Solid Subsequent Malignant Neoplasms (SMNs) With Extended Follow-Up Of Childhood Hodgkin Lymphoma (HL) Survivors Is Comparable To The Risk In Known High-Risk Groups Within The General Population: Report From The Late Effects Study Group (LESG)

BackgroundWe describe the pattern and incidence of SMNs with 10 additional years of follow-up of an international cohort (Bhatia, N Engl J Med, 1996; Bhatia, J Clin Oncol, 2003) of children with HL diagnosed between 1955 and 1986 at age 16 y or younger. MethodsMedical record review was used to identify SMNs, define vital status and describe therapeutic exposures. Pathology reports served to validate SMNs. Cumulative incidence (CI) utilized competing risk methods. Standardized incidence ratio (SIR) and absolute excess risk (AER/10,000 p-y) utilized age-, gender- and year-matched rates in the general population. Cox regression techniques (using calendar time as time scale) identified predictors of SMN risk. ResultsThe cohort included 1023 patients diagnosed with HL at a median age of 11 y, and followed for a median of 26.8 y (IQR, 16.4-33.7). Eighty-nine percent had received radiation, either alone (22%), or in combination with chemotherapy (67%). Alkylating agent (AA) score was defined as follows: 1 AA for 6 m = AA score of 1; 2 AA for 6 m or 1 AA for 12 m = AA score of 2, etc. The AA score was 1-2 for 54% and 3+ for 16%; 30% did not receive AA. A total of 188 solid SMNs developed in 139 patients (breast [54], thyroid [24], lung [11], colorectal [11], bone [8], other malignancies [80]. Table summarizes SIR (95%CI), CI, and AER by attained age. The cohort was at an 11.1-fold increased risk of developing solid SMNs (excluding non-melanoma skin cancers) compared with the general population (95% CI, 9.4-13.0). CI of solid SMNs was 25.2% at 40 y from HL diagnosis (Fig 1). Among patients aged ≥40 y, 79% of total AER was attributable to breast, thyroid, colorectal and lung SMNs (Table). Thirty-seven patients developed >1 solid SMN; the cumulative incidence of the 2nd SMN was 19.6% at 10 years from diagnosis of the 1st SMN. Breast Cancer: Females (n=41) had a 20.9-fold increased risk, and males (n=3) a 45.8-fold increased risk c/w general population. Age at HL of 10-16 y vs. <10 y (RR=9.7, 95%CI, 2.3-40.6, p=0.002), and exposure to chest radiation (RR=5.9, 95%CI, 1.4-25.9) were associated with increased risk. Among females aged 10-16 y at chest radiation, cumulative incidence was 24.3% by age 45 y, as opposed to 2.6% for those <10 y, p=0.001 (Fig 2). Exposure to AA was associated with a lower risk (RR=0.4, p=0.002). Diagnosis of HL after 1975 was associated with decreased risk (RR=0.25, 95%CI 0.12-0.53), explained, in part by the increasing use of AA after 1975 (78%) vs. before 1975 (61%). By age 40 y, the risk of breast cancer among females exposed to chest radiation at age 10-16 y (18.2%) was comparable to the risk for BRCA1 mutation carriers (15%-20% by age 40 y; Chen, J Clin Oncol, 2007). Lung cancer: Ten of 11 lung cancer cases were diagnosed in males (males: SIR=24.7; females: SIR=3.2, p=0.05); all had received neck/chest radiation. The CI of lung cancer among males was 3.8% by age 50 y, comparable to the risk among male smokers (2% by age 50 y, Bilello, Clinics Chest Med, 2002). Colorectal cancer: There was a 11.5-fold increased risk c/w general population. The CI among those with abdominal/pelvic radiation was 4.1% by age 50 y ; this risk is higher than that observed in individuals with ≥2 first degree relatives affected with colorectal cancer (1.2% by age 50 y, Butterworth, Eur J Cancer, 2006). Thyroid cancer: Survivors had a 22.2-fold increased risk; all developed within radiation field. Females (RR=4.3, 95%CI 1.8-10.4) were at increased risk. ConclusionIn this cohort of HL survivors with 20,344 p-y of follow-up, the greatest excess risk of SMNs among those > 40 y was attributable to breast, thyroid, colorectal and lung SMNs. Observed risks for the most common SMNs were comparable to or greater than known high-risk groups within the general population. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.Breast (n=44)Thyroid (n=24)Colorectal (n=11)Lung (n=11)Median age at diagnosis in yrs (range)37 (24-49)36 (17-53)36 (29-53)41 (22-46)Median latency from HL in yrs (range)25 ( 10-40)28 (8-45)25 (16-45)28 (12-34)SIR (95% CI)Overall21.7 (15.9-28.7)22.2 (14.4-32.2)11.5 (6.0-19.6)15.2 (7.9-26.1)Males45.8 (11.4-1118)31.4 (16.3-53.8)13.5 (6.2-25.1)24.7 (12.4-43.2)Females20.9 (15.1-27.9)17.7 (9.8-29.2)8.2 (2.0-21.2)3.2 (0.2-13.9)Cumulative Incidence in yrs form HL diagnosis20 y4.7% (F); 0% (M)1.0%0.3%0.2%30 y12.% (F); 0.2% (M)2.2%1.1%0.9%40 y20.5% (F); 1.1% (M)4.8%2.0%2.3%AER/ 10,000 p-y by attained age in y<20 y00.20020-39y2.51.20.50.4≥40 y7.43.62.02.5

Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer

We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors. We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors. M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82). We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.

American Society of Pediatric Hematology/Oncology 17th Annual Meeting. San Francisco, California, USA. April 29 - May 2, 2004. Abstracts.

American Society of Pediatric Hematology/Oncology 17th Annual Meeting. San Francisco, California, USA. April 29 - May 2, 2004. Abstracts.

High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group.

We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkin's disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up. Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years. An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy. Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.

A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers.

Survival of childhood cancer patients has increased remarkably in the last several decades due to therapeutic improvements. Associated with this progress is the emerging need to accurately assess/minimize late effects of cancer therapy in long-term survivors. This paper considers a methodological issue in assessing the risk of second-primary malignant neoplasms, a major late effect of concern, using second-primary female breast cancer as an example. In the assessment of second-primary malignant neoplasm risk, attained age is a critical factor that must be taken into account. Even with follow-up of decades, childhood-cancer survivors are still at relatively young ages for developing adult-onset diseases. Attained ages at follow-up, however, modify cancer risk considerably; for example, in the general population, women aged 40 years have about fivefold increased breast cancer risk compared with women aged 30 years. A failure to account for the natural age-associated increase of risk could alter, or even reverse, analytical conclusions. This problem was studied empirically by both descriptive and regression analyses of two major studies of long-term childhood-cancer survivors, the Childhood Cancer Survivor Study (1975-1999) and the Late Effects Study Group (1955-1994). These showed appreciable differences in the analytical results by not accounting for the natural age-associated increase of risk, illustrating a significant impact of this methodological issue on study conclusions.

Breast Cancer and Other Second Neoplasms after Childhood Hodgkin's Disease

Patients who survive Hodgkin's disease are at increased risk for second neoplasms. As survival times increase, solid tumors are emerging as a serious long-term complication. The Late Effects Study Group followed a cohort of 1380 children with Hodgkin's disease to determine the incidence of second neoplasms and the risk factors associated with them. In this cohort, there were 88 second neoplasms as compared with 4.4 expected in the general population (standardized incidence ratio, 18.1; 95 percent confidence interval, 14.3 to 22.3). The estimated actuarial incidence of any second neoplasm 15 years after the diagnosis of Hodgkin's disease was 7.0 percent (95 percent confidence interval, 5.2 to 8.8 percent); the incidence of solid tumors was 3.9 percent (95 percent confidence interval, 2.3 to 5.5 percent). Breast cancer was the most common solid tumor (standardized incidence ratio 75.3; 95 percent confidence interval, 44.9 to 118.4), with an estimated actuarial incidence in women that approached 35 percent (95 percent confidence interval, 17.4 to 52.6 percent) by 40 years of age. Older age (10 to 16 vs. <10 years) at the time of radiation treatment (relative risk, 1.9) and a higher dose (2000 to 4000 vs. <2000 cGy) of radiation (relative risk, 5.9) were associated with significantly increased risk of breast cancer. The estimated actuarial incidence of leukemia reached a plateau of 2.8 percent (95 percent confidence interval, 0.8 to 4.8 percent) 14 years after diagnosis. Treatment with alkylating agents, older age at the diagnosis of Hodgkin's disease, recurrence of Hodgkin's disease, and a late stage of disease at diagnosis were risk factors for leukemia. The risk of solid tumors, especially breast cancer, is high among women who were treated with radiation for childhood Hodgkin's disease. Systematic screening for breast cancer could be important in the health care of such women.

Second Cancers after Hodgkin's Disease in Childhood

The treatment of Hodgkin's disease is a model of successful therapy for childhood cancer, with cure rates of over 90 percent expected from chemotherapy regimens and low-dose radiation (15 to 25 Gy) to involved regions.1 The current therapy evolved to minimize previously recognized late effects of treatment, such as growth retardation and secondary malignant tumors. In this issue of the Journal, Bhatia et al.,2 representing the Late Effects Study Group, report that second cancers developed 18 times more often in patients who received treatment for Hodgkin's disease before the age of 16 years than would be expected in the general . . .

Bone sarcomas as second malignant neoplasms following childhood cancer

This study explores the relationship between histologic variants of bone sarcomas and previous therapy in patients in whom an unrelated malignant neoplasm had been diagnosed during childhood. Sarcomas of bone were the most common second malignant neoplasm (SMN) reported to the Late Effects Study Group, a 13-institution consortium consisting of pediatric oncology centers from western Europe, Canada, and the United States. The authors attempted to relate the histologic subtypes of the 91 bone tumors to clinical factors such as previous therapy and genetic predisposition because morphologic variants have been shown to have biologic significance in other tumors and may have etiologic import. The literature concerning the subtypes of bone tumors, clinical and experimental, is also reviewed. The authors also investigated the effect of several factors on the time interval from the first diagnosis to the SMN (i.e., the bone sarcoma). Anthracyclines significantly shortened the interval by about 3 years. The primary diagnosis also significantly affected the interval, with leukemia/lymphomas having the shortest interval and retinoblastoma the longest. The authors could not demonstrate any significant relationship between morphologic characteristics of the osteosarcoma and predisposing conditions. However, lesions diagnosed as chondrosarcoma and malignant fibrous histiocytoma occurred almost exclusively in patients who had received radiation therapy to the site in which the SMN developed.

Second malignant neoplasms following childhood Hodgkin's disease: Treatment and splenectomy as risk factors

The risk of second malignant neoplasm (SMN) was evaluated in 979 children with Hodgkin's disease. This cohort was diagnosed between 1955 and 1979 at one of the institutions of the Late Effects Study Group. Solid tumors, non-lymphocytic leukemia, and non-Hodgkin's lymphoma (NHL) developed in 18, 17, and 3 patients, respectively. The estimated cumulative probability of developing any SMN was 2% at 5 years from diagnosis, 5% at 10 years, and 9% at 15 years. The incidence is ninefold greater than the risk of acquiring cancer in 19 year-olds, the median age at which the diagnosis of SMN was made in this study population. For leukemia and NHL the corresponding probabilities were 1%, 3%, and 4% for the group as a whole but were increased (2%, 6%, and 8%) in patients who had suffered one or more recurrences. In order to analyze the risk of leukemia and NHL associated with alkylating agent chemotherapy, each patient was assigned a score of one for each alkylating agent administered for a 6-month period. Scores of 2, 4, 6, and 8 were associated with probabilities of leukemia or NHL of 2%, 3%, 6%, and 10%, respectively. In a multivariate analysis for leukemia/lymphoma that included AAD score, stage, and splenectomy, the effect of AAD score and splenectomy did not change substantially compared to the univariate results. AAD score remained statistically significant (P = .0001), and splenectomy was of borderline significance (P = .09). Of the 18 solid tumor SMNs, 15 developed within the field of radiation, and one other developed in tissue irradiated 34 years earlier for hemangioma. This study of a large and unselected group of children with Hodgkin's disease who received a variety of therapies demonstrates that children are as likely as adults to develop acute leukemia after alkylating agents and solid tumors in the field of radiation therapy.

Leukemia After Therapy With Alkylating Agents for Childhood Cancer2

The risk of leukemia was evaluated in 9,170 2-or-more-year survivors of childhood cancer in the 13 institutions of the Late Effects Study Group. Secondary leukemia occurred in 22 nonreferred individuals compared to 1.52 expected, based on general population rates [relative risk (RR) = 14; 95% confidence interval (CI), 9-22]. The influence of therapy for the first cancer on subsequent leukemia risk was determined by a case-control study conducted on 25 cases and 90 matched controls. Treatment with alkylating agents was associated with a significantly elevated risk of leukemia (RR = 4.8; 95% CI, 1.2-18.9). A strong dose-response relationship was also observed between leukemia risk and total dose of alkylating agents, estimated by an alkylator score. The RR of leukemia reached 23 in the highest dose category. Radiation therapy, however, did not increase risk. Although doxorubicin was also identified as a possible risk factor, the excess risk of leukemia following treatment for childhood cancer appears almost entirely due to alkylating agents.

Hodgkin's disease in pediatric patients with naturally occurring immunodeficiency.

A case/control study of pediatric patients with Hodgkin's disease (HD) was undertaken to compare clinical characteristics in patients with known underlying immunodeficiency (20 Immunodeficiency Cancer Registry cases) and without known immunodeficiency (100 Late Effects Study Group cases). Immunodeficiency Cancer Registry cases demonstrated a younger mean age at diagnosis (p = 0.03), and a significantly higher rate of failure to achieve remission (p = 0.001) than did the Late Effects Study Group controls. Also, Immunodeficiency Cancer Registry cases showed a proportional excess of unfavorable histologies when compared with large published pediatric series. These discrepancies are consistent with a common etiology of HD relating to underlying immune defect in Immunodeficiency Cancer Registry HD patients as well as HD patients (or a select subgroup) without known immunodeficiency disorders.

Second malignant neoplasms in children: an update from the Late Effects Study Group.

This paper presents an update from the Late Effects Study Group on 292 cases of second malignant neoplasms (SMN) occurring in individuals who were diagnosed with their first neoplasm in childhood. Data are presented regarding the types of first and second neoplasm, the therapy administered, and the predisposing factors. Of the 292 cases (308 SMN), the most common primary was retinoblastoma followed by Hodgkin's disease, soft-tissue sarcomas, and Wilms' tumor. This is not similar to the relative frequency of these cancers in children but rather reflects specific risk factors. Bone sarcomas were the most common SMN among the 208 SMN developing in previously irradiated sites while acute leukemia was the most common SMN unassociated with radiation. Known predisposing conditions to cancer were present in 73 cases; retinoblastoma was the most common of these, followed by neurofibromatosis. There were ten patients with three and three patients with four malignant neoplasms. In 14 patients, the cause of SMN was not suggested by known risk factors as these patients had negative family histories and received no radiation or chemotherapy. We note, therefore, that although most cases of SMN in survivors of childhood cancer can be attributed to radiation, genetic disease, chemotherapy, or combinations of these, unrecognized predisposition or chance may also play a role.