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Objective: The aim of this study was to determine the incidence of new primary malignancies after adult-type granulosa cell tumor (AGCT) and the incidence of AGCT after breast and uterine cancer using nationwide population-based registry data., Methods: We used the Finnish Cancer Registry to identify all patients diagnosed with AGCT in 1968 to 2013 (n = 986). The number of subsequent primary malignancies among women with AGCT and the number of AGCTs in women with previous breast or uterine cancer were compared with the expected number of cases and expressed as standardized incidence ratios (SIRs)., Results: There were 122 cases of subsequent cancers diagnosed at least 6 months after the primary diagnosis of AGCT (SIR, 1.09; 95% confidence interval [CI], 0.91-1.3). In particular, the observed number of cancers of the soft tissue (SIR, 4.13; 95% CI, 1.33-12.8), thyroid (SIR, 3.42; 95% CI, 1.54-7.62), and leukemia (SIR, 2.67; 95% CI, 0.98-5.82) exceeded the number of expected cases. The SIR for breast cancers after AGCT was 1.26 (95% CI, 0.92-1.73), and the SIR for AGCT after breast cancer was 1.59 (95% CI, 1.04-2.29). The risk for subsequent AGCT was more than 2-fold in breast cancer patients younger than 50 years, and over 15 years after primary diagnosis., Conclusions: There is an increased risk for thyroid and soft tissue cancer as well as leukemia after AGCT, which may be associated with late effects of carcinogenic treatments and possibly shared risk factors. After breast cancer, the risk for AGCT was higher, which may indicate a shared hormonal etiology.

Background: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear., Methods: Among 23 982 5-year TC survivors diagnosed during 1947-1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs)., Results: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated with a 2.9-fold (95% confidence interval (CI) 1.0-7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trend<0.001), with an OR of 4.6 (95% CI 1.9-11.0) for ⩾25 Gy vs <25 Gy. Radiation-related risks remained elevated ⩾20 years after TC diagnosis (P=0.020). The risk increased with the number of cycles of chemotherapy with alkylating or platinum agents (P=0.057), although only one case was exposed to platinum., Conclusions: A dose-response relationship exists between radiation to the pancreas and subsequent cancer risk, and persists for over 20 years. These excesses, although small, should be considered when radiotherapy with exposure to the pancreas is considered for newly diagnosed patients. Additional data are needed on the role of chemotherapy.

Purpose: The current study was designed to determine the risk of cancer in patients with neurofibromatosis type 1 (NF1) by cancer type, age, and sex with unprecedented accuracy to be achieved by combining two total population-based registers., Patients and Methods: A population-based series of patients with NF1 (N = 1,404; 19,076 person-years) was linked to incident cancers recorded in the Finnish Cancer Registry and deaths recorded in the national Population Register Centre between 1987 and 2012. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated for selected cancer types. Survival of the patients with cancer with and without NF1 was compared., Results: In malignant peripheral nerve sheath tumors and CNS tumors, the cancers traditionally associated with NF1, we observed SIRs of 2,056 (95% CI, 1,561 to 2,658), and 37.5 (95% CI, 30.2 to 46.0), respectively, and SMRs of 2,301 (95% CI, 1,652 to 3,122) and 30.2 (95% CI, 19.1 to 45.2), respectively. We found an unequivocally increased risk for breast cancer. In particular, SIR was 11.1 (95% CI, 5.56 to 19.5) for breast cancer in women with NF1 age < 40 years; the overall SMR for breast cancer was 5.20 (95% CI, 2.38 to 9.88). Particularly high overall SIRs were observed in patients with NF1 age < 15 years: women, 87.6 (95% CI, 58.6 to 125); men, 45.6 (95% CI, 28.4 to 68.5). An estimated lifetime cancer risk for patients with NF1 was 59.6%. The 5-year survival of patients with cancer and NF1, excluding nervous tissue cancers, was worse than that of comparable patients with cancers without NF1 (54.0% v 67.5%; P = .01)., Conclusion: Our results emphasize the general cancer proclivity of patients with NF1. These findings should translate to clinical practices to determine clinical interventions and focused follow-up of patients with NF1., (© 2016 by American Society of Clinical Oncology.)

The objective of this study was to assess the reciprocal association between non-Hodgkin lymphoma (NHL) and Merkel cell carcinoma (MCC) using the data of four Nordic Cancer Registries. Data for this study were drawn from the Danish, Finnish, Norwegian, and Swedish cancer registries. Standardized incidence ratios (SIRs) for MCC among NHL patients, and for NHL among MCC patients, were calculated. There were 109 838 individuals with NHL and 1411 individuals with MCC, of which 28 had joint occurrence of NHL and MCC. In 18 cases, NHL was diagnosed first, and in 10 cases, MCC was diagnosed first. The SIR for MCC after NHL was 4.34 (95% confidence interval 2.57-6.85). The SIR for NHL after MCC was 3.13 (1.50-5.77). Although the absolute frequency of joint occurrence of MCC and NHL is low, individuals suffering from one of the cancer forms have an increased risk of the other.

Survival after non-Hodgkin lymphoma (NHL) has increased thanks to improved treatment but NHL survivors have an increased risk of second neoplasms. The assessment of cancer risk patterns after NHL may help to quantify the late side-effects of therapy. Poisson regression was used to estimate relative risks (RRs) and absolute incidence rates for nine solid tumours based on a nationwide cohort of 60 901 NHL survivors from Finland, Norway and Sweden. Patients were diagnosed between 1980 and 2006 and developed 6815 s neoplasms. NHL patients showed an increased risk of each of the nine investigated cancer sites: prostate and pancreas (both RRs 1·28), breast (1·37), colorectum (1·48), urinary bladder (1·52), stomach and lung (both RRs 1·87), skin (melanoma 2·27) and kidney (2·56). The RRs showed a U-shaped relationship with time after NHL for all nine-second cancer types. NHL diagnosis early in life was a risk factor for the development of second cancers with the exception of melanoma, but a risk excess was even observed in patients diagnosed with NHL at age 80+ years. The present study provides accurate estimates on the adverse late effects of NHL therapy, which should guide the establishment of cancer prevention strategies in NHL survivors., (© 2013 John Wiley & Sons Ltd.)

Purpose: Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear., Patients and Methods: We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location., Results: Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m(2)) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m(2) (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m(2); however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses., Conclusion: Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.

Background: Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use., Design: Nested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records., Results: The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking)., Conclusions: Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

Objective: Uterine sarcomas (US) are rare malignancies with unclear aetiology. Studies on uterine sarcomas in the setting of second primary malignant tumours can provide clues to aetiology and identify side effects of different treatments., Methods: A cohort of 8606 cases of US was extracted from the data from 13 cancer registries and followed for second primary cancers within the period 1943-2000. Standardized incidence ratios (SIRs) were calculated, and Poisson regression analyses were performed., Results: There were 499 cancer cases observed after a first diagnosis of US (SIR 1.26, 95%CI 1.16-1.38). SIRs were elevated for cancers of the mouth and pharynx (2.16, 95%CI 1.15-3.69), colorectum (1.60, 95%CI 1.28-1.98), lung (1.73, 95%CI 1.27-2.29), breast (1.25, 95%CI 1.05-1.49), urinary bladder (1.74, 95%CI 1.02-2.79), kidney (2.00, 95%CI 1. 24-3.06), thyroid gland (2.74, 95%CI 1.42-4.79), and soft tissue sarcoma (5.23, 95%CI 2.51-9.62). The risk of breast cancer increased along with increasing age of US diagnosis (p trend 0.040). The risk of kidney cancer increased along with decreasing age of US diagnosis (p trend 0.004) and short time since the US diagnosis (p trend 0.018)., Conclusions: Our study demonstrated increased risk of certain cancers following a diagnosis of US. The elevated risk for breast cancer may indicate shared hormonal aetiology, while the increased risk of colorectal and bladder cancers after US may be caused by radiation therapy of US. The clustering of smoking-related cancers after US is worth exploring in the future., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Children diagnosed with noncentral nervous system solid cancers (NCNSSC) experience several adverse late effects, including second malignant neoplasm. The aim of our study was to assess the risk of specific second malignancies after a childhood NCNSSC. Diagnosis and follow-up data on 10,988 cases of NCNSSC in children (0-14 years) were obtained from 13 registries. Standardized incidence ratios (SIRs) with 95% confidence intervals (CI) and cumulative incidence of second malignancies were computed. We observed 175 second malignant neoplasms, yielding a SIR of 4.6, 95% CI: 3.9-5.3. When considering second cancers with at least 10 occurrences, highest relative risks were found for second malignant bone tumors (SIR = 26.4, 16.6-40.0), soft tissue sarcomas (SIR = 14.1, 6.7-25.8) and myeloid leukemia (SIR = 12.7, 6.3-22.8). Significant increased risks for all malignancies combined were observed after sympathetic nervous system tumors (SIR = 11.4, 5.2-21.6), retinoblastomas (SIR = 7.3, 5.4-9.8), renal tumors (SIR = 5.7, 3.8-8.0), malignant bone tumors (SIR = 5.6, 3.7-8.2), soft tissue sarcomas (SIR = 4.7, 3.2-6.8), germ-cell, trophoblastic and other gonadal neoplasms (SIR = 2.5, 1.1-4.9), carcinomas and other malignant epithelial neoplasms (SIR = 2.2, 1.4-3.3). The highest risk of a second malignancy of any type occurred 5 to 9 years after NCNSSC (SIR = 9.9, 6.8-13.9). The cumulative incidence of second malignancies 10 years after the first neoplasm was eight times higher among NCNSSC survivors than in the general population, with the absolute difference between observed and expected cumulative incidence still increasing after 50 years of follow-up. Children who survived a NCNSSC experience a large increased risk of developing a new malignancy, even many years after their initial diagnosis., (Copyright © 2011 UICC.)

Scanty data are available on the incidence (i.e., the absolute risk) of second cancers of the head and neck (HN) and its pattern with age. We investigated this issue using data from a multicentric study of 13 population-based cancer registries from Europe, Canada, Australia and Singapore for the years 1943-2000. A total of 99,257 patients had a first primary HN cancer (15,985 tongue, 22,378 mouth, 20,758 pharyngeal, and 40,190 laryngeal cancer), contributing to 489,855 person-years of follow-up. A total of 1,294 of the patients (1.3%) were diagnosed with second HN cancers (342 tongue, 345 mouth, 418 pharynx and 189 larynx). Male incidence rates of first HN cancer steeply increased from 0.68/100,000 at age 30-34 to 46.2/100,000 at age 70-74, and leveled off at older age; female incidence increased from 0.50/100,000 at age 30-34 to 16.5/100,000 at age 80-84. However, age-specific incidence of second HN cancers after a first HN cancer in men was around 200-300/100,000 between age 40-44 and age 70-74 and tended to decline at subsequent ages (150/100,000 at age 80-84); in women, incidence of second HN cancers was around 200-300/100,000 between age 45-49 and 80-84. The patterns of age-specific incidence were consistent for different subsites of second HN cancer and sexes; moreover, they were similar for age-specific incidence of first primary HN cancer in patients who subsequently developed a second HN cancer. The incidence of second HN cancers does not increase with age, but remains constant, or if anything, decreases with advancing age., (Copyright © 2010 UICC.)

Background: Patterns of second primary cancers (SPCs) following first primary lung cancers (FPLCs) may provide aetiological insights into FPLC., Methods: Cases of FPLCs in 13 cancer registries in Europe, Australia, Canada, and Singapore were followed up from the date of FPLC diagnosis to the date of SPC diagnosis, date of death, or end of follow-up. Standardised incidence ratios (SIRs) were calculated to estimate the magnitude of SPC development following squamous cell carcinoma (SCC), small cell lung carcinoma (SCLC), and adenocarcinoma (ADC)., Results: Among SCC patients, male SIR=1.58 (95% confidence interval (CI)=1.50-1.66) and female SIR=2.31 (1.94-2.72) for smoking-related SPC. Among SCLC patients, the respective ratios were 1.39 (1.20-1.60) and 2.28 (1.73-2.95), and among ADC patients, they were 1.73 (1.57-1.90) and 2.24 (1.91-2.61). We also observed associations between first primary lung ADC and second primary breast cancer in women (SIR=1.25, 95% CI=1.05-1.48) and prostate cancer (1.56, 1.39-1.79) in men., Conclusion: The FPLC patients carried excess risks of smoking-related SPCs. An association between first primary lung ADC and second primary breast and ovarian cancer in women at younger age and prostate cancers in men may reflect an aetiological role of hormones in lung ADC.

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin. MCCs and some other skin cancers, such as basal cell carcinomas, frequently harbour Merkel cell polyomavirus DNA. The purpose of the study was to investigate the frequency of second cancers following the diagnosis of MCC. We studied the incidence of second primary cancers after the diagnosis of MCC from the files of the Finnish Cancer Registry in 1979-2006. Among the 172 MCC patients identified a total of 34 second primary cancers were detected in 30 individuals after the diagnosis of MCC. Female MCC patients were diagnosed with 25 subsequent cancers (SIR, 2.35; 95% CI, 1.52-3.47; p<0.001) and male patients with 9 cancers (SIR, 2.32, 95% CI, 1.06-4.40; p<0.05). The MCC patients had an increased risk for a subsequent cancer (any site) compared to age-, gender- and calendar period-matched general population (standardized incidence ratio [SIR] 2.34; 95% confidence interval [CI], 1.62-3.27). The risks for basal cell carcinoma of the skin (O=11), SIR, 3.48; 95% CI, 1.74-6.22 and chronic lymphocytic leukemia (O=2), SIR, 17.9; 95% CI, 2.16-64.6 were significantly elevated. The SIRs for an overall second primary cancer risk did not change markedly with time since the diagnosis of MCC. We conclude that patients diagnosed with MCC have an increased risk for a second cancer. This risk may in part result from shared etiological factors between MCC and other tumour types, such as immunosuppression or possibly Merkel cell polyomavirus infection.

Purpose: Although cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) are both caused by human papillomavirus (HPV) infection, they differ in cofactors such as cigarette smoking. We assessed whether these cofactor differences translate into differences in second cancer risk., Patients and Methods: We assessed second cancer risk among 85,109 cervical SCC and 10,280 AC survivors reported to population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Risks compared to the general population were assessed using standardized incidence ratios (SIR)., Results: Overall cancer risk was significantly increased among both cervical SCC survivors (n = 10,559 second cancers; SIR, 1.31; 95% CI, 1.29 to 1.34) and AC survivors (n = 920 second cancers; SIR, 1.29; 95% CI, 1.22 to 1.38). Risks of HPV-related and radiation-related cancers were increased to a similar extent among cervical SCC and AC survivors. Although significantly increased in both groups when compared with the general population, risk of smoking-related cancers was significantly higher among cervical SCC than AC survivors (P = .015; SIR for cervical SCC = 2.07 v AC = 1.78). This difference was limited to lung cancer (SIR for cervical SCC = 2.69 v AC = 2.18; P = .026). The increased lung cancer risk among cervical AC survivors was observed for both lung SCC and lung AC. SIRs for second cancers of the colon, soft tissue, melanoma, and non-Hodgkin's lymphoma were significantly higher among cervical AC than SCC survivors., Conclusion: The second cancer profiles among cervical SCC and AC survivors mirror the similarities and differences in cofactors for these two histologies. Because smoking is not a cofactor for cervical AC, the increased lung cancer risk suggests a role for additional factors.

The objective of the study was to assess the risk of second primary cancers (SPCs) following a primary head and neck cancer (oral cavity, pharynx and larynx) and the risk of head and neck cancer as a SPC. The present investigation is a multicenter study from 13 population-based cancer registries. The study population involved 99,257 patients with a first primary head and neck cancer and contributed 489,855 person-years of follow-up. To assess the excess risk of SPCs following head and neck cancers, we calculated standardized incidence ratios (SIRs) by dividing the observed numbers of SPCs by the expected number of cancers calculated from accumulated person-years and the age-, sex- and calendar period-specific first primary cancer incidence rates in each of the cancer registries. During the observation period, there were 10,826 cases of SPCs after head and neck cancer. For all cancer sites combined, the SIR of SPCs was 1.86 (95% CI = 1.83-1.90) and the 20-year cumulative risk was 36%. Lung cancer contributed to the highest proportion of the SPCs with a 20-year cumulative risk of 13%. Excess second head and neck cancer risk was observed 10 years after diagnosis with lymphohaematopoietic cancers. The most common SPC following a first primary head and neck cancer was lung cancer. However, the highest excess of SPCs was in the head and neck region. These patterns were consistent with the notion that the pattern of cancer in survivors of head and neck cancer is dominated by the effect of tobacco smoking and alcohol drinking., ((c) 2008 Wiley-Liss, Inc.)

Background: The objective of this study is to assess the risk of second primary cancers following a first primary esophageal cancer as well as the risk of esophageal cancer as a second primary, following first primary cancers of other sites., Methods: The present investigation is a multicenter study of 13 population-based cancer registries in Europe, Australia, Canada, and Singapore. To assess excess occurrence of second cancers after esophageal cancers, we calculated standardized incidence ratios (SIR) by dividing the observed numbers of second cancers by the expected number of cancers calculated from the accumulated person-years and the age-, sex-, calendar period-, and registry-specific first primary cancer incidence rates., Results: During the study period, 959 cases of second primary cancers occurred after an initial esophageal cancer, resulting in a SIR of 1.15 (95% confidence interval, 1.08-1.22). Second primary stomach cancers were associated with first primary esophageal adenocarcinomas (SIR, 2.13; 95% confidence interval, 1.26-3.37) and second primary cancers of the oral cavity and pharynx (6.68; 5.33-8.26), stomach (1.53; 1.14-2.01), larynx (3.24; 1.88-5.18), lung (1.55; 1.28-1.87), kidney (1.88; 1.18-2.85), and thyroid (2.92; 1.18-6.02) were associated with first primary squamous cell carcinomas of the esophagus. An excess of esophageal cancer as a second primary were observed following first primary cancers of the aerodigestive tract, female breast, cervix, testis, bladder, Hodgkin's lymphoma, and non-Hodgkin lymphoma., Conclusion: We observed associations of esophageal cancer with second primary head and neck cancers and lung cancer regardless of years of follow-up, which may suggest that common risk factors play a role in multiple tumor development.

Purpose: The aim of this study is to quantify excess absolute risk (EAR) and excess relative risk (ERR) of secondary leukemia among a large population-based group of testicular cancer survivors., Methods: We identified 42,722 1-year survivors of testicular cancer within 14 population-based cancer registries in Europe and North America (1943-2002). Poisson regression analysis was used to model EAR (per 100,000 person-years [PY]) and ERR of secondary leukemia. Cumulative risks were calculated using a competing risk model., Results: Secondary leukemia developed in 89 patients (EAR = 10.8 per 100,000 PY, 95% confidence interval [CI] = 7.6-14.6; ERR = 1.6, 95%CI = 1.0-2.2). Statistically significantly elevated risks were observed for acute myeloid leukemia (AML) (EAR = 7.2, 95%CI = 4.7-10.2) and acute lymphoblastic leukemia (EAR = 1.3, 95%CI = 0.4-2.8). In multivariate analyses, AML risk was higher among patients whose initial management included chemotherapy compared to those receiving radiotherapy alone (p = 0.1). Excess cumulative leukemia risk was approximately 0.23% by 30 years after testicular cancer diagnosis., Conclusions: Although ERR of leukemia following testicular cancer is large, EAR and cumulative risk, which are better gauges of the population burden, are small.

Purpose: The aim of this study was to assess the risk of second malignant neoplasms (SMNs) other than central nervous system (CNS) neoplasms after childhood CNS cancer in an international multicentre study., Methods: Individual data on cases of CNS cancer in children (0-14 years) and on subsequent SMNs were obtained from 13 population-based cancer registries contributing data for different time periods in 1943-2000. Standardised incidence ratios (SIRs) with 95% confidence intervals (CI), absolute excess risk and cumulative incidence of SMNs were computed., Results: We observed 43 SMNs in 8431 CNS cancer survivors. The SIR was 10.6 (4.85-20.1) for thyroid cancer (nine cases), 2.75 (1.01-5.99) for leukaemia (six cases) and 2.47 (0.90-5.37) for lymphoma (six cases). The SIRs were highest in the first 10 years after CNS cancer diagnosis. The cumulative incidence of non-CNS SMNs was 3.30% (0.95-5.65%) within 45 years after a CNS cancer diagnosis. Within 15 years, the cumulative incidence was highest for cases diagnosed after 1980 (0.56%, 95% CI: 0.29-0.82%)., Conclusion: This population-based study indicates that about one every 180 survivors of a childhood CNS cancer will develop a non-CNS SMN within the following 15 years. The excess is higher after glioma and embryonal malignant tumour than after another CNS tumour.

Background and Objective: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy., Methods: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression., Results: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent., Conclusions: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.

Breast cancer survivors are at increased risk of treatment-related second cancers. This study is the first to examine risk 30 or more years after diagnosis and to present absolute risks of second cancer which accounts for competing mortality. We identified 23,158 second non-hematological malignancies excluding breast in a population-based cohort of 376,825 one-year survivors of breast cancer diagnosed from 1943 to 2002 and reported to four Scandinavian cancer registries. We calculated standardized incidence ratios (SIR) and utilized a competing-risk model to calculate absolute risk of developing second cancers. The overall SIR for second cancers was 1.15 (95% confidence interval [CI] = 1.14-1.17). The SIR for potentially radiotherapy-associated cancers 30 or more years after breast cancer diagnosis was 2.19 (95% CI = 1.87-2.55). However, the largest SIRs were observed for women aged <40 years followed for 1-9 years. At 20 years after breast cancer diagnosis, the absolute risk of developing a second cancer ranged from 0.6 to 10.3%, depending on stage and age; the difference in the absolute risk compared to the background population was greatest for women aged <40 years with localized disease, 2.3%. At 30 years post breast cancer diagnosis, this difference reached 3.2%. These risks were small compared to the corresponding risk of dying from breast cancer. Although the absolute risks were small, we found persistent risks of second non-hematological malignancies excluding breast 30 or more years after breast cancer diagnosis, particularly for women diagnosed at young ages with localized disease.

Background: Given the extended survival of patients diagnosed with cervical cancer, the large number of these women treated with radiotherapy, and the presence in this population of established cancer risk factors such as human papillomavirus (HPV) infection and cigarette smoking, it is important to clarify long-term trends in second cancer risk., Methods: Using data from 104,760 one-year survivors of cervical cancer reported to 13 population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States, we calculated standardized incidence ratios (SIRs) for second cancers overall and cancers at particular sites among women with cervical cancer, including cervical cancer patients who were treated or not treated with radiation, over more than 40 years of follow-up. Cox regression models were used to assess the time-varying association of radiotherapy with risk of second cancers and to assess the interaction of radiation treatment with age at diagnosis. All statistical tests were two-sided., Results: Among 104,760 one-year survivors of cervical cancer, the risk of all second cancers taken together was increased to a statistically significant extent (n = 12,496; SIR = 1.30; 95% confidence interval [CI] = 1.28 to 1.33). Compared with the general population, in both radiotherapy (N = 52,613) and no-radiotherapy groups (N = 27,382), risks for HPV-related cancers (of the pharynx, genital sites, and rectum/anus) and smoking-related cancers (of the pharynx, trachea/bronchus/lung, pancreas, and urinary bladder) were elevated to a statistically significant extent. Cervical cancer patients treated with radiotherapy, but not those who did not receive radiotherapy, were at increased risk for all second cancers and cancers at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, and genital sites) beyond 40 years of follow-up compared with women in the general population. The association of radiotherapy with second cancer risk was modified by age at cervical cancer diagnosis for rectum/anus, genital sites, and urinary bladder, with higher hazard ratios for second cancer at younger ages of cervical cancer. After adjustment for competing mortality, the 40-year cumulative risk of any second cancer was higher among women diagnosed with cervical cancer before age 50 (22.2%; 95% CI = 21.5% to 22.8%) than among women diagnosed after age 50 (16.4%; 95% CI = 16.1% to 16.9%)., Conclusion: Cervical cancer patients treated with radiotherapy are at increased risk of second cancers at sites in close proximity to the cervix beyond 40 years of follow-up.

Purpose: To quantify long-term temporal trends in the excess absolute risk (EAR) of secondary leukemia among breast cancer (BC) survivors, using multivariate analyses to evaluate the effects of subtype, age at BC diagnosis, attained age, and calendar year., Patients and Methods: We identified 376,825 1-year survivors of BC within 4 nationwide, population-based cancer registries in Sweden, Denmark, Finland, and Norway (1943-2001). Estimates of EAR (per 100,000 person-years) were modeled using Poisson regression methods and cumulative risks calculated using a competing risk model., Results: A total of 687 non-chronic lymphocytic leukemias (EAR = 9.05; 95% confidence interval (CI) = 7.5-10.7) was reported. Significantly elevated risks were observed for the first time for chronic myeloid leukemia (CML) (EAR = 2.06; 95% CI = 1.3-2.9) and acute lymphoblastic leukemia (ALL) (EAR = 0.62; 95% CI = 0.2-1.1), in addition to acute myeloid leukemia (AML) (EAR = 5.00; 95% CI = 3.9-6.2). Excesses of CML, ALL, AML and all leukemias combined persisted over 25 years after BC diagnosis. For all leukemias, EAR decreased with increasing calendar year (P = 0.04) of BC diagnosis. Risk for all leukemia and AML by calendar year of BC diagnosis depended on age at diagnosis. For women diagnosed with BC after 1985, the 10-year cumulative risk of leukemia for those diagnosed before and after age 50 was small, 0.10% and 0.14%, respectively., Conclusions: Although secondary leukemia is a rare event, BC survivors experience statistically significant excesses for at least 25 years after diagnosis, including CML and ALL. Decreasing leukemia risks in recent calendar years likely reflect changes in treatment.

We evaluated the risk of angiosarcoma after radiotherapy among all patients with cancers of breast, cervix uteri, corpus uteri, lung, ovary, prostate, or rectum, and lymphoma diagnosed in Finland during 1953-2003, identified from the Finnish Cancer Registry. Only angiosarcomas of the trunk were considered, this being the target of radiotherapy for the first cancer. In the follow-up of 1.8 million person-years at risk, 19 angiosarcomas developed, all after breast and gynaecological cancer. Excess of angiosarcomas over national incidence rates were observed after radiotherapy without chemotherapy (standardised incidence ratio (SIR) 6.0, 95% confidence interval (CI) 2.7-11), after both radiotherapy and chemotherapy (SIR 100, 95% CI 12-360), and after other treatments (SIR 3.6, 95% CI 1.6-7.1). In the regression analysis however, the adjusted rate ratio for radiotherapy was 1.0 (95% CI 0.23-4.4). Although an increased risk of angiosarcoma among cancer patients is evident, especially with breast and gynaecological cancer, the excess does not appear to be strongly related to radiotherapy.

Background: Skin cancers are known to be associated with sun exposure, whereas sunlight through the production of vitamin D may protect against some cancers. The aim of this study was to assess whether patients with skin cancer have an altered risk of developing other cancers., Methods: The study cohort consisted of 416,134 cases of skin cancer and 3,776,501 cases of non-skin cancer as a first cancer extracted from 13 cancer registries. 10,886 melanoma and 35,620 non-melanoma skin cancer cases had second cancers. The observed numbers (O) of 46 types of second primary cancer after skin melanoma, basal cell carcinoma or non-basal cell carcinoma, and of skin cancers following non-skin cancers were compared to the expected numbers (E) derived from the age, sex and calendar period specific cancer incidence rates in each of the cancer registries (O/E=SIR, standardised incidence ratios). Rates from cancer registries classified to sunny countries (Australia, Singapore and Spain) and less sunny countries (Canada, Denmark, Finland, Iceland, Norway, Scotland, Slovenia and Sweden) were compared to each other., Results: SIR of all second solid primary cancers (except skin and lip) after skin melanoma were significantly lower for the sunny countries (SIR(S)=1.03; 95% CI 0.99-1.08) than in the less sunny countries (SIR(L)=1.14; 95%CI 1.11-1.17). The difference was more obvious after non-melanoma skin cancers: after basal cell carcinoma SIR(S)/SIR(L)=0.65 (95%CI=0.58-0.72); after non-basal cell carcinoma SIR(S)/SIR(L)=0.58 (95%CI=0.50-0.67). In sunny countries, the risk of second primary cancer after non-melanoma skin cancers was lower for most of the cancers except for lip, mouth and non-Hodgkin lymphoma., Conclusions: Vitamin D production in the skin seems to decrease the risk of several solid cancers (especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder and kidney cancers). The apparently protective effect of sun exposure against second primary cancer is more pronounced after non-melanoma skin cancers than melanoma, which is consistent with earlier reports that non-melanoma skin cancers reflect cumulative sun exposure, whereas melanoma is more related to sunburn.

Primary fallopian tube cancer (PFTC) is a rare disease, and its aetiological factors are poorly understood. Studies on PFTC in the setting of 2nd primary malignant neoplasms can provide clues on aetiology and also define the possible side effects of different treatment modalities for PFTC. A cohort of 2,084 cases with first PFTC was extracted from the data from 13 cancer registries from Europe, Canada, Australia and Singapore and followed for second primary cancers within the period 1943-2000. Standardized incidence ratios (SIRs) were calculated and Poisson regression analyses were done to find out the RRs related to age at, period of and time since the PFTC diagnosis. There were 118 cancer cases observed after first PFTC (SIR 1.4, 95%CI 1.1-1.6). Elevated SIRs were seen for colorectal cancer (1.7, 95%CI 1.0-2.6), for breast cancer (1.5, 95%CI 1.1-2.2), for bladder cancer (2.8, 95%CI 1.0-6.0), for lung cancer (1.8, 95% CI 0.9-3.2) and for nonlymphoid leukaemia (3.7, 95%CI 1.0-9.4). Significant risk increases were detected for colorectal cancer during the 2nd to 5th year after the first PFTC diagnosis, for breast cancer in follow-up 10+ and for nonlymphoid leukaemia during the 2nd to 10th year. The clustering of cancers of the lung and bladder in PFTC patients may suggest shared smoking aetiology. The excess of colorectal and breast cancers after PFTC may indicate a genetic aetiology., ((c) 2007 Wiley-Liss, Inc.)

Purpose: Hodgkin's lymphoma (HL) survivors are known to be at substantially increased risk of solid cancers (SC). However, no investigation has used multivariate modeling to estimate the relative risk (RR), excess absolute risk (EAR), and cumulative incidence for specific attained ages and ages at HL diagnosis., Patients and Methods: We identified 18,862 5-year HL survivors from 13 population-based cancer registries in North America and Europe. Poisson regression was used to evaluate the effects of age at diagnosis, attained age, latency, sex, treatment, and year of diagnosis on the RR and EAR of SC., Results: Among 1,490 identified SC, 850 were estimated to be in excess. For most cancer sites, both RR and EAR decreased with age at HL diagnosis and showed strong dependencies on attained age. For a patient diagnosed at age 30 years and survived to > or = 40 years, modeled risks were significantly elevated for cancers of the breast (RR = 6.1), other supradiaphragmatic sites (RR = 6.0), and infradiaphragmatic sites (RR = 3.7); the largest RR (20-fold) was observed for malignant mesothelioma. Thirty-year cumulative risks of SC for men and women diagnosed at 30 years were 18% and 26%, respectively, compared with 7% and 9%, respectively, in the general population. For young HL patients, risks of breast and colorectal cancers were elevated 10 to 25 years before the age when routine screening would be recommended in the general population., Conclusion: Multivariable modeling demonstrates for the first time temporal changes in SC risk not evident in unadjusted analyses, and can facilitate the development of individualized risk assessment and the creation of screening strategies for early detection.

Objective: To study the risk of second primary cancers in nasopharyngeal carcinoma (NPC) patients and the risk of NPC as second primary cancer., Methods: We used data from the cancer registries from Singapore and from 12 low-incidence areas, including a total of 8,947 first occurring NPC cases, and 167 second occurring cases. We calculated standardized incidence ratios (SIRs) by comparing the second cancer incidence in NPC patients to the first primary cancer incidence in non-cancer population. We also calculated SIRs of second NPC after other primaries., Results: In Singapore, the risk of cancers of the lung (SIR=0.42), stomach (SIR=0.41), and colon (SIR=0.23) was significantly decreased after NPC, whereas that of cancer of the tongue (SIR=11.1) was significantly increased. In Australia, Canada, and Europe, the risk of non-Hodgkin's lymphoma (NHL) (SIR=3.06), tongue cancer (SIR=5.29), brain cancer (SIR=3.89), myeloid leukemia (SIR=3.85), and non-melanoma skin cancer (NMSC) (SIR=3.47) was significantly increased after NPC. Incidences of second occurring NPCs following various primary cancers were not significantly altered compared to the incidence of first occurring NPCs., Conclusions: Immune suppression (NHL, NMSC), shared genetic factors (lung cancer, NHL, myeloid leukemia), and shared environmental risk factors (tongue and brain cancers) might explain the associations. Except for NHL, there was no evidence of association with other Epstein-Barr virus-related cancers.

We investigated the risk of second malignancies among 29,511 survivors of germ-cell testicular cancer recorded in 13 cancer registries. Standardized incidence ratios (SIRs) were estimated comparing the observed numbers of second malignancies with the expected numbers obtained from sex-, age-, period- and population-specific incidence rates. Seminomas and nonseminomas, the 2 main histological groups of testicular cancer, were analyzed separately. During a median follow-up period of 8.3 years (0-35 years), we observed 1,811 second tumors, with a corresponding SIR of 1.65 (95% confidence interval (CI): 1.57-1.73). Statistically significant increased risks were found for fifteen cancer types, including SIRs of 2.0 or higher for cancers of the stomach, gallbladder and bile ducts, pancreas, bladder, kidney, thyroid, and for soft-tissue sarcoma, nonmelanoma skin cancer and myeloid leukemia. The SIR for myeloid leukemia was 2.39 (95% CI: 1.41-3.77) after seminomas, and 6.77 (95% CI: 4.14-10.5) after nonseminomas. It increased to 37.9 (95% CI: 18.9-67.8; based on 11 observed cases of leukemia) among nonseminoma patients diagnosed since 1990. SIRs for most solid cancers increased with follow-up duration, whereas they did not change with year of testicular cancer diagnosis. Among subjects diagnosed before 1980, 20 year survivors of seminoma had a cumulative risk of solid cancer of 9.6% (95% CI: 8.7-10.5%) vs. 6.5% expected, whereas 20 years survivors of nonseminoma had a risk of 5.0% (95% CI: 4.2-6.0%) vs. 3.1% expected. In conclusion, survivors of testicular cancers have an increased risk of several second primaries, where the effect of the treatment seems to play a major role.

Ocular melanoma is a rare neoplasm with a poorly understood etiology, especially concerning its link with ultraviolet-light exposure. Studying the risk of second primary cancers may help to formulate causal hypotheses. We used data from 13 cancer registries, including 10,396 first occurring ocular melanoma cases, and 404 second occurring cases. To compare the second cancer incidence in ocular melanoma patients to that in noncancer population, we calculated standardized incidence ratios (SIRs) of 32 types of cancer. We also calculated SIRs of second ocular melanoma after other primaries. Ocular melanoma patients had significantly increased risk of cutaneous melanoma (SIR = 2.38, 95% CI 1.77-3.14), multiple myeloma (SIR = 2.00, 1.29-2.95), and of liver (SIR = 3.89, 2.66-5.49), kidney (SIR = 1.70, 1.22-2.31), pancreas (SIR = 1.58, 1.16-2.11), prostate (SIR = 1.31, 1.11-1.54), and stomach (SIR = 1.33, 1.03-1.68) cancers. Risks of cutaneous melanoma were highly variable between registries and were mainly increased in females, in younger patients, in first years following diagnosis, and for patients diagnosed after 1980. The risk of ocular melanoma was significantly increased only after prostate cancer (SIR = 1.41, 1.08-1.82). Risk of cutaneous melanoma after ocular melanoma had epidemiological patterns, similar to cutaneous melanoma screening in the general population. The increased risk of cutaneous melanoma would be largely due to greater skin cancer surveillance in ocular melanoma patients, and not to common etiological factors. The high SIR found for liver cancer may be explained by misclassification bias. Common etiological factors may be involved in ocular and prostate cancers.

Purpose: To assess the risk of esophageal cancer as second cancer among breast-cancer patients treated with radiotherapy., Methods and Materials: The records of the Finnish Cancer Registry from 1953 to 2000 were used to assess the risk of esophageal cancer as second cancer among 75,849 breast-cancer patients. Patients were treated with surgery (n = 33,672), radiotherapy (n = 35,057), chemotherapy and radiotherapy (n = 4673), or chemotherapy (n = 2,447). The risk of a new primary cancer was expressed as standardized incidence ratio (SIR), defined as the ratio of observed to expected cases., Results: By the end of 2000, the number of observed cases esophageal cancers was 80 vs. 72 expected cases (standardized incidence ratio (SIR) = 1.1, 95% Confidence Interval (CI) = 0.9 to 1.5). Among patients followed for 15 years and treated with radiotherapy, the SIR for esophageal cancer was 2.3 (95% CI = 1.4 to 5.4). No increase in risk was seen for patients treated without radiotherapy. The risk of esophageal cancer was increased among patients diagnosed during 1953 to 1974, although age at the treatment did not have marked effect on the risk estimate., Conclusion: Increased risk of second cancer in the esophagus was observed for breast-cancer patients in Finland, especially among patients with over 15 years of follow-up and treated in the earliest period, which may relate to the type of radiotherapy.

Studies of pancreatic cancer in the setting of second primary malignant neoplasms can provide etiologic clues. An international multicenter study was carried out using data from 13 cancer registries with a registration period up to year 2000. Cancer patients were followed up from the initial cancer diagnosis, and the occurrence of second primary malignant neoplasms was compared with expected values derived from local rates, adjusting for age, sex, and period of diagnosis. Results from individual registries were pooled by use of a fixed-effects model. People were at higher risk of developing pancreatic cancer within 10 years of a diagnosis of cancers of the pharynx, stomach, gallbladder, larynx, lung, cervix, corpus uteri, bladder, and eye and 10 years or later following a diagnosis of cancers of the stomach, colon, gallbladder, breast, cervix, placenta, corpus uteri, ovary, testis, bladder, kidney, and eye, as well as Hodgkin's and non-Hodgkin's lymphomas. Pancreatic cancer was connected with smoking-related cancers, confirming the etiologic role of tobacco. The associations with uterine and ovarian cancers suggest that reproductive factors might be implicated in pancreatic carcinogenesis. The elevated pancreatic cancer risk in young patients observed among several types of cancer implies a role of genetic factors. Radiotherapy is also suggested as a risk factor.

Treatments for Hodgkin lymphoma are associated with large relative risks of acute myeloid leukemia (AML), but there are few estimates of the excess absolute risk (EAR), a useful measure of disease burden. One-year Hodgkin lymphoma survivors (N = 35,511) were identified within 14 population-based cancer registries in Nordic countries and North America from January 1, 1970, through December 31, 2001. We used Poisson regression analysis to model the EAR of AML, per 10,000 person-years. A total of 217 Hodgkin lymphoma survivors were diagnosed with AML (10.8 expected; unadjusted EAR = 6.2; 95% confidence interval = 5.4 to 7.1). Excess absolute risk for AML was highest during the first 10 years after Hodgkin lymphoma diagnosis but remained elevated thereafter. In subsequent analyses, adjusted for time since Hodgkin lymphoma diagnosis and presented for the 5-9 year interval, the EAR was statistically significantly (P < .001) larger in patients diagnosed with Hodgkin lymphoma at age 35 years and older than in those diagnosed before 35 years of age. The EAR of AML declined statistically significantly after 1984 (7.0 to 4.2 and 16.4 to 9.9 in the < 35 and > or = 35 age groups, respectively), which may be associated with modifications in chemotherapy.

Cancer of the small intestine is a rare neoplasm, and its etiology remains poorly understood. Analysis of other primary cancers in individuals with small intestine cancer may help elucidate the causes of this neoplasm and the underlying mechanisms. We included 10,946 cases of first primary small intestine cancer from 13 cancer registries in a pooled analysis. The observed numbers of 44 types of second primary cancer were compared to the expected numbers derived from the age-, gender- and calendar period-specific cancer incidence rates in each registry. We also calculated the standardized incidence ratios (SIR) for small intestine cancer as a second primary after other cancers. There was a 68% overall increase in the risk of a new primary cancer after small intestine carcinoma (SIR = 1.68, 95% confidence interval [CI] = 1.47-1.71), that remained constant over time. The overall SIR was 1.18 (95% CI = 1.05-1.32) after carcinoid, 1.29 (1.01-1.63) after sarcoma, and 1.27 (0.78-1.94) after lymphoma. Significant (p < 0.05) increases were observed for cancers of the oropharynx, colon, rectum, ampulla of Vater, pancreas, corpus uteri, ovary, prostate, kidney, thyroid gland, skin and soft tissue sarcomas. Small intestine cancer as a second primary was increased significantly after all these cancers, except after oropharyngeal and kidney cancers. Although some of the excess may be attributable to overdiagnosis, it is plausible that most additional cases of second primary cancers were clinically relevant and were due to common genetic (e.g., defects in mismatch or other DNA repair pathways) and environmental (e.g., dietary) factors., (Copyright 2005 Wiley-Liss, Inc.)

Objective: To study the long term risk of cervical and other cancers after treatment for cervical intraepithelial neoplasia., Design: Retrospective cohort study., Setting: University Hospital, Helsinki, Finland., Participants: 7564 women treated for cervical intraepithelial neoplasia during 1974 and 2001 and followed up through the Finnish cancer registry until 2003., Main Outcome Measures: Standardised incidence ratio for cervical cancer and other cancers., Results: During follow-up 22 cases of invasive cervical cancer occurred in women treated for cervical intraepithelial neoplasia (standardised incidence ratio 2.8, 95% confidence interval 1.7 to 4.2). The highest risk was during the second decade (10 cases observed: 3.1, 1.5 to 5.7). The standardised incidence ratio for cervical intraepithelial cancer type 1 was 3.1 (1.4 to 6.2) and for type 2 was 3.7 (0.9 to 10.7)., Conclusions: The risk of cervical cancer in the first 20 years after treatment for cervical intraepithelial neoplasia is higher than in the average population. The risk of smoking related cancers is also increased.

The importance of genetic and other risk factors in the development of breast cancer after radiotherapy (RT) for Hodgkin lymphoma (HL) has not been determined. We analyzed data from a breast cancer case-control study (105 patients, 266 control subjects) conducted among 3 817 survivors of HL diagnosed at age 30 years or younger in 6 population-based cancer registries. Odds ratios (ORs) and excess relative risks (ERRs) were calculated using conditional regression. Women who received RT exposure (> or = 5 Gy radiation dose to the breast) had a 2.7-fold increased breast cancer risk (95% confidence interval (CI) 1.4-5.2), compared with those given less than 5 Gy. RT exposure (> or = 5 Gy) was associated with an OR of 0.8 (95% CI, 0.2-3.4) among women with a first- or second-degree family history of breast or ovarian cancer, and 5.8 (95% CI, 2.1-16.3) among all other women (interaction P = .03). History of a live birth appeared to increase the breast cancer risk associated with RT among women not treated with ovarian-damaging therapies. Breast cancer risk following RT varied little according to other factors. The additional increased relative risk of breast cancer after RT for HL is unlikely to be larger among women with a family history of breast or ovarian cancer than among other women.

Background: Many women develop breast cancer after treatment for Hodgkin lymphoma (HL) at a young age. We estimated this future risk, taking into account age and calendar year of HL diagnosis, HL treatment information, population breast cancer incidence rates, and competing causes of death., Methods: Relative risks of breast cancer for categories defined by radiation dose to the chest (0, 20- < 40 Gy, or > or = 40 Gy) and use of alkylating agents (yes or no) were estimated from a case-control study conducted within an international population-based cohort of 3817 female 1-year survivors of HL diagnosed at age 30 years or younger from January 1, 1965, through December 31, 1994. To compute cumulative absolute risks of breast cancer, we used modified standardized incidence ratios to relate cohort breast cancer risks to those in the general population, enabling application of population-based breast cancer rates, and we allowed for competing risks by using population-based mortality rates in female HL survivors., Results: Cumulative absolute risks of breast cancer increased with age at end of follow-up, time since HL diagnosis, and radiation dose. For an HL survivor who was treated at age 25 years with a chest radiation dose of at least 40 Gy without alkylating agents, estimated cumulative absolute risks of breast cancer by age 35, 45, and 55 years were 1.4% (95% confidence interval [CI] = 0.9% to 2.1%), 11.1% (95% CI = 7.4% to 16.3%), and 29.0% (95% CI = 20.2% to 40.1%), respectively. Cumulative absolute risks were lower in women treated with alkylating agents., Conclusions: Breast cancer projections varied considerably by type of HL therapy, time since HL diagnosis, and age at end of follow-up. These estimates are applicable to HL survivors treated with regimens of the past and can be used to counsel such patients and plan management and preventive strategies. Projections should be used with caution, however, in patients treated with more recent approaches, including limited-field radiotherapy and/or ovary-sparing chemotherapy.

Background: Although second primary cancers are a leading cause of death among men with testicular cancer, few studies have quantified risks among long-term survivors., Methods: Within 14 population-based tumor registries in Europe and North America (1943-2001), we identified 40,576 1-year survivors of testicular cancer and ascertained data on any new incident solid tumors among these patients. We used Poisson regression analysis to model relative risks (RRs) and excess absolute risks (EARs) of second solid cancers. All statistical tests were two-sided., Results: A total of 2,285 second solid cancers were reported in the cohort. The relative risk and EAR decreased with increasing age at testicular cancer diagnosis (P < .001); the EAR increased with attained age (P < .001) but the excess RR decreased. Among 10-year survivors diagnosed with testicular cancer at age 35 years, the risk of developing a second solid tumor was increased (RR = 1.9, 95% confidence interval [CI] = 1.8 to 2.1). Risk remained statistically significantly elevated for 35 years (RR = 1.7, 95% CI = 1.5 to 2.0; P < .001). We observed statistically significantly elevated risks, for the first time, for cancers of the pleura (malignant mesothelioma; RR = 3.4, 95% CI = 1.7 to 5.9) and esophagus (RR = 1.7, 95% CI = 1.0 to 2.6). Cancers of the lung (RR = 1.5, 95% CI = 1.2 to 1.7), colon (RR = 2.0, 95% CI = 1.7 to 2.5), bladder (RR = 2.7, 95% CI = 2.2 to 3.1), pancreas (RR = 3.6, 95% CI = 2.8 to 4.6), and stomach (RR = 4.0, 95% CI = 3.2 to 4.8) accounted for almost 60% of the total excess. Overall patterns were similar for seminoma and nonseminoma patients, with lower risks observed for nonseminoma patients treated after 1975. Statistically significantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2). For patients diagnosed with seminomas or nonseminomatous tumors at age 35 years, cumulative risks of solid cancer 40 years later (i.e., to age 75 years) were 36% and 31%, respectively, compared with 23% for the general population., Conclusions: Testicular cancer survivors are at statistically significantly increased risk of solid tumors for at least 35 years after treatment. Young patients may experience high levels of risk as they reach older ages. The statistically significantly increased risk of malignant mesothelioma in testicular cancer survivors has, to our knowledge, not been observed previously in a cohort of patients treated with radiotherapy.

An analysis of other primary cancers in individuals with non-Hodgkin's lymphoma (NHL) can help to elucidate this cancer aetiology. In all, 109 451 first primary NHL were included in a pooled analysis of 13 cancer registries. The observed numbers of second cancers were compared to the expected numbers derived from the age-, sex-, calendar period- and registry-specific incidence rates. We also calculated the standardised incidence ratios for NHL as a second primary after other cancers. There was a 47% (95% confidence interval 43-51%) overall increase in the risk of a primary cancer after NHL. A strongly significant (P<0.001) increase was observed for cancers of the lip, tongue, oropharynx*, stomach, small intestine, colon*, liver, nasal cavity*, lung, soft tissues*, skin melanoma*, nonmelanoma skin*, bladder*, kidney*, thyroid*, Hodgkin's lymphoma*, lymphoid leukaemia* and myeloid leukaemia. Non-Hodgkin's lymphoma as a second primary was increased after cancers marked with an asterisk. Patterns of risk indicate a treatment effect for lung, bladder, stomach, Hodgkin's lymphoma and myeloid leukaemia. Common risk factors may be involved for cancers of the lung, bladder, nasal cavity and for soft tissues, such as pesticides. Bidirectional effects for several cancer sites of potential viral origin argue strongly for a role for immune suppression in NHL.

An international multicentre study of first and second primary neoplasms associated with male breast cancer was carried out by pooling data from 13 cancer registries. Among a total of 3409 men with primary breast cancer, 426 (12.5%) developed a second neoplasia; other than breast cancer, a 34% overall excess risk of second primary neoplasia, affecting the small intestine (standardised incidence ratio, 4.95, 95% confidence interval, 1.35-12.7), rectum (1.78, 1.20-2.54), pancreas (1.93, 1.14-3.05), skin (nonmelanoma, 1.65, 1.16-2.29), prostate (1.61, 1.34-1.93) and lymphohaematopoietic system (1.63, 1.12-2.29). A total of 225 male breast cancers was recorded after cancers other than breast cancer, but an increase was found only after lymphohaematopoietic neoplasms. BRCA2 (and to some extent BRCA1) mutations may explain the findings for pancreatic and prostate cancers. Increases at other sites may be related to unknown factors or to chance. This large study shows that the risks for second discordant tumours after male breast cancer pose only a moderate excess risk.

Context: Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk., Objective: To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD., Design, Setting, and Subjects: Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998., Main Outcome Measures: Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents., Results: Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P =.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P =.003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses., Conclusions: Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.

Purpose: To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkin's disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment., Patients and Methods: Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed., Results: Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377; O/E = 2.9), digestive tract (Obs = 376; O/E = 1.7), and female breast (Obs = 234; O/E = 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 51 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect., Conclusion: Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested.

Twenty-four Finnish families with 2 or more glioma patients were identified through questionnaires sent to 369 consecutive glioma patients receiving surgery at Tampere University Hospital during 1983-94. To explore whether unusual cancer susceptibility is involved, the cancer risk of 2,664 family members was estimated using population-based data from the Finnish Cancer Registry. Among the total cohort of relatives, 88 cancers were observed during 1953-97. The overall cancer risk among 12 families with juvenile onset gliomas was significantly decreased (standardized incidence ratio [SIR] 0.6, 95% confidence interval [CI]: 0.4-0.9). Among 12 families with adult onset gliomas, the overall cancer risk was equal to that of the reference population (SIR 1.1, 95% CI: 0.8-1.4) whereas the risk of skin melanoma (SIR 4.0, 95% CI: 1.5-8.8) and meningioma (SIR 5.5, 95% CI: 1.1-16) were significantly increased. Several other tumors, including those associated with neurofibromatosis 1 and 2, tuberous sclerosis and Li-Fraumeni and Turcot syndromes were surveyed, but no elevated risks were observed. In conclusion, the presence of meningiomas and skin melanomas in glioma families may indicate a novel association as a cancer susceptibility trait., (Copyright 2001 Wiley-Liss, Inc.)

Background: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use., Methods: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided., Results: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment., Conclusions: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.

The risk of a new primary cancer (NPC) among 77548 Finnish lung cancer patients from 1953 to 1995 was analysed by the histological type of the lung cancer. The relative risks were expressed as standardised incidence ratios (SIR, ratio of the observed and expected numbers of cases). During the follow-up, 1148 NPCs were observed among men and 152 among women. After exclusion of lung cancers, the risk of NPC was elevated in both males (SIR 1.07; 95% confidence interval (CI) 1.00-1.14) and females (SIR 1.21; 95% CI 1.02-1.42). The excess was larger among lung cancer patients with small-cell carcinoma and adenocarcinoma than those with squamous-cell carcinoma. In all major histological groups of lung cancer, significant excess risks were found for cancers of the larynx (SIRs 2.94-4.25), and bladder (SIRs 2.16-2.86). Significantly elevated SIRs were also found for cancers of the stomach (SIR 1.42; 95% CI 1.12-1.76) and kidney (SIR 2.18; 95% CI 1.56-2.97) in squamous-cell carcinoma; for brain tumours (SIR 3.26; 95% CI 1.20-7.09) in small-cell carcinoma; and for cancers of the prostate (SIR 1.68; 95% CI 1.21-2.27) and thyroid (SIR 3.79; 95% CI 1.23-8.85), and brain tumours (SIR 2.34; 95% CI 1.07-4.43) in adenocarcinoma. The risk of contracting NPC at sites where the majority of tumours are adenocarcinomas was elevated among patients with adenocarcinoma of the lung, but not among squamous-cell or small-cell carcinoma patients. In adenocarcinoma, the excess risks of several smoking-related cancers tended to be somewhat lower than those in the other two histological categories. The relative risk of a NPC among patients diagnosed with lung cancer in 1985-1995 was higher than that of patients from earlier periods in all comparable follow-up categories (up to 10 years), possibly suggesting that the increased use of cytostatic drugs had increased the risk of NPC.

Background: Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of leukemia following radiotherapy and chemotherapy for testicular cancer., Methods: Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case-control study of leukemia was undertaken. Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided., Results: Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend =.02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend =.001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5-8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks., Conclusions: Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose-response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.

The aim of this study was to investigate whether patients with basal-cell carcinoma (BCC) of the skin have an increased risk of developing other cancers. A total of 71,924 patients diagnosed with BCC between 1953 and 1995 were identified from the Finnish Cancer Registry. They were followed up for subsequent primary cancers from the date of the first BCC diagnosis to the end of 1995. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated based on national rates. Altogether 11,042 subsequent primary cancers occurred among the study cohort during 625,000 person-years of follow-up. Risk increases were observed for non-melanoma skin cancer (SIR 3.79, 95% CI 3.59-4.00) and skin melanoma (SIR 2.34, 95% CI 2.08-2.61). The five other primary sites presenting the highest SIRs were salivary glands (SIR 3.30), lip (2. 19), small intestine (1.85), nose (1.73) and pharynx (1.71). Patients who were less than 40 years of age at the time of BCC diagnosis had a significantly higher relative risk for a subsequent new cancer than the older patients (ratio of the SIRs 1.29, 95% CI 1. 10-1.51). Time since BCC diagnosis did not materially influence the overall relative risk of subsequent cancers. Part of the increase in the risk of skin cancer is likely to be due to enhanced diagnostic activity after an initial diagnosis of BCC. However, the increases in the risk of several non-cutaneous cancers suggest a generalized carcinogenic role of some factors in the BCC pathogenic pathways., (Copyright 2000 Wiley-Liss, Inc.)

Purpose: To quantify the risk of second cancers among long-term survivors of Hodgkin's disease (HD) diagnosed before 21 years of age and to explore sex-, age-, and site-related differences., Patients and Methods: We analyzed data from 5,925 pediatric HD patients, including 2,646 10-year and 755 20-year survivors, who were reported to 16 population-based cancer registries in North America and Europe between 1935 and 1994., Results: A total of 157 solid tumors (observed/expected ratio [O/E] = 7.0; 95% confidence interval [CI], 5.9 to 8.2.) and 26 acute leukemias (O/E = 27.4; 95% CI, 17.9 to 40. 2) were reported. Risk of solid tumors remained significantly increased among 20-year survivors (O/E = 6.6, observed [O] = 40, cumulative risk = 6.5%) and persisted for 25 years (O/E = 4.6, O = 15, cumulative risk = 11.7%). Temporal trends for cancers of thyroid, female breast, bone/connective tissue, stomach, and esophagus were consistent with the late effects of radiotherapy. Greater than 50-fold increased risks were observed for tumors of the thyroid and respiratory tract (one lung and one pleura) among children treated before age 10. At older ages (10 to 16 years), the largest number of second cancers occurred in the digestive tract (O/E = 19.3) and breast (O/E = 22.9). Risk of solid tumors increased with decreasing age at HD on a relative but not absolute scale., Conclusion: Children and adolescents treated for HD experience significantly increased risks of second cancers at various sites for 2 to 3 decades. Although our results reflect the late effects of past therapeutic modalities, they underscore the importance of lifelong follow-up of pediatric HD patients given early, more aggressive treatments.

The records of the Finnish Cancer Registry from 1953 to 1994 were used to assess the risk of subsequent primary cancer among 14,493 brain tumour patients. They had been treated with surgery only (n = 9804), radiotherapy (n = 4099), chemotherapy and radiotherapy (n = 493) or chemotherapy alone (n = 97). By the end of 1994, 403 subsequent primary cancers were registered in these patients, whilst the expected number based on national incidence was 332. The standardised incidence ratio (SIR) was 1.2 (95% confidence interval (CI) 1.1-1.3). A significant excess risk of tumours in the central nervous system (CNS) including meningeomas (SIR 2.6, 95% CI 1.7-3.8), non-Hodgkin's lymphoma (SIR 2.6, 95% CI 1.6-4.1) and skin melanoma (SIR 1.9, 95% CI 1.0-3.1) was observed. CNS tumours were observed in excess among patients treated with surgery alone (SIR 2.0, 95% CI 1.2-3.2) and with radiotherapy (SIR 5.1, 95% CI 2.5-9.4). In conclusion, brain tumours are associated with an increased risk of both CNS second tumours and non-CNS second cancers, especially non-Hodgkin's lymphoma and melanoma. A moderately increased risk of second tumours in the CNS was observed among brain tumour patients treated with surgery only and a larger excess among those treated with radiotherapy.

This study is based on 194 patients with primary breast cancer treated with adjuvant CNF combination chemotherapy, who were followed-up for the risk of subsequent neoplasms. During an average follow-up of 4.8 years, 16 cases of new cancers were detected. Nine non-breast cancers were observed versus 2.2 expected (standardized incidence ratio 4.2). Of the patients with subsequent malignancies, 88% had received antiestrogen (chemohormonal adjuvant therapy); the percentage among all patients was 25%. We conclude that the benefit derived from adjuvant therapy of breast cancer may be reduced because of an increased risk of subsequent cancers.

An association between Kaposi's sarcoma (KS) and malignant lymphoma has been suspected for many years. Both cancers belong to the group of malignancies associated with immune suppression and have been known to occur in the same individual. Accordingly, a common etiology has been suspected. Through linkage within the Nordic cancer registries, we studied the occurrence of cancers in a population-based cohort of 741 patients with classical KS. The relative risk of subsequent malignancies was expressed as the ratio of the observed numbers of cancer to the numbers expected based on age-, sex-, period- and country-specific incidence rates, i.e., the standardized incidence ratio (SIR). A total of 104 cancers was observed during 5,802 person-years of follow-up, which was close to the expected 98.8 cases (SIR, 1.05). During the first year of follow-up, 3 lymphomas were observed, which is in significant excess of the 0.2 lymphomas expected (SIR, 13.0). In contrast, no lymphomas occurred in the period beyond the first year of follow-up vs. 2.3 expected. Cancers of the buccal cavity and pharynx (SIR, 10.6; n = 4) and of the colon (SIR, 2.7; n = 7) occurred in excess among women but not among men. Accordingly, our results indicate that patients with classical KS are not at increased risk of cancer in general. In particular, the overall risk of lymphomas was not significantly increased. The high relative risk of malignant lymphoma immediately after KS was based on a limited number of cases, and this observation is unlikely to indicate a common etiology.