Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects.

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Increased pancreatic cancer risk following radiotherapy for testicular cancer.

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.

Stomach cancer risk after treatment for hodgkin lymphoma.

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.

Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study.

PURPOSE: Cancers of the digestive system constitute a major risk for childhood cancer survivors treated with radiotherapy once they reach adulthood. The aim of this study was to determine therapy-related risk factors for the development of a second malignancy in the digestive organs (SMDO) after a childhood cancer. METHODS AND MATERIALS: Among 4,568 2-year survivors of a childhood solid cancer diagnosed before 17 years of age at eight French and British centers, and among 25,120 patients diagnosed as having a malignant neoplasm before the age of 20 years, whose data were extracted from the Nordic Cancer Registries, we matched 58 case patients (41 men and 17 women) of SMDO and 167 controls, in their respective cohort, for sex, age at first cancer, calendar year of occurrence of the first cancer, and duration of follow-up. The radiation dose received at the site of each second malignancy and at the corresponding site of its matched control was estimated. RESULTS: The risk of developing a SMDO was 9.7-fold higher in relation to the general populations in France and the United Kingdom. In the case-control study, a strong dose-response relationship was estimated, compared with that in survivors who had not received radiotherapy; the odds ratio was 5.2 (95% CI, 1.7-16.0) for local radiation doses between 10 and 29 Gy and 9.6 (95% CI, 2.6-35.2) for doses equal to or greater than 30 Gy. Chemotherapy was also found to increase the risk of developing SMDO. CONCLUSIONS: This study confirms that childhood cancer treatments strongly increase the risk of SMDO, which occur only after a very long latency period.

Late and very late mortality in 5-year survivors of childhood cancer: changing pattern over four decades--experience from the Nordic countries.

Long-term survivors of childhood cancer suffer from a higher mortality than the general population. Here we evaluate late and very late mortality, and patterns of causes of death, in 5-year survivors after childhood and adolescent cancer in cases diagnosed during four decades in the five Nordic countries. The study is population-based and uses data of the nationwide cancer registries and the cause of death registers. There were in all 37,515 incident cases, diagnosed with cancer before the age of 20 years, between 1960 and 1999. The 5-year survivor cohort used in the mortality analyses consisted of 21,984 patients who were followed up for vital status until December 31, 2005 (Norway, Sweden) or 2006 (Denmark, Finland, Iceland). At the latest follow-up, 2,324 patients were dead. The overall standardized mortality ratio was 8.3 and the absolute excess risk was 6.2 per 1,000 person-years. The pattern of causes of death varied markedly between different groups of primary cancer diagnosis, and was highly dependent on time passed since diagnosis. With shorter follow-up the mortality was mainly due to primary cancer, while with longer follow-up, mortality due to second cancer and noncancer causes became more prominent. Mortality between 5 and 10 years after diagnosis continued to decrease in patients treated during the most recent period of time, 1990-1999, compared to previous periods, while mortality after 10 years changed very little with time period. We conclude that improvement of definite survival demands not only reducing early but also late and very late mortality.

Effect of screening mammography on breast-cancer mortality in Norway.

BACKGROUND: A challenge in quantifying the effect of screening mammography on breast-cancer mortality is to provide valid comparison groups. The use of historical control subjects does not take into account chronologic trends associated with advances in breast-cancer awareness and treatment. METHODS: The Norwegian breast-cancer screening program was started in 1996 and expanded geographically during the subsequent 9 years. Women between the ages of 50 and 69 years were offered screening mammography every 2 years. We compared the incidence-based rates of death from breast cancer in four groups: two groups of women who from 1996 through 2005 were living in counties with screening (screening group) or without screening (nonscreening group); and two historical-comparison groups that from 1986 through 1995 mirrored the current groups. RESULTS: We analyzed data from 40,075 women with breast cancer. The rate of death was reduced by 7.2 deaths per 100,000 person-years in the screening group as compared with the historical screening group (rate ratio, 0.72; 95% confidence interval [CI], 0.63 to 0.81) and by 4.8 deaths per 100,000 person-years in the nonscreening group as compared with the historical nonscreening group (rate ratio, 0.82; 95% CI, 0.71 to 0.93; P<0.001 for both comparisons), for a relative reduction in mortality of 10% in the screening group (P=0.13). Thus, the difference in the reduction in mortality between the current and historical groups that could be attributed to screening alone was 2.4 deaths per 100,000 person-years, or a third of the total reduction of 7.2 deaths. CONCLUSIONS: The availability of screening mammography was associated with a reduction in the rate of death from breast cancer, but the screening itself accounted for only about a third of the total reduction. (Funded by the Cancer Registry of Norway and the Research Council of Norway.)

Widespread but not localized neoplasia in inflammatory bowel disease worsens the prognosis of colorectal cancer.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC). Recently, new phenotypes of CRC in IBD have been suggested. Studies of the prognosis of CRC in IBD have shown conflicting results. The aim of the study was to analyze factors for prognosis in CRC-IBD, including the impact of the new phenotypes. METHODS: By using the nationwide, population-based Cancer Registry of Norway, we compared survival of a CRC-IBD cohort with CRC in the background population (all-CRC), adjusting for the topographical distribution of dysplasia at cancer diagnosis (widespread versus localized neoplasia in IBD) and other factors. We also analyzed prognostic factors within CRC-IBD. RESULTS: The mean age at CRC diagnosis was 43 years in widespread, 52 years in localized neoplasia IBD, and 70 years in all-CRC (P < 0.05). Adjusted for cofactors, prognosis of CRC-IBD was poorer compared to all-CRC (mortality rate ratio [MRR] 3.71, 95% confidence interval [CI]: 2.54-5.42, P < 0.001). Prognosis of widespread neoplasia IBD was poorer compared to all-CRC (MRR 4.27, 95% CI: 2.83-6.44, P < 0.001) and compared to localized neoplasia IBD (MRR 3.58, 95% CI: 0.87-14.72, P = 0.076). Survival was not significantly different between localized neoplasia IBD and all-CRC (P = 0.132). CONCLUSIONS: The results demonstrate lower age and poorer survival of CRC in IBD compared to CRC in the background population. The unfavorable effect of IBD on prognosis of CRC was pronounced in widespread neoplasia IBD. The diagnosis of this phenotype seems to be an important prognostic sign in patients with CRC in IBD.

Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries.

BACKGROUND: The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. METHODS: We obtained a cohort of 47,697 children and adolescents aged 0-19 years with cancer as defined by the country-wide cancer registries of Denmark, Finland, Iceland, Norway, and Sweden during 1943-2005. Cohort members were followed through age 79 years for subsequent primary cancers notified to the registries, and the age-specific risk pattern of the survivors was compared with that of the national populations using country and sex standardized incidence ratios (SIRs). We used a multiplicative Poisson regression model to estimate relative risk of cancer for attained age, with adjustment for calendar period and age at diagnosis of primary cancer. We also calculated excess absolute risk (EAR) attributable to status as childhood cancer survivor and determined the cumulative incidence of second primary cancer as a function of attained age for three subcohorts defined by period of treatment for childhood cancer. RESULTS: A total of 1180 asynchronous second primary cancers were observed in 1088 persons, yielding an overall SIR of 3.3 (95% confidence interval = 3.1 to 3.5). The relative risk was statistically significantly increased in all age groups, even for cohort members approaching 70 years of age. The EAR for second primary cancer among survivors increased gradually from one additional case per 1000 person-years of observation in early life to six additional cases per 1000 person-years in the age group 60-69 years. For children treated in the prechemotherapy era (1943-1959), the cumulative risk for a second primary cancer reached 18%, 34%, and 48% at ages 60, 70, and 80 years, respectively. The age-specific incidence rates were highest for cohort members treated in the era of intensive, multiple-agent chemotherapy (1975-2005). CONCLUSION: Survivors of childhood cancer have a persistent excess risk for a second primary cancer throughout their lives, accompanied by continuous changes in the risk of cancers at specific sites.

Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness.

AIM: To provide a comprehensive evaluation of the quality of the data collected on both solid and non-solid tumours at the Cancer Registry of Norway (CRN). METHODS: Established quantitative and semi-quantitative methods were used to assess comparability, completeness, accuracy and timeliness of data for the period 1953-2005, with special attention to the registration period 2001-2005. RESULTS: The CRN coding and classification system by and large follows international standards, with some further subdivisions of morphology groupings performed in-house. The overall completeness was estimated at 98.8% for the registration period 2001-2005. There remains a variable degree of under-reporting particularly for haematological malignancies (C90-95) and tumours of the central nervous system (C70-72). For the same period, 93.8% of the cases were morphologically verified (site-specific range: 60.0-99.8%). The under-reporting in 2005 due to timely publication is estimated at 2.2% overall, based on the number of cases received at the registry during the following year. CONCLUSION: This review suggests the routines in place at the CRN yields comparable data that can be considered reasonably accurate, close-to-complete and timely, thereby justifying our policy of the reporting of annual incidence one year after the year of diagnosis.

Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix.

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.

Relationship between clinical parameters and the colitis-colorectal cancer interval in a cohort of patients with colorectal cancer in inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC), but more knowledge is needed about the possible relationship between clinical parameters and the time to development of cancer in IBD. The aim of the study was to determine the variability of the colitis-CRC interval and to analyze the association with clinical variables in an attempt to gain information on predictive factors of time to cancer within a relatively large cohort of CRC patients. MATERIAL AND METHODS: Patients diagnosed with IBD prior to 1 May 2005 at three university hospitals in Oslo were matched against the CRC files at the Cancer Registry of Norway. Only histological re-confirmed IBD and adenocarcinoma of the colorectum were included. RESULTS: Sixty-one patients with CRC in ulcerative colitis and 6 in Crohn's disease, including 13 CRC in primary sclerosing cholangitis (PSC), covering a follow-up of 1625 patient years,were identified. The median time from diagnosis of IBD to CRC was 17 years. Seven of 58 patients (12%) developed CRC within 10 years from onset of IBD symptoms and 14/67 (21%) within 10 years after the diagnosis of IBD. The colitis-CRC interval decreased by a factor of 0.154 (p = 0.018) when age at onset of IBD increased by one year. Mean age at onset of IBD was 30 years in patients with Dukes' stage C or D compared with 20 years in Dukes' stage A or B patients (p = 0.017). The colitis-CRC interval decreased by a factor of 0.138 (p = 0.003) when the percentage of the colitis-CRC interval with active symptoms increased by 1%. Patients with PSC were significantly younger at onset of IBD symptoms (PSC: 19 years versus no PSC:29 years, p = 0.04), but the colitis-CRC interval was similar to IBD without PSC (17 years versus 20 years, p = 0.236). Mean duration of the colitis-CRC interval was not related to family history or drug consumption prior to CRC. CONCLUSIONS: In the present cohort, for whom the median time from diagnosis of IBD to CRC was 17 years, 21% of the cancers developed before 10 years of disease, which is before colonoscopic screening is usually recommended. High age at onset of IBD may be related to a more aggressive development of CRC in IBD and early inclusion in screening programs might be considered for this group of patients. Symptom activity but not the diagnosis of PSC, family history of CRC or IBD or drug treatment seems to have an effect on the colitis-CRC interval.

Two distinct groups of colorectal cancer in inflammatory bowel disease.

BACKGROUND: The histological variability in colitis-associated colorectal cancer (CRC in inflammatory bowel disease [IBD]) and the association to clinical factors is unknown. METHODS: In population-based material including 67 patients with CRC in IBD, histopathology of the cancers and tissue samples from different colorectal localizations were reevaluated, and relationships to clinical factors analyzed. RESULTS: Forty-three of 60 patients (75%) showed dysplasia in the colorectum apart from the cancer, while 17 (25%) had no dysplasia at cancer diagnosis. Mean age at onset of IBD was 22 years in patients with and 34 years in patients without dysplasia (P = 0.01). The mean duration of colitis-CRC interval was 21 years in patients with and 16 years in patients without dysplasia (P = 0.02). The latter group included all patients with a colitis-CRC interval <10 years. Active inflammation was more likely to occur in patients with dysplasia (odds ratio [OR] 4.2). The 2 groups were not discriminated by gender, family history of CRC or IBD, diagnosis of PSC, medical treatment, active symptoms, or histological features like type of cancer and differentiation. In multiple logistic regression analysis the age at onset of IBD was the strongest predictive variable for dysplasia at cancer diagnosis (P = 0.025). CONCLUSIONS: Widespread neoplasia occurs in the majority of cases with CRC in IBD and is associated with early onset of IBD. Localized neoplasia occurs in about a quarter of the patients and shows an association with late-onset IBD. The 2 groups probably represent different pathogenetic entities of neoplasia in IBD. This might have consequences for surveillance strategies.

[Is registration of multiple myeloma in the Norwegian Cancer Registry good enough?]. / Er registreringen av myelomatose i Kreftregisteret god nok?

BACKGROUND: The last 15 years several studies have evaluated the quality of the Norwegian Cancer Registry. A pilot study from 1981 showed that the registration quality of non-solid tumours was significantly weaker than that for solid tumours. We wanted to study the registration quality of multiple myeloma in the Norwegian Cancer Registry during the 1990s. MATERIAL AND METHODS: In the 1990s, the majority of younger Norwegian patients with multiple myeloma diagnosed in certain time periods were included in clinical studies. 348 patients were included, whereas 440 patients were registered in the Norwegian Cancer Registry during the same time period. We compared the patients included in studies with those in the Registry. When a discrepancy was found the diagnostic data and the registration process were looked into. RESULTS: Registration of multiple myeloma in the Norwegian Cancer Registry in the 1990s had a completeness of 92.7 % and an accuracy of 92.5 %. INTERPRETATION: The quality of multiple myeloma registration in the Norwegian Cancer Registry has improved from the 1970s (the data had a completeness of 77-82%) to the 1990s, but is still not as good as the registration of solid tumours. Increased awareness of this problem at pathological and haematological departments can probably improve the quality of registration further.

Risk of leukemia among survivors of testicular cancer: a population-based study of 42,722 patients.

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.

Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas.

The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population-based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n = 738 alive per April 2004) were invited to participate. Three-hundred-and-ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty-one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1alpha and the 5' part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A mutations was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study.

Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk.

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.

Time trends in the incidence of acute lymphoblastic leukemia among children 1976-2002: a population-based Nordic study.

We studied the incidence of childhood acute lymphoblastic leukemia in Denmark, Finland, Norway, and Sweden during 1976-2002, on the basis of data from national cancer registries. The incidence of acute lymphoblastic leukemia increased with the calendar period until 1983, and with the birth cohort until 1980, but incidence has been stable thereafter.

Long-term risk of cancer in membranous nephropathy patients.

BACKGROUND: There is a well-known association between membranous nephropathy (MN) and cancer, and patients with MN usually are examined for cancer at the time of diagnosis. The long-term risk of cancer after MN is not well studied. STUDY DESIGN: Cohort study with record linkage between the Norwegian Kidney Biopsy Registry and Norwegian Cancer Registry. SETTING & PARTICIPANTS: 161 patients with MN from 1988 to 2003. PREDICTOR: Patients with MN compared with the age- and sex-adjusted general Norwegian population. OUTCOMES: Cancer diagnosis reported through 2003. RESULTS: Mean duration of follow-up was 6.2 years (range, 0.1 to 15 years). 33 patients developed cancer; including 24 patients with cancer after the diagnosis of MN. Median time from diagnosis of MN to diagnosis of cancer was 60 months (range, 0 to 157 months). Mean annual incidence ratio of cancer was 2.4/100 person-years (2.1/100 person-years in the 0- to 5-year period and 2.8/100 person-years for the 5 to 15 years after kidney biopsy). During the 0 to 15 years after the diagnosis of MN, the expected number of cancers was 10.7, resulting in a standardized incidence ratio of cancer of 2.25 (95% confidence interval, 1.44 to 3.35). In the 5 to 15 years after diagnosis, standardized incidence ratio was 2.30 (95% confidence interval, 1.19 to 4.02). Patients with MN who developed cancer were older (65 versus 52 years; P < 0.001). Patients with cancer and MN had a greater mortality rate than patients without cancer (67% versus 26%; P < 0.001). LIMITATIONS: Follow-up treatment after MN with cytotoxic and immunosuppressive medications is not known. CONCLUSIONS: An increased risk of developing cancer is observed after the diagnosis of MN, which persists for many years.

Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma.

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.