Type Of First Cancer Research Articles

Subsequent cancers within 5years from initial diagnosis of childhood cancer. Patterns and risks in the population of Great Britain.

Patterns and risks of subsequent primary tumours (SPTs) among long-term survivors of childhood cancer have been extensively described, but much less is known about early SPTs (ESPTs) occurring within 5 years after initial diagnosis. We carried out a population-based study of ESPTs following childhood cancer throughout Britain, using the National Registry of Childhood Tumours. The full study series comprised all ESPTs occurring among 56,620 children whose initial cancer diagnosis was in the period 1971-2010. Frequencies of ESPT were calculated for the entire cohort. For analyses of risk, follow-up began 92days after initial diagnosis. ESPT developed in 0.4% of children overall, 0.52% of those initially diagnosed at age less than 1year and 0.38% of those diagnosed at age 1-14years. Standardised incidence ratio (SIR) was 7.7 (95% confidence interval [CI]: 6.7-8.9), overall 9.5 (95% CI: 7.1-12.5) for children initially diagnosed in 1981-1990 and 6.5-7.5 for those from earlier and later decades. SIR by type of first cancer ranged from 4.4 (95% CI: 1.8-9.1) for Wilms tumour to 13.1 (95% CI: 7.7-21.0) for non-Hodgkin lymphoma. SIR by type of ESPT ranged from 2.0 (95% CI: 1.0-3.4) for acute lymphoblastic leukaemia to 66.6 (95% CI: 52.3-83.6) for acute myeloid leukaemia. Predisposition syndromes were known to be implicated in 21% of children with ESPT and suspected in another 5%. This study provides an overview of the patterns and risks of ESPTs in a large population where many children received therapy that is still in widespread use. Further research will be needed to monitor and understand changes in risk as childhood cancer treatment continues to evolve.

P02-16 Implementation of a program based on adapted physical activity and recommendations for second cancers prevention for adolescents and young adults with cancer: PREVAPAJA study

Background/ObjectivesAbout 1,000,000 new cases of cancer in Adolescent and Young Adults (AYAs) are diagnosed annually worldwide. . While their long term survival is about 80%, they are six times more likely to develop a second primary cancer (SPC) compared to their peers. This risk is multifactorial and depends on the type of first cancer, treatment received and prevalence of risk factors. PREVAPAJA aimed to implement a clinical program based on physical activity (PA) and cancer prevention recommendations for AYAs with cancer at Centre Léon Bérard-AYAs Department.MethodsThe study was conducted at Leon Berard Comprehensive Cancer Centre among patients aged 15-25 years. AYAs attended PA sessions during the active treatment period and were individually informed on SPC risk prevention. PA, sedentary, anthropometrics, quality of life and fatigue were assessed at baseline (T1) and at the end of treatment (T2). PA level and intention of changes in health behaviors were assessed by phone 1 year after T1.Results68 AYAs (median age=19 years) were enrolled in 2016-2017). The results showed an improvement in PA level during and at distance of the intervention, with also a reduction of sitting time. Fatigue decreased between T1 and T2 (p>0.003) and overall quality of life improved significantly between T1 and T2 (p>0.001).ConclusionsThis study showed the feasibility of implementing a clinical program based on PA intervention and cancer prevention recommendations for AYAs with cancer. It responded to AYAs' needs for support and discussions regarding PA recommendations and ways to prevent SPC. Beneficial outcomes of this program should encourage to systematically proposing PA intervention in combination with information exchanges with AYAs with cancer.

The relative risk of second primary cancers in Switzerland: a population-based retrospective cohort study

BackgroundMore people than ever before are currently living with a diagnosis of cancer and the number of people concerned is likely to continue to rise. Cancer survivors are at risk of developing a second primary cancer (SPC). This study aims to investigate the risk of SPC in Switzerland.MethodsThe study cohort included all patients with a first primary cancer recorded in 9 Swiss population-based cancer registries 1981–2009 who had a minimum survival of 6 months, and a potential follow-up until the end of 2014. We calculated standardized incidence ratios (SIR) to estimate relative risks (RR) of SPC in cancer survivors compared with the cancer risk of the general population. SIR were stratified by type of first cancer, sex, age and period of first diagnosis, survival period and site of SPC.ResultsA total of 33,793 SPC were observed in 310,113 cancer patients. Both male (SIR 1.18, 95%CI 1.16–1.19) and female (SIR 1.20, 95%CI 1.18–1.22) cancer survivors had an elevated risk of developing a SPC. Risk estimates varied substantially according to type of first cancer and were highest in patients initially diagnosed with cancer of the oral cavity and pharynx, Hodgkin lymphoma, laryngeal, oesophageal, or lung cancer. Age-stratified analyses revealed a tendency towards higher RR in patients first diagnosed at younger ages. Stratified by survival period, risk estimates showed a rising trend with increasing time from the initial diagnosis. We observed strong associations between particular types of first and SPC, i.e. cancer types sharing common risk factors such as smoking or alcohol consumption (e.g. repeated cancer of the oral cavity and pharynx (SIRmales 20.12, 95%CI 17.91–22.33; SIRfemales 37.87, 95%CI 30.27–45.48).ConclusionSwiss cancer survivors have an increased risk of developing a SPC compared to the general population, particularly patients first diagnosed before age 50 and those surviving more than 10 years. Cancer patients should remain under continued surveillance not only for recurrent cancers but also for new cancers. Some first and SPCs share lifestyle associated risk factors making it important to promote healthier lifestyles in both the general population and cancer survivors.

Risk of a second cancer in Canadians diagnosed with a first cancer in childhood or adolescence

BackgroundSecond cancers are an adverse outcome experienced by childhood cancer survivors. We quantify the risk and correlates of a second cancer in Canadians diagnosed with a first cancer prior to age 20 years. MethodsUsing death-linked Canadian Cancer Registry data, a population-based cohort diagnosed with a first cancer between 1992 and 2014, prior to age 20 years, were followed for occurrence of a second cancer to the end of 2014. We estimate standardized incidence ratios (SIR), absolute excess risks (AER), cumulative probabilities, and hazard ratios (HR). Findings22,635 people contributed 204,309•1 person-years of follow-up. Overall risk of a second cancer was 6•5 (95% CI: 5•8–7•1) times greater than expected resulting in an AER of 16•5 (14•4–18•5) cancers per 10,000 person-years and a 4•8% (3•8%–6•0%) cumulative probability of a second cancer at 22•6 years of follow-up. SIRs decreased with increasing age at diagnosis and time since diagnosis; were larger in more recent calendar periods of diagnosis; and varied by type of first cancer. Large SIRs in the first year after diagnosis and in those diagnosed in 2010–2014 were partly associated with changing registry practices. For the whole cohort, factors associated with the hazard of a second cancer included: being female vs. male [HR = 1•439 (95%CI: 1•179–1•760)]; being diagnosed in 2005–2014 vs. 1992–2004 [2•084 (1•598–2•719)]; having synchronous first cancers [4•814 (2•042–9•509)]; and being diagnosed with certain types of cancer. Factors varied, however, by type of first cancer. InterpretationRisks of a second cancer are not equally distributed and can be impacted by changes in registry practice and the methods used to define second cancers.

Implementation of a program based on adapted physical activity and recommendations for second cancers prevention for adolescents and young adults with cancer

Introduction Around 700 adolescents and young adults aged from 15 to 25 years old (AYAs) are diagnosed each year with cancer in the French Auvergne-Rhone-Alpes region. While long-term survival is about 80%, they are six times more likely to develop a second primary cancer (SPC) compared to their peers. This risk is multifactorial and depends on the type of first cancer, the treatment received and the prevalence of risk factors (smoking, overweight, sedentary lifestyle, environmental exposures…). Objectives This project aims to implement a clinical program based on adapted physical activity and cancer prevention recommendations for AYAs with cancer. Methods Patients attended adapted physical activity sessions during the active treatment period (4–6 months). They were given questionnaires about physical activity (IPAQ) and quality of life (QLQ-C30) at baseline (T1) and at the end of treatment (T2). They participated to individual information meetings on SPC risk prevention (T3), and responded to a final QoL questionnaire by phone 1 year after T1 (T4). Results So far, 63 AYAs (39 boys, 24 girls; median age = 19 [15–25]) have been included and completed T1 and T2. On average, they participated in 4 supervised sessions at the hospital and 16 unsupervised sessions at home during 3.5 months [2–6]. Preliminary results indicate an increase in the level of physical activity between T1 360 MET-min/week [0–2373] and T2 1059 MET-min/week [0–9690] and an increase in the six-minute walk test from T1 391 m [205–714] to T2 464 m [305–690]. Sedentary time seems to decrease on average from 53.3 h/week [10–100] at T1 to 37.5 h/week [7–73] at T2. Currently, 37 AYAs have completed the T3 assessment and were highly satisfied with the program. Perspectives This study responds to AYAs’ needs for support and information regarding physical activity and SPC prevention. To improve the quality of the program and its implementation, a gym room will be built at the hospital, and a therapeutic education program dedicated to AYAs will be developed.

The characteristics of breast cancer patients with metachronous primary malignancies

Introduction. The risk of developing subsequent primary cancers varies from 1% to 18% and it depends on the type of first cancer and treatment methods applied. Considering the time of occurrence, multiple primary cancers generally fall into two categories: synchronous and metachronous. In breast cancer patients, 10.5% developed multiple primary cancers, from which 23.8% had synchronous, 79% had metachronous and the remaining 2.8% had both synchronous and metachronous malignancies. In patients with breast cancer, elevated risk is observed especially in the development of contralateral breast cancer, endometrial cancer, esophageal cancer, ovarian cancer and thyroid cancer. Aim. This paper presented the characteristics of breast cancer patients with metachronous primary malignancies in relation to the type of metachronous primaries (breast versus non-breast) and to analyse the impact of the type of metachronous cancers on survival rate. Material and methods. Among patients treated for breast cancer between 1963 and 2010, 354 patients (2.1%) developed metachronous primary malignancies and these made up 13.8% of all patients with multiple primary cancers. The mean age at diagnosis of the first breast cancer was 53 ± 11.5 years; positive family cancer history was noted in 127 patients (35.9%). Metachronous malignancies are defined as primaries following the diagnosis of breast cancer in a time interval greater than or equal to than 6 months. In our group, the mean time interval between the diagnosis of breast cancer and the appearance of metachronous malignancies was 100.9 ± 74.9 months (range: 6–543 months, median: 83 months). For comparison of the two groups (patients with second breast vs non-breast cancer) we used the Pearson’s Chi-square test for independence (for categorized variables) and variance analysis with Student’s t-test (for continuous variables). The survival rate was evaluated with the Kaplan-Meier method, and the log rank test was applied to assess the influ­ence of some factors on the evaluated results. The significance level at α = 0.05 was adopted for all statistical analyses. Results. The probability of occurrence of new cancer averaged from 38.1% to 67.8% for 5 and 10 years after diagnosis of first breast cancer, respectively. In our group, 380 cases of metachronous carcinomas were noted in 354 analysed patients. The most frequent metachronous malignancy was breast cancer (194 cases — 54.8%), which occurred as second (192 cases) or third (2 cases) cancer. Patients with contralateral breast cancer in comparison to other types of metachronous malignancies were significantly (p < 0.05): younger (under 50 years: 56.2% vs 34.4%), premenopausal (69.6% vs 48.8%), had a lobular type of first breast cancer (6.7% vs 1.3%), and rarely received tamoxifen (25.3% vs 48.2%). The type of me­tachronous cancers significantly influenced survival rate: 10-year overall survival rates were 80.1% vs 67.8%, (p = 0.0271). Conclusions. The risk of occurrence of second malignancies in breast cancer survivors makes early detection of metachronous malignancies obligatory because it is an important factor which influences the quality of life in breast cancer survivors.

Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation.

Risks of acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) are known to increase after cancer treatments. Their rise-and-fall dynamics and their associations with radiation have, however, not been fully characterized. To improve risk definition we developed SEERaBomb R software for Surveillance, Epidemiology and End Results second cancer analyses. Resulting high-resolution relative risk (RR) time courses were compared, where possible, to results of A-bomb survivor analyses. We found: (1) persons with prostate cancer receiving radiation therapy have increased RR of AML and MDS that peak in 1.5-2.5 years; (2) persons with non-Hodgkin lymphoma (NHL), lung and breast first cancers have the highest RR for AML and MDS over the next 1-12 years. These increased RR are radiation specific for lung and breast cancer but not for NHL; (3) AML latencies were brief compared to those of A-bomb survivors; and (4) there was a marked excess risk of acute promyelocytic leukemia in persons receiving radiation therapy. Knowing the type of first cancer, if it was treated with radiation, the interval from first cancer diagnosis to developing AML or MDS, and the type of AML, can improve estimates of whether AML or MDS cases developing in this setting are due to background versus other processes.

Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study

Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose-response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8-31.5). At thyroid radiation doses >20 Gy, a downturn in the dose-response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.

New malignancies following childhood cancer in the United States, 1973–2002

The objectives of our study were to quantify risks for developing new malignancies among childhood cancer survivors, identify links between particular types of first and subsequent cancer, and evaluate the possible role of treatment. A cohort of 25,965 2-month survivors of childhood cancer diagnosed in the U.S. during 1973-2002 was identified and followed through SEER cancer registries. Observed-to-expected ratios (O/E) were calculated, and Poisson regression was used to compare risks among treatment groups. Childhood cancer survivors were at nearly 6-fold risk of developing a new cancer relative to the general population (O/E = 5.9, 95% CI: 5.4-6.5). Most common were subsequent primary cancers of the female breast, central nervous system, bone, thyroid gland and soft tissue, as well as cutaneous melanoma and acute non-lymphocytic leukemia (ANLL). The greatest risks of subsequent cancers occurred among patients diagnosed previously with Hodgkin lymphoma (HL), Ewing sarcoma, primitive neuroectodermal tumor, or retinoblastoma. Risk of subsequent solid cancers was higher among persons whose initial treatment for childhood cancer included radiotherapy, whereas the excess of subsequent ANLL was strongly related to chemotherapy. The O/E for subsequent ANLL increased with increasing calendar year of initial cancer diagnosis among survivors of cancers other than HL, most likely due to increasing use of leukemogenic drugs for solid cancers and non-Hodgkin lymphoma. Childhood cancer survivors are at markedly increased risk of developing a variety of new cancers relative to the general population, but the magnitude of excess risk and specific types of second cancer vary widely by type of first cancer.

Concomitant chemo‐radiotherapy and local dose of radiation as risk factors for second malignant neoplasms after solid cancer in childhood: A case–control study

Radiotherapy and chemotherapy are associated with an increased risk of a second malignant neoplasm (SMN) after a cancer during childhood. This study specified the dose-effect relationship between radiotherapy, chemotherapy and the risk of a SMN, and investigated the effect of chemo-radiotherapy on the risk of SMN. A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred and fifty three cases with a SMN and 442 controls were matched according to sex, age at first cancer, calendar year, type of first cancer and follow-up. The local radiation dose was estimated at the site of the SMN, for each case and at the same site, for the matched controls. The local dose of radiation significantly increased the risk of a SMN. The best model was linear with an excess relative risk per Gray equal to 0.13 (95% CI, 0.06; 0.26). Any chemotherapy significantly increased the risk of a SMN, odd ratio(adjusted) (OR(adjusted)) = 2.4 (95% confidence interval (95% CI), 1.4-4.1), but no dose-effect relationship was observed between any drug category and the risk of a SMN. Patients who had received concomitant chemo-radiotherapy were significantly more at risk of developing a SMN than patients who had been treated with sequential chemo-radiotherapy, even after adjustment for the local dose of radiation and the 6 most frequently administered drugs, OR(adjusted) = 2.3 (95%CI, 1.1-4.8). Radiation was found to be the foremost treatment-related risk factor for the occurrence of a SMN. Compared to sequential treatment, concomitant chemo-radiotherapy may lead to a higher risk of a SMN.

Malignant Breast Tumors After Radiotherapy for a First Cancer During Childhood

To assess the specific role of treatment and type of first cancer (FC) in the risk of long-term subsequent breast cancer (BC) among childhood cancer survivors. In a cohort of 1,814 3-year female survivors treated between 1946 and 1986 in eight French and English centers, data on chemotherapy and radiotherapy were collected. Individual estimation of radiation dose to each breast was performed for the 1,258 patients treated by external radiotherapy; mean dose to breast was 5.06 Gy (range, 0.0 to 88.0 Gy) delivered in 20 fractions (mean). Mean follow-up was 16 years; 16 patients developed a clinical BC, 13 after radiotherapy. The cumulative incidence of BC was 2.8% (95% CI, 1.0% to 4.5%) 30 years after the FC and 5.1% (95% CI, 2.1% to 8.2%) at the age of 40 years. The annual excess incidence increased as age increased, whereas the standardized incidence ratio decreased. On average, each Gray unit received by any breast increased the excess relative risk of BC by 0.13 (< 0.0 to 0.75). After stratification on castration and attained age, and adjusting for radiation dose, FC type, and chemotherapy, a higher risk of a subsequent BC was associated with Hodgkin's disease (relative risk, 7.0; 95% CI, 1.4 to 30.9). The reported high risk of BC after childhood Hodgkin's disease treatment seems to be due not only to a higher radiation dose to the breasts, but also to a specific susceptibility.

Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood.

Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3-year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case-control study, we matched 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow-up. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95%CI: 34-89)). The SIR was 113 (95% CI: 62-185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95%CI: 2-125) after chemotherapy alone (1 STS) and 19 (95%CI: 3-60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case-control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of Procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and Procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended.

Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood.

Osteosarcoma is the most frequent second primary cancer occurring during the first 20 years following treatment for a solid cancer in childhood. Using a cohort study of children treated for a solid cancer, we investigated the incidence and etiology of osteosarcoma as a second malignant neoplasm after childhood cancer in a cohort and a case-control study. We analysed the relationship between the local dose of radiation and the risk of osteosarcoma, taking into account chemotherapy received. A cohort study of 4,400 3-year survivors of a first solid cancer during childhood diagnosed in France or the United Kingdom, between 1942 and 1986, revealed 32 subsequent osteosarcomas. In a nested case-control study, we matched 32 cases and 160 controls for sex, type of first cancer, age at first cancer and the duration of follow-up. Parameters studied were the incidence of osteosarcoma, the cumulative local dose of irradiation and the cumulative dose of chemotherapy received by cases and controls. The risk of a osteosarcoma was found to be a linear function of the local dose of radiation (excess relative risk per gray=1.8), and was found to increase with the number of moles of electrophilic agents per square meter but not with other drugs. No interaction was noted between radiotherapy and chemotherapy. Bilateral retinoblastoma, Ewing's sarcoma and soft tissue sarcoma were found to render patients susceptible to a higher risk of developing an osteosarcoma as a second malignant neoplasm. We recommend long-term surveillance of patients who were treated during childhood for bilateral retinoblastoma, Ewing's sarcoma, soft tissue sarcoma, as well as other first cancer treated with radiotherapy plus high doses of chemotherapy, without focusing exclusively on the radiation field.

Radiotherapy, Alkylating Agents, and Risk of Bone Cancer After Childhood Cancer

Individuals who had cancer in childhood are at higher risk of developing bone cancer than any other type of second primary cancer. Using the population-based National Registry of Childhood Tumours in Britain, we investigated the incidence and etiology of second primary bone cancer after childhood cancer in a cohort study and in a case-control study. A cohort study of 13,175 3-year survivors of childhood cancer diagnosed in Britain between 1940 and 1983 revealed 55 subsequent bone cancers. A largely nested case-control study comprised 59 case subjects developing second primary bone cancer, and 220 control subjects were selected and matched for sex, type of first cancer, age at first cancer, and interval between diagnosis of first cancer and subsequent bone cancer. Outcome measures were the incidence of bone cancer after childhood cancer, the cumulative dose of radiation received at the site of the second cancer in the case subject and at the corresponding anatomic site in the matched control subjects, and the cumulative dose of alkylating agents and vinca alkaloids received by case and control subjects. The percentage of 3-year survivors developing bone cancer within 20 years did not exceed 0.9%, except following heritable retinoblastoma (7.2%), Ewing's sarcoma (5.4%), and other malignant bone tumors (2.4%). The risk of bone cancer increased substantially with increased cumulative dose of radiation to the bone (P< .001, linear trend). At the highest levels of exposure, however, the risk appeared to decline somewhat (P=.065, nonlinearity). Exposure to less than 10 Gy was at worst, associated with only a small increased relative risk (RR) of bone cancer (RR= 0.7; 95% confidence interval = 0.2-2.2). The risk of bone cancer increased linearly (P= .04, one-tailed test) with increased cumulative dose of alkylating agents. This population-based study provides grounds for reassurance of the majority of survivors in that their risk of developing bone cancer within 20 years of 3-year survival did not exceed 0.9%. The higher risks found for bone cancer following the other specific rare types of childhood cancer provide a rational basis for surveillance. The RRs reported for bone cancer after specified levels of exposure to radiation should help in making decisions concerning future treatment protocols.

Second malignant neoplasms after cancer in childhood or adolescence. Nordic Society of Paediatric Haematology and Oncology Association of the Nordic Cancer Registries.

To assess the relative risk of developing a second malignant neoplasm in people with a diagnosis of cancer in childhood and adolescence. Register based follow up study. Populations of Nordic countries. 30,880 people under the age of 20 with a first malignant neoplasm diagnosed during the period 1943-87. Relative and attributable risks of second malignant neoplasms by type of first cancer, age at first diagnosis, calendar period, sex, and country. Expected figures were based on the appropriate national incidence rates for cancer. 247 cases of second malignant neoplasms were observed in 238 patients, yielding a relative risk for cancer of 3.6 (95% confidence interval 3.1 to 4.1). The risk changed significantly from 2.6 in people first diagnosed during the 1940s and 1950s to 6.9 among cohort members included in the late 1970s and 1980s. Increases were observed for most types of cancer. Highest levels of the relative risk were seen during the 10 years immediately after first malignant diagnosis. The incidence of second malignant neoplasms attributable to the first cancer and associated treatments, however, showed a consistent rise throughout the 45 years of follow up. The estimated risks for a second malignant neoplasm were significantly lower than those found in most large hospital based studies but compatible with the results from a similar population based study in the United Kingdom. Extent of risk and cancer pattern were similar among the Nordic countries and are believed to be representative for a large part of the European population.

Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. Cohort study and a case-control study. Britain and population based National Register of Childhood Tumours. Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer.

Role of radiotherapy and chemotherapy in the risk of second malignant neoplasms after cancer in childhood.

Of a cohort of 634 children treated from 1942 to 1969 at the Gustave Roussy Institute for a first cancer and alive 5 years after treatment, 32 later developed second malignant neoplasms (SMN). A case-control study was performed to determine the relationship between the dose of radiotherapy received on a given anatomical site for the treatment of a first cancer, and the risk of SMN development at the same anatomical site. Another aim of the study was to analyse the effects of the association of radiotherapy with chemotherapy on the risk of SMN. The 32 cases of second malignant neoplasms were individually matched with one to nine patients of the cohort (a total of 162) who did not develop a SMN after a first cancer, matching on age, sex, type of first cancer and follow-up duration. The doses of radiotherapy delivered for the treatment of the first cancer were retrospectively estimated at the 26 anatomical sites of SMN. When the SMN was a leukaemia, the mean active bone-marrow dose was estimated as a weighted mean of the doses received by 20 bone sites. As compared to anatomical sites in children who had not received radiotherapy, the sites which had received 50 Gy or more had a relative risk of SMN of 5.8 (P less than 0.05). When taking into account the dose received at the site of the SMN, neither the number of fractions nor the type of radiations were related to the risk of SMN. Children who had received chemotherapy had a relative risk of SMN of 2.7 (95% CI: 1.2-6.4), adjusted for the dose of radiotherapy, as compared to those who had not. The relative risk of SMN did not vary with the dose nor the duration of the chemotherapy. Dactinomycin was found to increase the relative risk of second soft tissue and bone sarcomas. Cyclophosphamide was found to be less carcinogenic than the other alkylants. The relative risk of SMN was equal to 2.0 (n.s.) after radiotherapy of more than 25 Gy, to 4.4 (n.s.) after chemotherapy, and to 21.4 (P less than 0.01) after the combination of these two treatments modalities, as compared to patients treated by surgery alone. This study suggests that the oncogenic effect of radiations might be increased by chemotherapy, and that the combination of the two treatment modalities might be one of the major factors responsible for overall risk of SMN.