Chronic fatigue in childhood cancer survivors is associated with lifestyle and psychosocial factors; a DCCSS LATER study.

BACKGROUND: The purpose of this study was to determine factors associated with chronic fatigue (CF) in childhood cancer survivors (CCS). PATIENTS AND METHODS: Participants were included from the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort, a nationwide cohort of CCS (≥5 years after diagnosis) and siblings as controls. Fatigue severity was assessed with the 'fatigue severity subscale' of the Checklist Individual Strength ('CIS-fatigue'). CF was defined as scoring ≥35 on the 'CIS-fatigue' and having fatigue symptoms for ≥6 months. Twenty-four parameters were assessed, categorized into assumed fatigue triggering, maintaining and moderating factors. Multivariable logistic regression analyses were carried out to investigate the association of these factors with CF. RESULTS: A total of 1927 CCS participated in the study (40.7% of invited cohort), of whom 23.6% reported CF (compared with 15.6% in sibling controls, P < 0.001). The following factors were associated with CF: obesity [versus healthy weight, odds ratio (OR) 1.93; 95% confidence interval (CI) 1.30-2.87], moderate physical inactivity (versus physical active, OR 2.36; 95% CI 1.67-3.34), poor sleep (yes versus no, OR 2.03; 95% CI 1.54-2.68), (sub)clinical anxiety (yes versus no, OR 1.55; 95% CI 1.10-2.19), (sub)clinical depression (yes versus no, OR 2.07; 95% CI 1.20-3.59), pain (continuous, OR 1.49; 95% CI 1.33-1.66), self-esteem (continuous, OR 0.95; 95% CI 0.92-0.98), helplessness (continuous, OR 1.13; 95% CI 1.08-1.19), social functioning (continuous, OR 0.98; 95% CI 0.97-0.99) and female sex (versus male sex, OR 1.79; 95% CI 1.36-2.37). CONCLUSION: CF is a prevalent symptom in CCS that is associated with several assumed maintaining factors, with lifestyle and psychosocial factors being the most prominent. These are modifiable factors and may therefore be beneficial to prevent or reduce CF in CCS.

Health-related quality of life in Dutch adult survivors of childhood cancer: A nation-wide cohort study.

AIM: To investigate the health-related quality of life (HRQOL) of Dutch adult childhood cancer survivors (CCS) and to identify risk factors of impaired HRQOL. METHODS: Adult CCS (age >18, diagnosed <18, ≥5 years since diagnosis) from the Dutch LATER registry completed the Medical Outcome Study Short Form 36 (SF-36) to measure HRQOL and provided sociodemographic characteristics. Age-adjusted mean SF-36 scale scores of CCS were compared to the Dutch general population for men and women separately using t-tests, with effect size d. Multivariate logistic regression models were built to identify sociodemographic and cancer-related risk factors for impaired physical and mental HRQOL. RESULTS: Both male and female CCS (N = 2301, mean age = 35.4 years, 49.6% female) reported significantly (p ≤ .005) worse HRQOL than the general population on almost all scales of the SF-36 (-.11 ≤ d ≤ -.56). Largest differences were found on vitality and general health perceptions. Significant risk factors (p ≤ .05) for impaired physical HRQOL were female sex, older age at diagnosis, not having a partner, low educational attainment, disease recurrence and exposure to radiotherapy, specifically to lower extremity radiation. Odds ratios (ORs) ranged from 1.6 to 3.7. Significant risk factors for impaired mental HRQOL were age 26-35 years, male sex, not having a partner and low educational attainment. ORs ranged from 1.3 to 2.0. CONCLUSION: Adult CCS had worse HRQOL than the general population. CCS most at risk were those with low educational attainment and without a partner. Adult CCS could benefit from routine surveillance of their HRQOL. Special attention for CCS' vitality and health perceptions and beliefs is warranted.

Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

Pregnancy, time to pregnancy and obstetric outcomes among female childhood cancer survivors: results of the DCOG LATER-VEVO study.

PURPOSE: To evaluate pregnancy rates, time to pregnancy (TTP) and obstetric outcomes in female childhood cancer survivors (CCSs) and to identify specific diagnosis- and treatment-related factors associated with these outcomes. METHODS: The study is part of the DCOG LATER-VEVO study, a nationwide multicenter cohort study evaluating fertility among long-term Dutch female CCSs. Data were collected by questionnaire. The current study included 1095 CCSs and 812 controls, consisting of sisters of CCSs and a random sample of women from the general population. RESULTS: Among the subgroup of women who ever had the desire to become pregnant, the chance of becoming pregnant was significantly lower for CCSs than controls (OR 0.5, 95%CI 0.4-0.8). Moreover, TTP was 1.1 times longer for CCSs compared to controls (p = 0.09) and was significantly longer in survivors of CNS and renal tumours. Overall, no differences were found between CCSs and controls regarding the probability of ever having had a miscarriage, still birth, or induced abortion. However, CCSs had a significantly increased risk of delivering preterm (OR 2.2, 95%CI 1.3-3.7) and delivering via caesarean section (OR 1.8, 95%CI 1.2-2.6). Treatment with lower abdominal/pelvic radiotherapy was strongly associated with several adverse obstetric outcomes. CONCLUSION: CCSs are less likely to have ever been pregnant. Among those who do become pregnant, certain subgroups of CCSs are at increased risk of longer TTP. Moreover, as pregnant CCSs, especially those treated with lower abdominal/pelvic radiotherapy, are more likely to develop various adverse obstetric outcomes, appropriate obstetric care is highly advocated.

Pediatric Normal Tissue Effects in the Clinic (PENTEC): An International Collaboration to Analyse Normal Tissue Radiation Dose-Volume Response Relationships for Paediatric Cancer Patients.

With advances in multimodality therapy, childhood cancer cure rates approach 80%. However, both radiotherapy and chemotherapy can cause debilitating or even fatal late adverse events that are critical to understand, mitigate or prevent. QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) identified radiation dose constraints for normal tissues in adults and pointed out the uncertainties in those constraints. The range of adverse events seen in children is different from that in adults, in part due to the vulnerability/characteristics of radiation damage to developing tissues, and in part due to the typical body sites affected by childhood cancer that lead to collateral irradiation of somewhat different normal tissues and organs compared with adults. Many childhood cancer survivors have a long life expectancy and may develop treatment-induced secondary cancers and severe organ/tissue injury 10, 20 or more years after treatment. Collaborative long-term observational studies and clinical research programmes for survivors of paediatric and adolescent cancer provide adverse event data for follow-up periods exceeding 40 years. Data analysis is challenging due to the interaction between therapeutic and developmental variables, the lack of radiation dose-volume data and the fact that most childhood malignancies are managed with combined modality therapy. PENTEC (Pediatric Normal Tissue Effects in the Clinic) is a volunteer research collaboration of more than 150 physicians, medical physicists, mathematical modellers and epidemiologists organised into 18 organ-specific working groups conducting a critical review and synthesis of quantitative data from existing studies aiming to: (1) establish quantitative, evidence-based dose/volume/risk guidelines to inform radiation treatment planning and, in turn, improve outcomes after radiation therapy for childhood cancers; (2) explore the most relevant risk factors for toxicity, including developmental status; (3) describe specific physics and dosimetric issues relevant to paediatric radiotherapy; and (4) propose dose-volume outcome reporting standards for publications on childhood cancer therapy outcomes. The impact of other critical modifiers of normal tissue radiation damage, including chemotherapy, surgery, stem cell transplantation and underlying genetic predispositions are also considered. The aims of the PENTEC reports are to provide clinicians with an analysis of the best available data to make informed decisions regarding radiation therapy normal organ dose constraints for planning childhood cancer treatment, and to define future research priorities.

Long-term effects of radioiodine treatment on salivary gland function in adult survivors of pediatric differentiated thyroid carcinoma.

Pediatric differentiated thyroid cancer (DTC) is a rare disease. Initial treatment of DTC consists of a (near) total thyroidectomy and radioactive iodine (131I) therapy. Previous studies in adults showed that 131I treatment may result in a reduced salivary gland function. Studies regarding salivary gland function in children treated for DTC are sparse. Our aim was to assess long-term effects of 131I treatment on salivary gland function in survivors of pediatric DTC. Methods: In a nationwide cross-sectional study, salivary gland function of patients treated for pediatric DTC between 1970 and 2013 (>5 years after diagnosis, ≥18 years old at time of evaluation) was studied. Salivary gland function was assessed by sialometry, sialochemistry and a xerostomia inventory. Salivary gland dysfunction was defined as unstimulated whole saliva flow ≤0.2mL/min and/or a stimulated whole saliva flow ≤0.7 mL/min. Results: Sixty-five patients (median age at evaluation 33 [IQR, 25-40] years, 86.2% female, median follow-up period 11 [IQR, 6-22] years) underwent 131I treatment. Median cumulative 131I activity was 5.88 [IQR, 2.92-12.95] GBq, 47.7% underwent multiple 131I administrations. Salivary gland dysfunction was present in 30 (47.6%) patients. Levels of amylase and total protein in saliva were reduced. Moderate to severe xerostomia was present in 22 (35.5%) patients. Stimulated salivary secretion was lower and severity of xerostomia complaints higher in patients treated with higher cumulative 131I activity. Conclusion: In survivors of pediatric DTC, clinically significant salivary gland dysfunction was found in 35.5% and was related to the cumulative 131I activity of the treatment.

Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve.

STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Endocrine disorders among long-term survivors of childhood head and neck rhabdomyosarcoma.

PURPOSE: Head and neck rhabdomyosarcoma (HNRMS) survivors are at increased risk of developing pituitary dysfunction as an adverse event of radiotherapy. Our aim was to investigate the frequency and risk factors for pituitary dysfunction in these survivors. Secondly, we aimed to compare the prevalence of pituitary dysfunction between survivors treated with external beam radiation therapy (EBRT) and survivors treated with the ablative surgery, moulage technique after loading brachytherapy, and surgical reconstruction (AMORE) procedure. METHODS: Eighty HNRMS survivors treated in London (EBRT based) and Amsterdam (AMORE based: AMORE if feasible, otherwise EBRT) in the period 1990-2010 and alive ≥ 2 years post-treatment were evaluated. Survivors were evaluated in multidisciplinary late-effects clinics, with measurement of linear growth, determination of thyroid function, and growth hormone parameters. Additional data, such as baseline characteristics, anthropometrics, pubertal stage, and the results of additional laboratory investigations, were retrieved from patient charts. RESULTS: Pituitary dysfunction was diagnosed in 24 in 80 (30%) survivors, after a median follow-up time of 11 years. Median time to develop pituitary dysfunction after HNRMS diagnosis was 3.0 years. Risk factors were EBRT-based therapy (odds ratio [OR] 2.06; 95% confidence interval [CI] 1.79-2.46), parameningeal tumour site (OR 1.83; 95% CI 1.60-2.17) and embryonal RMS histology (OR 1.49; 95% CI 1.19-1.90). CONCLUSIONS: Radiotherapy used for the treatment of HNRMS confers a significant risk of the development of pituitary dysfunction. AMORE-based treatment in children with HNRMS resulted in less pituitary dysfunction than treatment with conventional EBRT. Our findings underscore the importance of routine early endocrine follow-up in this specific population.

Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review.

BACKGROUND: Treatment of differentiated thyroid carcinoma (DTC) often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. As DTC has favorable outcome and the incidence is increasing, concerns have been raised about the possible adverse effects of I-131 therapy. We systematically reviewed the literature to examine the risk of intermediate and long-term adverse effects of I-131 therapy in DTC patients. METHODS: Multiple electronic databases were searched up to November 2014 for English-language, controlled studies that reported on the risk of salivary gland dysfunction, lacrimal gland dysfunction, gonadal dysfunction, female reproductive outcomes or second primary malignancies (SPM) after I-131 exposure. The certainty of the evidence found was assessed using GRADE. RESULTS: In total, 37 articles met all inclusion criteria, no studies reporting on adverse effects after I-131 treatment focused solely on children. After exposure to I-131 for DTC, patients experienced significantly more frequently salivary gland dysfunction (prevalence range: 16-54%, moderate-level evidence), lacrimal gland dysfunction (prevalence: 11%, low-level evidence), transient male gonadal dysfunction (prevalence: 35-100%, high-level evidence), transient female gonadal dysfunction (prevalence: 28%, low-level evidence) and SPM (prevalence: 2.7-8.7%, moderate-level evidence) compared to unexposed patients. I-131 therapy seems to have no deleterious effects on female reproductive outcomes (very-low level evidence). The prevalence and severity of adverse effects were correlated to increasing cumulative I-131 activity. CONCLUSION: Treatment with I-131 for DTC may have significant adverse effects, which seem to be dose dependent. These adverse effects of treatment must be balanced when choosing for I-131 therapy in patients with DTC.

Is outcome of differentiated thyroid carcinoma influenced by tumor stage at diagnosis?

BACKGROUND: There is no international consensus on surveillance strategies for differentiated thyroid carcinoma (DTC) after radiotherapy for childhood cancer. Ultrasonography could allow for early detection of DTC, however, its value is yet unclear since the prognosis of DTC is excellent. We addressed the evidence for the question: 'is outcome of DTC influenced by tumor stage at diagnosis?'. METHODS: A multidisciplinary working group answered the sub-questions: 'is recurrence or mortality influenced by DTC stage at diagnosis? Does detection of DTC at an early stage contribute to a decline in adverse events of treatment?' The literature was systematically reviewed, and conclusions were drawn based on the level of evidence (A: high, B: moderate to low, C: very low). RESULTS: In children, level C evidence was found that detection of DTC at an early stage is associated with lower recurrence and mortality rates. No evidence was found that it influences morbidity rates. In adults, clear evidence was found that less advanced staged DTC is a favorable prognostic factor for recurrence (level B) and mortality (level A). Additionally, it was found that more extensive surgery increases the risk to develop transient hypoparathyroidism (level A) and that higher doses of radioiodine increases the risk to develop second primary malignancies (level B). CONCLUSION: Identification of DTC at an early stage is beneficial for children (very low level evidence) and adults (moderate to high level evidence), even considering that the overall outcome is excellent. These results are an important cornerstone for the development of guidelines for childhood cancer survivors at risk for DTC.

[No convincing evidence for a causal relationship between childhood nasopharyngeal radium irradiation and head-neck tumors or hormone-related disorders later in life; a retrospective cohort study]. / Geen overtuigend bewijs voor een causaal verband tussen nasofaryngeale radiumbestraling op de kinderleeftijd en latere hoofd-halstumoren en hormonale aandoeningen; een historisch cohortonderzoek.

OBJECTIVE: To study the risk of malignant and benign tumours and hormone-related disorders among patients treated with nasopharyngeal radium irradiation for hypertrophic adenoid or hearing loss caused by otitis media serosa. DESIGN: Retrospective cohort study. METHOD: The medical record registries of 9 hospitals were used to identify a radium-exposed group (n = 5358) and a control group of unexposed patients (n = 5265), who were treated by an otolaryngologist in the period 1945-1981. The vital status of the subjects was determined using municipal resident registries, and the cause of death of decedents was retrieved from Statistics Netherlands (1950-1997). The data was also coupled with the Netherlands Cancer Registry (1989-1996). For the subjects still alive in 1997, the prevalence of relevant disorders was determined using a self-administered questionnaire and disorders reported by the participants were medically verified. The risk of disease in the radium group was then compared with that of the control group. RESULTS: The average radiation doses were 2.75, 0.109 and 0.015 Gy for nasopharynx, pituitary, and thyroid, respectively. There was no statistically significantly elevated risk for malignancies of the head and neck area (radium-exposed group; n = 14; control group: n = 11 (relative risk (RR): 1.2; 95% CI: 0.6-2.8)). Four of the five thyroid carcinomas were found in the radium-exposed group (RR: 3.8; 0.5-76). Elevated risks were observed for breast cancer (RR: 1.6; 0.9-2.7) and non-Hodgkin's lymphoma (RR: 2.7; 1.0-8.7). There was an increased risk for skin basal cell carcinoma (BCC) of the head and neck (odds ratio (OR): 2.6; 1.0-6.7), but the risk of BCC of other body parts was lower (OR: 0.3; 0.1-1.3). There were no major differences between radium and control subjects with respect to benign head and neck tumours (OR: 1.0; 0.5-1.7) or hormonal disorders. Exposed men reported slightly more fertility disorders than men in the control group (OR: 1.4; 1.0-2.1), but there was no clear dose-response relationship. CONCLUSION: After a mean follow-up of 31 years, there was no strong evidence for an elevated risk of head and neck tumours or hormone-related disorders in adulthood among subjects who had been treated with nasopharyngeal radium irradiation during childhood.

Cancer mortality after nasopharyngeal radium irradiation in the Netherlands: a cohort study.

BACKGROUND: Nasopharyngeal radium irradiation (NRI) was used widely from 1940 through 1970 to treat otitis serosa in children and barotrauma in airmen and submariners. We assessed whether NRI-exposed individuals were at higher risk for cancer-related deaths than were nonexposed individuals. METHODS: We conducted a retrospective cohort study of all-cause and cancer-related mortality in 5358 NRI-exposed subjects and in 5265 frequency-matched nonexposed subjects, who as children were treated at nine ear, nose, and throat clinics in The Netherlands from 1945 through 1981. We recorded personal and medical data from original patient medical records and assessed vital status through follow-up at municipal population registries. Risk of mortality was evaluated by standardized mortality ratios (SMRs). All statistical tests were two-sided. RESULTS: The average radiation doses were 275, 10.9, 1.8, and 1.5 cGy for the nasopharynx, pituitary, brain, and thyroid, respectively. The median follow-up was 31.6 years. Three hundred two NRI-exposed subjects had died, with 269.2 deaths expected (SMR = 1.1; 95% confidence interval [CI] = 1.0 to 1.3); among nonexposed subjects, 315 died, with 283.5 deaths expected (SMR = 1.1; 95% CI = 0.99 to 1.2). Cancer-related deaths of 96 exposed subjects (SMR = 1.2; 95% CI = 0.95 to 1.4) and 87 nonexposed subjects (SMR = 1.0; 95% CI = 0.8 to 1.3) were documented. There were no excess deaths from cancers of the head and neck area among exposed subjects. However, there were excess deaths from cancers of lymphoproliferative and hematopoietic origin (SMR = 1.9; 95% CI = 1.1 to 3.0), mainly from non-Hodgkin's lymphoma (SMR = 2.6; 95% CI = 1.0 to 5.3). We found no evidence that breast cancer deaths were less than expected (SMR = 1.7; 95% CI = 0.9 to 2.8) in contrast to an earlier study. CONCLUSIONS: Our findings do not indicate an increased cancer mortality risk in a population exposed to NRI in childhood. More prolonged follow-up of this and other NRI cohorts is recommended.

Height, weight weight change, and postmenopausal breast cancer risk: The Netherlands Cohort Study.

The association between several anthropometric indices and breast cancer risk was evaluated within the Netherlands Cohort Study on diet and cancer, which began in 1986 and is conducted among 62,573 women aged 55 to 69 years at baseline. After 4.3 years of follow-up, data on 626 women with incident breast cancer were available with complete information on height and weight at baseline. In multivariate case-cohort analyses, a significantly positive association between adult height and breast cancer was found (P trend < 0.001). Compared with women with height < or = 155 cm, the rate ratios of breast cancer for women with heights up to 160, 165, 170, 175, and > or = 175 cm were 1.22, 1.19, 1.44, 1.77, and 2.06, respectively. For weight at baseline, the significant positive association with breast cancer observed in age-adjusted analysis disappeared in multivariate analysis with adjustment for height and other confounders. For body mass index (BMI) (wt[kg]/ht[m]2) at baseline, no association was observed with breast cancer in multivariate analysis; compared with women with a BMI less than 23, the RR for women with a BMI of 30 or more was 0.98 with P trend = 0.46. Weight and BMI at age 20 showed weak inverse associations with breast cancer risk. For gain in weight or BMI between age 20 and cohort baseline age, inconsistent increases in risk were found, with no significant trends. These data support a positive association between height and breast cancer risk among postmenopausal women. Further study is needed to evaluate the role of early diet and breast cancer in this population, and its relationship to height.