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Background The survival of Ewing sarcoma (ES) patients has improved since the 1970s but is associated with considerable future health risks. Methods The study population consisted of long-term ([greater than or equal to] 5-year) survivors of childhood ES diagnosed before age 21 from 1970 to 1986. Cause-specific mortality was evaluated in eligible survivors (n = 568), and subsequent malignant neoplasms, chronic health conditions, infertility, and health status were evaluated in the subset participating in the Childhood Cancer Survivor Study (n = 403). Outcomes were compared with the US population and sibling control subjects (n = 3899). Logistic, Poisson, or Cox proportional hazards models, with adjustments for sex, age, race/ethnicity, and potential intrafamily correlation, were used. Statistical tests were two-sided. Results Cumulative mortality of ES survivors was 25.0% (95% confidence interval [CI] = 21.1 to 28.9) 25 years after diagnosis. The all-cause standardized mortality ratio was 13.3 (95% CI = 11.2 to 15.8) overall, 23.1 (95% CI = 17.6 to 29.7) for women, and 10.0 (95% CI = 7.9 to 12.5) for men. The nonrecurrence-progression non-external cause standardized mortality ratio (subsequent non-ES malignant neoplasms and cardiac and pulmonary causes potentially attributable to ES treatment) was 8.7 (95% CI = 6.2 to 12.0). Twenty-five years after ES diagnosis, cumulative incidence of subsequent malignant neoplasms, excluding nonmelanoma skin cancers, was 9.0% (95% CI = 5.8 to 12.2). Compared with siblings, survivors had an increased risk of severe, life-threatening, or disabling chronic health conditions (relative risk = 6.0, 95% CI = 4.1 to 9.0). Survivors had lower fertility rates (women: P= .005; men: P< .001) and higher rates of moderate to extreme adverse health status (P< .001). Conclusion Long-term survivors of childhood ES exhibit excess mortality and morbidity. DOI: 10.1093/jnci/djq278

Background We sought to measure self-reported neurocognitive functioning among survivors of non-central nervous system (CNS) childhood cancers, overall and compared with a sibling cohort, and to identify factors associated with worse functioning. Methods In a retrospective cohort study, 5937 adult survivors of non-CNS cancers and 382 siblings completed a validated neuropsychological instrument with subscales in task efficiency, emotional regulation, organization, and memory. Scores were converted to T scores; scores in the worst 10% of siblings' scores (ie, T score [greater than or equal to] 63) were defined as impaired. Non-CNS cancer survivors and siblings were compared with multivariable linear regression and log-binomial regression. Among survivors, log-binomial models assessed the association of patient and treatment factors with neurocognitive dysfunction. All statistical tests were two-sided. Results Non-CNS cancer survivors had similar or slightly worse ( Conclusion A statistically and clinically significantly higher percentage of self-reported neurocognitive impairment was found among survivors of non-CNS cancers than among siblings. DOI: 10.1093/jnci/djq156

Background Previous studies of educational attainment among childhood cancer survivors were small, had contradictory findings, and were not population based. This study investigated educational attainment in a large population-based cohort of survivors of all types of childhood cancer in Great Britain. Methods Four levels of educational attainment among 10183 cancer survivors--degree, teaching qualification, advanced (A') levels, and ordinary (O') levels were compared with expected levels in the general population. A questionnaire was used to obtain educational attainment data for survivors, and comparable information for the general population was available from the General Household Survey. Factors associated with level of educational attainment achieved by cancer survivors were identified using multivariable logistic regression together with likelihood ratio tests. Logistic regression adjusting for age and sex was used for comparisons with the general population. All statistical tests were two-sided. Results Childhood cancer survivors had lower educational attainment than the general population (degree: odds ratio [OR] = 0.77, 99% confidence interval [CI] = 0.68 to 0.87; teaching qualification: OR = 0.85, 99% CI = 0.77 to 0.94; A'level: OR = 0.85, 99% CI = 0.78 to 0.93; O'level: OR = 0.81, 99% CI = 0.74 to 0.90; P< .001, all levels). Statistically significant deficits were restricted to central nervous system (CNS) neoplasm and leukemia survivors. For leukemia, only those treated with radiotherapy were considered. Odds ratios for achievement by irradiated CNS tumor survivors were 50%-74% of those for cranially irradiated leukemia or nonirradiated CNS tumor survivors. Survivors at greater risk of poorer educational outcomes included those treated with cranial irradiation, diagnosed with a CNS tumor, older at questionnaire completion, younger at diagnosis, diagnosed with epilepsy, and who were female. Conclusions Specific groups of childhood cancer survivors achieve lower-than-expected educational attainment. Detailed educational support and implementation of regular cognitive assessment may be indicated for some groups to maximize long-term function. J Natl Cancer Inst 2010;102:254-270 DOI: 10.1093/jnci/djp498

Background Racial disparities in cancer outcomes have been observed in several malignancies. However, it is unclear if survival differences persist after adjusting for clinical, demographic, and treatment variables. Our objective was to determine whether racial disparities in survival exist among patients enrolled in consecutive trials conducted by the Southwest Oncology Group (SWOG). Methods We identified 19457 adult cancer patients (6676 with breast, 2699 with lung, 1244 with colon, 1429 with ovarian, and 1843 with prostate cancers; 1291 with lymphoma; 2067 with leukemia; and 2208 with multiple myeloma) who were treated on 35 SWOG randomized phase III clinical trials from October 1, 1974, through November 29, 2001. Patients were grouped according to studies of diseases with similar histology and stage. Cox regression was used to evaluate the association between race and overall survival within each disease site grouping, controlling for available prognostic factors plus education and income, which are surrogates for socioeconomic status. Median and ten-year overall survival estimates were derived by the Kaplan--Meier method. All statistical tests were two-sided. Results Of 19457 patients registered, 2308 (11.9%, range = 3.9%-21.6%) were African American. After adjustment for prognostic factors, African American race was associated with increased mortality in patients with early-stage premenopausal breast cancer (hazard ratio [HR] for death = 1.41, 95% confidence interval [CI] = 1.10 to 1.82; P= .007), early-stage postmenopausal breast cancer (HR for death = 1.49, 95% CI = 1.28 to 1.73; P< .001), advanced-stage ovarian cancer (HR for death = 1.61, 95% CI = 1.18 to 2.18; P= .002), and advanced-stage prostate cancer (HR for death = 1.21, 95% Cl = 1.08 to 1.37; P = .001). No statistically significant association between race and survival for lung cancer, colon cancer, lymphoma, leukemia, or myeloma was observed. Additional adjustments for socioeconomic status did not substantially change these observations. Ten-year (and median) overall survival rates for African American vs all other patients were 68% (not reached) vs 77% (not reached), respectively, for early-stage, premenopausal breast cancer; 52% (10.2 years) vs 62% (13.5 years) for early-stage, postmenopausal breast cancer; 13% (1.3 years) vs 17% (2.3 years) for advanced ovarian cancer; and 6% (2.2 years) vs 9% (2.7 years) for advanced prostate cancer. Conclusions African American patients with sex-specific cancers had worse survival than white patients, despite enrollment on phase III SWOG trials with uniform stage, treatment, and follow-up.

Background Adult survivors of childhood central nervous system (CNS) malignancies are at high risk for long-term morbidity and late mortality. However, patterns of late mortality, the long-term risks of subsequent neoplasms and debilitating medical conditions, and sociodemographic outcomes have not been comprehensively characterized for individual diagnostic and treatment groups. Methods We collected information on treatment, mortality, chronic medical conditions, and neurocognitive functioning of adult 5-year survivors of CNS malignancies diagnosed between 1970 and 1986 within the Childhood Cancer Survivor Study. Using competing risk framework, we calculated cumulative mortality according to cause of death and cumulative incidence of subsequent neoplasms according to exposure and dose of cranial radiation therapy (RT). Neurocognitive impairment and socioeconomic outcomes were assessed with respect to dose of CNS radiotherapy to specific brain regions. Cumulative incidence of chronic medical conditions was compared between survivors and siblings using Cox regression models. All tests of statistical significance were two-sided. Results Among all eligible 5-year survivors (n = 2821), cumulative late mortality at 30 years was 25.8% (95% confidence interval [CI = 23.4% to 28.3%), due primarily to recurrence and/or progression of primary disease. Patients who received cranial RT of 50 Gy or more (n = 813) had a cumulative incidence of a subsequent neoplasm within the CNS of 7.1% (95% CI = 4.5% to 9.6%) at 25 years from diagnosis compared with 1.0% (95% CI = 0% to 2.3%) for patients who had no RT. Survivors had higher risk than siblings of developing new endocrine, neurological, or sensory complications 5 or more years after diagnosis. Neurocognitive impairment was high and proportional to radiation dose for specific tumor types. There was a dose-dependent association between RT to the frontal and/or temporal lobes and lower rates of employment, and marriage. Conclusions Survivors of childhood CNS malignancies are at high risk for late mortality and for developing subsequent neoplasms and chronic medical conditions. Care providers should be informed of these risks so they can provide risk-directed care and develop screening guidelines.

Background The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. Methods We obtained a cohort of 47697 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.

Background Subsequent malignant neoplasms are a major cause of premature death in survivors of hereditary retinoblastoma. Radiotherapy further increases the risk of death. Mortality information is limited among long-term survivors who were irradiated for hereditary retinoblastoma. Methods We examined cause-specific mortality among 1854 retinoblastoma survivors who were diagnosed from January 1, 1914, through December 31, 1996, at two US institutions. Standardized mortality ratios (SMRs) were calculated by use of US mortality data to estimate expected numbers of deaths. The relative rates (RRs) of mortality due to subsequent malignant neoplasms associated with multiple risk factors were evaluated with Poisson regression models. Cumulative mortality from subsequent malignant neoplasms was calculated by treating other causes of death as competing risks. Results A total of 151 deaths due to subsequent malignant neoplasms occurred among 1092 hereditary retinoblastoma survivors (SMR = 35, 95% confidence interval [CI] = 30 to 41) compared with 12 deaths among 762 nonhereditary retinoblastoma survivors (SMR = 2.5, 95% CI = 1.3 to 4.4). In this extended follow-up of retinoblastoma survivors, we found no evidence of excess mortality from non-neoplastic causes compared with the general population. However, excess mortality from subsequent malignant neoplasms (particularly sarcomas, melanomas, and cancers of the brain and other parts of the nervous system) among hereditary retinoblastoma survivors extended beyond 40 years after retinoblastoma diagnosis. The additional 13 years of follow-up since our last mortality study revealed a previously unreported increased risk of death due to cancers of the corpus uteri (primarily sarcomas) and confirmed the previously reported elevated risk of death from lung cancer among hereditary retinoblastoma survivors. Among hereditary and nonhereditary retinoblastoma survivors, the relative rates of mortality from subsequent malignant neoplasm were higher in those who had been treated with radiotherapy than in those who had not. Cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis was 25.5% (95% Cl = 20.8% to 30.2%) for hereditary retinoblastoma survivors and 1.0% (95% CI = 0.2% to 1.8%) for nonhereditary retinoblastoma survivors. Conclusions The temporal patterns of site-specific excess risks of subsequent malignant neoplasms in retinoblastoma survivors should inform screening programs designed for the early detection and treatment of subsequent malignant neoplasms.

Background Instruments are needed to measure the influence of cancer on quality of life in the expanding population of long-term cancer survivors. We conducted refinement and psychometric evaluation of the Impact of Cancer (IOC) scale by use of data from a large sample of long-term breast cancer survivors and developed an instrument, the Impact of Cancer version 2 (IOCv2), to measure quality of life outcomes. Methods Questionnaires including 81 potential IOC scale items, the Center for Epidemiologic Studies-Depression (CES-D) scale, and the Breast Cancer Prevention Trial (BCPT) symptom scales, as well as demographic, treatment, and medical information, were completed by 1188 disease-free breast cancer survivors 5-10 years after diagnosis. We used exploratory factor analysis to identify scales and assessed reproducibility by split-sample cross-validation. Higher-order scales were extracted and all scales were evaluated for internal consistency and construct and concurrent validity. Results The analysis yielded a factor structure relating IOC items to psychosocial impact domains that exhibited high factor loadings (factor-item correlations of 0.59-0.94), high internal consistency (Cronbach's [alpha] statistics of 0.76-0.89), and a total congruence of 0.98 across the split samples. The Impact of Cancer version 2 (IOCv2) scales consist of a Positive Impact Summary scale with four subscales (Altruism and Empathy, Health Awareness, Meaning of Cancer, and Positive Self-Evaluation), a Negative Impact Summary scale with four subscales (Appearance Concerns, Body Change Concerns, Life Interferences, and Worry), and subscales for Employment and Relationship Concerns. Patterns of association between IOCv2 scale scores and CES-D and BCPT scores indicated good concurrent validity. Patterns of associations between IOCv2 scale scores and demographic, medical, and treatment characteristics indicated good construct validity. Conclusion The IOCv2 scales provide a validated tool for measuring the impact of cancer on quality of life in longterm cancer survivors.

Background The proportion of pediatric and adolescent cancer patients surviving 5 years has increased during the past four decades. This growing population of survivors remains at risk for disease- and treatment-associated late mortality. Methods A total of 20483 five-year survivors of childhood and adolescent cancer diagnosed between January 1, 1970, and December 31, 1986, and enrolled in the Childhood Cancer Survivor Study (CCSS) were included in a National Death Index search for deaths occurring between January 1, 1979, and December 31, 2002. Treatment information was abstracted from primary medical records. Survival probabilities, standardized mortality ratios (SMRs), and absolute excess risks were calculated for overall and cause-specific deaths. Diagnosis- and sex-specific survival probabilities were estimated by the product-limit method. All statistical tests were two-sided. Results Among the CCSS cohort, 2821 (13.8%) 5-year survivors had died by the end of the follow-up period. The cause of death was obtained for 2534 individuals, with 57.5% of deaths attributed to recurrent disease. Estimated probability of survival 30 years from diagnosis was 82%. When compared with the US population, the absolute excess risk of death from any cause was 7.36 deaths per 1000 person-years. The overall SMR was 8.4 (95% confidence interval [CI] = 8.0 to 8.7). Increases in cause-specific mortality were seen for deaths due to subsequent malignancy (SMR = 15.2, 95% CI = 13.9 to 16.6) and cardiac (SMR = 7.0, 95% CI = 5.9 to 8.2), pulmonary (SMR = 8.8, 95% CI = 6.8 to 11.2), and other medical (SMR = 2.6, 95% CI = 2.3 to 3.0) causes. At 20 years of follow-up (25 years after first cancer diagnosis), the death rate due to a subsequent malignancy exceeded that due to all other causes. Conclusion Our extended follow-up of 5-year survivors of pediatric and adolescent cancer indicates that excess mortality persists long after diagnosis. Continued observation is needed to further define lifetime risk and to determine the potential contribution of chronic health conditions and modifiable health behaviors.

Background Smoking should be particularly discouraged among survivors of childhood cancer, who are at increased risk of adverse effects of the cancer and its treatment. We examined the extent of cigarette smoking, factors associated with being a current smoker, and age at initiation of regular smoking among adult survivors of childhood cancer and compared the survivors' smoking habits with those of the general population. Methods We used data from the British Childhood Cancer Survivor Study (BCCSS), a population-based cohort of 17981 individuals who were diagnosed with childhood cancer between 1940 and 1991 in Britain and had survived for at least 5 years after diagnosis. The 14836 cohort members who were alive and aged 16 years or older up to September 2006 were eligible to receive a mailed questionnaire that ascertained smoking status and other factors. The general population data were from the 2002 General Household Survey in Britain. Logistic regression was used to investigate factors associated with being a current regular smoker and to compare the prevalence of current regular smoking in the study cohort with that in the general population. Cox regression was used to examine associations between explanatory factors and age at smoking initiation. All statistical tests were two-sided. Results Of the 10326 childhood cancer survivors who returned completed questionnaires, 20.0% were current regular smokers and 29.8% were ever regular smokers, whereas in the comparable general population 28.1% were current regular smokers and 48.8% were ever regular smokers. Current regular smoking was more prevalent among survivors of Wilms tumor or Hodgkin lymphoma than survivors of a central nervous system (CNS) neoplasm; in those aged 10-14 years at diagnosis than 0-4 years; in those not treated with radiotherapy; in those in manual occupations; in those who were separated, widowed, or divorced; in those with lower educational attainment; and in those not currently on long-term regular hospital follow-up. Rates of smoking initiation were lower in women; in those treated with chemotherapy or radiotherapy; and in those with a third party-completed questionnaire. The rate of smoking initiation was highest among those diagnosed at 10-14 years of age. The odds ratio for being a current regular smoker among the survivors compared with the general population was 0.51 (99% confidence interval [CI] = 0.46 to 0.57). Survivors who smoked, smoked fewer cigarettes per day than smokers in the general population; the difference in the multivariable model was 1.5 fewer cigarettes per day (95% CI = 1.03 to 1.99). Conclusion The prevalence of smoking varies by subgroup among adult survivors of childhood cancer in the BCCSS but is substantially less overall than that in the general population.

Background Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up. Methods HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and [chi square] tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone. Results Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test). Conclusion After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

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 104760 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 104760 one-year survivors of cervical cancer, the risk of all second cancers taken together was increased to a statistically significant extent (n = 12496; SIR = 1.30; 95% confidence interval [CI] = 1.28 to 1.33). Compared with the general population, in both radiotherapy (N = 52613) and no-radiotherapy groups (N = 27382), 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. J Natl Cancer Inst 2007;99:1634-43

Background Testicular cancer survivors, many of whom have undergone radiotherapy, are at substantial risk of second cancers. Treatment for testicular cancer may limit treatment options for second cancers, thereby adversely affecting survival after the second cancer. However, no data on outcomes of testicular cancer survivors with second cancers compared to patients with comparable first cancers exist. Methods Among 29356 white testicular cancer patients reported to the Surveillance, Epidemiology, and End Results (SEER) program (1973-2002), 621 developed a second cancer with known stage and were matched to a random sample of 12420 white male first cancer patients in the SEER program by cancer site, stage, diagnosis year, and age at diagnosis. Mortality was ascertained through 2002. Cancer-specific and all-cause mortality following second cancers were compared with those of matched first cancers, and rate ratios (RRs) were estimated using proportional hazards analysis. Survival functions were calculated using product-limit estimates. Results During the study period, 284 testicular cancer survivors with second cancers died, 191 from their second cancer; 5443 matched first cancer patients died, 3929 from their first cancer. Rate ratios for cancer-specific and all-cause mortality for second cancers compared with matched first cancers were 1.05 (95% confidence interval [CI] = 0.90 to 1.23) and 1.09 (95% CI = 0.96 to 1.23), respectively. However, among testicular cancer patients who were diagnosed during 1973-1979, an era in which radiation therapy was given at high doses and to the chest area, all-cause mortality following second cancers at sites below the diaphragm (79 deaths) and second lung cancers (29 deaths) was statistically significantly higher than that from matched first cancers (RR = 1.44, 95% CI = 1.13 to 1.83, and RR = 1.65, 95% CI = 1.12 to 2.42, respectively). Conclusions Mortality from second cancers following testicular cancer was similar to matched first cancers, except for selected tumors in the radiotherapy field among testicular cancer patients who were diagnosed during 1973-1979, a time when radiotherapy doses for treatment of testicular cancer were high and chest irradiation was an option in standard practice.

Background Decreased libido is one of several changes in sexual function that are often experienced by female cancer patients. Transdermal testosterone therapy has been associated with increased libido among estrogen-replete women who report low libido. Methods In a phase III randomized, placebo-controlled crossover clinical trial, we evaluated whether transdermal testosterone would increase sexual desire in female cancer survivors. Postmenopausal women with a history of cancer and no current evidence of disease were eligible if they reported a decrease in sexual desire and had a sexual partner. Eligible women were randomly assigned to receive 2% testosterone in Vanicream for a testosterone dose of 10 mg daily or placebo Vanicream for 4 weeks and were then crossed over to the opposite treatment for an additional 4 weeks. The primary endpoint was sexual desire or libido, as measured using the desire subscales of the Changes in Sexual Functioning Questionnaire, as assessed at baseline and at the end of 4 and 8 weeks of treatment. Serum levels of bioavailable testosterone were measured at the same times. All statistical tests were two-sided. Results We enrolled 150 women. Women who were on active testosterone cream had higher serum levels of bioavailable testosterone than women on placebo (mean change from baseline, testosterone versus placebo, week 4, 11.57% versus 0%, difference = 11.57%, 95% confidence interval [CI] = 8.49% to 14.65%; week 8, 10.21% versus 0.28%, difference = 9.92%, 95% CI = 5.42% to 14.42%; P Conclusion Increased testosterone level did not translate into improved libido, possibly because women on this study were estrogen depleted.

Background Radiotherapy for breast cancer as delivered in the 1970s has been associated with increased risk of cardiovascular disease, but recent studies of associations with modern regimens have been inconclusive. Few data on long-term cardiovascular disease risk according to specific radiation fields are available, and interaction with known cardiovascular risk factors has not been examined. Methods We studied treatment-specific incidence of cardiovascular disease in 4414 10-year survivors of breast cancer who were treated from 1970 through 1986. Risk of cardiovascular disease in these patients was compared with general population rates and evaluated in Cox proportional hazards regression models. All statistical tests were two-sided. Results After a median follow-up of 18 years, 942 cardiovascular events were observed (standardized incidence ratio = 1.30, 95% confidence interval [CI] = 1.22 to 1.38; corresponding to 62.9 excess cases per 10 000 patient-years). Breast irradiation only was not associated with increased risk of cardiovascular disease. However, radiotherapy to either the left or right side of the internal mammary chain was associated with increased cardiovascular disease risk for the treatment period 1970-1979 (for myocardial infarction, hazard ratio [HR] = 2.55, 95% CI = 1.55 to 4.19; P Conclusions Radiotherapy as administered from the 1980s onward is associated with an increased risk of cardiovascular disease. Irradiated breast cancer patients should be advised to refrain from smoking to reduce their risk for cardiovascular disease.

Background Childhood cancer survivors are at increased risk for the development of secondary sarcomas. Exposure to radiation therapy is a known risk factor for the development of these sarcomas. Other risk factors for secondary sarcomas have not been well described for childhood cancer survivors. We analyzed a large cohort of childhood cancer survivors to determine the true incidence of secondary sarcomas and to examine factors associated with the risk of developing secondary sarcomas. Methods The history of secondary sarcomas in 14372 participants in the Childhood Cancer Survivor Study was determined from self-reports in three questionnaires. Risk of secondary sarcoma was evaluated by use of standardized incidence ratios (SIRs) and excess absolute risks (EARs) as calculated by use of data from the Surveillance, Epidemiology, and End Results Program. Cox regression models were used to estimate hazard ratios of developing subsequent sarcomas. Hazard ratios were reported as relative risks (RRs). Results We identified 108 patients with sarcomas that were diagnosed a median of 11 years after the diagnosis of childhood cancer. The risk of sarcoma was more than ninefold higher among childhood cancer survivors than among the general population (SIR = 9.02, 95% confidence interval [CI] = 7.44 to 10.93). The excess absolute risk of secondary sarcoma was 32.5 per 100000 person-years (95% CI = 26.1 to 40.3 per 100000 person-years). Higher standardized incidence ratios and excess absolute risks were associated with young age at primary diagnosis, primary sarcoma diagnosis, and a family history of cancer. In a multivariable model, increased risk of secondary sarcoma was associated with radiation therapy (RR = 3.1, 95% CI = 1.5 to 6.2), with a primary diagnosis of sarcoma (RR = 10.1, 95% CI = 4.7 to 21.8), with a history of other secondary neoplasms (RR = 2.2, 95% CI = 1.1 to 4.5), and with treatment with higher doses of anthracyclines (RR = 2.3, 95% CI = 1.2 to 4.3) or alkylating agents (RR = 2.2, 95% CI = 1.1 to 4.6). Conclusion Childhood cancer survivors appear to be at increased risk for secondary sarcomas compared with general population rates.

Some breast cancer survivors experience cognitive decline following chemotherapy. We prospectively examined changes in cognitive performance among high-risk breast cancer patients who had received high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTC group; n = 28) or standard-dose chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC group; n = 39); stage-I breast cancer patients who had received no systemic chemotherapy (no-CT group; n = 57); and healthy control subjects (n = 60). All patients underwent neuropsychologic testing before and 6 months after treatment (12-month interval); control subjects underwent repeated testing over a 6-month interval. No differences in cognitive functioning between the four groups were observed at the first assessment. More of the CTC group than the control subjects experienced a deterioration in cognitive performance over time (25% versus 6.7%; odds ratio [OR] = 5.3, 95% confidence interval [CI] = 1.3 to 21.2, P = .02). No such difference was observed for the FEC or the no-CT groups (FEC versus control: OR = 2.2, 95% CI = 0.5 to 9.1, P = .27; no-CT versus Control: OR = 2.2, 95% CI = 0.6 to 8.0; P = .21). Some cytotoxic treatment for breast cancer affects cognition in a subset of women.

Background: Subsequent primary neoplasms of the central nervous system (CNS) have frequently been described as late events following childhood leukemia and brain tumors. However, the details of the dose-response relationships, the expression of excess risk over time, and the modifying effects of other host and treatment factors have not been well defined. Methods: Subsequent primary neoplasms of the CNS occurring within a cohort of 14361 5-year survivors of childhood cancers were ascertained. Each patient was matched with four control subjects by age, sex, and time since original cancer diagnosis. Tumor site-specific radiation dosimetry was performed, and chemotherapy information was abstracted from medical records. Conditional logistic regression was used to estimate odds ratios (ORs), to calculate 95% confidence intervals (CIs), and to model the excess relative risk (ERR) as a function of radiation dose and host factors. For subsequent gliomas, standardized incidence ratios (SIRs) and excess absolute risks (EARs) were calculated based on Surveillance, Epidemiology, and End Results data. Results: Subsequent CNS primary neoplasms were identified in 116 individuals. Gliomas (n = 40) occurred a median of 9 years from original diagnosis; for meningiomas (n = 66), it was 17 years. Radiation exposure was associated with increased risk of subsequent glioma (OR = 6.78, 95% CI = 1.54 to 29.7) and meningioma (OR = 9.94, 95% CI = 2.17 to 45.6). The dose response for the excess relative risk was linear (for glioma, slope = 0.33 [95% CI = 0.07 to 1.71] per Gy, and for meningioma, slope = 1.06 [95% CI = 0.21 to 8.15] per Gy). For glioma, the ERR/Gy was highest among children exposed at less than 5 years of age. After adjustment for radiation dose, neither original cancer diagnosis nor chemotherapy was associated with risk. The overall SIR for glioma was 8.7, and the EAR was 19.3 per 10000 person-years. Conclusions: Exposure to radiation therapy is the most important risk factor for the development of a new CNS tumor in survivors of childhood cancers. The higher risk of subsequent glioma in children irradiated at a very young age may reflect greater susceptibility of the developing brain to radiation.

For the Cancer and Leukemia Group B To determine the accuracy with which Medicare claims data measure disease-free survival in elderly Medicare beneficiaries with cancer, we performed a criterion validation study. We merged gold-standard clinical trial data of 45 elderly patients with node-positive breast cancer who were treated on the Cancer and Leukemia Group B (CALGB) adjuvant breast trial 9344 with Centers for Medicare and Medicaid Services (CMS) data files and compared the results of a CMS-based algorithm with the CALGB disease-free survival information to determine sensitivity and specificity. For 5-year disease-free survival, the sensitivity of the CMS-based algorithm was 100% (95% confidence interval [CI] = 81% to 100%), the specificity was 97% (95% CI = 83% to 100%), and the area under the receiver operator curve was 97% (95% CI = 90% to 100%). For 2-year disease-free survival, the test characteristics were less favorable: sensitivity was 83% (95% CI = 36% to 100%), specificity was 95% (95% CI = 83% to 100%), and area under the receiver operator curve was 84% (95% CI = 66% to 100%).

Background: The elderly population, including many who are long-term cancer survivors, is increasing. Aspects of quality of life in elderly cancer survivors are not well understood. Methods: Subjects were women who enrolled in a population-based cohort study in 1986. At follow-up in 1997, 25719 women, at a median age of 72 years, reported on functional limitations. We used logistic regression to calculate prevalence odds ratios (ORs) and proportional hazards regression to calculate prevalence ratios (PRs) for associations between cancer survivor status and functional limitations, adjusting for baseline (precancer) characteristics including obesity, smoking, and diabetes. Results: Women who were cancer survivors for less than 2 years reported the most functional limitations, but long-term (5 or more years) cancer survivors remained more likely than cohort members who had not had cancer to report that they were unable to do heavy household work (42% of 1068 5-year survivors, versus 31% of 23501 who never had cancer, multivariable OR = 1.47, 95% confidence interval [CI] = 1.27 to 1.69; PR = 1.22, 95% CI = 1.10 to 1.34), unable to walk a half mile (26% versus 19%, OR = 1.31, 95% CI = 1.1 to 1.54; PR = 1.16, 95% CI = 1.02 to 1.32), and unable to walk up and down stairs (9% versus 6%, OR = 1.34, 95% CI= 1.05 to 1.72; PR = 1.25, 95% CI = 1.00 to 1.56). The increased prevalence of functional limitations was apparent for 5-year survivors of breast cancer and also certain other cancers. Conclusions: Our findings support the need to target elderly cancer survivors for interventions to maintain or regain physical function. [J Natl Cancer Inst 2006;98:521-9]

Background: Although second primary cancers are a leading cause of death among men with testicular cancer, few studies have quantified risks among long-term survivors. Methods: Within 14 population-based tumor registries in Europe and North America (1943-2001), we identified 40576 1-year survivors of testicular cancer and ascertained data on any new incident solid tumors among these patients. We used Poisson regression analysis to model relative risks (RRs) and excess absolute risks (EARs) of second solid cancers. All statistical tests were two-sided. Results: A total of 2285 second solid cancers were reported in the cohort. The relative risk and EAR decreased with increasing age at testicular cancer diagnosis (P

Approximately 30% of women successfully treated for breast cancer suffer persistent fatigue of unknown origin. Recent studies linking inflammatory processes to central nervous system-mediated fatigue led us to examine cellular immune system status in 20 fatigued breast cancer survivors and 19 matched non-fatigued breast cancer survivors. Fatigued survivors, compared with non-fatigued survivors, had statistically significantly increased numbers of circulating T lymphocytes (mean 31% increase, 95% confidence interval [CI] = 6% to 56%; P = .015 by two-sided analysis of variance [ANOVA]), with pronounced elevation in the numbers of [CD4.sup.+] T lymphocytes (mean 41% increase, 95% CI = 15% to 68%; P = .003 by two-sided ANOVA) and [CD56.sup.+] effector T lymphocytes (mean 52% increase, 95% CI = 4% to 99%; P = .027 by two-sided ANOVA). These changes were independent of patient demographic and treatment characteristics. Absolute numbers of B cells, natural killer cells, granulocytes, and monocytes were not altered. The increased numbers of circulating T cells correlated with elevations in the level of serum interleukin 1 receptor antagonist (for [CD3.sup.+] cells, r = .56 and P = .001; for [CD3.sup.+]/[CD4.sup.+] cells, r = .68 and P

Background: Female survivors of Hodgkin's disease (HD) have a strongly elevated risk of breast cancer, but factors responsible for the increased risk are not well known. Methods: We investigated the effects of radiation dose, chemotherapy (CT), and reproductive factors on breast cancer risk in a nested case-control study in The Netherlands in a cohort of 770 female patients who had been diagnosed with HD before age 41. Detailed treatment information and data on reproductive factors were collected for 48 case patients who developed breast cancer 5 or more years after diagnosis of HD and 175 matched control subjects. The radiation dose was estimated to the area of the breast where the case patient's tumor had developed and to a comparable location in matched control subjects. Relative risks (RRs) of breast cancer were calculated by conditional logistic regression. Statistical tests were two-sided. Results: The risk of breast cancer increased statistically significantly with radiation dose ([P.sub.trend] = .01); patients who received 38.5 Gy or more had an RR of 4.5 (95% confidence interval [CI] = 1.3 to 16) times that of patients who received less than 4 Gy. Patients who received both CT and radiotherapy (RT) had a statistically significantly lower risk than those treated with RT alone (RR = 0.45, 95% CI = 0.22 to 0.91). Breast cancer risk increased with increasing radiation dose among patients who received RT only (RR = 12.7, 95% CI = 1.8 to 86, for patients receiving [greater than or equal to] 38.5 Gy) but not among patients treated with CT and RT. Sixty-nine percent of control subjects treated with RT and more than six cycles of CT, but only 9% of those who received RT alone, reached menopause before age 41. Reaching menopause before age 36 was associated with a strongly reduced risk of breast cancer (RR = 0.06, 95% CI = 0.01 to 0.45). Conclusion: Breast cancer risk increases with increasing radiation dose up to at least 40 Gy. The substantial risk reduction associated with CT may reflect its effect on menopausal age, suggesting that ovarian hormones promote tumorigenesis after radiation has produced an initiating event.

Background: Women with breast cancer are the largest group of female survivors of cancer. There is limited information about the long-term quality of life (QOL) in disease-free breast cancer survivors. Methods: Letters of invitation were mailed to 1336 breast cancer survivors who had participated in an earlier survey and now were between 5 and 10 years after their initial diagnosis. The 914 respondents interested in participating were then sent a survey booklet that assessed a broad range of QOL and survivorship concerns. All P values were two-sided. Results: A total of 817 women completed the follow-up survey (61% response rate), and the 763 disease-free survivors in that group, who had been diagnosed an average of 6.3 years earlier, are the focus of this article. Physical well-being and emotional well-being were excellent; the minimal changes between the baseline and follow-up assessments reflected expected age-related changes. Energy level and social functioning were unchanged. Hot flashes, night sweats, vaginal discharge, and breast sensitivity were less frequent. Symptoms of vaginal dryness and urinary incontinence were increased. Sexual activity with a partner declined statistically significantly between the two assessments (from 65% to 55%, P = .001). Survivors with no past systemic adjuvant therapy had a better QOL than those who had received systemic adjuvant therapy (chemotherapy, tamoxifen, or both together) (physical functioning, P = .003; physical role function, P = .02; bodily pain, P = .01; social functioning, P = .02; and general health, P = .03). In a multivariate analysis, past chemotherapy was a statistically significant predictor of a poorer current QOL (P = .003). Conclusions: Long-term, disease-free breast cancer survivors reported high levels of functioning and QOL many years after primary treatment. However, past systemic adjuvant treatment was associated with poorer functioning on several dimensions of QOL. This information may be useful to patients and physicians who are engaging in discussion of the risks and benefits of systemic adjuvant therapy. [J Natl Cancer Inst 2002;94:39-49]

To learn whether female cancer survivors are more likely to terminate a pregnancy by choice than other women, the occurrence of induced abortions was determined in a population-based cohort of 1688 childhood cancer survivors. Proportion ratios (PRs) were estimated from the ratio of the proportion of pregnancies that resulted in induced abortions among the survivors (or 16 700 randomly selected population control subjects) to the proportion among 2737 sisters of the survivors. The proportion of induced abortions among survivors (292 of 1479 [19.7%]) was marginally higher but not statistically significantly different from that among sisters (961 of 5092 [18.9%]; PR = 1.08, 95% confidence interval [CI] = 0.96 to 1.22) and similar to that of the population control subjects (5505 of 27 989 [19.7%]; PR = 1.07, 95% CI = 1.01 to 1.14). Survivors were not more likely than sisters and population control subjects to elect a second-trimester abortion because of physical and mental conditions or fetal abnormalities.