Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function.

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.

Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking ( P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased ( P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.

Perceived needs for different components in a rehabilitation program among cancer survivors with chronic fatigue compared to survivors without chronic fatigue.

BACKGROUND: Knowledge about the user' needs is important to develop targeted rehabilitation for cancer patients with chronic fatigue (CF). The aims of the study were to examine prevalence of CF in cancer survivors attending an one-week inpatient educational program (IEP) and to identify characteristics of those with CF. Further to examine the perceived needs for different components in a rehabilitation program, need of complex rehabilitation (at least two components) and aspects of health-related quality of life (HRQoL) among survivors with CF versus those without CF. MATERIAL AND METHODS: Cancer survivors ≥18 years, diagnosed with different types of cancer within the last 10 years and attending a one-week IEP were invited to this cross-sectional study. CF was assessed by the Fatigue Questionnaire, perceived needs by asking a question about needs for different components in a rehabilitation program and HRQoL was assessed by The Medical Outcomes Study Short Form 36. RESULTS: Of 564 participants, 45% reported CF. Breast cancer, mixed cancer types (including small groups with different cancer types) and comorbidities increased the risk for having CF. Compared to participants without CF, the participants with CF reported more frequently need for physical training (86% vs. 65%, p < 0.001), physiotherapy (71% vs. 55%, p < 0.001) and nutrition counseling (68% vs. 53%, p = 0.001). Among participants with CF, 75% reported need for three or more components whereas 54% reported need for the same number of components among those without CF (p < 0.001). CONCLUSION: Almost half of the cancer survivors attending the IEP had CF. Physical training, physiotherapy and nutrition counseling were the most frequently reported needs and significantly more often observed in participants with CF than without CF. A higher percentage of those with CF reported need for a complex rehabilitation compared to those without CF. More research is necessary to obtain more knowledge to further make targeted programs to better match cancer survivors' needs.

Providing information about late effects after childhood cancer: lymphoma survivors' preferences for what, how and when.

OBJECTIVE: Childhood cancer survivors need information about risks of late effects to manage their health. We studied how and when adult, long-term survivors prefer to receive information about late effects. METHODS: Five focus-groups with adult survivors of childhood lymphomas who had completed routine follow-up care and participated in a preceding follow-up study (n = 34, 19 females, mean age = 39). We used thematic analysis to identify themes regarding providing late effects information. RESULTS: The survivors wanted information about late effects (symptoms, prevention and treatment), lifestyle and social security rights. Information should be tailored, carefully timed, given "face-to-face" and in written format. Many expressed ambivalence regarding receiving information as adolescents, but it was seen as essential "to know" once a late effect occurred. A "re-information" consultation about late effects around age 25 was suggested as beneficial. CONCLUSION: Although ambivalent, all survivors wanted information about late effects. They preferred individualized information, disclosed "step-by-step" and in a "re-information consultation" when reaching young adulthood. PRACTICE IMPLICATIONS: Providing information about late effects should be an on-going process across the cancer care trajectory. (Re-)Informing survivors when older would enhance their understanding of their health risks and could aid better health self-management beyond completion of follow-up care.

A cohort study of permanently reduced work ability in breast cancer patients.

PURPOSE: The aims of this cohort study were to explore various longitudinal aspects of employment and disability pension due to permanently reduced work ability among women with breast cancer and to investigate the impact of breast cancer on income. PATIENTS AND METHODS: In a national register-based controlled cohort study from Norway, 1,548 women diagnosed with breast cancer (all stages) between 1992 and 1996 at the age 45-54 years and 1,548 cancer-free women matched for age, municipality and civil status were followed for up to 14 years. Medical data from the Cancer Registry of Norway were linked with longitudinal data on employment, social security benefits and socio-demography collected from other national official registries. RESULTS: Compared to cancer-free controls, breast cancer patients were significantly more likely to receive disability pension (hazard ratio (HR) 2.7, 95% CI 2.3-3.2) after adjustment for unmatched socio-demographic variables (education, income and children <18 years in the household). Adjusted HR in breast cancer stage I patients was 1.8 (95% CI 1.5-2.3) and 3.0 (95% CI 2.4-3.8) in stage II/III patients compared to controls. The risk increased with mastectomy compared to breast-conserving surgery (HR 1.5, 95% CI 1.2-1.9). At the end of the observation period, employment rates were higher in non-disabled patients than in non-disabled controls (82% vs. 77%, p = 0.008). Working breast cancer patients experienced a temporary negative effect on employment income. CONCLUSION: A considerable proportion of women with breast cancer will over time experience permanently reduced work ability and become disability pension holders. In case of reduced work ability in breast cancer survivors, medical personel caring for them should consider and discuss with them rehabilitation and workplace adjustment in order to prevent early disability pension.

Cancer patients' needs for rehabilitation services.

PURPOSE: To examine cancer patients' needs for rehabilitation services and factors associated with such needs, and secondly identify unmet needs for rehabilitation services and related factors. MATERIAL AND METHODS: In 2008 persons aged 25-60 years, diagnosed in 2005/2006 with the ten most prevalent cancers in Norway were identified through the Cancer Registry of Norway. These patients were contacted by their treating hospital receiving a mailed questionnaire. Main outcomes for the present study were measured by two questions assessing a) needs for rehabilitation services and b) rehabilitation services offered/used. For each question seven services were listed; physical therapy, physical training, psychological counseling, consultations with social worker, occupational therapy, supportive group sessions and admittance to a convalescent home. The respondents then rated to what extent they had experienced needs and if they had been offered and used each service. Those who reported need for a service that not had been offered were defined as having unmet need. Associations between demographic, health-related and outcome variables were analyzed by multivariate logistic and linear regression analyses. RESULTS: Among the 1 325 respondents, the mean age was 52 years and 70% were women. Sixty-three percent reported need for at least one rehabilitation service. Need for physical therapy was most frequently reported (43%), followed by physical training (34%), psychological counseling (27%), supportive group sessions (24%), admittance to a convalescent home (24%), consultation with social worker (19%) and occupational therapy (6%). Changes in employment status and ongoing or previous chemotherapy were associated with reporting needs for all rehabilitation services. Forty percent reported unmet needs, which most frequently was reported among persons living alone, who had changed their employment status, receiving or had received chemotherapy or reported comorbidities. CONCLUSIONS: The majority reported need for at least one rehabilitation service, and 40% reported unmet needs. Prospective studies are recommended in order to better understand needs for rehabilitation services, such as needs in relation to time since treatment, extent of disease and treatment intensity.

A comparative study of cancer patients with short and long sick-leave after primary treatment.

BACKGROUND: Sick-leave after primary cancer treatment has hardly been studied. This study compares Norwegian cancer patients (CPs) with shorter (≤8 months) and longer (≥9 months) sick-leave after primary cancer treatment. Our aim was to characterize factors associated with these two types of sick-leave in order to identify possible factors for interventions by which long-term sick-leaves may be avoided. METHODS: A mailed questionnaire was completed by a sample of Norwegian CPs 15 to 39 months after primary treatment of the ten most common invasive types of cancer. The groups with shorter (n=359) and longer (n=481) sick-leaves (SSL vs LSL) were compared with each other by self-reported information as to socio-demographic and cancer-related variables, health, quality of life, work ability, work situation and supportive interventions. RESULTS: The LSL consisted of 78% females, and 76% of them had breast or gynaecological cancer. A higher proportion of patients with low level of education, economical problems, treated with chemotherapy, hormones and multimodal treatment belonged to LSL compared to SSL. Significantly more LSL had recurrences of cancer, co-morbidity, regular use of medication, and poorer self-rated health, quality of life and work ability. Compared to SSL, more LSL reported needs for and offers of supportive care such as physiotherapy, physical activities and psychosocial support. A multivariate regression analysis showed that reduced work ability, changes in employment due to cancer, lack of support from supervisors at work, and having had combined treatment were significantly associated with being LSL. CONCLUSIONS: Longer sick-leave after primary cancer treatment is associated with combined cancer treatment, lack of support from supervisors and reduced overall work ability. Interventions and counselling related to the work place and reduced work ability could be of value for prevention of long-term sick-leaves.

Radiological and functional assessment of radiation-induced pulmonary damage following breast irradiation.

PURPOSE: The purpose of this study was to compare late radiation-induced radiological abnormalities of the lung with spirometric observations. Radiological abnormalities were also related to theoretical calculations, in order to predict late effects based on dose-volume histograms. PATIENTS AND METHODS: Sixty-one breast cancer patients who had received postoperative radiotherapy were included. During a follow-up examination 3 years or more after start of radiotherapy, computed tomography (CT) scans and pulmonary function tests were performed. Grading of radiological abnormalities (fibrosis) was performed based on CT images. Based on the dose volume histograms of the lung, effective dose was calculated. RESULTS: There was a positive correlation between the effective radiation dose and the fraction of patients that developed radiation induced fibrosis. No significant association was found between the normalized forced vital capacity (FVC) and the radiological abnormality score or the effective radiation dose. CONCLUSION: In this study we found no correlation between local radiation-induced changes in the lung tissue and overall lung function. The effective dose was a better predictive factor for radiation induced fibrosis than for overall lung function.

The associations between living conditions, demography, and the 'impact of cancer' scale in tumor-free cancer survivors: a NOCWO study.

GOALS OF WORK: The "impact of cancer" scale (IOC) is a new questionnaire that explores attitudes in the physical, psychological, social, and spiritual/existential domains in cancer survivors. This study explores the associations between demography, living conditions (LCs), and the IOC dimensions in disease-free Norwegian survivors who have been treated for breast, prostate, or testicular cancer. MATERIALS AND METHODS: A questionnaire covering demography, LCs, and the IOC was mailed to 852 cancer survivors; 459 (54%) participated. A living condition index (LCI) was calculated based on self-reported education, employment, annual income, health, housing expenditures, and social participation. MAIN RESULTS: Survivors with a low LCI level viewed their situation significantly worse on four of five negative IOC dimensions than those with high LCI level. No significant LCI-related differences were observed for the mean scores of positive IOC dimensions. Significant associations were observed between gender, health status, employment, and five to six IOC dimensions. LCs were more often associated with the negative IOC dimensions than the positive ones. CONCLUSIONS: The significant associations between LCs and dimensions of the IOC in tumor-free cancer survivors show that LCs should be considered when health care professionals assist cancer survivors in dealing with the impact the cancer experience had on their lives.

Late relapses of germ cell malignancies: incidence, management, and prognosis.

Late relapses of malignant germ cell tumors (MGCTs) are rare and occur, by definition, 2 years or later after successful treatment. They represent a major challenge of today's treatment of MGCTs. Because of the rarity and heterogeneity of late relapses, many aspects of their main characteristics remain obscure. We present relevant literature on relapsing MGCTs to highlight the following issues: incidence, impact of initial treatment on the subsequent risk of late relapse, treatment, and survival. In a pooled analysis, the incidence is 1.4% and 3.2% in seminoma and nonseminoma patients, respectively. The predominant site of relapse is the retroperitoneal space in both histologic types. The initial treatment appears to be important for the risk and localization of late relapses. The treatment of late relapses should be based on a representative presalvage biopsy and includes radical surgery and salvage chemotherapy in most cases. Five-year cancer-specific survival is above 50% in the recent large series and reaches 100% in case of single-site teratoma. Diagnosis and treatment of late-relapsing MGCT patients is challenging and should be performed in experienced centers only. Referral of late-relapsing patients to high-volume institutions ensures the best chances of cure and enables increasing understanding of tumor biology and the clinical course of these patients.

Primary caregivers of cancer patients in the palliative phase: a path analysis of variables influencing their burden.

Research has shown that several variables influence the burden of primary caregivers of cancer patients staying at home in the palliative phase, but the associations between these variables have hardly been explored. The aim of this study was to examine the associations of theory-driven variables with the caregivers' burden by means of path analysis. The sample consisted of 96 caregivers of cancer patients in the palliative phase staying at home recruited from a hospital trust in Norway. The dimensions of burden from the Caregiver Reaction Assessment, namely self esteem, lack of family support, impact on finances, and impact on daily schedule, were used as the dependent variable. The following independent variables were tested in the models: the patients' levels of pain, fatigue, and nausea; and the caregivers' physical quality of life, anxiety and depression, and social support. The Partial Least Squares approach to structural equation modelling was used for the path analysis. Model 1 shows the direct associations between the independent variables and the dependent variable, explaining 16% of the variance in caregiver burden. Model 1 supports the finding that only caregivers' depression has a direct significant association with caregiver burden, and shows further that the effects of the other independent variables on burden are mediated through depression. In Model 2, anxiety and depression are mediating factors between three other independent variables and caregiver burden, and 12% of the variance is explained. Model 2 supports none of the independent variables as antecedents of burden. Testing of the models suggested that caregivers' depression was the main factor associated with caregiver burden, but also an important mediator of indirect associations of indirect associations of caregivers' anxiety and physical health.

Assessment of male sexual function by the Brief Sexual Function Inventory.

OBJECTIVE: To present normative data from Norway using the Brief Male Sexual Function Inventory (BSFI, the first patient self-administered questionnaire to assess male sexuality, and used in the USA) in men aged 20-79 years, examine the psychometric properties of the BSFI, explore the impact of sexual function and other variables on overall sexual satisfaction, and compare American and Norwegian normative data. SUBJECTS AND METHODS: From public official address lists 3500 men aged 20-79 years were invited to take part in an anonymous questionnaire study, including the BSFI. Altogether 1185 (34%) responded, and the response rates varied with age. RESULTS: There was increasingly reduced sexual function concerning drive, erection, ejaculation, and problem assessment with age, and most of the age-effect started at >50 years old. Overall sexual satisfaction followed the same trend, but with a weaker association with age. Analyses of factor structure and internal consistency of the BSFI supported a one-factor solution with good internal consistency. Drive, erection, ejaculation, and problem assessment explained 28% of the variance in overall sexual satisfaction. Being younger and having a sexual partner were also associated with high scores of overall sexual satisfaction. American and Norwegian normative data in the BSFI dimensions were markedly similar. CONCLUSION: The BSFI is a short and discrete screening tool for sexual function, and for most clinical and research purposes we recommend using the BSFI as a one-dimensional scale.

The caregiver reaction assessment: psychometrics, and temporal stability in primary caregivers of Norwegian cancer patients in late palliative phase.

BACKGROUND: Limited research has been done on the situation of primary caregivers (PCs) to patients staying at home with cancer in the palliative phase. This study uses the Caregiver Reaction Assessment (CRA) to examine PCs caregiver burden and well-being. PATIENTS AND METHODS: The sample consisted of 85 PCs examined at baseline, among them 42 were re-examined four months later. We explored the psychometric properties of the CRA at baseline, and introduced a CRA sum score. The CRA sum score was correlated with the Short Form 36 (SF-36) and The Hospital Anxiety and Depression Scale (HADS) scores. RESULTS: The internal consistency of the CRA dimensions varied between alpha 0.57 and 0.85, and the factor structure was in line with earlier studies. The CRA sum score correlated significantly with all mental dimensions on the SF-36 and the HADS. At baseline the PCs showed significantly worse scores except for family support when compared to newly diagnosed cancer patients. The mean scores on the CRA dimensions as well as the total score did not change significantly from baseline to follow-up. CONCLUSION: We have confirmed the psychometric properties of the CRA, which seems to be an appropriate instrument for assessment the PCs caregiver situation.

Self-reported health and use of health care services in long-term cancer survivors.

Owing to an increasing number of long-term cancer survivors, the use of health care services and somatic health problems were compared between cancer survivors and a noncancer population. Data from the Nord-Trondelag Health Survey 2 (HUNT 2, 1995-1997) was merged with the Cancer Registry of Norway. Six cancer subgroups were constructed with diagnosis 5 years prior HUNT 2: testicular cancer (n= 59), colorectal cancer (n= 175), prostate cancer (n= 87), breast cancer (n= 258), gynaecological cancer (n= 153) and lymphoma/leukaemia (n= 83). For each cancer survivor 3 matched noncancer controls were selected from the HUNT 2 survey. The prevalence of common health problems, use of health care services and unfavourably life style parameters were compared between the 2 groups. Cancer survivors used health care services and received social welfare benefits more often than the controls. There was an increased risk of perceiving poor health after a history of cancer. Common health problems and/or unfavourable life style parameters could not explain poor health or the increased use of health care services among cancer survivors. Further studies are needed to investigate the reasons for increased use of health care services and perceived poor health in cancer survivors.