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In this first reported study of weekly paclitaxel administered as first-line chemotherapy for metastatic breast cancer, paclitaxel 100 mg/m2 was administered in a 1-h infusion on a weekly basis to 35 patients who may previously have received adjuvant chemotherapy (but not taxane-containing regimens), but not for advanced or metastatic disease. A median of 14 infusions per patient was given at a mean delivered dose intensity of 94 mg/m2 per week. In 33 assessable patients, a complete response (CR) was observed in 1 patient and partial responses (PRs) in 12 patients, producing an overall response rate of 40%. Stable disease (SD) was observed in 17 patients, of whom 9 were stabilized for more than 24 weeks. Thus, clinical benefit (CR+PR+SD(> or = 24 weeks)) was observed in 67% of the patients. Time to progression was 189 days, the duration of response 180 days and overall survival 544 days. Five patients developed grade 3 neutropenia and five patients grade 3 neurotoxicity. Thus, this study has shown that weekly paclitaxel as first-line therapy for metastatic or advanced breast cancer produces comparable response rates and less toxicity than when the drug is given every three weeks. [ABSTRACT FROM AUTHOR]

Background: Breast cancer risk remains higher in high-income compared with low-income countries. However, it is unclear to what degree metabolic factors influence breast cancer development in women 30 years after immigration from low- to a high-incidence country., Methods: Using Cox regression models, we studied the association between pre-diagnostic metabolic factors and breast cancer development, and whether this association varied by ethnicity among 13,802 women participating in the population-based Oslo Ethnic Breast Cancer Study. Ethnic background was assessed and pre-diagnostic metabolic factors (body mass index, waist:hip ratio, serum lipids and blood pressure) were measured. A total of 557 women developed invasive breast cancer, and these women were followed for an additional 7.7 years., Results: Among women with an unfavorable metabolic profile, women from south Asia, compared with western European women, had a 2.3 times higher breast cancer risk (HR 2.30, 95% CI 1.18-4.49). Compared with the western European women, the ethnic minority women were more likely to present with triple-negative breast cancer (TNBC) (OR 2.11, 95% CI 0.97-4.61), and less likely to complete all courses of planned taxane treatment (OR 0.26, 95% CI 0.08-0.82). Among TNBC women, above-median triglycerides:HDL-cholesterol (>0.73) levels, compared with below-median triglycerides:HDL-cholesterol (≤0.73) levels, was associated with 2.9 times higher overall mortality (HR 2.88, 95% CI 1.02-8.11)., Conclusions: Our results support the importance of metabolic factors when balancing breast cancer prevention and disease management among all women, and in particular among non-western women migrating from a breast cancer low-incidence to a high-incidence country.

Background: High triglycerides and low levels of high density lipoprotein (HDL)-cholesterol are observed to promote tumor growth. However, whether breast cancer heterogeneity may explain the contradictory influence of triglycerides and cholesterol observed on breast cancer prognosis remains unclear., Methods: A population-based survival study among 464 breast cancer cases identified within the Tromsø study was conducted. Pre-diagnostic triglycerides, total-cholesterol and HDL-cholesterol were measured, and detailed clinical and histopathological data were obtained. Using tissue microarray, all breast cancer cases were reclassified into the following subtypes: Luminal A, Luminal B, HER2-enriched, and triple negative breast cancer (TNBC). Multivariable Cox proportional hazards regression models were used to study the associations between pre-diagnostic lipids and breast cancer recurrence, mortality, and survival., Results: A total of 464 breast cancer patients, with mean age at diagnosis of 57.9 years, were followed for a mean 8.4 years. TNBC patients in the highest tertile of triglycerides (≥ 1.23 mmol/l) had 3 times higher overall mortality compared to TNBC patients in the lowest tertile (≤ 0.82 mmol/l) (HR 2.99, 95% CI 1.17-7.63), and the 5-year overall survival was 19% lower for TNBC patients in the highest vs. lowest tertile of triglycerides (65% vs. 84%). TNBC patients in the highest tertile of the HDL-cholesterol/total-cholesterol ratio (≥0.35), compared to those in the lowest tertile (≤0.27), had a 67% reduced overall mortality risk (HR 0.33, 95% CI 0.12-0.89). No associations were observed between lipids and prognostic outcome among breast cancer patients overall, or among patients with luminal A and luminal B subtypes. Among HER2-enriched patients, pre-diagnostic triglyceride level was inversely associated with overall mortality., Conclusion: Our study suggests that pre-diagnostic triglycerides and the HDL-cholesterol/total-cholesterol ratio may independently provide unique information regarding prognostic outcome among triple negative breast cancer patients. However, a small sample size underlines the need for additional studies.

Background: The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) pN0 patients not treated with chemotherapy., Methods: Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995-1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS)., Results: Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2- patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2- patients) yielded strong prognostic information. Among the HR+/HER2- pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2- pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2- population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%)., Conclusions: The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.

Growing evidence indicates that adiposity is associated with breast cancer risk and negatively affects breast cancer recurrence and survival, a paracrine role of mammary adipose tissue being very likely in this process. In contrast to other adipose depots, occurrence of a sub-inflammatory state of mammary adipose tissue defined by dying adipocytes surrounded by macrophages forming crown-like structures in overweight and obese subjects, remains only partially described. In a general population of breast cancer patients (107 patients) mostly undergoing breast-conserving surgery, we found a positive association between patient's body composition, breast adipocytes size, and presence of crown-like structures in mammary adipose tissue close to the tumor. Overweight (BMI: 25.0-29.9 kg/m 2 ) and obese (BMI ≥ 30.0 kg/m 2 ) patients have 3.2 and 6.9 times higher odds ratio of crown-like structures respectively, compared with normal weight patients. The relatively small increase in adipocyte size in crown-like structures positive vs. negative patients suggests that mammary adipose tissue inflammation might occur early during hypertrophy. Our results further highlight that body mass index is an adequate predictor of the presence of crown-like structures in mammary adipose tissue among postmenopausal women, whereas in premenopausal women truncal fat percentage might be more predictive, suggesting that mammary adipose tissue inflammation is more likely to occur in patients exhibiting visceral obesity. Finally, the presence of crown-like structures was positively associated with systemic markers such as the Triglyceride/High-density lipoprotein-cholesterol ratio serum C-reactive protein and glucose/(HbA1c) glycated Haemoglobin. These compelling results demonstrate that excess adiposity, even in overweight patients, is associated with mammary adipose tissue inflammation, an event that could contribute to breast cancer development and progression.

Background: Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown., Methods: We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol., Results: We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002-0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m 2. ). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3-6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025-0.079) that the level of 17β-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype., Conclusion: Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.

Background: High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear., Methods: Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics., Results: The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5%. Most (93%) of the patients had estrogen receptor (ER) positive tumors (≥ 1% ER+), and 82% had progesterone receptor (PgR) positive tumors (≥ 10% PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (β 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (β 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (β 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (β 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (β -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression., Conclusion: Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies.

Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromsø study (1994-2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose-response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01-1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01-2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8-1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31-4.03) and 2.08 (95 % CI 1.16-3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70-0.97), and a 22 % reduction in overall mortality (95 % CI 0.62-0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre-diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution.

High-density lipoprotein-cholesterol (HDL-C) may influence the proliferation of breast tumor cells, but it is unclear whether low HDL-C levels, alone or in combination with cyclic estrogen and progesterone, are associated with mammographic density, a strong predictor of breast cancer development. Fasting morning serum concentrations of HDL-C were assessed in 202 premenopausal women, 25 to 35 years of age, participating in the Norwegian Energy Balance and Breast Cancer Aspects (EBBA) I study. Estrogen and progesterone were measured both in serum, and daily in saliva, throughout an entire menstrual cycle. Absolute and percent mammographic density was assessed by a computer-assisted method (Madena), from digitized mammograms (days 7-12). Multivariable models were used to study the associations between HDL-C, estrogen and progesterone, and mammographic density phenotypes. We observed a positive association between HDL-C and percent mammographic density after adjustments (P = 0.030). When combining HDL-C, estradiol, and progesterone, we observed among women with low HDL-C (<1.39 mmol/L), a linear association between salivary 17β-estradiol, progesterone, and percent and absolute mammographic density. Furthermore, in women with low HDL-C, each one SD increase of salivary mid-menstrual 17β-estradiol was associated with an OR of 4.12 (95% confidence intervals; CI, 1.30-13.0) of having above-median percent (28.5%), and an OR of 2.5 (95% CI, 1.13-5.50) of having above-median absolute mammographic density (32.4 cm(2)). On the basis of plausible biologic mechanisms linking HDL-C to breast cancer development, our findings suggest a role of HDL-C, alone or in combination with estrogen, in breast cancer development. However, our small hypothesis generating study requires confirmation in larger studies., (©2015 American Association for Cancer Research.)

Introduction: High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women., Methods: Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models., Results: The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m(2)) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm(2)); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3))., Conclusion: Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.

Purpose: The presence of disseminated tumor cells (DTCs) in bone marrow (BM) predicts survival in early breast cancer. This study explores the use of DTCs for identification of patients insufficiently treated with adjuvant therapy so they can be offered secondary adjuvant treatment and the subsequent surrogate marker potential of DTCs for outcome determination., Patients and Methods: Patients with early breast cancer who had completed six cycles of adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy underwent BM aspiration 2 to 3 months (BM1) and 8 to 9 months (BM2) after FEC. Presence of DTCs in BM was determined by immunocytochemistry using pan-cytokeratin monoclonal antibodies. If one or more DTCs were present at BM2, six cycles of docetaxel (100 mg/m(2), once every 3 weeks) were administered, followed by DTC analysis 1 and 13 months after the last docetaxel infusion (after treatment). Cox regression analysis was used to evaluate disease-free interval (DFI)., Results: Of 1,066 patients with a DTC result at BM2 and available follow-up information (median follow-up, 71.9 months from the time of BM2), 7.2% were DTC positive. Of 72 docetaxel-treated patients analyzed for DTCs after treatment, 15 (20.8%) had persistent DTCs. Patients with remaining DTCs had markedly reduced DFI (46.7% experienced relapse) compared with patients with no DTCs after treatment (adjusted hazard ratio, 7.58; 95% CI, 2.3 to 24.7). The docetaxel-treated patients with no DTCs after treatment had comparable DFI (8.8% experienced relapse) compared with those with no DTCs both at BM1 and BM2 (12.7% experienced relapse; P = .377, log-rank test)., Conclusion: DTC status identifies high-risk patients after FEC chemotherapy, and DTC monitoring status after secondary treatment with docetaxel correlated strongly with survival. This emphasizes the potential for DTC analysis as a surrogate marker for adjuvant treatment effect in breast cancer., (© 2014 by American Society of Clinical Oncology.)

Background: The objective of this study was to assess markers of spermatogenesis in long-term survivors of testicular cancer (TC) according to treatment, and to explore correlations between the markers and associations with achieved paternity following TC treatment., Methods: In 1191 TC survivors diagnosed between 1980 and 1994, serum-follicle stimulating hormone (s-FSH; n=1191), s-inhibin B (n=441), and sperm counts (millions per ml; n=342) were analysed in a national follow-up study in 1998-2002. Paternity was assessed by a questionnaire., Results: At median 11 years follow-up, 44% had oligo- (<15 millions per ml; 29%) or azoospermia (15%). Sperm counts and s-inhibin B were significantly lower and s-FSH was higher after chemotherapy, but not after radiotherapy (RT), when compared with surgery only. All measures were significantly more abnormal following high doses of chemotherapy (cisplatin (Cis)>850 mg, absolute cumulative dose) compared with lower doses (Cis ≤ 850 mg). Sperm counts were moderately correlated with s-FSH (-0.500), s-inhibin B (0.455), and s-inhibin B : FSH ratio (-0.524; all P<0.001). All markers differed significantly between those who had achieved post-treatment fatherhood and those with unsuccessful attempts., Conclusion: The RT had no long-term effects on the assessed markers of spermatogenesis, whereas chemotherapy had. At present, the routine evaluation of s-inhibin B adds little in the initial fertility evaluation of TC survivors.

Background. We performed a randomized phase II study comparing efficacy and toxicity of weekly paclitaxel 80 mg/m(2) (Weetax) with three weekly docetaxel 75 mg/m(2) (Threetax), both in combination with oral capecitabine 1000 mg/m(2) twice daily for 2 weeks followed by a 1-week break. Patients. Thirty-seven women with confirmed metastatic breast cancer were randomized. Results. Median TTF was 174 (Weetax) versus 147 days (Threetax) (P=0.472). Median OS was 933 (Weetax) versus 464 days (Threetax) (P=0.191). Reasons for TTF were PD 8/18 (Weetax), 9/19 (Threetax); and toxicity: 8/18 (Weetax), 8/19 (Threetax). ORR was 72% (Weetax) versus 26% (Threetax) (P = 0.01). The Threetax-combination resulted in a higher incidence of leuco-/neutropenia compared to Weetax. Grade II anemia was more pronounced in the Weetax group. No difference was found in quality of life. Conclusion. Taxanes in combination with capecitabine resulted in a high level of toxicity. Taxanes and capecitabine should be considered given sequentially and not in combination.

Background: Preserved fertility is an important issue for testicular cancer (TC) survivors., Objective: Our aim was to examine any difference regarding paternity and testicular function following two, three, or four cycles of cisplatin-based chemotherapy for TC., Design, Setting, and Participants: A national multicentre follow-up survey assessing morbidity among survivors of unilateral TC diagnosed from 1980 to 1994 was conducted during the period 1998 to 2002. Of the 1814 men invited, 1462 (80.6%) participated by responding to a mailed questionnaire and/or undergoing a clinical examination including laboratory assessments. The present study includes the 316 participants up to 65 yr of age treated with two to four cycles of standard cisplatin-based chemotherapy without additional treatment beyond surgery., Measurements: Self-reported paternity following treatment for TC according to number of cycles was assessed among men who reported antegrade ejaculation and attempts at posttreatment conception (n=106). Kaplan-Meier analysis, log-rank test, and Cox regression were applied. Gonadal hormones (n=305-314) and sperm counts (n=71) by number of cycles were assessed by linear by linear association or Mann-Whitney tests., Results and Limitations: At median 12-yr follow-up, 80% (85 of 106) had succeeded in their attempts of achieving posttreatment paternity (two cycles: 100%; three: 83%; four: 76%; p=0.022). For all patients the 15-yr actuarial paternity rate was 85%. The association between posttreatment paternity and number of cycles remained significant in the multivariate analysis (p=0.032). High serum follicle-stimulating hormone values were more common with increasing number of cycles (p=0.037), but there were no differences in serum luteinising hormone, serum testosterone, or sperm counts. Few men treated with two cycles and a limited number of sperm samples are the main limitations of this study., Conclusions: The prospects of future paternity after two to four cycles of cisplatin-based chemotherapy are good, and our data suggest that the prospects improve with decreasing number of cycles., (Copyright 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Sensory neuropathy (paresthesias), tinnitus, hearing impairment, and Raynaud phenomena are side effects of cisplatin-based chemotherapy used to treat testicular cancer patients. We assessed the long-term occurrence of these side effects among testicular cancer survivors according to the treatment they received., Methods: A total of 1814 men who were treated for unilateral testicular cancer in Norway during 1980-1994 were invited to participate in a national multicenter follow-up survey conducted during 1998-2002. The men were allocated to six groups according to the treatment they had received. Self-reported symptoms were assessed by a mailed questionnaire that included the Scale for Chemotherapy-Induced Neurotoxicity. A total of 1409 participants who responded to the questionnaire and/or underwent audiometry were assessable in this study. Respondents to the questionnaire (n = 1402) scored the relevant symptoms according to how troubled they were by each (not at all, a little, quite a bit, or very much). Hearing impairment was objectively assessed by audiometry at 4000 Hz in 755 men (seven of whom did not respond to the questionnaire). Group comparisons of symptom assessments were performed with chi2 or Kruskal-Wallis tests. Associations between relevant factors and self-reported symptoms or hearing impairment measured by audiometry were assessed using proportional odds ordinal logistic regression models and linear regression models, respectively. All statistical tests were two-sided., Results: The median follow-up for the 1409 assessable men was 10.7 years (range = 4-21 years). All chemotherapy groups had statistically significantly higher odds for increasing severity of all assessed symptoms and inferior audiometric results compared with men who did not receive chemotherapy. Among chemotherapy-treated men, 39% (95% confidence interval [CI] = 35% to 43%) reported Raynaud-like phenomena (defined as white or cold hands or fingers [or feet or toes] on cold exposure), 29% (95% CI = 25% to 33%) reported paresthesias in the hands or feet, 21% (95% CI = 18% to 25%) reported hearing impairment, and 22% (95% CI = 19% to 26%) reported tinnitus as major symptoms troubling them quite a bit or very much. Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group. Men who were treated with radiotherapy had higher odds of self-reported paresthesias in feet compared with those not treated with radiotherapy (OR = 1.5, 95% CI = 1.01 to 2.1, P = .04)., Conclusion: Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy.

Background: Adult height and insulin are thought to modify the development of breast cancer. However, little is known about the association between height and 17beta-estradiol, a key factor in breast carcinogenesis, and whether insulin modifies such an association., Methods: Among 204 healthy women, ages 25 to 35 years, who participated in the Energy Balance and Breast Cancer Aspect I study, adult height (in centimeters) and fasting serum concentrations of insulin (pmol/L) were measured. 17beta-Estradiol concentrations were measured in daily saliva samples throughout an entire menstrual cycle through RIA. Age and multivariate linear regression models were used to study the association between adult height and 17beta-estradiol levels throughout an entire menstrual cycle and whether serum levels of fasting insulin may modify such an association., Results: The women had a mean age of 30.7 years, adult height of 166.9 cm, and serum insulin of 85.7 pmol/L. For each increase of one SD in insulin levels in the upper tertile of adult height, the adjusted level of 17beta-estradiol increased by 3.1 pmol/L (95% confidence interval, 1.1-5.2), equivalent to a 17.3% higher mean average concentration of 17beta-estradiol. Women with an adult height > or =170 cm (upper tertile) and insulin levels >101 pmol/L (upper quartile) experienced, on average, 41% higher 17beta-estradiol levels throughout the entire menstrual cycle compared with women with the same adult height and insulin levels <101 pmol/L., Conclusion: Our findings support that premenopausal levels of 17beta-estradiol vary in response to adult height and insulin levels, of possible importance for breast cancer risk.

Introduction: We examined if testicular cancer (TC) treatment is associated with any risk for cardiovascular morbidity or predicted mortality according to the SCORE model, in which a 10-year future risk of >or=5% for developing a fatal cardiovascular event qualify for high-risk status., Methods: One thousand one hundred thirty-four TC survivors treated 1980-1994 participated in this study (1998-2002). Patients were categorised in four treatment groups: surgery (n = 225), radiotherapy (n = 445), and two chemotherapy groups: cumulative cisplatin dose 850 mg (cis>850, n = 89). Patients with cardiovascular disease, diabetes or SCORE >or=5% constituted a high-risk group, and those with SCORE >1% an intermediate/high risk group., Results: Age-adjusted mean SCORE was 0.93% for the surgery group. In comparison, chemotherapy treated patients had significantly higher SCORE (1.07%, p = 0.01). Only 15% of patients were scored to be at high-risk, while 53% qualified for the intermediate/high risk group. Patients in the cis>850 group had increased odds for having intermediate/high risk, compared with the surgery group (OR 3.4, 95% CI 1.3-8.7). Only 23 cardiovascular events had occurred since the testicular cancer diagnosis., Conclusion: The SCORE model indicates that patients treated with cisplatin-based chemotherapy have a significantly increased future risk of a fatal cardiovascular event., Implications for Cancer Survivors: TC survivors should be followed regularly with respect to cardiovascular risk profile beyond the routine 10-year clinical follow-up.

Background: A possible explanation of the excess cardiovascular risk in testicular cancer (TC) survivors is development of metabolic syndrome. The association between metabolic syndrome and TC treatment is examined in long-term survivors., Patients and Methods: In a national follow-up study (1998-2002), 1463 TC survivors (diagnosed 1980-1994) participated. Patients >60 years were excluded in the present study, leaving 1135 patients eligible. The patients were divided in four treatment groups: surgery (n = 225); radiotherapy (n = 446) and two chemotherapy groups: cumulative cisplatin dose (Cis) 850 mg (n = 88). A control group consisted of 1150 men from the Tromsø Population Study. Metabolic syndrome was defined according to a modified National Cholesterol Education Program definition., Results: Both chemotherapy groups had increased odds for metabolic syndrome compared with the surgery group, highest for the Cis >850 group [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.6-4.7]. Also, the Cis >850 group had increased odds (OR 2.1, 95% CI 1.3-3.4) for metabolic syndrome compared with the control group. The association between metabolic syndrome and the Cis >850 group was strengthened after adjusting for testosterone, smoking, physical activity, education and family status., Conclusion: TC survivors treated with cisplatin-based chemotherapy have an increased risk of developing metabolic syndrome compared with patients treated with other modalities or with controls.

Trastuzumab has shown activity in early breast cancer patients that overexpress HER2. Significant resources have to be allocated to finance this therapy, underlining the need for cost-effectiveness analysis. A model was set up, societal costs were calculated and the discount rate was 3%. Life expectancy data were based on the literature and prolonged according to qualified guess (10% and 20% absolute improvement in overall survival (OS)). The comparator was the FEC(100) regimen. The median additional health care cost per patient treated was 33,597 euros. The yielding cost per life year gained (LYG) was 15,341 euros with a 20% improved OS and 35,947 euros with 10% improved OS. The corresponding net health care cost per quality adjusted life year (QALY) was 19,176 euros and 44,934 euros. Including all resource use the figures were 8148 euros and 30,290 euros per LYG. Sensitivity analyses documented survival gain, price of trastuzumab, production gain and discount rate to be the major factors influencing cost-effectiveness ratio. Trastuzumab is indicated cost effective in Norway.

Background: Studies of fertility in men treated for testicular cancer have mainly addressed serum follicle-stimulating hormone levels and sperm parameters. We assessed post-treatment paternity among long-term survivors of testicular cancer., Methods: Men (n = 1814) who had been treated for unilateral testicular cancer in Norway during 1980 through 1994 were invited to participate in a national multi-center follow-up survey in 1998 through 2002. The participants were allocated to five groups according to the treatment received after orchiectomy, including treatment at relapse (surveillance, retroperitoneal lymph node dissection, radiotherapy, low-dose chemotherapy [i.e., < or = 850 mg cisplatin], and high-dose chemotherapy [i.e., > 850 mg cisplatin]). Cox proportional hazards analysis was used to assess predictive factors for post-treatment paternity. Statistical tests were two-sided., Results: A total of 1433 men were assessable, of whom 827 were fathers at diagnosis. Post-treatment conception was attempted by 554 men, among whom the overall 15-year actuarial post-treatment paternity rate was 71% (95% confidence interval [CI] = 66% to 75%) without the use of cryopreserved semen. This rate ranged from 48% (95% CI = 30% to 69%) in the high-dose chemotherapy group to 92% (95% CI = 78% to 98%) in the surveillance group (P < .001). The median actuarial time from diagnosis to the birth of the first child after treatment was 6.6 years overall but varied according to treatment. Assisted reproductive technologies were used by 22% of the couples who attempted conception after treatment. Dry ejaculation, treatment group, pretreatment fatherhood, and marital status were statistically significant independent predictors for post-treatment fatherhood, with dry ejaculation as the most important negative factor., Conclusions: Although the overall paternity rate after treatment for testicular cancer was high, the ability to conceive and the time to conception reflected the intensity of treatment. These data may help inform patients about their future ability to father biological children.

Purpose: To evaluate blood pressure and body mass index (BMI) in long-term survivors of testicular cancer (TC) treated with different modalities., Patients and Methods: One thousand eight hundred fourteen patients treated for unilateral TC in Norway (1980 to 1994) were invited to participate in a follow-up study (1998 to 2002), including measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. Of these patients, 1,289 patients (71%) participated in the study. The patients were categorized into four treatment groups: surgery (n = 242), radiotherapy (n = 547), and two chemotherapy groups, cumulative cisplatin dose < or = 850 mg (n = 402) and cumulative cisplatin dose more than 850 mg (n = 98). A control group consisted of healthy males from the Tromsø Population Study (n = 2,847)., Results: At diagnosis, age-adjusted regression analyses showed no differences between the treatment groups for any variables. After a median follow-up time of 11.2 years, age-adjusted SBP and DBP were significantly higher for both chemotherapy groups compared with the surgery group. Chemotherapy-treated patients had increased odds for hypertension at follow-up compared with the surgery group, and the odds were highest for the cisplatin more than 850 mg group (odds ratio = 2.4; 95% CI, 1.4 to 4.0). The cisplatin more than 850 mg group had a significantly higher 10-year BMI increase and a higher prevalence of obesity at follow-up than the surgery group. Compared with healthy controls, chemotherapy-treated patients had, at follow-up, increased SBP, increased DBP, excessive BMI increase, and a higher prevalence of hypertension., Conclusion: Five to 20 years after therapy, cured TC patients treated with cisplatin-based chemotherapy had significantly higher levels of blood pressure, a higher prevalence of hypertension, and an excessive weight gain compared with patients treated with other modalities and compared with healthy controls.

This study reports on oncology professionals' knowledge and attitude toward complementary and alternative medicines (CAM), classified according to their primary application as complementary or alternative methods. In June 2002, we conducted a national, multicentre survey of 828 Norwegian oncologists, nurses, clerks and therapeutic radiographers. A response rate of 61% was achieved. Only a few physicians (4%) described their reactions to alternative medicine as positive compared with nurses (33%), therapeutic radiographers (32%) and clerks (55%) (P<0.0001). Females showed a more positive view than males (33% versus 14%, P<0.0001). More participants expressed a positive attitude to complementary versus alternative medicines. Most respondents regarded healing by hand or prayer, homeopathy, and Iscador (mistletoe) as alternative therapies. In contrast, most respondents classified acupuncture, meditation, reflexology, music/art-therapy, aromatherapy and massage as complementary therapies. This survey demonstrates major differences, by gender as well as oncology health profession in views about and the classification of various CAM methods.

An open-label, non-randomized, compassionate-use study was carried out to investigate the effects of oral capecitabine at a dose of 1 250 mg/m2 twice daily on days 1 to 14 every 21 days in anthracycline- and taxane-pretreated advanced/metastatic breast cancer patients. Forty-eight patients were enrolled from April 2000 to December 2001. Twenty-four patients (50%) had metastases to the liver, 18 to bone, 13 to lung, 10 to regional lymph nodes, 8 to pleura, 7 to the thoracic wall, 5 to skin, 3 to the mediastinum, 1 to breast and 1 had metastasis to the abdomen. Thirty-three patients (69%) had metastases to more than one site. Median age of the patients was 55 years (range 35-74). Three patients had an ECOG performance status (PS) of 0, 32 PS 1 and 13 PS 2, respectively. Fourteen patients (29%; 95% CI 16 to 42%) obtained a partial response (PR) while 16 (33%) had stable disease (SD) as the best response, of whom 6 had stabilization for more than 24 weeks. This gives a clinical benefit (PR + SD > 24 weeks) of 42% (95% CI 28 to 56). Dose reduction was necessary in 29% of the patients. Median dose reduction was 25%. Grades 2 and 3 hand-foot syndrome (PPE) was observed in 17 patients (36%). Eleven patients experienced grades 2 and 3 gastrointestinal toxicity, and haematological toxicity grade 3 was observed in 3 patients (6%). Median time to progression was 107 days (CI 95% 85 to 129), and median overall survival was 281 days (CI 95% 164 to 398). Third-line, oral capecitabine in anthracycline- and taxane-pretreated metastatic breast cancer appears to be effective and has an acceptable toxicity profile.

Background: This study compares attitudes to the proposed new Alternative medicine act that would give Norwegian practitioners of alternative medicine more scope in treating patients with cancer., Material and Methods: In June 2002 a questionnaire on alternative and complementary medicine was distributed among 156 physicians, 414 nurses, 164 radiation therapists and 94 administrative staff members in the five Norwegian university hospitals responsible for cancer treatment. 61% returned the questionnaire., Results: Of all respondents, 29% described themselves as having a positive attitude to alternative medicine. When the health services can offer no healing or palliative treatment to offer, 41% of the physicians and 60% of other health care workers were of the opinion that alternative practitioners could treat cancer. More than 50% of respondents were of the opinion that the patients themselves had the right to determine whether or not to use alternative medicine. When health authorities require communication between practitioners and physicians more than 70% of all health care workers felt that this contact had to be in writing., Interpretation: Most health care workers treating cancer are of the opinion that practitioner of alternative medicine might treat cancer if the health services have no healing or palliative treatment. Required contact between physicians and alternative practitioners must be in writing.

This study examines the association between alternative medicines (AM) and cancer survival. A national multicentre study was carried out in Norway in December 1992 to assess the prevalence of AM use among cancer patients. One of the aims of this study was to assess the association between AM and long-time survival. In January 2001, survival data were obtained with a follow-up of 8 years for 515 cancer patients. A total of 112 (22%) assessable patients used AM. During the follow-up period, 350 patients died. Death rates were higher in AM users (79%) than in those who did not use AM (65%). In a Cox regression model adjusted for demographic, disease and treatment factors, the hazard ratio of death for any use of AM compared with no use was 1.30, (95% Confidence Interval (CI) 0.99, 1.70; P=0.056), suggesting that AM use may predict a shorter survival. Sensitivity analyses strengthened the negative association between AM use and survival. AM use had the most detrimental effect in patients with an ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0 (hazard ratio for use=2.32, 95% CI, 1.44, 3.74, P=0.001), when compared with an ECOG PS of 1 or higher. The use of AM seems to predict a shorter survival from cancer. The effect appears predominantly in patients with a good PS.

From July 1990 to July 1991 252 cancer patients admitted consecutively to the Department of Oncology, University Hospital of Tromsø, were included in a questionnaire-based study. The aim of the study was to examine the delays involved in the diagnosis and treatment of cancer. The study also focused on the psychological distress related to these periods of delay. A significant correlation between psychological distress and the actual length of delay (weeks) was revealed (p < 0.01). psychological distress was also correlated positively to the degree of depression (p < 0.01). Women found delays more distressing than men (p < 0.01). Patients from the northern areas (Troms and Finnmark counties) considered a cancer unit in Northern Norway to be of greater importance than those living in the southern area (Nordland county).

In the last decade, breast cancer patients have enjoyed an increase in breast conserving surgery (BCS). At present, modified radical mastectomy (MRM) and BCS offers equal expectations of survival. During the last few years, however, a drop in the frequency of BCS has been reported by several authors. Is this new trend due to economic concerns? To clarify the costs of breast cancer therapy (stage I and II), we review the literature and include a cost-utility and a cost-minimisation analysis comparing MRM and BCS. The treatment cost (per patient) of BCS and MRM in Norway was calculated at $9,564 and $5,596, respectively. Employing a quality of life gain in BCS of 0.03 (0-1 scale) and a 5% discount rate, the cost per QALY in BCS compared to MRM was $20,508. In cost-minimising analysis, BCS and mastectomy followed by reconstructive surgery had a cost of $10,748 and $8,538, respectively. This indicates that BCS remains within reasonable cost and should not be displaced by mastectomy on economic grounds.

New biomedical knowledge may improve the diagnostic procedures and treatment provided by the Health Services, but at additional cost. In a social democratic health care system, the hospital budgets have no room for expensive, new procedures or treatments, unless these are funded through extra allocation from the central authorities. High dose therapy with autologous stem cell support in malignant disorders is an example of a new and promising, but rather expensive treatment, but its role in cancer therapy has yet to be established. The indications for testing high dose therapy with autologous stem cell support in various malignancies are discussed, with emphasis on the principles for deciding which categories of disease should have priority. The authors suggest some malignant disorders for which high dose therapy with stem cell support should be explored versus conventional treatment in randomised prospective trials.

Cancer patients' attitudes to chemotherapy were compared with those of doctors, nurses, and healthy controls. 98 cancer patients, 42 healthy subjects, 44 oncologists, 35 surgeons, 32 oncology nurses, and 70 surgical nurses received a questionnaire presenting a hypothetical situation involving a toxic chemotherapy regimen. Each of them was asked to indicate the minimal benefit with respect to chance of cure, prolongation of life and relief of symptoms they would demand in order to accept the treatment. The patients and surgical nurses were the most reluctant towards the treatment. The subgroup of patients under 50 years which matched the oncologists, surgeons, and controls with respect to age, cohabitant status, and children were significantly more willing to accept the regimen than the control persons and professional groups were. Patients under 40 years would accept the toxic treatment even with hardly any benefit in terms of chance of cure (7%, median), prolongation of life (three months), and relief of symptoms (8%). Among the professionals, oncologists were most willing to accept the therapy, whereas surgical nurses and surgeons were the least willing.

The great majority of patients with Hodgkin's disease (HD) are successfully treated. However, several reports on treatment sequela have been published. The object of this study was to examine the quality of life (QOL) among survivors of HD focusing on gender and treatment modalities. All patients treated for HD at our oncological unit between 1985 and 1993 (n = 55) were registered. In December 1994, 49 survivors were mailed a questionnaire consisting of the EORTC QLQ-C30. Forty-two patients responded (86%). They reported a low frequency of symptoms and a high level of functioning. There was a significant correlation between mantle field irradiation and dyspnoea (p = 0.023). Females reported a significantly superior global quality of life (p = 0.016) and a lower fatigue score (p = 0.040) compared to males. Almost half of the patients reported financial difficulties. To improve QOL among survivors of HD, groups at risk have to be identified. Patients treated with mantle field irradiation and males seems to be at a higher risk. Should the treatment of HD be altered towards less radiotherapy and more chemotherapy?

From July 1990 to July 1991, 263 consecutive cancer patients admitted to our oncological unit for the first time were invited to participate in a questionnaire based study. 252 patients responded and were included in the final analysis. The aim of the survey was to examine the delays involved in diagnosis and treatment of cancer and the possible psychological distress associated to the different periods of delay. A shorter patient delay was found among patients under the age of 30 years (P < 0.005). Patients with higher education had a significantly shorter delay from the time of contact with the GP to admittance to the local hospital (P <0.005). The diagnostic delay was reported to be significantly more distressing for females compared to males (P <0.05). The reported psychological distress, however, correlated positively to the actual length of total delay (P<0.005) for both sexes. All patients reported that the delay between local hospital referral and admittance to the oncological unit to be the most distressing delay period to cope with.

Background: We retrospectively compared two different palliative chemotherapy regimens for advanced colorectal carcinoma with respect to efficacy and toxicity., Patients and Methods: Between April 1986 and September 1994, 84 patients started treatment with 5-fluorouracil (5-FU)-based combination chemotherapy [MFL (Sequential MTX and 5-FU, N=39) or FLV (Sequential 5-FU and FA, N=45)] in our clinic. Treatment was initially administered every two weeks., Results: In the MFL and FLV group, 37 and 41 patients, respectively, were evaluable. The objective response rates were 16% in the MFL group and 26% in the FLV group. Median survival was 10 months in both groups, and the median time to progression was not significantly different. With regard to subjective response, 39% of patients in both groups obtained partial or complete relief of tumor related symptoms. A significantly larger part of the patients in the MFL group (54%) complained about adverse effects when compared to the FLV group (27%)., Conclusions: With regard to efficacy the chemotherapeutic regimens were equivalent, however the MFL regimen appeared more toxic when compared to FLV.

Cancer patients' attitude to chemotherapy were compared with those of doctors, nurses and healthy controls. 98 cancer patients, 42 healthy subjects, 44 oncologists, 35 surgeons, 32 oncology nurses and 70 surgical nurses received a questionnaire presenting a hypothetical situation involving a toxic chemotherapy regimen. Each were asked to indicate the minimal benefit with respect to chance of cure, life prolongation and symptom relief they would demand to accept the treatment. The patients and the surgical nurses were most reluctant with regard to the treatment. The subgroup of patients under 50 years which matched the oncologists, surgeons and controls with respect to age, cohabitant status and children were significantly more willing to accept the regimen than the controls and professional groups. Patients under 40 years would accept the toxic treatment with hardly any benefit as chance of cure (7%, median), life prolongation (3 months) and symptom relief (8%). Among the professionals, oncologists were most willing to accept therapy, whereas surgical nurses and surgeons were least willing.

WR 2721 protected 'artificial' lung metastases of Lewis lung carcinoma against the cytotoxic effects of cyclophosphamide and melphalan. When mice were pretreated with WR 2721 30 min before exposure to the alkylating agents a significant increase in the number of lung metastases could be observed. This protection of micrometastases had a significant impact on survival in the case of cyclophosphamide treatment, but not in the case of melphalan treatment. The degree of protection at a standard dose of WR 2721 was dose dependent.

The toxicity of melphalan in mice was reduced by the injection of S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR2721). This was seen in terms of reduced toxicity to the stem cells of the bone marrow and intestinal epithelium as well as improved animal survival. Using human melanoma xenografts and growth delay as an end-point, it was demonstrated that WR2721 did not protect this tumor from melphalan. With radio-labelled WR2721, it was shown that WR2721 was rapidly cleared from the blood and actively accumulated by all normal tissues except the CNS. Intact human tumor xenografts and Lewis lung tumors were less able to accumulate WR2721 than normal tissues, but in vitro studies showed that tissue fragments or single cell suspensions of tumors were as efficient as liver fragments or bone marrow cells in accumulating the drug. The rapid clearance of WR2721 and poor vascularity of the intact tumors were thought to be responsible for the differential uptake and protection of normal tissues by WR2721.

Misonidazole (MISO) has produced differential enhancement of tumor cell killing with a range of cytotoxic drugs including 5-fluorouracil (FU) in experimental mouse tumors and human xenografts. Since concomitant enhancement of normal tissue damage has been observed, a Phase I study of MISO and FU has been undertaken in patients with advanced colorectal cancer. Mild nausea and vomiting occurred more frequently after MISO and FU compared with FU alone; however, the incidence of leucopenia was similar with both treatment. No patients receiving the MISO/FU combination developed central nervous system toxicity or peripheral neuropathy. Twenty-four hour plasma nitroimidazole kinetics were analyzed and were not modified by the concomitant administration of the cytotoxic drug. Thus, in this preliminary study FU has been safely combined with MISO without significant modification of plasma nitroimidazole pharmacokinetics. Tumor regression was documented in 2/9 (22%) patients receiving more than 2 courses of MISO/FU. A Phase II study is proposed to investigate tumor response.