Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.

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/m2.). 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 17ß-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.

Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival.

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.

Sperm counts and endocrinological markers of spermatogenesis in long-term survivors of testicular cancer.

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.

Weekly Paclitaxel plus Capecitabine versus Docetaxel Every 3 Weeks plus Capecitabine in Metastatic Breast Cancer.

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.

Predicted cardiovascular mortality and reported cardiovascular morbidity in testicular cancer survivors.

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.

Trastuzumab in adjuvant breast cancer therapy. A model based cost-effectiveness analysis.

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.

Components of the metabolic syndrome in long-term survivors of testicular cancer.

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.

Blood pressure and body mass index in long-term survivors of testicular cancer.

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.

Knowledge of and attitudes toward complementary and alternative therapies; a national multicentre study of oncology professionals in Norway.

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.

Does use of alternative medicine predict survival from cancer?

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.

[Cancer patients' perception of the examination period prior to treatment]. / Kreftpasienters oppfatning av utredningstid før behandling.

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).

Lumpectomy or mastectomy? Is breast conserving surgery too expensive?

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.

[High dose therapy with autologous stem cell support in malignant disorders. Excerpt from the statement by the advisory group of the State Health Services]. / Høydosebehandling med autolog stamcellestøtte ved maligne lidelser. Utdrag fra innstilling fra rådgivende gruppe nedsatt av Statens helsetilsyn.

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.

[Attitudes to treatment with cytostatic agents. Do cancer patients, physicians, nurses and healthy individuals vary in their views?]. / Holdninger til cellegiftbehandling. Er det forskjeller blant kreftpasienter, leger, sykepleiere og friske personer?

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.

Quality of life in survivors of Hodgkin's disease.

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?

Palliative chemotherapy in metastatic colorectal carcinoma: comparison of two chemotherapeutic regimens.

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.

Diagnostic delay causes more psychological distress in female than in male cancer patients.

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.

Cancer patients, doctors and nurses vary in their willingness to undertake cancer chemotherapy.

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.

Effect of the radioprotector WR 2721 on the response of metastatic Lewis lung carcinoma colonies to alkylating agents.

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.