The aim of the study was to compare the quality of life (QL) of patients treated with single-agent paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer. 331 patients with advanced breast cancer were randomised, with 294 eligible for analysis. Patients completed both the EORTC QLQ-C30 questionnaire and the Rotterdam Symptom Checklist (RSCL) with six additional items, at baseline and after the third, fifth and seventh cycles of chemotherapy. A significant difference in progression-free survival in favour of doxorubicin caused a bias in the data with differences in expected completion rates of questionnaires beyond cycle three. Therefore, statistical comparisons were performed only for the first three cycles. Baseline compliance was 64% and 61% for the QLQ-C30 and RSCL questionnaires, respectively. Doxorubicin was associated with significantly more nausea/vomiting (P=0.001), loss of appetite (P=0.010) and a greater burden of disease and treatment (P=0.044), but with less bone pain (P=0.042) and rash (P=0.045) than paclitaxel. Both treatments were associated with improved emotional function and reduction in psychological distress at cycle 3. Longitudinal data suggested that doxorubicin was associated with less pain, specifically bone pain. Doxorubicin was more active but may have had more side-effects during the first three cycles. Long-term QL outcomes could not be assessed.

Intraventricular chemotherapy with radiotherapy is the standard treatment of leptomeningeal metastasis (LM) from breast cancer; this treatment increases median survival only to about 3 months and is frequently complicated by serious side effects. The authors describe two patients with LM from breast cancer who were treated with hormonal therapy, which provided a neurologic response of at least 12 months and a survival of 14+ and 19 months. Hormonal therapy can be effective and nontoxic for patients with LM from breast cancer.

Insulin‐like growth factor I (IGF‐I) is a systemic hormone with potent mitogenic and anti‐apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre‐menopausal ages. In a prospective case‐control study nested within a cohort of New York City women, IGF‐I, IGF‐binding protein 3 (IGFBP‐3) and C peptide were measured in frozen serum samples from 172 pre‐menopausal and 115 post‐menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post‐menopausal breast cancer was not associated with serum IGF‐I, IGFBP‐3 or C‐peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF‐I in pre‐menopausal women. The odds ratio (OR) for the highest quartile of IGF‐I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91–2.81]. The OR decreased to 1.49 (95% CI 0.80–2.79) after adjustment for IGFBP‐3. In analyses restricted to subjects who were pre‐menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07–4.94). Adjustment for IGFBP‐3 reduced the OR to 1.90 (95% CI 0.82–4.42). There was no association between pre‐menopausal breast cancer and IGFBP‐3, IGF‐I:IGFBP‐3 ratio or non‐fasting levels of C peptide. Elevated circulating levels of IGF‐I may be an indicator of increased risk of breast cancer occurring before age 50. Int. J. Cancer 88:828–832, 2000. © 2000 Wiley‐Liss, Inc.

Background Excessive body weight is known to increase the risk of postmenopausal, but not premenopausal breast cancer. Some studies have suggested that being overweight is protective against premenopausal breast cancer, but the evidence is not compelling. Much less is known about the role of body fat distribution in either pre- or postmenopausal breast cancer.Methods Breast cancer risk was examined in relation to body weight, height, Quetelet index (kg/m(2)), and waist/hip ratio (WHR) in the New York University Women's Health Study, a prospective cohort study. Cases were 109 premenopausal and 150 postmenopausal women diagnosed with breast cancer between 1985 and 1994. Non-cases were 8157 cohort members free of breast cancer.Results Among premenopausal women, there was an increasing risk of breast cancer with increasing WHR. The relative risk (RR) of breast cancer increased to 1.72 (95% confidence interval [CI]:1.0-3.1) in the upper quartile of WHR. The association was limited to subjects who had elevated Quetelet index, but not among those with lower weight. Overall, Quetelet index itself was not related to breast cancer risk in the premenopausal group, but there was a protective association among those ranking below the median WHR. Ln postmenopausal women, the RR for breast cancer increased to 2.36 (95% CI : 1.4-3.9) in the upper quartile of Quetelet index, but there was no association with WHR. Height was not associated with breast cancer in this study.Conclusions The study confirms that excessive body weight increases breast cancer risk in postmenopausal women. On the contrary, in premenopausal women, excessive body weight may be protective among women who have a lower-body type of fat accumulation (low WHR). An upper-body fat accumulation (high WHR) is a predictor of breast cancer risk in premenopausal women, and this effect is especially pronounced among subjects who are overweight.

BACKGROUND, A number of patients who have undergone adjuvant (CMF) chemotherapy for operative primary breast carcinoma have reported impaired cognitive function, sometimes even pears after completion of therapy. The possible role of cytostatic treatment as a causative factor has scarcely been investigated. The objective of the current study was to examine the late effects on neuropsychologic functioning of CMF adjuvant chemotherapy given to patients with breast carcinoma.METHODS. Thirty-nine breast carcinoma patients who had been treated with adjuvant CMF (6 courses) followed (n = 20) by 3 years of tamoxifen 20 mg daily or not (n = 19) were examined with neuropsychologic tests and interviews. The control group consisted of 34 age-matched axillary lymph node negative breast carcinoma patients who received the same surgical and radiation therapy but no systemic adjuvant treatment. The CMF patients were examined a median of 1.9 years after the sixth CMF course, and the controls a median of 2.4 years after surgery of the primary tumor.RESULTS, Patients treated with CMF reported significantly more problems with concentration (31% vs. 6%, P = 0.007) and with memory (21% vs. 3%, P = 0.022) than the control patients. No relation was found between reported complaints and results on the neuropsychologic tests. Impairment in cognitive function was found in 28% of the patients treated with chemotherapy compared with 12% of the patients in the control group (odds ratio 6.4 [95% confidence interval 1.5-27.6] P = 0.013). Hormonal therapy had no influence on patients' self-reports of symptoms or cognitive function. Cognitive impairment Following chemotherapy was noticed in a broad domain of functioning, including attention, mental flexibility, speed of information processing, visual memory, and motor function.CONCLUSIONS. Breast carcinoma patients treated with adjuvant CMF chemotherapy have a significantly higher risk of late cognitive impairment than breast carcinoma patients not treated with chemotherapy (OR 6.4). This cognitive impairment is unaffected by anxiety, depression, fatigue, and time since treatment, and not related to the self-reported complaints of cognitive dysfunction. Cancer 1999;85:640-50. (C) 1999 American Cancer Society.

The new non-steroidal aromatase inhibitor vorozole (R83842) was administered orally at a single daily dose of 2.5 mg to 27 postmenopausal women with advanced breast cancer in a phase II trial as second-line endocrine treatment. The observed objective response rate of 30% and good tolerability of the drug confirm other recent reports. Endocrine determinations during 6 months of treatment demonstrated reduction of serum estrogens: estrone sulfate by more than 60%, estrone by 30-40%, but estradiol by only 10-20%. The ratios of serum androstenedione/estrone and testosterone/estradiol increased significantly, consistent with the inhibition of peripheral aromatase activity. Levels of progesterone, 17-alpha-hydroxyprogesterone, cortisol, dehydroepiandrosterone sulfate, androstenedione and aldosterone remained normal, indicating no interference with adrenocortical steroid synthesis. A general lack of correlation between the observed serum concentrations of vorozole and its effect on hormone serum levels or clinical response was found. This suggests that the determination of such serum levels gives a poor impression of the unambiguous anti-tumor activity of vorozole which may well have its main effect with the tumor tissue itself. The present results are in support of aromatase inhibition, but the possibility of an additional effect on the sulfation of estrogens merits further investigation.

The authors examined the relation between postmenopausal serum levels of testosterone and dehydroepiandrosterone sulfate (DHEAS) and subsequent risk of breast cancer in a case-control study nested within the New York University Women's Health Study cohort. A specific objective of their analysis was to examine whether androgens had an effect on breast cancer risk independent of their effect on the biologic availability of estrogen. A total of 130 cases of breast cancer were diagnosed prior to 1991 in a cohort of 7,054 postmenopausal women who had donated blood and completed questionnaires at a breast cancer screening clinic in New York City between 1985 and 1991. For each case, two controls were selected, matching the case on age at blood donation and length of storage of serum specimens. Biochemical analyses were performed on sera that had been stored at -80 degrees C since sampling. The present report includes a subset of 85 matched sets, for whom at least 6 months had elapsed between blood donation and diagnosis of the case, In univariate analysis, testosterone was positively associated with breast cancer risk (odds ratio (OR) for the highest quartile=2.7, 95% confidence interval (CI) 1.1-6.8, p <0.05, test for trend), However, after including % estradiol bound to sex hormone-binding globulin (SHBG) and total estradiol in the statistical model, the odds ratios associated with higher levels of testosterone were considerably reduced, and there was no longer a significant trend (OR for the highest quartile=1.2, 95% CI 0.4-3.5). Conversely, breast cancer risk remained positively associated with total estradiol levels (OR for the highest quartile=2.9, 95% CI 1.0-8.3) and negatively associated with % estradiol bound to SHBG (OR for the highest quartile=0.05, 95% CI 0.01-0.19) after adjustment for serum testosterone levels. These results are consistent with the hypothesis that testosterone has an indirect effect on breast cancer risk, via its influence on the amount of bioavailable estrogen. No evidence was found of an association between DHEAS and risk of breast cancer in postmenopausal women.

Background. Chylous leakage is an uncommon complication after neck dissection for which several treatment modalities have been described in literature. It occurs in 1% to 2.5% of radical neck dissections, with the majority (75% to 92%) being on the left side. In a consecutive series of patients, we investigated the effect of a systematic approach to the complication.Methods. Over a period of 5 years, the drain production of 221 patients who underwent a neck dissection was analyzed. One hundred thirty-two right-sided and 139 left-sided neck dissections were performed. In 11 patients a chyle fistula occurred, 1 right-sided and 10 left-sided. In all cases closed vacuum suction drainage was continued and dietary modifications (medium-chain triglycerides [MCT]/Peptison(R) nasogastric tube feeding [PNTF]) were made.Results. In 5 patients dietary modifications were sufficient to stop the leak. In the other 6 patients total parenteral nutrition via the subclavian vein (TPN) was started. In 2 cases with a severe intractable hypoalbuminemia, surgical intervention was necessary. The leak was closed by a pectoralis major muscle flap transfer, after local application of fibrin sealant (Tissucol(R)).Conclusions. Chylous leakage is a controllable complication after neck dissection for which in most cases a stepwise conservative approach consisting of dietary modifications, maintaining closed vacuum suction drainage, seems to be sufficient. Hematologic and serum values should be monitored very carefully and corrected appropriately. To initiate planned postoperative radiotherapy in a timely fashion, the conservative treatment should be limited to about 30 days. (C) 1996 John Wiley & Sons, Inc.

The suitability of measuring the S-phase fraction in human breast cancer by labelling tumour cells from fine needle aspirates (FNAs) in vitro with iododeoxyuridine (IdU) was studied in 11 patients. The S-phase fraction was measured both in preoperative FNAs labelled in vitro with IdU, and in FNAs taken from the same tumour when surgically removed after intravenous administration of IdU. Frozen sections were also immunostained for incorporated IdU. The mean S-phase fraction measured in FNAs after in vitro or in vivo labelling and in sections after in vivo labelling was 4.0, 3.6, and 3.1, respectively. Results of in vitro and in vivo labelling of FNAs with IdU were similar. However, as the S-phase fraction in breast cancer is generally low, the variation between the different measurements is too large; therefore, the S-phase fraction is not a suitable indicator of response to treatment.

Insulin‐like growth factor 1 (IGF‐1) is a potent mitogen for human breast‐cancer cells in vitro. In circulation, most of IGF‐1 is bound to IGF‐binding protein 3 (IGFBP‐3). This high‐affinity binding is thought to have an important limiting effect on the availability of IGF‐1 for biological activity. To assess the availability of IGF‐1 for receptor binding, we determined serum levels of IGF‐1 and IGFBP‐3 and IGF‐1/IGFBP‐3 ratios. In a case‐control study, 150 women aged 38 to 75 years presenting with stage‐l or‐II breast cancer were investigated just prior to surgery (n = 76), or to irradiation one month after surgery (n = 74). The population‐based control group consisted of 441 women of the same age having no breast cancer. Women reporting diabetes mellitus or other hormonal abnormalities were excluded. Premenopausal cases showed elevated IGF‐1 serum concentrations, decreased IGFBP‐3 levels and increased IGF‐1/IGFBP‐3 ratios. The IGF‐1/IGFBP‐3 ratio was a significant breast‐cancer risk factor, also after adjustment for age, family history, height, body‐mass index, body‐fat distribution, and serum levels of C‐peptide. The relative risk was 7.34 for the highest compared with the lowest quintile of IGF‐1/IGFBP‐3. The presence or absence of tumor had no influence on these results. Increased levels of available IGF‐1 in the circulation of pre‐menopausal women may contribute to the development of breast cancer. © 1995 Wiley‐Liss Inc.

Pamidronate is a potent biphosphonate which modulates tumour-induced osteolysis (TIO) by inhibiting osteoclast-mediated bone resorption. In a phase II trial, 69 breast cancer patients with symptomatic progressive bone metastases were given infusions of pamidronate 60 mg over 1 or 4 h every 2 weeks for a maximum of 13 infusions or until progressive disease (PD) at any site. No other systemic anticancer therapy was allowed. Pain was measured using a visual analogue scale, mobility using a detailed eight-point questionnaire and analgesic intake using a six-point scale. Improvements in pain, mobility and analgesic scores occurred in 61, 50 and 30% of patients, respectively, with 33, 21 and 16% achieving a 40% improvement for > or = 8 weeks. At trial discontinuation, baseline levels of pain and mobility had improved by 27% (P = 0.001) and 20% (P = 0.004), respectively, despite a one category reduction in analgesic intake in 27% of patients. Using this relatively high dose of pamidronate, symptomatic response was independent of the number of bone metastases and also of infusion rate. The infusions were well tolerated with no major toxicities reported. Pamidronate infusions provide useful palliation for breast cancer patients with symptomatic bone metastases.

BACKGROUND:The heterogenous composition of tumors is a major obstacle for the measurement of mRNA levels in cancer cells. We report here a combination of immunomagnetic purification of cancer cells and reverse transcriptase polymerase chain reaction (RT-PCR) that enables highly sensitive detection of multidrug resistance gene 1 (MDR1)-mRNA levels in human breast carcinoma cells obtained from fine needle aspirates (FNA).EXPERIMENTAL DESIGN:Murine mAb 115D8 directed against episialin (MUC1/MAM6, epithelial membrane Ag) was used in combination with goat anti-mouse-coated magnetic microbeads to purify human T47D breast carcinoma cells (115D8+, MDR1-) from different mixtures with COLO320 human colon carcinoma cells (115D8-, MDR1+) and to purify carcinoma cells from FNA taken from axillary lymph node metastases in breast cancer patients. The efficacy of the purification was determined by FACS-analysis and by measurement of MDR1-mRNA levels by semiquantitative RT-PCR.RESULTS:FACS-analysis demonstrated that T47D cells could be purified up to 99.8% from mixtures with COLO320 cells ranging from 3:1 to 1:3. The MDR1-mRNA level in these enriched mixtures, as detected by RT-PCR, was reduced 250-fold. It was demonstrated that MDR1 expression present in an FNA from a lymph node metastasis of breast carcinoma could be attributed completely to the leukocytes present in this FNA, because MDR1 expression was no longer detectable after purification of the tumor cells.CONCLUSION:The combination of immunomagnetic purification of breast carcinoma cells and RT-PCR enables the measurement of cancer-specific MDR1 mRNA levels in small cell samples obtained by FNA.

Myocardial adrenergic neuron integrity and function were evaluated in 21 patients who had received doxorubicin or epirubicin for various malignancies. Myocardial uptake of iodine-123 metaiodobenzylguanidine ([123I]MIBG), a marker suitable for the study of myocardial neuron injury, was calculated from planar scintigraphic images after 4 h and the washout between 15 min and 4 h. In 13 patients with normal left ventricle ejection fraction (LVEF) analysed at three cumulative dose levels (no, low and middle dose), [123I]MIBG uptake tended to be significantly impaired (z = -2.772, P = 0.0056), at higher cumulative dose levels, before significant LVEF changes were observed. [123I]MIBG values were considerably decreased in 2/7 patients investigated at low cumulative dose and in 3/8 cases at the middle dose level. On follow-up, 1 of these patients, who had normal LVEF after completion of chemotherapy but whose [123I]MIBG values had progressively deteriorated during anthracycline therapy, subsequently developed congestive heart failure; another patient, whose [123I]MIBG values were impaired at the middle dose level, developed persistent reduced LVEF 5 months after completing therapy. In 8 patients, who had developed persistently, reduced LVEF at high doxorubicin cumulative dose levels, [123I]MIBG, performed in the period after chemotherapy discontinuation, was invariably abnormal. These data suggest that myocardial adrenergic derangement plays a role in anthracycline-associated cardiotoxicity: its appearance, even at low cumulative anthracycline dose levels, may reflect impairment of the intravesicular norepinephrine storage by incipient anthracycline-associated cardiac neuron injury. [123I]MIBG scintigraphy may be useful to assess myocardial adrenergic derangement during and in the follow-up of anthracycline therapy and potentially detect patients who are at risk.

BACKGROUND:The large majority of studies of the quality of life of cancer survivors has been carried out in the United States, and has employed a follow-up period of less than 10 years. As one cannot assume that the results of these studies can be generalized to the European setting, a study was undertaken of the quality of life of long-term survivors of Hodgkin's disease in The Netherlands.PATIENTS AND METHODS:The patient sample was composed of 81 former Hodgkin's disease patients who had been treated in The Netherlands Cancer Institute in the period between 1972 and 1979, and who had remained disease-free since the time of initial treatment. One hundred sixteen hospital visitors, matched for age and statistically adjusted for gender, formed a control group. A Dutch translation of the MOS 36-Item Short-Form Health Survey (SF-36) was used to assess a range of health status and quality-of-life domains. Also included were two multi-item scales assessing intimacy and sexuality, and a range of single items assessing finances, insurance and work status.RESULTS:In comparison with the healthy controls, cases reported significantly: (1) more restrictions in physical functioning (primarily in strenuous levels of activity) and in role functioning (work and daily activities); (2) lower perceived overall health; (3) less satisfaction with their sexual lives; (4) greater difficulty in obtaining financial loans and life insurance; and (5) more health-related employment limitations. No significant differences were noted between cases and controls in social functioning, bodily pain, mental health, vitality, satisfaction with the (non-sexual side of the) partner relationship, or in obtaining health insurance.CONCLUSIONS:The self-reported health status and quality of life of recurrence-free survivors of Hodgkin's disease is still affected 10 to 18 years after treatment. In particular, physical and role functioning, sexuality, and overall health perceptions appear to be compromised. While some evidence of discrimination against former cancer patients was found, the magnitude of such problems appears to be lower in the Netherlands than in the United States.

Background: In patients with cardiac dysfunction due to anthracycline-induced myocyte damage, continuation of anthracyclines carries a high risk, and modification of chemotherapy is thus indicated. The condition, however, must be distinguished from other causes of cardiac dysfunction, e.g., the transient negative inotropic effect which may accompany and follow the intravenous administration of anthracyclines. In the present study the efficacy of In-111-antimyosin in confirming myocyte injury and its potential applicability in differentiating causes of cardiac dysfunction during anthracycline therapy are evaluated.Patients and methods: Twenty-seven patients with asymptomatic left ventricle ejection fraction (LVEF) decrease (median LVEF 47%, range 38%-50%) during chemotherapy with anthracyclines (dose range 100-700 mg/m2 doxorubicin or equivalent) were subsequently studied with In-111-antimyosin cardiac scintigraphy. The degree of myocardial uptake, an indicator of heart muscle cell injury, evaluated both visually and quantitatively by means of heart-to-lung ratios (HLR) obtained from 48-hour planar images, was analyzed in relation to the further clinical and LVEF course. The results were also compared with In-111-antimyosin data from 5 patients wo had normal LVEF during chemotherapy and 5 patients who had received no anthracyclines. The distribution pattern of myocardial uptake was assessed by means of single photon emission computed tomography (SPECT).Results: a) Fourteen patients presented with persistent LVEF decrease (median LVEF 42.5%, range 32%-47%) after discontinuation of anthracycline therapy. In 11 of these patients intense and diffuse, as shown by SPECT, cardiac uptake of In-111-antimyosin (HLR 1.87-2.45) was observed. In two patients with intense antimyosin cardiac uptake, spurious HLR values (1.23-1.55) were found which were caused by unexpected lung uptake and focal heart uptake, respectively. All patients with intense cardiac In-111-antimyosin uptake showed persistently decreased LVEF on follow-up (4-26 weeks) and 4 of them subsequently developed congestive heart failure. In another patient with no intense uptake (HLR 1.15) and persistent decrease in LVEF, metastatic cardiac involvement was found. b) In 13 patients with improvement or normalisation of the LVEF (median LVEF 53%, range 51%-63%), generally less intense or slight cardiac uptake (HLR range: 1.20-1.88) was seen; the HLR in these patients, who continued chemotherapy without complications, was consistently lower (p < 0.01) than in patients with persistently decreased LVEF, and comparable to values of patients who had normal LVEF.Conclusions: In-111-antimyosin scintigraphy can be useful to differentiate cardiac dysfunction caused by severe myocardial injury from temporary decreases in LVEF, without severe concomitant myocyte damage, which may occur during anthracycline therapy. Intense myocardial uptake of In-111-antimyosin can be used as an important confirmatory criterium for the clinical decision to discontinue anthracycline therapy.

The particular use of lymphoscintigraphy to document retention and drainage in cystic lymphangioma of the neck is reported. Radionuclide examination using Tc-99m colliod particles, performed before sclerosing treatment with tetracycline in a patient with a large lymphangioma located in the neck, demonstrated a satisfactory tumor retention and slow outflow, enabling the administration of tetracycline without (risk of) organ toxicity. The treatment was successfully performed.