Prescription opioid analgesics for pain management in Australia: 20 years of dispensing.

BACKGROUND: Opioid prescribing/dispensing data can inform policy surrounding regulation by informing trends and types of opioid prescribed and geographic variations. In Australia so far only partial data on dispensing have been published, and data for states/territories remain unknown. AIM: Using a range of measures, this study examines 20-year (1992-2011) trends in prescription opioid analgesics in Australia - both nationally and for individual jurisdictions. METHODS: Dispensing data were obtained from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) websites. Trends in numbers of prescriptions and daily defined dose (DDD)/1000 people/day were examined over time and across states/territories. Seasonal variations in PBS/Repatriation Pharmaceutical Benefits Scheme (RPBS) items for nationwide dispensing were adjusted using a centred moving smoothing technique. RESULTS: In two decades, 165.32 million prescriptions for opioids were dispensed, with codeine and its derivatives the most prescribed formulation (50.1%) followed by tramadol (13.5%) and oxycodone derivatives (12.7%). In terms of DDD/1000 people/day, dispensing increased from 5.38 in 1992 to 14.46 in 2011. There are significant increasing trends for total, PBS/RPBS and under co-payment prescriptions (priced below patient co-payment). The DDD/1000 people/day for items dispensed through PBS/RPBS was highest in Tasmania. CONCLUSION: Prescription opioid dispensing increased substantially over the study period. With an ageing population, this trend is likely to continue in future. A growing concern about harms associated with opioid use warrants balanced control measures so that harms could be minimised without reducing effective pain treatment. Research examining utilisation in small geographic areas may help design spatially tailored interventions. A real-time drug-monitoring programme may reduce undue prescribing and dispensing.

Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians.

BACKGROUND: Clinically relevant genetics knowledge is essential for appropriate assessment and management of inherited cancer risk, and for effective communication with patients. This national physician survey assessed knowledge regarding basic cancer genetics concepts early in the process of introduction of predictive genetic testing for breast/ovarian and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. METHODS: A stratified random sample was selected from the American Medical Association Masterfile of all licensed physicians. In total, 1251 physicians (820 in primary care, 431 in selected subspecialties) responded to a 15 minute questionnaire (response rate 71%) in 1999-2000. Multivariate logistic regression analyses were conducted to identify demographic and practice characteristics associated with accurate response to three knowledge questions. RESULTS: Of the study population, 37.5% was aware of paternal inheritance of BRCA1/2 mutations, and 33.8% recognised that these mutations occur in <10% of breast cancer patients. Only 13.1% accurately identified HNPCC gene penetrance as >or=50%. Obstetrics/gynaecology physicians, oncologists, and general surgeons were significantly more likely than general and family practitioners to respond accurately to the breast/ovarian questions, as were gastroenterologists to the HNPCC question. CONCLUSIONS: These nationally representative data indicate limited physician knowledge about key cancer genetics concepts in 1999-2000, particularly among general primary care physicians. Specialists were more knowledgeable about syndromes they might treat or refer elsewhere. Recent dissemination of practice guidelines and continued expansion of relevant clinical literature may enhance knowledge over time. In addition to educational efforts to assist physicians with the growing knowledge base, more research is needed to characterise the organisational changes required within the healthcare system to provide effective cancer genetics services.

Effect of estrogen replacement therapy on the specificity and sensitivity of screening mammography.

BACKGROUND: Previous studies have demonstrated that mammographic breast density increases following the initiation of estrogen replacement therapy (ERT). The effect, if any, that this increase in density has on the specificity (related to false-positive readings) and the sensitivity (related to false-negative readings) of screening mammography is unknown. PURPOSE: Using a retrospective cohort study design, we assessed the effects of ERT on the specificity and the sensitivity of screening mammography. METHODS: Participants (n = 8779) were postmenopausal women, aged 50 years or older, who were enrolled in a health maintenance organization located in western Washington state and who entered a breast cancer screening program between January 1988 and June 1993. Two-view mammography was performed as part of a comprehensive breast cancer screening visit. Menopausal status, as well as demographic and risk-factor information, was recorded via self-administered questionnaires. Hormonal replacement therapy type and use were determined from questionnaire data and from an automated review of pharmacy records. Individuals diagnosed with breast cancer within 12 months of their first screening-program mammograms were identified through use of a regional cancer registry. Risk ratios (RRs) plus 95% confidence intervals (CIs) of false-positive as well as false-negative examinations among current and former ERT users (with never users as the reference group) were calculated. Reported P values are two-sided. RESULTS: The specificity of mammographic screening was lower for current users of ERT than for never users or former users. Defining a positive mammographic reading as any non-normal reading (either suspicious for cancer or indeterminate), the adjusted RR (95% CI) of a false-positive reading for current users versus never users was 1.33 (1.15-1.54) (P < .001); for former users versus never users, the RR (95% CI) was 1.00 (0.87-1.15). The adjusted mammographic specificities (95% CIs) for never users, former users, and current users of ERT were 86% (84%-88%), 86% (84%-87%), and 82% (80%-84%), respectively. Defining a positive reading more rigorously (i.e., as suspicious for cancer only), the adjusted RRs (95% CIs) of false-positive readings for current users and former users (versus never users) were 1.71 (1.37-2.14) (P < .001) and 1.16 (0.93-1.45), respectively. Sensitivity was also lower in women currently receiving ERT. The unadjusted RR (95% CI) of a false-negative reading for current users versus never users was 5.23 (1.09-25.02) (P = .04); for former users versus never users, the RR (95% CI) was 1.06 (0.10-10.87). The unadjusted mammographic sensitivities (95% CI) for never users, former users, and current users of ERT were 94% (80%-99%), 94% (69%-99%), and 69% (38%-91%), respectively. CONCLUSIONS AND IMPLICATIONS: Current use of ERT is associated with lower specificity and lower sensitivity of screening mammography. Lower specificity could increase the cost of breast cancer screening, and lower sensitivity may decrease its effectiveness.

Cost comparison of mastectomy versus breast-conserving therapy for early-stage breast cancer.

BACKGROUND: Choice of treatment for early-stage breast cancer depends on many factors, including the size and stage of the cancer, the woman's age, comorbid conditions, and perhaps the costs of treatment. We compared the costs of all medical care for women with early-stage breast cancer cases treated by breast-conserving therapy (BCT) or mastectomy. METHODS: A total of 1675 women 35 years old or older with incident early-stage breast cancer were identified in a large regional nonprofit health maintenance organization in the period 1990 through 1997. The women were treated with mastectomy only (n = 183), mastectomy with adjuvant hormonal therapy or chemotherapy (n = 417), BCT with radiation therapy (n = 405), or BCT with radiation therapy and adjuvant hormonal therapy or chemotherapy (n = 670). The costs of all medical care for the period 1990 through 1998 were computed for each woman, and monthly costs were analyzed by treatment, adjusting for age and cancer stage. All statistical tests were two-sided. RESULTS: At 6 months after diagnosis, the mean total medical care costs for the four groups differed statistically significantly (P:<.001), with BCT being more expensive than mastectomy. The adjusted mean costs were $12 987, $14 309, $14 963, and $15 779 for mastectomy alone, mastectomy with adjuvant therapy, BCT plus radiation therapy, and BCT plus radiation therapy with adjuvant therapy, respectively. At 1 year, the difference in costs was still statistically significant (P:<.001), but costs were influenced more by the use of adjuvant therapy than by type of surgery. The 1-year adjusted mean costs were $16 704, $18 856, $17 344, and $19 081, respectively, for the four groups. By 5 years, BCT was less expensive than mastectomy (P:<.001), with 5-year adjusted mean costs of $41 930, $45 670, $35 787, and $39 926, respectively. Costs also varied by age, with women under 65 years having higher treatment costs than older women. CONCLUSIONS: BCT may have higher short-term costs but lower long-term costs than mastectomy.

Stage, age, comorbidity, and direct costs of colon, prostate, and breast cancer care.

PURPOSE: This study was conducted to evaluate the effect of stage at diagnosis, age, and level of comorbidity (presence of other illness) on the costs of treating three types of cancer among members of a health maintenance organization. METHODS: Among 388,000 members enrolled anytime during 1990 and 1991 in Group Health Cooperative (GHC) of Puget Sound (Washington State), we estimated the total and net direct costs of medical care for colon, prostate, and breast cancers, including both incident (290, 554, and 645 patients, respectively) and prevalent (1046, 1295, and 2299 patients, respectively) cases. We summarized costs for initial, continuing, and terminal phases of care. Net costs were the difference between the costs of the care of each case subject and the average costs of the care for all enrollees without the cancer of interest who were of the same sex and in the same 5-year age group. Differences in estimated total and net costs by stage at diagnosis, age, and comorbidity were separately evaluated using multivariate regression modeling. All P values were two-sided. Comorbidity was based on a score calculated from 1988 pharmacy data. RESULTS: Total costs of initial care increased with stage at diagnosis for colon (P = .0013) and breast (P < .0001) cancer cases, but not for prostate cancer cases. Total initial costs decreased with age for prostate (P = .0225) and breast (P = .0002) cancers but did not change with degree of comorbidity for any of the three cancers. Total continuing medical care costs increased with stage at diagnosis for colon (P < .0001) and breast (P < .0001) cancer cases but not for prostate cancer cases. Total terminal care costs were similar by stage for all three cancers. Net initial costs differed with stage for all three cancers (P < .05). Net continuing care costs increased with stage (P < .0001) and decreased with age (P < .001) for colon and breast cancers but not for prostate cancer. Net continuing care costs decreased with comorbidity for all three cancers (P = .004, P = .011, and P < .0001 for colon, prostate, and breast cancers, respectively). Among regional stage cancers, continuing care costs decreased with age for colon (P < .0017) and breast (P = .033) cancers but not for prostate cancers. CONCLUSIONS: The results show that total costs vary by stage at diagnosis and age, but the patterns of variation differ for each cancer. Costs of cancer are not simply additive to costs of other conditions. IMPLICATIONS: More needs to be done to explore the reasons and implications of age-related cost differences. Cost-effectiveness analyses of cancer control interventions that shift cancer stage distributions may need to consider both the age and comorbidity of the target populations.

Testing reminder and motivational telephone calls to increase screening mammography: a randomized study.

BACKGROUND: Prospective randomized trials have demonstrated that motivational telephone calls increase adherence to screening mammography. To better understand the effects of motivational calls and to maximize adherence, we conducted a randomized trial among women aged 50-79 years. METHODS: We created a stratified random sample of 5062 women due for mammograms within the Group Health Cooperative of Puget Sound, including 4099 women with prior mammography and 963 without it. We recruited and surveyed 3743 (74%) of the women before mailing a recommendation. After 2 months, 1765 (47%) of the 3743 women had not scheduled a mammogram and were randomly assigned to one of three intervention groups: a reminder post-card group (n = 590), a reminder telephone call group (n = 585), and a motivational telephone call addressing barriers group (n = 590). The telephone callers could schedule mammography. We used Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence interval (CI) for documented mammography use by 1 year. RESULTS: Women who received reminder calls were more likely to get mammograms (HR = 1.9; 95% CI = 1.6-2.4) than women who were mailed postcards. The motivational and reminder calls (average length, 8.5 and 3.1 minutes, respectively) had equivalent effects (HR = 0.97; 95% CI = 0.8-1.2). After we controlled for the intervention effect, women with prior mammography (n = 1277) were much more likely to get a mammogram (HR = 3.4; 95% CI = 2.7-4.3) than women without prior use (n = 488). Higher income, but not race or more education, was associated with higher adherence. CONCLUSIONS: Reminding women to schedule an appointment was as efficacious as addressing barriers. Simple intervention groups should be included as comparison groups in randomized trials so that we better understand more complex intervention effects.

Breast cancer survival and treatment in health maintenance organization and fee-for-service settings.

BACKGROUND: Enrollment in health maintenance organizations (HMOs) has increased rapidly during the past 10 years, reflecting a growing emphasis on health care cost containment. To determine whether there is a difference in the treatment and outcome for female patients with breast cancer enrolled in HMOs versus a fee-for-service setting, we compared the 10-year survival and initial treatment of patients with breast cancer enrolled in both types of plans. METHODS: With the use of tumor registries covering the greater San Francisco-Oakland and Seattle-Puget Sound areas, respectively, we obtained information on the treatment and outcome for 13,358 female patients with breast cancer, aged 65 years and older, diagnosed between 1985 and 1992. We linked registry information with Medicare data and data from the two large HMOs included in the study. We compared the survival and treatment differences between HMO and fee-for-service care after adjusting for tumor stage, comorbidity, and sociodemographic characteristics. RESULTS: In San Francisco-Oakland, the 10-year adjusted risk ratio for breast cancer deaths among HMO patients compared with fee-for-service patients was 0.71 (95% confidence interval [CI] = 0.59-0.87) and was comparable for all deaths. In Seattle-Puget Sound, the risk ratio for breast cancer deaths was 1.01 (95% CI = 0.77-1.33) but somewhat lower for all deaths. Women enrolled in HMOs were more likely to receive breast-conserving surgery than women in fee-for-service (odds ratio = 1.55 in San Francisco-Oakland; 3.39 in Seattle). HMO enrollees undergoing breast-conserving surgery were also more likely to receive adjuvant radiotherapy (San Francisco-Oakland odds ratio = 2.49; Seattle odds ratio = 4.62). CONCLUSIONS: Long-term survival outcomes in the two prepaid group practice HMOs in this study were at least equal to, and possibly better than, outcomes in the fee-for-service system. In addition, the use of recommended therapy for early stage breast cancer was more frequent in the two HMOs.

Variation in mammographic breast density by time in menstrual cycle among women aged 40-49 years.

BACKGROUND: Mammography is less effective for women aged 40-49 years than for older women, which has led to a call for research to improve the performance of screening mammography for younger women. One factor that may influence the performance of mammography is breast density. Younger women have greater mammographic breast density on average, and increased breast density increases the likelihood of false-negative and false-positive mammograms. We investigated whether breast density varies according to time in a woman's menstrual cycle. METHODS: Premenopausal women aged 40-49 years who were not on exogenous hormones and who had a screening mammogram at a large health maintenance organization during 1996 were studied (n = 2591). Time in the menstrual cycle was based on the woman's self-reported last menstrual bleeding and usual cycle length. RESULTS: A smaller proportion of women had "extremely dense" breasts during the follicular phase of their menstrual cycle (24% for week 1 and 23% for week 2) than during the luteal phase (28% for both weeks 3 and 4) (two-sided P = .04 for the difference in breast density between the phases, adjusted for body mass index). The relationship was stronger for women whose body mass index was less than or equal to the median (two-sided P<.01), the group who have the greatest breast density. CONCLUSIONS/IMPLICATIONS: These findings are consistent with previous evidence suggesting that scheduling a woman's mammogram during the follicular phase (first and second week) of her menstrual cycle instead of during the luteal phase (third and fourth week) may improve the accuracy of mammography for premenopausal women in their forties. Breast tissue is less radiographically dense in the follicular phase than in the luteal phase.

Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers.

BACKGROUND: Screening mammography is the best method to reduce mortality from breast cancer, yet some breast cancers cannot be detected by mammography. Cancers diagnosed after a negative mammogram are known as interval cancers. This study investigated whether mammographic breast density is related to the risk of interval cancer. METHODS: Subjects were selected from women participating in mammographic screening from 1988 through 1993 in a large health maintenance organization based in Seattle, WA. Women were eligible for the study if they had been diagnosed with a first primary invasive breast cancer within 24 months of a screening mammogram and before a subsequent one. Interval cancer case subjects (n = 149) were women whose breast cancer occurred after a negative or benign mammographic assessment. Screen-detected control subjects (n = 388) were diagnosed after a positive screening mammogram. One radiologist, who was blinded to cancer status, assessed breast density by use of the American College of Radiology Breast Imaging Reporting and Data System. RESULTS: Mammographic sensitivity (i.e., the ability of mammography to detect a cancer) was 80% among women with predominantly fatty breasts but just 30% in women with extremely dense breasts. The odds ratio (OR) for interval cancer among women with extremely dense breasts was 6.14 (95% confidence interval [CI] = 1.95-19.4), compared with women with extremely fatty breasts, after adjustment for age at index mammogram, menopausal status, use of hormone replacement therapy, and body mass index. When only those interval cancer cases confirmed by retrospective review of index mammograms were considered, the OR increased to 9.47 (95% CI = 2.78-32.3). CONCLUSION: Mammographic breast density appears to be a major risk factor for interval cancer.

Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers.

BACKGROUND: Although mammographic screening is useful for detecting early breast cancer, some tumors are detected in the interval between screening examinations. This study attempted to characterize fully the tumors detected in the two different manners. METHODS: Our study utilized a case-control design and involved a cohort of women undergoing mammographic screening within the defined population of a health maintenance organization (the Group Health Cooperative of Puget Sound). Women were classified as having "interval" or "interval-detected" cancers (n = 150) if their diagnosis was made within 24 months after a negative-screening mammogram or one that indicated a benign condition. Cancers were classified as "screen detected" (n = 279) if the diagnosis occurred after a positive assessment by screening mammography. Tumors from women in each group were evaluated for clinical presentation, histology, proliferative characteristics, and expression of hormone receptors, p53 tumor suppressor protein, and c-erbB-2 protein. RESULTS: Interval-detected cancers occurred more in younger women and were of larger tumor size than screen-detected cancers. In unconditional logistic regression models adjusted for age and tumor size, tumors with lobular (odds ratio [OR] = 1.9; 95% confidence interval [CI] = 0.9-4.2) or mucinous (OR = 5.5; 95% CI = 1.5-19.4) histology, high proliferation (by either mitotic count [OR = 2.9; 95% CI = 1.5-5.7] or Ki-67 antigen expression [OR = 2.3; 95% CI = 1.3-4.1]), high histologic grade (OR = 2.1; 95% CI = 1.2-4.0), high nuclear grade (OR = 2.0; 95% CI = 1.0-3.7), or negative estrogen receptor status (OR = 1.8; 95% CI = 1.0-3.1) were more likely to surface in the interval between screening examinations. Tumors with tubular histology (OR = 0.2; 95% CI = 0.0-0.8) or with a high percentage of in situ components (50%) (OR = 0.5; 95% CI = 0.2-1.2) were associated with an increased likelihood of screen detection. CONCLUSIONS: Our data from a large group of women in a defined population indicate that screening mammography may miss tumors of lobular or mucinous histology and some rapidly proliferating, high-grade tumors.

Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys.

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.

Repeat mammography use among women ages 50-75.

It has been demonstrated clearly that the use of regular screening mammography reduces mortality among women ages 50 years and over. The primary objective of this study was to investigate factors associated with repeat mammography participation. A random sample of women ages 50-75 years residing in four Washington State counties was surveyed by telephone during mid-1989. The Health Belief Model was used as a conceptual framework for the analysis. Three groups of women with different mammography experiences in the previous 5 years were compared: (a) nonusers; (b) onetime users; and (c) repeat users. The survey response rate was 72%, and the study sample included 1357 women. One time users were more likely to have health insurance coverage, to visit a gynecologist or other primary care physician regularly, and to believe mammography is more effective than breast self-examination; they were less likely to think that at least 1 in 10 women are diagnosed with breast cancer or that mammography is inconvenient to obtain than were nonusers. Factors associated with repeat versus onetime use included routinely visiting a gynecologist, thinking the lifetime risk of breast cancer is at least 10%, and perceiving a high personal susceptibility to disease. Women who perceive themselves as being vulnerable to breast cancer are more likely to report repeat mammograms. Visiting a gynecologist regularly is associated with repeat as well as initial mammography use. These factors could be considered as the focus of promotional efforts moves from encouraging women to obtain their first mammogram to encouraging repeat use.

Exploring environmental barriers to participation in mammography screening in an HMO.

Despite an upward trend in mammography screening rates, rates among some demographic subgroups and rates of annual mammography remain low. Behavioral-based interventions which move beyond invitational strategies to help women overcome their personal barriers may be necessary to increase participation. We developed a heuristic model based on the Health Belief Model and Social Learning Theory with the central hypothesis that the relative importance of environmental barriers in predicting screening behavior is a function of the woman's perceived risk, preventive orientation, and/or concerns about mammography. We completed telephone interviews with 313 women who did not obtain a mammogram and 350 women who had a mammogram within 365 days of an invitation from a Health Maintenance Organization-based breast cancer screening program. Results of multivariate analyses indicated that perceived risk did not mitigate the influence of logistic inconveniences associated with obtaining a mammogram. Preventive orientation as measured by smoking status interacted with belief that symptoms are a necessary prerequisite to a mammogram as a powerful predictor of participation; the greatest negative impact of concerns on participation was found among smokers. A similar relationship between concerns and participation, although only marginally significant, was observed among those who perceived it to be difficult to get to the screening center. Implications of the results for development of behavioral interventions and additional research are discussed.

Mammography diffusion and trends in late-stage breast cancer: evaluating outcomes in a population.

The purpose of this study was to assess mammography diffusion in a population offered an organized breast cancer screening program, using intervals of 1-3 years, and to evaluate its effect on the late-stage cancer (tumors > or = 3 cm2) rates compared to rates in the surrounding community. We measured "ever-use" of mammography (1986-1992) among women enrollees of a consumer-controlled health care organization (n > or = 60,000/year; ages > or = 40), Group Health Cooperative of Puget Sound (GHC). Among these same women and the surrounding community (n = > or = 745,000/year), we measured late-stage cancer rates. Using unconditional logistic regression, we compared annual rates of ever-use among GHC women ages 40-49 and > or = 50 (1986-1992) and late-stage breast cancer (1983/84-1991/92) among all women. Among all GHC women ages 40 to 49, and 50 years of age and older, 67.4 and 82.8%, respectively, ever-used mammography by 1992. By 1992, approximately one-third of the mammograms among GHC women occurred in each of the three previous years. The rate of late-stage tumors declined significantly in the GHC and non-GHC populations among women 50 years of age and older (P < 0.001) but not among women ages 40 to 49. In conclusion, implementing a system of automated reminders was not sufficient to maximize mammography use in a population. Reductions in late-stage disease occurred among women ages > or = 50, even when regular" was not synonymous with "annual."

Trimetrexate: review and current clinical experience in advanced colorectal cancer.

Unresectable metastatic colorectal cancer remains a significant cause of morbidity and mortality in both the United States and Europe. To date, no chemotherapeutic regimen for this disease has demonstrated a definitive survival advantage compared with 5-fluorouracil (5-FU) plus leucovorin (LV). However, recent trials have raised the possibility that the combination of trimetrexate (TMTX) plus 5-FU/LV may improve response rates and survival in patients with metastatic colorectal cancer. Trimetrexate is a nonclassical antifolate that has demonstrated antitumor activity against a number of malignancies, including those resistant to the classical antifolate methotrexate. While the single-agent activity of TMTX remains modest in metastatic colorectal cancer, the combination of TMTX/5-FU/LV has shown significant activity in several phase II trials. Reported studies include a phase II trial in chemotherapy failures that demonstrated a 20% response rate, and two multicenter phase II trials in previously untreated patients that demonstrated 50% and 38% overall response rates, respectively. Diarrhea was the dose-limiting toxicity in all trials, although a regimen of scheduled loperamide was quite effective in mitigating this complication. These studies are being followed up with two confirmatory phase II studies in chemorefractory patients and two randomized phase III trials comparing TMTX/5-FU/LV with standard 5-FU/LV.

Nursing care strategies for the management of side effects in patients treated for colorectal cancer.

Oncology nurses play a critical role in the detection and management of adverse effects resulting from the toxicity of colorectal cancer (CRC) treatment regimens. Standard chemotherapy for CRC involves combination 5-fluorouracil plus leucovorin, a regimen with a well-characterized toxicity profile that includes abdominal cramping and diarrhea, nausea and vomiting, skin and hypersensitivity reactions, fatigue, stomatitis, neutropenia and thrombocytopenia, and alopecia. Diarrhea is the principal dose-limiting toxicity. Trimetrexate, a nonclassical antifolate, is currently being investigated in combination with 5-fluorouracil/leucovorin in phase II/III trials. In addition to the management of side effects, the psychosocial and educational needs of CRC patients require attention. The rigorous treatment schedule presents patients with multiple obstacles in daily living, significantly impacting their quality of life. The oncology nurse is vital in managing the care of CRC patients and ensuring that their physical, psychosocial, and educational needs are met. Educating patients about adverse treatment effects empowers them to manage their symptoms and enables them to alleviate serious or life-threatening treatment complications. Three case studies are provided to illustrate and reinforce nursing management strategies for hypersensitivity reactions, fatigue, and psychosocial issues related to CRC treatment.

Variation in mammographic breast density by race.

PURPOSE: Because of the observed racial differences in risk of developing breast cancer, the authors conducted a study to determine the variation in breast density, a strong predictor of breast cancer risk, by race and age. METHODS: Study subjects were women enrolled in Group Health Cooperative of Puget Sound, Seattle, WA, aged 20-79 years, who had a screening mammogram between 6/1/96 and 8/1/97. Women with increased breast density (BI-RADS "heterogeneously dense" and "extremely dense") (n = 14,178) were compared to those with fatty breasts (BI-RADS "almost entirely fat" and "scattered fibroglandular tissue") (n = 14,323). Logistic regression was used with adjustment for age, parity, age at first birth, menopausal status, current use of hormone replacement therapy, and body mass index. RESULTS: The odds ratio (OR) for having dense breasts versus fatty breasts, comparing Asian to White women, increased from 1.2 [95% confidence interval (CI) 0.9-1.6] for women age <45 to 1.6 (95% CI 1.3-2.2) for women over 65. Conversely, the OR for Black compared to White women was highest for the women age 65 and younger (OR 1.7 (1.2-2.3), 1.3(1.0-1.7), and 1.7 (1.2-2.3) for women age <45, 46-55, and 56-65, respectively), whereas Black women over 65 had similar density as Whites. Hispanic women had similar density compared to Whites for all ages. CONCLUSIONS: These racial differences in breast density generally do not conform to differences in race and age-specific breast cancer incidence rates.

Assessing mammographers' accuracy. A comparison of clinical and test performance.

Direct estimation of mammographers' clinical accuracy requires the ability to capture screening assessments and correctly identify which screened women have breast cancer. This clinical information is often unavailable and when it is available its observational nature can cause analytic problems. Problems with clinical data have led some researchers to evaluate mammographers using a single set of films. Research based on these test film sets implicitly assumes a correspondence between mammographers' accuracy in the test setting and their accuracy in a clinical setting. However, there is no evidence supporting this basic assumption. In this article we use hierarchical models and data from 27 mammographers to directly compare accuracy estimated from clinical practice data to accuracy estimated from a test film set. We found moderate positive correlation [ rho; = 0.206 with 95% credible interval (-0.142-0. 488)] between mammographers' overall preponderance to call a mammogram positive. However, we found no evidence of correlation between clinical and test accuracy [ rho; = -0.025 with 95% credible interval (-0.484-0.447)]. This study is limited by the relatively small number of mammographers evaluated, by the somewhat restricted range of observed sensitivities and specificities, and by differences in the types of films evaluated in test and clinical datasets. Nonetheless, these findings raise important questions about how mammographer accuracy should be measured.

Change in the use of breast-conserving surgery in western Washington after the 1990 NIH Consensus Development Conference.

OBJECTIVE: To evaluate the use of breast-conserving surgery in western Washington before and after the National Institutes of Health Consensus Development Conference (June 18-21, 1990) during which breast-conserving surgery was recommended for most women with early invasive breast cancer. DESIGN: Survey. SETTING: Population-based cancer registry in the Seattle-Puget Sound (Washington) region. PARTICIPANTS: The survey included 13541 women in whom American Joint Committee on Cancer stage I or II breast cancer was diagnosed between January 1, 1983, and December 31, 1993. MAIN OUTCOME MEASURE: Proportion of participants who underwent breast-conserving surgery. RESULTS: From April 1985, after results of a US randomized controlled trial showing equivalent survival in women undergoing mastectomy or breast-conserving surgery were published, to the time of the Conference, breast-conserving surgery was performed on 44.8% of women with stage I and 25.8% with stage II breast cancer. These percentages increased to 54.9% and 35.2%, respectively, during the post-Conference period. While women with stage II breast cancer were less likely than women with stage I breast cancer to undergo breast-conserving surgery before and after the Conference, trends for age and education were attenuated after the Conference. Differences in the use of breast-conserving surgery observed before the Conference between countries of residence and among hospital types were also reduced after the Conference. CONCLUSIONS: These findings suggest that the Conference recommendations had an effect on the adoption of breast-conserving surgery, particularly among groups who were previously least likely to undergo such surgery. Despite progress toward the Conference recommendation that the majority of women with early invasive breast cancer undergo breast-conserving surgery, the majority of women with stage II breast cancer undergo mastectomy.

Quality assurance for screening mammography: an international comparison.

STUDY OBJECTIVE: In 1998, the International Breast Cancer Screening Network (IBSN) sponsored an assessment of quality assurance policies and practices to define their scope for population-based screening mammography programmes across IBSN countries. DESIGN: Analysis of data from a survey designed to assess multiple elements of screening programme quality assurance, including organisation of quality assurance activities, mechanisms for site visits and accreditation, requirements for quality control and data systems, and inclusion of treatment, follow up, and programme evaluation in screening mammography quality assurance activities. PARTICIPANTS AND SETTING: IBSN representatives in 23 countries completed a comprehensive questionnaire between May and December 1998. MAIN RESULTS: Completed questionnaires were obtained from all 23 countries. Responses indicated that countries vary in their approaches to implementing quality assurance, although all monitor components of structure, process, and outcome. Nearly all have in place laws, surveillance mechanisms, or standards for quality assurance. In all countries, quality assurance activities extend beyond the screening mammography examination. CONCLUSIONS: The assessment has enhanced understanding of the organisation of screening mammography programmes across countries, as well as the comparability of screening mammography data. All countries have established mechanisms for assuring the quality of screening mammography in population-based programmes, although these mechanisms vary across countries.