Using family history forms in pediatric oncology to identify patients for genetic assessment.

OBJECTIVE: We set out to identify and offer genetic testing to the 5%-10% of pediatric cancer patients who have been estimated to carry germline mutations in inherited cancer predisposition syndromes. Clinical genetic testing has become widely available, and thus in busy oncology clinics, tools are needed to identify patients who could benefit from a referral to genetics. METHODS: We studied the clinical utility of administering a family history form in the pediatric oncology long-term follow-up clinic to identify patients who might have an inherited cancer predisposition syndrome. Genetic testing involved primarily Sanger sequencing in clia (Clinical Laboratory Improvement Amendments)-certified laboratories. RESULTS: Of 57 patients who completed forms, 19 (33.3%) met criteria for referral to genetics. A significant family history of cancer was present for 4 patients, and 12 patients underwent genetic testing. Of 18 genetic tests ordered, none identified a pathogenic mutation, likely because of a small sample size and a candidate-gene approach to testing. Three families were also identified for further assessment based on a family history of breast cancer, with two of families having members eligible for BRCA1 and BRCA2 testing. CONCLUSIONS: Genetic testing in pediatric oncology patients is important to guide the management of patients who have an inherited cancer predisposition syndrome and to identify other family members at risk when mutations are identified. When no mutations are identified, that information is often reassuring to families who are worried about siblings. However, in the absence of an identified genetic cause in a patient, some uncertainty remains.

Reflex testing for Lynch syndrome: if we build it, will they come? Lessons learned from the uptake of clinical genetics services by individuals with newly diagnosed colorectal cancer (CRC).

The aim of this qualitative study was to examine the experience of individuals facing a choice about genetic counselling/testing in the context of newly diagnosed colorectal cancer (CRC). Nineteen individuals with newly diagnosed CRC, including 12 individuals who accepted genetic counselling ("acceptors") and 7 individuals who declined genetic counselling ("refusers"), were interviewed using a standardized questionnaire guide which focused on motivations and barriers experienced in the decision process. Data were analyzed using Karlsson's Empirical Phenomenological method of data analysis (Karlsson in Psychological qualitative research from a phenomenological perspective. Almgvist and Wiksell International, Stockholm, 1993). Three major themes were identified: facing challenges in health literacy; mapping an unknown territory; and adjusting to cancer. The study participants' testimonies provided novel insights into potential reasons for patient non-engagement in pilot studies of reflex testing for Lynch syndrome, and allowed us to formulate several recommendations for enhancing patient engagement. Our study findings suggest that patient engagement in clinical cancer genetics services, including reflex testing for Lynch syndrome, can only be achieved by addressing current health literacy issues, by deconstructing current misconceptions related to potential abuses of genetic information, by emphasizing the clinical utility of genetic assessment, and by adapting genetics practices to the specific context of cancer care.

Living with the BRCA1 and BRCA2 genetic mutation: learning how to adapt to a virtual chronic illness.

The objective of this study was to understand how women living with the BRCA1 and BRCA2 genetic mutation adapt to this life transition and to identify the main adaptive tasks. A qualitative inquiry inspired by grounded theory revealed that participants cognitively appraised their test result in the same manner as women who have been diagnosed with breast cancer. Consequently, participants had to adapt to a condition that they perceived as a chronic illness. The following three main tasks were identified: Physical Task: Attempting to Limit the Impact of the Test Result, Psychological Task: Living with Uncertainty, and Social Task: Finding Effective Support. In conclusion, although these women live with the possibility of developing breast cancer, their experiences mirror those of individuals living with a chronic illness, and they must therefore adapt accordingly in a physical, psychological, and social manner.

Living with the BRCA genetic mutation: an uncertain conclusion to an unending process.

Women carrying a BRCA1 or BRCA2 genetic mutation have an up to 80% lifetime risk of developing breast cancer. It is especially important to understand the experiences of these women, as their lives are permeated with the threat of cancer. This qualitative study examined the experiences of six young women of reproductive age (age < 45 years) who were identified as carriers. The analysis of the semi-structured interviews inspired by grounded theory methodology, showed that participants experienced the same type of uncertainty demonstrated by women who have already been diagnosed with breast cancer.

Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families.

BACKGROUND: Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families. METHODS: The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions. RESULTS: We identified one previously reported deleterious mutation, p.Arg186(*) (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186(*) segregated with the disease in the family and two ovarian carcinomas available for analysis showed loss of the wild-type allele, but the novel variants are likely neutral. CONCLUSION: RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.

The lived experience of hope among parents of a child with Duchenne muscular dystrophy: perceiving the human being beyond the illness.

OBJECTIVES: Duchenne muscular dystrophy (DMD) is genetically determined, progressive and incurable. Our study's primary objective was to describe the lived experience of hope among parents of a child with DMD. METHODS: Semi-structured interviews were conducted with 12 parents having a child with DMD. A qualitative/ phenomenological approach was utilized to analyse the essential aspects of this experience. RESULTS: We show that the experience of parental hope emerges from the cognitive appraisal of DMD. The child's illness can be perceived in three ways: as a severe loss, a call to adapt or a way to rediscover the child. Each of these appraisals leads to different ways of hoping. Parents can hope for a cure, the child's well-being or to see their child becoming a whole person. Hope can help parents absorb the initial crisis, sustain their adaptation or prepare for the fatal outcome. DISCUSSION: Previous research has demonstrated that cognitive appraisal plays a central role in psychosocial adaptation to illness. Our research indicates that perception can also shape the nature of hope and suggests that health professionals should pay particular attention to the nature of parental hope. The fabric of parental hope can give an indication of how parents are coping and adjusting.

Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115.

BACKGROUND: Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans. METHODS: This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose. RESULTS: Thirty-seven patients were accrued on study. Doses ranged from 80 microg/m(2) to 1500 microg/m(2)/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 microg/m(2) and 1350 microg/m(2)/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 microg/m(2) daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer. CONCLUSIONS: Aplidine given at a dose of 1200 microg/m(2) daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.

Psychological and genetic counseling implications for adolescent daughters of mothers with breast cancer.

Adolescent daughters of women with breast cancer (BC) are themselves at risk for heritable BC. Although some preliminary evidence suggests this group is at an increased risk for emotional problems, evidence is limited to studies with small samples and no comparison groups. This study examined psychological and family functioning, health attitudes and beliefs about genetic risks in adolescent females. A case-comparison design was used to compare 55 mother-daughter pairs in which the mother had been treated for BC (BC group) to 55 families from the general population (GP). Participants completed an assessment battery measuring perceptions of personal risk for BC and attitudes about gene testing for BC susceptibility, family functioning, and adolescent psychological adjustment. Based on manova, no significant differences were found between the two groups on measures of the psychological functioning. However, BC group adolescents reported significant (p < 0.01) worries about their future health and genetic risk for BC. About 68% of BC adolescents compared with 12% of GP adolescents reported being moderately to greatly concerned about their susceptibility to genetic mutations. Further, 85% of BC group adolescents believed they were susceptible to BC compared with 10% of GP adolescents. The results indicated no evidence of emotional, behavioral, or familial distress in these families. However, BC adolescents have significant worries about their future health. The results of this study demonstrate the need to develop a comprehensive model of care where accurate information about genetics and health risks can be provided. The adolescents also need support to help them cope and communicate with their mothers their worries about BC.

Functional status is well maintained in older women during adjuvant chemotherapy for breast cancer.

BACKGROUND: While adjuvant chemotherapy is known to improve survival in older women with breast cancer, there is little information about its effects on physical function and health-related quality of life. PATIENTS AND METHODS: 'Young' (<65 years of age) and 'older' (> or = 65 years of age) postmenopausal women completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core Module (QLQ-C30) and BR23 questionnaires and other measures prior to, during and at the completion of anthracycline-based adjuvant chemotherapy, and then 6 and 12 months later. RESULTS: Physical, role and social function decreased during chemotherapy and emotional function improved (all P <0.01). The decline in physical function was more marked in young (age range 31-64 years; n = 45) than in older women (65-80 years; n = 20) (P <0.05), despite similar baseline values and drug dose intensities. Physical and role function had recovered at 6 months post-chemotherapy. Older patients had consistently better emotional function (P <0.01). CONCLUSIONS: Physical function and other functional domains are impaired in postmenopausal women during adjuvant chemotherapy for breast cancer, but recover subsequently. Physical function appeared to be better maintained in the older women, who tolerated adjuvant chemotherapy well overall. A knowledge of these effects is important for clinical decision-making and when defining social support needs during adjuvant chemotherapy.

Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study.

PURPOSE: To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer. PATIENTS AND METHODS: Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to 14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen. RESULTS: A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P =.94). CONCLUSION: Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients.

A rapid reversed phase high performance liquid chromatographic method for determination of etoposide (VP-16) in human plasma.

A rapid, simple and sensitive isocratic High Performance Liquid Chromatography (HPLC) method was developed to measure the concentration of etoposide in plasma samples with UV detection at 220 nm. The method uses a Bondapac C18 column at 60 degrees C. The mobile phase consists of Methanol: water (45:55 v/v) at a flow rate of 2.8 ml/min. Phenacetin was used as an internal standard. The plasma samples were extracted using ether with the organic layer evaporated under nitrogen. The residue was dissolved in 200 microl methanol with 20 microl injected into the HPLC column. The extraction method showed a recovery of 91.5+/-3% for etoposide. In this system, the retention time of phenacetin and etoposide were 3.3 and 4.4 min, respectively. The limit of detection of etoposide in plasma is 20 ng/ml and the limit of quantitation is 40 ng/ml. This analytical method has very good reproducibility (8.1% between-day variability at a concentration of 50 ng/ml). It is a fast, sensitive and economic method applicable for clinical and pharmacokinetic studies.

A phase III study of high-dose intensification without hematopoietic progenitor cells support for patients with high-risk primary breast carcinoma.

Patients with more than nine ipsilateral lymph node involvement or inflammatory breast cancer have a 5-year survival rate of approximately 50%. We studied the efficacy of high-dose intensification, comparing it with the standard dose chemotherapy for patients with high-risk primary breast cancer. Patients with inflammatory breast cancer or more than nine ipsilateral lymph node involvement without evidence of distant metastasis were randomized to receive either standard dose 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for nine courses (control) or six courses of FAC followed by two courses of cyclophosphamide (5.25 g/m2), etoposide (1,500 mg/m2), and cisplatin (165 mg/m2) (HDCVP). The study was terminated in 1998 because of slow accrual of patients. Forty-six patients were entered in the study. At 4 years, the overall survival was 72.8% (SE 11.9%) and 61.7% (SE 12.4%), and disease-free survival were 45.5% (SE 12.3%) and 33.7% (SE 11.9%) for the control and HDCVP groups, respectively (p = 0.757 and 0.720). With the small number of patients in our study, a small overall survival benefit of high-dose intensification compared with the standard therapy cannot be excluded. However, any substantial benefit is unlikely.

Estimates of the lifetime costs of breast cancer treatment in Canada.

A comprehensive understanding of the cost components of common illnesses is a necessary first step towards ensuring optimal use of scarce healthcare resources. Since breast cancer is the commonest malignancy affecting Canadian women, we estimated the direct healthcare costs associated with the lifetime management of a cohort of 17700 women diagnosed in 1995. Using a multiplicity of data sources, treatment algorithms, follow-up and disease progression patterns were determined by age (<50; >/=50 years) for all four stages of breast cancer at diagnosis, as well as for the management of local and distant recurrence. Statistics Canada's Population Health Model (POHEM) was used to integrate the data from the different sources and to estimate the lifetime costs, discounted at 0, 3 and 5% rates. The average undiscounted lifetime cost per case of treating women diagnosed with breast cancer varied by stage, from $36,340 for stage IV or metastatic disease, to $23,275 for stage I patients. The total cost of treatment for the cohort diagnosed in 1995 was estimated to be over 454 million Canadian dollars. Hospitalisation (mainly for initial treatment and terminal care) represented 63% of the lifetime costs of care delivery. Disease costing models are valuable tools for optimising the use of scare resources without compromising the health status of individual patients. The breast cancer costing model has recently been used to assess the cost impact and cost-effectiveness of providing radiotherapy to all patients undergoing breast surgery, and of performing outpatient breast surgery.

Clinical characteristics and the impact of surgery and chemotherapy on survival of patients with advanced and metastatic bronchioloalveolar carcinoma: a retrospective study.

We retrospectively analyzed data from the clinical charts of 126 patients with bronchioloalveolar carcinoma (BAC) referred to the Ottawa Regional Cancer Center. The patient group consisted of 49 men (39%) and 77 women (61%). The mean age at diagnosis was 64 years. Most patients were smokers (85%). At diagnosis, 53% were stage Ia-IIIa and 47% were stage IIIb and IV. Forty-one percent of the patients with advanced and metastatic stages (IIIb, IV) underwent surgery. Multifocal disease was present at diagnosis in 41% of the patients, including 6% who had stage IIIb multifocal disease confined to a single lobe. Surgery was associated with prolonged survival in patients with multifocal unilobar or multilobar disease (P = 0.0001). While this apparent benefit of surgery may have been due to selection bias, it supports further exploration of surgery as therapy for multifocal disease. While patients receiving chemotherapy for advanced disease did not survive longer than patients not receiving chemotherapy, chemotherapy was used primarily in patients with more aggressive disease, suggesting that selection bias may have contributed to its apparent lack of benefit. Of the 30 patients treated with chemotherapy, only 3 (10%) achieved an objective response. One third of the patients (34%) developed distant metastases, with a predilection for the brain and bone.

Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer.

PURPOSE: To determine whether the neurotoxicity of paclitaxel 250 mg/m(2) given over 3 hours every 3 weeks could be reduced by pretreatment with amifostine 910 mg/m(2). Secondary objectives included comparing myelosuppression, myalgias, and response rates of the two groups. PATIENTS AND METHODS: Forty women with metastatic breast cancer were randomized to receive either paclitaxel alone (arm 1) or paclitaxel preceded by amifostine (arm 2). All were assessable for toxicity, and 37 were assessable for response. At baseline and after each cycle, all patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. In addition, standard follow-up assessments for other toxicities and tumor response were undertaken. Changes from baseline after courses 1, 2, and 3 were assessed. The sample size was sufficient to detect a 50% improvement in the expected determination in sensory change. RESULTS: There were no differences observed in any of the measures of neurotoxicity. Other toxicity was similar in arms 1 and 2, including hair loss (95% v 90%), neurosensory changes (100% v 100%), fatigue/lethargy (85% v 90%), myalgia (95% v 90%), and grade 4 neutropenia (47% v 60%). Nausea, vomiting, dizziness, hypotension, and sneezing were more common in the amifostine arm. Response rates (22.2% v 36.8%) and paclitaxel pharmacokinetics were not significantly different. CONCLUSION: There was no protection from paclitaxel-related neurotoxicity or hematologic toxicity in this study. These results suggest that the mechanism of action of paclitaxel-related toxic effects is not amenable to the cytoprotective action of amifostine.

Concurrent use of multiple low dose chemotherapy agents with differing mechanisms of action as a strategy vs passive resistance: A pilot study.

Resistance may be classified as active (or competitive) (due to excess amount of a factor) vs passive (or non-competitive) (due to a deficiency of a factor). Passive resistance may be important in human solid tumors. In passive resistance, the dose-response curve may be shallow, or may flatten at a relatively low dose. We hypothesized that, if passive resistance were important, it might be advantageous to use low doses of multiple concurrent chemotherapy agents with differing mechanisms of action, rather than using high doses of 2 or 3 drugs. We combined single day cisplatin 60 mg/m2, cyclophosphamide 250 mg/m2, epirubicin 40 mg/m2, paclitaxel 60 mg/m2, and vinblastine 2.5 mg/m2, with 5 days of 5-fluorouracil 200 mg/m2, folinic acid 20 mg/m2 and dexamethasone 4 mg orally q.i.d. every 3 weeks. In later cohorts, doses were escalated, and tamoxifen and verapamil were added. Twenty-three patients were entered. ECOG performance status was 1 in 15 patients and 2 in 8. Number of prior chemotherapy regimens was 0 in 4 patients, 1 in 4, 2 in 8, 3 in 4, 4 in 2, and 7 in 1. Sixteen patients had prior radiotherapy, and 3 had no prior therapy. Myelosuppression and febrile neutropenia were frequent, and 4 heavily pretreated patients died of pneumonia contracted while neutropenic. Diarrhea, nausea and vomiting, and fatigue were also prominent. Among 9 patients with non-small cell lung cancer, one had a partial remission, 4 had stable disease (including 3 with minor objective responses). Two additional non-small cell lung cancer patients also had objective tumor regression, but were coded as failures, since one had tumor progression in <6 weeks and the other died of respiratory failure (thought to be due to severe mucous plugging) one week after his first course of treatment. Among 14 patients with other tumor types, there was one partial response (esophageal carcinoma), 6 patients with stable disease for >6 weeks (including minor responses in one patient each with adenocarcinomas of kidney and breast), and 7 failures (including one patient with adenocarcinoma unknown primary who had minor tumor regression lasting 4 weeks). Despite the unacceptably high toxic death rate, median survival time was 24 weeks (range, 1 week to >104 weeks). This regimen is toxic, but survival duration is longer than would be expected in this heavily pre-treated population. Doses recommended for further study are those used in the first treatment cohort (as described above). Since myelosuppression is the major toxic effect, hemopoietic growth factors might prove helpful with this regimen.

Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group.

PURPOSE: This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy. PATIENTS AND METHODS: Patients (n=392) were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every 3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2 i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles. RESULTS: In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 1 weeks, P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups. CONCLUSION: Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy.

Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer.

OBJECTIVES: We evaluated the effect of hyperfractionated accelerated radiotherapy combined with low dose radiosensitisers followed by standard dose chemotherapy in the treatment of unresectable stage III non small cell lung cancer (NSCLC). METHODS: Forty-seven patients received thoracic radiotherapy (1.5 bid x 5 days x 4 weeks) in combination with low dose daily (3-6 mg/m2) cisplatin +/- weekly vinblastine chemotherapy (step I), followed by three cycles of standard dose chemotherapy alone consisting of cisplatin (75-80 mg/m2) and vinblastine (8-16 mg/m2) given at 3-4 week intervals (step II). RESULTS: The overall response rate was 70% (21% CR). The progression free interval and the median survival duration were 10.4 months and 17.3 months, respectively. The 3 year survival rate was 21%. The site of first progression was local in 44%, distant in 41%, and simultaneous in 15% of patients. Levels of esophageal toxicity were significant but acceptable with the use of prophylactic therapy. Grade 3 or 4 esophageal toxicity was observed in 28 and 19% of patients during step I and II of the study, respectively. There were three deaths associated with esophageal toxicity. All occurred prior to the implementation of the prophylactic therapy for esophagitis. Acute pulmonary symptoms were reported in 25% of patients in step I, and pulmonary fibrosis, primarily asymptomatic, was observed in 51% of patients. Hematological toxicity was moderate. Two patients died of neutropenic sepsis/pneumonia. CONCLUSION: Concurrent chemotherapy and hyperfractionated accelerated radiotherapy followed by chemotherapy appears moderately effective in controlling tumour growth as measured by response rates and survival estimates. Toxicity is considerable but manageable and compatible with results from other combined modality studies.

Diagnostic and therapeutic approaches for nonmetastatic breast cancer in Canada, and their associated costs.

In an era of fiscal restraint, it is important to evaluate the resources required to diagnose and treat serious illnesses. As breast cancer is the major malignancy affecting Canadian women, Statistics Canada has analysed the resources required to manage this disease in Canada, and the associated costs. Here we report the cost of initial diagnosis and treatment of nonmetastatic breast cancer, including adjuvant therapies. Treatment algorithms for Stages I, II, and III of the disease were derived by age group (< 50 or > or = 50 years old), principally from Canadian cancer registry data, supplemented, where necessary, by the results of surveys of Canadian oncologists. Data were obtained on breast cancer incidence by age, diagnostic work-up, stage at diagnosis, initial treatment, follow-up practice, duration of hospitalization and direct care costs. The direct health care costs associated with 'standard' diagnostic and therapeutic approaches were calculated for a cohort of 17,700 Canadian women diagnosed in 1995. Early stage (Stages I and II) breast cancer represented 87% of all incident cases, with 77% of cases occurring in women > or = 50 years. Variations were noted in the rate of partial vs total mastectomy, according to stage and age group. Direct costs for diagnosis and initial treatment ranged from $8014 for Stage II women > or = 50 years old, to $10,897 for Stage III women < 50 years old. Except for Stage III women < 50 years old, the largest expenditure was for hospitalization for surgery, followed by radiotherapy costs. Chemotherapy was the largest cost component for Stage III women < 50 years old. This report describes the cost of diagnosis and initial treatment of nonmetastatic breast cancer in Canada, assuming current practice patterns. A second report will describe the lifetime costs of treating all stages of breast cancer. These data will then be incorporated into Statistics Canada's Population Health Model (POHEM) to perform cost-effectiveness studies of new therapeutic interventions for breast cancer, such as the cost-effectiveness of day surgery, or of radiotherapy to all breast cancer patients undergoing breast surgery.

A rapid reversed phase high performance liquid chromatographic method for the determination of docetaxel (Taxotere) in human plasma using a column switching technique.

A rapid, simple and sensitive isocratic high performance liquid chromatography (HPLC) method was developed to measure the concentration of docetaxel in plasma samples with UV detection at 227 nm. The method uses a column switching technique with an Ultrasphere C18 column (75 x 4.6 mm ID, 3 mu, Altex, USA) as clean-up column and a CSC-nucleosil C8 column (150 x 4.6 mm ID, 5 mu, CSC, Montreal, Canada) as the analytical column. The mobile phase consisted of Phosphate buffer (30 mM, pH = 3)-acetonitrile (47:53, v/v) with the flow rates of 1.1 and 1.3 ml min-1 for clean-up and analytical columns, respectively. Paclitaxel was used as an internal standard. The plasma samples were extracted using a solid phase extraction method with Ammonium acetate (30 mM, pH = 5)-acetonitrile (50:50, v/v) as final eluent. The extraction method showed a recovery of 92% for docetaxel. In this system, the retention times of docetaxel and Paclitaxel were 7.2 and 8.5 min, respectively. The detection limit of docetaxel in plasma is 2.5 ng ml-1. This analytical method has a very good reproducibility (7.2% between-day variability at a concentration of 10 ng ml-1). It is applicable in clinical and pharmacokinetic studies.