Interpreting febrile neutropenia rates from randomized, controlled trials for consideration of primary prophylaxis in the real world: a systematic review and meta-analysis.

BACKGROUND: Guidelines recommend primary prophylaxis (PP) with granulocyte-colony-stimulating factors (G-CSF) for patients above a febrile neutropenia (FN) risk threshold of 20%. Practitioners often use FN rates of regimens based on data from randomized, controlled trials (RCTs), which are often comprised of highly selected patients. Patients in the community setting may be at higher risk of FN. MATERIALS AND METHODS: A systematic literature search was conducted for full-length articles reporting FN rates for breast cancer-related chemotherapies between January 1996 and February 2014. A regimen was included if there was at least one RCT and one observational study. Meta-regression was used to model the odds of FN. RESULTS: 130 studies involving 29 regimens and 50 069 patients were identified. Sixty-five observational study (n = 7812) and 110 RCT (n = 42 257) cohorts were included. The unadjusted FN rate was 11.7% in observational and 7.9% in RCT cohorts. The univariable odds ratio (OR) for FN in the observational study compared with RCT cohorts was 1.58 [95% confidence interval (CI) 1.09-2.28; P = 0.017]. The FN rates remained significantly higher in the observational study compared with RCT cohorts (OR = 1.74; 95% CI 1.15-2.62; P = 0.012) after adjusting for age, chemotherapy intent, and regimen; this meant that a 13% (95% CI 8.7% to 17.9%) FN rate in RCT would translate into 20% FN rate in observational study. CONCLUSIONS: FN rates in the observational studies are significantly higher than suggested by RCTs. Guidelines should clarify how FN rates from RCTs should be applied in clinical practice. Large population-based studies are needed to confirm FN rates in the real world.

Outcome of patients with pregnancy during or after breast cancer: a review of the recent literature.

BACKGROUND: An increasing number of young women are delaying childbearing; hence, more are diagnosed with breast cancer (bca) before having a family. No clear recommendations are currently available for counselling such a population on the safety of carrying a pregnancy during bca or becoming pregnant after treatment for bca. METHODS: Using a Web-based search of PubMed we reviewed the recent literature about bca and pregnancy. Our objective was to report outcomes for patients diagnosed with bca during pregnancy, comparing them with outcomes for non-pregnant women, and to evaluate prognosis in women diagnosed with and treated for bca who subsequently became pregnant. RESULTS: "Pregnancy and bca" should be divided into two entities. Pregnancy-associated bca tends to be more aggressive and advanced in stage at diagnosis than bca in control groups; hence, it has a poorer prognosis. With respect to pregnancy after bca, there is, despite the bias in reported studies and meta-analyses, no clear evidence for a different or worse disease outcome in bca patients who become pregnant after treatment compared with those who do not. CONCLUSIONS: Pregnancy-associated bca should be treated as aggressively as and according to the standards applicable in nonpregnant women; pregnancy after bca does not jeopardize outcome. The guidelines addressing risks connected to pregnancy and bca lack a high level of evidence for better counselling young women about pregnancy considerations and preventing unnecessary abortions. Ideally, evidence from large prospective randomized trials would set better guidelines, and yet the complexity of such studies limits their feasibility.

Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: This systematic review addresses the question "What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)-positive breast cancer?" METHODS: The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. RESULTS: Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach), was not superior in dfs. The results of the completed aphinity trial, evaluating the role of dual her2 blockade with trastuzumab and pertuzumab, are highly anticipated. Ongoing trials are evaluating trastuzumab as a single agent without adjuvant chemotherapy (respect) and in patients with low her2 expression (National Surgical Adjuvant Breast and Bowel Project B-47). CONCLUSIONS: Taking into consideration disease characteristics and patient preference, 1 year of trastuzumab should be offered to all patients with her2-positive breast cancer who are receiving adjuvant chemotherapy. Cardiac function should be regularly assessed in this patient population.

Optimal systemic therapy for early breast cancer in women: a clinical practice guideline.

The Breast Cancer Disease Site Group of Cancer Care Ontario identified the need for new guidelines for the adjuvant systemic therapy of early-stage breast cancer. The specific question to be addressed was "What is the optimal adjuvant systemic therapy for female patients with early-stage operable breast cancer, when patient and disease factors are considered?" A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period January 2008 to March 5, 2012, and updated to May 12, 2014. Guidelines were located from that search, from the Standards and Guidelines Evidence directory of cancer guidelines, and from the Web sites of major guideline organizations. The literature located was subdivided into the broad categories of chemotherapy, hormonal therapy, and therapy targeted to her2 (human epidermal growth factor receptor 2). Although several of the systemic therapies discussed in this guideline can be considered in the neoadjuvant setting, the review focused on trials with rates of disease-free and overall survival as endpoints and thus excluded several trials that used pathologic complete response as a primary endpoint. Based on the systematic review, the working group drafted recommendations on the use of chemotherapy, hormonal therapy, and targeted therapy; based on their professional experience, they also drafted recommendations on patient and disease characteristics and recurrence risk. The literature review and draft recommendations were circulated to a consensus panel of medical oncologists who had expertise in breast cancer and who represented the regions of Ontario. Items without initial consensus were discussed at an in-person consensus meeting held in Toronto, November 23, 2012. The final recommendations are those for which consensus was reached before or at the meeting. Some of the key evidence was revised after the updated literature search. Evidence reviews for systemic chemotherapy, endocrine therapy, and targeted therapy for her2-positive disease are reported in separate articles in this supplement. The full three-part 1-21 evidence-based series, including complete details of the development and consensus processes, can be found on the Cancer Care Ontario Web site at https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs.

Adjuvant chemotherapy for early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: The Program in Evidence-Based Care (pebc) of Cancer Care Ontario recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and human epidermal growth factor receptor 2 (her2)-directed therapy. METHODS: For the systematic review, the medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS: Several hundred documents that met the inclusion criteria were retrieved. The Early Breast Cancer Trialists' Collaborative Group meta-analyses encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Chemotherapy was reviewed mainly in three classes: anti-metabolite-based regimens (for example, cyclophosphamide-methotrexate-5-fluorouracil), anthracyclines, and taxane-based regimens. In general, single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population. Anthracycline-taxane-based polychemotherapy regimens are, overall, considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes. Regimens with varying anthracycline and taxane doses and schedules are options; in general, paclitaxel given every 3 weeks is inferior. Evidence does not support the use of bevacizumab in the adjuvant setting; other systemic therapy agents such as metformin and vaccines remain investigatory. Adjuvant bisphosphonates for menopausal women will be discussed in later work. CONCLUSIONS: The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. Use of cytotoxic chemotherapy is presented here; the results addressing endocrine therapy and her2-targeted treatment, and the final clinical practice recommendations, are published separately in this supplement.

Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.

BACKGROUND: Cancer Care Ontario's Program in Evidence-Based Care (pebc) recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and her2 (human epidermal growth factor receptor 2)-targeted therapy. METHODS: For the systematic review, the literature in the medline and embase databases was searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. RESULTS: Several hundred documents that met the inclusion criteria were retrieved. Meta-analyses from the Early Breast Cancer Trialists' Collaborative Group encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. SUMMARY: The results of the systematic review constitute a comprehensive compilation of high-level evidence, which was the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. The review of the evidence for systemic endocrine therapy (adjuvant tamoxifen, aromatase inhibitors, and ovarian ablation and suppression) is presented here; the evidence for chemotherapy and her2-targeted treatment-and the final clinical practice recommendations-are presented separately in this supplement.

Economic evaluation of hormonal therapies for postmenopausal women with estrogen receptor-positive early breast cancer in Canada.

BACKGROUND: Aromatase inhibitor (ai) therapy has been subjected to numerous cost-effectiveness analyses. However, with most ais having reached the end of patent protection and with maturation of the clinical trials data, a re-analysis of ai cost-effectiveness and a consideration of ai use as part of sequential therapy is desirable. Our objective was to assess the cost-effectiveness of the 5-year upfront and sequential tamoxifen (tam) and ai hormonal strategies currently used for treating patients with estrogen receptor (er)-positive early breast cancer. METHODS: The cost-effectiveness analysis used a Markov model that took a Canadian health system perspective with a lifetime time horizon. The base case involved 65-year-old women with er-positive early breast cancer. Probabilistic sensitivity analyses were used to incorporate parameter uncertainties. An expected-value-of-perfect-information test was performed to identify future research directions. Outcomes were quality-adjusted life-years (qalys) and costs. RESULTS: The sequential tam-ai strategy was less costly than the other strategies, but less effective than upfront ai and more effective than upfront tam. Upfront ai was more effective and less costly than upfront tam because of less breast cancer recurrence and differences in adverse events. In an exploratory analysis that included a sequential ai-tam strategy, ai-tam dominated based on small numerical differences unlikely to be clinically significant; that strategy was thus not used in the base-case analysis. CONCLUSIONS: In postmenopausal women with er-positive early breast cancer, strategies using ais appear to provide more benefit than strategies using tam alone. Among the ai-containing strategies, sequential strategies using tam and an ai appear to provide benefits similar to those provided by upfront ai, but at a lower cost.

A population-based study of the epidemiology of pancreatic cancer: a brief report.

OBJECTIVE: Administrative data are used to describe the pancreatic cancer (pcc) population. The analysis examines demographic details, incidence, site, survival, and factors influencing mortality in a cohort of individuals diagnosed with pcc. METHODS: Incident cases of pcc diagnosed in Ontario between 1 January 2004 and 31 December 2011 were extracted from the Ontario Cancer Registry. They were linked by encrypted health card number to several administrative databases to obtain demographic and mortality information. Descriptive, bivariate, and survival analyses were conducted. RESULTS: During the period of interest, 9221 new cases of pcc (4548 in men, 4673 in women) were diagnosed, for an age-adjusted standardized annual incidence in the range of 8.6-9.5 per 100,000 population. Mean age at diagnosis was 70.3 ± 12.5 years (standard deviation). Five-year survival was 7.2% (12.8% for those <60 years of age and 3.6% for those >80 years of age). Survival varied by sex, older age, rural residence, lower income, site of involvement in the pancreas, and presence of comorbidity. CONCLUSIONS: The mortality rate in pcc is exceptionally high. With an increasing incidence and a mortality positively associated with age, additional support will be needed for this highly fatal disease as demographics in Ontario continue to trend toward a higher proportion of older individuals.

Patients' perceptions of gene expression profiling in breast cancer treatment decisions.

INTRODUCTION: Determining the likely benefit of adjuvant chemotherapy for early-stage breast cancer patients depends on estimating baseline recurrence risk. Gene expression profile (gep) testing of tumours informs risk prediction, but evidence of its clinical utility is limited. We explored patient perceptions of gep testing and the impact of those perceptions on chemotherapy decisions. METHODS: We conducted one focus group (n = 4) and individual interviews (n = 24) with patients who used gep testing, recruited through clinics at two hospitals in Ontario. Data were analyzed using content analysis and constant comparison techniques. RESULTS: Patients' understanding of gep testing was variable, and misapprehensions were common. Patients valued the test because it provided them with certainty amidst confusion, with options and a sense of empowerment, and with personalized, authoritative information. They commonly believed that the test was better and fundamentally different from other clinical tests, attributing to it unique power and truth-value. This kind of "magical thinking" was derived from an amplified perception of the test's validity and patients' need for reassurance about their treatment choices. Despite misperceptions or magical thinking, gep was widely considered to be the deciding factor in treatment decisions. CONCLUSIONS: Patients tend to overestimate the truth-value of gep testing based on misperceptions of its validity. Our results identify a need to better support patient understanding of the test and its limitations. Findings illustrate the deep emotional investment patients make in gep test results and the impact of that investment on their treatment decisions.

Population-based home care services in breast cancer: utilization and costs.

OBJECTIVE: To determine utilization and costs of home care services (hcs) for individuals with a diagnosis of breast cancer (bc). METHODS: Incident cases of invasive bc in women were extracted from the Ontario Cancer Registry (2005-2009) and linked with other Ontario health care administrative databases. Control patients were selected from the population of women never diagnosed with any type of cancer. The types and proportions of hcs used were determined and stratified by disease stage. Attributable home care utilization and costs for bc patients were determined. Factors associated with hcs costs were assessed using regression analysis. RESULTS: Among the 39,656 bc and 198,280 control patients identified (median age: 61.6 years for both), 75.4% of bc patients used hcs (62.1% stage i; 85.7% stage ii; 94.6% stage iii; 79.1% stage iv) compared with 14.6% of control patients. The number of hcs used per patient-year were significantly higher for the bc patients than for the control patients (14.97 vs. 6.13, p < 0.01), resulting in higher costs per patient-year ($1,210 vs. $325; $885 attributable cost to bc, p < 0.01). The number of hcs utilized and the associated costs increased as the bc stage increased. In contrast, hcs costs decreased as income increased and as previous health care exposure decreased. INTERPRETATION: Patients with bc used twice as many hcs, resulting in costs that were almost 4 times those observed in a matched control group. Less than an additional $1000 per bc patient per year were spent on hcs utilization in the study population.

Reimbursement recommendations for cancer drugs supported by phase II evidence in Canada.

Background: Phase ii data are increasingly being used as primary evidence for public reimbursement for oncologic drugs. We compared the frequency of reimbursement recommendations for phase ii and phase iii submissions and assessed for variables associated with a positive or conditional recommendation. Methods: We identified submissions made to the pan-Canadian Oncology Drug Review's Expert Review Committee (perc), of the Canadian Agency for Drugs and Technologies in Health, July 2011 to July 2019, that were supported only by phase ii data. We identified variables within the perc's deliberative framework, including clinical and economic factors, associated with the final reimbursement recommendation. We conducted a multivariable analysis with logistic regression for these variables: feasibility of phase iii study, hematologic indication, and unmet need. Results: We identified 139 submissions with a perc final recommendation. In 27 instances (19%), the submission had only phase ii evidence, and a positive recommendation was issued for 63% of them (the positive recommendation rate was 82% for submissions with phase iii evidence). Clinical benefit (p < 0.001), unmet need (p = 0.047), and patient alignment (p = 0.015) were associated with a positive recommendation. If a future phase iii study was deemed feasible for submissions with only phase ii evidence, then in univariable (p = 0.040) and multivariable analysis (p = 0.024), the perc was less likely to recommend reimbursement (odds ratio: 0.132). Conclusions: Although more than half the oncologic submissions with phase ii data were recommended for public reimbursement, compared with submissions having phase iii data, they were less likely to be recommended. A positive or conditional recommendation was more likely if clinical benefit and alignment with patient values was demonstrated. The perc was less likely to recommend reimbursement for submissions with phase ii evidence if a phase iii trial was deemed possible.

A framework for the organization and delivery of systemic treatment.

BACKGROUND: Increasing systemic treatment and shortages of oncology professionals in Canada require innovative approaches to the safe and effective delivery of intravenous (IV) cancer treatment. We conducted a systematic review of the clinical and scientific literature, and an environmental scan of models in Canada, the United Kingdom, Australia, and New Zealand. We then developed a framework for the organization and delivery of IV systemic treatment. METHODS: The systematic review covered the medline, embase, cinahl, and HealthStar databases. The environmental scan retrieved published and unpublished sources, coupled with a free key word search using the Google search engine. The Systemic Treatment Working Group reviewed the evidence and developed a draft framework using evidence-based analysis, existing recommendations from various jurisdictions, and expert opinion based on experience and consensus. The draft was assessed by Ontario stakeholders and reviewed and approved by Cancer Care Ontario. RESULTS: The poor quantity and quality of the evidence necessitated a consensus-derived model. That model comprises four levels of care determined by a regional systemic treatment program and three integrated structures (integrated cancer programs, affiliate institutions, and satellite institutions), each with a defined scope of practice and a specific organizational framework. INTERPRETATION: New models of care are urgently required beyond large centres, particularly in geographically remote or rural areas. Despite limited applicable evidence, the development and successful implementation of this framework is intended to create sustainable, accessible, quality care and to measurably improve patient outcomes.

Conditional approval of cancer drugs in Canada: accountability and impact on public funding.

Background: We examined how conditional market approval of cancer pharmaceuticals by Health Canada (hc) affects public funding recommendations by the pan-Canadian Oncology Review (pcodr). We were also interested to see how often hc conditions are enforced. Methods: Health Canada and pcodr databases for 2010-2017 were analyzed for patterns in hc conditional authorization and post-authorization reviews of cancer drugs and for correlation with pcodr reimbursement recommendations. Results: Between 2010 and 2017, pcodr reviewed 105 unique drug-indication pairings; 21% (n = 22) had conditional hc authorization. In all cases, conditional authorization was given on the basis of preliminary data in a surrogate endpoint and was contingent on further data showing benefit in more robust outcome measures (for example, overall survival). Of those 22 drugs, 36% did not have updated data, 36% had updated data that met hc conditions, and 27% had data that met some, but not all, conditions. During the period considered, hc never revoked conditional authorization for failure to meet conditions. None of the 22 drugs was given an unconditional positive recommendation for public reimbursement by pcodr. A conditional recommendation was given to 11 of the drugs (50%), and reimbursement was not recommended for 6 drugs (27%) because of insufficient evidence. Conclusions: One fifth of the cancer drugs reviewed for public reimbursement in Canada were conditionally authorized by hc based on preliminary data. Conditional authorization was associated with a recommendation against public funding by pcodr. No drugs had their conditional market authorization revoked for failure to meet conditions, suggesting that a more robust hc reappraisal framework is needed.

Factors associated with imaging in patients with early breast cancer after initial treatment.

Background: Overuse of surveillance imaging in patients after curative treatment for early breast cancer (ebc) was recently identified as one of the Choosing Wisely Canada initiatives to improve the quality of cancer care. We undertook a population-level examination of imaging practices in Ontario as they existed before the launch of that initiative. Methods: Patients diagnosed with ebc between 2006 and 2010 in Ontario were identified from the Ontario Cancer Registry. Records were linked deterministically to provincial health care databases to obtain comprehensive follow-up. We identified all advanced imaging exams [aies: computed tomography (ct), bone scan, positron-emission tomography] and basic imaging exams (bies: ultrasonography, chest radiography) occurring within the first 2 years after curative treatment. Poisson regression was used to assess associations between patient or provider characteristics and the rate of aies. Results: Of 30,006 women with ebc, 58.6% received at least 1 bie, and 30.6% received at least 1 aie in year 1 after treatment. In year 2, 52.7% received at least 1 bie, and 25.7% received at least 1 aie. The most common aies were chest cts and bone scans. The rate of aies increased with older age, higher disease stage, comorbidity, chemotherapy exposure, and prior staging investigations (p < 0.001). Imaging was ordered mainly by medical oncologists (38%), followed by primary care physicians (23%), surgeons (13%), and emergency room physicians (7%). Conclusions: Despite recommendations against its use, imaging is common in ebc survivors. Understanding the factors associated with aie use helps to identify areas for further research and is required to lower imaging rates and to improve survivorship care.

Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study to assess the efficacy and toxicity of edatrexate, a folate antagonist, in 35 patients with metastatic breast cancer. PATIENTS AND METHODS: The planned dose of edatrexate was 80 mg/m2/wk administered intravenously as first-line therapy. Prior adjuvant chemotherapy was allowed provided at least 12 months had elapsed from the completion of treatment to the development of recurrence. RESULTS: Mucositis was the dose-limiting toxicity in 34 assessable patients, resulting in a mean delivered dose-intensity of 57 mg/m2/wk. Other toxicities included myelosuppression, rash, pneumonitis, and increased AST. Side effects were generally mild to moderate. The complete plus partial remission rate (13 patients; 41%) was impressive. CONCLUSION: Edatrexate is an active agent against metastatic breast cancer, with acceptable toxicity. A lower than planned delivered dose-intensity was mainly due to mucositis.

Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: superiority of doxorubicin.

PATIENTS AND METHODS: We conducted a randomized, multicenter study of intravenous cyclophosphamide 500 mg/m2 plus fluorouracil 500 mg/m2 combined with either mitoxantrone (Novantrone, Lederle Cyanamid Canada Ltd, Willowdale, Ontario) 10 mg/m2 (CNF) or doxorubicin (Adriamycin, Adria Laboratories of Canada Ltd, Mississauga, Ontario) 50 mg/m2 (CAF) every 3 weeks in advanced breast cancer. RESULTS: The response rate in 249 randomized patients was 36% with CNF (44 of 121) and 48% with CAF (62 of 128) (P = .054), with complete remissions in 10 patients (8.3%) on CNF and in 13 (10.2%) on CAF. If only fully assessable patients are considered, the response rate was 48% (44 of 91) with CNF and 60% (62 of 103) with CAF (P = .098). At time of analysis, all except 10 patients (one CNF and nine CAF) had died. The median survival time with CAF was longer than with CNF (15.2 v 10.9 months; P = .003), and time to progression was also longer with CAF (5.3 v 3.2 months; P < .03). Survival differences remained significant (P = .006) if patients who failed to meet all eligibility criteria were excluded. Favorable prognostic factors for survival in a Cox regression model included good performance status (P < .0001); less than two organ systems involved by tumor (P < .0001); no involvement of lung, liver, or brain (P < .003); involvement of bone or bone marrow (P < .009), prior surgery for breast cancer (P < .006); being premenopausal (P < .03); > or = 3 years from diagnosis until randomization on this study (P < .03); and treatment with CAF (P < .03). Alopecia > or = grade 3 was reported in 55% of patients with CAF and 12% of patients with CNF (P < .001), while other > or = grade 3 toxicities did not differ significantly. Priestman-Baum quality-of-life assessment was comparable on the two study arms. CONCLUSION: In patients with advanced breast cancer, CAF was associated with longer survival than was CNF, with an increase in alopecia, but not in other toxicities.

Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: The National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) conducted a phase II study to assess the efficacy and toxicity of docetaxel as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-one patients with measurable MBC were studied. Three patients were ineligible and were excluded from analysis. The planned dose of docetaxel was 100 mg/m2 intravenously (i.v.) every 3 weeks. Prior adjuvant chemotherapy was allowed if at least 12 months had elapsed from completion of treatment to recurrence. RESULTS: The most severe toxicity was granulocytopenia. Ten patients (20.8%) were hospitalized for febrile neutropenia. The protocol was amended to a starting dose of 75 mg/m2 for the last 16 patients. Sixty percent of patients experienced hypersensitivity reactions (HSRs). After two protocol amendments, the use of a premedication regimen of oral dexamethasone and i.v. H1 and H2 blockers prevented significant HSRs. Edema developed in 62% of patients and was cumulative, was present in 50% who received greater than 400 mg/m2, and was not improved by premedication regimens. Following an independent radiology review, 22 partial remissions and four complete responses in 47 assessable patients were confirmed (response rate, 55%; 95% confidence interval [CI], 40% to 69%). The response rate for 15 assessable patients registered at 75 mg/m2 was 40% (95% CI, 16% to 67%); for 32 assessable patients registered at 100 mg/m2, the response rate was 63%, (95% CI, 43% to 78%). CONCLUSION: Docetaxel is an active agent in MBC. Its activity as a single agent is comparable to many combination chemotherapy regimens and is not affected by prior adjuvant chemotherapy. Studies are ongoing to improve its therapeutic index and to incorporate docetaxel in combination chemotherapy regimens.

An improved statistical approach: can it clarify the role of new prognostic factors for breast cancer?

Recently, there has been a proliferation of new biomarkers, some of which may lead to an improved prognostic index or may influence treatment selection. However, there are methodological and statistical issues that require attention in assessing the role and use of these prognostic factors. Between 1977 and 1986, 1097 primary breast cancer patients were accrued for multidisciplinary research at the Henrietta Banting Breast Centre, Women's College Hospital; follow-up to 1990 is complete for 96% of the patients. Data for these patients are used here to illustrate strategies: (1) for the comparison of results from diverse assessments of biomarkers; (2) for the improved comparability of inter-laboratory results; (3) for the examination of the results from monoclonal or polyclonal antibody assays for possible clinically relevant bimodality; (4) for good statistical resolution of overlapping distributions; (5) that involve the use of quantitative values for prognostic factors whenever possible; and (6) for improved multivariate analyses. Good data handling and analyses may enable more accurate and rapid assessment of new prognostic factors, thereby expediting and improving their clinical application.

Docetaxel (Taxotere): an overview of first-line monotherapy.

Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) has demonstrated significant activity in five phase II studies as first-line chemotherapy in the treatment of metastatic breast cancer. Overall response rates range from 55.3% to 67.7%, with responses seen at all sites of disease, including lung (40%) and liver (60%). The median duration of response was 8.3 months, and the median duration of survival was 16.4 months. The dose-limiting toxicity was neutropenia. Alopecia was common but reversible. Severe hypersensitivity reactions, such as flushing, chest tightness, dyspnea, or bronchospasm, were improved by corticosteroid-based premedication. Skin reactions (erythema, dermatitis) were common but generally mild, and nail toxicities (ridging, pain, onycholysis) were seldom severe. Fluid retention was dose related, but was delayed with 5-day steroid administration. Nausea, diarrhea, and vomiting were mild, as was neurotoxicity, consisting of dysesthesias in the hands and feet. Docetaxel is an active agent in the treatment of metastatic breast cancer. The level of activity as a single agent is comparable to that of most anthracycline and non-anthracycline combination chemotherapy regimens. Its activity does not appear to be affected by prior adjuvant chemotherapy. Further studies are ongoing to incorporate docetaxel in combination chemotherapy regimens.