Improving the Transition From Oncology to Primary Care Teams: A Case for Shared Leadership.

This article discusses the case of a 47-year-old woman who underwent primary therapy with curative intent for breast cancer. The case illustrates a number of failure events in transferring information and responsibility from oncology to primary care teams. The article emphasizes the importance of shared leadership, as multiple team members, dispersed in time and space, pursue their own objectives while achieving the common goal of coordinating care for survivors of cancer transitioning across settings. Shared leadership is defined as a team property comprising shared responsibility and mutual influence between the patient and the patient's family, primary care providers, and oncology teams, whereby they lead each other toward quality and safety of care. Teams, including the patient-family, should achieve leadership when their contribution is relevant in managing task interdependence during transition. Shared leadership fosters coordinated actions to enable functioning as an integrated team-of-teams. This article illustrates how shared leadership can make a difference to coordinate interfaces and pathways, from therapy with curative intent to the follow-up and management of survivors of breast cancer. The detailed case is elaborated as a clinical vignette. It can be used by care providers and researchers to consider the need for new models of care for survivors of cancer by addressing the following questions. Who accepts shared leadership, how, with whom, and under what conditions? What is the evidence that supports the answers to these questions? The detailed case is also valuable for medical and allied health professional education.

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial.

BACKGROUND: The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. METHODS: This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. FINDINGS: Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). INTERPRETATION: Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. FUNDING: GERCOR and F Hoffmann-La Roche.

Adherence to adjuvant endocrine therapy in estrogen receptor-positive breast cancer patients with regular follow-up.

BACKGROUND: Adjuvant hormonal therapy is crucial in the treatment of estrogen receptor-positive breast cancer. The nonadherence rate to hormonal treatment is reported to be as high as 60%. The goal of this study was to evaluate the factors evoked by the patients as well as the demographic and disease-related factors that could be associated with nonadherence to adjuvant hormonal therapy. METHODS: All consecutive patients treated for an estrogen receptor-positive breast cancer who showed up for regular follow-up with a single breast specialist between November 2008 and April 2009 were included in the study. We assessed adherence to hormonal therapy (either with tamoxifen or aromatase inhibitor). Reasons for adherence and nonadherence were collected. Records were also reviewed for demographic and cancer characteristics and for treatment components. RESULTS: We included 161 patients in the study; 150 (93.2%) adhered to hormonal treatment. Side effects and absence of conviction were the main reasons for nonadherence. The importance of the diagnosis of cancer, fear of recurrence and regular follow-up were reported as the main reasons for adherence. CONCLUSION: Severity of disease and side effects are associated with nonadherence to treatment. Strict follow-up appears to be a necessary adjunct in the adherence to treatment. The association between demographic and cancer characteristics and treatment components needs further investigation. However, these factors may help identify patients at risk of nonadherence and help the oncology team.

CONTEXTE: Le traitement hormonal adjuvant est crucial dans le traitement du cancer du sein avec récepteurs estrogéniques positifs. Le taux d'inobservance au traitement hormonal atteint 60 %. Le but de cette étude consiste à évaluer les facteurs évoqués par les patientes ainsi que les facteurs démographiques et pathologiques pouvant être associés à l'inobservance au traitement hormonal adjuvant. MÉTHODES: Toutes les patientes qui ont été traitées pour cancer du sein avec récepteurs estrogéniques positifs et suivies régulièrement par un spécialiste du cancer du sein de novembre 2008 à avril 2009 ont été incluses dans l'étude. L'adhérence au traitement hormonal (tamoxifène ou inhibiteur de l'aromatase) a été évaluée. Les dossiers des patientes ont aussi été révisés pour colliger les facteurs démographiques, pathologiques et thérapeutiques. RÉSULTATS: Il y a eu 161 patientes; 150 (93,2%) ont suivi le traitement hormonal. Les effets secondaires et l'absence de conviction des patientes face au bénéfice du traitement furent les principales raisons évoquées pour ne pas prendre la médication. L'importance du diagnostic de cancer, la peur de récidive et le suivi régulier furent les principales raisons rapportées pour suivre le traitement. CONCLUSION: La sévérité de la maladie et les effets secondaires sont associés avec l'inobservance au traitement hormonal. Le suivi rigoureux semble s'avérer nécessaire dans l'observance au traitement des patientes. La relation entre les facteurs démographiques, les caractéristiques du cancer et du traitement nécessite une investigation plus approfondie. Cependant, ces facteurs peuvent certainement permettre d'identifier les patients à risque d'inobservance et aider l'équipe d'oncologie à optimiser les discussions.

Integrated oncogeriatric approach: a systematic review of the literature using concept analysis.

OBJECTIVES: The purpose of this study was to provide a more precise definition of an integrated oncogeriatric approach (IOGA) through concept analysis. DATA SOURCES: The literature was reviewed from January 2005 to April 2011 integrating three broad terms: geriatric oncology, multidisciplinarity and integrated care delivery models. STUDY ELIGIBILITY CRITERIA: Citation selection was based on: (1) elderly cancer patients as the study population; (2) disease management and (3) case studies, intervention studies, assessments, evaluations and studies. Inclusion and exclusion criteria were refined in the course of the literature search. INTERVENTIONS: Initiatives in geriatric oncology that relate to oncology services, social support services and primary care services for elderly cancer patients. PARTICIPANTS: Elderly cancer patients aged 70 years old or more. STUDY APPRAISAL AND SYNTHESIS METHODS: Rodgers' concept analysis method was used for this study. The analysis was carried out according to thematic analysis based on the elements of the Chronic Care Model. RESULTS: The search identified 618 citations. After in-depth appraisal of 327 potential citations, 62 articles that met our inclusion criteria were included in the analysis. Three IOGA main attributes were identified, which constitute IOGA's core aspects: geriatric assessment (GA), comorbidity burden and treatment outcomes. The IOGA concept comprises two broad antecedents: coordinated healthcare delivery and primary supportive care services. Regarding the consequents of an integrated approach in geriatric oncology, the studies reviewed remain inconclusive. CONCLUSIONS: Our study highlights the pioneering character of the multidimensional IOGA concept, for which the relationship between clinical and organisational attributes, on the one hand, and contextual antecedents, on the other, is not well understood. We have yet to ascertain IOGA's consequents. IMPLICATIONS OF KEY FINDINGS: There is clearly a need for a whole-system approach to change that will provide direction for multilevel (clinical, organisational, strategic) interventions to support interdisciplinary practice, education and research.

A survey of APC mutations in Quebec.

This is an 11-year survey of molecular analysis of APC germline mutations for the province of Quebec done at the Molecular Pathology Unit of the Jewish General Hospital which offers genetic testing for hereditary forms of colorectal cancer for the whole of Quebec province. We report on 47 unique mutations seen in 66 families affected with familial adenomatous polyposis. Of these unique mutations, 60% are short indels, 28% are point mutations, and 6% are whole exon deletions. The absence of founder mutations and the variety of mutations encountered reinforce the value of RNA-based testing and the need for gene dosage techniques such as multiplex ligation-dependent probe amplification.

Evaluation of the impact of interdisciplinarity in cancer care.

BACKGROUND: Teamwork is a key component of the health care renewal strategy emphasized in Quebec, elsewhere in Canada and in other countries to enhance the quality of oncology services. While this innovation would appear beneficial in theory, empirical evidences of its impact are limited. Current efforts in Quebec to encourage the development of local interdisciplinary teams in all hospitals offer a unique opportunity to assess the anticipated benefits. These teams working in hospital outpatient clinics are responsible for treatment, follow-up and patient support. The study objective is to assess the impact of interdisciplinarity on cancer patients and health professionals. METHODS/DESIGN: This is a quasi-experimental study with three comparison groups distinguished by intensity of interdisciplinarity: strong, moderate and weak. The study will use a random sample of 12 local teams in Quebec, stratified by intensity of interdisciplinarity. The instrument to measure the intensity of the interdisciplinarity, developed in collaboration with experts, encompasses five dimensions referring to aspects of team structure and process. Self-administered questionnaires will be used to measure the impact of interdisciplinarity on patients (health care utilization, continuity of care and cancer services responsiveness) and on professionals (professional well-being, assessment of teamwork and perception of teamwork climate). Approximately 100 health professionals working on the selected teams and 2000 patients will be recruited. Statistical analyses will include descriptive statistics and comparative analysis of the impact observed according to the strata of interdisciplinarity. Fixed and random multivariate statistical models (multilevel analyses) will also be used. DISCUSSION: This study will pinpoint to what extent interdisciplinarity is linked to quality of care and meets the complex and varied needs of cancer patients. It will ascertain to what extent interdisciplinary teamwork facilitated the work of professionals. Such findings are important given the growing prevalence of cancer and the importance of attracting and retaining health professionals to work with cancer patients.

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS: Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. FINDINGS: ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. INTERPRETATION: Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. FUNDING: Amgen.

Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated.

PURPOSE Pharmacokinetics (PKs) and safety results from phase II/III trials suggest that, if high trastuzumab serum concentrations are reached early during treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, patients will gain clinical benefit, and the synergistic effects of trastuzumab and chemotherapy will be maximized. This phase I/II study evaluated the PKs, efficacy, and safety of a novel, intensive loading regimen of trastuzumab in women with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS An intensive loading regimen of trastuzumab was given (6 mg/kg intravenously on days 1, 8, and 15 followed by 6 mg/kg every 3 weeks from day 22) to women age 18 years or older with HER2-positive MBC who may have received previous surgery, radiotherapy, and/or chemotherapy. Study medication was continued until disease progression or withdrawal occurred. Results All eligible women (N = 72) received at least one dose of trastuzumab. Median estimated trough concentration of trastuzumab at the end of 3 weeks of the intensive loading regimen (total of 18 mg/kg of trastuzumab administered) of cycle 1 was 119 mg/L, which is higher than steady-state trough concentrations with a conventional weekly or every-3-week regimen (64.9 or 47.3 mg/L, respectively). No new or unexpected adverse events or increased cardiotoxicity were reported during the study. In patients with measurable disease (n = 47), response rate was 23.4%. Median time to progression was 7.7 months (in all patients). CONCLUSION An intensive loading regimen of trastuzumab achieved higher-than-steady-state serum concentrations during cycle 1, was well tolerated, and had a good efficacy profile.

Phase II multicenter trial of anthracycline rechallenge with pegylated liposomal doxorubicin plus cyclophosphamide for first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines.

PURPOSE: Anthracyclines are a component of breast cancer chemotherapy regimens in both adjuvant and metastatic settings. Anthracycline rechallenge for metastatic disease, for those previously exposed to adjuvant anthracyclines, may not be considered because of concerns about efficacy, tolerability, and cumulative cardiotoxicity. PATIENTS AND METHODS: This prospective, multicenter, single-arm, phase II trial examined the efficacy and safety of pegylated liposomal doxorubicin (PLD) 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) as first-line therapy, delivered every 3 weeks, in 70 patients who developed metastatic disease more than 12 months after completion of an adjuvant anthracycline-containing regimen. Seven patients discontinued treatment early and were excluded from the efficacy analysis. RESULTS: After a median of six cycles, the objective response rate was 38%. An additional 33% of patients achieved stable disease lasting more than 6 months, for an overall clinical benefit rate of 71%. The estimated median time to progression was 12.2 months. Median overall survival time was 16.5 months. Clinical response was equally robust in patients with and without prior taxane exposure. Treatment was well tolerated. The most common grade 3 to 4 toxicities were palmar-plantar erythrodysesthesia (PPE; 10%), dyspnea (9%), and neutropenia (9%). One (1.4%) of 70 patients discontinued treatment as a result of PPE. One patient (1.4%) experienced an infusion reaction requiring discontinuation. No symptomatic cardiac events were observed. CONCLUSION: PLD plus cyclophosphamide is effective and well tolerated in patients with metastatic breast cancer who have received prior adjuvant anthracycline-containing chemotherapy. The majority of patients experienced a clinical benefit without any significant impact on cardiac function.

High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families.

Lynch syndrome is one of the most common autosomal dominantly inherited cancer syndromes. Mutations in MLH1, MSH2, MSH6, and PMS2 account for greater than 98% of reported mutations in Lynch syndrome families. It has been reported that large genomic deletions in MLH1 and MSH2 are a frequent cause of Lynch syndrome in certain populations. Using a multimodal approach, we have identified mutations in MLH1, MSH2, and MSH6 in French Canadian families fulfilling the Amsterdam criteria for Lynch syndrome and who displayed abnormal staining for at least one of the Lynch syndrome proteins. Mutations were identified in 28 of our 29 French Canadian probands (97%). A total of 18 distinct mutations (nine in MLH1, seven in MSH2, two in MSH6) were identified, of which six (33%) were genomic exon deletions. Another four (22%) resulted in exon deletions in cDNA alone. Three (17%) are novel mutations. Five of these 18 mutations were detected in more than one distinct family (four in MLH1, one in MSH2) and haplotype analysis suggests the possibility of founder effects. Fifteen of the 29 (52%) families carried one of these five putative founder mutations. These findings may simplify genetic testing for Lynch syndrome in French Canadians.

Adaptation of clinical guidelines: literature review and proposition for a framework and procedure.

PURPOSE: The development and updating of high-quality clinical practice guidelines require substantial resources. Many guideline programmes throughout the world are using similar strategies to achieve similar goals, resulting in many guidelines on the same topic. One method of using resources more efficiently and avoiding unnecessary duplication of effort would be to adapt existing guidelines. The aim was to review the literature on adaptation of guidelines and to propose a systematic approach for adaptation of guidelines. DATA SOURCES: We selected and reviewed reports describing the methods and results of adaptation of guidelines from those found by searching Medline, Internet, and reference lists of relevant papers. On the basis of this review and our experience in guideline development, we proposed a conceptual framework and procedure for adaptation of guidelines. RESULTS: Adaptation of guidelines is performed either as an alternative to de novo guideline development or to improve guideline implementation through local tailoring of an international or national guideline. However, no validated process for the adaptation of guidelines produced in one cultural and organizational setting for use in another (i.e. trans-contextual adaptation) was found in the literature. The proposed procedure is a stepwise approach to trans-contextual adaptation, including searching for existing guidelines, quality appraisal, detailed analysis of the coherence between the evidence and the recommendations, and adaptation of the recommendations to the target context of use, taking into account the organization of the health care system and cultural context. CONCLUSIONS: Trans-contextual adaptation of guidelines is increasingly being considered as an alternative to de novo guideline development. The proposed approach should be validated and evaluated to determine if it can reduce duplication of effort and inefficient use of resources, although guaranteeing a high-quality product, compared with de novo development.

Selection of adjuvant chemotherapy for treatment of node-positive breast cancer.

Over the past two decades, several studies have suggested that regimens that contain anthracyclines are more effective than those that do not. A meta-analysis by the 2005 Early Breast Cancer Trialists' Collaborative Group confirmed that about 6 months of anthracycline-based polychemotherapy in the adjuvant setting reduced the yearly death rate from breast cancer by about 38% for women younger than 50 years and by 20% for women aged 50-69 years. Although this meta-analysis found that survival was better with regimens that contain anthracycline than with regimens based on cyclophosphamide, methotrexate, and fluorouracil, the best use of anthracycline-based regimens remains unclear. Adjuvant regimens in use can be categorised into three groups: standard-dose anthracycline; escalated-dose epirubicin; and anthracyclines and taxanes. The duration of treatment and combination of dose and drugs varies between these three categories. We reviewed the three types of regimen to establish which provide a better outcome in terms of safety, efficacy, cost, and convenience to patients. We found that both escalated-dose epirubicin and anthracycline-taxane regimens were most effective in terms of disease-free survival and overall survival. Of the specific anthracycline-based regimens, the docetaxel, doxorubicin, and cyclophosphamide regimen (TAC); the fluorouracil, 100 mg epirubicin, and cyclophosphamide regimen (FEC100); and the cyclophosphamide, epirubicin, and fluorouracil regimen (CEF) produced the greatest proportional decreases in 5-year death rate.

Investigating the correlation between hospital of primary treatment and the survival of women with breast cancer.

BACKGROUND: To understand the relation between hospital of initial treatment and the survival of women with breast cancer, the authors investigated the characteristics of the treatment center that were related most to outcome. METHODS: The authors selected women from 5 regions of Quebec, Canada, who were diagnosed with lymph node-negative breast cancer between 1988 and 1994. Data were collected by chart review, queries to physicians, and linkage with administrative data bases. Overall survival to the end of 1999 was analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: The study population included 1727 women with a median follow-up of 6.8 years. The 7-year survival rate was 82% (95% confidence interval [95%CI], 80-84%). Compared with women who were treated in centers with > or = 100 new cases per year, the hazard ratio (HR) of death from any cause was 1.80 (95%CI, 1.23-2.63), 1.44 (95%CI, 1.03-2.03), and 1.30 (95%CI, 0.96-1.76) among women who were treated in hospitals with < 25 new cases, 25-49 new cases, and 50-99 new cases per year after adjusting for case mix and characteristics of the attending physician. However, the significance of caseload disappeared after adjusting for the type of hospital. By contrast, women who were treated in centers with either on-site radiotherapy, research activity, or teaching status had significantly better outcomes, even after adjusting for caseload (HR, 0.68; 95%CI, 0.50-0.92). These associations were independent of primary treatment received, which was a strong determinant of outcome. CONCLUSIONS: Primary treatment of early-stage breast cancer in larger hospitals was associated with improved survival. This relation was mediated by factors related to proficiency of care, which tended to cluster within institutions.

Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial.

BACKGROUND: High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population. METHODS: Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received Vinorelbine 30 mg/m2, i.v., on days 1+8 every 3 weeks followed by Gemcitabine 1000 mg/m2, i.v., on days 1+8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on Vinorelbine or Gemcitabine according to the patient's preference. RESULTS: A total of 126 cycles of Vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of Gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on Vinorelbine, 5 patients on Gemcitabine; 12 patients (26%) had stable disease, 7 patients on Vinorelbine, 5 patients on Gemcitabine. Of 24 patients with progressive disease on Vinorelbine, 3 patients (12.5%) responded to Gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported. CONCLUSION: This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC.

A population-based study of the impact of delaying radiotherapy after conservative surgery for breast cancer.

BACKGROUND: Practice guidelines have set a maximum waiting time to radiation therapy for breast cancer. We evaluated if delaying radiotherapy resulted in worse outcomes in a large cohort of women with node-negative breast cancer. METHODS: We selected a random sample of cases among women diagnosed with localized breast cancer in five regions of Québec, Canada, between 1988 and 1994. Only women with pathologically (n = 926) or clinically (n = 136) negative axillary nodes, and stage 1 or 2 disease treated with conservative surgery and radiotherapy were eligible. Information was obtained by chart review, queries to physicians and linkage with administrative databases. Outcomes were estimated by Kaplan-Meier method and Cox proportional hazards analysis. Median follow-up was 7.1 years (range: 0.9-11.8). RESULTS: Median delay to radiotherapy was 12.4 weeks in those who received chemotherapy and 8.4 weeks in others. Overall survival at 7 years was 85.6%. Local relapse-free and distant disease-free survivals were 77.6 and 76.2%. There was no significant difference in survival according to delay to radiotherapy in crude or multivariate analysis adjusting for several prognostic factors, including systemic treatment. The risk of local failure conditional on survival in women who received radiotherapy more than 12 weeks after surgery was increased (hazard ratio: 1.75, 95% confidence interval: 1.00, 3.08, p-value = 0.052). CONCLUSIONS: Although longer waiting time to radiotherapy may compromise local control, it does not influence survival at 7 years when other predictors of outcomes are taken into account. Well controlled studies are needed to confirm and better characterize this relationship.

Compliance with consensus recommendations for systemic therapy is associated with improved survival of women with node-negative breast cancer.

PURPOSE: The impact of consensus recommendations for systemic therapy on outcome of disease is unclear. We evaluated if compliance with guidelines for systemic adjuvant treatment is associated with improved survival of women with node-negative breast cancer. PATIENTS AND METHODS: The study population included women diagnosed with invasive node-negative breast cancer in Québec, Canada, in 1988 to 1989, 1991 to 1992, and 1993 to 1994. Information was collected by chart review, linkage with administrative databases, and queries to attending physicians. Guidelines from the 1992 St Gallen conference were used as standard of care. Survival was estimated by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Among 1,541 women, 358 died before December 1999. Median follow-up was 6.8 years. Seven-year event-free and overall survivals were 66% and 81%, respectively. Survival was 88%, 84%, and 74% in women at minimal, moderate, or high risk of recurrence. Virtually all women at minimal risk were treated according to the consensus (98.4% of 370). In comparison, adjusted hazard ratios of death were 1.0 (95% CI, 0.6 to 1.7) and 2.3 (95% CI, 1.3 to 4.0) among women at moderate risk treated according to the consensus or not, respectively. Among women at high risk, adjusted hazard ratios of death were 2.0 (95% CI, 1.4 to 2.8) and 2.7 (95% CI, 1.9 to 3.9), respectively. Both risk category (P <.0005) and compliance with guidelines (P <.0005) were independent significant predictors of survival. CONCLUSION: Treatment according to consensus recommendations is associated with improved survival of women with breast cancer in the community. Promoting the adoption of guidelines for treatment is an effective strategy for disease control.

Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.

PURPOSE: To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. PATIENTS AND METHODS: Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. CONCLUSION: EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.