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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.
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Antineoplásicos , Reembolso de Seguro de Salud , Neoplasias , Antineoplásicos/uso terapéutico , Canadá , Ensayos Clínicos Fase II como Asunto , Análisis Costo-Beneficio , Costos de los Medicamentos , Humanos , Modelos Logísticos , Oncología Médica , Neoplasias/tratamiento farmacológicoRESUMEN
We propose a innovative concept to boost the electrochemical performance of cathode composite electrodes using surface-modified carbons with hydrophilic moieties to increase their dispersion in a Lithium Nickel Manganese Cobalt Oxide (NMC) cathode and in-situ generate Li-rich carbon surfaces. Using a rapid aqueous process, the hydrophilic carbon is effectively dispersed in NMC particles followed by the conversion of its acid surface groups (e.g. -COOH), which interact with the NMC particles due to their basicity, into grafted Li salt (-COO-Li+). The solid-state batteries prepared using the cathode composites with surface-modified carbon exhibit better electrochemical performance. Such modified carbons led to a better electronic conduction path as well as facilitating Li+ ions transfer at the carbon/NMC interface due to the presence of lithiated carboxylate groups on their surface.
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BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability. PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea. RESULTS: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold. CONCLUSIONS: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476.
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Neoplasias de la Mama , Quinolinas , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Humanos , Calidad de Vida , Quinolinas/uso terapéutico , Receptor ErbB-2/genética , Trastuzumab/uso terapéuticoRESUMEN
PURPOSE: This study aimed to identify optimal management decisions for surgeons preforming pancreatic head resection on patients with altered anatomy due to a previous Roux-en-Y gastric bypass (RYGB). METHODS: A multi-national (4), multi-center (28) collaborative of 55 pancreatic surgeons who have performed pancreatoduodenectomy or total pancreatectomy following RYGB for obesity (2005-2018) was created. Demographics, operative details, and perioperative outcomes from this cohort were analyzed and compared in a propensity-score matched analysis with a multi-center cohort of 5533 pancreatoduodenectomies without prior RYGB. RESULTS: Ninety-six patients with a previous RYGB undergoing pancreatic head resection were assembled. Pathologic indications between the RYGB and normal anatomy cohorts did not differ. Propensity score matching of RYGB vs. patients with unaltered anatomy demonstrated no differences in major postoperative outcomes. In total 20 distinct reconstructions were employed (of 37 potential options); the three most frequent reconstructions accounted for 52.1%, and none demonstrated superior outcomes. There were no differences in outcomes observed between original biliopancreatic limb use (66.7%) and those where a secondary Roux limb was created for biliopancreatic reconstruction. Remnant stomachs were removed in 54.7% of cases, with no outcome differences between resected and retained stomachs. Venting gastrostomy tubes were used in 36.2% of retained stomachs without obvious outcome benefits. Jejunostomy tubes were used infrequently (11.7%). CONCLUSIONS: Pancreatic head resection after RYGB is an infrequently encountered, unique and challenging scenario for any given surgeon. These patients do not appear to suffer higher morbidity than those with unaltered anatomy. Various technical reconstructive options do not appear to confer distinct benefits.
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Derivación Gástrica , Obesidad Mórbida/cirugía , Pancreatectomía , Enfermedades Pancreáticas/patología , Enfermedades Pancreáticas/cirugía , Pancreaticoduodenectomía , Adulto , Anciano , Anciano de 80 o más Años , Anastomosis en-Y de Roux , Femenino , Muñón Gástrico/patología , Muñón Gástrico/cirugía , Gastrostomía , Humanos , Yeyunostomía , Masculino , Persona de Mediana Edad , Obesidad Mórbida/complicaciones , Tempo Operativo , Enfermedades Pancreáticas/complicaciones , Puntaje de Propensión , Estudios RetrospectivosRESUMEN
Background: For women with lymph node (ln)-positive, estrogen receptor-positive, and her2 (human epidermal growth factor receptor 2)-negative breast cancer (bca), current guidelines recommend treatment with both hormonal therapy and chemotherapy. The 21-gene Recurrence Score (rs) assay might be helpful in selecting patients with bca who can be spared chemotherapy when they have 1-3 positive lns and a lower risk of recurrence. In the present study, we performed a cost-utility analysis comparing use of the 21-gene rs assay with current practice from the perspective of a Canadian health care payer. Methods: A Markov model was developed to determine costs and quality-adjusted life-years (qalys) over a patient's lifetime. Patient outcomes in both study groups were examined based on published clinical trials. Costs were derived primarily from published Canadian sources. Costs and outcomes were discounted at 1.5% annually, and costs are reported in 2016 Canadian dollars. A probabilistic analysis was used, and the model parameters were varied in a sensitivity analysis. Results: The results indicate that use of the 21-gene rs assay was less costly ($432 less) and more effective (0.22 qalys) than current practice. The probabilistic analysis revealed that 70% of the 10,000 simulated incremental cost-effectiveness ratios were in the southeast quadrant. The results were sensitive to the probability of a low rs and to the probability of receiving chemotherapy in the low-risk rs category and in current practice. Conclusions: Use of the 21-gene rs assay could be a cost-effective strategy for Ontario patients with estrogen receptor-positive, her2-negative early bca and 1-3 positive lns.
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Bioensayo/economía , Neoplasias de la Mama/economía , Neoplasias de la Mama/genética , Antineoplásicos/efectos adversos , Antineoplásicos/economía , Neoplasias de la Mama/tratamiento farmacológico , Análisis Costo-Beneficio , Femenino , Genes , Humanos , Años de Vida Ajustados por Calidad de VidaRESUMEN
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.
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Antineoplásicos/economía , Análisis Costo-Beneficio/métodos , Oncología Médica/economía , Neoplasias/tratamiento farmacológico , Neoplasias/economía , Canadá , Humanos , Responsabilidad SocialRESUMEN
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.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/terapia , Procedimientos Innecesarios/estadística & datos numéricos , Adulto , Anciano , Neoplasias de la Mama/patología , Diagnóstico por Imagen/métodos , Diagnóstico por Imagen/estadística & datos numéricos , Detección Precoz del Cáncer , Femenino , Adhesión a Directriz/estadística & datos numéricos , Humanos , Registro Médico Coordinado , Persona de Mediana Edad , Estadificación de Neoplasias , Ontario , Vigilancia de la Población/métodos , Guías de Práctica Clínica como Asunto , Práctica Profesional/estadística & datos numéricos , Sistema de RegistrosRESUMEN
Rapeseed (RS) is an abundant and inexpensive source of energy and AA in diets for monogastrics and a sustainable alternative to soybean meal. It also contains diverse bioactive phytochemicals that could have antinutritional effects at high dose. When the RS-derived feed ingredients (RSF) are used in swine diets, the uptake of these nutrients and phytochemicals is expected to affect the metabolic system. In this study, 2 groups of young pigs (17.8 ± 2.7 kg initial BW) were equally fed a soybean meal-based control diet and an RSF-based diet, respectively, for 3 wk. Digesta, liver, and serum samples from these pigs were examined by liquid chromatography-mass spectrometry-based metabolomic analysis to determine the metabolic effects of the 2 diets. Analyses of digesta samples revealed that sinapine, sinapic acid, and gluconapin were robust exposure markers of RS. The distribution of free AA along the intestine of RSF pigs was consistent with the reduced apparent ileal digestibility of AA observed in these pigs. Despite its higher fiber content, the RSF diet did not affect microbial metabolites in the digesta, including short-chain fatty acids and secondary bile acids. Analyses of the liver and serum samples revealed that RSF altered the levels of AA metabolites involved in the urea cycle and 1-carbon metabolism. More importantly, RSF increased the levels of multiple oxidized metabolites and aldehydes while decreased the levels of ascorbic acid and docosahexaenoic acid-containing lipids in the liver and serum, suggesting that RSF could disrupt redox balance in young pigs. Overall, the results indicated that RSF elicited diverse metabolic events in young pigs through its influences on nutrient and antioxidant metabolism, which might affect the performance and health in long-term feeding and also provide the venues for nutritional and processing interventions to improve the utilization of RSF in pigs.
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Aminoácidos/metabolismo , Brassica rapa , Metaboloma , Porcinos/metabolismo , Aminoácidos/sangre , Alimentación Animal/análisis , Animales , Cromatografía Liquida/veterinaria , Dieta/veterinaria , Fibras de la Dieta , Digestión , Ácidos Grasos Volátiles/metabolismo , Íleon/metabolismo , Hígado/metabolismo , Masculino , Espectrometría de Masas/veterinaria , Metabolómica , Oxidación-Reducción , Glycine max , Porcinos/sangreRESUMEN
BACKGROUND: This clinical practice guideline was developed to determine the level of evidence supporting the clinical utility of commercially available multigene profiling assays and to provide guidance about whether certain breast cancer patient populations in Ontario would benefit from alternative tests in addition to Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.). METHODS: A systematic electronic Ovid search of the medline and embase databases sought out systematic reviews and primary literature. A systematic review and practice guideline was written by a working group and was then reviewed and approved by Cancer Care Ontario's Molecular Oncology Advisory Committee. RESULTS: Twenty-four studies assessing the clinical utility of Oncotype dx, Prosigna (NanoString Technologies, Seattle, WA, U.S.A.), EndoPredict (Myriad Genetics, Salt Lake City, U.S.A.), and MammaPrint (Agendia, Irvine, CA, U.S.A.) were included in the evidence base. CONCLUSIONS: The clinical utility of multigene profiling assays is currently established for an appropriate subset of patients with estrogen receptor-positive, her2-negative, node-negative breast cancer for whom a decision to give chemotherapy is difficult to make. For patients with estrogen receptor-positive tumours who receive tamoxifen alone, Oncotype dx, Prosigna, and EndoPredict validly identify a low-risk population with favourable outcomes, indicating that a low-risk assay result is actionable and the decision to withhold chemotherapy is supported. Clinical evidence indicates that a high Oncotype dx recurrence score can predict for chemotherapy benefit, but a high Prosigna or EndoPredict score, although prognostic, is not, based on clinical trial evidence, directly actionable. Prosigna and EndoPredict are statistically more likely to identify a population at risk for recurrence beyond 5 years, but that information is currently not actionable because of a lack of interventional studies.
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BACKGROUND: Several Clostridium difficile infection (CDI) surveillance programs do not specify laboratory strategies to use. We investigated the evolution in testing strategies used across Quebec, Canada, and its association with incidence rates. METHODS: Cross-sectional study of 95 hospitals by surveys conducted in 2010 and in 2013-2014. The association between testing strategies and institutional CDI incidence rates was analyzed via multivariate Poisson regressions. RESULTS: The most common assays in 2014 were toxin A/B enzyme immunoassays (EIAs) (61 institutions, 64%), glutamate dehydrogenase (GDH) EIAs (51 institutions, 53.7%), and nucleic acid amplification tests (NAATs) (34 institutions, 35.8%). The most frequent algorithm was a single-step NAAT (20 institutions, 21%). Between 2010 and 2014, 35 institutions (37%) modified their algorithm. Institutions detecting toxigenic C difficile instead of C difficile toxin increased from 14 to 37 (P < .001). Institutions detecting toxigenic C difficile had higher CDI rates (7.9 vs 6.6 per 10,000 patient days; P = .01). Institutions using single-step NAATs, GDH plus toxigenic cultures, and GDH plus cytotoxicity assays had higher CDI rates than those using an EIA-based algorithm (P < .05). CONCLUSIONS: Laboratory detection of CDI has changed since 2010. There is an association between diagnostic algorithms and CDI incidence. Mitigation strategies are warranted.
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Clostridioides difficile/aislamiento & purificación , Pruebas Diagnósticas de Rutina/tendencias , Enterocolitis Seudomembranosa/diagnóstico , Enterocolitis Seudomembranosa/epidemiología , Técnicas para Inmunoenzimas/estadística & datos numéricos , Reacción en Cadena de la Polimerasa/estadística & datos numéricos , Anciano , Proteínas Bacterianas/análisis , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Toxinas Bacterianas/análisis , Toxinas Bacterianas/inmunología , Clostridioides difficile/genética , Clostridioides difficile/inmunología , Estudios Transversales , ADN Bacteriano/genética , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/patología , Enterotoxinas/análisis , Enterotoxinas/inmunología , Femenino , Glutamato Deshidrogenasa/genética , Humanos , Técnicas para Inmunoenzimas/métodos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Reacción en Cadena de la Polimerasa/métodos , Quebec/epidemiologíaRESUMEN
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.
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Neoplasias de la Mama/tratamiento farmacológico , Neutropenia Febril/epidemiología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neoplasias de la Mama/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Neutropenia Febril/inducido químicamente , Neutropenia Febril/patología , Femenino , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
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Solar water splitting is a key sustainable energy technology for clean, storable and renewable source of energy in the future. Here we report that Merocyanine-540 dye-sensitized and Rh nanoparticle-decorated molecular beam epitaxially grown In0.25Ga0.75N nanowire arrays have produced hydrogen from ethylenediaminetetraacetic acid (EDTA) and acetonitrile mixture solution under green, yellow and orange solar spectra (up to 610 nm) for the first time. An apparent quantum efficiency of 0.3% is demonstrated for wavelengths 525-600 nm, providing a viable approach to harness deep-visible and near-infrared solar energy for efficient and stable water splitting.
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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.
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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.
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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.
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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.
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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.