RESUMO
Inuit are the Indigenous Arctic peoples and residents of the Canadian territory of Nunavut who have the highest global rate of lung cancer. Given lung cancer's mortality, histological and genomic characterization was undertaken to better understand the disease biology. We retrospectively studied all Inuit cases from Nunavut's Qikiqtani (Baffin) region, referred to the Ottawa Hospital Cancer Center between 2001 and 2011. Demographics were compiled from medical records and tumor samples underwent pathologic/histologic confirmation. Tumors were analyzed by next generation sequencing (NGS) with a cancer hotspot mutation panel. Of 98 patients, the median age was 66 years and 61% were male. Tobacco use was reported in 87%, and 69% had a history of lung disease (tuberculosis or other). Histological types were: non-small cell lung carcinoma (NSCLC), 81%; small cell lung carcinoma, 16%. Squamous cell carcinoma (SCC) represented 65% of NSCLC. NGS on 55 samples demonstrated mutation rates similar to public lung cancer datasets. In SCC, the STK11 F354L mutation was observed at higher frequency than previously reported. This is the first study to characterize the histologic/genomic profiles of lung cancer in this population. A high incidence of SCC, and an elevated rate of STK11 mutations distinguishes this group from the North American population.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Idoso , Canadá , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Humanos , Inuíte , Neoplasias Pulmonares/genética , Masculino , Estudos RetrospectivosRESUMO
Importance: There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives: To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants: This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions: Intramuscular administration of 3A-HBV (10 µg) or 1A-HBV (20 µg) on days 0, 28, and 168. Main Outcomes and Measures: Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results: Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance: In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration: Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22.
Assuntos
Anticorpos Anti-Hepatite B/efeitos dos fármacos , Vacinas contra Hepatite B/normas , Imunogenicidade da Vacina/efeitos dos fármacos , Adolescente , Adulto , Método Duplo-Cego , Feminino , Antígenos de Superfície da Hepatite B/efeitos adversos , Antígenos de Superfície da Hepatite B/farmacologia , Antígenos de Superfície da Hepatite B/uso terapêutico , Vacinas contra Hepatite B/imunologia , Vacinas contra Hepatite B/farmacologia , Humanos , Imunogenicidade da Vacina/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Sci-B-Vac®, a 3-antigen hepatitis B vaccine (3A-HBV), contains all three recombinant hepatitis B virus (HBV) envelope proteins (S, pre-S1, and pre-S2). In 2005, 3A-HBV manufacturing transferred facilities (A to B), where it continues to be manufactured. METHODS: This phase 3, single-blind, randomized study, conducted at one site in Vietnam, compared efficacy and safety among two 3A-HBV lots, lot A and lot B, and a single-antigen hepatitis B vaccine (1A-HBV), Engerix-B®. Primary objective was to demonstrate equivalence at day 210 of two 3A-HBV lots in seroprotection rate (SPR; defined as percentage of participants achieving hepatitis B surface antigen antibody [anti-HBs] titers ≥ 10 mIU/mL). Secondary objectives were assessing immunogenicity at days 180, 210, and 360, and safety of 3A-HBV. RESULTS: 3A-HBV SPR equivalence was demonstrated at day 210 (lot A: 97.3% [95% CI: 92.4%, 99.4%] vs. lot B: 100.0% [97.0%, 100.0%]). Compared to 1A-HBV, lot B SPR was higher at day 180 (98.3% vs. 81.2%; difference: 17.1% [9.7%, 24.6%]) and non-inferior at day 210 (100% vs. 98.3%; difference: 1.7% [-0.6%, 4.1%]). 3A-HBV lot B showed the same SPR after 2 doses (98.3%) as 1A-HBV after 3 doses (98.3%). Adverse events (AEs) were comparable with both 3A-HBV lots (lot A: 68.7% vs. lot B: 54.2%), but higher than 1A-HBV (35.3%). Vaccination-related AEs included transient injection site pain (38.9%), myalgia (9.3%), and fatigue (7.5%). Eight serious AEs were reported (lot A: 3/134 [2.2%]; lot B: 1/134 [0.8%]; 1A-HBV: 4/133 [2.3%]). One serious AE, syncope, was noted as probably related to study vaccine, lot B. CONCLUSIONS: The two 3A-HBV lots had equivalent immunogenicity, but lot B elicited faster onset of seroprotection and higher anti-HBs titers than both lot A and 1A-HBV in an Asian population. This supports 3A-HBV lot B as an effective choice for HBV vaccination, with a favorable safety profile. ClinicalTrials.gov: NCT04531098.
Assuntos
Vacinas contra Hepatite B , Hepatite B , Adulto , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B , Vacinas contra Hepatite B/efeitos adversos , Humanos , Método Simples-Cego , VietnãRESUMO
BACKGROUND: The seroprotection rate (SPR) of hepatitis B vaccination in adults is suboptimal. The aim of this study was to compare the SPR of a tri-antigenic hepatitis B vaccine (TAV), with a mono-antigenic vaccine (MAV) in adults of all ages. METHODS: This was a multicentre, double-blind, phase 3, randomised controlled trial (PROTECT) comparing the immunogenicity and safety of TAV with MAV in 28 community and hospital sites in the USA, Finland, Canada, and Belgium. Adults (aged ≥18 years) seronegative for hepatitis B virus (HBV), including those with well-controlled common chronic conditions, were randomly assigned (1:1) and stratified by study centre and age according to a web-based permuted blocked randomisation. Participants received either TAV or MAV which were administered as an intramuscular dose (1 mL) of TAV (10 µg; Sci-B-Vac, VBI Vaccines [SciVac, Rehovot, Israel]) or MAV (20 µg; Engerix-B [GlaxoSmithKline Biologicals, Rixensart, Belgium]) on days 0, 28, and 168 with six study visits and 24 weeks of follow-up after the third vaccination. Participants, investigators, and those assessing outcomes were masked to group assignment. The co-primary outcomes were to show non-inferiority of the SPRs 4 weeks after the third vaccination with TAV versus MAV in adults aged 18 years and older, as well as superiority in adults aged 45 years and older. SPR was defined as the percentage of participants attaining anti-HBs titres of 10 mIU/mL or higher. Non-inferiority of TAV to MAV was concluded if the lower limit of the 95% CI for the between-group difference was greater than -5%. Non-inferiority was assessed in the per-protocol set of participants (aged ≥18 years) and superiority was assessed in all participants (aged ≥45 years) who received at least one vaccination and had at least one evaluable immunogenicity sample after baseline (full analysis set). Safety analyses were a secondary outcome and included all participants who received at least one injection. This trial is registered at Clinicaltrials.gov (NCT03393754) and EudraCT (2017-001819-36) and is closed to new participants. FINDINGS: Between Dec 13, 2017, and April 8, 2019, 1607 participants (796 allocated to TAV and 811 allocated to MAV) were randomly assigned and distributed across age cohorts of 18-44 years (299 of 1607; 18·6%), 45-64 years (716 of 1607; 44·6%), and 65 years and older (592 of 1607; 36·8%). In participants aged 18 years and older, SPR was 91·4% (656 of 718) in the TAV group versus 76·5% (553 of 723) in the MAV group (difference 14·9%, 95% CI 11·2-18·6), showing non-inferiority in the per-protocol set. In participants aged 45 years and older, SPR was 89·4% (559 of 625) in the TAV group versus 73·1% (458 of 627) in the MAV group (difference 16·4%, 95% CI 12·2-20·7), showing superiority in the full analysis set. TAV was associated with higher rates of mild or moderate injection site pain (63·2% [503 of 796] in TAV vs 36·3% [294 of 811] in MAV), tenderness (60·8% [484 of 796] in TAV vs 34·8% [282 of 811] in MAV), and myalgia (34·7% [276 of 796] vs 24·3% [197 of 811] in MAV). Otherwise, the safety profile of TAV was similar to that of MAV. INTERPRETATION: The safety and efficacy of TAV shows its usefulness for the prevention of HBV infection in adults, including those with stable and controlled chronic conditions. FUNDING: VBI Vaccines.
Assuntos
Antígenos Virais , Anticorpos Anti-Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Hepatite B/prevenção & controle , Imunogenicidade da Vacina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bélgica , Canadá , Método Duplo-Cego , Feminino , Finlândia , Vacinas contra Hepatite B/efeitos adversos , Humanos , Esquemas de Imunização , Israel , Masculino , Pessoa de Meia-Idade , Estados Unidos , Vacinação , Adulto JovemRESUMO
BACKGROUND: Sci-B-Vac® is a tri-antigenic recombinant Hepatitis B vaccine (TAV) containing the small (s), medium (pre-S2) and large (pre-S1) hepatitis B surface (HBs) antigens. To comply with vaccine licensure, a new reference standard batch was qualified by characterizing the seroprotection rate (SPR) for anti-HBs titers ≥10 mIU/mL, following vaccination. METHODS: Ninety-one healthy adults aged 20-40 years were enrolled in an open label, single-arm phase IV study receiving three IM doses of 10 µg TAV at 0, 1 and 6 months. Immunogenicity was evaluated monthly and at 7, 9 and 12 months. The primary endpoint to qualify the reference standard was an SPR ≥95% by month 7. Secondary endpoints were proportion of high responders (anti-HBs titers ≥100 mIU/mL) and geometric mean concentrations (GMC) of HBs antibodies each month. Participants were followed for safety to month 12. RESULTS: The primary endpoint was met 2 months after the second dose at month 3 [SPR 98.8%; 95% CI: 93.7%, 99.7%]. Proportion of high responders at months 3 and 7 were 81.4% and 97.6%, respectively. GMC at months 3 and 7 were 413.6 mIU/mL and 6799.9 mIU/mL, respectively. TAV was safe and well-tolerated. CONCLUSIONS: The new reference standard batch of TAV was qualified successfully, demonstrating efficacy, a favorable safety profile and a rapid onset of seroprotection, including after two vaccine doses. Clinical trial registry: NCT04179786.
Assuntos
Vacinas contra Hepatite B , Hepatite B , Adulto , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B , Antígenos de Superfície da Hepatite B , Humanos , Imunização Secundária , Adulto JovemRESUMO
Purpose: Patients with advanced or recurrent invasive vulvar squamous cell carcinoma (VSCC) have limited treatment options and a grave prognosis. Understanding the genomic landscape may facilitate the identification of new therapies and improve clinical outcomes.Experimental Design: A retrospective chart review and molecular analysis of patients with VSCC from 2000 to 2016 was performed at the Ottawa Hospital Research Institute. The presence of oncogenic human papillomavirus (HPV) was determined by nested PCR and amplified DNA was sequenced using the Ion AmpliSeq Cancer Hotspot v2 Panel. The patients were divided into two groups according to HPV status (HPV-positive versus HPV-negative) and clinical outcome correlated with mutation status using descriptive statistics.Results: In 43 VSCC patients, there was a high mutation rate in both HPV-positive (73%) and HPV-negative (90%) disease with the two subgroups expressing distinct genetic profiles. HPV-positive tumors were characterized by oncogenic mutations in PIK3CA (27%), FGFR3 (14%), and PTEN (9%), whereas HPV-negative tumors were found to have mutations in TP53 (57%), HRAS (24%), PI3KCA (19%), and CDKN2A (14%). Mutation S249C in FGFR3 occurred in 14% of HPV-positive tumors. While there were notable differences in the occurrence of TP53, HRAS, PTEN, and FGFR3 mutations according to HPV status, only the rate of TP53 mutations was statistically significant (P = 0.0004). No significant difference in prognosis was found between patients with HPV-positive and HPV-negative VSCC.Conclusions: HPV-positive VSCC is characterized by oncogenic FGFR3 mutations that helps classify this subtype as a separate disease. Inhibitors of FGFR3 merit consideration as a therapeutic strategy in this neglected cancer in women. Clin Cancer Res; 23(15); 4501-10. ©2017 AACR.
Assuntos
Carcinoma de Células Escamosas/genética , Infecções por Papillomavirus/diagnóstico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Vulvares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Prognóstico , Neoplasias Vulvares/classificação , Neoplasias Vulvares/patologia , Neoplasias Vulvares/virologiaRESUMO
Background. The prevalence and associated risks with adverse obstetrical outcomes among women living with HIV are not well measured. The objective of this study was to longitudinally investigate the prevalence and correlates of adverse obstetrical outcomes among women with HIV. Methods. This 20-year (1990-2010) clinical case series assessed the prevalence of adverse obstetrical outcomes among pregnant women with HIV receiving care at The Ottawa Hospital (TOH). General estimating equation modeling was used to identify factors independently associated with adverse obstetrical outcomes, while controlling for year of childbirth clustering. Results. At TOH, there were 127 deliveries among 94 women (1990-2010): 22 preterm births, 9 births with low birth weight, 12 births small for gestational age, and 4 stillbirths. Per year, the odds of adverse obstetrical outcomes increased by 15% (OR: 1.15, 95% CI: 1.03-1.30). Psychiatric illness (AOR: 2.64, 95% CI: 1.12-6.24), teen pregnancy (AOR: 3.35, 95% CI: 1.04-1.46), and recent immigrant status (AOR: 7.24, 95% CI: 1.30-40.28) were the strongest correlates of adverse obstetrical outcomes. Conclusions. The increasing number and proportion of adverse obstetrical outcomes among pregnant women with HIV over the past 20 years highlight the need for social supports and maternal and child health interventions, especially among adolescents, new immigrants, and those with a history of mental illness.
RESUMO
BACKGROUND: Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours. METHODS: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day × 2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated. RESULTS: All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1 ≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin. CONCLUSIONS: The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Rosuvastatina Cálcica/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Relação Dose-Resposta a Droga , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinética , Resultado do TratamentoRESUMO
UNLABELLED: Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined. IMPLICATIONS FOR PRACTICE: Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Humanos , Quimioterapia de Indução , Mutação , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
PURPOSE OF REVIEW: Targeted molecular therapy is playing an increasingly important role in the treatment of nonsmall cell lung cancer (NSCLC). Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated efficacy in the advanced disease setting. Preliminary findings suggest that EGFR-TKIs may also be beneficial as adjuvant therapy following complete resection in patients with EGFR-mutation-positive early-stage I-III NSCLC; however, many questions remain unanswered. RECENT FINDINGS: Single-arm trials of adjuvant EGFR-TKI therapy in patients with tumors harboring activating EGFR mutations show impressive 2-year disease-free survival (DFS). Phase III randomized trial data do not support adjuvant EGFR-TKI therapy in unselected completely resected stage I-III NSCLC, but show improved DFS in patients with completely resected EGFR-mutated NSCLC. Adverse events leading to treatment withdrawal and dose reductions are frequent with adjuvant EGFR-TKI therapy, and relapse following treatment withdrawal is common. Adjuvant EGFR-TKIs have not yet been shown to improve the overall survival (OS) in patients with tumors harboring activating EGFR mutations. SUMMARY: There are no data to support the use of adjuvant EGFR-TKIs in unselected early-stage NSCLC. Although EGFR-TKIs hold promise as adjuvant therapy in patients whose tumors harbor EGFR mutations, in the absence of definitive data confirming an OS benefit eligible patients should continue to receive adjuvant chemotherapy following complete resection.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Terapia Combinada , Intervalo Livre de Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular/tendências , Mutação , Estadiamento de Neoplasias , Seleção de PacientesRESUMO
Molecularly targeted agents are changing the therapeutic landscape in advanced non-small cell lung cancer. Since the discovery of sensitizing mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) domain, clinical investigations have focused on optimizing the efficacy of EGFR and ALK tyrosine kinase inhibitors by addressing therapeutic resistance that commonly develops within a year of treatment initiation. Here, we review the clinical trials of novel therapies and combination regimens that have been undertaken in response to our evolving understanding of the mechanisms of resistance to targeted therapy. The aim of these trials was to enhance the therapeutic efficacy of targeted therapies by improving blockade and/or inhibiting parallel or compensatory signaling pathways. We have documented the sequential conduct of EGFR and ALK biomarker-driven trials in order to highlight particular pitfalls and successes, which should be considered in the design of future trials. Although there remain significant challenges, substantial gains have been made in our understanding of cellular resistance. This knowledge will drive the design of future trials to the benefit of lung cancer patients.
RESUMO
Our ability to detect and directly target the oncogenic alterations responsible for tumor proliferation has contributed significantly to the management of lung cancer in the last decade. The therapeutic efficacy of molecularly targeted therapy is, however, mainly limited to patients harboring certain genetic mutations and is generally short-lived. Herein, we review primary and secondary drug resistance using the most well-studied of the molecularly targeted agents, the tyrosine kinase inhibitors targeting the epidermal growth factor (EGF) receptor, and the anaplastic lymphoma kinase (ALK) rearrangement, the current limitations of targeted therapies and their consequences on the management of patients with lung cancer.
RESUMO
INTRODUCTION: The MAINTAIN study is an on-going RCT comparing high-dose micronutrient and anti-oxidant supplementation versus recommended daily allowance (RDA) vitamins in slowing HIV immune deficiency progression in ART-naïve people with HIV infection. OBJECTIVE: We planned analysis of the first 127 participants to determine the baseline prevalence of serum micronutrient deficiencies and correlates, as well as tolerance and adherence to study interventions. METHODS: Participants receive eight capsules twice daily of 1) high-dose or 2) RDA supplements for two years and are followed-up quarterly for measures of immune deficiency progression, safety and tolerability. Regression analysis was used to identify correlates of micronutrient levels at baseline. Adherence was measured by residual pill count, self-report using the General Treatment Scale (GTS) and short-term recall HIV Adherence Treatment Scale (HATS). RESULTS: Prior micronutrient supplementation (within 30 days) was 27% at screening and 10% of study population, and was not correlated with baseline micronutrient levels. Low levels were frequent for carotene (24%<1 nmol/L), vitamin D (24%<40 nmol/L) and serum folate (20%<15 nmol/L). The proportion with B12 deficiency (<133 pmol/L) was 2.4%. Lower baseline levels of B12 correlated lower baseline CD4 count (râ=â0.21, pâ=â0.02) with a 21 pmol/L reduction in B12 per 100 cells/µL CD4. Vitamin D levels were higher in men (p<0.001). After a median follow-up of 1.63 years, there were 19 (15%) early withdrawals from the study treatment. Mean treatment adherence using pill count was 88%. Subjective adherence by the GTS was 81% and was moderately but significantly correlated with pill count (râ=â0.29, p<0.001). Adherence based on short-term recall (HATS) was >80% in 75% of participants. CONCLUSION: Micronutrient levels in asymptomatic HIV+ persons are in keeping with population norms, but micronutrient deficiencies are frequent. Adherence levels are high, and will permit a valid evaluation of treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00798772.
Assuntos
Suplementos Nutricionais , Infecções por HIV/dietoterapia , Micronutrientes/administração & dosagem , Cooperação do Paciente , Deficiência de Vitamina B 12/dietoterapia , Deficiência de Vitamina D/dietoterapia , Adulto , Fármacos Anti-HIV , Contagem de Linfócito CD4 , Carotenoides/administração & dosagem , Carotenoides/sangue , Dieta , Progressão da Doença , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/sangue , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Recomendações Nutricionais , Autorrelato , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/imunologia , Deficiência de Vitamina B 12/virologia , Vitamina D/administração & dosagem , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/imunologia , Deficiência de Vitamina D/virologiaRESUMO
The Africaid Trust is a grassroots South African non-profit organization that engages youth in HIV prevention by harnessing the popularity of football (i.e. soccer). WhizzKids United, the organization's primary program, operates a 12-week program in elementary schools in Pietermaritzburg, South Africa, which aims to impart knowledge and life skills critical to HIV prevention. The goal of this research was to compare elementary school youth who received the program to youth who only received traditional classroom-based HIV education on health behaviors and HIV-related knowledge and stigma. A secondary objective was to evaluate HIV knowledge, sexual behaviors, attitudes towards HIV and health care seeking behaviors among South African youth in grades 9-12. Elementary students who participated in the program reported greater HIV knowledge and lower HIV stigma (p < .001) than those who had not. The majority of youth in grades 9-12 report having sexual relations (55.6%), despite low levels of HIV testing (29.9%) in this high HIV prevalence region of South Africa. The results highlight the importance of supporting community-based HIV educational initiatives that engage high-risk youth in HIV prevention and the need for youth-friendly health services.
Assuntos
Infecções por HIV/prevenção & controle , Serviços de Saúde Escolar , Futebol , Adolescente , Criança , Feminino , Educação em Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Avaliação de Programas e Projetos de Saúde , Instituições Acadêmicas , África do Sul , EstereotipagemRESUMO
PURPOSE: Persistent disease after definitive external beam radiation therapy for head and neck (H&N) malignancies negatively impacts survival. In this series, the effectiveness of low-dose-rate brachytherapy in the management of persistent H&N disease is explored. METHODS: All patients who received brachytherapy for persistent H&N disease between 1987 and 2002 were identified. Tumor and treatment characteristics and toxicities were recorded. Progression-free survival and overall survival estimates were generated. The influence of prognostic factors was determined. RESULTS: Twelve patients were analyzable. Brachytherapy was given curatively (n=4) in patients not amenable to surgery or in combination with surgical dissection to avoid carotid resection (n=8). Seven patients had disease progression with a median time to progression of 11 months (95% confidence interval: 0-22.9). The only negative prognostic factor was time to re-treatment (brachytherapy >4 months) after definitive treatment (p=0.003). Overall survival at 1 and 5 years was 50% and 21%, respectively. Toxicity was limited to one major complication (fistula) and five minor toxicities: low-grade radionecrosis (n=2), cellulitis (n=1), and wound dehiscence (n=2). CONCLUSION: In patients with persistent disease, brachytherapy is an appealing re-treatment alternative. When combined with neck dissection, brachytherapy yields less morbidity than the surgical alternative of carotid resection.
Assuntos
Braquiterapia/métodos , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Análise de SobrevidaRESUMO
PURPOSE: To report long-term results of brachytherapy after local excision (LE) in the treatment of T1 and T2 rectal cancer at risk of recurrence due to residual subclinical disease. METHODS AND MATERIALS: Between 1989 and 2007, 32 patients undergoing LE and brachytherapy were followed prospectively for a mean of 6.2 years. Estimates of local recurrence (LR), disease-specific survival (DSS), and overall survival (OS) were generated. Treatment-related toxicity and the effect of known prognostic factors were determined. RESULTS: There were 8 LR (3 T1, 5 T2), of which 5 were salvaged surgically. Median time to the 8 LR was 14 months, and the 5-year rate of local control was 76%. Although there have been 9 deaths to date, only 5 were from disease. Five-year DSS and OS rates were 85% and 78%, respectively. There were 4 cases of Grade 2-3 radionecrosis and 1 case of mild stool incontinence. The sphincter was preserved in 27 of 32 patients. CONCLUSION: Local excision and adjuvant brachytherapy for T1 and T2 rectal cancer is an appealing treatment alternative to immediate radical resection, particularly in the frail and elderly who are unable to undergo major surgery, as well as for patients wanting to avoid a permanent colostomy.
Assuntos
Canal Anal , Braquiterapia/métodos , Neoplasias Retais/radioterapia , Neoplasias Retais/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Braquiterapia/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Neoplasia Residual , Prognóstico , Estudos Prospectivos , Lesões por Radiação/patologia , Radioterapia Adjuvante , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Terapia de SalvaçãoRESUMO
PURPOSE: This study analyzed patients enrolled in two large, prospectively randomized trials of systemic chemotherapy (adjuvant/palliative setting) for non-small-cell lung Cancer (NSCLC). The main objective was to determine if age and/or the burden of chronic medical conditions (comorbidity) are independent predictors of survival, treatment delivery, and toxicity. PATIENTS AND METHODS: Baseline comorbid conditions were scored using the Charlson comorbidity index (CCI), a validated measure of patient comorbidity that is weighted according to the influence of comorbidity on overall mortality. The CCI score (CCIS) was correlated with demographic data,(ie, age, sex, race), performance status (PS), histology, cancer stage, patient weight, hemoglobin, alkaline phosphatase, lactate dehydrogenase, outcomes of chemotherapy delivery (ie, type, total dose, and dose intensity), survival, and response. RESULTS: A total of 1,255 patients were included in this analysis. The median age was 61 years (range, 34 to 89 years); 34% of patients were elderly (at least 65 years of age); and 31% had comorbid conditions at randomization. Twenty-five percent of patients had a CCIS of 1, whereas 6% had a CCIS of 2 or greater. Elderly patients were more likely to have a CCIS equal to or greater than 1 compared with younger patients (42% v 26%; P < .0001), as were male patients (35% v 21%; P < .0001) and patients with squamous histology (36% v 29%; P = .001). Although age did not influence overall survival, the CCIS appeared prognostic (CCIS 1 v 0; hazard ratio 1.28; 95%CI, 1.09 to 1.5; P = .003). CONCLUSION: In these large, randomized trials, the presence of comorbid conditions (CCIS > or = 1), rather than age more than 65 years, was associated with poorer survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Cisplatino/administração & dosagem , Comorbidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
OBJECTIVE: Re-treatment for cure of the Head and Neck (H&N) region is therapeutically challenging. In this review we explore the long-term results of Ir(192) low-dose-rate (LDR) brachytherapy in the select subgroup of patients treated for a new H&N malignancy. METHODS & MATERIAL: Thirteen patients received brachytherapy between 1987-2004 for a new primary H&N cancer, six of whom had been retreated previously. Brachytherapy was given as a monotherapy in eight patients and delivered adjuvantly in five patients. Three of the thirteen patients had advanced disease at the time of diagnosis. MAIN OUTCOME MEASURES: In addition to the known prognostic factors of stage and site, intent of brachytherapy and prior re-treatment status were assessed for their influence on local control (LC) and overall survival (OS). RESULTS: Local control differed by disease stage of the new primary tumor. With a median follow-up of 50 months, mean progression-free survival was 50.2 months [95%CI = 30.1-70.4] and the 2-year rate of LC was 58%. Adjuvant brachytherapy following surgery resulted in poor LC and OS due to advanced disease at diagnosis. Prior retreatment did not appear to affect LC or OS. OS at 2 and 5 years was 69% and 38%, respectively. There were no cases of grade III toxicity. CONCLUSIONS: LDR Brachytherapy for a new primary H&N cancer is a well-tolerated retreatment alternative that results in good local control. Our results suggest that the best chance for long-term survival remains in the routine follow-up and early diagnosis of the new H&N malignancy.
Assuntos
Braquiterapia/métodos , Neoplasias de Cabeça e Pescoço/radioterapia , Recidiva Local de Neoplasia/radioterapia , Adulto , Idoso , Progressão da Doença , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Retratamento , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). METHODS AND MATERIALS: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. RESULTS: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. CONCLUSIONS: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs.