RESUMO
BACKGROUND: The standard of care for locoregional renal cell carcinoma is surgery, but many patients experience recurrence. The objective of the current study was to determine if adjuvant atezolizumab (vs placebo) delayed recurrence in patients with an increased risk of recurrence after resection. METHODS: IMmotion010 is a randomised, double-blind, multicentre, phase 3 trial conducted in 215 centres in 28 countries. Eligible patients were patients aged 18 years or older with renal cell carcinoma with a clear cell or sarcomatoid component and increased risk of recurrence. After nephrectomy with or without metastasectomy, patients were randomly assigned (1:1) to receive atezolizumab (1200 mg) or placebo (both intravenous) once every 3 weeks for 16 cycles or 1 year. Randomisation was done with an interactive voice-web response system. Stratification factors were disease stage (T2 or T3a vs T3b-c or T4 or N+ vs M1 no evidence of disease), geographical region (north America [excluding Mexico] vs rest of the world), and PD-L1 status on tumour-infiltrating immune cells (<1% vs ≥1% expression). The primary endpoint was investigator-assessed disease-free survival in the intention-to-treat population, defined as all patients who were randomised, regardless of whether study treatment was received. The safety-evaluable population included all patients randomly assigned to treatment who received any amount of study drug (ie, atezolizumab or placebo), regardless of whether a full or partial dose was received. This trial is registered with ClinicalTrials.gov, NCT03024996, and is closed to further accrual. FINDINGS: Between Jan 3, 2017, and Feb 15, 2019, 778 patients were enrolled; 390 (50%) were assigned to the atezolizumab group and 388 (50%) to the placebo group. At data cutoff (May 3, 2022), the median follow-up duration was 44·7 months (IQR 39·1-51·0). Median investigator-assessed disease-free survival was 57·2 months (95% CI 44·6 to not evaluable) with atezolizumab and 49·5 months (47·4 to not evaluable) with placebo (hazard ratio 0·93, 95% CI 0·75-1·15, p=0·50). The most common grade 3-4 adverse events were hypertension (seven [2%] patients who received atezolizumab vs 15 [4%] patients who received placebo), hyperglycaemia (ten [3%] vs six [2%]), and diarrhoea (two [1%] vs seven [2%]). 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo had a serious adverse event. There were no treatment-related deaths. INTERPRETATION: Atezolizumab as adjuvant therapy after resection for patients with renal cell carcinoma with increased risk of recurrence showed no evidence of improved clinical outcomes versus placebo. These study results do not support adjuvant atezolizumab for treatment of renal cell carcinoma. FUNDING: F Hoffmann-La Roche and Genentech, a member of the Roche group.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1 , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Método Duplo-Cego , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgiaRESUMO
IMPORTANCE: Interim analyses of the IMmotion151 trial (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) reported improved progression-free survival (PFS) for patients with programmed death ligand 1-positive (PD-L1+) metastatic renal cell carcinoma (mRCC) receiving the PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab vs the receptor tyrosine kinase inhibitor sunitinib. Overall survival (OS) results were immature at interim analyses. OBJECTIVE: To report the final OS results, safety, and exploratory biomarker analyses of the association of transcriptomic subgroups with OS in the IMmotion151 trial. DESIGN, SETTING, AND PARTICIPANTS: IMmotion151 was a multicenter, open-label, phase 3 randomized clinical trial that compared the efficacy and safety of atezolizumab plus bevacizumab vs sunitinib in patients with untreated mRCC. IMmotion151 included patients from 152 academic medical centers and community oncology practices in 21 countries. Adult patients with mRCC with components of clear cell or sarcomatoid histologic features, measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1.1), adequate performance status, hematologic and end organ function, and tumor tissue available for PD-L1 testing were included. IMmotion151 was initiated on May 20, 2015, and the study is ongoing. This final analysis was performed from May 20, 2015, to February 14, 2020. INTERVENTIONS: Receipt of 1200 mg of intravenous (IV) atezolizumab every 3 weeks and 15 mg/kg of IV bevacizumab every 3 weeks or 50 mg orally once daily of sunitinib (4 weeks on and 2 weeks off). MAIN OUTCOMES AND MEASURES: The coprimary end points were PFS (previously reported) in patients with PD-L1+ disease and OS in the intention-to-treat population. Additional exploratory outcomes included OS in the PD-L1+ population, association with transcriptomic subgroups, and safety. RESULTS: The IMmotion151 trial assessed 915 patients with metastatic renal cell carcinoma. Mean (IQR) age was 62 (56-69) years for patients receiving atezolizumab plus bevacizumab and 60 (54-66) years for patients receiving sunitinib; 669 (73.1%) were male and 246 (26.9%) were female. The final analysis showed similar median OS in patients receiving atezolizumab plus bevacizumab vs sunitinib in the intention-to-treat (36.1 vs 35.3 months) and PD-L1+ (38.7 vs 31.6 months) populations. No new safety signals were reported. The additional exploratory outcome of atezolizumab plus bevacizumab vs sunitinib showed improved median OS trends in patients whose tumors were characterized by T-effector/proliferative, proliferative, or small nucleolar RNA transcriptomic profiles (35.4 vs 21.2 months; hazard ratio, 0.70; 95% CI, 0.50-0.98). CONCLUSIONS AND RELEVANCE: The primary end point of PFS was met at interim analyses, although no improvement in OS was observed with atezolizumab plus bevacizumab at the final analysis. Biomarker analyses provided insight into which patients with mRCC may benefit from combined anti-PD-L1 and anti-VEGF therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02420821.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Sunitinibe/uso terapêutico , Fator A de Crescimento do Endotélio VascularRESUMO
PURPOSE: COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma (RCC). METHODS: This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety. RESULTS: A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs. CONCLUSION: The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Piridinas/administração & dosagemRESUMO
INTRODUCTION/BACKGROUND: In this randomized, double-blind, placebo-controlled phase 1b/2 study we assessed the efficacy/safety of rilotumumab or ganitumab combined with etoposide and carboplatin or cisplatin as first-line treatment in patients with extensive stage small-cell lung cancer (ES-SCLC). PATIENTS AND METHODS: In the phase 1b study, patients received rilotumumab 15 mg/kg or ganitumab 18 mg/kg with etoposide and carboplatin or cisplatin. In the phase 2 study, patients were randomly assigned 1:1:1 to receive placebo, rilotumumab, or ganitumab with etoposide and carboplatin or cisplatin. Chemotherapy was administered for ≤ 6 cycles; rilotumumab, ganitumab, or placebo was then continued as maintenance therapy. The primary end points were incidence of dose-limiting toxicities (DLTs; phase 1b) and overall survival (OS; phase 2). Secondary end points included progression-free survival (PFS) and safety. RESULTS: In the phase 1b study (n = 28), 1 patient treated with ganitumab experienced a DLT (Grade 4 neutropenia/thrombocytopenia lasting ≥ 7 days). In the phase 2 study, 185 patients were enrolled (placebo, n = 61; rilotumumab, n = 62; ganitumab, n = 62). Median OS was 10.8, 12.2 (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.56-1.25; P = .384), and 10.7 (HR, 0.95; 95% CI, 0.63-1.41; P = .787) months, in placebo, rilotumumab, or ganitumumab arms, respectively. Median PFS was 5.4, 5.4 (HR, 1.05; 95% CI, 0.71-1.54; P = .797), and 5.5 (HR, 1.05; 95% CI, 0.72-1.55; P = .780) months, respectively. Adverse events resulting in treatment discontinuation occurred in 11 (19%), 10 (16%), and 7 (12%) patients, respectively. Serum biomarker analysis showed improved survival for patients with baseline hepatocyte growth factor levels below the median in the rilotumumab arm. CONCLUSION: Although the combination of rilotumumab or ganitumab with chemotherapy was tolerable, overall outcomes were not improved in patients with ES-SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer. METHODS: We recruited patients (≥18 years old) with unresectable locally advanced or metastatic gastric or oesophagogastric junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had not received previous systemic therapy, from 43 sites worldwide. Phase 1b was an open-label, dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m(2) intravenously on day 1, cisplatin 60 mg/m(2) intravenously on day 1, capecitabine 625 mg/m(2) twice a day orally on days 1-21, respectively), administered every 3 weeks. The phase 1b primary endpoint was the incidence of dose-limiting toxicities in all phase 1b patients who received at least one dose of rilotumumab and completed the dose-limiting toxicity assessment window (first cycle of therapy). Phase 2 was a double-blind study that randomly assigned patients (1:1:1) using an interactive voice response system to receive rilotumumab 15 mg/kg, rilotumumab 7·5 mg/kg, or placebo, plus ECX (doses as above), stratified by ECOG performance status and disease extent. The phase 2 primary endpoint was progression-free survival (PFS), analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00719550. FINDINGS: Seven of the nine patients enrolled in the phase 1b study received at least one dose of rilotumumab 15 mg/kg, only two of whom had three dose-limiting toxicities: palmar-plantar erythrodysesthesia, cerebral ischaemia, and deep-vein thrombosis. In phase 2, 121 patients were randomly assigned (40 to rilotumumab 15 mg/kg; 42 to rilotumumab 7·5 mg/kg; 39 to placebo). Median PFS was 5·1 months (95% CI 2·9-7·0) in the rilotumumab 15 mg/kg group, 6·8 months (4·5-7·5) in the rilotumumab 7·5 mg/kg group, 5·7 months (4·5-7·0) in both rilotumumab groups combined, and 4·2 months (2·9-4·9) in the placebo group. The hazard ratio for PFS events compared with placebo was 0·69 (80% CI 0·49-0·97; p=0·164) for rilotumumab 15 mg/kg, 0·53 (80% CI 0·38-0·73; p=0·009) for rilotumumab 7·5 mg/kg, and 0·60 (80% CI 0·45-0·79; p=0·016) for combined rilotumumab. Any grade adverse events more common in the combined rilotumumab group than in the placebo group included haematological adverse events (neutropenia in 44 [54%] of 81 patients vs 13 [33%] of 39 patients; anaemia in 32 [40%] vs 11 [28%]; and thrombocytopenia in nine [11%] vs none), peripheral oedema (22 [27%] vs three [8%]), and venous thromboembolism (16 [20%] vs five [13%]). Grade 3-4 adverse events more common with rilotumumab included neutropenia (36 [44%] vs 11 [28%]) and venous thromboembolism (16 [20%] vs four [10%]). Serious adverse events were balanced between groups except for anaemia, which occurred more frequently in the combined rilotumumab group (ten [12%] vs none). INTERPRETATION: Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress. FUNDING: Amgen Inc.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Intervalos de Confiança , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Epirubicina/efeitos adversos , Epirubicina/uso terapêutico , Junção Esofagogástrica/efeitos dos fármacos , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m(2) i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS). RESULTS: One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP. CONCLUSIONS: Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/farmacocinética , Terapia de Alvo Molecular , Orquiectomia , Prednisona/administração & dosagem , Prednisona/farmacocinética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Proteínas Proto-Oncogênicas c-met/metabolismo , Resultado do TratamentoRESUMO
"The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply society endorsement of the final document."
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimioterapia Adjuvante , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Cuidados Pós-Operatórios/métodos , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Sociedades Médicas , Estados UnidosRESUMO
HYPOTHESIS: Malignant mesotheliomas (MMs) express vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and cKIT. Sorafenib is a potent inhibitor of the ras/raf/MEK pathway and also targets VEGFR and cKIT. We evaluated the activity of sorafenib in patients with unresectable mesothelioma. METHODS: MM patients who had received 0 to 1 prior chemotherapy regimens were treated with sorafenib 400 mg orally twice daily continuously. The primary end point was objective response. ERK1/2 phosphorylation in archival tissues was correlated with response and survival. RESULTS: A total of 51 patients were enrolled, 50 were evaluable and included in the analysis. Three patients had a partial response (6% [95% confidence interval = 1.3-16.6%]), and 27 (54% [95% confidence interval = 39.3-68.2%]) had stable disease. Median progression-free survival and median overall survival (OS) were 3.6 and 9.7 months, respectively. Median survival was superior in epithelioid histology versus other types (10.7 versus 3.7 months, p = 0.0179). The difference in median OS between pretreated and chemonaive patients was not statistically significant (13.2 versus 5 months, p = 0.3117). Low/negative baseline tumor phospho-ERK1/2 levels were associated with improved OS (13.9 versus 5.2 months, p = 0.0066). CONCLUSION: Sorafenib has limited activity in advanced MM patients, similar to that seen with other VEGFR tyrosine kinase inhibitors. Additional studies of sorafenib in MM are not warranted.
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Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Mesotelioma/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Piridinas/uso terapêutico , Idoso , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Humanos , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/análogos & derivados , Neoplasias Peritoneais/patologia , Compostos de Fenilureia , Fosforilação , Neoplasias Pleurais/patologia , Sorafenibe , Taxa de Sobrevida , Resultado do TratamentoRESUMO
UNLABELLED: Lung cancer is the leading cause of cancer death in the US. About 50% of lung cancer patients are current smokers at the time of diagnosis and up to 83% continue to smoke after diagnosis. A recent study suggests that people who continue to smoke after a diagnosis of early-stage lung cancer almost double their risk of dying. Despite a growing body of evidence that continued smoking by patients after a lung cancer diagnosis is linked with less effective treatment and a poorer prognosis, the belief prevails that treating tobacco dependence is useless. With improved cancer treatments and survival rates, smoking cessation among lung cancer patients has become increasingly important. There is a pressing need to clarify the role of smoking cessation in the care of lung cancer patients. OBJECTIVE: This paper will report on the benefits of smoking cessation for lung cancer patients and the elements of smoking cessation treatment, with consideration of tailoring to the needs of lung cancer patients. RESULTS: Given the significant benefits of smoking cessation and that tobacco dependence remains a challenge for many lung cancer patients, cancer care providers need to offer full support and intensive treatment with a smoking cessation program that is tailored to lung cancer patients' specific needs. CONCLUSION: A tobacco dependence treatment plan for lung cancer patients is provided.
Assuntos
Neoplasias Pulmonares/prevenção & controle , Abandono do Hábito de Fumar , Fumar/efeitos adversos , Tabagismo/complicações , Antidepressivos de Segunda Geração/uso terapêutico , Bupropiona/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Fumar/tratamento farmacológico , Tabagismo/tratamento farmacológico , Tabagismo/terapia , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
The optimal strategy for the non-surgical definitive treatment of patients with good performance status non-small cell lung cancer (mostly with locally advanced disease) has dramatically evolved over time. This article presents evidence-based data to review this literature. Several decades ago, the standard treatment for most stage III inoperable NSCLC was definitive radiation therapy alone. Randomized trials have since shown superior results with sequential chemotherapy and radiation, and more recently with concurrent chemoradiation, the current standard of care. Studies suggest a limited role for induction or adjuvant systemic therapy in addition to concurrent chemoradiation. The role of altered radiation fractionation techniques, such as hyperfractionation for locally advanced disease or hypofractionation for early stage disease is also discussed. More recently, the application of more advanced radiation techniques has been explored, including intensity modulated radiation therapy (IMRT) and proton beam radiation. Finally, various case variants are presented as examples of state-of-the-art treatment approaches.
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Carcinoma Pulmonar de Células não Pequenas/terapia , Fidelidade a Diretrizes , Neoplasias Pulmonares/terapia , Guias de Prática Clínica como Assunto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Dosagem Radioterapêutica , Taxa de SobrevidaAssuntos
Pesquisa Biomédica/tendências , Programas de Rastreamento/tendências , Oncologia/tendências , Neoplasias , Pesquisa Biomédica/economia , Medicina Baseada em Evidências , Feminino , Financiamento Governamental , Política de Saúde , Humanos , Masculino , Oncologia/economia , Neoplasias/diagnóstico , Neoplasias/economia , Neoplasias/mortalidade , Neoplasias/prevenção & controle , Neoplasias/terapia , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Qualidade da Assistência à Saúde , Qualidade de Vida , Apoio à Pesquisa como Assunto , Sociedades Médicas , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
PURPOSE: Systemic chemotherapy fails to access much of the tumor burden in patients with advanced cancer, significantly limiting its efficacy. In preclinical studies, brief high doses of tyrosine kinase inhibitors (TKI) targeting the human epidermal growth factor receptor (HER) family can prime tumor vasculature for optimal chemotherapeutic delivery and efficacy. This study investigates the clinical relevance of this approach. EXPERIMENTAL DESIGN: A phase I clinical study of escalating doses of the HER TKI lapatinib given as a 2-day pulse before a weekly infusion of nab-paclitaxel (100 mg/m(2)) was conducted in patients with advanced solid tumors. RESULTS: Twenty-five patients were treated. Treatment was associated with grade 1 to 2 toxicities including diarrhea, nausea, rash, neutropenia, neuropathy, fatigue, alopecia, and anemia. The two dose-limiting toxicities were grade 3 vomiting and grade 4 neutropenia, and the maximum tolerated dose of lapatinib was defined as 5250 mg/day in divided doses. Lapatinib concentrations increased with increasing dose. Dynamic Contrast Enhanced Magnetic Resonance Imaging studies in a subset of patients confirmed a decrease in tumor vascular permeability immediately following a lapatinib pulse. Sixty-five percent of evaluable patients experienced a partial or stable response on this therapy, 72% of whom were previously taxane-refractory. CONCLUSION: A 2-day pulse of high-dose lapatinib given before weekly nab-paclitaxel is a feasible and tolerable clinical regimen, suitable for testing this novel vascular-priming chemosensitization hypothesis developed in preclinical models.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Receptores ErbB/metabolismo , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Administração Oral , Paclitaxel Ligado a Albumina , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Lapatinib , Masculino , Pessoa de Meia-Idade , Nanopartículas/administração & dosagem , Neoplasias/patologia , Paclitaxel/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/toxicidade , Quinazolinas/efeitos adversosRESUMO
INTRODUCTION: Vorinostat is a small molecule inhibitor of histone deacetylase, and has shown preclinical activity in non-small cell lung cancer (NSCLC). METHODS: Patients with relapsed NSCLC were eligible. Patients received oral vorinostat, 400 mg daily. The primary objective was response rate, with the goal of at least one responder in the first 14 evaluable patients, according to the two-stage minimax design. Secondary objectives included time to progression (TTP), overall survival (OS), and safety. RESULTS: Sixteen patients enrolled from January 2006 to April 2007. The median age was 59.5 years. Thirteen patients were female. Two patients were not evaluable for response due to progressive disease within Cycle 1. No objective antitumor responses were seen in the 14 evaluable patients. Eight patients experienced stable disease (median 3.7 months, range 1.4-19.4). Median TTP was 2.3 months (range 0.9-19.4 months), median OS was 7.1 months (range 1.4-30.0+ months), and estimated 1 year OS rate was 19% (SE 10%). One patient died on study from an acute ischemic stroke; this event was deemed possibly related to treatment. Grade 3/4 adverse events possibly related to vorinostat included neutropenia, lymphopenia, fatigue, pulmonary embolus/deep vein thrombosis, dehydration, elevated alkaline phosphatase, and hypokalemia. CONCLUSIONS: No objective antitumor activity was detected with single agent vorinostat in this setting; however, it yields TTP in relapsed NSCLC similar to that of other targeted agents. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Feminino , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , VorinostatRESUMO
INTRODUCTION: Estrogen receptor beta (ERbeta) has been detected in non-small cell lung cancer (NSCLC) cell lines and tumor specimens. The ER down-regulator, fulvestrant, blocked estradiol-stimulation of tumor growth and gene transcription in NSCLC preclinical models and showed additive effects with the epidermal growth factor receptor (EGFR) inhibitor gefitinib. The safety and tolerability of combination therapy with the EGFR inhibitor, gefitinib, and fulvestrant was explored. METHODS: Post-menopausal women with advanced NSCLC received gefitinib 250 mg po daily and fulvestrant 250 mg IM monthly. RESULTS: Twenty-two patients were enrolled. Eight patients had adenocarcinoma, six NSCLC-NOS, four squamous cell, and four BAC. Seven patients were never-smokers. Eight patients received > or =2 lines of prior chemotherapy, six received one prior chemotherapy, and eight were treatment-naïve. One patient experienced grade 4 dyspnea possibly related to treatment; all other grade 3/4 toxicities were unrelated to treatment. Twenty patients were evaluable for response: three partial responses (PRs) were confirmed (response rate of 15%, 95% CI: 5-36%). The median progression-free survival (PFS), overall survival (OS), and estimated 1-year OS were 12 weeks (3-112 weeks), 38.5 weeks (7-135 weeks), and 41% (95% CI: 20-62%), respectively. Survival outcomes did not differ by prior lines of therapy. A subset analysis revealed that OS in the eight patients whose tumors exhibited at least 60% ERbeta nuclear IHC staining measured 65.5 weeks, while that of the five patients with ERbeta staining of less than 60% was 21 weeks. One patient with bronchioalveolar carcinoma (BAC) and a PR had an EGFR L858R mutation in exon 21. There was no correlation between ERbeta IHC expression and histology or smoking history. CONCLUSIONS: Combination therapy with gefitinib and fulvestrant in this population was well tolerated and demonstrated disease activity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pós-Menopausa , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Adenocarcinoma Bronquioloalveolar/secundário , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/secundário , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Feminino , Fulvestranto , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Quinazolinas/administração & dosagem , Segurança , Taxa de Sobrevida , Resultado do TratamentoAssuntos
Neoplasias Pulmonares , Programas de Rastreamento/métodos , Doença Pulmonar Obstrutiva Crônica/complicações , Fumar/efeitos adversos , Humanos , Incidência , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Prognóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco , Fumar/epidemiologia , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologiaAssuntos
Neoplasias Pulmonares , Antineoplásicos/administração & dosagem , Terapia Combinada , Genes erbB-1/genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Estadiamento de Neoplasias , Receptores da Neurocinina-1/fisiologiaRESUMO
The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Estadiamento de NeoplasiasRESUMO
Early screening, adjuvant and sequential systemic treatment, and hormonal therapy have benefits in treatment of breast cancer. Management of non-small-cell lung cancer (NSCLC) is progressing and will hopefully follow in the same footsteps as that of breast cancer. Only recently have clinical trials established adjuvant treatment as the standard of care in lung cancer. A growing number of effective cytotoxic and targeted agents have resulted in increased survival when used as sequential treatment in both breast cancer and NSCLC. The interaction between oestrogen receptors (ER) in the lung and epidermal growth factor receptor (EGFR) suggests a potential role for endocrine manipulation in the treatment of NSCLC. This complex interaction involves several types of ER receptors and different signalling pathways. Interactions between tobacco and oestrogen confound the effects of exogenous oestrogens on risk of lung cancer, but not on that of breast cancer. The optimum application of hormonal manipulation to prevent or treat lung cancer will depend on a more-complete understanding of lung-specific ER signalling. Early trials have assessed the interaction between the ER and EGFR signalling.