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PURPOSE: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617. EXPERIMENTAL DESIGN: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression models were used. All statistical tests were two sided, and a P value <0.05 was considered significant. RESULTS: A total of 17.1% (56/328) of patients had the KRAS-variant, and overall survival rates were similar between KRAS-variant and non-variant patients. However, there was a time-dependent effect of cetuximab seen only in KRAS-variant patients-while the hazard of death was higher in cetuximab-treated patients within year 1 [HR = 3.37, 95% confidence interval (CI): 1.13-10.10, P = 0.030], death was lower from year 1 to 4 (HR = 0.33, 95% CI: 0.11-0.97, P = 0.043). In contrast, in non-variant patients, the addition of cetuximab significantly increased local failure (HR = 1.59, 95% CI: 1.11-2.28, P = 0.012). CONCLUSIONS/DISCUSSION: Although an overall survival advantage was not achieved in KRAS-variant patients, there is potential impact of cetuximab for this genetic subset of patients. In contrast, cetuximab seems to harm non-variant patients. These findings further support the importance of genetic patient selection in trials studying the addition of systemic agents to radiotherapy. SIGNIFICANCE: The KRAS-variant is the first functional, inherited miRNA-disrupting variant identified in cancer. Our findings support that cetuximab has a potentially beneficial impact on KRAS-variant patients treated with radiation. The work confirms prior evidence that KRAS-variant patients are a subgroup who are especially sensitive to radiation. These findings further support the potential of this class of variants to enable true treatment personalization, considering the equally important endpoints of response and toxicity.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Cetuximab/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , BiomarcadoresRESUMO
Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment. Significance: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown.
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Neoplasias , Humanos , Biomarcadores Tumorais/genética , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: The American Society of Clinical Oncology (ASCO) surveyed cancer patients to assess practice patterns related to weight, diet, and exercise as a part of cancer care. METHODS: An online survey was distributed between March and June 2020 through ASCO channels and patient advocacy organizations. Direct email communication was sent to more than 25,000 contacts, and information about the survey was posted on Cancer.Net. Eligibility criteria included being aged at least 18 years, living in the United States, and having been diagnosed with cancer. Logistic regression was used to determine factors associated with recommendation and referral patterns. RESULTS: In total, 2419 individuals responded to the survey. Most respondents were female (60.1%), 61.1% had an early-stage malignancy, and 48.4% were currently receiving treatment. Breast cancer was the most common cancer (35.7%). The majority of respondents consumed ≤2 servings of fruits and vegetables/d (50.5%) and exercised ≤2 times/wk (50.1%). Exercise was addressed at most or some oncology visits in 56.8% of respondents, diet in 50.1%, and weight in 28.0%. Respondents whose oncology provider provided diet and/or exercise recommendations were more likely to report changes in these behaviors vs. those whose oncology provider did not (exercise: 79.6% vs 69.0%, P < .001; diet 81.1% vs 71.3%, P < .001; weight 81.0% vs 73.3%, P = .003). CONCLUSIONS: In a national survey of oncology patients, slightly more than one-half reported attention to diet and exercise during oncology visits. Provider recommendations for diet, exercise, and weight were associated with positive changes in these behaviors, reinforcing the importance of attention to these topics as a part of oncology care.
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Neoplasias da Mama , Exercício Físico , Adolescente , Adulto , Dieta , Feminino , Humanos , Masculino , Oncologia , Estados Unidos/epidemiologia , VerdurasRESUMO
Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.
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Guias como Assunto/normas , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Sociedades Médicas/normas , Humanos , Neoplasias/imunologiaRESUMO
INTRODUCTION: The CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study. METHODS: Patients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms. RESULTS: The final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board. CONCLUSION: A randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/uso terapêutico , Terapia Combinada , Etoposídeo/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Dosagem Radioterapêutica , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Resultado do TratamentoRESUMO
PURPOSE: RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). METHODS: The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). RESULTS: Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively (P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. CONCLUSION: A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Cetuximab/administração & dosagem , Quimiorradioterapia , Fracionamento da Dose de Radiação , Relação Dose-Resposta à Radiação , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
Lung cancer remains second most common cancer in men and women in the United States. More than 50% of patients are diagnosed in the advanced stage. Traditionally, chemotherapy has been the backbone of management of stage IV lung cancer. A better understanding of the molecular pathogenesis has led to rapid development of targeted therapy and immunotherapy. This has led to significant improvement in survival of patients with lung cancer stages III to IV. These drugs are being studied in early stage lung cancer. Several trials are ongoing to improve the survival and quality of life of our patients.
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Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Farmacogenética/métodos , Medicina de Precisão/tendências , Humanos , Neoplasias Pulmonares/genética , Medicina de Precisão/métodosRESUMO
As immunotherapy continues to translate to the clinic and is combined with existing modalities, such as radiation therapy, novel treatment response patterns have been observed which complicate conventional clinical assessment and management. Herein, we describe a case study of a patient with non-small cell lung cancer treated initially with definitive chemoradiation who subsequently developed oligorecurrent disease which was managed with nivolumab and then comprehensive salvage stereotactic radiation. Serial radiographic assessment had shown worsening at these limited sites of disease after initiating immunotherapy, improvement after radiation, and then heterogeneous response behavior across sites during longer-term follow-up. Given the dual effects ablative radiation may have in the context of global immune checkpoint inhibition, both cytotoxic and synergistic immune-related, assessment of treatment response to such treatment is complicated. Such assessment is further complicated by novel immunotherapy response phenomena, e.g. pseudoprogression, which are being uncovered and are not fully characterized. Current clinical and radiologic assessment strategies are inadequate to interrogate and discern between immunomodulation-influenced response behavior and further diagnostic innovation is warranted to meet the needs of evolving clinical practice in the era of immunotherapy.
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Lung cancer remains the leading cause of cancer death throughout the world. Despite new chemotherapeutic, immunomodulating and molecularly targeted agents, patients with locally advanced or metastatic disease still have a poor prognosis. This trial looked to combine antiangiogenic therapy with a first-line cytotoxic chemotherapy doublet, hoping to extend median progression-free survival (PFS) while minimizing toxicity in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). In this single institution, single-arm study, 51 patients (age >18 yo) were followed from 2007 to 2012. Patients with stage IV nonsquamous NSCLC and patients with recurrent unresectable disease (nonradiation candidates) were eligible. Treatment consisted of carboplatin AUC 5 IV 30-60 minutes, pemetrexed 500/mg2 IV 10 minutes, bevacizumab 15 mg/kg IV (90 minutes 1st dose, 60 minutes 2nd dose, 30 minutes subsequent doses). Treatment was administered every 21 days and planned for 6 cycles, in the absence of disease progression or unacceptable toxicities. Growth factor support was not permitted prophylactically but allowed for toxicities, as were dose reductions. Maintenance treatment for those with stable disease or better consisted of Bevacizumab 15 mg/kg every 3 weeks for up to 1 year. Between November 2007 and March 2012, 51 patients were followed in the phase II trial of carboplatin, pemetrexed, and bevacizumab. Patients were enrolled over a 24-month period. After the end of treatment visits, subjects were followed at least every 3 months for survival data. The median follow-up period was 49 weeks (6 weeks to 178), and the median number of treatment cycles was 6 (range, 1-6). Among the 50 patients assessable for response, median overall survival was 49 weeks (95% CI, 0-62.7) with median PFS of 28 weeks (95% CI, 0-132.4). A complete or partial response was seen in 28 (59.5%) patients. Grade 3-4 treatment-related adverse events occurred in 9 (17.6%) of 51 patients; the most common were thrombocytopenia (4 [7.8%]) and neutropenia (3 [5.9%]). Three (5.8%) of 51 patients were discontinued because of treatment-related adverse events (grade 3 diarrhea, thrombocytopenia, dehydration, fatigue, and grade 4 respiratory distress), and 1 patient (1.9%) was found to be ineligible due to anticoagulation use. A novel 3-drug combination for advanced nonsquamous NSCLC shows promising efficacy with modest toxicity.
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Purpose: We evaluated a Trop-2-targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients.Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1-7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints.Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis (N = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections.Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. Clin Cancer Res; 23(19); 5711-9. ©2017 AACR.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos de Neoplasias/imunologia , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Moléculas de Adesão Celular/imunologia , Imunoconjugados/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/imunologia , Moléculas de Adesão Celular/antagonistas & inibidores , DNA Topoisomerases Tipo I/genética , DNA Topoisomerases Tipo I/imunologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/química , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversosRESUMO
OBJECTIVES: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC. MATERIALS AND METHODS: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response. RESULTS: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response. CONCLUSIONS: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: This randomized, double-blind, phase 2 trial evaluated whether the addition of vandetanib to platinum plus etoposide for previously untreated extensive-stage small cell lung cancer (SCLC) prolonged the time to disease progression in comparison with chemotherapy alone. METHODS: Patients with previously untreated extensive-stage SCLC received platinum (cisplatin or carboplatin) with etoposide in combination with vandetanib (100 mg daily) or a placebo for up to 4 total cycles (no maintenance therapy). An initial safety run-in phase was conducted with the first 6 patients enrolled; all these patients received vandetanib with cisplatin and etoposide. With an overall sample size of 68 patients, the study had 80% power to detect a 3-month difference in the time to progression (TTP) from 4 to 7 months (significance level,.10 [1-sided log-rank test]). RESULTS: Seventy-four patients were enrolled between April 2008 and May 2013. Thirty-three patients were ultimately randomized to each arm. The baseline characteristics were well balanced, and the median number of treatment cycles was 4 for each arm. Thirty-one patients in each arm were evaluable for TTP; the median TTP was 5.62 months with vandetanib and 5.68 months with the placebo (P = .9518). The median overall survival was 13.24 months with vandetanib and 9.23 months with the placebo (P = .4577; 33 evaluable patients in each arm). Nonhematologic toxicity was increased with vandetanib versus the placebo. No correlation was seen between vascular endothelial growth factor polymorphisms and outcomes. CONCLUSIONS: The addition of vandetanib to platinum and etoposide did not improve outcomes for patients with newly diagnosed extensive-stage SCLC. Toxicity was increased in comparison with chemotherapy alone. Cancer 2017;123:303-311. © 2016 American Cancer Society.
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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 , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Progressão da Doença , Método Duplo-Cego , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Piperidinas/administração & dosagem , Quinazolinas/administração & dosagemRESUMO
Renal cell carcinoma (RCC) is responsible for 80 to 85 percent of all primary renal malignancies. In the United State%, there are about 63,000 new cases and almost :14,000 deaths per year from RCC. Surgical resection of localized RCC can be curative but many patients eventually recur. Immunotherapy appears to be a promising new modality for many malignancies, including RCC. Nivolumab, a specific immunotherapy agent indicated for advanced RCC, may restore antitumor immunity and allow for greater progression-free survival by targeting proteins that negatively regulate T cell immunity. This case study aims to demonstrate the integration of nivolumab into the management of a patient with advanced RCC and provide a stimulus for further investigation and research into this treatment modality.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Feminino , Neoplasias Femorais/tratamento farmacológico , Neoplasias Femorais/secundário , Humanos , Imunoterapia , Neoplasias Renais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/diagnóstico por imagem , Pessoa de Meia-Idade , NivolumabeRESUMO
INTRODUCTION: Adjuvant platinum-based chemotherapy is standard treatment for surgically resected stage II to IIIA NSCLC, but the relapse rate is high. The preferentially expressed antigen of melanoma (PRAME) tumor antigen is expressed in two-thirds of NSCLC and offers an attractive target for antigen-specific immunization. A phase I dose escalation study assessed the safety and immunogenicity of a PRAME immunotherapeutic consisting of recombinant PRAME plus proprietary immunostimulant AS15 in patients with surgically resected NSCLC (NCT01159964). METHODS: Patients with PRAME-positive resected stage IB to IIIA NSCLC were enrolled in three consecutive cohorts to receive up to 13 injections of PRAME immunotherapeutic (recombinant PRAME protein dose of 20 µg, 100 µg, or 500 µg, with a fixed dose of AS15). Adverse events, predefined dose-limiting toxicity, and the anti-PRAME humoral response (measured by enzyme-linked immunosorbent assay) were coprimary end points. Anti-PRAME cellular responses were assessed. RESULTS: A total of 60 patients were treated (18 received 20 µg of PRAME, 18 received 100 µg of PRAME, and 24 received 500 µg of PRAME). No dose-limiting toxicity was reported. Adverse events considered by the investigator to be causally related to treatment were grade 1 or 2, and most were injection site reactions or fever. All patients had detectable anti-PRAME antibodies after four immunizations. The percentages of patients with PRAME-specific CD4-positive T cells were higher at the dose of 500 µg compared with lower doses. No predefined CD8-positive T-cell responses were detected. CONCLUSION: The PRAME immunotherapeutic had an acceptable safety profile. All patients had anti-PRAME humoral responses that were not dose related, and 80% of those treated at the highest dose showed a cellular immune response. The dose of 500 µg was selected. However, further development was stopped after negative results with a similar immunotherapeutic in patients with NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , MasculinoRESUMO
Inflammatory myofibroblastic tumor (IMT) of the lung is a rare malignancy with few cases reported in the literature. Histologically, it is composed by spindle cells and an infiltrate of inflammatory cells. Children and young, non-smoking adults constitute the majority of cases, the clinical behavior ranges from a benign entity to a malignant process with rapid recurrence and metastatic progression. We present a case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) of the pleura, a malignant variant of IMT, which was initially treated with debulking surgical resection followed by systemic chemotherapy. The tumor was found to have an anaplastic lymphoma kinase (ALK) gene rearrangement. An ALK directed tyrosine kinase inhibitor was used with an impressive response, the patient remains in remission nearly 1 year after presentation. The pathogenesis, pathologic findings, clinical behavior and imaging of pulmonary EIMS are discussed.
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PURPOSE: To provide evidence-based recommendations to update the American Society of Clinical Oncology guideline on systemic therapy for stage IV non-small-cell lung cancer (NSCLC). METHODS: An Update Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of randomized controlled trials from January 2007 to February 2014. RESULTS: This guideline update reflects changes in evidence since the previous guideline. RECOMMENDATIONS: There is no cure for patients with stage IV NSCLC. For patients with performance status (PS) 0 to 1 (and appropriate patient cases with PS 2) and without an EGFR-sensitizing mutation or ALK gene rearrangement, combination cytotoxic chemotherapy is recommended, guided by histology, with early concurrent palliative care. Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 (bevacizumab may be added to carboplatin plus paclitaxel if no contraindications); combination or single-agent chemotherapy or palliative care alone for those with PS 2; afatinib, erlotinib, or gefitinib for those with sensitizing EGFR mutations; crizotinib for those with ALK or ROS1 gene rearrangement; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma. Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens, alternative chemotherapy, or a chemotherapy break. In the second-line setting, recommendations include docetaxel, erlotinib, gefitinib, or pemetrexed for patients with nonsquamous cell carcinoma; docetaxel, erlotinib, or gefitinib for those with squamous cell carcinoma; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib. In the third-line setting, for patients who have not received erlotinib or gefitinib, treatment with erlotinib is recommended. There are insufficient data to recommend routine third-line cytotoxic therapy. Decisions regarding systemic therapy should not be made based on age alone. Additional information can be found at http://www.asco.org/guidelines/nsclc and http://www.asco.org/guidelineswiki.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC). PATIENTS AND METHODS: The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m(2) or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m(2) per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67. RESULTS: One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks). CONCLUSION: Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC.