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BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20â weeks, a composite end-point including 1) successfully completing both treatments within 20â weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.
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Mesotelioma , Neoplasias Pleurais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pleurais/cirurgia , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/terapia , Idoso , Mesotelioma/cirurgia , Mesotelioma/tratamento farmacológico , Mesotelioma/mortalidade , Adulto , Mesotelioma Maligno/cirurgia , Mesotelioma Maligno/tratamento farmacológico , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Terapia Combinada , Pleura/cirurgia , Pneumonectomia/métodosRESUMO
BACKGROUND: Patients treated with immune checkpoint inhibitors (ICI) are at risk of adverse events (AEs) even though not all patients will benefit. Serum tumor markers (STMs) are known to reflect tumor activity and might therefore be useful to predict response, guide treatment decisions and thereby prevent AEs. OBJECTIVE: This study aims to compare a range of prediction methods to predict non-response using multiple sequentially measured STMs. METHODS: Nine prediction models were compared to predict treatment non-response at 6-months (nâ=â412) using bi-weekly CYFRA, CEA, CA-125, NSE, and SCC measurements determined in the first 6-weeks of therapy. All methods were applied to six different biomarker combinations including two to five STMs. Model performance was assessed based on sensitivity, while model training aimed at 95% specificity to ensure a low false-positive rate. RESULTS: In the validation cohort, boosting provided the highest sensitivity at a fixed specificity across most STM combinations (12.9% -59.4%). Boosting applied to CYFRA and CEA achieved the highest sensitivity on the validation data while maintaining a specificity >95%. CONCLUSIONS: Non-response in NSCLC patients treated with ICIs can be predicted with a specificity >95% by combining multiple sequentially measured STMs in a prediction model. Clinical use is subject to further external validation.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Biomarcadores Tumorais , Neoplasias Pulmonares/patologia , ImunoterapiaRESUMO
BACKGROUND: Discordance between physicians' and patients' prognostic perceptions in advanced cancer care threatens informed medical decision-making and end-of-life preparation, yet this phenomenon is poorly understood. We sought to: (1) describe the extent and direction of prognostic discordance, patients' prognostic information preferences in cases of prognostic discordance, and physicians' awareness of prognostic discordance; and (2) examine which patient, physician, and caregiver factors predict prognostic discordance. MATERIALS AND METHODS: Oncologists and advanced cancer patients (median survival ≤12 months; n = 515) from 7 Dutch hospitals completed structured surveys in a cross-sectional study. Prognostic discordance was operationalized by comparing physicians' and patients' perceptions of the likelihood of cure, 2-year mortality risk, and 1-year mortality risk. RESULTS: Prognostic discordance occurred in 20% (likelihood of cure), 24%, and 35% (2-year and 1-year mortality risk) of physician-patient dyads, most often involving patients with more optimistic perceptions than their physician. Among patients demonstrating prognostic discordance, the proportion who preferred not knowing prognosis varied from 7% (likelihood of cure) to 37% (1-year mortality risk), and 45% (2-year mortality risk). Agreement between physician-perceived and observed prognostic discordance or concordance was poor (kappa = 0.186). Prognostic discordance was associated with several patient factors (stronger fighting spirit, self-reported absence of prognostic discussions, an information source other than the healthcare provider), and greater physician-reported uncertainty about prognosis. CONCLUSION: Up to one-third of the patients perceive prognosis discordantly from their physician, among whom a substantial proportion prefers not knowing prognosis. Most physicians lack awareness of prognostic discordance, raising the need to explore patients' prognostic information preferences and perceptions, and to tailor prognostic communication.
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Neoplasias , Médicos , Humanos , Prognóstico , Prevalência , Estudos Transversais , Relações Médico-Paciente , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/terapiaAssuntos
Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Receptores ErbB/genéticaRESUMO
BACKGROUND: For some patients with advanced cancer not knowing prognosis is essential. Yet, in an era of informed decision-making, the potential protective function of unawareness is easily overlooked. We aimed to investigate 1) the proportion of advanced cancer patients preferring not to know prognosis; 2) the reasons underlying patients' prognostic information preference; 3) the characteristics associated with patients' prognostic information preference; and 4) the concordance between physicians' perceived and patients' actual prognostic information preference. METHODS: This is a cross-sectional study with structured surveys (PROSPECT). Medical and thoracic oncologists included patients (n = 524), from seven Dutch hospitals, with metastatic/inoperable cancer and an expected median overall survival of ≤ 12 months. For analysis, descriptive statistics and logistic regression models were used. RESULTS: Twenty-five to 31% of patients preferred not to know a general life expectancy estimate or the 5/2/1-year mortality risk. Compared to patients preferring to know prognosis, patients preferring unawareness more often reported optimism, avoidance and inability to comprehend information as reasons for wanting limited information; and less often reported expectations of others, anxiety, autonomy and a sense of control as reasons for wanting complete information. Females (p < .05), patients receiving a further line of systemic treatment (p < .01) and patients with strong fighting spirit (p < .001) were more likely to prefer not to know prognosis. Concordance between physicians' perceived and patients' actual prognostic information preference was poor (kappa = 0.07). CONCLUSIONS: We encourage physicians to explore patients' prognostic information preferences and the underlying reasons explicitly, enabling individually tailored communication. Future studies may investigate changes in patients' prognostic information preferences over time and examine the impact of prognostic disclosure on patients who prefer unawareness.
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Neoplasias , Relações Médico-Paciente , Comunicação , Estudos Transversais , Feminino , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Preferência do Paciente , PrognósticoRESUMO
BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .). CONCLUSIONS: Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ipilimumab/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Intervalo Livre de Doença , Feminino , Humanos , Ipilimumab/efeitos adversos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , NivolumabeRESUMO
OBJECTIVE: To assess perspectives and experiences of healthcare professionals and other relevant stakeholders regarding psychosocial support and palliative care in mesothelioma patients and their relatives, to identify gaps and to explore potential improvements in current healthcare. METHODS: Individual, semi-structured interviews were conducted with healthcare professionals and other relevant stakeholders. Interviews were transcribed verbatim and analysed thematically using ATLAS.ti. RESULTS: In total, 16 respondents participated in an interview (69% women; mean age: 51.8 years (SD 12.41; range 28-75)). Four key themes were identified: (1) availability of tailored psychosocial and palliative care, (2) timely integration and organisation of psychosocial support and palliative care, (3) differences in provided support and care between healthcare professionals and hospitals and (4) training of healthcare professionals and stakeholders on psychosocial problems. CONCLUSION: Our study showed that psychosocial support and palliative care for patients with mesothelioma could be improved. A more fluent transition between primary and secondary cancer care and early integration of psychosocial support and palliative care is advised. Lastly, more attention is needed for psychosocial and palliative care in the basic medical training of healthcare professionals.
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Mesotelioma , Cuidados Paliativos , Atenção à Saúde , Feminino , Pessoal de Saúde , Humanos , Masculino , Mesotelioma/terapia , Pessoa de Meia-Idade , Pesquisa QualitativaRESUMO
OBJECTIVE: Mesothelioma is a rare cancer with a poor prognosis caused by exposure to asbestos. Psychosocial support and care for mesothelioma patients and their carers is limited and not tailored to their specific needs. The aim of this study was to explore patients' and carers' needs and experiences regarding psychosocial support and their coping mechanisms dealing with psychosocial problems. METHODS: A qualitative study was performed using semi-structured interviews with both mesothelioma patients and their carers. Participants were recruited through two specialised hospitals and two patient organisations. All interviews were transcribed verbatim and thematically analysed. RESULTS: Ten patients (70% male, mean age 67.7) and five carers (20% male, mean age 65) participated in the study. The main themes identified for patients were active coping, limited needs and limited knowledge and awareness about psychosocial support. The main themes for carers were passive coping and 'it's all about the patient'. CONCLUSION: Mesothelioma patients do not seem to have high needs for psychosocial support, whereas carers do. However, knowledge about and awareness of psychosocial support is low among mesothelioma patients. The findings from this study should be used to adjust guidelines for psychosocial support in mesothelioma patients and their carers.
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Mesotelioma Maligno , Mesotelioma , Adaptação Psicológica , Idoso , Cuidadores , Feminino , Humanos , Masculino , Mesotelioma/terapia , Pesquisa QualitativaRESUMO
OPINION STATEMENT: The optimal treatment of patients with advanced malignant pleural mesothelioma (MPM) has not yet been discovered. With the aid of an increased insight in the molecular pathways and the development of combinations of Immuno-Oncology (IO), drugs new therapies are available. The personalization of treatment by cell cultures and pathway analysis attracts more attention nowadays. It is conceivable that in the near future the treatment of patients with MPM will consist of a combination of IO drugs or specific pathway inhibitors.
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Mesotelioma/patologia , Mesotelioma/terapia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Humanos , Imunoterapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Mesotelioma/etiologia , Mesotelioma/mortalidade , Mesotelioma Maligno , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM). METHODS: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts. RESULTS: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC. CONCLUSIONS: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.
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Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Osteonectina/metabolismo , Neoplasias Pleurais/metabolismo , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Masculino , Espectrometria de Massas , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Pessoa de Meia-Idade , Análise Multivariada , Transplante de Neoplasias , Neoplasias Pleurais/patologia , Prognóstico , Modelos de Riscos Proporcionais , Proteômica , Estudos Retrospectivos , Taxa de Sobrevida , Análise Serial de TecidosRESUMO
BACKGROUND: This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment. METHODS: Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m(2) at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m(2) at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored. At the maximal tolerable dose level of this schedule an expansion group was enrolled of which 15 patients were evaluable for response. RESULTS: Due to frequent neutropenic dose interruptions in the third week, the 28 day schedule was amended into a 21 day schedule. The maximal tolerable dose was 300 and 450 mg/m(2) of NAMI-A (21 day schedule). Main adverse events consisted of neutropenia, anemia, elevated liver enzymes, transient creatinine elevation, nausea, vomiting, constipation, diarrhea, fatigue, and renal toxicity. CONCLUSION: NAMI-A administered in combination with gemcitabine is only moderately tolerated and less active in NSCLC patients after first line treatment than gemcitabine alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Dimetil Sulfóxido/administração & dosagem , Dimetil Sulfóxido/efeitos adversos , Dimetil Sulfóxido/análogos & derivados , Dimetil Sulfóxido/farmacocinética , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/farmacocinética , Rutênio/administração & dosagem , Rutênio/efeitos adversos , Rutênio/sangue , Rutênio/farmacocinética , Compostos de Rutênio , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: To prospectively evaluate diagnostic computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for identification of histopathologic response to neoadjuvant erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with resectable non-small cell lung cancer (NSCLC). METHODS: This study was designed as an open-label phase 2 trial, performed in four hospitals in the Netherlands. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. CT and FDG-PET/CT were performed at baseline and after 3 weeks of treatment. CT was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. FDG-PET/CT, tumor FDG uptake, and changes were measured by standardized uptake values (SUV). Radiologic and metabolic responses were compared to the histopathological response. RESULTS: Sixty patients were enrolled onto this study. In 53 patients (22 men, 31 women), the combination of CT, FDG-PET/CT, and histopathological evaluation was available for analysis. Three patients (6 %) had radiologic response. According to European Organisation for Research and Treatment of Cancer (EORTC) criteria, 15 patients (28 %) showed metabolic response. In 11 patients, histopathologic response (≥50 % necrosis) was seen. In predicting histopathologic response, relative FDG change in SUVmax showed more SUVmax decrease in the histopathologic response group (-32 %) versus the group with no pathologic response (-4 %) (p = 0.0132). Relative change in tumor size on diagnostic CT was similar in these groups with means close to 0. CONCLUSIONS: FDG-PET/CT has an advantage over CT as a predictive tool to identify histopathologic response after 3 weeks of EGFR-TKI treatment in NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Cloridrato de Erlotinib , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos Prospectivos , Curva ROC , Compostos Radiofarmacêuticos , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND: Indwelling pleural catheters (IPCs) are increasingly used in the treatment of malignant pleural effusion (MPE). In general, these catheters have been reported to manage MPE efficiently. Unfortunately, insurance companies in the Netherlands do not reimburse these catheters in either first-line treatment or following failed talc pleurodesis. OBJECTIVES: Investigation of direct costs of IPC placement. METHODS: Retrospective analysis of a prospectively collected database. Direct costs for both catheters and vacuum bottles were calculated. Indicators for indirect costs such as adverse events and complications and the need for additional home care for drainage were registered. RESULTS: Mean costs for IPC amounted to EUR 2,173 and were different between tumor types - mesothelioma: EUR 4,028, breast: EUR 2,204, lung: EUR 1,146 and other: EUR 1,841; p = 0.017. Four patients were admitted to hospital for treatment of complications. Mean costs for IPC placement was similar when inserted as frontline treatment and after failed pleurodesis. Approximately 75% of patients did not need any help from specialized home care. CONCLUSION: Direct costs for IPC placement turn out to be acceptable when compared with estimated hospitalization costs for pleurodesis treatment. Randomized controlled trials have to be performed to compare the cost-effectiveness of IPCs compared to pleurodesis.
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Cateteres de Demora/economia , Derrame Pleural Maligno/economia , Derrame Pleural Maligno/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateteres de Demora/efeitos adversos , Feminino , Custos Hospitalares , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Pleura , Estudos RetrospectivosRESUMO
The ideal airway stent is still not available. Indications for 3D stents currently are limited to rare cases. Therefore, further research is required to investigate whether personalised airway stents will perform better than conventional stents. https://bit.ly/3GLjPa4.
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INTRODUCTION: Immune checkpoint inhibitors improved survival of advanced stage non-small cell lung cancer patients, but the overall response rate remains low. A biomarker that identifies non-responders would be helpful to allow treatment decisions. Clearance of immune checkpoint inhibitors is related to treatment response, but its prognostic potential early in treatment remains unknown. Our primary aim was to investigate the prognostic potential of nivolumab clearance for overall survival early in treatment. Our secondary aim was to evaluate the performance of nivolumab clearance as prognostic biomarker. PATIENTS AND METHODS: Individual estimates of nivolumab clearances at first dose, 6 and 12 weeks after treatment initiation were obtained via nonlinear mixed-effects modelling. Prognostic value of nivolumab clearance was estimated using univariate Cox regression at first dose and for the ratios between 6 and 12 weeks to first dose. The performance of nivolumab clearance as biomarker was assessed by calculating sensitivity and specificity. RESULTS: During follow-up of 75 months, 69 patients were included and 865 died. Patients with a nivolumab clearance ≥ 7.3 mL/h at first dose were more likely to die compared to patients with a nivolumab clearance < 7.3 mL/h at first dose (hazard ratio [HR] = 3.55, 955 CI 1.75-7.20). The HRs of dose nivolumab clearance ratios showed similar results with a HR of 3.93 (955 CI 1.66-9.32) for 6 weeks to first-dose clearance ratio at a 0.953 cut-point and a HR of 2.96 (955 CI 1.32-6.64) for 12 weeks to first-dose clearance ratio at a cut-point of 0.814. For nivolumab clearance at all early time points, sensitivity was high (≥ 0.95) but specificity was low (0.11-0.29). CONCLUSION: Nivolumab clearance is indicative of survival early in treatment. Our results encourage to further assess the prognostic potential of immunotherapy clearance.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Nivolumabe/uso terapêutico , Nivolumabe/farmacologia , Prognóstico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , BiomarcadoresRESUMO
The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.
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BACKGROUND: The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy. METHODS: In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity. RESULTS: The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01). CONCLUSIONS: To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Polimorfismo Genético , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Feminino , Células Germinativas , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: The level of evidence for efficacy of local treatment of pulmonary metastases is low; therefore, complication rates should be minimized. Minimally invasive techniques may have the potential to reduce morbidity but potentially lead to more local and/or ipsilateral recurrences. The objective of this study was to evaluate the introduction of a new treatment strategy incorporating the increased use of video-assisted thoracic surgery (VATS) and radiofrequency ablation (RFA), weighing complications against recurrence rates. METHODS: We retrospectively reviewed results of all local treatment of pulmonary metastases in the Netherlands Cancer Institute from 2002 to 2007. Each of 158 identified interventions was analyzed separately to retrieve procedure-related data. Overall survival data were analyzed per patient. To evaluate the introduction of a strategy incorporating minimally invasive techniques, the study period was split in two (before and after the introduction of this strategy in July 2004). RESULTS: In Strategy I, 47 interventions (2 VATS, no RFA) were performed in 37 patients; in Strategy II 111 interventions (51 VATS and RFA) in 86 patients. Metastases of a variety of primary tumors were treated. Median hospital stay was shorter (5 vs. 7 days) and procedure-related morbidity was less with Strategy II (p < 0.01). Time-to-recurrence rates were comparable (p = 0.18), as were local and ipsilateral recurrence rates within 3 years (p = 0.72). Estimated overall 3-year survival was 59% for patients treated with Strategy I and 54% with Strategy II. CONCLUSIONS: Increased use of minimally invasive techniques for local treatment of pulmonary metastatic disease is associated with low morbidity, without apparent reduction in (local) disease control.
Assuntos
Ablação por Cateter/métodos , Laparoscopia/métodos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Cirurgia Torácica Vídeoassistida/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ablação por Cateter/mortalidade , Intervalo Livre de Doença , Humanos , Tempo de Internação , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/mortalidade , Países Baixos/epidemiologia , Reoperação , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida/mortalidade , Adulto JovemRESUMO
Serum tumor markers acquired through a blood draw are known to reflect tumor activity. Their non-invasive nature allows for more frequent testing compared to traditional imaging methods used for response evaluations. Our study aims to compare nine prediction methods to accurately, and with a low false positive rate, predict progressive disease despite treatment (i.e. non-response) using longitudinal tumor biomarker data. Bi-weekly measurements of CYFRA, CA-125, CEA, NSE, and SCC were available from a cohort of 412 advanced stage non-small cell lung cancer (NSCLC) patients treated up to two years with immune checkpoint inhibitors. Serum tumor marker measurements from the first six weeks after treatment initiation were used to predict treatment response at 6 months. Nine models with varying complexity were evaluated in this study, showing how longitudinal biomarker data can be used to predict non-response to immunotherapy in NSCLC patients.