RESUMO
BACKGROUND AND OBJECTIVES: The role of salvage thoracic surgery in managing advanced-stage lung cancer following treatment with immune checkpoint inhibitors is currently unclear. We present a series of nine patients with advanced non-small-cell lung cancer who underwent pulmonary resection following treatment with pembrolizumab. METHODS: We performed a single-institution retrospective analysis of pulmonary resection undertaken following treatment with pembrolizumab for advanced-stage lung cancer. Nine patients met the inclusion criteria. RESULTS: In six cases, surgery was indicated for persistent localized disease after treatment, and in three cases for nonresponsive synchronous/metachronous lung nodules while on treatment for stage IV lung cancer. Dense hilar fibrosis was present in all patients. Minimal access surgery was achieved in five cases (video-assisted n = 2, robotic-assisted n = 3). There was no in-hospital mortality. One patient died within 60 days from community-acquired COVID-19 pneumonitis. Seven patients remain free of disease between 5 and 22 months follow-up. CONCLUSIONS: Pulmonary resection is safe and technically feasible following treatment with immune checkpoint inhibitors. Surgical challenges relate to postimmunotherapy fibrosis, but with increased experience and a robotic approach, minimal access surgery is achievable. Further prospective studies are required to assess the surgical impact on disease control and overall survival in this patient cohort.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Terapia de SalvaçãoRESUMO
Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-α) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-α, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-α/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-α/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Membro Posterior/patologia , Vírus Oncolíticos/fisiologia , Sarcoma Experimental/terapia , Vaccinia virus/fisiologia , Animais , Apoptose , Linhagem Celular Tumoral , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Membro Posterior/efeitos dos fármacos , Humanos , Masculino , Melfalan/administração & dosagem , Transplante de Neoplasias , Ratos Endogâmicos , Sarcoma Experimental/irrigação sanguínea , Sarcoma Experimental/patologia , Fator de Necrose Tumoral alfa/administração & dosagemRESUMO
BACKGROUND AND PURPOSE: We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. MATERIALS AND METHODS: Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. RESULTS: EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated (131)I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed (131)I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. CONCLUSION: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.
Assuntos
Neoplasias Colorretais/terapia , Neoplasias de Cabeça e Pescoço/terapia , Radioisótopos do Iodo/uso terapêutico , Isoquinolinas/uso terapêutico , Vírus do Sarampo/fisiologia , Terapia Viral Oncolítica , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/fisiologia , Pirazinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Animais , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Terapia Combinada , Humanos , Camundongos , Simportadores/genética , Replicação Viral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Locally advanced head and neck cancer carries a poor prognosis, even with standard combination (surgery, radiotherapy, chemotherapy) treatment regimens. There is a pressing need for novel therapies with activity against this tumour type. Oncolytic reovirus type 3 (Dearing) is preferentially cytotoxic in tumour cells with an activated Ras signalling pathway and represents a promising novel therapy with relevance in head and neck cancer. AREAS COVERED: In this review, we discuss the pre-clinical and clinical data that have underpinned the translational development of oncolytic reovirus thus far. In particular, we describe the iterative nature of the research programme through initial studies testing single-agent reovirus therapy and on to subsequent work in which reovirus has been combined with either radiotherapy or cytotoxic chemotherapy. We will trace the process by which oncolytic reovirus has reached Phase III evaluation in combination with carboplatin/paclitaxel in patients with platin-refractory, relapsed/metastatic head and neck cancer. EXPERT OPINION: Reovirus is a self-amplifying, cancer-selective agent that offers huge potential advantages over standard chemotherapy, targeted small molecules or monoclonal antibodies. However, it is most likely that reovirus will show efficacy and be approved in combination with standard modalities (cytotoxic chemotherapy or radiotherapy) or other targeted agents, especially those that modulate signal transduction pathways. The next 5 years are critical for the development of oncolytic reovirus as an anti-cancer therapy and hinge on the ongoing Phase III trial in head and neck cancer and other Phase II programmes.
Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Orthoreovirus Mamífero 3 , Terapia Viral Oncolítica , Ensaios Clínicos como Assunto , HumanosRESUMO
BACKGROUND: Reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. METHODS: To test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. RESULTS: Correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells. CONCLUSIONS: In summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue.
Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Vírus Oncolíticos/metabolismo , Infecções por Reoviridae/metabolismo , Transdução de Sinais/fisiologia , Western Blotting , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Citometria de Fluxo , Humanos , ReoviridaeRESUMO
PURPOSE: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. EXPERIMENTAL DESIGN: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer. RESULTS: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. CONCLUSIONS: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Orthoreovirus Mamífero 3/fisiologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Terapia Combinada , Diarreia/induzido quimicamente , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/patologia , Vírus Oncolíticos/fisiologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Estomatite/induzido quimicamente , Resultado do TratamentoRESUMO
As a result of improved effectiveness of first-, second-line and maintenance therapeutic regimens in non-small cell lung cancer, there is need for new options as third-line treatment. Erlotinib and gefitinib are currently the only drugs of proven efficacy in the third-line setting. Chemotherapy drugs, such as pemetrexed, are being investigated, as are many new agents, such as cetuximab, sunitinib, sorafenib, everolimus, enzastaurin, afilbercept. These novel targeted therapies seem to improve response rates and progression-free survival and their toxicity is tolerable. In an effort to prolong survival while maintaining quality of life, large prospective studies are needed to examine the effectiveness and safety of third-line regimens in these patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/uso terapêutico , Cloridrato de Erlotinib , Gefitinibe , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Guanina/uso terapêutico , Humanos , Terapia de Alvo Molecular , Pemetrexede , Quinazolinas/uso terapêutico , Terapia de Salvação/métodosRESUMO
Metastin, the product of the KISS-1 gene, seems to represent a strong suppressant of metastasis for some types of cancer. The aim of this study is to explore whether circulating levels of metastin could be used as a marker for the metastatic potential of non-small cell lung cancer (NSCLC) as well as a diagnostic marker in NSCLC patients. The possible correlation between metastin and leptin circulating levels was also evaluated. Fasting serum levels of metastin and leptin were determined in 96 NSCLC patients at diagnosis (76 with metastatic disease and 21 with locally advanced disease) and 49 healthy volunteers using commercial available ELISA. Serum metastin levels presented no differences between NSCLC patients and healthy volunteers (1.18 ± 0.98 vs. 1.17 ± 0.39 ng/ml, P = 0.979) as well as between patients with metastatic and locally advanced disease (1.17 ± 1.05 vs. 1.21 ± 0.64 ng/ml, P = 0.872). There was no statistically significant correlation between circulating metastin and leptin levels in NSCLC patients and patients with locally advanced and metastatic disease. This study shows a lack of direct involvement of metastin in the diagnosis and metastatic potential of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Proteínas Supressoras de Tumor/sangue , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Kisspeptinas , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de NeoplasiasAssuntos
Adenocarcinoma/tratamento farmacológico , Hipertricose/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Pestanas , Face , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
PURPOSE: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses. EXPERIMENTAL DESIGN: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 x 10(8) and 1 x 10(10) TCID(50). In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 x 10(10) TCID(50). End points were safety, viral replication, immunogenicity, and antitumoral activity. RESULTS: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease. CONCLUSIONS: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent.
Assuntos
Orthoreovirus Mamífero 3 , Neoplasias/terapia , Terapia Viral Oncolítica , Adulto , Idoso , Anticorpos Antivirais/análise , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/radioterapia , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Dosagem Radioterapêutica , Distribuição Tecidual , Replicação Viral , Eliminação de Partículas ViraisRESUMO
Prostate cancer is one of the leading causes of cancer related death in men, and remains incurable in the metastatic setting. Despite the initial response to androgen deprivation, the disease gradually progresses to a hormone-refractory state due to cumulative genetic alterations in tumour cells or the microenvironment. Docetaxel represents the first chemotherapeutic agent with a small survival benefit for metastatic hormone-refractory prostate cancer (HRPC). In an attempt to improve survival benefit, several novel drugs targeting specific pathways involved in cell signaling, proliferation, angiogenesis, apoptosis and immune modulation are currently under investigation either as single agents or in combination with cytotoxic drugs. Clinical trials evaluate the inhibition of prostate cancer cells growth by targeting the nuclear receptor of vitamin D alongside cytotoxic therapy. Angiogenesis inhibitors as well as epidermal growth factor receptor blockage are also under clinical investigation in several combinations. Immunomodulatory agents and autologous dendritic cells or allogenic whole cell vaccines have progressed up to phase III trials. New drugs targeting bone microenvironment or apoptotic and proliferation pathways may enhance antitumour activity of chemotherapy in HRCP. Given the complexity of mechanisms underlying prostate cancer progression, future therapeutic strategies should rely on multidisciplinary approaches, thus exploiting newer molecular targets in concert with immunotherapy and cytotoxic chemotherapy. Here, we review the latest clinical evidence regarding the use of novel agents in HRPC.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoterapia/métodos , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/administração & dosagem , Quimioterapia Combinada , Humanos , Masculino , PrognósticoRESUMO
The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Ósseas/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Osteoclastos/metabolismo , Osteoclastos/patologia , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/patologiaRESUMO
BACKGROUND: The aim of this study was to determine the progression-free survival (PFS) and toxicity associated with adjuvant administration of carboplatin and pemetrexed for completely resected patients with stage IB, II and IIIA non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-five eligible NSCLC patients received surgical resection for pathological stage IB, II or IIIA followed by postoperative adjuvant chemotherapy with carboplatin AUC5 and pemetrexed administered on days 1 and 14 on a 28-day cycle. Recombinant human granulocyte colony-stimulating factor (rhG-CF) was given prophylactically. RESULTS: The mean time to disease progression of patients was 26 months. Toxicities were generally mild to moderate and entirely manageable. CONCLUSION: The administration of carboplatin and pemetrexed is a safe, well-tolerated and convenient regimen in the adjuvant setting of completely resected NSCLC, with efficacy similar to that reported in other regimens but less toxicity.
Assuntos
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 , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PemetrexedeRESUMO
BACKGROUND: We recorded the epidemiologic and clinical features of hypersensitivity reactions (HSRs) to oxaliplatin in colorectal cancer (CRC) patients in order to provide information on the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. For these reasons, we analyzed retrospectively the records of 215 CRC patients treated with oxaliplatin-containing regimens either as an adjuvant, first-line, second-line, or more. PATIENTS AND METHODS: Data from 52 patients with HSRs were analyzed according to the Common Toxicity Criteria for Adverse Events (CTCAE), v3.0. Three patients were chosen for the desensitization protocol. After determining the starting point for desensitization, we applied the standard protocol for parenteral desensitization to b-lactam antibiotics. Oxaliplatin treatment was then carried out with serial 10-fold dilutions in sufficient volume to administer the total dose. A total of 52 patients (24.2%) were recorded as having an allergic reaction to oxaliplatin. RESULTS: Hypersensitivity reactions were recorded after a mean of 6.5 (SD +/- 4.5) cycles. Only 4 patients (4 of 215; 1.8%) developed CTCAE grade 3/4 HSRs. Hypersensitivity reactions were seen more likely in patients receiving second-line or more of chemotherapy compared with chemotherapy-naive patients. No other correlations were seen (the presence of atopic disease, positive skin prick test). The 3 patients, having completed the parenteral desensitization protocol, completed their treatment uneventfully as well. CONCLUSION: Hypersensitivity reactions from oxaliplatin respond quickly to the discontinuation of the drug and appropriate support. Premedication and an increased infusion time could allow for readministration. The desensitization protocol we developed can provide a reliable alternative to permanent discontinuation of oxaliplatin.
Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/terapia , Compostos Organoplatínicos/efeitos adversos , Adulto , Idoso , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/epidemiologia , Feminino , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Estudos RetrospectivosRESUMO
The purpose of this study was to investigate various serum markers of bone turnover in non-small cell lung cancer patients (NSCLC) in the presence or absence of bone metastasis. Our retrospective study included 79 newly diagnosed NSCLC patients. Group A included 51 patients with bone metastasis and group B included 28 patients that never developed bone metastasis. The measurement of bone formation markers, bone resorptive markers and osteoclastogenesis markers as well as routine biochemical analysis was determined. Patients with bone metastasis had an increase in receptor activator of nuclear factor kappaB ligand, osteopontin and osteoprotegerin. Patients who later developed bone metastasis had decreased osteocalcin and tartrate-resistant acid phosphatase isoform 5b levels (TRACP-5b). We also found an unusually low TRACP-5b/RANKL ratio for patients who have or later developed metastasis. In patients that never developed bone metastases, cross-linked carboxy-terminal telopeptide of type I collagen was increased. Positive correlations were found between osteopontin and TRACP-5b, and also between bone alkaline phosphatase with osteocalcin and TRACP-5b. In conclusion, serum markers of bone turnover may be able to determine the time-to-tumor progression, metastatic potential and overall survival of the NSCLC patient. In addition, they may contribute to a more accurate follow-up and tailored treatment options.
Assuntos
Biomarcadores/sangue , Reabsorção Óssea , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Neoplasias Pulmonares/sangue , Prognóstico , Estudos RetrospectivosRESUMO
Background: We recorded the epidemiologic and clinical features of hypersensitivity reactions (HSRs) to oxaliplatin in colorectal cancer (CRC) patients in order to provide information on the management of these patients. We also developed a desensitization protocol and evaluated its clinical application. For these reasons, we analyzed retrospectively the records of 215 CRC patients treated with oxaliplatin-containing regimens either as an adjuvant, first-line, second-line, or more. Patients and Methods: Data from 52 patients with HSRs were analyzed according to the Common Toxicity Criteria for Adverse Events (CTCAE), v3.0. Three patients were chosen for the desensitization protocol. After determining the starting point for desensitization, we applied the standard protocol for parenteral desensitization to b-lactam antibiotics. Oxaliplatin treatment was then carried out with serial 10-fold dilutions in sufficient volume to administer the total dose. A total of 52 patients (24.2%) were recorded as having an allergic reaction to oxaliplatin. Results: Hypersensitivity reactions were recorded after a mean of 6.5 (SD +/- 4.5) cycles. Only 4 patients (4 of 215; 1.8%) developed CTCAE grade 3/4 HSRs. Hypersensitivity reactions were seen more likely in patients receiving second-line or more of chemotherapy compared with chemotherapy-naive patients. No other correlations were seen (the presence of atopic disease, positive skin prick test). The 3 patients, having completed the parenteral desensitization protocol, completed their treatment uneventfully as well. Conclusion: Hypersensitivity reactions from oxaliplatin respond quickly to the discontinuation of the drug and appropriate support. Premedication and an increased infusion time could allow for readministration. The desensitization protocol we developed can provide a reliable alternative to permanent discontinuation of oxaliplatin.
RESUMO
UNLABELLED: Pulmonary toxicity induced by novel antineoplastic agents has not been well characterized because of the simultaneous or sequential use of drugs and a multimodality therapeutic approach. To further investigate this topic, relevant studies were identified through Medline. The generic names of novel antineoplastic agents and the key words pulmonary toxicity, dyspnea and pneumonitis were used for the search. References from the articles identified were also reviewed for additional sources. Most novel antineoplastic drugs may induce pulmonary toxicity. The most recognized patterns of lung toxicity consist of unspecified dyspnea and interstitial lung disease (ILD). Exclusion diagnosis of possible underlying diseases is necessary. Genetic predisposition, autoimmune conditions or superimposed disease may also be involved in the development of lung toxicity. CONCLUSION: Clinicians should be aware of potential pulmonary toxicity as a complication in the treatment of cancer and focus on its early detection or prediction.
Assuntos
Antineoplásicos/efeitos adversos , Pneumopatias/induzido quimicamente , Terapia Combinada/efeitos adversos , Humanos , Pneumopatias/etiologia , Radioterapia/efeitos adversosRESUMO
The human epidermal growth factor receptor (EGFR) signaling is overexpressed in many solid malignancies, making it an appealing target for biologic agents. A number of agents that target this receptor are in use or in development. A specific adverse effect common to this class of agents is an acneiform-like skin rash that has been related to EGFR inhibition in the skin. Little is known about the etiology of this rash, and there are no clear evidence-based management recommendations. Findings suggest that there is a relationship between the development of rash and response and/or survival, making rash a potential surrogate marker of activity. This review summarizes and updates the current knowledge of the clinical presentation, etiology, and predictive and prognostic value of erlotinib-induced skin rash and establishes a treatment strategy to help treat dermatologic adverse events and allow patients to continue therapy without dose interruption or drug discontinuation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/complicações , Exantema/induzido quimicamente , Neoplasias Pulmonares/complicações , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Exantema/tratamento farmacológico , Exantema/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
OBJECTIVE: Ghrelin is an orexigenic peptide implicated in body weight regulation, while cachexia is a multifactorial effect of non-small cell lung cancer (NSCLC) presented in patients with advanced disease. The aim of this study was to detect the role of ghrelin in cachexia and systemic inflammation of advanced NSCLC patients as well as its role as a diagnostic and prognostic tool. METHODS: Ghrelin serum levels were measured in 101 inoperable NSCLC patients before receiving any therapy (75 patients with weight loss and 26 without weight loss) and 60 healthy control volunteers. Epidemiological, anthropometrical and laboratory data were assessed for all participants (patients and healthy volunteers). RESULTS: NSCLC patients presented significantly higher ghrelin serum levels than healthy individuals, adjusted for sex, age and BMI (0.5+/-0.4 ng/ml vs. 0.4+/-0.3 ng/ml, P<0.001). NSCLC patients with weight loss presented significantly increased ghrelin serum levels (0.56+/-0.24 ng/ml vs. 0.52+/-0.44 ng/ml, P=0.017), compared to NSCLC patients without weight loss. CONCLUSIONS: Ghrelin serum levels are significantly increased in NSCLC patients, mainly in the subgroup of patients diagnosed with cachexia, indicating a possible implication in the pathogenesis of lung cancer. Further studies are needed to determine its potential role as predictive and prognostic marker.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Grelina/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/fisiopatologia , Redução de Peso , Idoso , Caquexia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Heat shock proteins (HSP) play an essential role as molecular chaperones by assisting correct holding and folding in human cells. At the same time they present implications in tumor cell proliferation, differentiation, matrix invasion, angiogenesis, metastasis and cell death. They also possess the ability to present tumor molecules to the immune system and elicit an immune response. New agents targeting HSP, as anticancer treatment, are under clinical evaluation. OBJECTIVE: The aim of this review is to explore the role of HSP90 inhibitors as anticancer agents as well as to evaluate the benefit from the use of autologous HSP vaccines in both the adjuvant setting and first-line treatment. METHODS: The latest evidence regarding the use of geldanamycin analogues or newer water-soluble and synthetics molecules that inhibit the binding of HSP90 to client proteins was reviewed. Immunization using tumor-derived HSP in several cancer types was also evaluated. CONCLUSIONS: HSP90 inhibitors represent a promising therapeutic option although further evaluation in larger clinical trials is needed. On the other hand, HSP vaccination has already an established role in our armory against cancer.