RESUMO
BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
Assuntos
Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Paclitaxel/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/efeitos adversos , Cisplatino/farmacocinética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinéticaRESUMO
PURPOSE: The purpose of the trial was to assess the efficacy and tolerability of Sym004, a novel 1:1 mixture of two chimeric monoclonal antibodies (992 and 1024) targeting non-overlapping epitopes of the anti-epidermal growth factor receptor (EGFR), in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Incurable, recurrent and/or metastatic SCCHN patients with acquired resistance to anti-EGFR monoclonal antibody-containing treatment received weekly infusions of 12 mg/kg Sym004 until disease progression or unacceptable toxicity. RESULTS: Among the 26 patients treated with Sym004, the proportion of patients alive without disease progression at 6 months was 12 % (95 % CI 1-39 %). The median duration of progression-free survival was 82 days (95 % CI 41-140 days). Of 19 patients evaluable for response, eight showed a decrease in the sum of the largest diameter in their target lesions (median 11 %; range 7-27 %). The best overall response was stable disease in 13 patients (50 %). Paired biopsies showed a significant down-regulation of EGFR in both skin and tumors following exposure to Sym004. All patients had EGFR-related adverse events, including grade 3 skin toxicities and grade ≥3 hypomagnesemia reported in 13 (50 %) and 10 (38 %) of 26 patients, respectively. One event fulfilling the protocol-defined criteria for infusion-related reactions (grade 2) was reported. No anti-drug antibodies were detected. CONCLUSIONS: The marked EGFR down-regulation shown in target tissues supports the proposed mechanism of action of Sym004. This trial revealed modest anti-tumor activity of Sym004 in extensively pretreated advanced SCCHN patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/enzimologia , Linhagem Celular Tumoral , Progressão da Doença , Intervalo Livre de Doença , Receptores ErbB/imunologia , Feminino , Neoplasias de Cabeça e Pescoço/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K-AKT-mTOR axis is commonly detected in recurrent or metastatic SCCHN, and provided the rationale for the clinical phase II trial in pretreated SCCHN. PATIENTS AND METHODS: The primary end point was the progression-free survival rate (PFR) at 12 weeks. Forty eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A preplanned futility analysis was successfully passed after ≥1 success was detected in 20 patients. Secondary objectives consisted of progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence. RESULTS: A total of 40 patients were eligible. The PFR at 12 weeks was 40% (95% CI 25.0-54.6). The median PFS and OS were 56 days (95% CI 36-113 days) and 152 days (76-256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6%, with tumor shrinkage in 13 patients (39.4%). Overall, the treatment was well tolerated. Fatigue (47.5%), anemia (25.0%), nausea (20.0%), and pneumonia (20.0%) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF. CONCLUSION: Tumor shrinkage and efficacy parameter indicate that inhibition of the PI3K-AKT-mTOR axis was a putative novel treatment paradigm for SCCHN. We could not identify parameters predictive for treatment success of temsirolimus, which underscores the need for refinement of the molecular analysis in future studies. CLINICAL TRIALS NUMBER: NCT01172769.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sirolimo/análogos & derivados , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , Intervalo Livre de Doença , Feminino , Alemanha/epidemiologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Sirolimo/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16(INK4a) expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16(INK4A)-positive and p16(INK4A)-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Papillomavirus Humano 16/patogenicidade , Infecções por Papillomavirus/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/virologia , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/mortalidade , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Venenos de Serpentes/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Cetuximab , Cisplatino/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Feminino , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Venenos de Serpentes/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
BACKGROUND: Pt-(GpG) intrastrand crosslinks are the major DNA adducts induced by platinum-based anticancer drugs. In the cell lines and mouse models, the persistence of these lesions correlates significantly with cell damage. Here we studied Pt-(GpG) DNA adducts in circulating tumour cells (CTC) treated with cisplatin in medium upfront to systemic therapy from patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Blood was drawn before systemic treatment and the CD45/CD15-depleted fraction of mononuclear cells was exposed to cisplatin, verified for the presence of CTC by pan-cytokeratin (pCK) staining and immunoanalysed for the level of Pt-(GpG) in DNA. RESULTS: Immunostaining for pCK, CD45 and subsequently for Pt-(GpG) adducts in the cisplatin-exposed cells (ex vivo) at different time points depicted distinct differences for adduct persistence in CTC between responders vs non-responders. CONCLUSION: Pt-(GpG) adducts can be detected in CTC from NSCLC patients and assessing their kinetics may constitute a clinically feasible biomarker for response prediction and dose individualisation of platinum-based chemotherapy. This functional pre-therapeutic test might represent a more biological approach than measuring protein factors or other molecular markers.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Adutos de DNA/biossíntese , Fosfatos de Dinucleosídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Platina/química , Idoso , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Adutos de DNA/genética , Humanos , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Antígenos CD15/metabolismo , Pessoa de Meia-Idade , Células Neoplásicas Circulantes , Células Tumorais CultivadasRESUMO
PURPOSE: Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. METHODS: Patients received cetuximab 250 mg/m(2) (loading dose: 400mg/m(2))days 1, 8 and 15; pemetrexed 500 mg/m(2)+cisplatin 75 mg/m(2) on day 1, q3w up to six cycles and folic acid, vitamin B12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated. RESULTS: Sixty-six patients received ≥1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. CONCLUSIONS: Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Cetuximab , Cisplatino/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Europa (Continente) , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pemetrexede , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Cetuximab and docetaxel have single-agent activity in squamous cell carcinoma of the head and neck (SCCHN). The efficacy of their combination was evaluated in platinum-pretreated patients with recurrent and/or metastatic SCCHN. PATIENTS AND METHODS: A total of 84 patients were treated with docetaxel 35 mg/m(2) weekly for a maximum of 6 cycles and concomitant cetuximab 250 mg/m(2) weekly until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate and secondary endpoints included the response rate in relation to platinum sensitivity, progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Nine (11%) patients achieved a partial response and 34 (40%) stable disease, resulting in a disease control rate of 51%. Response to treatment was 49% in previously platinum-sensitive and 50% in previously platinum-resistant disease. The median PFS was 3.1 months and the median OS 6.7 months. The most common grade 3 or 4 adverse events were mucositis (8%), pneumonia (8%), fatigue (8%) and skin reactions (14%). Sepsis occurred in 3 patients. CONCLUSION: Cetuximab plus docetaxel is an active treatment regimen with moderate toxicity in SCCHN patients. However, no superiority in comparison with monotherapy could be shown. Responsiveness and survival were independent of previous platinum sensitivity.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Taxoides/administração & dosagem , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Cetuximab , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study. METHODS: AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash. RESULTS: Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash. CONCLUSION: The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.
Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas/genética , Quinazolinas/uso terapêutico , Proteínas ras/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Capecitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Receptores ErbB/biossíntese , Receptores ErbB/genética , Cloridrato de Erlotinib , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/biossíntese , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras) , GencitabinaRESUMO
In order to improve the prognosis for patients with head and neck squamous cell cancer (HNSCC) the introduction of new therapeutic strategies is necessary. The concept of immunotherapy has been applied and improved for several years and recent studies have used tumor-specific antigens which facilitates targeted oncologic therapy. However, immunotherapy is hampered by the fact that immunosuppressive mechanisms are pronounced and relevant effector cells are suppressed, especially in patients with HNSCC. Successful immunotherapy could induce an antitumor immune response by restitution of these cell populations. Current anti-tumor immunotherapy includes unspecific immune stimulation, genetic modification of tumor and immune cells, the use of monoclonal antibodies, e.g. cetuximab, adoptive cell transfer and tumor vaccination. In the future, these biologic therapies alone or in combination with conventional therapeutic regimens could present a valuable therapeutic option for HNSCC patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/prevenção & controle , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/prevenção & controle , Imunossupressores/uso terapêutico , Imunoterapia/tendências , Anticorpos Monoclonais/imunologia , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/imunologia , Previsões , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunossupressores/imunologia , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Tubulin-binding agents (TBAs) are effective in non-small cell lung cancer (NSCLC) treatment. Both ßIII- and ßV-tubulins are expressed by cancer cells and may lead to resistance against TBAs. METHODS: Pre-treatment samples from 65 locally advanced or oligometastatic NSCLC patients, who underwent uniform induction chemotherapy with paclitaxel and platinum followed by radiochemotherapy with vinorelbine and platinum were retrospectively analysed by immunohistochemistry. Protein expression of ßIII- and ßV-tubulin was morphometrically quantified. RESULTS: Median pre-treatment H-score for ßIII-tubulin was 110 (range: 0-290), and 160 for ßV-tubulin (range: 0-290). Low ßIII-tubulin expression was associated with improved overall survival (OS) (P=0.0127, hazard ratio (HR): 0.328). An association between high ßV-tubulin expression and prolonged progression-free survival (PFS, median 19.2 vs 9.4 months in high vs low expressors; P=0.0315, HR: 1.899) was found. Further, high ßV-tubulin expression was associated with objective response (median H-score 172.5 for CR+PR vs 120 for SD+PD patients, P=0.0104) or disease control following induction chemotherapy (170 for CR+PR+SD vs 100 for PD patients, P=0.0081), but not radiochemotherapy. CONCLUSION: Expression of ßV-tubulin was associated with treatment response and PFS following paclitaxel-based chemotherapy of locally advanced and oligometastatic NSCLC patients. Prolonged OS was associated with low levels of ßIII-tubulin. Prospective evaluation of ßIII/ßV-tubulin expression in NSCLC is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Tubulina (Proteína)/biossíntese , Adulto , Idoso , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxoides/administração & dosagem , Transfecção , Resultado do Tratamento , Tubulina (Proteína)/genéticaRESUMO
BACKGROUND: The objective of this multicenter, prospective uncontrolled phase II trial was to determine efficacy, safety and tolerability of vatalanib, an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor receptors, in the second-line treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC-proven tumor progression during or after one platinum-based chemotherapy regimen received a fixed dose of 1250 mg vatalanib either once-daily dosing (QD) or two divided daily dosing (TDD: 500 mg a.m. + 750 mg p.m.) until disease progression or unacceptable toxicity. Primary end point was the disease control rate (DCR) at 12 weeks. RESULTS: Fifty-four and 58 patients were enrolled to the QD and TDD arms. DCR at 12 weeks was 35% in the QD and 37% in the TDD arm. The best overall response included one (2%) patient with confirmed partial response with QD and three (5%) with TDD. Median progression-free survival and overall survival were 2.1/7.3 months in the QD arm and 2.8/9.0 months with TDD arm. This therapy showed a moderate toxicity profile for the majority of patients. CONCLUSIONS: In the chosen patient population, vatalanib QD and TDD dosing demonstrated potential benefits in tumor size reduction, DCR, and survival.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Ftalazinas/administração & dosagem , Piridinas/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Ftalazinas/efeitos adversos , Piridinas/efeitos adversos , Recidiva , Terapia de Salvação/métodosRESUMO
BACKGROUND: This trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive carboplatin area under the curve 5 mg x min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1-3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity. RESULTS: Of 226 patients, 216 were eligible. Median PFS was 6.0 months [95% confidence interval (CI) 5.0-7.0] in the IP arm and 6.0 months (95% CI 5.2-6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4-11.6) and 9.0 months (95% CI 7.6-10.4) in the IP and EP arm (P = 0.06), respectively. Hazard ratios for disease progression and OS were 1.29 (95% CI 0.96-1.73, P = 0.095) and 1.34 (95% CI 0.97-1.85, P = 0.072), respectively. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm. CONCLUSION: This trial failed to show superiority of irinotecan over etoposide in combination with carboplatin.