RESUMO
Durvalumab has been administered to patients with unresectable stage III non-small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty-one patients were EGFR positive and 311 were EGFR negative. In the EGFR-positive group, there were higher proportions of females, never-smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression-free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64-1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment-related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients.
Assuntos
Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Feminino , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Quimiorradioterapia , Mutação , Receptores ErbB/genéticaRESUMO
In the open-label, phase III CheckMate 816 study (NCT02998528), neoadjuvant nivolumab plus chemotherapy demonstrated statistically significant improvements in event-free survival (EFS) and pathological complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC). Here we report efficacy and safety outcomes in the Japanese subpopulation. Patients with stage IB-IIIA, resectable NSCLC were randomized 1:1 to nivolumab plus chemotherapy or chemotherapy alone for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. The primary end-points (EFS and pCR) and safety were assessed in patients enrolled at 16 centers in Japan. Of the Japanese patients randomized, 93.9% (31/33) in the nivolumab plus chemotherapy arm and 82.9% (29/35) in the chemotherapy arm underwent surgery. At 21.5 months' minimum follow-up, median EFS was 30.6 months (95% confidence interval [CI], 16.8-not reached [NR]) with nivolumab plus chemotherapy versus 19.6 months (95% CI, 8.5-NR) with chemotherapy; hazard ratio, 0.60 (95% CI, 0.30-1.24). The pCR rate was 30.3% (95% CI, 15.6-48.7) versus 5.7% (95% CI, 0.7-19.2), respectively; odds ratio, 7.17 (95% CI, 1.44-35.85). Grade 3/4 treatment-related adverse events were reported in 59.4% versus 42.9% of patients, respectively, with no new safety signals identified. Neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate versus chemotherapy alone in Japanese patients, consistent with findings in the global population. These data support nivolumab plus chemotherapy as a neoadjuvant treatment option in Japanese patients with resectable NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Japão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Terapia Neoadjuvante , Nivolumabe/efeitos adversosRESUMO
It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) should be selected for patients with advanced non-small-cell lung cancer (NSCLC) exhibiting high PD-L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0-1) in the COMB group (p < 0.01). With a median follow-up time of 10.6 (range: 0.1-20.6) months, the median progression-free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first-line treatment for NSCLC with high PD-L1 expression and good performance status.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Estudos Multicêntricos como Assunto , Estudos RetrospectivosRESUMO
PURPOSE: Survival time after bisphosphonate use has been increasingly recognized to be associated with the incidence of medication-related osteonecrosis of the jaw (MRONJ); however, this has not been elucidated sufficiently in the literature. This study aimed to clarify the incidence of MRONJ and the corresponding survival rate of patients treated with zoledronic acid (ZA) for each type of cancer and obtain useful information for the oral/dental supportive care of cancer patients. METHODS: We evaluated 988 patients who were administered ZA at our hospital; among them, 862 patients with metastatic bone tumors or myeloma were included. RESULTS: The median survival time (MST) after ZA initiation was 35, 34, 8, 41, 12, and 6 months for patients with breast, prostrate, lung, myeloma, renal, and other cancers, respectively. Patients with cancers that had a short survival time (lung and other cancers [MST = 8 and 6 months, respectively] and cancers with MST < 10 months) did not develop MRONJ; this could be attributed to the shorter duration of ZA administration. The cumulative incidence of MRONJ in breast cancer, prostate cancer, and multiple myeloma was related to the frequency of anti-resorptive drug use and the increased risk over time. In renal cancer, the cumulative incidence of MRONJ increased early, although the MST was 12 months. CONCLUSION: For the dentists in charge of dental management, it is essential to be aware of prognosis-related factors, predict MRONJ risk for each cancer treatment, and use risk prediction in dental management planning, particularly for cancers with non-poor prognosis.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Neoplasias Ósseas , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Denosumab/uso terapêutico , Difosfonatos/efeitos adversos , Humanos , Incidência , Masculino , Prognóstico , Estudos Retrospectivos , Ácido Zoledrônico/efeitos adversosRESUMO
OBJECTIVES: Only a few prospective studies have been conducted to examine the efficacy and safety of systemic chemotherapy for patients with pulmonary sarcomatoid carcinomas (PSCs). There is, thus, a crucial need to develop novel treatment strategies for this rare tumor. PATIENTS AND METHODS: Chemotherapy-naïve patients with histologically confirmed PSCs were assigned to receive either carboplatin/paclitaxel alone (CP) or with bevacizumab (CPB) followed by bevacizumab maintenance. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. RESULTS: This study was closed before accumulating the expected number of cases due to slow patient accrual. Eventually, 16 patients were enrolled. The ORR was 25.0% and disease control rate was 56.3%. CPB was administered in all four patients with an objective response [partial response (PR)]; among the four PR cases, two patients had pleomorphic carcinoma, and two had carcinosarcoma. Median PFS and median survival time (MST) in all the enrolled patients were 2.6 months and 8.8 months, respectively. Median PFS was 1.2 months in the CP group and 4.2 months in the CPB group. In addition, MST was 7.9 months in the CP group and 11.2 months in the CPB group. Hematological and non-hematological adverse events were common and reversible, although ileus (grade 4) and nasal bleeding (grade 3) occurred in one case each in the CPB group. CONCLUSIONS: CPB might be effective as first-line treatment for PSCs. Further study is warranted to clarify the role of cytotoxic chemotherapy for this rare and aggressive tumor. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000008707).
Assuntos
Carcinoma , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Paclitaxel/efeitos adversos , Estudos ProspectivosRESUMO
BACKGROUND: Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete-scute homolog-1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. MATERIALS AND METHODS: We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. RESULTS: Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3-high expression (≥75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. CONCLUSION: DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. IMPLICATIONS FOR PRACTICE: This article examines the relationship between delta-like protein 3 (DLL3) and achaete-scute homolog-1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early-stage SCLC, including with Rova-T.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/cirurgiaRESUMO
BACKGROUND: This study evaluated the efficacy and safety of switch maintenance erlotinib and bevacizumab after induction therapy with carboplatin/pemetrexed/bevacizumab for non-squamous non-small cell lung cancer (NSCLC) with wild-type EGFR. METHODS: Enrolled patients had treatment-naïve, advanced non-squamous NSCLC with wild-type EGFR. Carboplatin [area under the curve (AUC) 5.0], pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered on day 1 every 3 weeks for 4-6 cycles. Maintenance therapy with erlotinib (150 mg/body) on day 1 through 21 plus bevacizumab on day 1 every 3 weeks was continued until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), toxicity, and quality of life (QOL). RESULTS: Fifty-one patients were enrolled between September 2011 and June 2014. The median number of cycles for induction and maintenance therapy was 4 (range 1-6) and 4 (range 1-20). Twenty-nine patients (58%) received maintenance therapy. The 6-month PFS rate was 59.5% [95% confidence interval (CI) 45.0-72.6%]. The ORR was 48.0% (95% CI 34.8-61.5%), and disease control rate was 86.0% (95% CI 73.8-93.0%). The median PFS and OS were 6.5 months (95% CI 5.8-7.2 months) and 21.4 months (95% CI 15.9-26.9 months), respectively. Although grades ≥ 3 adverse events were observed in 33 patients (66.0%), most were hematologic; there was no febrile neutropenia. QOL was maintained throughout treatment. CONCLUSIONS: Carboplatin/pemetrexed/bevacizumab followed by erlotinib and bevacizumab maintenance showed modest efficacy and was well tolerated in non-squamous NSCLC patients with wild-type EGFR. TRIAL REGISTRATION: UMIN000005872.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Pemetrexede/administração & dosagem , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Taxa de Sobrevida , Adulto JovemAssuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Neoplasias Ósseas , Mieloma Múltiplo , Osteonecrose , Humanos , Mieloma Múltiplo/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose/induzido quimicamente , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Prognóstico , Conservadores da Densidade Óssea/efeitos adversos , DifosfonatosRESUMO
BACKGROUND: The Notch receptor plays an important role in various cell fate decisions during development and in cancer. We have previously reported that Notch3 is upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines and that the Notch pathway inhibitor γ secretase inhibitor GSI (gamma-secretase inhibitor), when combined with radiation therapy, significantly suppressed the growth of lung cancer cells. However, little is known about the mechanism of Notch upregulation induced by radiation. Based on reports of Notch expression being activated through the hypoxia inducible factor 1 (HIF-1) under hypoxic conditions, we hypothesized that HIF-1 would be involved in radiation-induced Notch activation in NSCLC. METHODS: Changes in HIF-1 and Notch expression in two Notch expressing NSCLC cells line after radiation treatment were examined using Western blotting. Notch expression was evaluated after the suppression of HIF-1α by small interfering RNA. The cytotoxic effect of YC-1, a HIF inhibitor, GSI and radiation was examined using the MTT assay in vitro and the xenograft model. RESULT: We found radiation-induced expression of HIF-1α protein at 2-6 h after treatment and upregulated expression of Notch3 protein at 24 h after treatment under hypoxic conditions. Specific suppression of HIF-1α expression downregulated the radiation-induced Notch3 activation, suggesting that the Notch pathway is activated though HIF-1α after radiation. An antitumor effect of YC-1 was evident under hypoxic conditions only when there was simultaneous radiation treatment. GSI and YC-1 had a synergistic antitumor effect in vitro, and the combination of GSI and YC-1 showed the greatest radiosensitivity in vivo. CONCLUSION: Radiation-induced upregulation of the Notch pathway and HIF-1α protein may be potential therapeutic targets for more effective radiation therapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neoplasias Pulmonares/radioterapia , Receptores Notch/antagonistas & inibidores , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/efeitos da radiação , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos da radiação , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Indazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos Nus , Terapia de Alvo Molecular/métodos , Oligopeptídeos/farmacologia , RNA Interferente Pequeno , Receptores Notch/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Inhibition of Notch by γ-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis. METHODS: The Notch-expressing NSCLC cell lines H460, A549, H1793, and HCC2429 were used. The combined antitumor effect of GSI and ABT-737 was evaluated using the MTT proliferation assay in vitro and in xenograft mouse models. The expression of the Notch pathway and Bcl-2 family was analyzed using Western blotting analysis when cells were treated with a single drug treatment or a combination treatment. RESULTS: GSI XX or ABT-737 alone inhibited cell proliferation in a dose-dependent manner, and combination drug treatment showed a synergistic antitumor effect in vitro. In vivo, this drug combination significantly suppressed tumor proliferation compared to the single drug treatment. Phospho-Bcl-2 was downregulated and Bax was upregulated by both the single and combination drug treatments. Bim was induced by a single drug treatment and was enhanced by combination treatment. Combination treatment-induced apoptosis was decreased by Bim inhibition, suggesting that the antitumor effect of the drug combination was dependent on Bim. CONCLUSION: Based on our data, we propose that the combination treatment is a promising strategy for NSCLC therapy.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Dibenzazepinas/farmacologia , Neoplasias Pulmonares/patologia , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quimioterapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Piperazinas/farmacologia , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non-small-cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3-deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co-treatment with 3-deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co-treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co-treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co-treatment strongly suppressed EGFR signaling, not only in EGFR-wild-type NSCLC cells, but also in EGFR-mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co-treatment suppressed the in vivo tumor growth of EGFR-mutant, EGFR-tyrosine kinase-resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Acetilação/efeitos dos fármacos , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina A/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Sinergismo Farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/deficiência , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Metilação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Fosforilação/efeitos dos fármacos , Complexo Repressor Polycomb 2/deficiência , Complexo Repressor Polycomb 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vorinostat , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Epidermal growth factor receptor tyrosine kinase inhibitors are effective as first-line therapy for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations. However, it is unknown whether second-line platinum-based chemotherapy after epidermal growth factor receptor tyrosine kinase inhibitor therapy could lead to better outcomes. We evaluated the efficacy of second-line platinum-based chemotherapy after gefitinib for advanced non-small cell lung cancers harboring epidermal growth factor receptor mutations (the NEJ002 study). METHODS: Seventy-one non-small cell lung cancers, treated with gefitinib as first-line therapy and then receiving platinum-based chemotherapy as second-line therapy were evaluated in NEJ002. Patients were evaluated for antitumor response to second-line chemotherapy by computed tomography according to the criteria of the Response Evaluation Criteria in Solid Tumors group (version 1.0). RESULTS: Of the 71 patients receiving platinum-based chemotherapy after first-line gefitinib, a partial response was documented in 25.4% (18/71), stable disease in 43.7% (31/71) and progression of disease in 21.1% (15/71). The objective response and disease control rates were 25.4% (18/71) and 69% (49/71), respectively. There was no significant difference between first- and second-line chemotherapy in objective response and disease control rates for advanced non-small cell lung cancer harboring activating epidermal growth factor receptor mutations. In the analysis of epidermal growth factor receptor mutation types, the objective responses of deletions in exon 19 and a point mutation in exon 21 (L858R) were 27.3% (9/33) and 28.1% (9/32), respectively, but these differences between objective response rates were not significant. CONCLUSIONS: The efficacy of second-line platinum-based chemotherapy followed at progression by gefitinib was similar to first-line platinum-based chemotherapy, and epidermal growth factor receptor mutation types did not influence the efficacy of second-line platinum-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Deleção de Sequência , Adulto , Idoso , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Esquema de Medicação , Éxons , Feminino , Gefitinibe , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Quinazolinas/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Ground-glass opacity (GGO) lesions are difficult to diagnose by transbronchial biopsy (TBB). OBJECTIVES: We attempted to diagnose solitary peripheral GGO predominant-type lesions by TBB using endobronchial ultrasonography with a guide sheath (EBUS-GS) under X-ray fluoroscopic guidance, and to evaluate several factors associated with diagnostic yield. METHODS: The medical records of 67 patients with GGO predominant-type lesions who underwent TBB using EBUS-GS under X-ray fluoroscopic guidance were retrospectively reviewed. RESULTS: Of the 67 lesions, 38 (57%) were successfully diagnosed by EBUS-GS (5/11 pure GGO lesions and 33/56 mixed GGO lesions). The diagnosable lesions were significantly larger than the nondiagnosable lesions (24 vs. 17 mm, respectively; p < 0.01). Regarding the diagnostic yield by signs on computed tomography, the lesions with a bronchus leading directly to a lesion had a significantly higher diagnostic yield than the others (p < 0.05). When GGO lesions were confirmed under X-ray fluoroscopic guidance, the diagnostic yield was 79% (vs. 40% in lesions not visible on X-ray fluoroscopy; p < 0.05). CONCLUSIONS: EBUS-GS is a useful and valuable diagnostic modality, even for GGO predominant-type lesions located at the lung periphery.
Assuntos
Adenocarcinoma/diagnóstico , Broncoscopia , Neoplasias Pulmonares/diagnóstico , Ultrassonografia de Intervenção , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluoroscopia , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
BACKGROUND: CD133 is a membrane glycoprotein containing five transmembrane loops. Previous reports suggest that a CD133-positive subpopulation of multipotent cells with extensive proliferative and self-renewal characteristics has biological features of a cancer stem cell. In addition, the presence of CD133-positive cells was associated with a significantly poorer prognosis for some solid tumors, compared to those with CD133-negative cells. However, the clinicopathological significance of CD133 in non-small cell lung cancer (NSCLC) remains controversial. METHODS: We conducted immunohistochemical assessment of 161 NSCLCs surgically resected at Hokkaido University Hospital between 1982 and 1994 to evaluate correlations between CD133 expression and various clinicopathological features. RESULTS: CD133 expression was significantly correlated with pathological stages (pStages) II, III, and IV for the various NSCLC types analyzed and was an independent factor for unfavorable prognosis in this population (hazard ratio = 3.157, P = 0.015). CONCLUSION: CD133 expression was correlated with pStage and was predictive of unfavorable prognosis in patients with pStages II, III, and IV NSCLC. These results suggest the possibility of using CD133 as a novel prognostic marker in these patients.
Assuntos
Antígenos CD/análise , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Glicoproteínas/análise , Neoplasias Pulmonares/mortalidade , Peptídeos/análise , Antígeno AC133 , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
RATIONALE: In bronchoscopy, an ultrathin bronchoscope can be advanced to more peripheral bronchi. Because virtual bronchoscopic navigation (VBN) is a method to guide a bronchoscope under direct observation using VB images, VBN may be particularly useful when combined with ultrathin bronchoscopy. OBJECTIVES: This prospective multicenter study evaluated the value of VBN-assisted ultrathin bronchoscopy for diagnosing peripheral pulmonary lesions. METHODS: We randomly assigned 350 patients with peripheral pulmonary lesions (diameter, ≤30 mm) to VBN-assisted or non-VBN-assisted groups. An ultrathin bronchoscope (outer diameter, 2.8 mm) was introduced to the target bronchus using a VBN system in the VBN-assisted group, whereas only computed tomography axial images were referred to in the non-VBN-assisted group. Specimen sampling sites were verified using X-ray fluoroscopy. MEASUREMENTS AND MAIN RESULTS: Subjects for analysis included 334 patients. There was no significant difference in the diagnostic yield between the VBN-assisted group (67.1%) and the non-VBN-assisted group (59.9%; P = 0.173). The subgroup analysis showed that the diagnostic yield was significantly higher in the VBN-assisted group than in the non-VBN-assisted group for right upper lobe lesions (81.3% vs. 53.2%; P = 0.004); lesions invisible on posterior-anterior radiographs (63.2% vs. 40.5%; P = 0.043); and lesions in the peripheral third of the lung field (64.7% vs. 52.1%; P = 0.047). CONCLUSIONS: VBN-assisted ultrathin bronchoscopy does not improve the diagnostic yield for peripheral pulmonary lesions. However, the method improves the diagnostic yield for lesions in the subcategories (right upper lobe, invisible, peripheral third), warranting further study. Clinical trial registered with www.umin.ac.jp/ctr/ (UMIN 000001536).
Assuntos
Broncoscópios , Broncoscopia/métodos , Neoplasias Pulmonares/diagnóstico , Miniaturização/instrumentação , Nódulo Pulmonar Solitário/diagnóstico , Interface Usuário-Computador , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Diagnóstico Diferencial , Desenho de Equipamento , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
Introduction: Lorlatinib was found to have improved efficacy versus crizotinib in the global phase 3 CROWN study (NCT03052608). Similar results were revealed for the Japanese population as for the overall population. We present results from the unplanned 3-year follow-up from the CROWN study in Japanese patients. Methods: Patients were randomized to either lorlatinib 100 mg once daily (n = 25) or crizotinib 250 mg twice daily (n = 23). The primary end point was progression-free survival assessed by blinded independent central review. Secondary end points included objective and intracranial responses assessed by blinded independent central review and safety. Results: At the data cutoff of September 20, 2021, median progression-free survival was not reached with lorlatinib and 11.1 months with crizotinib (hazard ratio = 0.36). Objective response rate was 72.0% with lorlatinib and 52.2% with crizotinib. For patients with baseline brain metastases, intracranial response rate was 100.0% versus 28.6% with lorlatinib versus crizotinib. Nine patients in the lorlatinib group received more than or equal to 1 subsequent anticancer systemic therapy, with ALK tyrosine kinase inhibitor as the most common first subsequent therapy. The safety profile was consistent with that reported previously, with no new safety signals. Conclusions: This updated analysis in the Japanese population revealed prolonged benefits of lorlatinib over crizotinib in patients with treatment-naive advanced ALK-positive NSCLC with and those without brain metastases.
RESUMO
Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.
RESUMO
Amrubicin, a third-generation synthetic anthracycline agent, has favorable clinical activity and acceptable toxicity for the treatment of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer. We conducted this study to evaluate the efficacy and safety of amrubicin for advanced NSCLC patients as a third- or fourth-line therapy. Eligible patients had recurrent or refractory advanced NSCLC after second- or third-line therapy. Patients received amrubicin, 35 mg/m(2) i.v. on days 1-3 every 3 weeks. The primary endpoint was the disease control rate (DCR). Secondary endpoints were the overall survival (OS) time, progression-free survival (PFS) time, response rate, and toxicity profile. Of the 41 patients enrolled, 26 received amrubicin as a third-line and 15 received it as a fourth-line therapy. The median number of treatment cycles was two (range, 1-9). Objective responses were complete response (n = 0), partial response (n = 4), stable disease (n = 21), progressive disease (n = 15), and not evaluable (n = 1), resulting in a DCR of 61.0% (95% confidence interval, 46.0%-75.9%). The overall response rate was 9.8% (95% confidence interval, 0.6%-18.8%). The median PFS interval was 3.0 months, median OS time was 12.6 months, and 1-year survival rate was 53.7%. Grade 3 or 4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Nonhematological toxicities were mild and reversible. No treatment-related deaths were observed. Amrubicin showed significant clinical activity with manageable toxicities as a third- or fourth-line therapy for patients with advanced NSCLC. This study provides relevant data for routine practice and future prospective trials evaluating third- or fourth-line treatment strategies for patients with advanced NSCLC.
Assuntos
Antraciclinas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Adulto , Idoso , Antraciclinas/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Terapia Combinada , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. METHODS: We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. RESULTS: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)