RESUMO
Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy. We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model. The doses of carboplatin in CPH and CPCC treatments were 150 µL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 µg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation. Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.
Assuntos
Carbonato de Cálcio , Carboplatina , Glioma , Hidrogéis , Camundongos Endogâmicos C57BL , Animais , Glioma/patologia , Glioma/tratamento farmacológico , Glioma/radioterapia , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Carboplatina/farmacologia , Hidrogéis/química , Linhagem Celular Tumoral , Carbonato de Cálcio/química , Camundongos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapiaRESUMO
Treatment of relapsed or refractory diffuse large B-cell lymphoma is difficult. The de novo diffuse large B-cell lymphoma has better prognosis than the transformed diffuse large B-cell lymphoma. The response of CHOP or a similar regimen has an important role in determining response to salvage therapy, in relapse or refractory diffuse large B-cell lymphoma patients. Patients who are non-responder to initial treatment have a very poor chance of responding to therapy for relapse. This was a small scale observational study and was conducted from January 2017 to December 2020 in National Institute of Cancer Research and Hospital, Bangladesh. A total of 34 patients with relapsed or refractory diffuse large B-cell lymphoma were identified at hematology department in National Institute of Cancer Research and Hospital, 28 of them were treated with ICE chemotherapy and 6 with R-ICE chemotherapy as second line regimen. Overall response rate to 2nd line chemotherapy was 64.8%, with 32.4% (11 patients) complete remission and 32.4% (11 patients) partial remission. Median overall survival to second line regimen was 10 months, corresponding to a 4 year overall survival of 32.4% and a 4 year progression free survival was 17.6%. Patient with stable disease/progressive disease median overall survival was 7 months compared with 15 months for complete remission and 9 months for partial remission (p<0.001). Median overall survival was significantly better in patients with international prognostic index 0-2 compared in those with international prognostic index >2 (p=0.010). However improvement of salvage efficacy is an urgent need with new drugs. Further studies are necessary to determine whether this regimen will improve outcomes of relapsed or refractory diffuse large B-cell lymphoma patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Etoposídeo , Ifosfamida , Linfoma Difuso de Grandes Células B , Rituximab , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Masculino , Feminino , Ifosfamida/administração & dosagem , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rituximab/uso terapêutico , Rituximab/administração & dosagem , Adulto , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , IdosoRESUMO
Immunotherapy with anti-PD-1 antibodies significantly improved the prognosis in advanced melanoma patients, but most of them develop primary or secondary resistance to the treatment. In this study, we evaluated efficacy and safety of a chemotherapy regimen with weekly carboplatin plus paclitaxel (wCP) in patients previously treated with anti-PD-1 antibodies. We retrospectively identified 30 patients with advanced melanoma treated at our Institute over the last eight years with wCP. The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). In addition, we evaluated treatment tolerability. For this patient cohort, median PFS and OS were 3.25 and 7.69 months, respectively. All included patients had previously received anti-PD-1 immunotherapy, most of them had ECOG PS 0-1, and only 5 patients had a BRAF V600 mutation. In univariable analysis, we observed shorter OS in patients with > 2 involved metastatic sites, superficial spreading histology, and serum lactate dehydrogenase (LDH) values above the median. Liver metastases were associated with worse outcomes, while radiotherapy treatment of brain metastases was associated with improved OS. However, in a multivariable Cox regression model, only LDH above the median, superficial spreading histology, and female sex were significantly associated with worse OS. We reported grade 3 and 4 treatment-related toxicities in 4 and 0 patients, respectively. In conclusion, chemotherapy with wCP is a valid palliative treatment in advanced melanoma who progressed with anti-PD-1 antibodies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Melanoma , Paclitaxel , Humanos , Feminino , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/mortalidade , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Estudos Retrospectivos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Adulto , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Idoso de 80 Anos ou maisRESUMO
OBJECTIVES: This qualitative study explored patients' experiences and perceptions of the SCOPE2 trial. SCOPE2 examined radiotherapy dose escalation in patients with inoperable oesophageal cancer treated with definitive chemoradiotherapy (dCRT). SETTING: Recruitment at five clinical sites in England and Wales, UK. PARTICIPANTS: SCOPE2 trial participants were invited to take part in interviews from across five clinical sites. Participants self-selected to take part in up to three interviews across four different time points: baseline (before treatment) and at 2-3 months, 3-6 months or 6 months+ after baseline. There were five female and five male interview participants. INTERVENTIONS: Participants were randomised to standard dose dCRT prescribed carboplatin/paclitaxel or cisplatin/capecitabine, or an escalated dose dCRT prescribed carboplatin/paclitaxel or cisplatin/capecitabine. METHODS: This qualitative study used semistructured longitudinal interviews to explore the impact of treatment on patient outlook and quality of life and the impact of the COVID-19 pandemic. Interview data were thematically analysed. RESULTS: 10 patients participated in 16 longitudinal interviews. Three participants were accompanied by companions. Participants experienced side-effects from radiotherapy and chemotherapy including nausea, throat pain, difficulties eating and regaining appetite, thrombosis and fatigue, although most of these symptoms gradually improved. Participants required more ongoing information and support regarding treatment side-effects and cancer status in order to improve their overall quality of life. Best practice examples involved key contacts providing practical advice and signposting support. CONCLUSION: Participants of the SCOPE2 trial reported short and longer-term side-effects from chemoradiotherapy, but these usually lessened over time. Participants attempted to be positive about their survival prospects by readjusting their expectations, priorities and lifestyles. Providing patients with ongoing opportunities to discuss detailed and timely information regarding treatment side-effects, aftercare and cancer status could improve the overall health and well-being of patients during oesophageal cancer trials and pathways. TRIAL REGISTRATION NUMBER: NCT02741856; ISRCTN: 97125464.
Assuntos
Quimiorradioterapia , Neoplasias Esofágicas , Paclitaxel , Pesquisa Qualitativa , Qualidade de Vida , Humanos , Masculino , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/psicologia , Feminino , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Pessoa de Meia-Idade , Idoso , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , COVID-19 , Cisplatino/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/administração & dosagem , Carboplatina/uso terapêutico , Carboplatina/administração & dosagem , Inglaterra , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/uso terapêutico , Capecitabina/administração & dosagem , SARS-CoV-2 , País de GalesRESUMO
AIM: Dostarlimab plus carboplatin-paclitaxel (CP) significantly increased progression-free survival in patients with primary advanced or recurrent endometrial cancer (pA/rEC) vs CP alone in the RUBY trial (NCT03981796). This analysis estimated the per-member-per-month (PMPM) costs of introducing dostarlimab + CP as a treatment alternative from a third-party US payer perspective. MATERIALS AND METHODS: A budget impact model was developed to estimate the costs of introducing dostarlimab + CP into commercial and Medicare health plans over a 3-year time horizon (2023-2025). Costs were sourced from relevant literature and US-specific databases and were calculated using epidemiology data, clinical inputs, treatment costs, and market share estimates. Clinical inputs were sourced from primary clinical trials for each respective treatment (i.e. dostarlimab + CP, CP, pembrolizumab, pembrolizumab plus lenvatinib, bevacizumab + CP, and pembrolizumab + CP). Current and future market shares assumed dostarlimab + CP reduced the market share of CP only. Analyses were performed in mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations using a US 2023 cost year. RESULTS: For a commercial plan, the model estimated (dMMR/MSI-H and overall populations) that 7 and 26 patients would be treated with dostarlimab + CP, respectively; average annual budget impacts per patient treated were $118,257 and $116,094; average budget impacts per patient treated per month (PPPM) were $9,855 and $9,675; average budget impacts PMPM were $0.02 and $0.06. For a Medicare plan, the model estimated that 28 and 93 patients, respectively, would be treated with dostarlimab + CP. Average annual budget impacts per patient treated and PPPM were the same as those for the commercial plan in both populations; average budget impacts PMPM were $0.07 and $0.22, respectively. CONCLUSIONS: Introducing dostarlimab + CP as a first-line treatment for patients with pA/rEC results in minimal budget impact PMPM from a US third-party payer's perspective. Together with the efficacy and safety results from RUBY, these results support the use of dostarlimab + CP as a treatment option.
Dostarlimab with carboplatinpaclitaxel is a recently approved treatment for newly diagnosed advanced or recurrent endometrial cancer. This analysis was done to estimate the added costs that US commercial and Medicare health plans would have over 3 years if this treatment was covered. This analysis found that the budget increase for covering dostarlimab with carboplatinpaclitaxel was small ($0.02$0.06 per commercial plan member per month; $0.07$0.22 per Medicare plan member per month).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Neoplasias do Endométrio , Paclitaxel , Humanos , Feminino , Carboplatina/uso terapêutico , Carboplatina/economia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/economia , Paclitaxel/uso terapêutico , Paclitaxel/economia , Paclitaxel/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estados Unidos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/economia , Análise Custo-Benefício , Recidiva Local de Neoplasia/tratamento farmacológico , Orçamentos , Intervalo Livre de Progressão , Modelos EconométricosRESUMO
BACKGROUND: Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC. PATIENTS AND METHODS: This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. RESULTS: From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 - mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 - subtype. The median treatment was 6 cycles (range, 2 - 8 cycles). In the full cohort, TNBC, and HR + HER2 - subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed. CONCLUSION: ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Furanos , Cetonas , Receptor ErbB-2 , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Pessoa de Meia-Idade , Cetonas/uso terapêutico , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Furanos/uso terapêutico , Furanos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Adulto , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/mortalidade , Estudos de Coortes , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Metástase Neoplásica , Policetídeos de PoliéterRESUMO
Patients with non-small cell lung cancer (NSCLC) are easily resistant to first-line chemotherapy with paclitaxel (PTX) or carboplatin (CBP). N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) has crucial functions in m6A modification and tumorigenesis. However, its role in chemoresistance of NSCLC is still elusive. Here, we demonstrated that METTL3 inhibitor STM2457 significantly reduced the IC50 values of PTX or CBP in NSCLC cells, and they showed a synergistic effect. Comparing with monotherapy, a combination of STM2457 and PTX or CBP exhibited more potent in vitro and in vivo anti-tumor efficacy. In addition, we found that ATP binding cassette subfamily C member 2 (ABCC2) was responsively elevated in cytomembrane after PTX or CBP treatment, and targeting METTL3 could reverse this effect. Mechanistically, targeting METTL3 decreased the m6A modification of ABCC2 mRNA and accelerated its mRNA degradation. Further studies revealed that YTHDF1 could bind and stabilize the m6A-modified mRNA of ABCC2, while YTHDF1 knockdown promoted it mRNA degradation. These results, taken together, demonstrate that targeting METTL3 enhances the sensitivity of NSCLC cells to PTX or CBP by decreasing the cytomembrane-localized ABCC2 in an m6A-YTHDF1-dependent manner, and suggest that METTL3 may be a potential therapeutic target for acquired resistance to PTX or CBP in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Metiltransferases , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proteínas de Ligação a RNA , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Metiltransferases/metabolismo , Metiltransferases/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína 2 Associada à Farmacorresistência Múltipla/metabolismo , Linhagem Celular Tumoral , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Camundongos Nus , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologiaRESUMO
OBJECTIVES: We aimed to evaluate the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) prophylaxis during chemoimmunotherapy with carboplatin plus etoposide and atezolizumab in extensive-stage small cell lung cancer (ES-SCLC). METHODS: This retrospective, multicenter study enrolled ES-SCLC patients receiving carboplatin plus etoposide and atezolizumab, categorized into G-CSF and non-G-CSF groups. Demographic and disease-related data were collected. Response rates, progression-free survival (PFS), overall survival (OS), and toxicity were analyzed. RESULTS: Of 119 patients (median age: 63 years), the overall response rate (ORR) and disease control rate (DCR) were 72.3% and 81.5%, respectively. In the G-CSF group, the ORR was 76.4% compared to 60.0% in the non-G-CSF group (p = 0.33), and the DCR was 85.4% versus 70.0%, respectively (p = 0.46). Median PFS was 8.3 months (95% CI, 6.8-9.8) in the G-CSF group and 6.8 months (95% CI, 6.2-7.5) in the non-G-CSF group (p = 0.24). Median OS was 13.8 months (95% CI, 9.6-18.1) for the G-CSF group and 10.6 months (95% CI, 7.9-13.3) for the non-G-CSF group (p = 0.47). Grade 3 ≥ adverse events were similar between groups (49.4% vs. 33.3%, respectively, p = 0.12). CONCLUSION: G-CSF prophylaxis can be safely used in ES-SCLC patients undergoing carboplatin plus etoposide and atezolizumab regimen without significantly altering efficacy or increasing toxicity.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Etoposídeo , Fator Estimulador de Colônias de Granulócitos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Adulto , Imunoterapia/métodos , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Taxa de Sobrevida , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Platinum-based chemotherapy (ChT) has been the standard first-line treatment for metastatic urothelial carcinoma (mUC). The purpose of this study was to evaluate the use of induction avelumab followed by avelumab in combination with carboplatin-gemcitabine (carbo/gem) followed by avelumab maintenance. We tested the hypothesis that induction immunotherapy (IO) could enhance the response to ChT and prevent its detrimental effect on immune cells. MATERIALS AND METHODS: INDUCOMAIN is a multicenter, randomized, investigator-initiated, open-label phase II study evaluating the safety and efficacy of induction avelumab before carboplatin-gemcitabine-avelumab, followed by avelumab maintenance (arm A), compared to carbo/gem (arm B). Eligibility criteria included patients with mUC, no prior systemic therapy, and ineligibility for cisplatin by Galsky criteria. Patients were stratified by the presence/absence of visceral metastasis and Eastern Cooperative Oncology Group performance status 0-1 versus 2. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Eighty-five patients were included and randomized to arm A (n = 42) and arm B (n = 43), respectively. ORR was similar between treatment arms: 59.5% in arm A and 53.5% in arm B (P = 0.57). Fourteen patients (33%) in arm A early progressed/died before or at first response assessment, compared to three patients (7%) in arm B. Median OS was 11.1 months in arm A and 13.2 months in arm B [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.57-1.46, P = 0.69]. Median PFS was 6.9 months in arm A versus 7.4 months in arm B (HR 0.99, 95% CI 0.61-1.60, P = 0.95). Treatment-related adverse events of grade 3-4 occurred in 70.7% of patients in arm A and in 72.1% in arm B. No predictive role of programmed death-ligand 1 expression was found. CONCLUSIONS: The hypothesis that induction avelumab could enhance the efficacy of subsequent ChT was not proven. Administering IO alone as induction before ChT is not an adequate strategy.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Gencitabina , Imunoterapia/métodos , Carcinoma de Células de Transição/tratamento farmacológico , Idoso de 80 Anos ou mais , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Quimioterapia de Indução/métodos , Quimioterapia de Manutenção/métodos , Neoplasias Urológicas/tratamento farmacológicoRESUMO
BACKGROUND: Autologous stem cell transplantation (ASCT) is a pivotal treatment for lymphoma patients. The BeEAM regimen (Bendamustine, Etoposide, Cytarabine, Melphalan) traditionally relies on cryopreservation, whereas the CEM regimen (Carboplatin, Etoposide, Melphalan) has been optimized for short-duration administration without the need for cryopreservation. This study rigorously compares the clinical and safety profiles of the BeEAM and CEM regimens. METHODS: A controlled, randomized clinical trial was conducted with 58 lymphoma patients undergoing ASCT at the International Medical Center (IMC) in Cairo, Egypt. Patients were randomly assigned to either the BeEAM (n = 29) or CEM (n = 29) regimen, with an 18-month follow-up period. Clinical and safety outcomes were meticulously compared, focusing on time to engraftment for neutrophils and platelets, side effects, length of hospitalization, transplant-related mortality (TRM), and survival rates. RESULTS: The findings demonstrate a significant advantage for the CEM regimen. Neutrophil recovery was markedly faster in the CEM group, averaging 8.5 days compared to 14.5 days in the BeEAM group (p < 0.0001). Platelet recovery was similarly expedited, with 11 days in the CEM group versus 23 days in the BeEAM group (p < 0.0001). Hospitalization duration was substantially shorter for CEM patients, averaging 18.5 days compared to 30 days for those on BeEAM (p < 0.0001). Furthermore, overall survival (OS) was significantly higher in the CEM group at 96.55% (95% CI: 84.91-99.44%) compared to 79.31% (95% CI: 63.11-89.75%) in the BeEAM group (p = 0.049). Progression-free survival (PFS) was also notably superior in the CEM group, at 86.21% (95% CI: 86.14-86.28%) versus 62.07% (95% CI: 61.94-62.20%) in the BeEAM group (p = 0.036). CONCLUSION: The CEM regimen might demonstrate superiority over the BeEAM regimen, with faster neutrophil and platelet recovery, reduced hospitalization time, and significantly improved overall and progression-free survival rates. Future studies with longer duration and larger sample sizes are warranted. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under the registration number NCT05813132 ( https://clinicaltrials.gov/ct2/show/NCT05813132 ). (The first submitted registration date: is March 16, 2023).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina , Carboplatina , Citarabina , Etoposídeo , Transplante de Células-Tronco Hematopoéticas , Linfoma , Melfalan , Condicionamento Pré-Transplante , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Masculino , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Adulto , Linfoma/terapia , Linfoma/mortalidade , Linfoma/tratamento farmacológico , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Adulto Jovem , Adolescente , Resultado do TratamentoRESUMO
BACKGROUND: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose ([18F]FDG)-PET results. METHODS: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 intravenously on day 1 and 60 mg/m2 orally [or 30 mg/m2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 intravenously and vinorelbine 20 mg/m2 intravenously on day 1 and 40 mg/m2 orally (or 20 mg/m2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. FINDINGS: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). INTERPRETATION: A thoracic radiotherapy boost, based on interim [18F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. FUNDING: Programme Hospitalier de Recherche Clinique National 2014.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Fluordesoxiglucose F18 , Neoplasias Pulmonares , Estadiamento de Neoplasias , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Masculino , Feminino , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/uso terapêutico , Tomografia por Emissão de Pósitrons , Dosagem Radioterapêutica , Quimiorradioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Paclitaxel/administração & dosagemRESUMO
Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.
Assuntos
Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Carboplatina/uso terapêutico , Carboplatina/farmacologia , Cisplatino/uso terapêutico , Cisplatino/farmacologia , Transdução de Sinais/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Platina/uso terapêutico , Platina/farmacologia , Reparo do DNA/efeitos dos fármacosRESUMO
Purpose: To study the effects of prior pelvic radiotherapy on bone marrow suppression in recurrent cervical cancer patients during chemotherapy. Methods and materials: The cases of 129 patients with recurrent cervical cancer were reviewed, of which 77 patients had pelvic radiotherapy history and another 52 patients with no pelvic radiotherapy history were used as control group. All patients received a chemotherapy regimen of paclitaxel combined with carboplatin (TC) per 21 days for 5-6 times. Hematologic toxicity, including count of red blood cell, white blood cell and neutrophil cell and platelet, was defined by using Common Terminology Criteria for Adverse Events (version 4.0). The relationship between age, body mass index, disease free survival, pathological types, FIGO stages, radiotherapy methods and the degree of bone marrow suppression during chemotherapy was statistically analyzed, respectively, for all recurrent cervical cancer patients. Results: Among 77 patients with previous radiotherapy history, 73 recurrent patients (94.8%) had bone marrow suppression followed by chemotherapy. Recurrent cervical cancer patients without prior radiotherapy (n=52) showed a lower risk of bone marrow suppression followed by chemotherapy (n=39, 75.0%, P < 0.05). The probability of severe bone marrow suppression (grade III-IV) after chemotherapy in recurrent cervical patients with or without history of radiotherapy was 41.6% and 13.5%, respectively (P < 0.05). In univariate analysis, radiotherapy methods were associated with the incidence of grade III-IV bone marrow suppression in recurrent cervical cancer patients (P=0.005). In multivariate analysis, radiotherapy methods and extended-field radiotherapy were the risk factor of grade III-IV bone marrow suppression (χ2=16.975, P=0.001). No significant differences in the counts of white blood cell, hemoglobin and platelet were observed before chemotherapy at relapse between patients with and without prior radiotherapy. Reduction of white blood cell counts, absolute value of neutrophil cell and platelet counts composited majority type of grade III and IV bone marrow suppression. Conclusions: The prior pelvic radiotherapy significantly increased the incidence of bone marrow suppression during chemotherapy in recurrent cervical cancer patients. When treating recurrent cervical cancer patients with chemotherapy who had prior radiotherapy, especially for those experienced external beam radiation therapy, essential attention and timely intervention are recommended to ensure completion of chemotherapy and clinical efficacy.
Assuntos
Medula Óssea , Recidiva Local de Neoplasia , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Medula Óssea/efeitos da radiação , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Adulto , Idoso , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Carboplatina/efeitos adversos , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Pelve/efeitos da radiação , Pelve/patologia , Estudos Retrospectivos , Intervalo Livre de DoençaRESUMO
PURPOSE: To report the outcomes of platinum-based neoadjuvant chemotherapy (NACT) for eyelid and periocular sebaceous gland carcinoma (eSGC). METHODS: Retrospective study of 25 patients. RESULTS: The mean age at presentation of eSGC was 59 years. The mean tumor basal diameter was 46 mm. By the 8th edition of AJCC classification, tumors belonged T2 (n = 2, 8%), T3 (n = 6, 24%), and T4 (n = 17, 68%); N1 (n = 12,48%); and M1 (n = 1, 4%). NACT with 5-fluorouracil (5-FU) and cisplatin/carboplatin was administered in 21 (84%)/4 (16%) patients, respectively. The mean number of cycles of neoadjuvant systemic chemotherapy per patient was 2 (median, 3). The mean percentage reduction of tumor basal volume after neoadjuvant chemotherapy was 65% (median, 60%). After NACT, 12 (48%) patients underwent surgical treatment, 6 (12%) patients underwent EBRT, and 4 (8%) underwent adjuvant chemotherapy. A total of 11 (44%) patients were lost to follow-up during the course of treatment, of whom 3 died from metastatic disease. In 16 patients followed up for ≥ 3 months, complete tumor control was achieved in 11 (69%) patients, local tumor control in 14 (88%), and globe salvage in 7 (44%) at a mean follow-up of 25 months (median, 7 months; range, 3 to 110 months). No tumor recurrence was seen in any case. One (4%) serious adverse event of cardiotoxicity was noted. CONCLUSION: Platinum-based NACT is a suitable option for eSGC with advanced tumors and locoregional metastasis. Adverse events are rare and in patients compliant with treatment, NACT-based combination therapy offers globe salvage and systemic tumor control.
Assuntos
Neoplasias Palpebrais , Terapia Neoadjuvante , Neoplasias das Glândulas Sebáceas , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Estudos Retrospectivos , Neoplasias Palpebrais/tratamento farmacológico , Neoplasias Palpebrais/diagnóstico , Neoplasias Palpebrais/patologia , Neoplasias das Glândulas Sebáceas/tratamento farmacológico , Neoplasias das Glândulas Sebáceas/cirurgia , Neoplasias das Glândulas Sebáceas/diagnóstico , Neoplasias das Glândulas Sebáceas/patologia , Terapia Neoadjuvante/métodos , Idoso , Adulto , Adenocarcinoma Sebáceo/tratamento farmacológico , Adenocarcinoma Sebáceo/diagnóstico , Adenocarcinoma Sebáceo/patologia , Adenocarcinoma Sebáceo/cirurgia , Seguimentos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Idoso de 80 Anos ou mais , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Quimioterapia Adjuvante/métodos , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do TratamentoRESUMO
The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m2/d iv on days 1-3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H0 50%, H1 72%, ß 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Tumores Neuroendócrinos , Nivolumabe , Neoplasias Pancreáticas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/mortalidade , Adulto , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Intervalo Livre de Progressão , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/patologia , Neoplasias Intestinais/mortalidade , Gradação de Tumores , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêuticoRESUMO
Background: High dose rate (HDR) image-guided brachytherapy with Cobalt-60 isotope is a relatively recent approach. The aim of the study is to evaluate the clinical and dosimetric parameters in terms of tumour response, bladder, and rectal toxicity in patients undergoing Co-60 HDR brachytherapy. Materials and Method: All patients were initially treated with chemoradiation (CT-RT) at our center or other referral centers with external beam radiation therapy (EBRT) for a dose of 45 Gy-60 Gy at 1.8-2Gy/fraction (including nodal boost) with concomitant chemotherapy with either cisplatin or carboplatin. Patients were then scheduled for brachytherapy within 1 week after completion of CT-RT and are assessed by local examination. Depending on local examination parameters at the time of brachytherapy they were eligible either for intracavitary brachytherapy (ICBT) or interstitial brachytherapy (ISBT). Results: The complete response (CR) observed in stage I, II, III, IVA were 60%, 79.4%, 86% and 76.2% respectively. Complete response was seen in patients with mean EQD2 of 78.67 Gy10, 83.33 Gy10, 84.23 Gy10, 85.63 Gy10 in stages I, II, III, IVA respectively. 79.2% of cisplatin-treated patients and 87.5% of carboplatin-treated patients had a complete response indicating that patients treated with either chemotherapy had similar response rates. Conclusions: According to results obtained from the study we conclude by saying that higher rates of complete response to treatment in cervical cancer is seen in patients with shorter overall treatment time (OTT), shorter interval between end of definitive CT-RT and beginning of brachytherapy and squamous cell histology. The study also noted the trend of increasing mean EQD2 to tumor with increasing stage for achieving complete response. Higher acute bladder and rectal toxicity is seen in patients who received EQD2 of ¿70-90Gy3 and ¿70Gy3 respectively. The study findings suggest that the clinical outcomes and the toxicities are clinically comparable with other radioisotope based HDR brachytherapy treatment.
Assuntos
Braquiterapia , Radioisótopos de Cobalto , Dosagem Radioterapêutica , Bexiga Urinária , Neoplasias do Colo do Útero , Humanos , Braquiterapia/efeitos adversos , Braquiterapia/métodos , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Radioisótopos de Cobalto/uso terapêutico , Radioisótopos de Cobalto/efeitos adversos , Idoso , Adulto , Bexiga Urinária/efeitos da radiação , Bexiga Urinária/patologia , Bexiga Urinária/efeitos dos fármacos , Reto/efeitos da radiação , Reto/patologia , Reto/diagnóstico por imagem , Resultado do Tratamento , Cisplatino/uso terapêutico , Cisplatino/efeitos adversos , Carboplatina/uso terapêutico , Carboplatina/efeitos adversos , Carboplatina/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Lesões por Radiação/etiologiaRESUMO
A 73-year-old man with lung squamous cell carcinoma was administered carboplatin + nab-paclitaxel + pembrolizumab for four cycles. Subsequently, he presented with multiple purpuras on his extremities, joint swelling on his fingers, abdominal pain, and diarrhea, accompanied by acute kidney injury (AKI), increased proteinuria, hematuria, and elevated C-reactive protein levels. Skin biopsy showed leukocytoclastic vasculitis as well as IgA and C3 deposition in the vessel walls. Based on these findings, the patient was diagnosed with IgA vasculitis as an immune-related adverse event (irAE) induced by carboplatin + nab-paclitaxel + pembrolizumab. After discontinuation of pembrolizumab and glucocorticoids, the symptoms immediately resolved. Regular monitoring of skin, blood tests, and urinalysis are necessary, and the possibility of irAE IgA vasculitis should be considered in cases of purpura and AKI during treatment with immune checkpoint inhibitors.
Assuntos
Albuminas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Paclitaxel , Humanos , Masculino , Idoso , Carboplatina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Paclitaxel/efeitos adversos , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Albuminas/efeitos adversos , Albuminas/administração & dosagem , Vasculite por IgA/induzido quimicamente , Vasculite por IgA/diagnóstico , Imunoglobulina A , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
BACKGROUND: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. METHODS: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. RESULTS: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively. CONCLUSIONS: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Inibidores de Poli(ADP-Ribose) Polimerases , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Camundongos , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Indóis/uso terapêutico , Indóis/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8-not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4-15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7-63.5) and 69.7% (95% CI: 55.7-87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Masculino , Feminino , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Pessoa de Meia-Idade , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Carboplatina/uso terapêutico , Carboplatina/administração & dosagem , Intervalo Livre de Progressão , Quimiorradioterapia/métodos , AdultoRESUMO
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive cancer-related disease with a dismal clinical course. The patient in this report was a 43-year-old man with metastatic salivary duct carcinoma arising from the parotid gland. Combined androgen blockade therapy was administered started as first-line treatment, but failed after 5 months, followed by docetaxel plus carboplatin therapy as second-line treatment, which failed after 3 months. Genomic profiling revealed a BRAF V600E mutation, and combined BRAF and MEK inhibitor therapy was started as third-line treatment. The cancer remained stable during the first 10 months of third-line treatment, but treatment was subsequently discontinued due to the onset of symptoms of fatigue, myalgia and arthritis. Twenty days after the onset of these symptoms and interruption of third-line treatment, the patient was urgently admitted to hospital with respiratory distress and severe thrombocytopenia. CT images at the time of admission led our radiologist to the possibility of PTTM, but the patient died the day after admission and autopsy findings indicated that PTTM was the cause of death. This report describes a very informative case of PTTM with sequential imaging and detailed autopsy findings were available and provides a literature review.