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BACKROUND: Real-world, long-term survival outcomes of neoadjuvant, docetaxel-based therapy for esophageal and junctional adenocarcinoma are lacking. This study describes the long-term survival outcomes of patients with esophageal and junctional adenocarcinoma treated with neoadjuvant docetaxel-based chemotherapy and en bloc transthoracic esophagectomy. METHODS: A retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada, was performed. From January 2007 to December 2021, all patients with locally advanced (cT3 and/or N1) esophageal/Siewert I/II adenocarcinoma treated with neoadjuvant DCFx3 (Docetaxel/Cisplatin/5FU) or FLOTx4 (5FU/Leucovorin/Oxaliplatin/Docetaxel) and transthoracic en bloc esophagectomy were identified. Postoperative, pathological, and survival outcomes were compared. RESULTS: Overall, 236 of 420 patients met the inclusion criteria. Tumor location was esophageal/Siewert I/Siewert II (118/33/85), most were cT3-4 (93.6%) and cN+ (61.0%). DCF and FLOT were used in 127 of 236 (53.8%) and 109 of 236 (46.2%). All neoadjuvant cycles were completed in 87.3% with no difference between the regimens. Operative procedures included Ivor Lewis (81.8%), left thoraco-abdominal esophagectomy (10.6%) and McKeown (7.6%) with an R0 resection in 95.3% and pathological complete response in 9.7% (DCF 12.6%/FLOT 6.4%, p = 0.111). The median lymph node yield was 32 (range 4-79), and 60.6% were ypN+. Median follow-up was longer for the DCF group (74.8 months 95% confidence interval [CI] 4-173 vs. 37.8 months 95% CI 2-119, p <0.001. Overall survival was similar between the groups (FLOT 97.3 months, 78.6-115.8 vs. DCF 92.9, 9.2-106.5, p = 0.420). CONCLUSIONS: Neoadjuvant DCF and FLOT followed by transthoracic en bloc resection are both highly effective regimens for locally advanced esophageal adenocarcinoma with equivalent survival outcomes despite high disease load.
Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Humanos , Docetaxel , Terapia Neoadjuvante/métodos , Estudos Retrospectivos , Esofagectomia/métodos , Estadiamento de Neoplasias , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Fluoruracila , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , CisplatinoRESUMO
Single-agent regorafenib is approved in Canada for metastatic colorectal cancer (mCRC) patients who have failed previous lines of therapy. Identifying prognostic biomarkers is key to optimizing therapeutic strategies for these patients. In this clinical study (NCT01949194), we evaluated the safety and efficacy of single-agent regorafenib as a second-line therapy for mCRC patients who received it after failing first-line therapy with an oxaliplatin or irinotecan regimen with or without bevacizumab. Using various omics approaches, we also investigated putative biomarkers of response and resistance to regorafenib in metastatic lesions and blood samples in the same cohort. Overall, the safety profile of regorafenib seemed similar to the CORRECT trial, where regorafenib was administered as ≥ 2 lines of therapy. While the mutational landscape showed typical mutation rates for the top five driver genes (APC, KRAS, BRAF, PIK3CA, and TP53), KRAS mutations were enriched in intrinsically resistant lesions. Additional exploration of genomic-phenotype associations revealed several biomarker candidates linked to unfavorable prognoses in patients with mCRC using various approaches, including pathway analysis, cfDNA profiling, and copy number analysis. However, further research endeavors are necessary to validate the potential utility of these promising genes in understanding patients' responses to regorafenib treatment.
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Neoplasias do Colo , Proteínas Proto-Oncogênicas p21(ras) , Piridinas , Humanos , Biomarcadores , Compostos de Fenilureia/uso terapêuticoRESUMO
BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Fluoruracila/efeitos adversos , Humanos , Irinotecano , Leucovorina/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/efeitos adversos , Oxaliplatina , Modelos de Riscos Proporcionais , Estudos Prospectivos , GencitabinaRESUMO
BACKGROUND: Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. METHODS: We randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. RESULTS: A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). CONCLUSIONS: The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT00943826.).
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Bevacizumab , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Temozolomida , Adulto JovemRESUMO
Poorly differentiated pancreatic neuroendocrine carcinoma (PD pNECs) is a rare disease that has a poor prognosis and is treated with systemic chemotherapy as the standard of care. We present 6 cases of chemo-naïve patients diagnosed with PD pNECs who refused systemic chemotherapy and received targeted therapies with sunitinib (37.5 mg/day, 5 patients) or the mammalian target of rapamycin (mTOR) inhibitor everolimus (10 mg/day, 1 patient) as the first-line treatment. We evaluated the drugs' toxicities and survival. The median age of the patients was 55 years (4 males, 2 females, functioning tumor in 1 of 6 patients). The median of the Ki67 index was 45% (range 20-80). Targeted therapies were combined with somatostatin analogues in 4 of 6 patients (30 mg Sandostatine LAR monthly). Toxicities (acute and late) were manageable and no toxicities necessitated cessation of treatment. All patients had progression-free survival during the 15-month treatment and an overall survival of more than 2 years after diagnosis. Even though this is a small cohort of selected patients, we conclude that sunitinib or everolimus are both feasible and safe and have encouraging results of efficacy as first-line therapies for PD pNEC.
Assuntos
Carcinoma Neuroendócrino/tratamento farmacológico , Everolimo/uso terapêutico , Indóis/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Diferenciação Celular/efeitos dos fármacos , Everolimo/efeitos adversos , Feminino , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pirróis/efeitos adversos , Sunitinibe , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
BACKGROUND: BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients. METHODS: Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas. RESULTS: BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/ß-catenin. Pathway analysis revealed enrichment of WNT/ß-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15% p < 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58; p < 0.0001). CONCLUSIONS: Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.
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BACKGROUND: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. RESULTS: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (nâ¯=â¯5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (nâ¯=â¯7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. CONCLUSION: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. GOV IDENTIFIER: ClinicalTrials.gov; NCT03374254.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Neoplasias Colorretais , Fluoruracila , Leucovorina , Compostos Organoplatínicos , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Idoso , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Camptotecina/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Adulto , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Instabilidade de Microssatélites/efeitos dos fármacos , Reparo de Erro de Pareamento de DNA , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Oxaliplatina/administração & dosagem , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Neoplasias Colorretais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Feminino , Masculino , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso , Adulto , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Oxaliplatina/administração & dosagem , Reparo de Erro de Pareamento de DNA , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/efeitos adversos , Instabilidade de Microssatélites , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN-38 (10-hydroxy-7-ethyl-camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN-38 (EZN-2208) increases the solubility, exposure, and half-life of SN-38. Preclinical studies demonstrated superior in vitro efficacy of EZN-2208 when it was tested in irinotecan-refractory human CRC cell lines. METHODS: Patients with metastatic or locally recurrent CRC who had previously received 5-flurouracil (5-FU), oxaliplatin, and irinotecan were assigned to receive EZN-2208 monotherapy (9 mg/m(2) on days 1, 8, and 15 every 28 days for patients with KRAS-mutant tumors only [arm A]), and patients with KRAS wild-type tumors were randomized (2:1) to receive either EZN-2208 plus cetuximab (400 mg/m(2) loading dose on day 1 followed by 250 mg/m(2) weekly starting on day 8 [arm B]) or irinotecan 125 mg/m(2) on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C). RESULTS: The overall response rate and progression-free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2-5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1-5.8 months), respectively, in arm C. EZN-2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2-11.2 months) and arm C (9.1 months; 95% CI, 6.0-13.0 months). CONCLUSIONS: EZN-2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression-free survival were similar in the cetuximab plus irinotecan arm and the EZN-2208 arm.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Cetuximab , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Intervalo Livre de Doença , Feminino , Genes ras , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Polietilenoglicóis/administração & dosagem , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Adulto Jovem , Proteínas ras/genéticaRESUMO
Great advances in analytical technology coupled with accelerated new drug development and growing understanding of biological challenges, such as tumor heterogeneity, have required a change in the focus for biobanking. Most current banks contain samples of primary tumors, but linking molecular signatures to therapeutic questions requires serial biopsies in the setting of metastatic disease, next-generation of biobanking. Furthermore, an integration of multidimensional analysis of various molecular components, that is, RNA, DNA, methylome, microRNAome and post-translational modifications of the proteome, is necessary for a comprehensive view of a tumor's biology. While data using such biopsies are now regularly presented, the preanalytical variables in tissue procurement and processing in multicenter studies are seldom detailed and therefore are difficult to duplicate or standardize across sites and across studies. In the context of a biopsy-driven clinical trial, we generated a detailed protocol that includes morphological evaluation and isolation of high-quality nucleic acids from small needle core biopsies obtained from liver metastases. The protocol supports stable shipping of samples to a central laboratory, where biopsies are subsequently embedded in support media. Designated pathologists must evaluate all biopsies for tumor content and macrodissection can be performed if necessary to meet our criteria of >60% neoplastic cells and <20% necrosis for genomic isolation. We validated our protocol in 40 patients who participated in a biopsy-driven study of therapeutic resistance in metastatic colorectal cancer. To ensure that our protocol was compatible with multiplex discovery platforms and that no component of the processing interfered with downstream enzymatic reactions, we performed array comparative genomic hybridization, methylation profiling, microRNA profiling, splicing variant analysis and gene expression profiling using genomic material isolated from liver biopsy cores. Our standard operating procedures for next-generation biobanking can be applied widely in multiple settings, including multicentered and international biopsy-driven trials.
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Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Testes Genéticos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Medicina de Precisão , Bancos de Tecidos , Processamento Alternativo , Biópsia com Agulha de Grande Calibre , Canadá , Hibridização Genômica Comparativa , Metilação de DNA , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/análise , Análise de Sequência com Séries de Oligonucleotídeos , Seleção de Pacientes , Fenótipo , Medicina de Precisão/métodos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Manejo de Espécimes , Fluxo de TrabalhoRESUMO
BACKGROUND: Bevacizumab, a humanized recombinant anti-vascular endothelial growth factor antibody, was approved in Canada in 2010 for the treatment of high-grade glioma. We report the effectiveness and safety of bevacizumab in the treatment of patients with recurrent high-grade gliomas at a single institution. METHODS: Twenty-seven consecutive patients with high-grade glioma (anaplastic glioma and glioblastoma) at first or subsequent relapse were treated with bevacizumab alone or in combination with chemotherapy. The primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate, six month PFS, overall survival (OS), and safety profile. RESULTS: The clinical benefit rate (complete and partial responses plus stable disease) was 59%. Median PFS was 4.3 (95% CI, 3.0-10.9) months, with a six month PFS rate of 43%. Median OS after current relapse was 8.9 (95% CI, 5.8-not reached) months. Ten episodes of grade 3/4 adverse events were observed in nine patients, including fatigue (n = 3), thrombocytopenia (n = 4), and myelotoxicity, febrile neutropenia, and pulmonary embolism (each n = 1). CONCLUSIONS: We consider the efficacy and safety profile of bevacizumab is comparable to other cohorts of patients treated for recurrent high-grade glioma at other international institutions.
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Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Adulto , Bevacizumab , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/mortalidade , Canadá , Feminino , Glioma/mortalidade , Hospitais Universitários , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented. METHODS: Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200â¯mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%-46.0%) in cohort A and 34.9% (95% CI, 23.3%-48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1-8.1) in cohort A and 4.1 months (95% CI, 2.1-18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4-58.0) in cohort A and 47.0 months (95% CI, 19.2-NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response. CONCLUSIONS: Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC. CLINICAL TRIAL REGISTRY INFORMATION: ClinicalTrials.gov, NCT02460198.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Instabilidade de Microssatélites , Reparo de Erro de Pareamento de DNA , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genéticaRESUMO
Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Intervention: Durvalumab plus tremelimumab or best supportive care. Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Hepáticas , Neoplasias Retais , Idoso , Feminino , Humanos , Masculino , Biomarcadores Tumorais/análise , Canadá , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Intervalo Livre de Progressão , Neoplasias Retais/tratamento farmacológico , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
PURPOSE: This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. PATIENTS AND METHODS: Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression. Temozolomide was administered at a starting dose of 150 mg/m(2)/day for 5 days every 28 days, and everolimus was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles. RESULTS: Thirteen patients receiving EIAEDs and 19 not receiving EIAEDs were enrolled and received 83 and 116 cycles respectively. Everolimus 10 mg daily plus TMZ 150 mg/m(2)/day for 5 days was declared the recommended phase II dose for the NEIAEDs cohort. In the EIAEDs group, doses were well tolerated without DLTs, and pharmacokinetic parameters indicated decreased everolimus exposure. Temozolomide pharmacokinetic parameters were unaffected by EIAEDs or everolimus. In the subset of 28 patients with measurable disease, 3 had partial responses (all NEIAEDs) and 16 had stable disease. CONCLUSION: A dosage of 10 mg everolimus daily with TMZ 150 mg/m(2)/day for five consecutive days every 28 days in patients is the recommended dose for this regimen. Everolimus clearance is increased by EIAEDs, and patients receiving EIAEDs should be switched to NEIAEDs before starting this regimen.
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Anticonvulsivantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Encefálicas/metabolismo , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Dacarbazina/sangue , Dacarbazina/farmacocinética , Combinação de Medicamentos , Everolimo , Feminino , Glioblastoma/metabolismo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sirolimo/sangue , Sirolimo/farmacocinética , Temozolomida , Adulto JovemRESUMO
This phase II trial was undertaken to evaluate the efficacy of TLN-4601 in patients with glioblastoma (GBM) at first progression. TLN-4601 inhibits the Ras-MAPK signaling pathway, and in animal models crosses the blood-brain barrier and accumulates in implanted gliomas, possibly by binding specifically to the peripheral benzodiazepine receptor. A maximum of 40 patients with recurrent GBM were to be enrolled in this study. TLN-4601 was administered at a dose of 480 mg/m(2)/day by continuous intravenous (CIV) administration. Each 21-day cycle consisted of a 14-day CIV administration and a 7-day recovery period. Samples were obtained from all patients for pharmacokinetic evaluations (PK) and for Raf-1 and pERK biomarker assessment using immunohistochemistry and flow cytometry. Following enrollment of 20 patients, this study was terminated due to a lack of efficacy. Of 17 evaluable patients, 14 had MR scans performed after two cycles of TLN-4601. Of these 14 patients, three had stable disease and 11 had disease progression. Only three patients had MR scans performed after four cycles and all had evidence of radiographic progression. Serum PKs confirmed that patients were exposed to TLN-4601 at targeted drug levels. TLN-4601 was generally well tolerated although two patients discontinued treatment due to adverse events. Biomarker analysis did not show consistent changes. TLN-4601 infused via CIV at 480 mg/m(2)/day for 14 of 21 days is well tolerated by patients with progressive GBM. However, this agent is ineffective in progressive GBM when administered as monotherapy in this schedule.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dibenzazepinas/uso terapêutico , Glioblastoma/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/mortalidade , Cromatografia Líquida , Dibenzazepinas/sangue , Receptores ErbB/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/sangue , Glioblastoma/mortalidade , Humanos , Infusões Intraventriculares , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Espectrometria de Massas em TandemRESUMO
OBJECTIVES: This study describes the management of patients with bilobar colorectal liver metastases (CRLM). METHODS: A retrospective collection of data on all patients with CRLM who were considered for staged resection (n= 85) from January 2003 to January 2011 was performed. Patients who underwent one hepatic resection were considered to have had a failed staged resection (FSR), whereas those who underwent a second or third hepatic resection to produce a cure were considered to have had a successful staged resection (SSR). Survival was calculated from the date of diagnosis of liver metastases. Complete follow-up and dates of death were obtained from the Government of Quebec population database. RESULTS: Median survival was 46 months (range: 30-62 months) in the SSR group and 22 months (range: 19-29 months) in the FSR group. Rates of 5-year survival were 42% and 4% in the SSR and FSR groups, respectively. Fifteen of the 19 patients who remained alive at the last follow-up date belonged to the SSR group. CONCLUSIONS: In patients in whom staged resection for bilobar CRLM is feasible, surgery would appear to offer benefit.
Assuntos
Neoplasias Colorretais/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Idoso , Distribuição de Qui-Quadrado , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Hepatectomia/efeitos adversos , Hepatectomia/mortalidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Quebeque , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVES: Portal vein embolization (PVE) can facilitate the resection of previously unresectable colorectal cancer (CRC) liver metastases. Bevacizumab is being used increasingly in the treatment of metastatic CRC, although data regarding its effect on post-embolization liver regeneration and tumour growth are conflicting. The objective of this observational study was to assess the impact of pre-embolization bevacizumab on liver hypertrophy and tumour growth. METHODS: Computed tomography scans before and 4 weeks after PVE were evaluated in patients who received perioperative chemotherapy with or without bevacizumab. Scans were compared with scans obtained in a control group in which no PVE was administered. Future liver remnant (FLR), total liver volume (TLV) and total tumour volume (TTV) were measured. Bevacizumab was discontinued ≥ 4 weeks before PVE. RESULTS: A total of 109 patients and 11 control patients were included. Portal vein embolization induced a significant increase in TTV: the right lobe increased by 33.4% in PVE subjects but decreased by 34.8% in control subjects (P < 0.001), and the left lobe increased by 49.9% in PVE subjects and decreased by 33.2% in controls (P= 0.022). A total of 52.8% of the study group received bevacizumab and 47.2% did not. There was no statistical difference between the two chemotherapy groups in terms of tumour growth. Median FLR after PVE was similar in both groups (28.8% vs. 28.7%; P= 0.825). CONCLUSIONS: Adequate liver regeneration was achieved in patients who underwent PVE. However, significant tumour progression was also observed post-embolization.
Assuntos
Neoplasias Colorretais/patologia , Embolização Terapêutica/efeitos adversos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Regeneração Hepática , Veia Porta , Carga Tumoral , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Regeneração Hepática/efeitos dos fármacos , Masculino , Terapia Neoadjuvante , Quebeque , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
Glioblastoma is an aggressive form of central nervous system tumor. Recurrence rates following primary therapy are high, and few second-line treatment options provide durable clinical benefit. Aberrations of the epidermal growth factor receptor (EGFR) gene are observed in up to 57% of glioblastoma cases and EGFR overexpression has been identified in approximately 60% of primary glioblastomas. In preclinical studies, afatinib, a second-generation ErbB blocker, inhibited cell proliferation in cells harboring mutations commonly found in glioblastoma. In two previous Phase I/II studies of afatinib plus temozolomide in patients with glioblastoma, limited efficacy was observed; however, there was notable benefit in patients with the EGFR variant III (EGFRvIII) mutation, EGFR amplification, and those with loss of phosphatase and tensin homolog (PTEN). This case series report details treatment histories of three long-term responders from these trials. Next-generation sequencing of tumor samples identified alterations in a number of cancer-related genes, including mutations in, and amplification of, EGFR. Tumor samples from all three patients shared favorable prognostic factors, eg O6-methylguanine-DNA methyl-transferase (MGMT) gene promoter methylation; however, negative prognostic factors were also observed, suggesting that these shared genetic features did not completely account for the favorable responses. The genetic profile of the tumor from Patient 1 showed clear differences from the other two tumors: lack of involvement of EGFR aberrations but with a mutation occurring in PTPN11. Preclinical studies showed that single-agent afatinib and temozolomide both separately inhibit the growth of tumors with a C-terminal EGFR truncation, thus providing further rationale for combining these two agents in the treatment of glioblastomas harboring EGFR aberrations. These findings suggest that afatinib may provide treatment benefit in patients with glioblastomas that harbor ErbB family aberrations and, potentially, other genetic aberrations. Further studies are needed to establish which patients with newly diagnosed/recurrent glioblastomas may potentially benefit from treatment with afatinib.
RESUMO
BACKGROUND: We explored image-guided adaptive endorectal brachytherapy patients electing non-operative management for rectal cancer. We present the first pre-planned interim analysis. METHODS: In this open-label phase II-III randomized study, patients with operable cT2-3ab N0 M0 rectal cancer received 45 Gy in 25 fractions of pelvic external beam radiotherapy (EBRT) with 5-FU/Capecitabine. They were randomized 1:1 to receive either an EBRT boost of 9 Gy in 5 fractions (Arm A) or three weekly adaptive brachytherapy (IGAEBT) boosts totaling 30 Gy (Arm B). Patient characteristics and toxicity are presented using descriptive analyses; TME-free survival between arms with the intention to treat the population is explored using the Kaplan-Meier method. RESULTS: A total of 40 patients were in this analysis. Baseline characteristics were balanced; acute toxicities were similar. Complete clinical response (cCR) was 50% (n = 10/20) in Arm A and 90% in Arm B (n = 18/20). Median follow-up was 1.3 years; 2-year TME-free survival was 38.6% (95% CI: 16.5-60.6%) in the EBRT arm and 76.6% (95% CI: 56.1-97.1%) in the IGAEBT arm. CONCLUSIONS: Radiation intensification with IGAEBT is feasible. This interim analysis suggests an improvement in TME-free survival when comparing IGAEBT with EBRT, pending confirmation upon completion of this trial.
RESUMO
Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status.