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1.
Artigo em Inglês | MEDLINE | ID: mdl-33609319

RESUMO

BACKGROUND: The high operative mortality rate after hepatopancreatoduodenectomy (HPD) is still a major issue. The present study explored why the operative mortality differs significantly by hospital volume. METHOD: Surgical case data were extracted from the National Clinical Database (NCD) in Japan from 2011 to 2014. Surgical procedures were categorized as major (≥2 sections) and minor (<2 sections) hepatectomy. Hospitals were categorized according to the certification system by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) based on the number of major hepato-biliary-pancreatic surgeries performed per year. The FTR rate was defined as death in a patient with at least one postoperative complication. RESULTS: A total of 422 patients who underwent HPD were analyzed. The operative mortality rates in board-certified A training institutions, board-certified B training institutions, and non-certified institution were 7.2%, 11.6%, and 21.4%, respectively. Multiple logistic regression showed that certified A institutions, major hepatectomy, and blood transfusion were the predictors of operative mortality. Failure to rescue rates were lowest in certified A institutions (9.3%, 17.0%, and 33.3% in certified A, certified B, and non-certified, respectively). CONCLUSIONS: To reduce operative mortality after HPD, further centralization of this procedure is desirable. Future studies should clarify specific ways to improve the failure-to-rescue rates in certified institutions.

3.
Cancer Med ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33600074

RESUMO

Autophagy removes damaged organelles to inhibit malignant transformation during tumor initiation. Once a cancer matures, it uses the autophagic pathway as an energy source. Optineurin (OPTN) is an autophagy adaptor protein that recruits microtubule-associated protein 1 light chain 3, an autophagosome marker, to the autophagosome. Despite studies of the relation between cancer progression and autophagy adaptor proteins, there are no reports to our knowledge of a correlation between hepatocellular carcinoma (HCC) and OPTN. We aimed here to investigate the effects of OPTN expression on HCC progression through autophagy. Immunohistochemistry was used to measure the OPTN expression in the tissues of 141 Japanese patients with HCC. The effects of OPTN expression on HCC progression and mitophagy were assessed using an OPTN knockout (KO) cell line in vitro. We used this KO cell line to establish and exploit a mouse model of HCC to determine the effects of OPTN expression on tumor progression. Immunohistochemical analysis showed that patients with elevated expression of OPTN experienced shorter overall survival (OS) and recurrence-free survival (RFS). OPTN KO cells proliferated relatively slower versus wild-type (WT) cells in vitro. Western blot analysis showed that mitophagy was suppressed in OPTN KO cells, and ATP synthesis and beta-oxidation were reduced. The mouse model of HCC showed that OPTN KO cells formed smaller tumors versus WT cells less 10 weeks after implantation. Overall, the present findings suggest that OPTN is a key mediator of mitophagy that contributes to HCC progression through mitochondrial energy production.

4.
Histopathology ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33595141

RESUMO

AIMS: Histologic categorization of the desmoplastic reaction (DR) is an independent prognostic factor in colorectal cancer. However, it is unknown whether DR categorization is predictive of oesophageal squamous cell carcinoma (OSCC) outcomes. This study aimed to evaluate the prognostic value of DR categorization in OSCC patients. METHODS: Data were collected from 118 patients with OSCC who underwent a curative oesophagectomy with T2 or deeper wall invasion. The DR in each tumour was classified as mature, intermediate, or immature based on the presence or absence of keloid-like collagen and myxoid stroma. RESULTS: We identified 49 mature DR tumours, 41 intermediate DR tumours, and 28 immature DR tumours. The 5-year overall survival (OS) rate was highest in the mature DR group (42.8%), followed by the intermediate DR group (25.0%), and the immature DR group (19.9%) (P = 0.022, log-rank test; P = 0.006, log-rank trend test). The 5-year disease-specific survival (DSS) rate was also highest in the mature DR group (48.5%), followed by the intermediate DR group (30.8%), and the immature DR group (26.8%) (P = 0.031, log-rank test; P = 0.010, log-rank trend test). Multivariate analysis revealed that an immature DR was an independent poor prognostic factor of OS and DSS (P=0.002 and P=0.004). CONCLUSIONS: DR categorization of OSCC stroma following oesophagectomy is a useful diagnostic tool and an independent prognostic marker.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33595705

RESUMO

PURPOSE: Systemic inflammation score (SIS) is a novel prognostic score (0, 1, or 2) for various cancers, based on preoperative serum albumin level and lymphocyte-to-monocyte ratio (LMR); modified SIS (mSIS) uses a different LMR cutoff value and was thought to be a more accurate predictor for cancer prognosis. Here, we assessed the prognostic value of SIS and mSIS in patients who receive hepatic resection for hepatocellular carcinoma (HCC). METHODS: We retrospectively evaluated SIS and mSIS of 314 patients after hepatic resection for HCC, against their clinicopathological factors and outcomes, using receiver operating characteristics (ROC) analysis over time. RESULTS: Among patients with preoperative SIS 2, significantly more HCC specimens were poorly differentiated (P = 0.0281), larger (P = 0.0006), and had more microscopic vascular invasion (P = 0.0136) than the SIS 0-1 group; the mSIS 2 group also had significantly larger tumors (P = 0.0039) than the mSIS 0-1 group. In ROC analysis, SIS was a better predictor of overall survival (OS) and recurrence-free survival (RFS) than mSIS. The SIS 2 group had shorter OS (P = 0.0015) and RFS (P = 0.0065) than other patients. In multivariate analysis, SIS 2 was an independent risk factor for shorter OS (hazard ratio (HR) 1.53, P = 0.0497) and RFS (HR 1.58, P = 0.0053). CONCLUSION: SIS is superior to mSIS in predicting prognosis of patients with HCC. mSIS is not a great predictor of prognosis in resected HCC.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33492082

RESUMO

BACKGROUND: Various techniques have been reported for esophagogastric anastomosis to prevent anastomotic leakage. Recently, not only postoperative anastomotic leakage but also anastomotic stricture is considered important because stricture contributes to the patient's postoperative quality of life. However, the best procedure for anastomosis has not been established. MATERIALS AND METHODS: The authors divided 101 patients with thoracic or abdominal esophageal cancer who underwent cervical triangulating esophagogastric anastomosis using a linear stapler between May 2017 and May 2020 into 2 groups: surgery with a short (45 mm) linear stapler (SS group, n=59) or a long (60 mm) stapler (LS group, n=42). The frequencies of anastomotic leakage and stricture were compared between the 2 groups. RESULTS: The incidence of anastomotic leakage and stricture without leakage were significantly lower in the LS versus SS group (respectively: leakage: 15% vs. 0%, P=0.01; stricture: 36% vs. 7%, P=0.01). A short linear stapler and anastomotic leakage were independent risk factors for anastomotic stricture in the multivariate analysis (short stapler: odds ratio, 3.27; 95% confidence interval, 1.08-9.9; P=0.03; anastomotic leakage: odds ratio, 2.78; 95% confidence interval, 1.02-8.5; P=0.04). CONCLUSION: A long linear stapler is preferable for cervical triangulating esophagogastric anastomosis.

7.
Sci Rep ; 11(1): 1324, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446685

RESUMO

Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10-1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06-0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33389013

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become a standard therapy in non-small cell lung cancer (NSCLC). Although lung cancer adjoining emphysematous bullae (Ca-ADJ) were reported to express higher programmed cell death-ligand 1 (PD-L1), the predictive impact of Ca-ADJ on the response to ICIs is unknown. METHODS: Two hundred and fifty-seven advanced or recurrent NSCLC patients treated with ICI monotherapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed. RESULTS: Of the 257 patients, 55 had Ca-ADJ. Patients with Ca-ADJ were significantly associated with younger age (P = 0.0343), male sex (P = 0.0070), and smoking (P = 0.0080). The objective response rate of cases with Ca-ADJ was significantly higher than that of those without Ca-ADJ (36.4% vs. 20.8%, respectively; P = 0.0167). The disease control rate of cases with Ca-ADJ was also significantly higher than tumors without Ca-ADJ (63.6% vs. 47.5%, respectively; P = 0.0341). The IPTW-adjusted Kaplan-Meier curves showed that patients with Ca-ADJ had significantly longer progression-free survival (PFS) and overall survival (OS) than those without Ca-ADJ (P = 0.0407 and P = 0.0126, respectively). On IPTW-adjusted Cox analysis, Ca-ADJ was an independent predictor of PFS and OS (P < 0.0001 and P < 0.0001, respectively). CONCLUSIONS: Patients with Ca-ADJ may be good candidates for ICIs. These findings should be validated prospectively.

9.
Clin J Gastroenterol ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33421028

RESUMO

No cases of late recurrence of colorectal cancer liver metastasis (CRLM) over 10 years have been reported in the literature. A 72-year-old woman had a surgical history of sigmoid colectomy and partial hepatic resections for sigmoid colon cancer and multiple liver metastases 15 years previously. The patient had been postoperatively treated with chemotherapy for 6 months and was observed regularly with no recurrence. Computed tomography (CT) performed due to high carcinoembryonic antigen (CEA) revealed a tumor of 70 mm in diameter at the anterior segment of the liver and a 6-mm nodule at the left lateral segment. There was no other malignant finding. We performed central bisegmentectomy and partial resection of the liver. Pathological findings showed the tumors to be well to moderately differentiated adenocarcinoma, and positive cytokeratin 20 (CK20) and caudal-type homeobox transcription factor 2 (CDX2) expression with negative expression of cytokeratin 7 (CK7). In addition, the tumors showed cluster of differentiation 44 (CD44) and 133 (CD133) positive signified cancer stem cell immunohistochemically. The postoperative diagnosis was recurrence of hepatic metastasis of sigmoid colon cancer. We report a rare case of late recurrence of CRLM more than 15 years after the primary diagnosis.

10.
BMC Cancer ; 21(1): 23, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402130

RESUMO

BACKGROUND: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT. METHODS: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety. RESULTS: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable. CONCLUSION: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases. TRIAL REGISTRATION: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.

11.
Ann Surg Oncol ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33454878

RESUMO

OBJECTIVE: The aim of this study was to develop a radiomics-based prediction model for the response of colorectal liver metastases to oxaliplatin-based chemotherapy. METHODS: Forty-two consecutive patients treated with oxaliplatin-based first-line chemotherapy for colorectal liver metastasis at our institution from August 2013 to October 2019 were enrolled in this retrospective study. Overall, 126 liver metastases were chronologically divided into the training (n = 94) and validation (n = 32) cohorts. Regions of interest were manually segmented, and the best response to chemotherapy was decided based on Response Evaluation Criteria in Solid Tumors (RECIST). Patients who achieved clinical complete and partial response according to RECIST were defined as good responders. Radiomics features were extracted from the pretreatment enhanced computed tomography scans, and a radiomics score was calculated using the least absolute shrinkage and selection operator regression model in a trial cohort. RESULTS: The radiomics score significantly discriminated good responders in both the trial (area under the curve [AUC] 0.8512, 95% confidence interval [CI] 0.7719-0.9305; p < 0.0001) and validation (AUC 0.7792, 95% CI 0.6176-0.9407; p < 0.0001) cohorts. Multivariate analysis revealed that high radiomics scores greater than - 0.06 (odds ratio [OR] 23.803, 95% CI 8.432-80.432; p < 0.0001), clinical non-T4 (OR 6.054, 95% CI 2.164-18.394; p = 0.0005), and metachronous disease (OR 11.787, 95% CI 2.333-70.833; p = 0.0025) were independently associated with good response. CONCLUSIONS: Radiomics signatures may be a potential biomarker for the early prediction of chemosensitivity in colorectal liver metastases. This approach may support the treatment strategy for colorectal liver metastasis.

12.
Clin J Gastroenterol ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33471251

RESUMO

Fascioliasis is a parasitic infestation caused by the digenetic trematodes Fasciola hepatica and F. gigantica. It is not commonly seen in developed countries, so diagnosis there is always difficult as a result of confusion with other hepatic or biliary disorders. A 56-year-old man presented at our hospital with a hepatic mass that had been inadvertently discovered by ultrasonography. Abdominal computed tomography revealed a multi-cystic lesion distributed along the branch of the right bile duct. Endoscopic retrograde cholangiopancreatography showed serrated changes ranging from the upper level of the common bile duct to the right hepatic bile duct. Eosinophilia was not observed and tumor marker levels were within normal ranges. Following right lobectomy combined with bile duct reconstruction, a histological examination revealed cholangitis with inflammatory cell infiltration accompanied by parasite egg-like structures and Charcot-Leyden crystals. An additional serologic test was positive for F. hepatica antibodies. A diagnosis of fascioliasis was thus confirmed by histopathology and serology. Fascioliasis should be suspected if imaging findings such as multiple small hypodense lesions in the liver are observed, and serologic tests can be useful for differential diagnosis.

13.
Lung Cancer ; 152: 27-33, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33341085

RESUMO

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have become one of the standard therapies in non-small-cell lung cancer (NSCLC). Although inflammatory indices, including Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS), and C-reactive protein/albumin ratio (CAR) were reported to be reliable predictors for survival in cancer patients, their clinical utility in NSCLC patients treated with ICIs is unknown. MATERIALS AND METHODS: Advanced or recurrent NSCLC patients (n = 304) treated with ICI monotherapy at the National Hospital Organization Kyushu Cancer Center and Kyushu University Hospital between January 2016 and December 2019 were analyzed. Information on patient demographics, GPS, mGPS, and CAR at diagnosis were collected. The time-dependent area under curves (AUCs) of receiver operating characteristic curves for the prediction of overall survival (OS) for each factor were compared. RESULTS: Of the three indices, GPS was the most significantly correlated with the degree of disease control rate (DCR) (DCR of GPS of 0, 1, and 2: 63.6 %, 49.4 %, and 41.4 %, respectively). The time-dependent AUC values of GPS for the prediction of OS were superior to those of mGPS and CAR (time-dependent AUC values of GPS, mGPS, and CAR for the prediction of 1-year OS: 0.7005, 0.6736, and 0.6565, respectively). GPS was significantly correlated with performance status (PS) (P < 0.0001) and clinical stage (P = 0.0139). GPS in combination with PS effectively predicted survival at 1 year ranging from 83.5 % (GPS = 0, PS = 0) to 25.0 % (GPS = 2, PS = 2, 3). A multivariable analysis revealed that GPS was an independent predictor of PFS and OS (P = 0.0009 and P = 0.0100, respectively). CONCLUSIONS: We report for the first time that GPS represents a simple and useful prognostic factor in NSCLC patients treated with ICIs and should be validated prospectively.

15.
Cancer Med ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33274848

RESUMO

Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8%). Clinically actionable alterations were identified in 76% of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6%), PIK3CA (38.5%), GATA3 (11.0%), PTEN (11.0%), and BRCA1 (10.1%), and structural variants were in ERBB2 (24.8%), MYC (21.1%), RAD21 (21.1%), CCND1 (11.9%), FGF19 (10.1%), and PTEN (10.1%). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2%) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.

16.
ESC Heart Fail ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300689

RESUMO

A 66-year-old man with a history of gastric pull-up reconstruction for oesophageal cancer was hospitalized because of prolonged chest pain. Chest X-ray demonstrated pneumopericardium. Computed tomography revealed ulceration and abscess in the gastric conduit adjacent to the heart, suggesting gastropericardial fistula. As the patient did not show tamponade physiology, he was conservatively treated with antibiotics. The pneumopericardium diminished; however, he developed effusive-constrictive pericarditis with overt heart failure symptoms. Because pericardiocentesis failed to relieve the symptoms, pericardiectomy was performed. Intraoperative exploration revealed remarkably thickened pericardium and epicardium constituting multiple layers with purulent effusion. Epicardiectomy as well as pericardiectomy were required to achieve the effective reduction of central venous pressure. Perforation of the gastric conduit into the pericardial cavity was identified and repaired. Histopathology demonstrated thickened pericardium composed of hyalinized stroma, collagenous bundles, and infiltration of inflammatory cells. Streptococcus anginosus and Candida tropicalis were identified by culture of the resected tissue.

18.
Ann Surg Oncol ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33216264

RESUMO

BACKGROUND: The transcription factor capicua (CIC) regulates mammalian development and homeostasis. Growing evidence shows that CIC suppresses various human cancers by directly repressing the downstream cancer-related target genes. This study investigated the clinical and biologic significance of CIC expression in pancreatic cancer (PC). METHODS: The study reviewed 132 patients with PC who underwent curative resection. The patients were divided into two groups according to CIC immunoreactivity score by immunohistochemistry, and the associations between CIC expression, clinicopathologic characteristics, and postoperative prognosis were investigated. Moreover, the influence of CIC expression on the malignant potential of PC cells was assessed with cell proliferation, motility assays, and use of quantitative real time-polymerase chain reaction and Western blot on the downstream target genes of CIC in knockdown experiments. RESULTS: The low-CIC expression group showed a higher proportion of lymphatic invasion (72.9% vs. 53.1%; p = 0.024), intrapancreatic neural invasion (94.1% vs. 81.3%; p = 0.021), and extrapancreatic plexus invasion (30.9% vs. 7.8%; p = 0.0006) than the high-CIC expression group as well as significantly worse overall survival (p = 0.0002) and recurrence-free survival (p = 0.0041) rates. Low CIC expression was an independent risk factor for poor prognosis (p = 0.038). Pancreatic cancer cells with knockdown CIC significantly enhanced cell motilities and cell cycle progression, promoted expression levels of ETV4 and MMP-9, and induced EMT. CONCLUSIONS: The study elucidated the association of low CIC expression with a poor prognosis for patients with PC and suggested that the CIC-ETV4-MMP-9 axis might control PC progression.

19.
JMA J ; 3(3): 284-285, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33150265
20.
BMC Cancer ; 20(1): 1116, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203393

RESUMO

BACKGROUND: FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. METHODS: EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. DISCUSSION: This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs071190003 . Registered April 18, 2019.

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