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Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer.

ABSTRACT: Add systemic bevacizumab (Bev) to adjuvant hepatic arterial infusion (HAI) plus systemic therapy after liver resection to increase recurrence-free survival (RFS).Patients were randomly assigned to HAI plus systemic therapy with or without Bev. If 1-year RFS of ? 80% was obtained in Bev arm, then the regimen would be studied further. HAI with fluorodeoxyuridine plus dexamethasone was given on days 1 to 14 of a 5-week cycle. Systemic therapy and Bev 5 mg/kg was delivered on days 15 and 29: oxaliplatin 85 mg/m², leucovorin 400 mg/m², and fluorouracil 2,000 mg/m² infusion for 2 days (if patients received prior oxaliplatin, then irinotecan 150 mg/m² was used). RFS and survival were estimated by using the Kaplan-Meier method and compared by using the log-rank test.The two arms had similar characteristics: synchronous disease (66% v 63%), more than one metastasis (84% v 74%), and clinical risk score ? 3 (50% v 46%) for no Bev versus Bev arms, respectively. With a median follow-up of 30 months, 4-year survival was 85% and 81% (P = .5), and 4-year RFS was 46% versus 37%; 1-year RFS was 83% and 71% (P = .4) for no Bev versus Bev arms. Bilirubin > 3 mg/dL was seen in zero of 38 versus five of 35 patients (P = .02) and biliary stents were placed in zero versus four patients (P = .05) in no Bev versus Bev arms.The addition of Bev to adjuvant HAI plus systemic therapy after liver resection did not seem to increase RFS or survival but appeared to increase biliary toxicity. Four-year survival was 85% and 81% for no Bev and Bev arms, respectively.

SUBMITTER: Kemeny NE

PROVIDER: S-EPMC3646323 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer.

Kemeny Nancy E NE Jarnagin William R WR Capanu Marinela M Fong Yuman Y Gewirtz Alexandra N AN Dematteo Ronald P RP D'Angelica Michael I MI

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20101228 7

<h4>Purpose</h4>Add systemic bevacizumab (Bev) to adjuvant hepatic arterial infusion (HAI) plus systemic therapy after liver resection to increase recurrence-free survival (RFS).<h4>Patients and methods</h4>Patients were randomly assigned to HAI plus systemic therapy with or without Bev. If 1-year RFS of ≥ 80% was obtained in Bev arm, then the regimen would be studied further. HAI with fluorodeoxyuridine plus dexamethasone was given on days 1 to 14 of a 5-week cycle. Systemic therapy and Bev 5 m ...[more]

PMID: 21189384

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Project description:BackgroundDespite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy.MethodsPatients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis.ResultsOf 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001).ConclusionsAltered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.

Project description:BackgroundGallbladder cancer (GBC) is different from other biliary tract cancers in terms of molecular phenotype and microenvironment. Specific treatments for GBC need to be urgently explored. This study preliminarily investigated the clinical value of hepatic artery infusion chemotherapy (HAIC) combined with bevacizumab plus a programmed death receptor-1 (PD-1) inhibitor for treatment of GBC with hepatic oligometastasis.MethodsWe retrospectively collected data on GBC patients with hepatic oligometastasis, who received this combination therapy. The clinical data, conversion rate, treatment response, adverse events (AEs), and short-term survival were summarized. The responses of primary gallbladder lesions and hepatic metastasis, and their effect on prognosis, were investigated.ResultsA total of 27 patients were included in the analysis. No grade 4 AEs were observed. The overall objective response rate (ORR) was 55.6% and the disease control rate (DCR) was 85.2%. Median overall survival (OS) time was 15.0 months and the 1-year survival rate was 64.0%. Median progression-free survival (PFS) time was 7.0 months and the 1-year PFS rate was 16.2%. Six patients (22.2%) were successfully converted to resection. Compared with primary gallbladder lesions, it appeared more difficult for patients with hepatic metastasis to achieve remission (ORR: 40.7% vs. 77.8%; P=0.012), but its response appeared to be closely related to the prognosis [median OS: 16.0 months in the complete response (CR) or partial response (PR) group vs. 11.0 months in the stable disease (SD) or progressive disease (PD) group, P=0.070; median PFS: 12.0 months in the CR or PR group vs. 6.5 months in the SD or PD group, P<0.001]. Preoperative CA19-9 of >1,900 U/mL and >5 cm metastatic lesions were associated with an unsatisfactory response, whereas a significant decrease of 18F-fluorodeoxyglucose (18F-FDG) uptake may be a marker of tumor remission.ConclusionsThe combination of HAIC, a PD-1 inhibitor, and bevacizumab shows potential for advanced GBC with hepatic oligometastasis. The therapeutic response of hepatic metastasis had a greater influence on prognosis than that of primary gallbladder lesions.

Project description:BackgroundAntineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver.MethodsSixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity.FindingsOverall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm.InterpretationAntineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver.Trial registration informationClinicalTrials.gov UMIN000012099.

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Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer.

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Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer.

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