scholarly journals Sorafenib-Induced Liver Failure: A Case Report and Review of the Literature

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Anneleen Van Hootegem ◽  
Chris Verslype ◽  
Werner Van Steenbergen
Keyword(s):  
Liver Failure ◽  
Lung Metastases ◽  
Hypersensitivity Syndrome ◽  
Phase Iii ◽  
Severe Liver ◽  
Drug Induced ◽  
Randomized Controlled ◽  
Phase Iii Trials ◽  
Severe Liver Dysfunction ◽  
Type Of Injury

In patients with hepatocellular carcinoma characterized by vascular invasion and/or extrahepatic disease, Sorafenib is considered treatment of choice. Although mild liver test abnormalities were reported in less than 1% of the patients in the two large randomized, controlled phase III trials, four cases of severe acute Sorafenib-induced hepatitis have been described. One of these four cases died from liver failure. In this paper, a patient with HCC with lung metastases developed high fever and a severe hepatitis that rapidly evolved into liver coma and death, two weeks after the initiation of Sorafenib. Biochemical parameters pointed to a hepatocellular type of injury. Clinical and biochemical presentations were compatible with a drug-induced hypersensitivity syndrome such as it has mainly been described for aromatic anticonvulsants, sulphonamides, and allopurinol. We hypothesize that an underlying cytochrome P450 dysfunction with the presence of reactive drug metabolites might lead to this potentially fatal Sorafenib-induced severe liver dysfunction.

Clinical Equipoise for Trials of Novel Biologic Therapies, Therapeutic Success Rates, and Predictors of Success: A Meta-Analysis

2017 ◽  
pp. 1-12
Author(s):  
Doah Cho ◽  
Felicia T. Roncolato ◽  
Johnathan Man ◽  
John Simes ◽  
Sarah J. Lord ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Predictors Of Success ◽  
Biologic Therapies ◽  
Therapeutic Success ◽  
Free Survival ◽  
Randomized Controlled ◽  
Phase Iii Trials

Purpose The demand for more rapid access to novel biologic therapies than randomized controlled trials can deliver is a topic of ongoing study and debate. We aimed to inform this debate by estimating therapeutic success from phase III trials comparing novel biologic therapies with standard of care and identifying predictors of success. Methods This was a meta-analysis of phase III trials evaluating novel biologic therapies in advanced breast, colorectal, lung, and prostate cancers. Therapeutic success was defined as statistically significant results for the primary end point favoring novel biologic therapies. Results Of 119 included phase III trials (76,726 patients), therapeutic success was 41%, with a statistically significant relative reduction in disease progression and death for novel biologic therapies over standard of care of 20% and 8%. Therapeutic success did not improve over time (pre-2010, 33%; 2010 to 2014, 44%; P = .2). Predictors of success were a biomarker-selected population (odds ratio, 4.74; 95% CI, 2.05 to 10.95) and progression-free survival end point compared with overall survival (odds ratio, 5.22; 95% CI, 2.41 to 11.39). Phase III trials with a biomarker-selected population showed a larger 28% progression-free survival benefit than phase III trials overall (hazard ratio, 0.72; 95% CI, 0.70 to 0.75) but similar 8% overall survival benefit (hazard ratio, 0.92; 95% CI, 0.90 to 0.94). Therapeutic success of phase III trials with and without a preceding phase II trial were 43% and 30%, respectively Conclusion Therapeutic success of novel biologic therapies in phase III trials, including therapies with a matching predictive biomarker, was modest and has not significantly improved over time. Equipoise remains and supports the ongoing ethical and scientific requirement for phase III randomized controlled trials to estimate treatment efficacy and assess the value of potential biomarkers.

Public Availability of Results of Trials Assessing Cancer Drugs in the United States

2013 ◽  
Vol 31 (24) ◽  
pp. 2998-3003 ◽  
Author(s):  
Thi-Anh-Hoa Nguyen ◽  
Agnes Dechartres ◽  
Soraya Belgherbi ◽  
Philippe Ravaud
Keyword(s):  
United States ◽  
The United States ◽  
Phase Iii ◽  
Cancer Drugs ◽  
Randomized Controlled ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Completion Date ◽  
Public Availability ◽  
Over Time

Purpose To evaluate to what extent results of completed trials of cancer drugs conducted in the United States are publicly available at ClinicalTrials.gov, as required by the Food and Drug Administration Amendments Act (FDAAA), or are published in journals. Methods We searched ClinicalTrials.gov for cancer trials governed by the FDAAA: phase II to IV trials assessing drugs in the United States with a primary completion date between December 26, 2007, and May 31, 2010. For each trial, we also searched PubMed to identify the publication of results. We assessed the cumulative percentages of posted or published results over time by using the Kaplan-Meier method. Results We identified 646 trials, including 209 randomized controlled trials (RCTs). At 12 months after completion of the trials, the cumulative percentages of trials with results posted at ClinicalTrials.gov, published in journals, and available either at ClinicalTrials.gov or in journals were 9% (95% CI, 7% to 11%), 12% (95% CI, 10% to 15%), and 20% (95% CI, 17% to 23%), respectively, and for RCTs, the percentages were 12% (95% CI, 8% to 16%), 5% (95% CI, 2% to 8%), and 17% (95% CI, 12% to 22%), respectively. At 36 months, these percentages were 31% (95% CI, 28% to 35%), 35% (95% CI, 31% to 39%), and 55% (95% CI, 51% to 59%), respectively, and for RCTs, they were 38% (95% CI, 31% to 45%), 32% (95% CI, 25% to 39%), and 56% (95% CI, 48% to 62%), respectively. Public availability of phase III trials was 15% (95% CI, 7% to 23%) at 12 months, 39% (95% CI, 27% to 49%) at 24 months, and 64% (95% CI, 50% to 73%) at 36 months. Conclusion Despite the FDAAA, results for nearly half the trials of cancer drugs in the United States were not publicly available 3 years after completion of the trials.

Irinotecan/5-FU/FA (I-FU) or 5-FU/FA (FU) first-line therapy in older and younger patients with metastatic colorectal cancer: Combined analysis of 2,691 patients in randomized controlled trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4071-4071 ◽  
Author(s):  
G. Folprecht ◽  
M. T. Seymour ◽  
L. Saltz ◽  
J. Y. Douillard ◽  
R. J. Stephens ◽  
...  
Keyword(s):  
Phase Iii ◽  
First Line ◽  
Younger Patients ◽  
Randomized Controlled ◽  
First Line Therapy ◽  
Line Therapy ◽  
Source Data ◽  
Phase Iii Trials ◽  
Receive Treatment ◽  
Ecog Ps

4071 Background: Irinotecan containing first line therapy has been shown to improve efficacy in first line therapy. Pooled analyses demonstrated that elderly patients benefit in a similar way as younger patients if 5-FU or 5-FU/oxaliplatin is administered as palliative or adjuvant treatment within clinical trials (Sargent, NEJM 2001, Folprecht, Ann Oncol 2004, Goldberg JCO 2006). Methods: We present an updated metaanalysis using source data of randomized trials (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986] and Seymour 2005 [FOCUS]) and compared the efficacy and toxicity in older (=70 years) and younger (<70 years) patients receiving first line 5- FU/FA with or without irinotecan. Randomized patients who did not receive treatment were excluded. Results: A total of 2,691 pts. was enrolled into the analysis ( table 1 ). There was no imbalance regarding risk factors (ECOG PS, WBC, No. of tumor sites, alkal. phosphatase, LDH) between elderly and younger patients. Older and younger patients had significantly improved response rates and PFS with I-FU compared to FU. Younger patients had significantly longer OS with I-FU, older patients a trend to longer OS with I-FU ( table 1 ). I- FU was associated with more grade >= 3 toxicity in the general population, but there were no significant differences regarding toxicity between older and younger patients ( table 1 ). Conclusion: Patients over 70 yrs who are selected for inclusion in phase III trials derive similar benefits from irinotecan-containing chemotherapy, and with similar risks of toxicity, compared with younger patients. [Table: see text] [Table: see text]

Evaluation of Early and Late Toxicities in Chemoradiation Trials

2007 ◽  
Vol 25 (26) ◽  
pp. 4096-4103 ◽  
Author(s):  
Søren M. Bentzen ◽  
Andrea Trotti
Keyword(s):  
Adverse Effects ◽  
Tissue Injury ◽  
Late Toxicity ◽  
Standard Of Care ◽  
Phase Iii ◽  
Serious Adverse Events ◽  
Randomized Controlled ◽  
Solid Malignancies ◽  
Phase Iii Trials ◽  
Low Incidence

Combined chemoradiotherapy is increasingly becoming a standard of care for the nonoperative management of a variety of solid malignancies. A string of randomized controlled phase III trials have shown statistically significant and clinically relevant improvements in outcome, ostensibly without any apparent increase in late toxicity. However, the reliability and the sensitivity of toxicity reporting in most trials are questionable. Audits and phase IV studies suggest that the chemoradiotherapy success comes at a price in terms of late toxicity. This review presents some of the challenges in recording, analyzing, and reporting toxicity data. Methods for summarizing toxicity are reviewed, and a new investigational metric, the TAME reporting system, is discussed. The need for special vigilance in the era of molecular-targeted agents is emphasized because of the possibility that unexpected serious adverse events with a low incidence may occur. Finally, we discuss how progress in molecular pathology and radiation biology may provide novel opportunities for stratifying patients according to risk of adverse effects, interventional targets for reducing or treating adverse effects, and surrogate markers of normal-tissue injury.

Prescribing preferences (PPrefs) of U.S.-based medical oncologists (MOs) for choice of therapy after failure of first-line FOLFOX plus bevacizumab (FFB) in patients with metastatic colorectal cancer (MCC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 533-533
Author(s):  
Johanna C. Bendell ◽  
Susan L. Britton ◽  
Maria Lankford ◽  
Arden Buettner ◽  
Mark R. Green ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Real Life ◽  
Phase Iii ◽  
Audience Response ◽  
Second Line ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Best Response ◽  
Phase Iii Trials

533 Background: Phase III trials have tested biologic (bio) agents (bevacizumab [bev], anti-EGFR antibodies, ziv aflibercept [ziv]) plus chemotherapy (CT) vs. CT alone after failure of first-line therapy in patients given CT + bev first line. Several have shown improvements in progression-free and overall survival (OS) with the CT + bio approach, but it is not clear how these therapies are being used in the “real life” setting. Methods: Since 3/2013 PPrefs for this setting among 276 MOs were studied using a validated, proprietary, live, case-based market research tool. A core scenario and variations based on KRAS status and first-line therapy outcome were tested (S1, S2, S3, S4). PPref data acquired using blinded audience response technology. All sources of research support were blinded. Core scenario: 49 yr old female with cecal mass, liver/lung metastases, confirmed wt KRAS for S1-3, given FFB first line. S1: FFB x 16 wks → excellent PR → 5FU bev X 16 wks → progressive disease [PD]; S2: FFB x 16 wks → excellent PR → bev alone x 16 wks → PD; S3: FFB → stable disease [SD] x 5 months as best response [BR] → PD; 4) Here changed to mutKRAS; FFB x 8 wks → PD as BR. Results: Findings shown below (Table). Conclusions: In scenarios with wt KRAS, first-line response to FFB, a majority plan bev again second line. If BR to FFB is SD in WT KRAS, anti-EGFR antibody-based therapy is used more often. In S 1-3, ziv is the PPref of 7 - 14% of MOs studied. With mutKRAS and PD as BR to FFB, use of an antiangiogenic + second-line CT is preferred by > 80%, nearly equally split between bev and ziv. Recent phase III trial data showing OS benefits are reflected in current MOs first failure PPrefs. [Table: see text]

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