Sorafenib off-target effects predict outcomes in patients treated for hepatocellular carcinoma

Costanzo, Giovan Giuseppe Di; Stefano, G. de; Tortora, Raffaella; Farella, Nunzia; Addario, Luigi; Lampasi, F.; Lanza, A; Cordone, G; Imparato, Michele; Caporaso, Nicola

doi:10.2217/fon.14.291

Cited by 29 publications

(31 citation statements)

References 38 publications

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“…A number of studies have reported off-target effects of sorafenib as prognostic factors, including diarrhoea and skin toxicities [22–31]. Bettinger et al [29] al reported survival was twice as long in patients who developed diarrhoea on sorafenib compared to those who did not (7.1 months versus 14.1 months), findings that have been replicated by others [26, 32]. The current study is the largest to date reporting the association between treatment-related diarrhoea and survival, lending strength to these findings.…”

Section: Discussionmentioning

confidence: 96%

Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib

et al. 2017

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Background and AimsResponse to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy.Results442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p<0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115-1.290, p<0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108-1.322, p<0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373-0.763, p=0.001). The combination of RD-CLIP score (CLIP score multiplied by RDW) ≥ 70 and no treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734-0.882), positive predictive value of 86.4% and negative predictive value of 83.3%), compared with CLIP (AUC=0.642) or BCLC score alone (AUC=0.579). RD-CLIP score ≥ 35 and no treatment-related diarrhoea had an AUC of 0.787 for predicting 12-month survival.MethodsPatients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib.ConclusionThe novel prognostic index of CLIP score combined with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib.

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Section: Discussionmentioning

confidence: 96%

Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib

et al. 2017

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“…Although to date this is the first analysis showing a potential correlation between the onset of these forms of side effects and regorafenib efficacy, a similar correlation can be observed once again in HCC patients receiving sorafenib. In particular, Di Costanzo et al 24. recently published results of a cohort analysis comparing the outcome of patients who experienced these forms of toxicities while on treatment and those who experienced the same “side-effects” prior to treatment.…”

Section: Discussionmentioning

confidence: 99%

Off-target effects and clinical outcome in metastatic colorectal cancer patients receiving regorafenib: The TRIBUTE analysis

Prete

Prochilo

Puzzoni

et al. 2017

Sci Rep

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Regorafenib is an orally administered multikinase inhibitor indicated for the treatment of heavily pretreated metastatic colorectal cancer patients with good performance status, albeit less than 50% treated patients achieve disease stabilisation or better at the first radiological evaluation. In addition to that a particularly broad spectrum of toxicities (experienced as G3 or more NCI CTCAE graded by 50% of patients treated) have led to reconsider its widespread use in the majority of patients. We retrospectively collected data about the magnitude of off-target effects experienced during the first 8-weeks of regorafenib monotherapy and analysed their correlation with overall survival, progression free survival and disease control rate. Our findings suggest that skin rash (Exp (B): 0.52, p = 0.0133) or hypothyroidism (Exp (B): 0.11, p = 0.0349) were significantly correlated with improved overall survival at multivariate regression analysis. It was also demonstrated a statistically significant role of diarrhea as predictor of improved survival but its independent prognostic role was lost at multivariate analysis (Exp (B): 0.63, p = 0.162). This is the first analysis showing a potential correlation between the onset of these forms of side effects and regorafenib efficacy, however sample size limitations and the retrospective nature of our analysis prevent us from drawing definitive conclusions.

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“…When considering sorafenib, Fucile and colleagues, demonstrated no relationship between dose and plasma concentration of sorafenib in cirrhotic patients with HCC. 5 Interestingly, they also report no difference in the plasma concentration of patients on full dose vs. reduced dose due to toxicity. To complicate matters further, a number of groups have also reported a reduction in plasma sorafenib concentration over time, suggesting that dose should be increased with prolonged exposure.…”

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confidence: 99%

“…The cohorts used in these studies are generally homogenous with regard to liver disease aetiology and ethnicity which gives poor generalisability of the study results. [5][6][7] The advantage of Howell et al's research is that it is a prospective, multicentred study with a very limited patient exclusion criteria. The specialist centres involved in this study span various areas in Europe and Asia, where HCC is highly prevalent.…”

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confidence: 99%

“…To complicate matters further, a number of groups have also reported a reduction in plasma sorafenib concentration over time, suggesting that dose should be increased with prolonged exposure. 5,6 It is unclear how the severity of any toxicity changes over time. Having little evidence to support a relationship between adverse events and plasma drug levels, mechanisms driving the onset of these toxicities need to be delineated in order to try and ascertain response biomarkers for sorafenib.…”

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confidence: 99%

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Editorial: sorafenib toxicity, a biomarker of effect?

Clare

Miller

Dillon

2017

Aliment Pharmacol Ther

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Sorafenib off-target effects predict outcomes in patients treated for hepatocellular carcinoma

Abstract: In hepatocellular carcinoma patients, on-treatment variables are the best predictors of survival. Among these, sorafenib off-target effects may be the most useful indicators for prognostication in field practice.

Cited by 29 publications

References 38 publications

Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib

Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib

Off-target effects and clinical outcome in metastatic colorectal cancer patients receiving regorafenib: The TRIBUTE analysis

Editorial: sorafenib toxicity, a biomarker of effect?

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