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Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma.

ABSTRACT: Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient's weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 days) by comparing the relationship between 2M-DBR, 2M-RDI (RDI at 60 days), and the therapeutic response. The therapeutic response to lenvatinib was evaluated in 45 patients who underwent computed tomography 8-12 weeks after treatment initiation. We also investigated the clinical factors associated with high 2M-DBR. The area under the receiver operating characteristic of 2M-DBR that predicts the response to lenvatinib was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR achieved significantly better objective responses and disease control rates than those with low 2M-DBR (p < 0.0001 and 0.0008). Patients with high 2M-DBR experienced significantly longer progression-free survival (PFS) than those with low 2M-DBR (p = 0.0001), while there was no significant correlation between 2M-RDI levels and PFS (p = 0.2198). Patients who achieved higher levels of 2M-DBR had a significantly better modified ALBI grade (p = 0.0437), better CONUT score (p = 0.0222), and higher BTR (p = 0.0281). Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS. In conclusion, 2M-DBR could be an important factor that reflects treatment intensity and useful for predicting the response to lenvatinib against HCC, instead of 2M-RDI.

SUBMITTER: Eso Y

PROVIDER: S-EPMC7016578 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma.

Eso Yuji Y Nakano Shigeharu S Mishima Masako M Arasawa Soichi S Iguchi Eriko E Nakamura Fumiyasu F Takeda Haruhiko H Takai Atsushi A Takahashi Ken K Taura Kojiro K Seno Hiroshi H

Cancers 20191222 1

Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient's weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 d ...[more]

PMID: 31877859

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Project description:BackgroundLenvatinib monotherapy and combination therapy with immune checkpoint inhibitors (ICI) were widely applied for unresectable hepatocellular carcinoma (uHCC). However, many patients failed to benefit from the treatments. A prognostic model was needed to predict the treatment outcomes and guide clinical decisions.Methods304 patients receiving lenvatinib monotherapy or lenvatinib plus ICI for uHCC were retrospectively included. The risk factors derived from the multivariate analysis were used to construct the predictive model. The C-index and area under the receiver-operating characteristic curve (AUC) were calculated to assess the predictive efficiency.ResultsMultivariate analysis revealed that protein induced by vitamin K absence or antagonist-II (PIVKA-II) (HR, 2.05; P=0.001) and metastasis (HR, 2.07; P<0.001) were independent risk factors of overall survival (OS) in the training cohort. Herein, we constructed a prognostic model called PIMET score and stratified patients into the PIMET-low group (without metastasis and PIVKA-II<600 mAU/mL), PIMET-int group (with metastasis or PIVKA-II>600 mAU/mL) and PIMET-high group (with metastasis and PIVKA-II>600 mAU/mL). The C-index of PIMET score for the survival prediction was 0.63 and 0.67 in the training and validation cohort, respectively. In the training cohort, the AUC of 12-, 18-, and 24-month OS was 0.661, 0.682, and 0.744, respectively. The prognostic performances of the model were subsequently validated. The AUC of 12-, 18-, and 24-month OS was 0.724, 0.726, and 0.762 in the validation cohort. Subgroup analyses showed consistent predictive value for patients receiving lenvatinib monotherapy and patients receiving lenvatinib plus ICI. The PIMET score could also distinguish patients with different treatment responses. Notably, the combination of lenvatinib and ICI conferred survival benefits to patients with PIMET-int or PIMET-high, instead of patients with PIMET-low.ConclusionThe PIMET score comprising metastasis and PIVKA-II could serve as a helpful prognostic model for uHCC receiving lenvatinib monotherapy or lenvatinib plus ICI. The PIMET score could guide the treatment decision and facilitate precision medicine for uHCC patients.

Project description:BackgroundImmune checkpoint inhibitor (ICI)-based combination therapy has opened a new avenue for the treatment of multiple malignancies including hepatocellular carcinoma (HCC). However, considering the unsatisfactory efficacy, biomarkers are urgently needed to identify the patients most likely to benefit from ICI-based combination therapy.MethodsA total of 194 patients undergoing ICI-based combination therapy for unresectable HCC were retrospectively enrolled and divided into a training cohort (n = 129) and a validation cohort (n = 65) randomly. A novel circulating immune index (CII) defined as the ratio of white blood cell count (×109/L) to lymphocyte proportion (%) was constructed and its prognostic value was determined and validated.ResultsPatients with CII ≤ 43.1 reported prolonged overall survival (OS) compared to those with CII > 43.1 (median OS: 24.7 vs 15.1 months; 6-, 12-, 18-month OS: 94.2%, 76.7%, 66.1% vs 86.4%, 68.2%, 22.8%, P = 0.019), and CII was identified as an independent prognostic factor for OS (hazard ratio, 2.24; 95% confidence interval, 1.17-4.31; P = 0.015). These results were subsequently verified in the validation cohort. Additionally, patients with low CII levels had improved best radiological tumor response (complete response, partial response, stable disease, progressive disease: 3%, 36%, 50%, 11% vs 0%, 27%, 46%, 27%; P = 0.037) and disease control rate (89% vs 73%; P = 0.031) in the pooled cohort and better pathologic response (pathologic complete response, major pathologic response, partial pathologic response, no pathologic response: 20%, 44%, 28%, 8% vs 0%, 0%, 40%, 60%; P = 0.005) in the neoadjuvant cohort. Detection of lymphocyte subsets revealed that an elevated proportion of CD4+ T cells was related to better OS, while the proportion of CD8+ T cells was not.ConclusionsWe constructed a novel circulating immune biomarker that was capable of predicting OS and therapeutic efficacy for HCC patients undergoing ICI and lenvatinib combination therapy.

Dataset Information

Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma.

Publications

Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma.

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