Comparison of Child-Pugh (CP) criteria and NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic dysfunction (HD): Implications for chemotherapy dosing

Patel, H.; Egorin, Merrill J.; Remick, Scot C.; Mulkerin, Daniel; Takimoto, Chris H.; Doroshow, J. H.; Potter, Douglas M.; Ivy, S. Percy; Murgo, Anthony J.; Ramanathan, R. K.

doi:10.1200/jco.2004.22.14_suppl.6051

Cited by 37 publications

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“…In contrast, the National Cancer Institute Organ Dysfunction Working Group recommends a classification based on total bilirubin and AST. A recent comparison showed that the National Cancer Institute Organ Dysfunction Working Group index, using total bilirubin and AST, provided a simple and objective way of assessing hepatic dysfunction that could be applied in outpatient clinics and clinical trials for chemotherapy dose modification (44). Although the current trial also used total bilirubin and AST, the precise definitions of hepatic dysfunction categories are different in this trial compared with National Cancer Institute Organ Dysfunction Working Group criteria.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction

Schaaf

Hammond²,

Tipping

et al. 2006

Clinical Cancer Research

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Purpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/ alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 Â institutional upper limit of normal (IULN) and ALT/AST V5.0 Â IULN; Group 2 (n = 7): total bilirubin 3.1to 5.0 Â IULN and ALT/AST V5.0 Â IULN; Group 3 (n = 6): total bilirubin V1.5 Â IULN and ALT/AST 5.1 to 20.0 Â IULN; Group 4 (n = 10): total bilirubin 1.5 to 3.0 Â IULN and ALT/AST 5.1to 20.0 Â IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m 2 . After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups. Results: Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m 2 were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m 2 . Conclusions: Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m 2 for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.The broad-spectrum, cytotoxic drug irinotecan (CPT-11; Camptosar irinotecan hydrochloride injection) is a semisynthetic, water-soluble derivative of the plant product, camptothecin. Irinotecan is a prodrug that is metabolized by carboxylesterases to the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin), which seems to be primarily responsible for the antitumor effects of irinotecan (1). The clinical pharmacology and anticancer applications of irinotecan have been the subject of several recent reviews (2 -6).Based on the results of several phase 3 survival trials (7 -11), irinotecan administered i.v. has been approved for first-and

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Section: Discussionmentioning

confidence: 99%

Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction

Schaaf

Hammond²,

Tipping

et al. 2006

Clinical Cancer Research

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“…Importantly, as Minami and colleagues noted, this recommendation needs to be validated prospectively. The Child-Pugh (8) and NCI-ODWG (9) grouping systems are established classification criteria for grading the severity of liver dysfunction. Both grouping systems rely on liver function markers to risk-stratify patients.…”

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confidence: 99%

Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study

et al. 2016

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Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We carried out the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1, normal; Category 2, mild -alkaline phosphatase, aspartate aminotransferase, and ⁄ or alanine aminotransferase ≤53 upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate -any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5-103 ULN, and ⁄ or total bilirubin ≤1-1.53 ULN. Category 1, 2 and 3 patients received starting dosages of 40, 30, and 20 mg ⁄ m 2 docetaxel, respectively. Pharmacokinetics were evaluated on day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was carried out weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P < 0.001). Median clearance was 22.8, 16.4, and 11.3 L ⁄ h ⁄ m 2 in Categories 1, 2, and 3, respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (area under the concentration-time curve) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median area under the concentration-time curve was 1.74, 1.83, and 1.77 mgÁh ⁄ L in Categories 1, 2, and 3, respectively. The most common Grade 3 ⁄ 4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group grouping systems suggests that the proposed classification system appears to more effectively discriminate patients by docetaxel clearance and dose requirements. (ClinicalTrials.gov registration no. NCT00703378).H epatic dysfunction is a rare comorbidity affecting approximately 0.2% of cancer patients, (1) making it particularly challenging to accrue patients with hepatic dysfunction in oncology trials that assess its effects on the pharmacokinetics and safety profile of chemotherapeutic agents. The paucity of guidance on the treatment of this patient subpopulation can be a real practice issue in clinical oncology; many drugs that form the backbone of chemotherapy have narrow therapeutic windows and are often dosed close to maximally tolerable levels. Unacceptable toxicities can quickly set in if the implications of a reduced hepatic metabolic capacity are not properly regarded, as hepatic drug biotransformation is the predominant route of elimination for many cytotoxic agents.(2) We therefore propose that it may be helpful to risk-stratify cancer patients before starting them on a personalized d...

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“…The Child-Pugh system has commonly been employed to classify patients with hepatic impairment but more recently the NCI scale has been adopted since it provides an objective way of assessing hepatic dysfunction and has more discriminatory power to segregate patients accurately [33,34] .…”

Section: Discussionmentioning

confidence: 99%

A Review of Regulatory Guidance for Conducting Hepatic Impairment Studies: A Case Study in Oncology

Lin¹,

D’Cunha²

2018

JOCR

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Running Title: Review of regulatory guidance for hepatic impairment studies ABSTRACTThe liver is a vital organ that plays a central role in the metabolism and elimination of drug molecules. Impairment of this vital organ can lead to increased accumulation of parent drug or active metabolites, affecting systemic drug disposition, clinical efficacy, safety and tolerability. Hepatic disease in cancer patients is generally associated with the metastatic spread of the primary tumor to or near the liver, or by toxicities associated with treatment using chemotherapeutic agents. Over the last decade, the understanding of cancer has changed the field of drug development and has resulted in novel, oral targeted therapies that interfere with dysregulated pathways in cancer. Many of these orally administered agents are dependent on the liver for drug metabolism and so understanding hepatic impairment in cancer is imperative to achieve appropriate dose adjustments and to avoid toxicity. This mini-review will focus on how published guidance from the US Food & Drug Administration (FDA) and European Medicines Agency (EMEA) on hepatic impairment studies can be tailored to guide study design and subsequent dosage modification in cancer patients with varying degrees of hepatic dysfunction.

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Comparison of Child-Pugh (CP) criteria and NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic dysfunction (HD): Implications for chemotherapy dosing

Cited by 37 publications

References 0 publications

Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction

Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction

Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study

A Review of Regulatory Guidance for Conducting Hepatic Impairment Studies: A Case Study in Oncology

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