Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program–Sponsored Single-Agent Phase I Studies

Abstract

See accompanying editorial on page 103Alterations in renal clearance of anticancer drugs can affect the occurrence of toxicities related to drug exposure. The National Cancer Institute and the US Food and Drug Administration (FDA) use different criteria to classify renal dysfunction. We examined those discrepancies and their potential association with the incidence of toxicities in patients enrolled onto Cancer Therapy Evaluation Program-sponsored single-agent phase I studies over three decades (1979 to 2010). MethodsData to estimate creatinine clearance according to the Cockcroft-Gault and Jelliffe formulas were available from 10,236 patients, and data to estimate creatinine clearance according to the six-and four-variable Modification of Diet in Renal Disease formulas were available from a subset (n 5 4,084). Patients were classified according to National Cancer Institute and FDA criteria, and the rates of clinically relevant toxicities were evaluated within groups and compared among groups. ResultsCockcroft-Gault estimated renal function improved over time, which may be attributed to an increase in weight of patients in the same time frame. Approximately 36% of patients enrolled onto phase I trials had mild renal dysfunction by FDA criteria. Relative to normal function, mild renal dysfunction was associated with a statistically significant but small increase in grade 3 or 4 nonhematologic toxicity and any relevant toxicities. ConclusionPatients with mild renal dysfunction by FDA criteria have routinely been enrolled onto phase I studies of antineoplastics without clinically meaningful increase in the risk of toxicity. In future oncology renal dysfunction trials based on the FDA classification, the FDA mild group may only need to be activated when the moderate and normal groups differ substantially in tolerability or pharmacokinetics. J Clin Oncol 34:110-116. © 2015 by American Society of Clinical Oncology INTRODUCTIONPhase I studies of antineoplastics characterize toxicities and pharmacokinetic and pharmacodynamic properties, defining the maximumtolerated dose (MTD), dose-limiting toxicities, and recommended phase II doses. Patients with renal dysfunction are often excluded because impaired renal function might be associated with increased toxicity, requiring dose adjustments to maintain safety. 1 Typical phase I eligibility has included a serum creatinine concentration (S Cr ) # 1.5 mg/dL or an estimated creatinine clearance (CrCl) $ 60 mL/min. Pioneered by the Cancer and Leukemia Group B (CALGB) 2 and adopted by the National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG), these criteria were the starting point for defining mild, moderate, and severe renal dysfunction groups based on intervals of 20 mL/min (Fig 1). The NCI/CALGB classification differs from generic guidance published by the US Food and Drug Administration (FDA), which defines severe, moderate, and mild renal dysfunction differently using unequal group intervals. 3 Importantly, CrCl $ 60 mL/min or S Cr # 1.5 mg/dL is considered ...

How Adequate is the Adequate Kidney Function for Clinical Trial Enrollment of Novel Anticancer Drugs?

“…A retrospective analysis of the Gynecologic Oncology Group 182 trial concluded that a cutoff value of CrCl >60 mL/min would exclude 15% of patients from treatment 15 . On the other hand, The National Cancer Institute concludes that patients with mild kidney dysfunction can be enrolled without a significant increase in the risk of toxicity 16 . This creates a conflict between the current practices and what should be done and makes us question the current eligibility policies and seek more precise guidelines.…”

Estimation of Kidney Function in Oncology

“…Most patients with cancer and impaired kidney function have stage 2 or 3 (eGFR560-89 and 30-59 ml/min per 1.73 m 2 , respectively) kidney disease (approximately 40%-50% and 15%-20% of all patients with cancer, respectively) according to NKF-KDOQI classification (2,11,13). These two stages straddle many important drug dose, drug selection, and clinical trial enrollment thresholds (16)(17)(18).…”

“…Therefore, there is a proportion of patients with only mild kidney impairment according to FDA classification who are disqualified from potentially effective clinical trials due to their kidney function. However, a retrospective analysis of over 10,000 patients from 373 single-agent phase 1 clinical trials found that there was no clinically meaningful increase in grade 3 or 4 nonhematologic, grade 4 hematologic, or any clinically relevant toxicities in the approximately 36% of enrolled patients with mild kidney impairment compared with those with normal kidney function (18). Therefore, expanding inclusion of patients to the full FDA classification range of mild impairment (i.e., CrCl.50 ml/min) may increase eligibility of patients without any clinically meaningful difference in determination of the dose-limiting toxicity.…”

Palliative care and advance care planning for pancreas and other cancers

“…Early specialty palliative care for patients with advanced colorectal and pancreatic cancers is also feasible and effective in its application in larger health care networks, such as the United States Veterans Affairs Health System (48). In spite of its potential advantages, patients with pancreatic cancer still may feel overwhelmed to participate and maintain attendance at additional outpatient palliative care clinics, especially as they cope with their new diagnoses and treatment plans (49). Moreover, in patients with incurable non-colorectal gastrointestinal cancers, changes in quality of life and mood over time did not significantly differ between patients who were randomly assigned to early integrated palliative care versus those who received usual care (50).…”