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Table 1.  
Characteristics of Randomized Clinical Trials of Anticancer Drugs Examined for the Exclusion of Patients With Chronic Kidney Disease
Characteristics of Randomized Clinical Trials of Anticancer Drugs Examined for the Exclusion of Patients With Chronic Kidney Disease
Table 2.  
Thresholds Used for Exclusion of Patients With Kidney Disease in Randomized Clinical Trials of Anticancer Drugs (N = 264 Trials)a
Thresholds Used for Exclusion of Patients With Kidney Disease in Randomized Clinical Trials of Anticancer Drugs (N = 264 Trials)a
1.
Launay-Vacher  V, Oudard  S, Janus  N,  et al.  Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management.  Cancer. 2007;110(6):1376-1384. doi:10.1002/cncr.22904PubMedGoogle ScholarCrossref
2.
Iff  S, Craig  JC, Turner  R,  et al.  Reduced estimated GFR and cancer mortality.  Am J Kidney Dis. 2014;63(1):23-30. doi:10.1053/j.ajkd.2013.07.008PubMedGoogle ScholarCrossref
3.
Coca  SG, Krumholz  HM, Garg  AX, Parikh  CR.  Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease.  JAMA. 2006;296(11):1377-1384. doi:10.1001/jama.296.11.1377PubMedGoogle ScholarCrossref
4.
Navaneethan  SD, Schold  JD, Arrigain  S, Jolly  SE, Nally  JV  Jr.  Cause-specific deaths in non-dialysis-dependent CKD.  J Am Soc Nephrol. 2015;26(10):2512-2520. doi:10.1681/ASN.2014101034PubMedGoogle ScholarCrossref
5.
Torres da Costa E Silva  V, Costalonga  EC, Coelho  FO, Caires  RA, Burdmann  EA.  Assessment of kidney function in patients with cancer.  Adv Chronic Kidney Dis. 2018;25(1):49-56. doi:10.1053/j.ackd.2017.10.010PubMedGoogle ScholarCrossref
6.
Ryman  JT, Meibohm  B.  Pharmacokinetics of monoclonal antibodies.  CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576-588. doi:10.1002/psp4.12224PubMedGoogle ScholarCrossref
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Research Letter
June 19, 2018

Representation of Patients With Chronic Kidney Disease in Trials of Cancer Therapy

Author Affiliations
  • 1University Health Network, Toronto, Ontario, Canada
  • 2St Michael’s Hospital, Toronto, Ontario, Canada
  • 3Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 4London Health Sciences Centre, London, Ontario, Canada
JAMA. 2018;319(23):2437-2439. doi:10.1001/jama.2018.7260

Chronic kidney disease (CKD) is common in patients with cancer, with reported prevalence ranging from 12% to 53% at cancer diagnosis.1 Cancer patients with concomitant CKD have worse cancer outcomes than those with normal kidney function.2 Despite the prevalence of kidney dysfunction and its prognostic implications, there is limited evidence to guide cancer treatment in patients with CKD. One reason may be the exclusion of CKD patients from clinical trials (as has been documented in cardiovascular studies).3 We sought to quantify and characterize the exclusion of patients with CKD in randomized clinical trials of anticancer drugs.

Methods

We performed a systematic search of MEDLINE for randomized trials of drugs for the 5 most common solid cancers (bladder, breast, colorectal, lung, and prostate) in 6 high-profile general medicine and oncology journals (selected based on impact factor, and listed in Table 1) from January 2012 through December 2017. We excluded trials of surgery, radiation, and supportive care. Nonrandomized studies and pooled analyses were also excluded.

Two reviewers independently assessed published articles, protocols, and supplementary materials for each trial to determine whether patients with CKD were excluded. Corresponding authors were contacted in cases of ambiguity regarding exclusions. Multivariable logistic regression was used to assess for trial characteristics associated with exclusion of CKD. Analyses were performed using SAS (SAS Institute), version 9.4. Two-sided P values less than .05 were considered statistically significant.

Results

A total of 1599 citations were obtained from the MEDLINE search, of which 1198 were excluded based on title and abstract screening, yielding 401 articles for detailed review. Of these, 310 articles met eligibility criteria and were included in this study.

Eighty-five percent of trials excluded patients with CKD (Table 1). Trials of endocrine-based therapies (vs other interventions) were less likely to exclude CKD patients. None of the other measured trial characteristics were associated with CKD exclusion.

Serum creatinine threshold values were the most common exclusion criteria (62%), followed by creatinine clearance (CrCl; 44%) (Table 2). Few trials used estimated glomerular filtration rate (eGFR) thresholds for exclusion (5%). Multiple exclusion criteria pertaining to kidney function were reported in 90 trials (34%).

Among trials using CrCl or eGFR exclusion criteria, thresholds were usually above 45 mL/min, which reflects mild or mild to moderate CKD (in total, 39% of trials excluding CKD). Severe CKD thresholds (CrCl or eGFR <40 mL/min) were infrequently used as exclusion criteria (11%).

Discussion

Eighty-five percent of recent trials of therapies for the 5 most common malignancies (published in selected high–impact factor journals) excluded patients with CKD. This proportion exceeds that observed in cardiovascular trials published from 1985 through 2005 (56%).3 This finding is concerning because it was estimated that 32% of deaths among patients with CKD in 2005-2009 were attributable to malignancy.4 As a result of trial underrepresentation, patients with CKD may not be considered for cancer therapies that have potential to improve morbidity and mortality.

Most trials used serum creatinine or CrCl thresholds to exclude patients, despite data demonstrating that these are suboptimal measures of kidney function in cancer patients.5 Given the availability of more accurate and validated methods for estimating kidney function (eg, eGFR formulas), use of serum creatinine alone is inadequate.

The exclusion of patients based on kidney function is appropriate when CKD is severe and prognosis-limiting or when concerns exist regarding potential nephrotoxicity or adverse events due to bioaccumulation of renally cleared drugs. However, this review suggests that patients with CKD with only mild to moderate kidney dysfunction are often excluded, and frequently from trials of interventions (eg, biologics or immunotherapies) for which there may be no pharmacologic basis for renal exclusions.6

Limitations of this study include the restrictions to common cancers and to articles in high–impact factor journals, which may have led to exclusion of negative or smaller trials that included patients with CKD. Also, the number of potential patients with CKD that were excluded could not be determined, as none of the studies assessed reported these data.

The exclusion of patients with CKD should be based on appropriate measures of kidney function and justifiable clinical or pharmacokinetic rationale. Judicious broadening of eligibility criteria in cancer trials to include the growing population of patients with CKD may enable more patients to benefit from novel cancer therapies while balancing the potential risk of adverse events.

Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Article Information

Accepted for Publication: May 10, 2018.

Corresponding Author: Abhijat Kitchlu, MD, FRCPC, Clinician Scientist Training Program, Division of Nephrology, Toronto General Hospital, 200 Elizabeth St, 8 Eaton N, Toronto, ON M5G 2C4, Canada (abhijat.kitchlu@uhn.ca).

Author Contributions: Drs Kitchlu and Harel had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kitchlu, Shapiro, Wald, Harel.

Acquisition, analysis, or interpretation of data: Kitchlu, Shapiro, Amir, Garg, Kim, Harel.

Drafting of the manuscript: Kitchlu, Amir, Wald, Harel.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kitchlu.

Obtained funding: Wald.

Administrative, technical, or material support: Kitchlu, Wald.

Supervision: Kim, Wald, Harel.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Amir reported personal fees from Apobiologix. Dr Kim reported grants from Astellas Pharma Canada to his institution. No other disclosures were reported.

Additional Contributions: We thank Teruko Kishibe, MIS (St Michael’s Hospital), for assistance with the search strategy. Ms Kishibe did not receive compensation for her contribution.

References
1.
Launay-Vacher  V, Oudard  S, Janus  N,  et al.  Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management.  Cancer. 2007;110(6):1376-1384. doi:10.1002/cncr.22904PubMedGoogle ScholarCrossref
2.
Iff  S, Craig  JC, Turner  R,  et al.  Reduced estimated GFR and cancer mortality.  Am J Kidney Dis. 2014;63(1):23-30. doi:10.1053/j.ajkd.2013.07.008PubMedGoogle ScholarCrossref
3.
Coca  SG, Krumholz  HM, Garg  AX, Parikh  CR.  Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease.  JAMA. 2006;296(11):1377-1384. doi:10.1001/jama.296.11.1377PubMedGoogle ScholarCrossref
4.
Navaneethan  SD, Schold  JD, Arrigain  S, Jolly  SE, Nally  JV  Jr.  Cause-specific deaths in non-dialysis-dependent CKD.  J Am Soc Nephrol. 2015;26(10):2512-2520. doi:10.1681/ASN.2014101034PubMedGoogle ScholarCrossref
5.
Torres da Costa E Silva  V, Costalonga  EC, Coelho  FO, Caires  RA, Burdmann  EA.  Assessment of kidney function in patients with cancer.  Adv Chronic Kidney Dis. 2018;25(1):49-56. doi:10.1053/j.ackd.2017.10.010PubMedGoogle ScholarCrossref
6.
Ryman  JT, Meibohm  B.  Pharmacokinetics of monoclonal antibodies.  CPT Pharmacometrics Syst Pharmacol. 2017;6(9):576-588. doi:10.1002/psp4.12224PubMedGoogle ScholarCrossref
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