CLINICAL CANCER RESEARCH | PRECISION MEDICINE AND IMAGING

CamGFR v2: A New Model for Estimating the Glomerular

Filtration Rate from Standardized or Non-standardized
Creatinine in Patients with Cancer
Edward H. Williams1, Thomas R. Flint2, Claire M. Connell1,3, Daniel Giglio4, Hassal Lee5, Taehoon Ha6,
Eva Gablenz6, Nicholas J. Bird2, James M.J. Weaver7,8, Harry Potts5, Cameron T. Whitley5,
Michael A. Bookman9, Andy G. Lynch1,10,11, Hannah V. Meyer6, Simon Tavare
1,12, and Tobias Janowitz6,13

ABSTRACT
◥
Purpose: Management of patients with cancer, specifically Results: A total of 3,083 IDMS- and 4,612 non-IDMS–
carboplatin dosing, requires accurate knowledge of glomerular standardized creatinine measurements were obtained from 7,240
filtration rate (GFR). Direct measurement of GFR is resource

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patients. IDMS-standardized creatinine values were lower than
limited. Available models for estimated GFR (eGFR) are non-IDMS–standardized values in within-center comparisons
optimized for patients without cancer and either isotope dilution (13.8% lower in Cambridge; P < 0.0001 and 19.3% lower in
mass spectrometry (IDMS)- or non-IDMS–standardized Manchester; P < 0.0001), and more consistent between centers.
creatinine measurements. We present an eGFR model for CamGFR v2 was the most accurate [root-mean-squared error for
patients with cancer compatible with both creatinine measure- IDMS, 14.97 mL/minute (95% confidence interval, 13.84–16.13) and
ment methods. non-IDMS, 15.74 mL/minute (14.86–16.63)], most clinically robust
Experimental Design: GFR measurements, biometrics, and [proportion with >20% error of calculated carboplatin dose for
IDMS- or non-IDMS–standardized creatinine values were col- IDMS, 0.12 (0.09–0.14) and non-IDMS, 0.17 (0.15–0.2)], and least
lected for adult patients from three cancer centers. Using statistical biased [median residual for IDMS, 0.73 mL/minute (
0.68 to 2.2)
modeling, an IDMS and non-IDMS creatinine-compatible and non-IDMS,
0.43 mL/minute (
1.48 to 0.91)] eGFR model,
eGFR model (CamGFR v2) was developed. Its performance was particularly when eGFR was larger than 60 ml/minute.
compared with that of the existing models Chronic Kidney Disease Conclusions: CamGFR v2 can utilize IDMS- and non-IDMS–
Epidemiology Collaboration (CKD-EPI), Modification of Diet standardized creatinine measurements and outperforms previous
in Renal Disease (MDRD), Full Age Spectrum (FAS), Lund– models. CamGFR v2 should be examined prospectively as a
Malm€o revised, and CamGFR v1, using statistics for bias, preci- practice-changing standard of care for eGFR-based carboplatin
sion, accuracy, and clinical robustness. dosing.

Introduction
The filtration function of the kidney is quantified as the glomerular
filtration rate (GFR). Knowledge of GFR informs clinical management
of many patients with cancer. For example, the dose of carboplatin, a
1
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, well-established treatment for ovarian, breast, lung, and germ cell
England, United Kingdom. 2Cambridge University Hospitals NHS Foundation cancers, is calculated from GFR using the Calvert equation (1). GFR
Trust, Cambridge, England, United Kingdom. 3University of Cambridge, Cam- can be measured directly (mGFR) using the clearance of chemical
bridge, England, United Kingdom. 4Department of Oncology, Sahlgrenska
tracers, for example, chromium-51 EDTA (51Cr-EDTA; ref. 2). This
Academy at the University of Gothenburg, Gothenburg, Sweden. 5University
of Cambridge School of Clinical Medicine, Cambridge, England, United Kingdom.
approach is accurate and precise, but costly and not widely available. In
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. 7The Christie practice, GFR is therefore estimated (eGFR) by modeling of readily
NHS Foundation Trust, Manchester, England, United Kingdom. 8University of available clinical and biochemical data.
Manchester, Manchester, England, United Kingdom. 9Gynecologic Oncology Most eGFR models are based on the serum concentrations
Therapeutics, Kaiser Permanente, San Francisco, California. 10School of of creatinine, a metabolite of creatine, because it has robust
Medicine, University of St Andrews, St Andrews, Scotland, United Kingdom.
11
steady-state concentrations and is freely filtered in the glomerulus,
School of Mathematics and Statistics, University of St Andrews, St Andrews,
Scotland, United Kingdom. 12Columbia University, New York, New York.
with minimal active secretion (3). However, because there are
13
Northwell Health, New York, New York. several methods to measure creatinine, results can vary significantly
between centers for technical reasons (4). To reduce these differ-
Note: Supplementary data for this article are available at Clinical Cancer
Research Online (http://clincancerres.aacrjournals.org/). ences and thereby to harmonize clinical management decisions
based on eGFR, isotope dilution mass spectrometry (IDMS)-stan-
Corresponding Author: Tobias Janowitz, Cold Spring Harbor Laboratory, 1
dardized creatinine assays have been developed and are now widely,
Bungtown Road, Cold Spring Harbor, NY 11724. Phone: 516-367-8422; E-mail:
[email protected] but not universally, used (5, 6). Another source of creatinine
variability is due to human physiology: underlying disease
Clin Cancer Res 2021;27:1381–90
processes, relative muscle mass, and/or ethnicity influence the
doi: 10.1158/1078-0432.CCR-20-3201 relationship between the serum creatinine concentration and
2020 American Association for Cancer Research. GFR in different patient populations (7, 8).

AACRJournals.org | 1381
 Williams et al.

many clinical scenarios, for example, prior to cisplatin administration

Translational Relevance (21). However, the model was developed and validated using only
An accurate and broadly applicable approach to determine the non-IDMS creatinine data, limiting the generalizability of findings
estimated glomerular filtration rate (eGFR) is an area of clinical across centers.
need, because eGFR informs the safe and effective prescription of In this article, we address this limitation. We quantify the differ-
chemotherapies. This is especially true for carboplatin therapy. To ences between non-IDMS and IDMS creatinine measurements using
date, models for eGFR were either developed using data from data from three cancer centers. Next, we expand our initial model
patients with chronic kidney disease, or were restricted to either (CamGFR v1) to allow for GFR estimation based on either IDMS- or
isotope dilution mass spectrometry (IDMS)- or non-IDMS– non-IDMS–standardized creatinine data (CamGFR v2). The accuracy,
standardized creatinine measurements. When applied to patients bias, and clinical robustness of CamGFR v2 are then compared with
with cancer, these variables introduce significant biases and inac- those of other published IDMS creatinine-based models, both in
curacies of eGFR that impact the quality of their care. Here, we patients with cancer and a small subset of patients who do not have
use gold-standard GFR measurements from 7,240 patients from cancer. We show that CamGFR v2 estimates GFR with the highest
three centers to develop and validate a broadly applicable linear accuracy and least bias for both IDMS- and non-IDMS–standardized
model, CamGFR v2, for eGFR in patients with cancer. This creatinine values, across all measured patient demographics.
new model outperforms all other tested models, irrespective

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of patient demographics or creatinine measurement methodology.
It also results in more clinically robust carboplatin dose calcula- Materials and Methods
tions. CamGFR v2 can now be utilized through our free online Data were collected from three cancer centers: Cambridge
application (https://sites.google.com/site/janowitzwilliamsgfr/), but University Hospitals NHS Foundation Trust (Cambridge, England,
requires independent validation to confirm it as a practice-changing United Kingdom), University Hospital of South Manchester NHS
standard of care. Foundation Trust (Manchester, England, United Kingdom), and
Sahlgrenska University Hospital (Gothenburg, Sweden). The study
was conducted at each institution according to regulatory and
ethical requirements.
In the context of cancer medicine, these considerations are highly We included patients aged 18 years or older whose GFR was
relevant. Most eGFR models have been developed using data from measured using tracer clearance in up to three plasma samples taken
patients without cancer, but with known kidney disease, and are valid over time (typically at timepoints 1, 2, and 3 hours) after intravenous
exclusively for IDMS or non-IDMS creatinine data. These features injection of 2 megabecquerels of 51Cr-EDTA or iohexol (2). Serum
limit the respective models' general utility in the management of creatinine was determined by the enzymatic or Jaffe method within
patients with cancer (9), most of whom do not have kidney disease. 30 days of the GFR measurement. If multiple measurements within
They also introduce clinically significant inaccuracies, particularly 30 days were available, the closest in relation to mGFR determination
when they are used to dose carboplatin (10–13). While the Calvert was used. Patients were excluded if their serum creatinine was below
equation has been prospectively validated as a predictor of carboplatin the limit of detection (0.20 mg/dL) or above 4.5 mg/dL (three times the
exposure from measured GFR (1, 14), a pervasive clinical practice is to upper limit of normal; ref. 21) or if the recorded height was below
input an eGFR value that has been determined using the Cockcroft– 130 cm. Creatinine data are reported in mg/dL, and these values can be
Gault equation for creatinine clearance (11, 15). The Cockcroft–Gault converted to mmol/L via the following formula: creatinine (mg/dL) 
equation was derived from data from 249 male patients at a single 88.4 ¼ creatinine (mmol/L). Body surface area (BSA) was calculated
center using non-IDMS–standardized creatinine values (16) and was using the DuBois-DuBois equation (22). Repeat GFR measurements
never revalidated with IDMS-standardized creatinine values, or for in a given patient were included if the time between the measure-
patients with cancer. Accordingly, this method systematically over- ments exceeded 1 year. Center-specific methods and details of
estimates GFR (3, 11, 13, 17) and is imprecise to the extent that it creatinine measurement methodologies over time are provided in
generates under- or overdosing of carboplatin of more than 20% in the Supplementary Materials and Methods.
more than one third of patients in study cohorts (10–12), risking
reduced response rates (18–20) or myelotoxicity (19), respectively. In Data analysis and modeling
summary, clinicians must be mindful that models for eGFR can be Creatinine values obtained using methods with calibration traceable
biased toward the characteristics of the patient population, as well as to an IDMS reference measurement procedure (6), hereafter termed
the creatinine measurement methods upon which they are built (9). “IDMS-standardized” creatinine values, were compared with non-
Previously, we addressed the need for an accurate and unbiased GFR IDMS–standardized creatinine values within and between centers. To
model for patients with cancer by developing a linear model of GFR on develop CamGFR v2, we randomly split the data into a model
a square root scale (CamGFR v1; ref. 21). Internal, external, and development dataset and a validation dataset at a ratio of 4:1. Using
multicenter validation studies have each shown that CamGFR v1 the development dataset, the new version of CamGFR was fitted with
estimates GFR in patients with cancer more accurately than other an additional interaction between the creatinine variables and an
published models, including Cockcroft–Gault, as well as the more indicator variable specifying the creatinine measurement type (IDMS
recently developed Chronic Kidney Disease Epidemiology Collabo- or non-IDMS). Other candidate models were explored as detailed in
ration (CKD-EPI) model and Modification of Diet in Renal Disease the Supplementary Materials and Methods.
(MDRD) study equation (10, 21). CamGFR v1 was distinct from The performances of models were compared using the non-BSA
previous models in that it provided accurate prediction intervals for adjusted units (mL/minute), as these are the units of the GFR term in
eGFR to help clinicians gauge the uncertainty of each GFR estimate. By the Calvert equation for calculating carboplatin dosage (1). As the
extension, clinicians could use the model to obtain the likelihood of the other models generate GFR estimates in ml/minute/1.73 m2, results
true GFR being above or below a critical value, as it is important in for these models were multiplied by BSA (as calculated by the

1382 Clin Cancer Res; 27(5) March 1, 2021 CLINICAL CANCER RESEARCH
 CamGFR v2 Estimates GFR in Patients with Cancer

Figure 1.
Schematic representation of data
acquisition, filtering, and study work-
flow. The partitioning into develop-
ment and validation datasets was
performed randomly. n, number
of GFR measurements (samples);
p, number of patients; nIDMS, number
of samples for which serum creati-
nine was measured with an IDMS-
standardized method; nEnzymatic,
number of samples for which serum
creatinine was measured with an
enzymatic method. The 7,695 sam-
ples in the “combined data filtered”
box include 4,983 from Cambridge,
2,056 from Manchester, and 656
from Gothenburg. The filter of
repeat measurements was the final

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filtering step prior to creation of the
“combined data filtered” dataset.

DuBois-DuBois equation; ref. 22) and divided by 1.73. In the case of the (AUC5) was calculated for all eGFR values generated using the Calvert
MDRD study equation, the IDMS- (23) and non-IDMS–adjusted (24) equation (1): dose (mg) ¼ AUC (mg/mL/minute)  [GFR (ml/
versions were used for the respective data subsets. The median residual minute) þ 25]. For all models, we determined the proportion of
(mGFR
eGFR) was used to assess bias, and the residual interquartile patients who would have received a dose with a percentage error
range (IQR) was used to assess precision. Accuracy is a combination of greater than 20% (P20) relative to what the dose would be if the
these two metrics and was estimated using the root-mean-squared measured GFR, rather than eGFR, was used for the calculation.
error (RMSE). Finally, we examined the clinical robustness of the A 95% confidence interval (CI) was calculated for each performance
estimation. A carboplatin dose for an AUC of 5 mg/mL/minute statistic using a bootstrap resampling procedure. Specifically, 2,000

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 Williams et al.

Table 1. Patient characteristics by center and creatinine assay The core patient demographics, by center and creatinine assay
type. methodology, are presented in Table 1. Further demographic infor-
mation, including patients’ ethnicities and cancer diagnoses, is pre-
IDMS Non-IDMS sented in Supplementary Tables S1–S3. Supplementary Table S1
Median IQR Median IQR P value stratifies IDMS creatinine measurements further according to whether
Cambridge (n ¼ 4,983; p ¼ 4,557) they were performed using Jaffe or enzymatic methods. Unless oth-
Age (years) 58.9 21.5 60.6 20.1 0.00199 erwise stated, results from these two methods are grouped together for
BSA (m2) 1.84 0.331 1.84 0.325 0.287 all analyses of IDMS creatinine values. The numbers of patients with
Creatinine (mg/dL) 0.781 0.283 0.905 0.305 <0.0001 repeat GFR measurements are presented in Supplementary Table S4.
GFR (mL/minute) 82 37 82 40 0.332
Height (cm) 168 14.5 168 15 0.63 Comparisons of IDMS- and non-IDMS–standardized creatinine
Weight (kg) 74.5 23.2 73.6 22.9 0.0661 values
Manchester (n ¼ 2,056; p ¼ 2,056)
We first compared IDMS- and non-IDMS–standardized creatinine
Age (years) 63.1 17.1 65.2 18.5 0.0483
BSA (m2) 1.78 0.331 1.76 0.33 0.196
values within centers. This comparison was possible because Cam-
Creatinine (mg/dL) 0.758 0.311 0.939 0.249 <0.0001 bridge and Manchester changed from non-IDMS–standardized to
GFR (mL/minute) 79 39.5 74 38 0.0362 IDMS-standardized creatinine measurements during the sampling

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Height (cm) 165 13 164 14 0.489 period of our study. These changes were associated with abrupt drops
Weight (kg) 71.6 24.6 69.7 24 0.139 in median creatinine levels from 0.905 to 0.781 (13.8% decrease; P <
Gothenburg (n ¼ 656; p ¼ 627) 0.0001) and from 0.939 to 0.758 (19.3% decrease; P < 0.0001), in
Age (years) 61 19 Cambridge and Manchester, respectively (Fig. 2). In contrast to the
BSA (m2) 1.83 0.298 differences in creatinine, there were modest differences in age in both
Creatinine (mg/dL) 0.792 0.271
centers, and mGFR in Manchester, but not in weight, height, or BSA
GFR (mL/minute) 84.8 35
(Table 1).
Height (cm) 170 15
Weight (kg) 70 20 Next, we compared IDMS- and non-IDMS–standardized creatinine
values between the centers. There was a significant difference in the
Note: “n” corresponds to sample number from each center, and “p” corresponds non-IDMS–standardized creatinine values between Cambridge and
to patient number from each center. P values of IDMS versus non-IDMS Manchester (0.905 vs. 0.939; 3.8% increase; P ¼ 0.0005), but not in
comparisons were calculated using the Mann–Whitney Wilcoxon test. their respective IDMS-standardized values (P ¼ 0.99). Moreover, no
significant differences in the IDMS-standardized creatinine values
resamples with replacement (where the sample size was the same as the between Cambridge and Gothenburg (P ¼ 0.85) or between Manche-
number of data points) were taken from the data. The metric was then ster and Gothenburg (P ¼ 0.92) were found (Fig. 2).
calculated for each of these 2,000 samples and using the normal Whereas the non-IDMS creatinine data were all acquired using Jaffe
approximation, a CI was constructed (25). To test whether the methods, the IDMS creatinine data were acquired using either Jaffe or
predictive accuracy of CamGFR v2 differed significantly from each enzymatic methods (see “center-specific methods” in the Supplemen-
of the previous models, a permutation test with 10,000 repetitions was tary Materials and Methods for details). No differences were found
used (26). These tests acknowledged the paired nature of the compar- between IDMS creatinine values obtained using Jaffe or enzymatic
isons, and evaluated the null hypothesis that the distributions of methods (Supplementary Fig. S1; P ¼ 0.15). Equally, no differences
squared residuals were equal (26). were observed for IDMS creatinine when the Jaffe or enzymatic
The code for all analyses of this article is available from the following methods were compared between centers (P ¼ 0.58 and 0.32, respec-
link: https://github.com/EdwardHWilliams/CamGFRv2. tively; Supplementary Fig. S1). As expected, significant differences
were found when IDMS creatinine values obtained using either Jaffe or
enzymatic methods were compared with non-IDMS creatinine values
Results obtained using Jaffe methods (0.769 for IDMS Jaffe vs. 0.916 for non-
Patient characteristics IDMS Jaffe; P < 0.0001 and 0.791 for IDMS enzymatic vs. 0.916 for
Data from 7,240 patients were collated and contained 7,695 GFR non-IDMS Jaffe; P < 0.0001; Supplementary Fig. S1).
measurements following data extraction and filtering (Fig. 1). These
GFR measurements included 4,983 (64.8%) from Cambridge, 2,056 Developing CamGFR v2 to model GFR based on non-IDMS– and
(26.7%) from Manchester, and 656 (8.5%) from Gothenburg. The IDMS-standardized creatinine
median mGFR value for the dataset (þ/
IQR) was 80 ml/minute For non-IDMS–standardized creatinine-based modeling, CamGFR
(þ/
39), and the medians of age, weight, height, and BSA were v1 is the most accurate and least biased GFR predictor in patients with
61.2 years, 72.6 kg, 167 cm, and 1.82 m2, respectively (Table 1). The cancer, as determined in a validation study with 3,786 patients from
numbers (and %) of samples from patients with solid cancers, patients seven centers (10). The inconsistency of creatinine measurement
with hematologic cancers, and patients without cancer were 6,647 between centers (Fig. 2B–D; ref. 4) and the systematic difference to
(86.4%), 786 (10.2%), and 262 (3.4%). IDMS-standardized assays were the current IDMS standard (Fig. 2C and D; ref. 17) may explain why
coupled with mGFR in 3,083 (40.1%) measurements, and non-IDMS CamGFR v1’s performance has varied when other groups have applied
assays were coupled with mGFR in 4,612 (59.9%) measurements. In it to smaller cohorts (12, 27, 28).
the cases of Cambridge and Manchester, where more detailed timing We hence sought to improve the overall accuracy of our model by
information was available, 90.6% of all creatinine measurements were rederiving it to incorporate creatinine assay factors. To this end, the
obtained within 10 days of the corresponding GFR measurement. All dataset of 7,695 samples from 7,240 patients was divided randomly in a
other creatinine measurements included were obtained within 30 days 4:1 ratio for model development (n ¼ 6,156) and validation (n ¼
of the corresponding GFR measurement. 1,539). The development and validation datasets exhibited no

1384 Clin Cancer Res; 27(5) March 1, 2021 CLINICAL CANCER RESEARCH
 CamGFR v2 Estimates GFR in Patients with Cancer

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Figure 2.
Comparison of creatinine measurement methods in patients with cancer. Serum creatinine (SCr) is shown on a logarithmic scale. Violin plots for IDMS (A) and non-
IDMS (B) creatinine measurements by center. The values above brackets across the violins correspond to the t test P values for the respective comparisons. The
numbers in the violin plots correspond to the respective number of samples. The horizontal lines correspond to the median serum creatinine in that group. Timeline of
serum creatinine measurements from Cambridge (C) and Manchester (D). The serum creatinine is log-transformed and the vertical line corresponds to the date when
the creatinine measurement methodology changed from non-IDMS standardized to IDMS standardized. The density plots show the log (serum creatinine)
distributions color coded by methodology (right). The P values were computed by t test. Smoothed lines were calculated using a generalized additive model with a
cubic spline basis. The gap in serum creatinine data around the start of 2018 in C was due to changes in the hospital database at that time.

significant differences in demographic parameters (Supplementary This survey of the possible models for GFR included other metho-
Table S5). We first refitted CamGFR v1 to the development dataset dologic approaches, namely stepwise regression or segmental regres-
including the additional variable of “creatinine type” (1 or 0 depending sion. However, performance metrics of these models were comparable
on the assay used), along with its interaction with the cubic log with those of CamGFR v2, and none of the other models had
(creatinine) terms. These features provided consistency with the significantly superior accuracy to the CamGFR v2 model across both
original model, while permitting independent adjustment of the IDMS and non-IDMS creatinine as assessed using permutation tests
coefficients for the cubic log(creatinine) terms in the IDMS- (ref. 26; Supplementary Materials and Methods; Supplementary Figs.
standardized data subset. The functional form of this model, hereby S2–S4; Supplementary Tables S7 and S8). To maintain consistency
termed “CamGFR v2,” is Equation A, and its non-IDMS–related with previous external validation work (10, 21), the CamGFR v2 model
coefficients did not differ significantly from their original counterparts was selected for further analysis.
in CamGFR v1 (ref. 21; Supplementary Table S6). As with the original CamGFR v1 (21), CamGFR v2 trained on the
pffiffiffiffiffiffiffiffiffi development set satisfied key assumptions of a linear model (Supple-
GFR ¼ b0 þ b1 Age þ b2 BSA þ b3 SexM þ b4 ScrIDMS
mentary Fig. S5), and thus permitted the generation of accurate
þb5 logðScrÞScrIDMS þb6 logðScrÞ2 ScrIDMS þb7 logðScrÞ3 ScrIDMS prediction intervals for eGFR.
þb8 logðScrÞScrnon-IDMS þ b9 logðScrÞ2 Scrnon-IDMS
þb10 logðScrÞ3 Scrnon-IDMS þ b11 AgeBSA þ b12 AgeSexM þ  Performance of CamGFR v2 in the non-IDMS and IDMS
creatinine validation datasets
ðAÞ
We next used the non-IDMS and IDMS validation datasets to
b ¼ coefficients fitted by least-squares regression (see Supplementary compare the performance of the CamGFR v2 model with CamGFR
Table S5); Age ¼ age (years); BSA ¼ BSA (m2); SexM ¼ 1 for male, 0 for v1 and previously published creatinine-based models, namely the
female; Scr ¼ serum creatinine (mg/dL); ScrIDMS ¼ 1 if IDMS, 0 if non- CKD-EPI (29), Lund–Malm€ o revised (30), and Full Age Spectrum
IDMS; and Scrnon-IDMS ¼ 0 if IDMS, 1 if non-IDMS. The error term “” (FAS; ref. 31) models, as well as the MDRD study equation (23, 24).
is an independent, mean zero normally distributed random variable All of these models, with the exception of CamGFR v1, were
with a constant variance. developed using creatinine data calibrated to IDMS-standardized
measurement methodologies. In the case of MDRD study equation,
In addition to deriving new coefficients for CamGFR v2, alternate the non-IDMS–adjusted version (24) was used for non-IDMS
models with different predictors to CamGFR v2 were also explored. input data.

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 Williams et al.

95% CI, 14.68–17.17) and only a slight bias toward overestimating

GFR (median residual,
2.33; 95% CI,
3.61 to
1.02; Fig. 3). As
expected, the CamGFR v1, which was developed on the basis of non-
IDMS creatinine data, was comparatively less accurate and biased
toward overestimating GFR. However, despite being developed on
IDMS creatinine data, the CKD-EPI model and the MDRD study
equation were also biased toward overestimating GFR (median
residual,
11.30; 95% CI,
12.68 to
9.90 and
9.18; 95% CI,

10.61 to
7.60, respectively; Fig. 3; Supplementary Table S9).
Subgroup analyses in the validation cohort, stratified by age, sex,
BSA, cancer diagnosis (i.e., solid, hematologic, or no cancer), and
eGFR, were performed. CamGFR v2 outperformed the other models
across all subgroups, including in the small subset of patients without
cancer, in both the IDMS- and non-IDMS datasets (Fig. 4; Supple-
mentary Figs. S6–S10; Supplementary Tables S10–S14). We also
evaluated the performance of CamGFR v2 in the validation set after

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excluding all samples from patients that had repeat measurements in
the development set. The numbers of samples excluded for this analysis
amounted to 74 (8.03%) of the non-IDMS samples and 72 (11.7%) of
the IDMS samples. With these samples excluded, CamGFR v2 still
outperformed all other tested models (Supplementary Table S15).
Finally, direct comparisons of predictive accuracy were performed
between CamGFR v2 and each of the other tested models using
permutation tests (26). CamGFR v2 was significantly more accurate
than all other models tested for both the IDMS and non-IDMS datasets
(Supplementary Table S16), all comparisons with CamGFR v2 for both
IDMS and non-IDMS creatinine were significant (P ¼ 0.006 for the
comparison with Lund–Malm€ o for IDMS creatinine and P < 0.0001 for
all other comparisons), with the expected exception of the comparison
with CamGFR v1 for non-IDMS creatinine (P ¼ 0.144).

Clinical robustness of CamGFR v2

Figure 3. To examine the clinical relevance of our findings, we assessed
Summary statistics comparing the CamGFR v1, CamGFR v2, CKD-EPI, Lund– clinical robustness, defined as the proportion of GFR estimates that
Malmo € (LM), and FAS models, as well as the MDRD study equation. Statistics would lead to >20% over- or underdosing of carboplatin using the
were calculated separately for patients with IDMS-standardized creatinine and Calvert equation (1), of each model in turn. This threshold was selected
patients with non-IDMS–standardized creatinine. The residual (measured GFR

on the basis of the review of the dose–response relationships docu-
eGFR) median (first row), residual IQR (second row), RMSE (third row), and the
clinical robustness, approximated as the proportion of patients who have a
mented for carboplatin AUC in the literature, where fluctuations in the
percentage error of more than 20% of calculated carboplatin dose (dose P20; order of 10%–20% were sufficient to impact upon rates of clinical
fourth row), are displayed. All error bars are 95% CIs calculated using bootstrap response and hematologic toxicities, respectively (14, 18–20, 32).
resampling with 2,000 repetitions and a normal distribution approximation. The In each of the IDMS and non-IDMS data subsets, and across all
Cockcroft–Gault model performed less well than any other model and has not measured patient demographics, CamGFR v2 was the most robust
been included because it was developed for non-IDMS–standardized creatinine.
model (Figs. 3 and 4; Supplementary Figs. S6–S10; Supplementary
Source data for this figure and results of testing for statistical significance by
permutation tests (26) are presented in Supplementary Tables S9 and S16.
Tables S9–S14). CamGFR v2 was also the most robust model when the
proportions of patients with estimates that would lead to >10% and
>30% over- or underdosing were examined (Supplementary Table S9).
The accuracy and bias of the models were compared for IDMS- The overall fractions (95% CI) of patients with a dosing inaccuracy
standardized (n ¼ 618) and non-IDMS–standardized (n ¼ 921) data of more than 20% for IDMS-standardized creatinine were 0.12
separately. For non-IDMS–standardized data, the CamGFR v2 model (0.09–0.14) for CamGFR v2, 0.16 (0.13–0.18) for Lund–Malm€ o,
was the most accurate (RMSE, 15.74 mL/minute; 95% CI, 14.86– 0.21 (0.17–0.24) for CamGFR v1, 0.26 (0.23–0.3) for FAS, 0.29
16.63), followed by CamGFR v1 (RMSE, 15.83 mL/minute; 95% CI, (0.25–0.32) for CKD-EPI, and 0.32 (0.29–0.36) for MDRD.
14.95–16.72; Fig. 3; Supplementary Table S9). CKD-EPI was the most
accurate of the other published models (RMSE, 16.94 ml/minute; 95% Performance of CamGFR v2 in an external, non-IDMS creatinine
CI, 16.01–17.86). These three models were also unbiased for non- multicenter dataset
IDMS–standardized creatinine data, while the Lund–Malm€ o model, The aim of our work was to deliver an accurate and broadly
FAS model, and MDRD study equation each showed significant bias applicable model that accepts input creatinine data from non-IDMS
(Fig. 3; Supplementary Table S9). or IDMS measurements. We compared CamGFR v2 with other models
For IDMS-standardized data, CamGFR v2 was the most accurate using an independent, non-IDMS creatinine dataset from our previous
(RMSE, 14.97; 95% CI, 13.84–16.13) and the only unbiased (median multicenter validation study (10), excluding data from Cambridge and
residual, 0.73; 95% CI,
0.68 to 2.20) model. The Lund–Malm€ o model Manchester that are presented elsewhere in this article. Data were
performed second best, in that it had a similar accuracy (RMSE, 15.91; included from 1,605 patients across five centers. Using this external

1386 Clin Cancer Res; 27(5) March 1, 2021 CLINICAL CANCER RESEARCH
 CamGFR v2 Estimates GFR in Patients with Cancer

Figure 4.
Residual (measured GFR
eGFR)
median, dose P20, and RMSE for the
CamGFR v1, CamGFR v2, CKD-EPI,
Lund–Malmo € (LM), and FAS models,
as well as the MDRD study equation, as
stratified by eGFR. Source data is pre-
sented in Supplementary Table S14.

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dataset, we confirmed that CamGFR v2 was unbiased and, as with prescription and dosing of chemotherapies, especially carboplatin
CamGFR v1 previously (10, 21), that it outperformed all other tested therapy. Here, we developed a method for more accurate GFR
models in terms of accuracy, precision, and clinical robustness (Sup- estimation in patients with cancer by addressing three major causes
plementary Table S17). of inaccurate eGFR modeling: the patient population, the creatinine
measurement method, and the modeling itself. Using data from
Generalizability of coefficients for IDMS and non-IDMS 7,240 patients across three centers, we confirmed that creatinine
creatinine across centers levels measured using IDMS-standardized assays were more con-
Unlike with non-IDMS creatinine, we did not have an external sistent between centers (5), but on average lower than those
dataset with which to validate CamGFR v2 for IDMS creatinine. measured using non-IDMS–standardized assays (Fig. 2; ref. 17).
However, we did assess generalizability of the coefficients of CamGFR These findings justified the development and validation of a broadly
v2 across centers by refitting the model using data from two centers applicable model, CamGFR v2, for eGFR. The new model out-
and testing performance on the third, for all combinations of centers. performed all other tested models, irrespective of patient demo-
In this analysis, CamGFR v2 outperformed all other tested models in graphics or creatinine measurement methodology (Figs. 3 and 4;
terms of accuracy, precision, and clinical robustness, irrespective of Supplementary Figs. S6–S10; Supplementary Tables S9–S14).
whether creatinine values were IDMS or non-IDMS standardized, and Our analyses were focused on the gain in the performance of GFR
irrespective of the combination of centers used for development and estimation, and were not directly linked to clinical outcomes. Never-
testing (Supplementary Table S18). The one exception to this was theless, we simulated carboplatin dosing using the prospectively
refitting CamGFR v2 using the data from Cambridge and Manchester validated and FDA-endorsed Calvert equation (1, 14), and observed
followed by testing on the data from Gothenburg, where CamGFR v2 that the frequencies of dosing errors that were more than 20%
was slightly outperformed by the Lund–Malm€ o model (Supplemen- were reduced in CamGFR v2 compared with other models (Fig. 3;
tary Table S18). Supplementary Table S9). Errors of this magnitude have been asso-
ciated with important outcomes, specifically reduced clinical response
rates in ovarian cancer (19), increased treatment failure risk in
Discussion metastatic nonseminomatous germ cell tumors (20), increased relapse
Accurate eGFR determination is essential for patient manage- rates in stage I seminoma (18), and both drug-induced thrombocy-
ment. For patients with cancer, this includes the safe and effective topenia and leukopenia (14, 19, 32). A clear advantage of CamGFR v2

AACRJournals.org Clin Cancer Res; 27(5) March 1, 2021 1387

 Williams et al.

for chemotherapy dosing is that its greatest gains in accuracy, relative C rather than creatinine into the CKD-EPI model leads to superior
to other models, are within the range of eGFRs commonly observed prediction of GFR, as well as of cardiovascular risk, end-stage renal
in patients with cancer (>60 mL/minute; Fig. 4; Supplementary disease, and all-cause mortality (39, 40). However, its usage is restricted
Table S14). It is also the only model other than CamGFR v1 that by cost, the lack of widespread standardized methodologies, and
generates accurate prediction intervals for each GFR estimate (Sup- altered physiology in the settings of thyroid dysfunction (41), inflam-
plementary Figs. S5 and S11). Applied to carboplatin, CamGFR v2 may mation (42), and cancer (43–48). Tumor size- and treatment
therefore represent a new standard of care. response–dependent fluctuations of cystatin C have been documented
A challenge inherent to modeling non-IDMS creatinine values is the in diverse cancer types (43–48) and represent significant obstacles to
significant variation in calibration between centers (Fig. 2; ref. 17). the use of cystatin C–informed eGFR in the management of patients
However, as adoption of IDMS standardization becomes more wide- with cancer and, in particular, the dosing of chemotherapy.
spread (6), this limitation will become less relevant to clinical practice. In summary, CamGFR v2 can incorporate either IDMS-
Currently, incorporation of either IDMS- or non-IDMS–standardized standardized or non-IDMS–standardized creatinine assays and is the
creatinine measurements best ensures robustness of CamGFR v2 to most accurate model for estimating GFR in patients with cancer. It is
technical variation between centers and internationally (Fig. 2; uniquely designed to assess the likelihood of clinically significant
refs. 5, 6, 17). Additional technical limitations to modeling the under- or overdosing, is most immediately relevant in the context of
relationship between creatinine and GFR come from the imprecision carboplatin, and should be examined and prospectively validated by

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of methods available for directly measuring GFR (33, 34): for example, other groups to determine whether it presents a new standard of care.
the Cambridge center has reported a coefficient of variation of 7.4%
from a study of repeat GFR measurements in healthy volunteers (35). Authors’ Disclosures
Future multicenter validation work is required to assess the effects of C.M. Connell reports other from EMI Clinical Lectureship, University of
ethnic diversity (8, 29, 36, 37), center- and country-specific biases, and Cambridge during the conduct of the study. E. Gablenz reports personal fees from
diagnoses other than solid or hematologic cancers (9, 10) on the Carl-Duisberg Scholarship, Bayer, and Studienstiftung des Deutschen Volkes outside
accuracy of CamGFR v2. The small size and restricted demographics of the submitted work. H.V. Meyer reports grants from Simons Center for Quantitative
Biology during the conduct of the study. S. Tavar
e reports personal fees from Kallyope
the population of patients in this study who did not have cancer
outside the submitted work. T. Janowitz reports grants from Cancer Research UK,
(Supplementary Tables S1–S3) limit our conclusions for the relative Pershing Square Foundation, and NIH/NCI Cancer Center Support grant during the
accuracy of CamGFR v2 in this setting. While these analyses of conduct of the study. No disclosures were reported by the other authors.
predicted carboplatin exposure are supported by the prospective
validation of the Calvert equation (14), the ability of CamGFR v2 to Authors’ Contributions
predict actual carboplatin exposures requires formal pharmacokinetic E.H. Williams: Conceptualization, data curation, software, formal analysis,
analysis. Toxicity and efficacy of eGFR-informed dosing of carboplatin investigation, visualization, methodology, writing-original draft, writing-review
using CamGFR v2, as opposed to carboplatin dosing that is informed and editing. T.R. Flint: Formal analysis, visualization, writing-original draft,
by direct GFR measurements or alternative eGFR models, requires writing-review and editing. C.M. Connell: Data curation, funding acquisition,
assessment in the form of randomized controlled trials. Here the investigation, writing-review and editing. D. Giglio: Resources, data curation,
investigation, writing-review and editing. H. Lee: Writing-review and editing.
comparison with other models is of particular relevance, because
T. Ha: Formal analysis, writing-review and editing. E. Gablenz: Data curation,
carboplatin doses are routinely calculated and adjusted at each treat- writing-review and editing. N.J. Bird: Resources, data curation, investigation,
ment cycle based on eGFR. To accelerate future large-scale validation writing-review and editing. J.M.J. Weaver: Funding acquisition, investigation,
efforts, our free online application for CamGFR v2 now has an analytic writing-review and editing. H. Potts: Data curation, investigation, writing-review
function whereby researchers can batch-analyze patient datasets from and editing. C.T. Whitley: Data curation, investigation, writing-review and editing.
uploaded .csv files (ref. 38; Supplementary Fig. S11). M.A. Bookman: Writing-review and editing. A.G. Lynch: Formal analysis, writing-
The Lund–Malm€ o model performed second best in the IDMS review and editing. H.V. Meyer: Formal analysis, writing-review and editing.
S. Tavar
e: Resources, formal analysis, writing-review and editing. T. Janowitz:
creatinine validation dataset in terms of bias, accuracy, and clinical Conceptualization, data curation, formal analysis, supervision, funding
robustness, outperforming the FAS as well as the more widely used acquisition, validation, investigation, methodology, writing-original draft, project
CKD-EPI model and MDRD study equations (Fig. 3; Supplementary administration, writing-review and editing.
Table S9), each of which were developed using data from patient
populations enriched for patients with chronic kidney disease (CKD; Acknowledgments
refs. 23, 24, 29). It is possible that the source of the bias in the CKD-EPI This work was supported, in part, by Developmental Funds from the Cold Spring
model and MDRD study equation when applied to our IDMS creat- Harbor Laboratory (CSHL) Cancer Center Support grant 5P30CA045508. Funding is
inine source data (Fig. 3; Supplementary Table S9) is a combination of acknowledged from Cancer Research UK (to E.H. Williams, S. Tavar
e, T. Janowitz,
and A.G. Lynch), from CSHL (to T. Ha, H.V. Meyer, and T. Janowitz), from the
differences in gold-standard GFR measurement (renal iothalamate Simons Center for Quantitative Biology (to H.V. Meyer), from the Pershing Square
clearance in CKD-EPI/MDRD vs. plasma 51Cr-EDTA clearance in Foundation (to T. Janowitz), from The Experimental Medicine Training Initiative (to
CamGFR v2), patient demographics (United States–based and CKD- C.M. Connell), from the National Institute for Health Research UK (to J.M.J. Weaver),
enriched in CKD-EPI/MDRD vs. United Kingdom/Sweden-based and and from a Carl-Duisberg Scholarship and a German National Merit Scholarship (to
cancer-enriched in CamGFR v2), nonspecificity bias in IDMS- E. Gablenz). S. Tavar
e is a consultant for Kallyope, Inc. We thank all patients who
standardized assays (5), and the effects of intercenter calibration participated in the study. We are grateful to the three anonymous reviewers for
constructive feedback.
procedures (17).
Creatinine is influenced by diet, muscle mass, therapeutics, and
The costs of publication of this article were defrayed in part by the payment of page
disease states, fundamentally limiting the accuracy of any creatinine- charges. This article must therefore be hereby marked advertisement in accordance
based eGFR model (39). Cystatin C, in contrast, is a 13 kDa protein with 18 U.S.C. Section 1734 solely to indicate this fact.
that is produced by most nucleated cells and is freely filtered by the
glomerulus without secretion or reabsorption. In addition, its levels are Received August 15, 2020; revised October 27, 2020; accepted December 4, 2020;
less influenced by muscle mass than creatinine. Incorporating cystatin published first December 10, 2020.

1388 Clin Cancer Res; 27(5) March 1, 2021 CLINICAL CANCER RESEARCH
 CamGFR v2 Estimates GFR in Patients with Cancer

References
1. Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, et al. 22. Du Bois D, Du Bois EF. Clinical calorimetry: a formula to estimate the
Carboplatin dosage: prospective evaluation of a simple formula based on renal approximate surface area if height and weight be known. Arch Intern Med
function. J Clin Oncol 1989;7:1748–56. 1916;XVII:863–71.
2. Chantler C, Garnett ES, Parsons V, Veall N. Glomerular filtration rate mea- 23. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, et al. Expressing
surement in man by the single injection methods using 51Cr-EDTA. Clin Sci the Modification of Diet in Renal Disease study equation for estimating
1969;37:169–80. glomerular filtration rate with standardized serum creatinine values.
3. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function - Clin Chem 2007;53:766–72.
measured and estimated glomerular filtration rate. N Engl J Med 2006;354: 24. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate
2473–83. method to estimate glomerular filtration rate from serum creatinine: a new
4. Coresh J, Astor BC, McQuillan G, Kusek J, Greene T, Van Lente F, et al. prediction equation. Ann Intern Med 1999;130:461–70.
Calibration and random variation of the serum creatinine assay as critical 25. Davison AC, Hinkley DV. Bootstrap methods and their application. Cambridge,
elements of using equations to estimate glomerular filtration rate. Am J Kidney UK: Cambridge University Press; 1997.
Dis 2002;39:920–9. 26. van der Voet H. Comparing the predictive accuracy of models using a simple
5. Myers GL, Miller WG, Coresh J, Fleming J, Greenberg N, Greene T, et al. randomization test. Chemom Intell Lab Syst 1994;25:313–23.
Recommendations for improving serum creatinine measurement: a report from 27. Chancharoenthana W, Wattanatorn S, Vadcharavivad S, Eiam-Ong S, Lee-
the Laboratory Working Group of the National Kidney Disease Education lahavanichkul A. Agreement and precision analyses of various estimated
Program. Clin Chem 2006;52:5–18. glomerular filtration rate formulae in cancer patients. Sci Rep 2019;9:19356.
6. National Institute of Diabetes and Digestive and Kidney Diseases. Creatinine 28. Garner AE, Barnfield MC, Waller ML, Hall GD, Bosomworth MP. Comparing

Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/5/1381/2067166/1381.pdf by guest on 20 September 2022

standardization recommendations. Available from: https://www.niddk.nih. glomerular filtration rate equations and the impact of different creatinine assays
gov/health-information/professionals/clinical-tools-patient-management/ on the assessment of renal function in cancer patients. Ann Clin Biochem 2019;
kidney-disease/laboratory-evaluation/glomerular-filtration-rate/creatinine- 56:266–74.
standardization/recommendations. 29. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, et al. A
7. Matsushita K, Mahmoodi BK, Woodward M, Emberson JR, Jafar TH, Jee SH, new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:
et al. Comparison of risk prediction using the CKD-EPI equation and the MDRD 604–12.
Study equation for estimated glomerular filtration rate. JAMA 2012;307: 30. Bj€ork J, Grubb A, Sterner G, Nyman U. Revised equations for estimating
1941–51. glomerular filtration rate based on the Lund-Malm€o Study cohort. Scand J Clin
8. Foley RN, Wang C, Ishani A, Collins AJ. NHANES III: influence of race on GFR Lab Invest 2011;71:232–9.
thresholds and detection of metabolic abnormalities. J Am Soc Nephrol 2007;18: 31. Pottel H, Hoste L, Dubourg L, Ebert N, Schaeffner E, Eriksen BO, et al. An
2575–82. estimated glomerular filtration rate equation for the full age spectrum.
9. Beumer JH, Inker LA, Levey AS. Improving carboplatin dosing based on Nephrol Dial Transplant 2016;31:798–806.
estimated GFR. Am J Kidney Dis 2018;71:163–5. 32. Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimisation of
10. Williams EH, Connell CM, Weaver JMJ, Beh I, Potts H, Whitley CT, et al. carboplatin. Clin Pharmacokinet 1997;33:161–83.
Multicenter validation of the CamGFR model for estimated glomerular filtration 33. Levey AS, Inker LA. GFR as the “gold standard”: estimated, measured, and true.
rate. JNCI Cancer Spectr 2019;3:4–7. Am J Kidney Dis 2016;67:9–12.
11. McLean L, Whittle JR, Graham J, Ismail H, Lichtenstein M, Hicks RJ, et al. 34. Levey AS, Coresh J, Tighiouart H, Greene T, Inker LA. Strengths and limitations
Carboplatin dosing in the era of IDMS-creatinine; the Cockroft-Gault formula of estimated and measured GFR. Nat Rev Nephrol 2019;15:784.
no longer provides a sufficiently accurate estimate of glomerular filtration rate for 35. Bird NJ, Peters C, Michell AR, Peters AM. Reproducibilities and responses to
routine use in clinical care. Gynecol Oncol 2020;157:793–98. food intake of GFR measured with chromium-51-EDTA and iohexol simulta-
12. White-Koning M, Paludetto MN, Le Louedec F, Gladieff L, Chevreau C, Chatelut neously and independently in normal subjects. Nephrol Dial Transplant 2008;23:
E, et al. Formulae recently proposed to estimate renal glomerular filtration rate 1902–9.
improve the prediction of carboplatin clearance. Cancer Chemother Pharmacol 36. Delanaye P, Mariat C, Maillard N, Krzesinski JM, Cavalier E. Are the
2020;85:585–92. creatinine-based equations accurate to estimate glomerular filtration
13. Murray B, Bates J, Buie L. Impact of a new assay for measuring serum creatinine rate in African American populations? Clin J Am Soc Nephrol 2011;6:
levels on carboplatin dosing. Am J Heal Pharm 2012;69:1136–41. 906–12.
14. Sørensen BT, Str€omgren A, Jakobsen P, Jakobsen A. Dose-toxicity relationship of 37. Praditpornsilpa K, Townamchai N, Chaiwatanarat T, Tiranathanagul K,
carboplatin in combination with cyclophosphamide in ovarian cancer patients. Katawatin P, Susantitaphong P, et al. The need for robust validation for
Cancer Chemother Pharmacol 1991;28:397–401. MDRD-based glomerular filtration rate estimation in various CKD popula-
15. Casal MA, Nolin TD, Beumer JH. Estimation of kidney function in oncology tions. Nephrol Dial Transplant 2011;26:2780–5.
implications for anticancer drug selection and dosing. Clin J Am Soc Nephrol 38. CamGFR v2 live app: Available from: https://sites.google.com/site/janowitzwil
2019;14:587–95. liamsgfr/. A screenshot of the interface is presented in the supplemental materials
16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum (Figure S11).
creatinine. Nephron 1976;16:31–41. 39. Lees JS, Welsh CE, Celis-Morales CA, Mackay D, Lewsey J, Gray SR, et al.
17. Stevens LA, Manzi J, Levey AS, Chen J, Deysher AE, Greene T, et al. Impact of Glomerular filtration rate by differing measures, albuminuria and prediction of
creatinine calibration on performance of GFR estimating equations in a pooled cardiovascular disease, mortality and end-stage kidney disease. Nat Med 2019;
individual patient database. Am J Kidney Dis 2007;50:21–35. 25:1753–60.
18. Oliver RTD, Mead GM, Rustin GJS, Joffe JK, Aass N, Coleman R, et al. 40. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al.
Randomized trial of carboplatin versus radiotherapy for stage I seminoma: Estimating glomerular filtration rate from serum creatinine and cystatin C.
mature results on relapse and contralateral testis cancer rates in MRC TE19/ N Engl J Med 2012;367:20–9.
EORTC 30982 study (ISRCTN27163214). J Clin Oncol 2011;29:957–62. 41. Pricker M, Wiesli P, Br€andle M, Schwegler B, Schmid C. Impact of thyroid
19. Jodrell DI, Egorin MJ, Canetta RM, Langenberg P, Goldbloom EP, Burroughs JN, dysfunction on serum cystatin C. Kidney Int 2003;63:1944–7.
et al. Relationships between carboplatin exposure and tumor response and 42. Okura T, Jotoku M, Irita J, Enomoto D, Nagao T, Desilva VR, et al. Association
toxicity in patients with ovarian cancer. J Clin Oncol 1992;10:520–8. between cystatin C and inflammation in patients with essential hypertension.
20. Childs WJ, Nicholls EJ, Horwich A. The optimisation of carboplatin dose in Clin Exp Nephrol 2010;14:584–8.
carboplatin, etoposide and bleomycin combination chemotherapy for good 43. Jones M, Denieffe S, Griffin C, Tinago W, Fitzgibbon MC. Evaluation of cystatin
prognosis metastatic nonseminomatous germ cell tumours of the testis. C in malignancy and comparability of estimates of GFR in oncology patients.
Ann Oncol 1992;3:291–6. Pract Lab Med 2017;8:95–104.
21. Janowitz T, Williams EH, Marshall A, Ainsworth N, Thomas PB, Sammut SJ, 44. Decock J, Obermajer N, Vozelj S, Hendrickx W, Paridaens R, Kos J. Cathepsin B,
et al. New model for estimating glomerular filtration rate in patients with cancer. cathepsin H, cathepsin X and cystatin C in sera of patients with early-stage and
J Clin Oncol 2017;35:2798–805. inflammatory breast cancer. Int J Biol Markers 2008;23:161–8.

AACRJournals.org Clin Cancer Res; 27(5) March 1, 2021 1389

 Williams et al.

45. Bodnar L, Wcislo GB, Smoter M, Gasowska-Bodnar A, Stec R, Synowiec A, et al. 47. Kos J, Stabuc B, Cimerman N, Br€ unner N. Serum cystatin C, a new marker of
Cystatin C as a parameter of glomerular filtration rate in patients with ovarian glomerular filtration rate, is increased during malignant progression. Clin Chem
cancer. Kidney Blood Press Res 2010;33:360–7. 1998;44:2556–7.
46. Kume M, Yasui H, Yoshikawa Y, Horinouchi M, Higashiguchi K, Kobayashi Y, 48. Aydin F, Tezcan G, Gungor O, Cengiz AK, Hazar V, Akman S, et al. Can serum
et al. Transient elevation of serum cystatin C concentrations during perioperative cystatin C reflect the glomerular filtration rate accurately in pediatric patients
cisplatin-based chemotherapy in esophageal cancer patients. Cancer Chemother under chemotherapeutic treatment? A comparative study with Tc-99m DTPA
Pharmacol 2012;69:1537–44. two-plasma sample method. Nucl Med Commun 2010;31:301–6.

Downloaded from http://aacrjournals.org/clincancerres/article-pdf/27/5/1381/2067166/1381.pdf by guest on 20 September 2022

1390 Clin Cancer Res; 27(5) March 1, 2021 CLINICAL CANCER RESEARCH