Utility of creatinine/cystatin C ratio as a predictive marker for adverse effects of chemotherapy in lung cancer: A retrospective study

Abstract

Objective

To determine whether the creatinine/cystatin C (Cr/CysC) ratio, which is influenced by muscle mass, can be used as a predictive marker of the adverse effects of chemotherapy.

Methods

This single-centre, retrospective, observational study assessed patients with lung cancer. Serum Cr and CysC levels were measured once within 1 month prior the commencement of chemotherapy.

Results

A total of 25 patients with lung cancer were enrolled in the study: 22 received first-line therapy; three received second-line therapy. A significant difference was noted regarding the Cr/CysC ratios between patients with nonsmall-cell lung cancer (NSCLC) and those with small-cell lung cancer (0.78 versus 0.92, respectively). A significant difference was also noted in the Cr/CysC ratios of patients with NSCLC with toxicity grades <3 and ≥3 (0.84 versus 0.70, respectively). Similar findings were observed in patients with NSCLC who received platinum-based combination therapy (toxicity grade < 3, 0.85; toxicity grade ≥3, 0.69).

Conclusion

The Cr/CysC ratio could serve as a useful predictive marker for chemotherapy-related adverse effects in patients with NSCLC.

Keywords

Creatinine/cystatin C chemotherapy sarcopenia adverse effect

Introduction

Precision or personalized treatment can be defined as using the biological characteristics of a patient’s disease to optimize therapeutic efficacy while minimizing toxicity.¹ Existing oncology performance status measures are applied to all adult cancer patients to estimate functional status, assess their eligibility for clinical trials, and predict treatment toxicity and patient survival.^2,3 Such assessments are used in daily oncology practice to assist in decision making; however, these tools were validated in relatively young patients and do not address the heterogeneity observed in more elderly patients. Patient-specific predictors for above-average risk of chemotherapy toxicity have been reported in several studies,^4,5 but none are used in practice, due to the difficulties in assessing such predictors.

Cancer anorexia–cachexia is a wasting syndrome that occurs in 80% of patients with incurable solid tumours, and 60% of lung cancer patients have already experienced substantial weight loss by the time of diagnosis.⁶ Cachexia has been shown to worsen prognosis and has also been associated with the impairment of physical function, increased psychological distress, and poor health-related quality-of-life.⁷

Cancer cachexia is not only observed in patients with a low body mass index (BMI) but is also observed in overweight patients.⁸ The body composition of cancer patients changes dramatically over the course of their disease, and there can be marked skeletal muscle wasting with a 75% reduction in skeletal muscle protein mass.⁹ Sarcopenic obesity, which is obesity with depleted muscle mass, is commonly observed in cancer patients; studies have reported that obesity (i.e. BMI ≥30 kg/m²) in the presence of sarcopenia is predictive of morbidity/mortality and chemotherapy toxicity.⁸

Serum creatinine (Cr) is the most commonly used index of renal function in clinical practice,¹⁰ but its measurement is affected by a variety of analytical interferences and significant standardization problems.¹¹ Serum Cr can be affected by age, sex, ethnicity, dietary protein intake and lean mass.¹¹ The muscle mass affects serum and urinary Cr; therefore, serum Cr has a low sensitivity for the early detection of kidney disease and is thus not a good predictor, especially in the elderly.¹²

Cystatin C (CysC), a cysteine protease inhibitor, could potentially be used as a surrogate marker for the glomerular filtration rate (GFR).¹³ Research has demonstrated that age, sex and muscle mass have a smaller influence on CysC than on serum Cr;¹⁴ therefore, the use of CysC may represent a better alternative for assessing renal function in patients with higher muscle mass and potential mild kidney impairment.¹¹ Because CysC is independent of body muscle mass, the Cr/CysC ratio, which is unrelated to renal function, is theoretically considered to be a quantitative surrogate marker of residual muscle mass.¹⁵

The purpose of the present study was to assess whether the reduced Cr/CysC ratio, which indicates reduced residual muscle mass, is a useful predictive marker for the adverse effects of chemotherapy in patients with lung cancer.

Patients and methods

Study design and population

A single-centre, retrospective, observational study was conducted in the First Department of Medicine, Toyama University Hospital, Toyama, Japan between 1 October 2012 and 30 June 2013. Patients with advanced, inoperable, stage IIIa, IIIb or IV lung cancer undergoing treatment with chemotherapy were eligible for sequential inclusion in the study. Patients were diagnosed via a biopsy collected using bronchoscopy or computed tomography-guided biopsy; histopathological findings were reported by two pathologists. The epidermal growth factor receptor mutation status of each tumour was tested using the polymerase chain reaction-invader method at the BML Laboratory, Tokyo, Japan on formalin-fixed paraffin wax-embedded tissue specimens collected during biopsy.^16,17

Patients were excluded if they met any of the following criteria: (i) obvious renal dysfunction, which also excluded them from receiving chemotherapy; (ii) regular use of systemic corticosteroids or cyclosporin; (iii) past history of thyroid dysfunction. The study protocol was approved by the Ethical Review Committee of the University of Toyama, Toyama, Japan (reference number: rin 25-22). Written informed consent was obtained from all of the patients.

It was hypothesized that the mean ± SD difference of the Cr/CysC ratio would be 1.0 ± 0.8 between the two groups stratified according to their toxicity grades (<3 versus ≥3); and a calculation using JMP® 9 software (SAS Institute, Cary, NC, USA) determined that 23 patients would be required to prove the hypothesis in this study (α = 0.05, β = 0.8). This a priori assumption was based on a previous report¹⁵ and our preliminary data.

Chemotherapy

All chemotherapy regimens were administered in accordance with international guidelines.¹⁸ All regimens were examined and approved by the Committee for Chemotherapy Regimens at Toyama University Hospital. All patients received chemotherapy until the disease progressed, as assessed by Response Evaluation Criteria in Solid Tumours version 1.1¹⁹ or a decision was made by the physicians or patients to stop chemotherapy. Different chemotherapy regimens were administered for patients with nonsmall-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), based on international guidelines.¹⁸ Toxicity profiles differed between the two groups of patients, based on their type of lung cancer and the corresponding chemotherapy that they received (NSCLC or SCLC), therefore the specific toxicities were assessed accordingly.

Data collection

Venous blood samples (5 ml) were collected in serum-separator tubes (VENOJECT® II plastic vacuum tube; TERUMO®, Tokyo, Japan) within 1 month prior to the start of chemotherapy. Blood was only drawn once from each patient. Serum samples were analysed for serum CysC and Cr immediately after preparation. Serum CysC levels were used as a marker of renal function prior to the commencement of chemotherapy and were measured using colloidal gold particles coated with anti-CysC antibodies at the SRL Laboratory, Tokyo, Japan (reference values: 0.63–0.95 mg/l in male patients; 0.56–0.95 mg/l in female patients).²⁰ Serum Cr levels were determined using an enzymatic method undertaken by an automatic analyser (LABOSPECT 008 Automatic Analyser; Hitachi, Tokyo, Japan) at the hospital biochemistry laboratory (reference values: 0.61–1.04 mg/dl in male patients; 0.47–0.79 mg/dl in female patients). The enzymatic assay for serum Cr involves a series of coupled enzymatic reactions, described previously.²¹

Clinical outcome data were retrospectively obtained from hospital-based registries and medical records. The Eastern Co-operative Oncology Group Performance Status was evaluated before the first cycle of chemotherapy by at least two attending physicians (K.S., S.O., K.K., and/or M.I.) according to the criteria.²² Chemotherapy-related toxicities were evaluated daily during the first cycle of chemotherapy by at least two attending physicians (K.S., S.O., K.K., and/or M.I.), and the maximum toxicity grade was assessed prior to the start of the next chemotherapy cycle by clinical examination and complete blood count. Decreased white blood cells, neutropenia, anaemia, decreased platelet counts, febrile neutropenia, complaints of diarrhoea, nausea and vomiting, anorexia, peripheral neuropathy, fatigue and allergic reaction/anaphylaxis were ascertained by reviewing medical records and laboratory results. A side-effect or adverse reaction was considered present if it was explicitly mentioned or discussed in the medical records. The chemotherapy toxicity grade was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (in Japanese, CTCAE v4.0 JCOG).^23,24 The CTCAE toxicity grade ranges between 1 and 5 as follows: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, death.²⁴

The Cr/CysC ratios in patients receiving chemotherapy were compared between patients with a CTCAE toxicity grade ≥3 and those with a toxicity grade <3.

Statistical analyses

All statistical analyses were performed using the JMP® 9 statistical package (SAS Institute, Cary, NC, USA) for Windows®. Descriptive statistics were used to describe patient characteristics and the distribution of variables. All data were expressed as the mean ± SD. Two-way analysis of variance was used to compare multiple groups of data, whereas the differences between two groups were analysed using an unpaired Student’s t-test. A P-value <0.05 was considered significant.

Results

A total of 25 patients met the inclusion criteria and their baseline characteristics are shown in Table 1. Of these 21/25 patients (84%) had received no previous chemotherapy. The chemotherapy regimens that were used are shown in Table 2. Severe adverse effects reported by patients with a CTCAE grade ≥3 are shown in Table 3. The proportion of patients experiencing severe haematological toxicities, such as decreased white blood cell and neutrophil counts, was significantly lower in patients treated with the NSCLC regimens than the SCLC regimens (P < 0.05 for all comparisons).

Table 1.

Demographic and clinical characteristics of patients (n = 25) with lung cancer who participated in a study to investigate if the creatinine/cystatin C ratio was a useful predictive marker for the adverse effects of chemotherapy.

Characteristic		n
Age, years		67
ECOG PS	0–1	22 (88)
	2	3 (12)
Disease stage	IIIa/b	11 (44)
	IV	11 (44)
	Recurrence	3 (12)
Tissue type	Adenocarcinoma	14 (56)
	Squamous cell carcinoma	4 (16)
	Small-cell carcinoma	6 (24)
	Large cell neuroendocrine carcinoma combined with small-cell carcinoma^a	1 (4)
EGFR status	Mutant type	1 (4)
	Wild type	11 (44)
	Unknown	13 (52)
Comorbidities	Heart disease	1 (4)
	COPD	1 (4)
	Other malignancies	1 (4)

Data presented as median or n of patients (%).

For analysis, this patient was grouped with the patients with small-cell lung cancer (SCLC) because they received an SCLC chemotherapy regimen.

ECOG PS, Eastern Co-operative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; COPD, chronic obstructive pulmonary disease.

Table 2.

Chemotherapy regimens used in patients (n = 25) with lung cancer

Regimen	n	n (%)
Previous course	0	21 (84)
	1	2 (8)
	2	2 (8)
Platinum combination		19 (76)
SCLC
CDDP + VP-16		2 (8)
CBDCA + VP-16		4 (16)
NSCLC
CDDP + PEM		1 (4)
CDDP + VNR		1 (4)
CBDCA + PEM		7 (28)
CBDCA + PTX		2 (8)
CBDCA + DOC		1 (4)
CBDCA + S-1		1 (4)
Monotherapy		6 (24)
SCLC
AMR		1 (4)
NSCLC
PEM		2 (8)
VNR		1 (4)
DOC		1 (4)
CBDCA		1 (4)

SCLC, small-cell lung cancer; CDDP, cisplatin; VP-16, etoposide; CBDCA, carboplatin; NSCLC, nonsmall-cell lung cancer; PEM, pemetrexed; VNR, vinorelbine; PTX, paclitaxel; DOC, docetaxel; S-1, tegafur-gimeracil-oteracil; AMR, amrubicin.

Table 3.

Patients with severe adverse effects, defined as a score ≥3 using the Common Terminology Criteria for Adverse Events version 4.0^23,24

Adverse effect	NSCLC regimens n = 18	SCLC regimens n = 7	Statistical significance^a
Haematological toxicities	4 (22)	7 (100)	P < 0.001
Decreased white blood cell count	3 (17)	4 (57)	P < 0.05
Decreased neutrophil count	3 (17)	7 (100)	P < 0.0001
Febrile neutropenia	2 (11)	0 (0)	NS
Nonhaematological toxicities	3 (17)	0 (0)	NS
Anorexia	3 (17)	0 (0)	NS
Hyponatraemia	1 (6)	0 (0)	NS

Data presented as n of patients (%).

Differences between the two groups analysed using unpaired Student’s t-test

NSCLC, nonsmall-cell lung cancer; SCLC, small-cell lung cancer; NS, no significant between-group difference (P ≥ 0.05).

There were no significant differences in the Cr/CysC ratios between patients aged ≤70 years old and patients aged >70 years old (n = 15 versus n = 10, respectively; mean ratios: 0.84 versus 0.80, respectively; unpaired Student’s t-test). When analysing the type of lung cancer, the Cr/CysC ratio was significantly higher in patients with SCLC than in patients with NSCLC (Figure 1; n = 7 versus n = 18, respectively; mean ratios: 0.92 versus 0.78, respectively; P < 0.05).

Figure 1.

Serum creatinine/cystatin C (Cr/CysC) ratios in patients with small-cell lung cancer (SCLC) or nonsmall-cell lung cancer (NSCLC). Data presented as mean ± SD. *P < 0.05, unpaired Student’s t-test

There was a significant difference between the Cr/CysC ratios in patients with NSCLC who experienced toxicity grades < 3 and those with a toxicity grade ≥3 (Figure 2; n = 10 versus n = 8, respectively; mean ratios: 0.84 versus 0.70, respectively; P < 0.05). Similar findings were also observed in the subgroup of patients with NSCLC (n = 13) who received platinum-based combination regimens and experienced toxicity grades <3, compared with those with toxicity grades ≥3 (n = 6 versus n = 7, respectively; mean ratios: 0.85 versus 0.69, respectively; P < 0.05). In the subgroup of patients with SCLC, all patients had grade 4 haematological toxicities, therefore it was not possible to undertake a comparison between those with toxicity grades <3 and those with toxicity grades ≥3.

Figure 2.

Serum creatinine/cystatin C (Cr/CysC) ratios in patients with nonsmall-cell lung cancer, grouped according to the level of toxicity they experienced using the Common Terminology Criteria for Adverse Events version 4.0 (grade < 3 versus ≥3). Patients were analysed based on the treatment received: all chemotherapy regimens (left hand column graph); platinum-based combination regimens (right hand column graph). Data presented as mean ± SD. *P < 0.05, unpaired Student’s t-test

Discussion

Both serum Cr and CysC are commonly used to determine the GFR.^10,13 However, in patients without renal impairment, the Cr/CysC ratio might be a quantitative surrogate marker for the assessment of residual muscle mass in those with liver cirrhosis²⁵ or amyotrophic lateral sclerosis (ALS).¹⁵ The correlation between the Cr/CysC ratio and muscle mass was higher than that for serum Cr levels, therefore, the Cr/CysC ratio might be a better and more reliable marker than Cr levels for monitoring muscle mass in ALS patients.¹⁵ These findings suggest that the Cr/CysC ratio eliminates the influence of potential differences in renal function.¹⁵

Muscle loss may be caused by an increase in catabolic factors such as inflammatory cytokines, and it is clear that several cytokines are capable of muscle amino acid export in vivo in rodents and, to some extent, in human beings.²⁶ The cytokines for which the most data are available are interleukin (IL)-1β,²⁷ tumour necrosis factor-α,²⁸ and IL-6.²⁹ Sarcopenia in overweight patients is an adverse prognostic indicator in patients with pancreatic,³⁰ respiratory and gastrointestinal cancer.⁸ Furthermore, sarcopenia is a significant predictor of toxicity and time-to-progression in patients with metastatic breast cancer treated with capecitabine.³¹ These findings highlight the importance of undertaking routine body assessment for risk stratification and treating sarcopenia in a clinical oncology setting. Moreover, sarcopenia is an occult condition that can occur in patients with any body weight and BMI,³¹ especially in Asian people (who tend to develop sarcopenia with a lower degree of obesity).³²

For the diagnosis of sarcopenia, the measurement of muscle mass requires the use of techniques not commonly used in clinical practice. Dual energy X-ray absorptiometry (DXA) is now widely considered an accurate method for body composition evaluation,³³ but even simpler techniques such as bioelectrical impedance analysis (BIA) have also been used.³⁴ While no universal surrogate anthropometric markers are available to evaluate muscle mass, both the DXA and BIA methods require specific techniques or machines. The advantage of the Cr/CysC ratio lies in the fact that it is a very convenient assay, which only requires a sample of the patient’s serum.

This present study hypothesized that the relationship between the Cr/CysC ratio and chemotherapy toxicity results from a pharmacokinetic effect and/or a nonoptimized dose of chemotherapy, especially in the case of carboplatin. Variability in the body composition of cancer patients alters the metabolism of cytotoxic agents and molecular target agents, such as sorafenib in hepatocellular carcinoma³⁵ and 5-fluorouracil.³⁶ Prado et al.³¹ reported that a lower body volume of distribution of a drug would result in a higher concentration in a shorter period of time; therefore, patients with sarcopenia would be less physiologically able than other patients to clear drugs from their systemic circulation.

In routine practice, the carboplatin dose is calculated using an estimated Cr clearance that is derived from formulae that incorporate the patient’s serum Cr level.³⁷ The Cockcroft–Gault formula is widely used for the calculation of the carboplatin dose, but this formula was developed using an outdated Jaffe assay for Cr measurement³⁸ and leads to an underestimation of GFR in the elderly.³⁹ The modified Thomas formula, which is obtained from model-based serum Cr, CysC, and covariates related to muscle mass (body weight, age, and sex), is the first equation that enables individual area-under-the-curve dosing of carboplatin, especially in obese and underweight patients.⁴⁰ Based on data shown in Figure 2, the findings of this present study suggest that the carboplatin overdose was due to an overestimation of Cr-predicted renal function caused by lower Cr/CysC ratios.

This present study had several limitations. First, it was not possible to measure the actual residual muscle mass using the DXA or BIA methods, due to a lack of specific equipment. Further studies are required to determine the correlation between residual muscle mass and the Cr/CysC ratio in patients with lung cancer. Secondly, the study did not determine if a change in the Cr/CysC ratio after chemotherapy affected the time-to-tumour progression and overall survival.

Severe chemotherapy-related toxicities have a negative impact on health-related quality-of-life and result in a poorer prognosis in patients with lung cancer,⁴¹ but it is difficult to predict how the patient will be affected by them and how they might be outweighed by the clinical benefits of chemotherapy. In contrast to BIA and DXA, the Cr/CysC ratio is easy to measure and requires no specific instruments to determine muscle mass. The Cr/CysC ratio may be a predictive marker of severe chemotherapy-related toxicity in patients undergoing chemotherapy. Determining the usefulness of the Cr/CysC ratio for the prospective selection of chemotherapy will require further studies, with larger sample sizes.

In conclusion, the present study demonstrated that lower Cr/CysC ratios correlated with a higher incidence of chemotherapy-related adverse effects in patients with NSCLC. Therefore, the Cr/CysC ratio could be a useful predictive marker for the adverse effects of chemotherapy in patients with NSCLC.

Footnotes

Acknowledgements

We thank Drs Kazuhiro Nomoto and Junya Fukuoka, for pathological diagnosis support.

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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