We performed a retrospective cohort study of 102 patients treated with sunitinib for mRCC at Showa University Hospital, Showa University Northern Yokohama Hospital, and Showa University Fujigaoka Hospital, between June 2008 and August 2020. The data collection limit date was September 30, 2020. All patients were diagnosed with mRCC based on computed tomography (CT) / magnetic resonance imaging (MRI), and, when appropriate, brain imaging, and bone scintigraphy. This study was approved by the Ethics Committee of the Showa University School of Pharmacy.
Collection of patient data
Patient data and baseline laboratory values were collected from medical records. AEs within the first 6 weeks of sunitinib treatment were collected. To assess early response to treatment, laboratory values within the first 6 weeks of sunitinib treatment were collected.
The patient background data included sex, age, Eastern Cooperative Oncology Group performance status (PS), histology type, prior nephrectomy, metastatic sites, number of metastatic sites, MSKCC risk groups (favorable-, intermediate-, and poor-risk groups), prior treatment (immunotherapy, targeted therapy), and treatment (first-, second-, and third-line). The drug-related data included the initial dose of sunitinib, treatment schedule, relative dose intensity (RDI) during the first 6 weeks of sunitinib treatment (6-week RDI), and duration of therapy. Blood test data included levels of hemoglobin (Hb), calcium (Ca), aspartate aminotransferase (AST), albumin (Alb), CRP, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), mGPS, neutrophil–lymphocyte ratio (NLR), PLT and COP-NLR.
To investigate prognostic factors, including COP-NLR within the first 6 weeks of sunitinib treatment, we used the MSKCC classification that did not include neutrophil and PLT levels, which are components of COPNLR. COP-NLR within the first 6 weeks of sunitinib treatment is an item reflecting AEs and the early response to sunitinib treatment.
The MSKCC model was based on five pretreatment variables (Karnofsky PS, LDH concentration, Hb concentration, serum Ca concentration, and time from initial diagnosis to start of systemic treatment) and divided into three risk groups: favorable-risk (0 risk factor), intermediate-risk (1, 2 risk factors), and poor-risk (≥ 3 risk factors) groups. Hypertension was defined as ≥ 140/90 mm Hg. Hypothyroidism was defined as elevated thyroid-stimulating hormone levels with normal triiodothyronine and thyroxine levels. mGPS was defined as follows: patients with elevated CRP levels (> 0.5 mg/dL) and hypoalbuminemia (< 3.5 g/dL) were allocated mGPS 2, patients with only one factor were allocated mGPS 1, and patients with neither factor were allocated mGPS 0. The COP-NLR was defined as follows: patients with elevated platelet levels (> 310 × 109/L) and NLR > 3.5 were allocated COP-NLR 2, patients with only one factor were allocated COP-NLR 1, and patients with neither factor were allocated COP-NLR 0.
CRP and Alb levels were divided into two groups according to the lower limit of normal values. AST and ALP levels were divided into two groups according to the upper limit of the normal values. LDH was divided into two groups based on the LDH levels (333 U/L) of the MSKCC model. mGPS and COP-NLR were divided into two groups: moderate (score, 1) or higher.
Assessment of response
The response was assessed by CT/MRI performed at 2- to 3- month intervals. Response data presented according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. were collected from medical records. Progressive disease (PD), which is treatment response data, was collected to calculate PFS.
The following AEs related to sunitinib treatment were collected: hypertension, hand-foot syndrome, stomatitis, dysgeusia, oedema, nausea/vomiting, hemorrhage, constipation, diarrhea, fatigue, hypothyroidism, leukopenia, thrombocytopenia, anemia, elevation of AST, elevation of serum creatinine, and elevation of ALP. AEs related to sunitinib treatment were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
The primary outcomes were time to treatment failure (TTF), PFS, and OS. Tumor progression was evaluated based on PD using RECIST.
Time-to-event variables were estimated using the Kaplan–Meier method. TTF was defined as the duration from the first day of sunitinib treatment until the date of discontinuation of sunitinib treatment or death from any cause, whichever came first. PFS was defined as the duration from the first day of sunitinib treatment to the date of tumor progression or death from any cause or the last follow-up visit, whichever came first. OS was defined as the duration from the first day of sunitinib treatment to the date of death from any cause or the last follow-up visit.
Baseline and 6-week laboratory value changes
NLR and PLT values at the baseline and within the first 6 weeks of sunitinib treatment were compared by Wilcoxon rank sum tests.
The Kaplan–Meier method
Survival curves were estimated using the Kaplan–Meier method. The log-rank test was used to compare survival times between the two groups.
Univariate and multivariable analyses
Univariate and multivariable analyses were performed using the Cox proportional hazards model. Significant variables (p < 0.05) extracted by univariate analysis were entered into the multivariable analysis. Significant independent variables contributing to the prognosis of patients with mRCC treated with sunitinib were extracted using a stepwise selection method. These data were analyzed by using the SPSS software, version 27 (IBM, Tokyo, Japan). Statistical significance was set at P < 0.05.
Prognostic model and assessment
Each prognostic model was developed using prognostic factors extracted by multivariable analysis. The β values for these factors were derived from the smallest β value among the prognostic factors, approximated to the nearest integer. For each factor, the approximate β values were scored as integers. For each patient, the scores were calculated as the sum of the scores for each factor. Patients were divided into three groups (low-, intermediate-, and high-risk) based on the distribution of their scores. Survival curves of the three groups were estimated using the Kaplan–Meier method. The log-rank test was used to compare survival times among the three groups in prognostic models for TTF, PFS, and OS.
A nomogram for possible prognostic factors was formulated to provide visualized risk prediction using R software with the rms package. A nomogram was established through Cox regression model analysis according to prognostic factors of OS (i.e., the number of metastatic sites, MSKCC risk group, non-hypertension, mGPS, and 6-week COP-NLR).
Calibration of the prognostic model and nomogram for OS was performed by comparing the predicted outcomes with the observed outcomes. The performance of the prognostic model and nomogram for predicting survival was evaluated with Harrell’s concordance index (c-index) which is a measure of discrimination. The maximum value of the c-index is 1.0, which indicates perfect discrimination. The c-index of 0.5 indicates a random chance to correctly discriminate the outcome.