1 Study patients
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 1 June 2008 and 31 December 2019. The data collection limit date was 30 September 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.
2 Collection of patient data
Data were collected from medical records at the baseline. AEs within the first 6 weeks of sunitinib treatment were collected. Laboratory values within the first 6 weeks of sunitinib treatment were collected at the lowest platelet count based on the occurrence of thrombocytopenia, which has been reported to be a predictor of sunitinib efficacy .
2.1 Patient characteristics
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 aspartate aminotransferase (AST), albumin (Alb), CRP, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), mGPS, and COP-NLR.
The MSKCC model was based on five pretreatment variables (Karnofsky PS, LDH concentration, hemoglobin concentration, serum calcium 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.
2.4 Assessment of response
The response was assessed by CT/MRI performed at 2- to 3- month intervals. Treatment efficacy was reported according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
2.5 Adverse events
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 progressive disease 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.
4 Statistical analysis
4.1 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.
4.2 Univariate and multivariate analyses
Univariate and multivariate analyses were performed using the Cox proportional hazards model. Significant variables (p < 0.05) extracted by a univariate analysis were entered into the multivariate analysis. Significant independent variables contributing to the prognosis of patients with mRCC treated with sunitinib were extracted using a stepwise selection method.
4.3 Prognostic model and assessment
Each prognostic model was developed using prognostic factors extracted by multivariate analysis. The hazard ratios (HRs) for these factors were derived from the smallest HR among the prognostic factors, approximated to the nearest integer. For each factor, the approximate HRs 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. All statistical analyses were performed using the SPSS software, version 27 (IBM, Tokyo, Japan). Statistical significance was set at P <0.05.