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Decreased relative dose intensity during the early phase of treatment impacts the therapeutic efficacy of sunitinib in metastatic renal cell carcinoma

Decreased relative dose intensity during the early phase of treatment impacts the therapeutic... Abstract Background Relative dose intensity is an indicator of therapeutic efficacy in sunitinib treatment for metastatic renal cell carcinoma. However, the number of studies investigating the influence of decreased relative dose intensity during the early phase on oncological outcome is limited. Methods A total of 105 patients who received first-line sunitinib treatment for metastatic renal cell carcinoma were evaluated. We assessed the relative dose intensity during the initial first cycle (1c-RDI). We found that an optimal threshold of 1c-RDI was associated with progression-free survival and overall survival after the initiation of sunitinib treatment. Additionally, predictive factors for decreased 1c-RDI were analyzed. Results The 1c-RDI threshold was determined at 60%. Patients with low 1c-RDI (<60%, n = 26, [24.8%]) had significantly shorter median progression-free survival (5.79 vs. 14.0 months, P = 0.0014) and overall survival (13.3 vs. 34.4 months, P = 0.0005) durations than those with high 1c-RDI (≥60%, n = 79 [75.2%]). Multivariate analysis showed that the development of dose-limiting toxicity was an independent factor for low 1c-RDI (odds ratio: 3.09, 95% confidence interval: 1.14–8.37, P = 0.0266) after adjustment with an initial dose of sunitinib. Conclusions More than 60% of 1c-RDI is needed for effective sunitinib treatment. Patient tolerability should be carefully monitored to avoid the development of dose-limiting toxicity during the early phase of treatment. renal cancer, targeted therapy, adverse event, tolerability, dose-limiting toxicity Introduction Sunitinib (SU) is an anticancer drug and a receptor tyrosine kinase inhibitor mainly targeting the vascular endothelial cell growth factor receptors and blocks vascular endothelial cell growth factor signaling. It is approved as a first-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC) (1). SU is more beneficial to patient survival than conventional cytokine therapy (2,3) and has been broadly applied in current clinical practice. However, its toxicity is a major issue. Frequent and severe adverse events (AEs) induced by SU can result in treatment withdrawal, dose reduction or treatment interruption, that is, dose-limiting toxicity (DLT) (2,4–9). In a previous pivotal trial, SU-induced toxicities, mainly gastrointestinal disorder, hypertension, hand–foot syndrome, general fatigue or hemototoxicity, led to dose reduction and treatment termination in 50 and 19% of the patients, respectively (2). DLTs can directly decrease relative dose intensity (RDI). Maintaining the RDI, particularly in the early phase of treatment, is essential to efficient and continuous treatment and is significantly associated with patient survival (10,11). However, the number of studies investigating the impact of decreased RDI during the early phase of treatment on the oncological outcome is limited, particularly in patients without prior cytokine therapy. Moreover, predicting the decreased RDI before initiation of treatment or during treatment is difficult. Thus, risk factors for such a possibility should be identified. In this study, we investigated the influence of decreased RDI during the early phase on the therapeutic efficacy of first-line SU treatment in patients with mRCC without prior cytokine therapy. Additionally, risk factors for decreased RDI were analyzed. Materials and methods Study design First of all, we nominated patients who received at least one dose of oral SU. In our department between January 2007 and July 2017, 112 patients received first-line SU treatment for mRCC without prior cytokine therapy. Of these, we excluded those who had either undergone a kidney transplantation (n = 1) or whose clinical data were lacking (n = 6). Finally, 105 patients were evaluated in this retrospective single-center analysis. All study procedures were approved by the Institutional Review Board of Tokyo Women’s Medical University and were in accordance with the Declaration of Helsinki (ID: 4551). To determine the influence of decreased RDI during the early phase of treatment on the therapeutic efficacy of first-line SU for mRCC, we calculated the RDI during the initial first cycle (1c-RDI) as RDI in early phase. Patients were classified into the following two groups, low and high 1c-RDI, based on the 1c-RDI threshold associated with oncological outcome, including progression-free survival (PFS) and overall survival (OS), after initiation of treatment. Furthermore, we analyzed the predictive factors for decreased 1c-RDI. Protocols of first-line SU treatment We followed the protocol for first-line SU treatment as described elsewhere (12,13). Briefly, the main agent for first-line molecular-targeted therapy was SU. Patients with mRCC were treated using a 4-week-on/2-week-off or a 2-week-on/1-week-off schedule. SU treatment was initiated at a dosage of 50 mg/day and was modified based on individual patient factors. Three factors were considered for the reduction of the initial dose: (i) age: >65 years, (ii) serum creatinine levels: >2 mg/dL and (iii) a body weight: <50 kg. If one of these three factors was observed, the initial dose was reduced to 37.5 mg. If two factors were observed, the initial dose was reduced to 25 mg. We never reduced the initial dose to <25 mg. The dose was subsequently increased by 12.5 mg until the highest tolerable dose was determined, although the dose never exceeded 50 mg. Toxicity was assessed at each visit (every 1–2 weeks during the first cycle) and then every month according to the patient’s condition. AEs were graded using the Common Terminology Criteria for Adverse Events of the National Cancer Institute, version 4.0. The dose was reduced or interrupted based on the guidelines for SU therapy. Statistical analysis Continuous and categorical variables were analyzed using the Mann–Whitney U-test and the χ2 test or Fischer’s extract test, respectively. PFS and OS were defined as the time from therapy initiation to the date of progression and date of death from any cause, respectively. Survival was calculated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate logistic regression analyses were used to identify risk factors for low 1c-RDI. Also, univariate and multivariate analyses using Cox proportional hazards regression models were used to identify the prognostic factors for PFS and OS. The risk was expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). All analyses were performed using JMP software (version 13; SAS Institute Inc., Cary, NC, USA), and P values <0.05 were considered statistically significant. Results Patient background We examined a threshold of 1c-RDI influencing PFS and OS. Consequently, a 1c-RDI threshold of 60% was determined to be strongly associated with PFS and OS after evaluating the P values of various thresholds of 1c-RDI and selecting the threshold with the lowest P values (Table 1). Based on the threshold, 26 patients (24.8%) were classified into the low-1c-RDI group (i.e. <60%). Female sex (P = 0.0053), low initial dose of SU (P = 0.0345) and higher incidence of DLT were more frequently observed in the low-1c-RDI group than in the high-1c-RDI group. Other clinicopathological factors, including age, body weight, pathological type, prior nephrectomy status, the Memorial Sloan Kettering Cancer Center risk classification, number of metastatic sites or treatment schedule did not significantly differ between the two groups (all P > 0.05) (Table 2). The follow-up period was significantly shorter in patients with low 1c-RDI than those with high 1c-RDI (P = 0.0037). Table 1. Determination of the cult-off value of 1c-RDI associated with survival Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 RDI, relative dose intensity; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. Table 1. Determination of the cult-off value of 1c-RDI associated with survival Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 RDI, relative dose intensity; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. Table 2. Patient background Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 ∗Median (interquartile). MSKCC, Memorial Sloan Kettering Cancer Center; DLT, dose-limiting toxicity. Table 2. Patient background Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 ∗Median (interquartile). MSKCC, Memorial Sloan Kettering Cancer Center; DLT, dose-limiting toxicity. Survival according to 1c-RDI In the follow-up period, 73 patients (69.5%) experienced disease progression and 59 patients (56.2%) died of any cause. Figure 1 shows that the median duration of PFS and OS were significantly shorter in patients with low 1c-RDI than those with high 1c-RDI (PFS: 5.79 [95% CI: 2.76–8.02] vs. 14.0 [95% CI: 10.7–20.7] months, P = 0.0014; OS: 13.3 [95% CI: 4.73–20.0] vs. 34.4 [95% CI: 26.1–52.6] months, P = 0.0005). Figure 1. View largeDownload slide PFS and OS according to 1c-RDI threshold. Median PFS and OS were significantly shorter in patients with low 1c-RDI (PFS: 5.79 vs. 14.0 months, P = 0.0014; OS: 13.3 vs. 34.4 months, P = 0.0005). 1c-RDI, relative dose intensity during the initial first cycle; PFS, progression-free survival; OS, overall survival. Figure 1. View largeDownload slide PFS and OS according to 1c-RDI threshold. Median PFS and OS were significantly shorter in patients with low 1c-RDI (PFS: 5.79 vs. 14.0 months, P = 0.0014; OS: 13.3 vs. 34.4 months, P = 0.0005). 1c-RDI, relative dose intensity during the initial first cycle; PFS, progression-free survival; OS, overall survival. Predictors for low 1c-RDI Table 3 shows the results of univariate and multivariate logistic regression analyses for 1c-RDI < 60%. Univariate analysis showed that female sex, lower initial dose and DLT development were associated with low 1c-RDI (all, P < 0.05). Multivariate analysis showed that DLT development (OR: 3.09, 95% CI: 1.14–8.37, P = 0.0266) and female sex (OR: 3.11, 95% CI: 1.16–8.34, P = 0.0240) were independent predictors for low 1c-RDI after adjustment for the initial dose of SU. Table 3. Univariate and multivariate logistic regression analyses for 1c-RDI < 60% Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) OR, odds ratio. Table 3. Univariate and multivariate logistic regression analyses for 1c-RDI < 60% Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) OR, odds ratio. Predictors for PFS and OS Supplementary Tables S1 and S2 show the results of univariate and multivariate analyses for PFS and OS, respectively. Multivariate analysis shows that 1c-RDI was an independent predictor (HR: 2.23, 95% CI: 1.27–3.79, P = 0.0063), along with sex (HR: 1.74, 95% CI: 1.02–2.90, P = 0.0415), histology (HR: 1.97, 95% CI: 1.15–3.31, P = 0.0135), MSKCC risk (P = 0.0154), and the number of metastatic sites (HR: 1.77, 95% CI: 1.10–2.88, P = 0.0195) for PFS. For OS, 1c-RDI was an independent predictor (HR: 2.64, 95% CI: 1.45–4.68, P = 0.0018), along with histology (HR: 2.07, 95% CI: 1.13–3.70, P = 0.0199), MSKCC risk (P = 0.0026), and the number of metastatic sites (HR: 2.65, 95% CI: 1.53–4.68, P = 0.0195), according to the multivariate analysis. Dose-limiting toxicities during the initial first cycle Table 4 shows the individual AEs that cause DLTs. The most frequent AE was thrombocytopenia (grade 2: n = 16 [30.8%], grade ≥3: n = 14 [26.9%]), followed by leukocytopenia (grade 2: n = 3 [5.77%], grade ≥3: n = 11 [21.2%]). Among the 52 patients who developed DLT, the dose was reduced and interrupted in 31 (59.6%) and 21 (40.4%) patients, respectively. Table 4. Individual AEs inducing DLTs N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) AE, adverse event. Table 4. Individual AEs inducing DLTs N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) AE, adverse event. Discussion The present study indicated that more than 60% of RDI during the initial first cycle was needed to maintain the therapeutic efficacy of first-line SU treatment for mRCC. Furthermore, we found that DLT development can decrease the level of sufficient RDI; therefore, patient tolerability should be carefully monitored to avoid the development of DLT during the first cycle. SU-induced toxicities can disrupt the maintenance of efficient treatment intensity, and this can result in poor prognosis in patients with mRCC. Kawashima et al. reported that continuing treatment for more than one course and ≥60% of 1 month RDI was important for optimal efficacy of SU treatment (11). Another study reported that dose intensity below 70% during several landmark periods, including the initial three cycles, was significantly associated with shorter OS in SU treatment (10). Considering these findings, a threshold of 60% obtained from our analysis was consistent with the findings from previous studies. Notably, a unique point of the present study was that it included patients who had not received prior cytokine therapy. Thus, our findings can be applied on the current treatment strategy for mRCC (14). As RDI is affected by various factors during treatment, predicting it before treatment initiation or during treatment is difficult. Moreover, despite the need for predictors for decreased RDI that can be used to prevent it during treatment, only a limited number of clinical researches have focused on such factors. As such, we found that the development of DLT during the initial first cycle should be avoided to maintain the efficient RDI. As the initial dose of SU would be directly associated with 1c-RDI, multivariate analyses were performed to adjust for the confounding factors. The results indicated that DLT development remains a statistical significant factor influencing the RDI. Treatment discontinuation induced by intolerable AEs was previously reported to negatively affect patient prognosis (10,15). Treatment was permanently discontinued after interruption during the early phase in 8 of the 31 patients (25.8%) in our study. In these eight patients, the median 1c-RDI was 46.5%, and the survival was extremely poor (median PFS and OS: 1.16 and 3.35 months, respectively). Also, in this study, total RDI (i.e. throughout the treatment) in patients with low 1c-RDI was lower than in those with high 1c-RDI (median: 45.6 vs. 64.2%, P < 0.0001), suggesting that deterioration of therapeutic efficacy in early period influences entire efficacy, leading to poor survival. In the current analysis, the most frequent DLTs were hematotoxicities, including thrombocytopenia and leukocytopenia, that could not be treated or prevented via symptomatic treatment. A similar finding was observed in a previous study by Kawashima et al. who reported that thrombocytopenia and leukocytopenia were the most frequent AEs in SU treatment (11). Furthermore, a modified treatment schedule was not associated with a maintenance of efficient RDI, although a 2-week-on/1-week-off schedule is a common alternative schedule with less toxicity (16–18). However, the deceased drug efficacy during the early phase of treatment can negate the benefit from the modified schedule. Thus, when severe hematotoxicities occur during the initial cycle, a conversion to other agents, such as pazopanib, which is more tolerable than SU with less hematotoxicity effects (4,5), may be a more effective approach than reduced dosage or schedule modification. The lower frequency of thrombocytopenia and leukocytopenia in pazopanib than that of SU has been demonstrated (4). Finally, our analysis showed that female patients had a higher risk of decreased RDI than males. This finding was similarly observed in several previous studies. Kawashima et al. reported that women tended to discontinue SU treatment within one course (11). In their review of SU treatment, Segarra et al. reported that female patients had a higher incidence of AEs than males (19). Kaymakcalan et al. suggested that further researches should be performed to determine the impact of sex on SU-induced toxicity (20). This study had several limitations. First, this study was retrospectively performed in a single center with a relatively small cohort. Our findings were affected by unavoidable biases in patient or treatment selection. Moreover, several unrecorded AEs might exist. Second, we should note that the safety profile of SU may differ between the Asian and Western populations (21). Third, an initial dose of SU was modified using a home-based protocol (based on age, body weight and renal function) according to previous studies showing a high concentration of SU and its active metabolite in plasma with a dosage of 50 mg (22) and higher incidence of AEs in Japanese than Western patients (23). Indeed, some studies reported the possibility of weak tolerability in elderly patients (24,25). Moreover, SU can deteriorate renal function (26,27). In this context, our own protocol can reflect the situation in real world, but we should recognize some possible bias in the protocol. In conclusion, more than 60% of 1c-RDI was needed to maintain the therapeutic efficacy of first-line SU treatment for mRCC. The development of DLT during the initial first cycle can deteriorate the 1c-RDI regardless of the initial dose or treatment schedule of SU. Patient tolerability should be monitored carefully during the early phase of treatment. Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Acknowledgements The authors thank Editage for English language editing and Nobuko Hata for secretarial work. Funding None. Conflict of interest statement Tsunenori Kondo received honoraria from Pfizer, Bayer and Novartis. All other authors have no conflicts of interest to declare. References 1 Ljungberg B , Bensalah K , Canfield S , et al. . EAU guidelines on renal cell carcinoma: 2014 update . Eur Urol 2015 ; 67 : 913 – 24 . Google Scholar CrossRef Search ADS PubMed 2 Motzer RJ , Hutson TE , Tomczak P , et al. . Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma . J Clin Oncol 2009 ; 27 : 3584 – 90 . Google Scholar CrossRef Search ADS PubMed 3 Motzer RJ , Hutson TE , Tomczak P , et al. . Sunitinib versus interferon alfa in metastatic renal-cell carcinoma . N Engl J Med 2007 ; 356 : 115 – 24 . Google Scholar CrossRef Search ADS PubMed 4 Motzer RJ , Hutson TE , Cella D , et al. . Pazopanib versus sunitinib in metastatic renal-cell carcinoma . N Engl J Med 2013 ; 369 : 722 – 31 . Google Scholar CrossRef Search ADS PubMed 5 Escudier B , Porta C , Bono P , et al. . Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study . J Clin Oncol 2014 ; 32 : 1412 – 8 . Google Scholar CrossRef Search ADS PubMed 6 Alasker A , Meskawi M , Sun M , et al. . A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma . Cancer Treat Rev 2013 ; 39 : 388 – 401 . Google Scholar CrossRef Search ADS PubMed 7 Cohen RB , Oudard S . Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities . Invest New Drugs 2012 ; 30 : 2066 – 79 . 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Importance of continuing therapy and maintaining one-month relative dose intensity in sunitinib therapy for metastatic renal cell carcinoma . Med Oncol 2012 ; 29 : 3298 – 3305 . Google Scholar CrossRef Search ADS PubMed 12 Ishihara H , Kondo T , Omae K , et al. . Sarcopenia and the modified Glasgow prognostic score are significant predictors of survival among patients with metastatic renal cell carcinoma who are receiving first-line sunitinib treatment . Target Oncol 2016 ; 11 : 605 – 17 . Google Scholar CrossRef Search ADS PubMed 13 Ishihara H , Kondo T , Yoshida K , et al. . Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy . Urol Oncol 2017 ; 35 : 542.e541 – 542.e549 . 14 Bedke J , Gauler T , Grunwald V , et al. . Systemic therapy in metastatic renal cell carcinoma . World J Urol 2017 ; 35 : 179 – 88 . Google Scholar CrossRef Search ADS PubMed 15 Iacovelli R , Massari F , Albiges L , et al. . Evidence and clinical relevance of tumor flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma . Eur Urol 2015 ; 68 : 154 – 60 . Google Scholar CrossRef Search ADS PubMed 16 Bracarda S , Iacovelli R , Boni L , et al. . Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis . Ann Oncol 2015 ; 26 : 2107 – 13 . Google Scholar CrossRef Search ADS PubMed 17 Najjar YG , Mittal K , Elson P , et al. . A 2 weeks on and 1 w eek off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell Eur J Cancer 2014 ; 50 : 1084 – 9 . Google Scholar CrossRef Search ADS PubMed 18 Kondo T , Takagi T , Kobayashi H , et al. . Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma—comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off . Jpn J Clin Oncol 2014 ; 44 : 270 – 7 . Google Scholar CrossRef Search ADS PubMed 19 Segarra I , Modamio P , Fernandez C , et al. . Sunitinib possible sex-divergent therapeutic outcomes . Clin Drug Investig 2016 ; 36 : 791 – 9 . Google Scholar CrossRef Search ADS PubMed 20 Kaymakcalan MD , Xie W , Albiges L , et al. . Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy: results from the International Metastatic Renal Cell Carcinoma Database Consortium . Cancer 2016 ; 122 : 411 – 9 . Google Scholar CrossRef Search ADS PubMed 21 Akaza H , Naito S , Ueno N , et al. . Real-world use of sunitinib in Japanese patients with advanced renal cell carcinoma: efficacy, safety and biomarker analyses in 1689 consecutive patients . Jpn J Clin Oncol 2015 ; 45 : 576 – 83 . Google Scholar CrossRef Search ADS PubMed 22 Motzer RJ , Hutson TE , Olsen MR , et al. . Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma . J Clin Oncol 2012 ; 30 : 1371 – 7 . Google Scholar CrossRef Search ADS PubMed 23 Tomita Y , Shinohara N , Yuasa T , et al. . Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma . Jpn J Clin Oncol 2010 ; 40 : 1166 – 72 . Google Scholar CrossRef Search ADS PubMed 24 Brunello A , Basso U , Sacco C , et al. . Safety and activity of sunitinib in elderly patients (>/= 70 years) with metastatic renal cell carcinoma: a multicenter study . Ann Oncol 2013 ; 24 : 336 – 42 . Google Scholar CrossRef Search ADS PubMed 25 Hutson TE , Bukowski RM , Rini BI , et al. . Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma . Br J Cancer 2014 ; 110 : 1125 – 32 . Google Scholar CrossRef Search ADS PubMed 26 Zhu X , Stergiopoulos K , Wu S . Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis . Acta Oncol 2009 ; 48 : 9 – 17 . Google Scholar CrossRef Search ADS PubMed 27 Ishihara H , Kondo T , Fukuda H , et al. . Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma . Jpn J Clin Oncol 2017 ; 47 : 1175 – 81 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Decreased relative dose intensity during the early phase of treatment impacts the therapeutic efficacy of sunitinib in metastatic renal cell carcinoma

Japanese Journal of Clinical Oncology , Volume Advance Article (7) – May 31, 2018
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Oxford University Press
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0368-2811
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10.1093/jjco/hyy078
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29860353
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Abstract

Abstract Background Relative dose intensity is an indicator of therapeutic efficacy in sunitinib treatment for metastatic renal cell carcinoma. However, the number of studies investigating the influence of decreased relative dose intensity during the early phase on oncological outcome is limited. Methods A total of 105 patients who received first-line sunitinib treatment for metastatic renal cell carcinoma were evaluated. We assessed the relative dose intensity during the initial first cycle (1c-RDI). We found that an optimal threshold of 1c-RDI was associated with progression-free survival and overall survival after the initiation of sunitinib treatment. Additionally, predictive factors for decreased 1c-RDI were analyzed. Results The 1c-RDI threshold was determined at 60%. Patients with low 1c-RDI (<60%, n = 26, [24.8%]) had significantly shorter median progression-free survival (5.79 vs. 14.0 months, P = 0.0014) and overall survival (13.3 vs. 34.4 months, P = 0.0005) durations than those with high 1c-RDI (≥60%, n = 79 [75.2%]). Multivariate analysis showed that the development of dose-limiting toxicity was an independent factor for low 1c-RDI (odds ratio: 3.09, 95% confidence interval: 1.14–8.37, P = 0.0266) after adjustment with an initial dose of sunitinib. Conclusions More than 60% of 1c-RDI is needed for effective sunitinib treatment. Patient tolerability should be carefully monitored to avoid the development of dose-limiting toxicity during the early phase of treatment. renal cancer, targeted therapy, adverse event, tolerability, dose-limiting toxicity Introduction Sunitinib (SU) is an anticancer drug and a receptor tyrosine kinase inhibitor mainly targeting the vascular endothelial cell growth factor receptors and blocks vascular endothelial cell growth factor signaling. It is approved as a first-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC) (1). SU is more beneficial to patient survival than conventional cytokine therapy (2,3) and has been broadly applied in current clinical practice. However, its toxicity is a major issue. Frequent and severe adverse events (AEs) induced by SU can result in treatment withdrawal, dose reduction or treatment interruption, that is, dose-limiting toxicity (DLT) (2,4–9). In a previous pivotal trial, SU-induced toxicities, mainly gastrointestinal disorder, hypertension, hand–foot syndrome, general fatigue or hemototoxicity, led to dose reduction and treatment termination in 50 and 19% of the patients, respectively (2). DLTs can directly decrease relative dose intensity (RDI). Maintaining the RDI, particularly in the early phase of treatment, is essential to efficient and continuous treatment and is significantly associated with patient survival (10,11). However, the number of studies investigating the impact of decreased RDI during the early phase of treatment on the oncological outcome is limited, particularly in patients without prior cytokine therapy. Moreover, predicting the decreased RDI before initiation of treatment or during treatment is difficult. Thus, risk factors for such a possibility should be identified. In this study, we investigated the influence of decreased RDI during the early phase on the therapeutic efficacy of first-line SU treatment in patients with mRCC without prior cytokine therapy. Additionally, risk factors for decreased RDI were analyzed. Materials and methods Study design First of all, we nominated patients who received at least one dose of oral SU. In our department between January 2007 and July 2017, 112 patients received first-line SU treatment for mRCC without prior cytokine therapy. Of these, we excluded those who had either undergone a kidney transplantation (n = 1) or whose clinical data were lacking (n = 6). Finally, 105 patients were evaluated in this retrospective single-center analysis. All study procedures were approved by the Institutional Review Board of Tokyo Women’s Medical University and were in accordance with the Declaration of Helsinki (ID: 4551). To determine the influence of decreased RDI during the early phase of treatment on the therapeutic efficacy of first-line SU for mRCC, we calculated the RDI during the initial first cycle (1c-RDI) as RDI in early phase. Patients were classified into the following two groups, low and high 1c-RDI, based on the 1c-RDI threshold associated with oncological outcome, including progression-free survival (PFS) and overall survival (OS), after initiation of treatment. Furthermore, we analyzed the predictive factors for decreased 1c-RDI. Protocols of first-line SU treatment We followed the protocol for first-line SU treatment as described elsewhere (12,13). Briefly, the main agent for first-line molecular-targeted therapy was SU. Patients with mRCC were treated using a 4-week-on/2-week-off or a 2-week-on/1-week-off schedule. SU treatment was initiated at a dosage of 50 mg/day and was modified based on individual patient factors. Three factors were considered for the reduction of the initial dose: (i) age: >65 years, (ii) serum creatinine levels: >2 mg/dL and (iii) a body weight: <50 kg. If one of these three factors was observed, the initial dose was reduced to 37.5 mg. If two factors were observed, the initial dose was reduced to 25 mg. We never reduced the initial dose to <25 mg. The dose was subsequently increased by 12.5 mg until the highest tolerable dose was determined, although the dose never exceeded 50 mg. Toxicity was assessed at each visit (every 1–2 weeks during the first cycle) and then every month according to the patient’s condition. AEs were graded using the Common Terminology Criteria for Adverse Events of the National Cancer Institute, version 4.0. The dose was reduced or interrupted based on the guidelines for SU therapy. Statistical analysis Continuous and categorical variables were analyzed using the Mann–Whitney U-test and the χ2 test or Fischer’s extract test, respectively. PFS and OS were defined as the time from therapy initiation to the date of progression and date of death from any cause, respectively. Survival was calculated using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate logistic regression analyses were used to identify risk factors for low 1c-RDI. Also, univariate and multivariate analyses using Cox proportional hazards regression models were used to identify the prognostic factors for PFS and OS. The risk was expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). All analyses were performed using JMP software (version 13; SAS Institute Inc., Cary, NC, USA), and P values <0.05 were considered statistically significant. Results Patient background We examined a threshold of 1c-RDI influencing PFS and OS. Consequently, a 1c-RDI threshold of 60% was determined to be strongly associated with PFS and OS after evaluating the P values of various thresholds of 1c-RDI and selecting the threshold with the lowest P values (Table 1). Based on the threshold, 26 patients (24.8%) were classified into the low-1c-RDI group (i.e. <60%). Female sex (P = 0.0053), low initial dose of SU (P = 0.0345) and higher incidence of DLT were more frequently observed in the low-1c-RDI group than in the high-1c-RDI group. Other clinicopathological factors, including age, body weight, pathological type, prior nephrectomy status, the Memorial Sloan Kettering Cancer Center risk classification, number of metastatic sites or treatment schedule did not significantly differ between the two groups (all P > 0.05) (Table 2). The follow-up period was significantly shorter in patients with low 1c-RDI than those with high 1c-RDI (P = 0.0037). Table 1. Determination of the cult-off value of 1c-RDI associated with survival Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 RDI, relative dose intensity; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. Table 1. Determination of the cult-off value of 1c-RDI associated with survival Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 Cut-off value of 1c-RDI n PFS OS ≥ vs. < HR 95% CI P HR 95% CI P 55 82 vs. 23 1.95 1.09–3.31 0.0256 2.21 1.22–3.83 0.0061 60 79 vs. 26 2.31 1.33–3.84 0.0035 2.55 1.45–4.36 0.0015 65 67 vs. 38 1.59 0.97–2.55 0.0664 1.88 1.11–3.15 0.0185 70 59 vs. 46 1.58 0.98–2.52 0.0582 1.82 1.09–3.05 0.0230 75 58 vs. 47 1.65 1.03–2.63 0.0373 1.81 1.08–3.04 0.0240 80 24 vs. 81 1.09 0.66–1.89 0.743 1.13 0.63–2.14 0.692 RDI, relative dose intensity; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. Table 2. Patient background Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 ∗Median (interquartile). MSKCC, Memorial Sloan Kettering Cancer Center; DLT, dose-limiting toxicity. Table 2. Patient background Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 Variables 1c-RDI ≥ 60 (n = 79) 1c-RDI < 60 (n = 26) P Sex 0.0053 Female (ref. male) 17 (21.5%) 13 (50.0%) Age, years 0.283 ≥65 (ref. <65) 36 (45.6%) 15 (57.7%) Body weight, kg 0.178 <50 (ref. ≥50) 12 (15.2%) 7 (26.9%) Histology 0.117 Clear-cell carcinoma 61 (77.2%) 16 (61.5%) Non-clear-cell carcinoma 18 (22.8%) 10 (38.5%) Papillary renal cell carcinoma 4 (5.06%) 2 (7.69%) Clear-cell carcinoma with spindle cell 5 (6.33%) 4 (15.4%) Others/unknown 9 (11.4%) 4 (15.4%) Prior nephrectomy 0.346 With 72 (91.1%) 22 (84.6%) Radical nephrectomy 68 (86.1%) 22 (84.6%) Partial nephrectomy 4 (5.06%) 0 Without 7 (8.86%) 4 (15.4%) MSKCC risk 0.830 Favorable 13 (16.5%) 3 (11.5%) Intermediate 55 (69.6%) 19 (73.1%) Poor 11 (13.9%) 4 (15.4%) Number of metastatic sites 0.611 Multiple (ref. single) 41 (51.9%) 12 (46.2%) Initial dose, mg 0.0345 50 (ref. ≤375) 26 (32.9%) 3 (11.5%) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 22 (27.9%) 8 (30.8%) DLT <0.0001 With 34 (43.0%) 18 (69.2%) Dose reduction 20 (25.3%) 1 (3.85%) Treatment interruption 14 (17.7%) 17 (65.4%) Without 45 (57.0%) 8 (30.8%) *Follow-up period, month 23.5 (11.0–39.3) 11.2 (4.43–20.6) 0.0037 ∗Median (interquartile). MSKCC, Memorial Sloan Kettering Cancer Center; DLT, dose-limiting toxicity. Survival according to 1c-RDI In the follow-up period, 73 patients (69.5%) experienced disease progression and 59 patients (56.2%) died of any cause. Figure 1 shows that the median duration of PFS and OS were significantly shorter in patients with low 1c-RDI than those with high 1c-RDI (PFS: 5.79 [95% CI: 2.76–8.02] vs. 14.0 [95% CI: 10.7–20.7] months, P = 0.0014; OS: 13.3 [95% CI: 4.73–20.0] vs. 34.4 [95% CI: 26.1–52.6] months, P = 0.0005). Figure 1. View largeDownload slide PFS and OS according to 1c-RDI threshold. Median PFS and OS were significantly shorter in patients with low 1c-RDI (PFS: 5.79 vs. 14.0 months, P = 0.0014; OS: 13.3 vs. 34.4 months, P = 0.0005). 1c-RDI, relative dose intensity during the initial first cycle; PFS, progression-free survival; OS, overall survival. Figure 1. View largeDownload slide PFS and OS according to 1c-RDI threshold. Median PFS and OS were significantly shorter in patients with low 1c-RDI (PFS: 5.79 vs. 14.0 months, P = 0.0014; OS: 13.3 vs. 34.4 months, P = 0.0005). 1c-RDI, relative dose intensity during the initial first cycle; PFS, progression-free survival; OS, overall survival. Predictors for low 1c-RDI Table 3 shows the results of univariate and multivariate logistic regression analyses for 1c-RDI < 60%. Univariate analysis showed that female sex, lower initial dose and DLT development were associated with low 1c-RDI (all, P < 0.05). Multivariate analysis showed that DLT development (OR: 3.09, 95% CI: 1.14–8.37, P = 0.0266) and female sex (OR: 3.11, 95% CI: 1.16–8.34, P = 0.0240) were independent predictors for low 1c-RDI after adjustment for the initial dose of SU. Table 3. Univariate and multivariate logistic regression analyses for 1c-RDI < 60% Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) OR, odds ratio. Table 3. Univariate and multivariate logistic regression analyses for 1c-RDI < 60% Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) Variables Univariate Multivariate OR (95% CI) P OR (95% CI) P Sex 0.0068 0.0240 Female (ref. male) 3.65 (1.43–9.31) 3.11 (1.16–8.34) Age, years 0.286 ≥65 (ref. <65) 1.63 (0.67–3.99) Body weight, kg 0.183 <50 (ref. ≥50) 2.06 (0.71–5.95) Histology 0.121 Non-clear-cell carcinoma (ref. clear-cell carcinoma) 2.12 (0.82–5.47) MSKCC risk 0.822 Favorable (ref. intermediate) 0.67 (0.17–2.60) 0.561 Poor (ref. intermediate) 1.06 (0.30–3.70) 0.936 Number of metastatic site 0.612 Multiple (ref. single) 0.79 (0.33–1.93) Initial dose, mg 0.0444 0.0632 ≤37.5 (ref. 50) 3.76 (1.03–13.7) 3.58 (0.93–13.8) Treatment schedule 0.775 4-week on/2-week off (ref. 2-week on/1-week off) 1.15 (0.44–3.03) DLT 0.0235 0.0266 With (ref. without) 2.98 (1.16–7.66) 3.09 (1.14–8.37) OR, odds ratio. Predictors for PFS and OS Supplementary Tables S1 and S2 show the results of univariate and multivariate analyses for PFS and OS, respectively. Multivariate analysis shows that 1c-RDI was an independent predictor (HR: 2.23, 95% CI: 1.27–3.79, P = 0.0063), along with sex (HR: 1.74, 95% CI: 1.02–2.90, P = 0.0415), histology (HR: 1.97, 95% CI: 1.15–3.31, P = 0.0135), MSKCC risk (P = 0.0154), and the number of metastatic sites (HR: 1.77, 95% CI: 1.10–2.88, P = 0.0195) for PFS. For OS, 1c-RDI was an independent predictor (HR: 2.64, 95% CI: 1.45–4.68, P = 0.0018), along with histology (HR: 2.07, 95% CI: 1.13–3.70, P = 0.0199), MSKCC risk (P = 0.0026), and the number of metastatic sites (HR: 2.65, 95% CI: 1.53–4.68, P = 0.0195), according to the multivariate analysis. Dose-limiting toxicities during the initial first cycle Table 4 shows the individual AEs that cause DLTs. The most frequent AE was thrombocytopenia (grade 2: n = 16 [30.8%], grade ≥3: n = 14 [26.9%]), followed by leukocytopenia (grade 2: n = 3 [5.77%], grade ≥3: n = 11 [21.2%]). Among the 52 patients who developed DLT, the dose was reduced and interrupted in 31 (59.6%) and 21 (40.4%) patients, respectively. Table 4. Individual AEs inducing DLTs N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) AE, adverse event. Table 4. Individual AEs inducing DLTs N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) N = 52 (%) Grade 2 Leukocytopenia 3 (5.77) Thrombocytopenia 16 (30.8) Hand–foot syndrome 2 (3.85) Nausea/vomiting/anorexia 4 (7.69) Diarrhea 1 (1.92) Fatigue 3 (5.77) Fever 4 (7.69) Hepatic injury 1 (1.92) Interstitial lung disease 1 (1.92) Hypertension 1 (1.92) Mucotitis 1 (1.92) Kidney injury 1 (1.92) UTI 1 (1.92) Grade 3 or more Leukocytopenia 11 (21.2) Thrombocytopenia 14 (26.9) Hand–foot syndrome 1 (1.92) Fatigue 1 (1.92) Hepatic injury 2 (3.85) Pancreatic injury 2 (3.85) Hyperkalemia 3 (5.77) Hepatic abscess 1 (1.92) Gastrointestinal perforation 1 (1.92) Components of DLTs Dose reduction 31 (59.6) Treatment interruption 21 (40.4) AE, adverse event. Discussion The present study indicated that more than 60% of RDI during the initial first cycle was needed to maintain the therapeutic efficacy of first-line SU treatment for mRCC. Furthermore, we found that DLT development can decrease the level of sufficient RDI; therefore, patient tolerability should be carefully monitored to avoid the development of DLT during the first cycle. SU-induced toxicities can disrupt the maintenance of efficient treatment intensity, and this can result in poor prognosis in patients with mRCC. Kawashima et al. reported that continuing treatment for more than one course and ≥60% of 1 month RDI was important for optimal efficacy of SU treatment (11). Another study reported that dose intensity below 70% during several landmark periods, including the initial three cycles, was significantly associated with shorter OS in SU treatment (10). Considering these findings, a threshold of 60% obtained from our analysis was consistent with the findings from previous studies. Notably, a unique point of the present study was that it included patients who had not received prior cytokine therapy. Thus, our findings can be applied on the current treatment strategy for mRCC (14). As RDI is affected by various factors during treatment, predicting it before treatment initiation or during treatment is difficult. Moreover, despite the need for predictors for decreased RDI that can be used to prevent it during treatment, only a limited number of clinical researches have focused on such factors. As such, we found that the development of DLT during the initial first cycle should be avoided to maintain the efficient RDI. As the initial dose of SU would be directly associated with 1c-RDI, multivariate analyses were performed to adjust for the confounding factors. The results indicated that DLT development remains a statistical significant factor influencing the RDI. Treatment discontinuation induced by intolerable AEs was previously reported to negatively affect patient prognosis (10,15). Treatment was permanently discontinued after interruption during the early phase in 8 of the 31 patients (25.8%) in our study. In these eight patients, the median 1c-RDI was 46.5%, and the survival was extremely poor (median PFS and OS: 1.16 and 3.35 months, respectively). Also, in this study, total RDI (i.e. throughout the treatment) in patients with low 1c-RDI was lower than in those with high 1c-RDI (median: 45.6 vs. 64.2%, P < 0.0001), suggesting that deterioration of therapeutic efficacy in early period influences entire efficacy, leading to poor survival. In the current analysis, the most frequent DLTs were hematotoxicities, including thrombocytopenia and leukocytopenia, that could not be treated or prevented via symptomatic treatment. A similar finding was observed in a previous study by Kawashima et al. who reported that thrombocytopenia and leukocytopenia were the most frequent AEs in SU treatment (11). Furthermore, a modified treatment schedule was not associated with a maintenance of efficient RDI, although a 2-week-on/1-week-off schedule is a common alternative schedule with less toxicity (16–18). However, the deceased drug efficacy during the early phase of treatment can negate the benefit from the modified schedule. Thus, when severe hematotoxicities occur during the initial cycle, a conversion to other agents, such as pazopanib, which is more tolerable than SU with less hematotoxicity effects (4,5), may be a more effective approach than reduced dosage or schedule modification. The lower frequency of thrombocytopenia and leukocytopenia in pazopanib than that of SU has been demonstrated (4). Finally, our analysis showed that female patients had a higher risk of decreased RDI than males. This finding was similarly observed in several previous studies. Kawashima et al. reported that women tended to discontinue SU treatment within one course (11). In their review of SU treatment, Segarra et al. reported that female patients had a higher incidence of AEs than males (19). Kaymakcalan et al. suggested that further researches should be performed to determine the impact of sex on SU-induced toxicity (20). This study had several limitations. First, this study was retrospectively performed in a single center with a relatively small cohort. Our findings were affected by unavoidable biases in patient or treatment selection. Moreover, several unrecorded AEs might exist. Second, we should note that the safety profile of SU may differ between the Asian and Western populations (21). Third, an initial dose of SU was modified using a home-based protocol (based on age, body weight and renal function) according to previous studies showing a high concentration of SU and its active metabolite in plasma with a dosage of 50 mg (22) and higher incidence of AEs in Japanese than Western patients (23). Indeed, some studies reported the possibility of weak tolerability in elderly patients (24,25). Moreover, SU can deteriorate renal function (26,27). In this context, our own protocol can reflect the situation in real world, but we should recognize some possible bias in the protocol. In conclusion, more than 60% of 1c-RDI was needed to maintain the therapeutic efficacy of first-line SU treatment for mRCC. The development of DLT during the initial first cycle can deteriorate the 1c-RDI regardless of the initial dose or treatment schedule of SU. Patient tolerability should be monitored carefully during the early phase of treatment. 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Journal

Japanese Journal of Clinical Oncology – Oxford University Press

Published: May 31, 2018

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