International Journal of Urology (2015) 22, 736--740
doi: 10.1111/iju.12803
Original Article: Clinical Investigation
Role of cytoreductive nephrectomy for Japanese patients with primary renal cell carcinoma in the cytokine and targeted therapy era Katsunori Tatsugami,1 Nobuo Shinohara,2 Tsunenori Kondo,3 Toshinari Yamasaki,4 Masatoshi Eto,5 Tomoyasu Tsushima,6 Toshiro Terachi7 and Seiji Naito1 on behalf of the Japanese Society of Renal Cancer 1
Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, 2Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, 3Department of Urology, Tokyo Women's Medical University, Tokyo, 4Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, 5Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto, 6Division of Urology, Okayama Medical Center, Okayama and 7Department of Urology, Tokai University School of Medicine, Kanagawa, Japan
Abbreviations & Acronyms CI = confidence interval CN = cytoreductive nephrectomy CRP = C‐reactive protein Cy = cytokine therapy HR = hazard ratio KPS = Karnofsky Performance Status LDH = lactate dehydrogenase mRCC = metastatic renal cell carcinoma MSKCC = Memorial Sloan Kettering Cancer Center OS = overall survival PS = performance status RCC = renal cell carcinoma Tg = targeted therapy Correspondence: Katsunori Tatsugami M.D., Ph.D., Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan. Email: [email protected]‐u.ac.jp Received 20 October 2014; accepted 30 March 2015. Online publication 18 May 2015
Objective: To assess the efficacy of cytoreductive nephrectomy for Japanese patients with primary metastatic renal cell carcinoma in the cytokine and targeted therapy era. Methods: The present retrospective study evaluated 330 Japanese patients with renal cell carcinoma who had synchronous metastases at diagnosis between 2001 and 2010. The characteristics of patients who did and did not undergo cytoreductive nephrectomy were compared. Results: Of the 330 patients, 254 (77.0%) underwent cytoreductive nephrectomy. Patients who underwent cytoreductive nephrectomy were younger; had better Karnofsky Performance Status; higher rates of lung metastases only and systemic therapy; lower rates of increased lactate dehydrogenase concentration and liver and multiple metastases; and a lower Memorial Sloan Kettering Cancer Center risk score. Independent predictors of poorer overall survival included clinical stage T3/4; poorer Memorial Sloan Kettering Cancer Center risk and Karnofsky Performance Status; increased C‐reactive protein concentration; and absence of cytoreductive nephrectomy and systemic therapy. Median overall survival was significantly longer in the patients who did rather than did not undergo cytoreductive nephrectomy, irrespective of systemic treatment. In patients without cytoreductive nephrectomy, median overall survival was significantly longer in those who received targeted (15.5 months; hazard ratio 0.45; 95% confidence interval 0.21–0.94), but not by cytokine (8.2 months; hazard ratio 0.72; 95% confidence interval 0.36–1.46) compared with no systemic treatment (4.4 months). Conclusions: Overall survival seems to be significantly longer in patients undergoing cytoreductive nephrectomy. However, prospective trials are required to confirm our results, as targeted therapy might improve the survival even in the absence of cytoreductive nephrectomy.
Key words: cytoreductive nephrectomy, Japanese, kidney, metastasis, renal cell carcinoma.
Introduction Many patients with mRCC undergo CN before systemic therapy. The introduction of targeted therapy has reduced the number of patients who undergo CN, because targeted therapy agents have a stronger antitumor effect than cytokines.1 A survey of 20 104 patients with mRCC from 1993 to 2010 in the Surveillance, Epidemiology, and End Results database showed that the proportion of patients who underwent CN declined beginning in 2005, after targeted therapy became the main treatment for mRCC.2 The role of CN in the targeted therapy era has become unclear. For example, targeted therapy has been found to prolong survival in patients with mRCC, regardless of whether they underwent CN. In contrast, CN was found to improve survival of mRCC patients, based on the condition of individual patients, showing that CN remains efficacious in the treatment of mRCC in the targeted therapy era.2,4 The prognosis of Japanese patients with mRCC was found to be better than that of patients from Western countries, with the rate of nephrectomy being higher in Japanese than in USA patients
736
© 2015 The Japanese Urological Association
Cytoreductive nephrectomy for Japanese patients
with mRCC (80.5% vs 45%).1,5 Although CN might prolong OS in Japanese mRCC patients, the effects of targeted therapy on OS in Japanese mRCC patients who do not undergo CN have not yet been determined. To confirm the efficacy and suitability of CN for Japanese patients in the cytokine and targeted therapy era, survival was investigated in RCC patients with synchronous metastases at diagnosis, as were factors influencing OS.
Methods Patients The study protocol was approved and overseen by the ethics committee review board of each participating institution. A retrospective review of seven institutions identified 330 Japanese patients diagnosed with RCC and synchronous metastases (mRCC) between 2001 and 2010. Clinical and laboratory data of these patients were collected and analyzed.
Statistical analysis Patients were divided into those who did and did not undergo CN. Categorical variables were compared using the χ2‐test or Fisher's exact test, and continuous variables were compared using Student's t‐tests. OS was measured from the date of diagnosis of mRCC to the date of death from any cause or date of last follow up. Univariable analysis of factors prognostic of OS was carried out; factors included patient age (above vs below median age), sex, KPS, symptoms, number of metastases, anemia, increased LDH, hypercalcemia, increased CRP, MSKCC risk group, clinical stage, lung metastasis, liver metastasis, cerebral metastasis, metastasectomy and type of systemic therapy (none vs cytokine therapy alone vs targeted therapy including pretreatment with cytokines). Cox proportional hazard regression models incorporating each factor were used to estimate their prognostic significance. Correlations between outcomes and assessed variables are expressed as HR and 95% CI. OS in groups stratified by type of systemic therapy was calculated by the Kaplan–Meier method. Data were analyzed using JMP pro version 11 (SAS Institute Japan, Tokyo, Japan), with a two‐sided P < 0.05 considered statistically significant.
Results From January 2001 to December 2010, 330 patients were diagnosed with RCC with synchronous metastasis, including 243 (73.6%) men and 87 (26.4%) women, of median age 63.5 years (range 11–87 years). Of these 330 patients, 254 (77.0%) underwent CN, including 47 who received no further treatment after CN. A total of 52 patients (15.8%) received systemic therapy without CN. Between January 2001 and April 2008, when the first tyrosine kinase inhibitors could be used in Japan, 182 of the 222 (82.0%) Japanese patients diagnosed with mRCC underwent CN. After April 2008, the start of the targeted therapy era, 72 of 108 (66.7%) patients underwent CN (data not shown). Figure 1 shows Kaplan–Meier curves of OS from diagnosis of mRCC in patients who did and did not undergo CN. Median OS was significantly longer in the patients who did rather than did not undergo CN (27.4 vs 10.3 months; HR 0.40; 95% CI 0.29–0.57; P < 0.001). © 2015 The Japanese Urological Association
Fig. 1 Kaplan–Meier curves showing OS from date of diagnosis in 330 patients with mRCC who did and did not undergo CN.
Table 1 shows the characteristics at diagnosis by CN status. Patients who underwent CN were younger; had better KPS; higher rates of lung metastases only and systemic therapy after CN; lower rates of increased LDH and liver and multiple metastases; and a lower MSKCC risk score. Table 2 shows univariate and multivariate analyses of factors that affected OS of these patients. Univariate analysis showed that male sex; KPS ≥80; incidental versus symptomatic at presentation; 1 versus >1 metastasis; absence of anemia; increased LDH, hypercalcemia; liver metastasis; CRP 1 mg/dL MSKCC risk group Intermediate Poor Clinical stage T1 T2 T3 T4 Lung metastasis only No Yes Liver metastasis No Yes Cerebral metastasis No Yes Metastasectomy No Yes Type of therapy Cy Tg None
330 330
Non‐CN group P‐value (n = 76)
63 (11–84) 67 (26–87) 187 (73.6) 67 (26.4)
56 (73.7) 20 (26.3)
178 (73.6) 64 (26.4)
42 (58.3) 30 (41.7)
65 (25.7) 188 (74.3)
16 (21.1) 60 (78.9)
139 (54.7) 115 (45.3)
17 (22.4) 59 (77.6)
104 (42.8) 139 (57.2)
25 (32.9) 51 (67.1)
219 (90.5) 23 (9.5)
54 (74.0) 19 (26.0)
171 (74.0) 60 (26.0)
51 (68.9) 23 (31.1)
103 (42.4) 140 (57.6)
23 (31.5) 50 (68.5)
141 (63.5) 81 (36.5)
28 (41.8) 39 (58.2)
62 32 135 23
22 7 29 17
314
0.0046 1.0000
Univariate analysis Age Sex KPS Presentation
0.0133
329
0.4104
330
doi: 10.1111/iju.12803
Original Article: Clinical Investigation
Role of cytoreductive nephrectomy for Japanese patients with primary renal cell carcinoma in the cytokine and targeted therapy era Katsunori Tatsugami,1 Nobuo Shinohara,2 Tsunenori Kondo,3 Toshinari Yamasaki,4 Masatoshi Eto,5 Tomoyasu Tsushima,6 Toshiro Terachi7 and Seiji Naito1 on behalf of the Japanese Society of Renal Cancer 1
Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, 2Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, 3Department of Urology, Tokyo Women's Medical University, Tokyo, 4Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, 5Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto, 6Division of Urology, Okayama Medical Center, Okayama and 7Department of Urology, Tokai University School of Medicine, Kanagawa, Japan
Abbreviations & Acronyms CI = confidence interval CN = cytoreductive nephrectomy CRP = C‐reactive protein Cy = cytokine therapy HR = hazard ratio KPS = Karnofsky Performance Status LDH = lactate dehydrogenase mRCC = metastatic renal cell carcinoma MSKCC = Memorial Sloan Kettering Cancer Center OS = overall survival PS = performance status RCC = renal cell carcinoma Tg = targeted therapy Correspondence: Katsunori Tatsugami M.D., Ph.D., Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan. Email: [email protected]‐u.ac.jp Received 20 October 2014; accepted 30 March 2015. Online publication 18 May 2015
Objective: To assess the efficacy of cytoreductive nephrectomy for Japanese patients with primary metastatic renal cell carcinoma in the cytokine and targeted therapy era. Methods: The present retrospective study evaluated 330 Japanese patients with renal cell carcinoma who had synchronous metastases at diagnosis between 2001 and 2010. The characteristics of patients who did and did not undergo cytoreductive nephrectomy were compared. Results: Of the 330 patients, 254 (77.0%) underwent cytoreductive nephrectomy. Patients who underwent cytoreductive nephrectomy were younger; had better Karnofsky Performance Status; higher rates of lung metastases only and systemic therapy; lower rates of increased lactate dehydrogenase concentration and liver and multiple metastases; and a lower Memorial Sloan Kettering Cancer Center risk score. Independent predictors of poorer overall survival included clinical stage T3/4; poorer Memorial Sloan Kettering Cancer Center risk and Karnofsky Performance Status; increased C‐reactive protein concentration; and absence of cytoreductive nephrectomy and systemic therapy. Median overall survival was significantly longer in the patients who did rather than did not undergo cytoreductive nephrectomy, irrespective of systemic treatment. In patients without cytoreductive nephrectomy, median overall survival was significantly longer in those who received targeted (15.5 months; hazard ratio 0.45; 95% confidence interval 0.21–0.94), but not by cytokine (8.2 months; hazard ratio 0.72; 95% confidence interval 0.36–1.46) compared with no systemic treatment (4.4 months). Conclusions: Overall survival seems to be significantly longer in patients undergoing cytoreductive nephrectomy. However, prospective trials are required to confirm our results, as targeted therapy might improve the survival even in the absence of cytoreductive nephrectomy.
Key words: cytoreductive nephrectomy, Japanese, kidney, metastasis, renal cell carcinoma.
Introduction Many patients with mRCC undergo CN before systemic therapy. The introduction of targeted therapy has reduced the number of patients who undergo CN, because targeted therapy agents have a stronger antitumor effect than cytokines.1 A survey of 20 104 patients with mRCC from 1993 to 2010 in the Surveillance, Epidemiology, and End Results database showed that the proportion of patients who underwent CN declined beginning in 2005, after targeted therapy became the main treatment for mRCC.2 The role of CN in the targeted therapy era has become unclear. For example, targeted therapy has been found to prolong survival in patients with mRCC, regardless of whether they underwent CN. In contrast, CN was found to improve survival of mRCC patients, based on the condition of individual patients, showing that CN remains efficacious in the treatment of mRCC in the targeted therapy era.2,4 The prognosis of Japanese patients with mRCC was found to be better than that of patients from Western countries, with the rate of nephrectomy being higher in Japanese than in USA patients
736
© 2015 The Japanese Urological Association
Cytoreductive nephrectomy for Japanese patients
with mRCC (80.5% vs 45%).1,5 Although CN might prolong OS in Japanese mRCC patients, the effects of targeted therapy on OS in Japanese mRCC patients who do not undergo CN have not yet been determined. To confirm the efficacy and suitability of CN for Japanese patients in the cytokine and targeted therapy era, survival was investigated in RCC patients with synchronous metastases at diagnosis, as were factors influencing OS.
Methods Patients The study protocol was approved and overseen by the ethics committee review board of each participating institution. A retrospective review of seven institutions identified 330 Japanese patients diagnosed with RCC and synchronous metastases (mRCC) between 2001 and 2010. Clinical and laboratory data of these patients were collected and analyzed.
Statistical analysis Patients were divided into those who did and did not undergo CN. Categorical variables were compared using the χ2‐test or Fisher's exact test, and continuous variables were compared using Student's t‐tests. OS was measured from the date of diagnosis of mRCC to the date of death from any cause or date of last follow up. Univariable analysis of factors prognostic of OS was carried out; factors included patient age (above vs below median age), sex, KPS, symptoms, number of metastases, anemia, increased LDH, hypercalcemia, increased CRP, MSKCC risk group, clinical stage, lung metastasis, liver metastasis, cerebral metastasis, metastasectomy and type of systemic therapy (none vs cytokine therapy alone vs targeted therapy including pretreatment with cytokines). Cox proportional hazard regression models incorporating each factor were used to estimate their prognostic significance. Correlations between outcomes and assessed variables are expressed as HR and 95% CI. OS in groups stratified by type of systemic therapy was calculated by the Kaplan–Meier method. Data were analyzed using JMP pro version 11 (SAS Institute Japan, Tokyo, Japan), with a two‐sided P < 0.05 considered statistically significant.
Results From January 2001 to December 2010, 330 patients were diagnosed with RCC with synchronous metastasis, including 243 (73.6%) men and 87 (26.4%) women, of median age 63.5 years (range 11–87 years). Of these 330 patients, 254 (77.0%) underwent CN, including 47 who received no further treatment after CN. A total of 52 patients (15.8%) received systemic therapy without CN. Between January 2001 and April 2008, when the first tyrosine kinase inhibitors could be used in Japan, 182 of the 222 (82.0%) Japanese patients diagnosed with mRCC underwent CN. After April 2008, the start of the targeted therapy era, 72 of 108 (66.7%) patients underwent CN (data not shown). Figure 1 shows Kaplan–Meier curves of OS from diagnosis of mRCC in patients who did and did not undergo CN. Median OS was significantly longer in the patients who did rather than did not undergo CN (27.4 vs 10.3 months; HR 0.40; 95% CI 0.29–0.57; P < 0.001). © 2015 The Japanese Urological Association
Fig. 1 Kaplan–Meier curves showing OS from date of diagnosis in 330 patients with mRCC who did and did not undergo CN.
Table 1 shows the characteristics at diagnosis by CN status. Patients who underwent CN were younger; had better KPS; higher rates of lung metastases only and systemic therapy after CN; lower rates of increased LDH and liver and multiple metastases; and a lower MSKCC risk score. Table 2 shows univariate and multivariate analyses of factors that affected OS of these patients. Univariate analysis showed that male sex; KPS ≥80; incidental versus symptomatic at presentation; 1 versus >1 metastasis; absence of anemia; increased LDH, hypercalcemia; liver metastasis; CRP 1 mg/dL MSKCC risk group Intermediate Poor Clinical stage T1 T2 T3 T4 Lung metastasis only No Yes Liver metastasis No Yes Cerebral metastasis No Yes Metastasectomy No Yes Type of therapy Cy Tg None
330 330
Non‐CN group P‐value (n = 76)
63 (11–84) 67 (26–87) 187 (73.6) 67 (26.4)
56 (73.7) 20 (26.3)
178 (73.6) 64 (26.4)
42 (58.3) 30 (41.7)
65 (25.7) 188 (74.3)
16 (21.1) 60 (78.9)
139 (54.7) 115 (45.3)
17 (22.4) 59 (77.6)
104 (42.8) 139 (57.2)
25 (32.9) 51 (67.1)
219 (90.5) 23 (9.5)
54 (74.0) 19 (26.0)
171 (74.0) 60 (26.0)
51 (68.9) 23 (31.1)
103 (42.4) 140 (57.6)
23 (31.5) 50 (68.5)
141 (63.5) 81 (36.5)
28 (41.8) 39 (58.2)
62 32 135 23
22 7 29 17
314
0.0046 1.0000
Univariate analysis Age Sex KPS Presentation
0.0133
329
0.4104
330
