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| Optimal sequential therapy using tyrosine kinase inhibitors as the first-line treatment in patients with metastatic renal cell carcinoma: A nationwide multicenter study |
Jung Ki Joa,*( ),Seong Il Seob,MinYong Kangb,Jinsoo Chungc,Cheol Kwakd,Sung-Hoo Honge,Cheryn Songf,Jae Young Parkg,Chang Wook Jeongd,Seok Hwan Choih,Sung Han Kimc,Eu Chang Hwangi,Chan Ho Leej,Hakmin Leek
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aDepartment of Urology, Medical and Digital Engineering, College of Medicine, Hanyang University, Seoul, Republic of Korea
bDepartment of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
cDepartment of Urology, National Cancer Center, Goyang, Republic of Korea
dDepartment of Urology, Seoul National University Hospital, Seoul, Republic of Korea
eDepartment of Urology, Kangnam St Mary’s Hospital, Seoul, Republic of Korea
fDepartment of Urology, Asan Medical Center, Seoul, Republic of Korea
gDepartment of Urology, Korea University Ansan Hospital, Ansan, Republic of Korea
hDepartment of Urology, Kyungpook National University Hospital, Daegu, Republic of Korea
iDepartment of Urology, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea
jDepartment of Urology, Inje University Busan Paik Hospital, Busan, Republic of Korea
kDepartment of Urology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea |
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Abstract Objective: The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor (TKI) as the first-line therapy for patients with metastatic renal cell carcinoma (mRCC) in terms of overall survival (OS), progression-free survival (PFS), and rates of discontinuation and adverse effects during the treatment period. Methods: This is a retrospective, nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017. We focused on patients at either “favorable” or “intermediate” risk according to the International mRCC Database Consortium criteria, and they were followed up (median 335 days). Finally, a total of 1409 patients were selected as the study population. We generated a Cox proportional hazard model adjusted for covariates, and the different therapy schemes were statistically tested in terms of OS as well as PFS. In addition, frequencies of discontinuation and adverse events were compared among the therapy schemes. Results: Of the primary patterns of treatment sequences (24 sequences), “sunitinib-pazopanib” and “sunitinib-everolimus-immunotherapy” showed the most beneficial results in both OS and PFS with significantly lower hazards than “sunitinib”, which is the most commonly treated agent in Korea. Considering that the “TKI-TKI” structure showed relatively higher discontinuation rates with higher adverse effects, the overall beneficial sequence would be “sunitinib-everolimus-immunotherapy”. Conclusion: Among several sequential therapy starting with TKIs, “sunitinib-everolimus- immunotherapy” was found to be the best scheme for mRCC patients with “favorable” or “intermediate” risks.
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Received: 26 May 2022
Available online: 20 July 2024
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Corresponding Authors:
*E-mail address: victorjo38@hanyang.ac.kr (J.K. Jo).
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The diagram of study population selection process. TKI, tyrosine kinase inhibitor; IMDC, the International Metastatic Renal Cell Carcinoma Database Consortium.
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| Characteristics | Sunitiniba (n=891) | Sorafeniba (n=194) | Pazopaniba (n=324) | p-Value | | Gender | | | | 0.0245b | | Female | 183 (20.54) | 51 (26.29) | 88 (27.16) | | | Male | 708 (79.46) | 143 (73.71) | 236 (72.84) | | | Age, year | 56.41±10.96 | 60.32±11.42 | 60.51±24.00 | <0.0001 | | BMI, kg/m2 | 23.82±3.49 | 23.53±3.51 | 24.00±3.58 | 0.3554 | | Comorbidity | | | | | | DM | 162 (18.18) | 56 (28.87) | 67 (20.68) | 0.0035b | | Hypertension | 360 (40.40) | 92 (47.42) | 153 (47.22) | 0.0417 | | Smoking status | | | | 0.0521b | | Non-smoker | 500 (56.12) | 127 (65.46) | 189 (58.33) | | | Ex-smoker | 211 (23.68) | 37 (19.07) | 90 (27.78) | | | Current smoker | 129 (14.48) | 22 (11.34) | 32 (9.88) | | | Unknown | 51 (5.72) | 8 (4.12) | 13 (4.01) | | | Metastasis | | | | 0.3398b | | Synchronous | 462 (51.85) | 103 (53.09) | 154 (47.53) | | | Metachronous | 429 (48.15) | 91 (46.91) | 170 (52.47) | | | Pathological stage | | | | 0.5498b | | T1 | 50 (5.61) | 17 (8.76) | 14 (4.32) | | | T2 | 43 (4.83) | 12 (6.19) | 10 (3.09) | | | T3 | 178 (19.98) | 43 (22.16) | 55 (16.98) | | | T4 | 20 (2.24) | 2 (1.03) | 9 (2.78) | | | NA | 600 (67.34) | 120 (61.86) | 236 (72.84) | | | IMDC risk | | | | 0.82 | | Favorable | 210 (23.57) | 47 (24.23) | 82 (25.31) | | | Intermediate | 681 (76.43) | 147 (75.77) | 242 (74.69) | | | No. of m-organs | 1.59±0.80 | 1.43±0.68 | 1.58±0.80 | 0.1333 | | Metastasis | | | | | | Liver | 33 (3.70) | 9 (4.64) | 12 (3.70) | 0.8484b | | Lung | 313 (35.13) | 72 (37.11) | 105 (32.41) | 0.9212b | | Bone | 115 (12.91) | 22 (11.34) | 29 (8.95) | 0.2815b | | Brain | 22 (2.47) | 4 (2.06) | 6 (1.85) | 0.8624b | | NA | 408 (45.79) | 87 (44.85) | 172 (53.09) | | | KPS (<80) | 152 (17.06) | 27 (13.92) | 54 (16.67) | 0.5642b | | Hb, g/dL | 12.65±2.32 | 12.80±2.37 | 12.39±2.44 | 0.3637 | | Platelet, 103/μL | 291.05±104.33 | 265.71±96.95 | 288.24±103.35 | 0.0903 | | Neutrophil, /μL | 5059.5±2117.7 | 5263.0±2773.3 | 4907.4±1982.5 | 0.4714 | | Lymphocyte, /μL | 1789.3±635.8 | 1786.5±745.7 | 1846.2±694.8 | 0.6616 |
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Clinical characteristics of the patients at TKI initiation (n=1409).
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| Sequence | First line | Second line | Third line | Patient, n (%) | | 1 | Sunitinib | | | 406 (28.81) | | 2 | Pazopanib | | | 255 (18.10) | | 3 | Sunitinib | Everolimus | | 197 (13.98) | | 4 | Pazopanib | Everolimus | | 89 (6.32) | | 5 | Sunitinib | Sorafenib | | 45 (3.19) | | 6 | Sorafenib | Everolimus | | 38 (2.70) | | 7 | Sunitinib | Everolimus | Pazopanib | 36 (2.56) | | 8 | Sunitinib | Everolimus | Sorafenib | 23 (1.63) | | 9 | Sunitinib | Sorafenib | Everolimus | 21 (1.49) | | 10 | Sunitinib | Pazopanib | Everolimus | 21 (1.49) | | 11 | Sunitinib | Temsirolimus | | 18 (1.28) | | 12 | Pazopanib | Everolimus | Sunitinib | 16 (1.14) | | 13 | Sunitinib | Everolimus | IFN+Chemo | 15 (1.06) | | 14 | Sunitinib | IFN+Chemo | | 13 (0.92) | | 15 | Sunitinib | Pazopanib | | 12 (0.85) | | 16 | Sorafenib | Sunitinib | | 10 (0.71) | | 17 | Pazopanib | Sunitinib | Everolimus | 5 (0.35) | | 18 | Sunitinib | Everolimus | Immunotherapy | 7 (0.50) | | 19 | Sorafenib | Everolimus | Pazopanib | 7 (0.50) | | 20 | Pazopanib | Everolimus | Sorafenib | 7 (0.50) | | 21 | Sunitinib | Axitinib | | 6 (0.43) | | 22 | Sorafenib | IFN+Chemo | | 6 (0.43) | | 23 | Pazopanib | Sunitinib | | 6 (0.43) | | 24 | Sunitinib | Everolimus | IL-2+Chemo (HDIV) | 6 (0.43) |
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The primary patterns of treatment sequences (n=1265).
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| Variable | OS | PFS | | HR | 95% CI | p-Value | HR | 95% CI | p-Value | | Age | 1.0195 | 1.0129-1.0262 | <0.0001??? | 1.0115 | 1.0060-1.0171 | <0.0001??? | | Metachronous type | 0.2275 | 0.1937-0.2719 | <0.0001??? | 0.8374 | 0.7339-0.9555 | 0.0084?? | | Intermediate risk | 1.4885 | 1.2383-1.7892 | <0.0001??? | 1.4173 | 1.2173-1.6503 | <0.0001??? | | No. of m-organs | 1.3018 | 1.2144-1.3955 | <0.0001??? | 1.1487 | 1.0801-1.2216 | <0.0001??? | | Seq 2 | 0.7288 | 0.5904-0.8995 | 0.0032?? | 0.8770 | 0.7462-1.0308 | 0.1114 | | Seq 3 | 1.1863 | 0.9739-1.4449 | 0.0896 | 0.5679 | 0.4777-0.6752 | <0.0001??? | | Seq 4 | 0.8666 | 0.6513-1.1531 | 0.3257 | 0.6325 | 0.5000-0.8001 | 0.0001??? | | Seq 5 | 1.7787 | 1.2821-2.4678 | 0.0006??? | 0.8910 | 0.6531-1.2154 | 0.4662 | | Seq 6 | 0.7995 | 0.5581-1.1454 | 0.2225 | 0.4587 | 0.3279-0.6417 | <0.0001??? | | Seq 7 | 0.9377 | 0.6344-1.3860 | 0.7469 | 0.3191 | 0.2250-0.4525 | <0.0001??? | | Seq 8 | 1.0102 | 0.6459-1.5801 | 0.9645 | 0.4469 | 0.2931-0.6814 | 0.0002??? | | Seq 9 | 0.7629 | 0.4781-1.2172 | 0.2562 | 0.3656 | 0.2353-0.5680 | <0.0001??? | | Seq 10 | 0.7998 | 0.4666-1.3709 | 0.4165 | 0.3973 | 0.2557-0.6172 | <0.0001 | | Seq 11 | 1.6704 | 1.0211-2.7326 | 0.0410? | 0.5697 | 0.3545-0.9154 | 0.0200? | | Seq 12 | 0.9127 | 0.4981-1.6726 | 0.7676 | 0.5159 | 0.3124-0.8520 | 0.0097?? | | Seq 13 | 0.9863 | 0.5639-1.7251 | 0.9613 | 0.4748 | 0.2781-0.8106 | 0.0063?? | | Seq 14 | 1.8608 | 1.0623-3.2594 | 0.0299? | 1.6462 | 0.9434-2.8728 | 0.0793 | | Seq 15 | 0.4098 | 0.1525-1.1008 | 0.0768 | 0.4244 | 0.2382-0.7562 | 0.0036?? | | Seq 16 | 3.5171 | 1.8610-6.6468 | 0.0001??? | 1.7267 | 0.9192-3.2437 | 0.0895 | | Seq 17 | 1.5506 | 0.8218-2.9257 | 0.1757 | 0.5763 | 0.3069-1.0821 | 0.0864 | | Seq 18 | 0.2698 | 0.0670-1.0870 | 0.0654 | 0.3691 | 0.1744-0.7814 | 0.0092?? | | Seq 19 | 0.6545 | 0.3076-1.3926 | 0.2712 | 0.2674 | 0.1261-0.5671 | 0.0006??? | | Seq 20 | 0.5579 | 0.2076-1.4996 | 0.2474 | 0.4091 | 0.1934-0.8653 | 0.0194? | | Seq 21 | 2.4362 | 1.0803-5.4942 | 0.0319? | 0.7690 | 0.3423-1.7272 | 0.5246 | | Seq 22 | 2.0009 | 0.8880-4.5085 | 0.0942 | 2.1333 | 0.9494-4.7934 | 0.0666 | | Seq 23 | 0.6443 | 0.2057-2.0181 | 0.4505 | 0.4795 | 0.2133-1.0779 | 0.0753 | | Seq 24 | 1.6718 | 0.6214-4.4976 | 0.3088 | 0.6952 | 0.3094-1.5621 | 0.3788 |
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Cox proportional hazard model for OS and PFS.
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| Treatment Seq type | Synchronous | Metachronous | p-Value | | Favorable | Intermediate | Favorable | Intermediate | Empty Cell | | Seq 1 | 2.70 (2.25-3.29) | 1.92 (1.72-2.20) | 9.21 (9.19-12.54) | 7.50 (6.23-8.88) | Ref | | Seq 2 | 3.45 (2.84-4.47) | 2.53 (2.16-2.98) | 13.41 (11.55-16.0) | 9.80 (8.43-11.86) | ??? | | Seq 3 | 2.32 (1.93-2.88) | 1.67 (1.48-1.96) | 9.27 (7.83-11.49) | 6.24 (4.85-8.07) | ? | | Seq 4 | 3.00 (2.36-4.27) | 2.18 (1.76-2.81) | 11.80 (9.56-15.20) | 8.53 (6.45-11.49) | NS | | Seq 5 | 1.66 (1.33-2.37) | 1.25 (0.99-1.64) | 6.12 (4.45-9.27) | 4.13 (3.17-6.19) | ??? | | Seq 6 | 3.20 (2.47-4.85) | 2.32 (1.78-3.29) | 12.54 (9.77-18.00) | 9.19 (6.51-12.78) | NS | | Seq 7 | 2.80 (2.12-4.45) | 2.03 (1.56-2.96) | 11.45 (8.37-16.19) | 8.07 (5.43-11.87) | NS | | Seq 8 | 2.65 (1.92-4.49) | 1.89 (1.47-3.05) | 10.82 (7.64-16.20) | 7.41 (4.74-12.42) | NS | | Seq 9 | 3.35 (2.39-6.29) | 2.39 (1.75-4.08) | 12.78 (9.59-21.08) | 9.53 (6.42-15.20) | NS | | Seq 10 | 3.20 (2.23-7.07) | 2.32 (1.63-4.39) | 12.54 (8.87-26.52) | 9.19 (5.77-16.20) | NS | | Seq 11 | 1.75 (1.27-3.17) | 1.31 (0.95-2.19) | 6.43 (4.31-12.42) | 4.34 (3.05-8.64) | ?? | | Seq 12 | 2.84 (1.93-7.58) | 2.06 (1.46-4.45) | 11.52 (7.64-26.52) | 8.16 (4.76-17.04) | NS | | Seq 13 | 2.72 (1.81-6.12) | 1.95 (1.39-3.79) | 10.93 (6.95-20.61) | 7.64 (4.53-14.94) | NS | | Seq 14 | 1.61 (1.16-3.19) | 1.20 (0.86-2.22) | 5.65 (3.72-12.59) | 3.98 (2.71-9.19) | ?? | | Seq 15 | 6.12 (3.14-NA) | 4.12 (2.28-NA) | 20.61 (12.52-NA) | 15.15 (9.12-NA) | ? | | Seq 16 | 0.99 (0.73-2.2) | 0.77 (0.56-1.56) | 3.18 (2.15-8.51) | 2.30 (1.54-5.55) | ??? | | Seq 17 | 1.82 (1.26-4.52) | 1.38 (0.93-3.03) | 7.07 (4.25-17.04) | 4.52 (3.00-11.87) | NS | | Seq 18 | 9.40 (3.91-NA) | 6.24 (2.76-NA) | 29.33 (14.90-NA) | 20.61 (11.27-NA) | ? | | Seq 19 | 3.80 (2.36-15.01) | 2.73 (1.72-9.94) | 14.90 (9.48-NA) | 11.25 (6.32-NA) | NS | | Seq 20 | 4.42 (2.47-NA) | 3.10 (1.76-NA) | 15.99 (9.64-NA) | 12.42 (6.48-NA) | NS | | Seq 21 | 1.33 (0.84-5.51) | 0.97 (0.67-3.68) | 4.42 (2.64-20.35) | 3.10 (1.87-14.80) | ?? | | Seq 22 | 1.53 (0.96-7.64) | 1.13 (0.75-4.31) | 5.30 (3.07-NA) | 3.69 (2.23-16.19) | NS | | Seq 23 | 3.91 (2.05-NA) | 2.76 (1.51-NA) | 14.94 (8.12-NA) | 11.27 (4.99-NA) | NS | | Seq 24 | 1.75 (378-NA) | 1.34 (0.79-NA) | 6.43 (3.35-NA) | 4.34 (2.39-NA) | ??? |
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The median time (year) to death based on OS with 95% CI estimation.
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The estimated survival functions. (A) Synchronous RCC (favorable risk); (B) Metachronous RCC (favorable risk); (C) Synchronous RCC (intermediate risk); (D) Metachronous RCC (intermediate risk). RCC, renal cell carcinoma; Seq, sequence.
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| Type | First line | Second line | Third line | Patient, n (%) | DISC, n (%) | AE, n (%) | | A | TKI | | | 661 (46.91) | 54 (8.17) | 15 (2.27) | | B | TKI | mTOR | | 348 (24.70) | 52 (14.94) | 13 (3.74) | | C | TKI | mTOR | TKI | 103 (7.31) | 23 (22.33) | 5 (4.85) | | D | TKI | TKI | | 88 (6.25) | 20 (22.73) | 17 (19.32) | | E | TKI | TKI | mTOR | 70 (4.97) | 18 (25.71) | 18 (25.71) | | F | TKI | mTOR | Cytokine | 35 (2.48) | 9 (25.71) | 1 (2.86) | | G | TKI | Cytokine | | 29 (2.06) | 3 (10.34) | 0 (0) | | H | TKI | Cytokine | mTOR | 16 (1.14) | 4 (25.00) | 1 (6.25) | | I | TKI | mTOR | Other Tx | 14 (0.99) | 1 (7.14) | 0 (0) | | J | TKI | Other Tx | | 13 (0.92) | 0 (0) | 0 (0) | | K | TKI | TKI | Cytokine | 6 (0.43) | 0 (0) | 1 (16.67) | | L | TKI | TKI | TKI | 6 (0.43) | 3 (50.00) | 4 (66.67) | | M | TKI | mTOR | mTOR | 6 (0.43) | 0 (0) | 1 (16.67) |
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Discontinuation and adverse effects by the types of received treatments.
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