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Original Article Systemic Treatments for Metastatic Renal Cell Carcinoma: 10-Year Experience of Immunotherapy and Targeted Therapy
Sung Han Kim, MD, PhD1, Weon Seo Park, MD, PhD1,2, Sun Ho Kim, MD, PhD3, Jae Young Joung, MD, PhD1, Ho Kyung Seo, MD, PhD1, Kang Hyun Lee, MD, PhD1, Jinsoo Chung, MD, PhD1
Cancer Research and Treatment : Official Journal of Korean Cancer Association 2016;48(3):1092-1101.
DOI: https://doi.org/10.4143/crt.2015.316
Published online: January 28, 2016

1Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, Goyang, Korea

2Department of Pathology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, Goyang, Korea

3Department of Radiology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, Goyang, Korea

Correspondence: Jinsoo Chung, MD, PhD  Department of Urology, Center for Prostate Cancer, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea 
Tel: 82-31-920-2456 Fax: 82-31-920-2474 E-mail: cjs5225@ncc.re.kr
• Received: August 19, 2015   • Accepted: January 11, 2016

Copyright © 2016 by the Korean Cancer Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Purpose
    The purpose of this study is to compare the outcomes of first-line systemic targeted therapy (TT) and immunotherapy (IT) in patients with metastatic renal cell carcinoma (mRCC).
  • Materials and Methods
    This study was a retrospective review of the data of 262 patients treated with systemic IT or TT with tyrosine kinase inhibitors between 2003 and 2013. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed using Response Evaluation Criteria in Solid Tumor ver. 1.0 criteria and the Kaplan-Meier method with log-rank test.
  • Results
    During the median 4.3-month treatment and the 24-month follow-up period, the ORR/PFS/OS of the overall first-line and second-line therapy were 41.9%/8.1 months/16.8 months and 27.5%/6.5 months/15.3 months, respectively. The first-line TT/IT/sequential IT had a PFS of 9.3/6.4/5.7 months and an OS of 15.8/16.5/40.6 months (all p < 0.05). The second-line of TT/IT had a PFS of 7.1/2.1 months (both p < 0.05) and an OS of 16.6/8.6 months (p=0.636), respectively. Pazopanib provided the best median PFS of 11.0 months (p < 0.001) and a quadruple IT regimen had a superior PFS (p=0.522). For OS, sequential treatment with IT and TT was superior compared to treatment with either IT or TT alone (40.6/16.5/15.8 months, p=0.014). The prognosis according to the Memorial Sloan Kettering Cancer Center model showed that favorable/intermediate/poor risk groups had a PFS of 8.5/10.4/2.3 months, and an OS of 43.1/20.4/5.6 months, respectively. The prognosis calculated using the Heng model showed that the favorable/intermediate/poor risk groups had a PFS of 9.2/3.9/2.7 months, and an OS of 32.4/16.5/6.1months, respectively (all p < 0.001).
  • Conclusion
    In patients with mRCC, TT provided a better PFS and OS compared with IT.
  • Key words: Immunotherapy, Molecular targeted therapy, Prognosis, Renal cell carcinoma, Neoplasm metastasis
Worldwide, metastases are observed in 20%-30% of patients with an initial diagnosis of renal cell carcinoma (RCC), even in those with localized RCC who undergo curative nephrectomy during follow-up. In the immunotherapy (IT) era, cytokine-mediated IT using interferon alpha (IFN-α) or interleukin-2 (IL-2) or both were the first-line systemic treatment modalities for metastatic RCC (mRCC) [1,2]. However, the outcomes of IT were often unsatisfactory. Further attempts to augment cytokine-based IT activity (e.g., inclusion of vinblastine and 5-fluorouracil [5-FU] chemotherapy) led to slightly improved objective response rate (ORR) [3,4]. However, the efficacy of such combinations was likely due to the cytokine effect, because the addition of vinblastine did not improve the progression-free survival (PFS) or overall survival (OS) [3]. The reported median survival time of mRCC in the IT era was 12 months and the 2-year survival rate was 10%-20%, mainly due to a low ORR of 10%-20%, with long-term durable responses only observed in 5%-7% of patients undergoing high-dose IL-2–based therapy [5,6].
Recent advances in understanding of the biology and genetics of RCC have led to the introduction of several novel multi-pathway targeted agents. Clinical trials in treatmentnaïve mRCC patients conducted in Western and Asian countries have shown that targeted therapy (TT) had superior efficacy when compared with cytokine-based IT [2,7]. In terms of PFS and OS, the clinical outcome of patients with mRCC has improved dramatically since the introduction of TT, which has now replaced IT as the standard systemic treatment for mRCC [1].
To facilitate prompt management strategies and achieve the optimal therapeutic response, physicians should be aware of the efficacies and limitations of systemic mono, combinational, and sequential therapies of diverse therapeutic agents for the treatment of mRCC. However, few large studies comparing the outcome of IT and TT in patients with mRCC have been reported, although small comparative studies have been conducted [8]. The current study assessed the outcome of systemic TT and IT administered to a large number of patients with mRCC over a 10-year period at a single Korean cancer institution.
1. Patients
Data from 262 patients with mRCC treated with systemic agents between 2003 and 2013 were evaluated retrospectively. Patients who were administered IT as a systemic therapy between 2003 and 2013 were selected from the prospectively recorded RCC database of the National Cancer Center Hospital, and those administered TT who were treated between 2006 and 2013 were selected. The clinicopathological data of all 262 patients are summarized in Table 1.
Of the 262 patients, 135 (51.5%) underwent first-line IT regimens based on mono or combinational therapy with IFN-α, IL-2, 5-FU, or vinblastine. The remaining 127 patients (48.5%) underwent first-line systemic TT. Eligible patients were 18-75 years old. Patients with no follow-up history and who had incomplete RCC treatment histories were excluded. Additional information about the clinical outcomes of 96 patients treated with either TT or IT as a sequential second-line systemic therapy was also evaluated.
2. Treatment regimens
The choice of IT or TT was at the discretion of the treating urologist (J.C.) and was based on the patient’s histopathology and coverage by the National Health Insurance System. Combination IT comprised different combinations of subcutaneous recombinant human IL-2 (Aldesleukin, Proleukin, Chiron Corporation, Emeryville, CA) or recombinant human IFN-α (IFN-alpha-2a, Roferon-A, Hoffmann-La Roche, Nutley, NJ), and intravenous 5-FU (JW Pharm, Seoul, Korea) or vinblastine (United Pharm, Seoul, Korea). The triple or quadruple regimens were administered as follows: IL-2, 20 MIU/m2 on days 3–5 of weeks 1 and 4, and 5 MIU/m2 IL-2 on days 1, 3, and 5 of weeks 2 and 3; IFN-α, 6 MIU/m2 on day 1 of weeks 1 and 4 and on days 1, 3, and 5 of weeks 2 and 3, and 9 MIU/m2 on days 1, 3, and 5 of weeks 5-8; 5-FU, 750 mg/m2 once weekly during weeks 5-8; with (quadruple) or without vinblastine (triple) at 0.1 mg/kg once weekly during weeks 5-8. The dual combination regimen of vinblastine plus IFN-α was administered as IFN-α at 9 MIU/m2 on days 1, 3, and 5 each week, and vinblastine at 0.1 mg/kg every 3 weeks.
3. Targeted therapy
All TT was administered orally. For sunitinib, each cycle consisted of 50 mg/day for 4 weeks followed by a 2-week hiatus. For sorafenib, each cycle consisted of consecutive 400 mg twice daily per week. For pazopanib, each cycle consisted of consecutive 800 mg once daily per week. Subjects were administered consecutive 10 mg of everolimus once a day per week and 5 mg of axitinib twice a day per week as the second-line TT. The treatment response was assessed every 4-6 weeks for sorafenib, pazopanib, everolimus, and axitinib.
4. Follow-up
During follow-up, meticulous history taking, physical examination, routine blood tests, abdominal computed tomography (CT), radionuclide bone scan, simple chest radiography, and/or chest CT, and electrocardiography were performed at regular intervals. In addition, mandatory thyroid function tests and echocardiography were performed in patients scheduled to receive TT. All responses were evaluated on CT imaging according to the Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0. Therapeutic responses were assessed at the end of each cycle (at 8 weeks for the triple and quadruple IT regimens) or every 3-4 cycles (at 9-12 weeks for the dual IT regimen). For TT, response was assessed at the end of two cycles and treatment was continued until disease progression.
5. Statistical analyses
Time to progression and death were assessed using Kaplan-Meier analysis with the log-rank test. The ORR, PFS, and OS of the first- and second-line therapies were assessed according to the systemic agent and the clinical outcomes of sequential treatment with IT and TT, and their prognostic stratifications, were also evaluated according to the Memorial Sloan Kettering Cancer Center (MSKCC) and Heng criteria [9,10]. Statistical analyses were performed using Stata software (Release 9.2, StataCorp., College Station, TX). A p-value of < 0.5 was considered statistically significant.
6. Ethical statements
Following approval by the Institutional Review Board (IRB) of the Research Institute and Hospital National Cancer Center (IRB No. NCC2015-0212), patient record/information was anonymized and de-identified prior to analysis. All study protocols were conducted according to the ethical guidelines of the World Medical Association Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects. The requirement for written consent was waived by the IRB.
During the treatment period (median duration, 4.3 months) and the 24-month follow-up period, the first-line ORR, PFS, and OS were 41.9%, 8.1 months, and 16.8 months, respectively (Table 1). During these same periods, the second-line ORR, PFS, and OS were 27.5%, 6.5 months, and 15.3 months, respectively. Significantly better prognostic outcomes of second-line PFS were observed in the TT group (7.1 months) compared with the IT group (2.1 months) (p=0.002). However, second-line OS was not significantly different between the TT (16.6 months) and IT (8.6 months) groups (p=0.636).
In subgroup analyses of first-line systemic therapies, the TT, IT, and sequential groups had a PFS of 9.3, 6.4, and 5.7 months (p=0.819), respectively, and an OS of 15.8, 16.5, and 40.6 months (p=0.014), respectively (Table 2, Fig. 1). Pazopanib provided the best median PFS response, followed by sorafenib, sunitinib, and IT (p=0.053) (Table 2, Fig. 2). The quadruple IT regimen had superior PFS to that of IT mono, dual, or triple regimens (p=0.522) (Table 2). Among the 14 IT-treated patients who achieved a complete response (CR), eight (5.9%) remained alive with a mean response duration of 104.5±42.8 months (median, 123 months; range, 33.1 to 156.7 months); four of these (3.15%) also received TT treatment. For the seven TT-treated patients who achieved a CR, four remained alive, with a median response duration of 22.8 months (range, 13.9 to 54.8 months) (Table 2).
For the risk-stratified subgroup analyses that were dependent on the MSKCC and Heng criteria (Table 3), the clinical outcomes of PFS for each stratified prognostic group were followed subsequently in order according to their consecutive risk groups. When stratified according to the MSKCC or Heng criteria, treatments had differential outcomes for median OS. For the favorable MSKCC risk group in the first-line therapy, TT showed a superior OS compared with IT or sequential IT plus TT (p < 0.001) (Table 3). In contrast, for the favorable Heng risk group, IT had superior OS compared with TT or IT plus TT (p < 0.001). Other prognostic outcomes of first-line therapies and PFS and OS of second-line therapies, as calculated using the MSKCC and Heng risk group models, are summarized in Table 3.
Since the introduction of TT, the therapeutic regimen paradigm has shifted from IT to TT in mRCC. The prognoses have also improved dramatically in the clinical setting. In the current study, differences in prognoses in mRCC patients treated either with IT, TT, or sequential therapy as the first- and second-line systemic therapies were examined at a single center during 10 years.
The current study showed that the median PFS and OS of IT regimens was superior or equivocal to those observed in other Western studies on IT [2,5,6,11], and their ORR of 41.9% and disease control rate of 69.5% (31.1% and 54.8%; including 59 follow-up loss and death patients) were superior to those reported in a previous Korean study on IT (18% and 51%, respectively) (Table 1) [8]. The use of 5-FU or vinblastine chemotherapy in conjunction with IT increased the PFS by 0.5-3 months in 40.0% of the patients undergoing IT treatment, and quadruple IT resulted in the best PFS (8.8 months) compared with all other IT combinations (5.8-6.2 months) (Table 2). This suggests that the clinical benefit of an IT with the addition of a chemotherapy regimen should be carefully considered in terms of whether the increased survival gains would outweigh the likely increase in adverse events.
Patients previously treated with high-dose IL-2 achieved a 15% of ORR with a median duration of 54 months [6], suggesting that high-dose IL-2 treatment may have been curative in a small minority of patients [5]. There are no clear guidelines regarding patient selection; however, retrospective studies have suggested that IL-2 was more efficacious in patients with a clear cell histology and favorable prognosis [12]. IFN-α, another systemic immunotherapeutic agent for mRCC, has consistently demonstrated low but reproducible responses (10%-20%) with occasional durable responses with a PFS and OS of 5-5.6 and 4.1-21.8 months, respectively [4,13,14]. This is similar to the data of the patients in the current study undergoing IFN-α monotherapy who had similar PFS and OS (5.8 months) (Table 2) and 19.3 months (19.3 months, data not shown).
A combination of IL-2 and IFN-α showed a better clinical outcome in terms of ORR and PFS when compared with IL-2 monotherapy (Table 2). In addition, sequential therapy with the combined IT and TT regimen resulted in a better OS (40.6 months) compared to single TT (15.8 months) and single IT (16.5 months) treatment regimens (p=0.014) (Table 2). However, this outstanding sequential therapy OS may have resulted from our selection of patients who were capable of surviving IT prior to TT and were expected to have a good performance based on favorable prognostic modeling with a fairly low tumor burden and a history of nephrectomy. In particular, patients with rapid progression might be excluded from participation before beginning TT. Therefore, conditional survival may be an important methodology when evaluating the prognosis of mRCC patients treated with sub-sequential TT.
In recent decades, compared with IT, multiple single TTs have shown greater activity in terms of PFS, specifically when compared with IFN-α [7,13]. However, a clinically relevant increase in CR and OS has not been reported and the role of TT in increasing the curability of mRCC has not been fully elucidated. From a pharmacological viewpoint, the unsatisfactory results of TT to induce a CR may be explained in part by their mechanism of action, which appears to be more cytostatic than cytotoxic [15]. The current study also showed that the OS (15.8 months), ORR (33.9%), and CR (5.6%) of TT were either similar or inferior to the OS (16.5 months), ORR (31.1%), and CR (10.4%) of IT (Table 2).
The percentage of patients reaching CR for sunitinib, sorafenib, and pazopanib as first-line TT was reported as 1%-3% in earlier real-world clinical trials, post-marketing all-patient surveillance trials, and pivotal trials [16-18]. The higher CR rate (5.6%) in this study would actually be much lower than observed because patients who stopped therapy after achieving CR during a substantial follow-up had a higher rate of relapse than patients who continued sequential therapy, as shown in a recent, large, retrospective study evaluating mRCC patients who were in CR during tyrosine kinase inhibitor treatment (either alone or in combination with local treatment) [19]. Another possible explanation for achievement of high CR would be that it is often integrated with TT with surgery, radiotherapy, or both. Johannsen et al. [20] reported a similarly increased CR rate in comparison with the current study in patients treated with tyrosine kinase inhibitors plus surgery (4.5%) when compared to those treated with medical therapy alone (1.8%). The current study also showed a significantly longer PFS (11.2 months) and greater CR rates (5.4%) in patients who underwent nephrectomy plus TT compared to patients who underwent TT alone (PFS, 5.6 months; CR rate, 1.0%; data not shown in tables).
Previous extended-access and post-marketing all-patient surveillance trials have reported 16-22%/25.9%/39% of ORRs and 5.2-9.4/6.0/13.7 months of PFSs for sunitinib, sorafenib, and pazopanib in mRCC patients, respectively [16-18,21]. The ORRs for sunitinib, sorafenib, and pazopanib reported in the current study were superior to those reported in previous studies (44.1%, 27.3%, and 62.5%, respectively; data not shown); except for the PFS inferior or similar to previous studies (8.5, 9.0, and 11.0 months, respectively) [16-18,21].
Additional evaluation of second-line systemic therapies for their ORR, PFS, and OS (27.5%, 6.5 months, and 15.3 months, respectively) was similar or superior to that of previous trials with second-line therapy in cytokine- or TT-refractory mRCC patients (ORR, 9% to 23%; PFS, 4 to 7.4 months; OS, 11.5 to 16.3 months) [7]. These differences of ORR, PFS, and OS are likely due to follow-up time, differences in clinical policies between clinicians surrounding various treatment modalities, differences in baseline study populations such as disease burden, nephrectomy rate, and physical body composition, as has been previously demonstrated for other malignancies [22,23].
Regarding the analyses of prognostic models, patients with favorable MSKCC or Heng risk group showed longer survival [24]. In agreement, in the current study, those with favorable MSKCC or Heng risk group of first- and second-line therapy had a significantly better prognosis compared to those with poor or intermediate risk group (Table 3). When stratified according to MSKCC and Heng criteria, the PFS for all groups in the first-line therapy was better in those treated with TT compared to those treated with IT. However, those with a favorable Heng risk group treated with IT showed a superior OS in the first-line therapy, compared to all other groups and treatments.
There are some limitations of the current study. It was a retrospective study with a small patient population, with a possible patient selection bias based on the era of when systemic therapy was initiated. The relevance of the stratified findings based on MSKCC and Heng criteria is not fully understood and should be developed further in future large-scale multicenter studies with a more diverse patient population.
Although the ORR of TT and IT were comparable in this study, TT demonstrated superior PFS and OS compared with IT in patients with mRCC. This supports the hypothesis that the clinical outcomes of patients with mRCC have shown significant improvement since the introduction of TT.

Conflict of interest relevant to this article was not reported.

Acknowledgements
This work was supported by a grant from the National Cancer Center (1510650-1), Republic of Korea.
Fig. 1.
Progression-free survival (PFS) (A) and overall survival (OS) (B) curves for first-line systemic therapies in patients with metastatic renal cell carcinoma treated with immunotherapy alone, targeted therapy alone, or both therapies in sequence. ICTx, immunotherapy; TT, targeted therapy.
crt-2015-316f1.gif
Fig. 2.
Progression-free survival curves for first-line systemic therapies in patients with metastatic renal cell carcinoma. ICTx, immunotherapy.
crt-2015-316f2.gif
Table 1.
Patient baseline demographics
Parameter No. (%) (n=262)
Age, mean±SD (yr) 57.3±11.6
Sex (male/female) 204 (77.9)/58 (22.1)
BMI, mean±SD (kg/m2) 23.4±3.2
Underlying disease
 Diabetes 46 (17.6)
 Hypertension 97 (37)
 Ischemic heart disease 2 (0.8)
 Cerebrovascular disease 4 (1.5)
Karnofsky performance score
 ≥ 80% 254 (96.9)
 50%-70% 8 (3.1)
MSKCC risk group
 Favorable 23 (11.2)
 Intermediate 131 (63.6)
 Poor 52 (25.2)
 Unknown 56
Heng risk group
 Favorable 41 (17)
 Intermediate 160 (66.4)
 Poor 40 (16.6)
 Unknown 22
Treatment duration, median (range, mo) 4.3 (0.1-68.4)
Metastatic site
 Lung 204 (77.3)
 Liver 44 (16.7)
 LN 116 (43.9)
 Bone 89 (33.7)
 Brain 23 (8.7)
 Other 36 (13.6)
Clinical T stage
 T1 25 (9.5)
 T2 32 (12.2)
 T3 71 (27.1)
 T4 21 (8)
 Tx 115 (43.6)
Clinical N stage
 N1 37 (14.1)
 Nx 109 (42)
 Renal embolization 16 (6.1)
 Nephrectomy 124 (47.3)
Pathologic T stage
 T1 22 (8.3)
 T2 27 (10.3)
 T3 53 (20.1)
 T4 8 (3)
 Tx 152 (57.9)
Pathologic N stage
 N1 12 (4.6)
 Nx 154 (59.1)
Fuhrmann grade
 1 7 (2.7)
 2 42 (16)
 3 82 (31.3)
 4 35 (13.4)
 Unknown 96 (36.6)
Histology
 Clear cell, pure 178 (67.4)
 Mixed 34 (12.9)
 Papillary 5 (1.9)
 Chromophobe 2 (0.8)
 Unclassified 5 (1.9)
 Unknown 38 (15.1)
Primary treatment drug
 Target therapy 127 (48.5)
  Sunitinib 92 (35.1)
  Sorafenib 17 (6.5)
  Pazopanib 18 (6.9)
 Immunotherapy 135 (51.5)
Secondary treatment drug 96
 Target therapy 83 (86.5)
  Sunitinib 33 (39.8)
  Sorafenib 23 (27.7)
  Pazopanib 3 (3.6)
  Everolimus 21 (25.3)
  Axitinib 3 (3.6)
 Immunotherapy 13 (13.5)
Second-line best response (RECIST criteria 1.0) 69 (100)
 PD 28 (40.6)
 SD 22 (31.9)
 PR 16 (23.2)
 CR 3 (4.3)
F/U loss or death 27
Second-line progression free survival, median (range, mo) 6.5 (4.9-8.0)
 Target therapy/Immunotherapy, median (range, mo) 7.1 (5.8-8.4)/2.1 (1.8-2.4)
Second-line overall survival, median (range, mo) 15.3 (8.9-21.7)
 Target therapy/Immunotherapy, median (range, mo) 16.6 (10-22.5)/8.6 (0.1-27.5)

SD, standard deviation; BMI, body mass index; MSKCC, Memorial Sloane Kettering Cancer Center; LN, lymph node; RECIST, Response Evaluation Criteria in Solid Tumors; PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response; F/U, follow-up.

Table 2.
Comparison of clinicopathological parameters between first-line IT and TT
Parameter IT (n=135) TT (n=127) p-value
Age, mean±SD (yr) 56.1±11.9 58.5±11.2 0.101
Sex (male/female) 104/31 (77/23) 100/27 (78.7/21.3) 0.768
BMI, mean±SD (kg/m2) 23.6±3.5 23.3±2.7 0.421
Underlying disease
 Diabetes 18 (13.3) 28 (22.0) 0.075
 Hypertension 42 (31.3) 55 (43.3) 0.055
 Ischemic heart disease 0 2 (1.6) 0.234
 Cerebrovascular disease 0 4 (3.1) 0.054
Karnofsky performance score
 > 80% 131 (97.0) 123 (96.9) 0.481
 50%-70% 4 (3.0) 4 (3.1)
MSKCC risk group
 Favorable 10 (7.4) 13 (10.3) 0.814
 Intermediate 63 (46.7) 68 (53.5)
 Poor 27 (20.0) 25 (19.7)
 Unknown 35 (25.9) 21 (16.5)
Heng risk group
 Favorable 20 (14.8) 21 (16.5) 0.795
 Intermediate 87 (64.4) 73 (57.5)
 Poor 21 (15.6) 19 (15.0)
 Unknown 7 (5.2) 14 (11.0)
Treatment duration, mean±SD (mo) 7.2±9.8 9.0±12.3 0.204
Metastatic site
 Lung 102 (75.6) 102 (80.3) 0.633
 Liver 20 (14.8) 24 (18.9) 0.496
 LN 52 (38.5) 64 (50.4) 0.099
 Bone 45 (33.3) 44 (34.6) 0.675
 Brain 9 (6.7) 14 (11.0) 0.433
 Other 15 (11.1) 21 (16.5) 0.421
Clinical T stage
 T1 13 (9.6) 12 (9.4) 0.049
 T2 18 (13.3) 14 (11.0)
 T3 36 (26.7) 35 (27.6)
 T4 10 (7.4) 11 (8.7)
 Tx 60 (44.4) 55 (43.3)
Clinical N stage
 N1 18 (13.3) 19 (15.0) 0.017
 Nx 58 (43.0) 51 (40.2)
Renal embolization 11 (8.1) 5 (3.9) 0.199
Nephrectomy 101 (74.8) 67 (52.8) < 0.001
Primary renal tumor in situ 25 (18.5) 56 (43.3) < 0.001
Fuhrmann grade
 1 2 (1.5) 5 (3.9) 0.116
 2 16 (11.9) 26 (20.5)
 3 47 (34.8) 35 (27.6)
 4 15 (11.1) 20 (15.7)
 Unknown 65 (48.1) 41 (32.3)
Histology
 Clear cell, pure 84 (62.2) 94 (74.0) 0.066
 Mixed 6 (4.4) 13 (10.2)
 Papillary 9 (6.7) 6 (4.7)
 Chromophobe 0 1 (0.7)
 Unclassified 0 5 (3.9)
 Unknown 36 (26.7) 10 (7.9)
Primary treating drug IL-2: 11 (8.1) Sunitinib: 92 (35.1) NA
IFN-α: 65 (48.1) Sorafenib: 17 (6.5)
IL-2+IFN-α: 57 (42.2) Pazopanib: 18 (6.9)
Others: 2 (1.5)
Best overall response
 CR 14 (10.4) 7 (5.6) 0.242
 PR 28 (20.7) 36 (28.3)
 SD 32 (23.7) 24 (18.9)
 PD 34 (25.2) 28 (22.0)
 F/U loss or death 29 (21.5) 32 (25.2)
PFS, median (range, mo) 6.4 (4.2-8.6) 9.3 (6.8-11.7) 0.026
5.7 (1.9-9.6)a) 0.819
IL-2: 3.3 (0.1-24.3) Sunitinib: 8.5 (0.2-68.4) 0.053
IFN-α: 5.8 (0.1-65.6) Sorafenib: 9.0 (0.1-22.3)
IL-2+IFN-α: 16.3 (0.4-20.2) Pazopanib: 11.0 (0.5-36.4)
PFS of IT, median (range)
 Monotherapy (n=48) 5.8 (0.1-65.6) NA 0.522
 Dual therapy (n=33) 7.5 (0.1-22.5)
 Triple therapy (n=46) 6.2 (0.7-15.5)
 Quadruple therapy (n=8) 8.8 (1.7-20.2)
OS, median (range, mo) 16.5 (0.7-156.7) 15.8 (0.3-78.4) 0.452
40.6 (38.2-43.0)a) 0.014

IT, immunotherapy; TT, targeted therapy; SD, standard deviation; BMI, body mass index; MSKCC, Memorial Sloane Kettering Cancer Center; LN, lymph node; Tx, treatment; IL-2, interleukin 2; NA, not available; IFN-α, interferon α; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; F/U, follow-up; PFS, progression-free survival; OS, overall survival.

a) Progression-free survival and overall survival for IT alone/IT with subsequent TT versus TT alone.

Table 3.
Comparison of PFS and OS of first-line and second-line immunotherapy and targeted therapy according to their Heng and MSKCC risks
PFS
 OS
No. First-line p-value No. Second-line p-value No. First-line No. Second-line p-value
MSKCC Favorable 21 8.5 (1.4-65.6) < 0.001 16 12.7 (9.7-15.7) 0.047 22 43.1 (18.3-134.7) 6 23.5 (9.8-37.3) < 0.001
Intermediate 107 10.4 (0.1-68.4) 42 5.6 (3.4-7.8) 128 20.4 (0.4-129.8) 42 13.0 (5.6-20.4)
Poor 35 2.3 (0.1-16.2) 10 4.1 (3.3-4.9) 0.010 52 5.6 (0.3-156.7) 10 4.6 (2.4-6.8)
Heng Favorable 38 9.2 (1.4-65.6) < 0.001 23 14.2 (1.4-65.6) 40 32.4 (3.6-149.6) 23 23.5 (13.6-33.4) < 0.001
Intermediate 128 3.9 (0.1-68.4) 48 4.6 (2.6-6.6) 159 16.5 (0.3-133.5) 48 14.5 (6.3-22.7)
Poor 27 2.7 (0.1-13.3) 6 4.1 (2.9-5.2) 40 6.1 (0.7-156.7) 6 4.6 (2.1-7.1)
MSKCC IT Favorable 10 34.9 (2.1-65.6) < 0.001 - - - 2 29.8 (29.8-134.7) - - -
Intermediate 54 24.6 (0.1-34.0) - - 45 21.2 (2.5-129.8) - -
Poor 19 6.6 (0.1-15.4) - - 22 6.0 (2.2-156.7) - -
MSKCC TT Favorable 16 39.6 (1.4-63.2) - - 17 43.1 (15.6-78.4) - -
Intermediate 57 13.1 (0.2-68.4) - - 70 14.6 (0.4-75.5) - -
Poor 16 4.7 (0.1-16.2) - - 25 4.7 (0.3-18.6) - -
MSKCC ICTx and TT Favorable - - - - 8 29.9 (20.4-94.6) - -
Intermediate - - - - 16 40.8 (5.8-123.5) - -
Poor - - - - 5 9 (5.5-39.3) - -
Heng IT Favorable 20 9.2 (2-65.6) < 0.001 - - - 7 66.2 (8.4-149.6) - - -
Intermediate 68 6.3 (0.1-34.0) - - 68 16.6 (1.0-133.5) - -
Poor 17 4.1 (0.1-13.3) - - 18 5.91 (0.7-156.7) - -
Heng TT Favorable 18 22.3 (1.4-63.2) - - 20 40.8 (3.6-68.3) - -
Intermediate 59 8.4 (0.1-68.4) - - 72 14.1 (0.3-78.4) - -
Poor 11 4.3 (0.5-9.8) - - 19 4.7 (0.9-16.4) - -
Heng IT and TT Favorable - - - - 13 41.9 (8.4-95.8) - -
Intermediate - - - - 17 40.7 (5.5-123.5) - -
Poor - - - - 3 9.0 (7.3-9.2) - -

Values are presented as median (range, mo). PFS, progression-free survival; OS, overall survival; MSKCC, Memorial Sloane Kettering Cancer Center; IT, immunotherapy; TT, targeted therapy; ICTx, immunotherapy.

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      Systemic Treatments for Metastatic Renal Cell Carcinoma: 10-Year Experience of Immunotherapy and Targeted Therapy
      Cancer Res Treat. 2016;48(3):1092-1101.   Published online January 28, 2016
      DOI: https://doi.org/10.4143/crt.2015.316
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    Systemic Treatments for Metastatic Renal Cell Carcinoma: 10-Year Experience of Immunotherapy and Targeted Therapy
    Image Image
    Fig. 1. Progression-free survival (PFS) (A) and overall survival (OS) (B) curves for first-line systemic therapies in patients with metastatic renal cell carcinoma treated with immunotherapy alone, targeted therapy alone, or both therapies in sequence. ICTx, immunotherapy; TT, targeted therapy.
    Fig. 2. Progression-free survival curves for first-line systemic therapies in patients with metastatic renal cell carcinoma. ICTx, immunotherapy.

    Fig. 1.

    Fig. 2.

    Systemic Treatments for Metastatic Renal Cell Carcinoma: 10-Year Experience of Immunotherapy and Targeted Therapy
    Parameter No. (%) (n=262)
    Age, mean±SD (yr) 57.3±11.6
    Sex (male/female) 204 (77.9)/58 (22.1)
    BMI, mean±SD (kg/m2) 23.4±3.2
    Underlying disease
     Diabetes 46 (17.6)
     Hypertension 97 (37)
     Ischemic heart disease 2 (0.8)
     Cerebrovascular disease 4 (1.5)
    Karnofsky performance score
     ≥ 80% 254 (96.9)
     50%-70% 8 (3.1)
    MSKCC risk group
     Favorable 23 (11.2)
     Intermediate 131 (63.6)
     Poor 52 (25.2)
     Unknown 56
    Heng risk group
     Favorable 41 (17)
     Intermediate 160 (66.4)
     Poor 40 (16.6)
     Unknown 22
    Treatment duration, median (range, mo) 4.3 (0.1-68.4)
    Metastatic site
     Lung 204 (77.3)
     Liver 44 (16.7)
     LN 116 (43.9)
     Bone 89 (33.7)
     Brain 23 (8.7)
     Other 36 (13.6)
    Clinical T stage
     T1 25 (9.5)
     T2 32 (12.2)
     T3 71 (27.1)
     T4 21 (8)
     Tx 115 (43.6)
    Clinical N stage
     N1 37 (14.1)
     Nx 109 (42)
     Renal embolization 16 (6.1)
     Nephrectomy 124 (47.3)
    Pathologic T stage
     T1 22 (8.3)
     T2 27 (10.3)
     T3 53 (20.1)
     T4 8 (3)
     Tx 152 (57.9)
    Pathologic N stage
     N1 12 (4.6)
     Nx 154 (59.1)
    Fuhrmann grade
     1 7 (2.7)
     2 42 (16)
     3 82 (31.3)
     4 35 (13.4)
     Unknown 96 (36.6)
    Histology
     Clear cell, pure 178 (67.4)
     Mixed 34 (12.9)
     Papillary 5 (1.9)
     Chromophobe 2 (0.8)
     Unclassified 5 (1.9)
     Unknown 38 (15.1)
    Primary treatment drug
     Target therapy 127 (48.5)
      Sunitinib 92 (35.1)
      Sorafenib 17 (6.5)
      Pazopanib 18 (6.9)
     Immunotherapy 135 (51.5)
    Secondary treatment drug 96
     Target therapy 83 (86.5)
      Sunitinib 33 (39.8)
      Sorafenib 23 (27.7)
      Pazopanib 3 (3.6)
      Everolimus 21 (25.3)
      Axitinib 3 (3.6)
     Immunotherapy 13 (13.5)
    Second-line best response (RECIST criteria 1.0) 69 (100)
     PD 28 (40.6)
     SD 22 (31.9)
     PR 16 (23.2)
     CR 3 (4.3)
    F/U loss or death 27
    Second-line progression free survival, median (range, mo) 6.5 (4.9-8.0)
     Target therapy/Immunotherapy, median (range, mo) 7.1 (5.8-8.4)/2.1 (1.8-2.4)
    Second-line overall survival, median (range, mo) 15.3 (8.9-21.7)
     Target therapy/Immunotherapy, median (range, mo) 16.6 (10-22.5)/8.6 (0.1-27.5)
    Parameter IT (n=135) TT (n=127) p-value
    Age, mean±SD (yr) 56.1±11.9 58.5±11.2 0.101
    Sex (male/female) 104/31 (77/23) 100/27 (78.7/21.3) 0.768
    BMI, mean±SD (kg/m2) 23.6±3.5 23.3±2.7 0.421
    Underlying disease
     Diabetes 18 (13.3) 28 (22.0) 0.075
     Hypertension 42 (31.3) 55 (43.3) 0.055
     Ischemic heart disease 0 2 (1.6) 0.234
     Cerebrovascular disease 0 4 (3.1) 0.054
    Karnofsky performance score
     > 80% 131 (97.0) 123 (96.9) 0.481
     50%-70% 4 (3.0) 4 (3.1)
    MSKCC risk group
     Favorable 10 (7.4) 13 (10.3) 0.814
     Intermediate 63 (46.7) 68 (53.5)
     Poor 27 (20.0) 25 (19.7)
     Unknown 35 (25.9) 21 (16.5)
    Heng risk group
     Favorable 20 (14.8) 21 (16.5) 0.795
     Intermediate 87 (64.4) 73 (57.5)
     Poor 21 (15.6) 19 (15.0)
     Unknown 7 (5.2) 14 (11.0)
    Treatment duration, mean±SD (mo) 7.2±9.8 9.0±12.3 0.204
    Metastatic site
     Lung 102 (75.6) 102 (80.3) 0.633
     Liver 20 (14.8) 24 (18.9) 0.496
     LN 52 (38.5) 64 (50.4) 0.099
     Bone 45 (33.3) 44 (34.6) 0.675
     Brain 9 (6.7) 14 (11.0) 0.433
     Other 15 (11.1) 21 (16.5) 0.421
    Clinical T stage
     T1 13 (9.6) 12 (9.4) 0.049
     T2 18 (13.3) 14 (11.0)
     T3 36 (26.7) 35 (27.6)
     T4 10 (7.4) 11 (8.7)
     Tx 60 (44.4) 55 (43.3)
    Clinical N stage
     N1 18 (13.3) 19 (15.0) 0.017
     Nx 58 (43.0) 51 (40.2)
    Renal embolization 11 (8.1) 5 (3.9) 0.199
    Nephrectomy 101 (74.8) 67 (52.8) < 0.001
    Primary renal tumor in situ 25 (18.5) 56 (43.3) < 0.001
    Fuhrmann grade
     1 2 (1.5) 5 (3.9) 0.116
     2 16 (11.9) 26 (20.5)
     3 47 (34.8) 35 (27.6)
     4 15 (11.1) 20 (15.7)
     Unknown 65 (48.1) 41 (32.3)
    Histology
     Clear cell, pure 84 (62.2) 94 (74.0) 0.066
     Mixed 6 (4.4) 13 (10.2)
     Papillary 9 (6.7) 6 (4.7)
     Chromophobe 0 1 (0.7)
     Unclassified 0 5 (3.9)
     Unknown 36 (26.7) 10 (7.9)
    Primary treating drug IL-2: 11 (8.1) Sunitinib: 92 (35.1) NA
    IFN-α: 65 (48.1) Sorafenib: 17 (6.5)
    IL-2+IFN-α: 57 (42.2) Pazopanib: 18 (6.9)
    Others: 2 (1.5)
    Best overall response
     CR 14 (10.4) 7 (5.6) 0.242
     PR 28 (20.7) 36 (28.3)
     SD 32 (23.7) 24 (18.9)
     PD 34 (25.2) 28 (22.0)
     F/U loss or death 29 (21.5) 32 (25.2)
    PFS, median (range, mo) 6.4 (4.2-8.6) 9.3 (6.8-11.7) 0.026
    5.7 (1.9-9.6)a) 0.819
    IL-2: 3.3 (0.1-24.3) Sunitinib: 8.5 (0.2-68.4) 0.053
    IFN-α: 5.8 (0.1-65.6) Sorafenib: 9.0 (0.1-22.3)
    IL-2+IFN-α: 16.3 (0.4-20.2) Pazopanib: 11.0 (0.5-36.4)
    PFS of IT, median (range)
     Monotherapy (n=48) 5.8 (0.1-65.6) NA 0.522
     Dual therapy (n=33) 7.5 (0.1-22.5)
     Triple therapy (n=46) 6.2 (0.7-15.5)
     Quadruple therapy (n=8) 8.8 (1.7-20.2)
    OS, median (range, mo) 16.5 (0.7-156.7) 15.8 (0.3-78.4) 0.452
    40.6 (38.2-43.0)a) 0.014
    PFS
    		 OS
    No. First-line p-value No. Second-line p-value No. First-line No. Second-line p-value
    MSKCC Favorable 21 8.5 (1.4-65.6) < 0.001 16 12.7 (9.7-15.7) 0.047 22 43.1 (18.3-134.7) 6 23.5 (9.8-37.3) < 0.001
    Intermediate 107 10.4 (0.1-68.4) 42 5.6 (3.4-7.8) 128 20.4 (0.4-129.8) 42 13.0 (5.6-20.4)
    Poor 35 2.3 (0.1-16.2) 10 4.1 (3.3-4.9) 0.010 52 5.6 (0.3-156.7) 10 4.6 (2.4-6.8)
    Heng Favorable 38 9.2 (1.4-65.6) < 0.001 23 14.2 (1.4-65.6) 40 32.4 (3.6-149.6) 23 23.5 (13.6-33.4) < 0.001
    Intermediate 128 3.9 (0.1-68.4) 48 4.6 (2.6-6.6) 159 16.5 (0.3-133.5) 48 14.5 (6.3-22.7)
    Poor 27 2.7 (0.1-13.3) 6 4.1 (2.9-5.2) 40 6.1 (0.7-156.7) 6 4.6 (2.1-7.1)
    MSKCC IT Favorable 10 34.9 (2.1-65.6) < 0.001 - - - 2 29.8 (29.8-134.7) - - -
    Intermediate 54 24.6 (0.1-34.0) - - 45 21.2 (2.5-129.8) - -
    Poor 19 6.6 (0.1-15.4) - - 22 6.0 (2.2-156.7) - -
    MSKCC TT Favorable 16 39.6 (1.4-63.2) - - 17 43.1 (15.6-78.4) - -
    Intermediate 57 13.1 (0.2-68.4) - - 70 14.6 (0.4-75.5) - -
    Poor 16 4.7 (0.1-16.2) - - 25 4.7 (0.3-18.6) - -
    MSKCC ICTx and TT Favorable - - - - 8 29.9 (20.4-94.6) - -
    Intermediate - - - - 16 40.8 (5.8-123.5) - -
    Poor - - - - 5 9 (5.5-39.3) - -
    Heng IT Favorable 20 9.2 (2-65.6) < 0.001 - - - 7 66.2 (8.4-149.6) - - -
    Intermediate 68 6.3 (0.1-34.0) - - 68 16.6 (1.0-133.5) - -
    Poor 17 4.1 (0.1-13.3) - - 18 5.91 (0.7-156.7) - -
    Heng TT Favorable 18 22.3 (1.4-63.2) - - 20 40.8 (3.6-68.3) - -
    Intermediate 59 8.4 (0.1-68.4) - - 72 14.1 (0.3-78.4) - -
    Poor 11 4.3 (0.5-9.8) - - 19 4.7 (0.9-16.4) - -
    Heng IT and TT Favorable - - - - 13 41.9 (8.4-95.8) - -
    Intermediate - - - - 17 40.7 (5.5-123.5) - -
    Poor - - - - 3 9.0 (7.3-9.2) - -
    Table 1. Patient baseline demographics

    SD, standard deviation; BMI, body mass index; MSKCC, Memorial Sloane Kettering Cancer Center; LN, lymph node; RECIST, Response Evaluation Criteria in Solid Tumors; PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response; F/U, follow-up.

    Table 2. Comparison of clinicopathological parameters between first-line IT and TT

    IT, immunotherapy; TT, targeted therapy; SD, standard deviation; BMI, body mass index; MSKCC, Memorial Sloane Kettering Cancer Center; LN, lymph node; Tx, treatment; IL-2, interleukin 2; NA, not available; IFN-α, interferon α; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; F/U, follow-up; PFS, progression-free survival; OS, overall survival.

    Progression-free survival and overall survival for IT alone/IT with subsequent TT versus TT alone.

    Table 3. Comparison of PFS and OS of first-line and second-line immunotherapy and targeted therapy according to their Heng and MSKCC risks

    Values are presented as median (range, mo). PFS, progression-free survival; OS, overall survival; MSKCC, Memorial Sloane Kettering Cancer Center; IT, immunotherapy; TT, targeted therapy; ICTx, immunotherapy.

    Table 1.

    Table 2.

    Table 3.

    Cancer Res Treat : Cancer Research and Treatment
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