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Changes in Treatment Reality and Survival of Patients With Advanced Clear Cell Renal Cell Carcinoma – Analyses From the German Clinical RCC-Registry

Open AccessPublished:June 22, 2018DOI:https://doi.org/10.1016/j.clgc.2018.06.006

      Abstract

      Introduction

      Because the treatment landscape for metastatic renal cell carcinoma (mRCC) has evolved dramatically over the past decade, data on patients' treatment and outcomes in routine practice, so called “real-world data,” are important to complement clinical trial data. We present choice of systemic first-/second-line treatments, number and sequences of treatment lines, and survival of patients with clear cell mRCC.

      Patients and Methods

      A total of 1085 patients with clear cell mRCC who were recruited at the start of first-line treatment into the prospective German clinical cohort study (RCC-Registry) by 122 sites between December 2007 and May 2017 were analyzed.

      Results

      The choice of first-/second-line treatment and changes over time reflect the chronologic approval of different targeted agents: from mainly tyrosine kinase inhibitors (TKIs), to TKIs/mechanistic target of rapamycin inhibitors, to now TKIs/mechanistic target of rapamycin inhibitors/checkpoint inhibitor. The median first-line overall survival ranged from 7.2 months (95% confidence interval [CI], 4.8-10.9 months) in high MSKCC (Memorial Sloan Kettering Cancer Center) risk to 36.7 months (95% CI, 27.9-43.0 months) in low-risk patients. For trial-ineligible routine patients meeting common exclusion criteria of clinical trials, the median overall survival was 14.6 months (95% CI, 11.5-18.0 months) compared with 26.2 months (95% CI, 22.1-31.5 months) for potentially trial-eligible patients.

      Conclusion

      This is the first prospective long-term cohort study showing changes in treatment reality and survival of routine patients with clear cell mRCC. Newly approved treatments are quickly applied in routine care. Patients with unfavorable prognosis, including trial-ineligible patients, have inferior outcomes. Survival times of potentially trial-eligible patients are similar to those reported from clinical trials.

      Keywords

      Introduction

      Approximately 15,000 new cases of malignant neoplasms of the kidney were registered in Germany in 2013.

      Robert-Koch-Institut, Zentrum für Krebsregisterdaten im Robert-Koch-Institut, ed. Bericht zum Krebsgeschehen in Deutschland 2016. Berlin; 2016.

      Renal cell carcinoma (RCC) accounts for more than 90% of the malignant neoplasms of the kidney, with clear cell carcinoma being the most common histologic subtype (70%).
      • Znaor A.
      • Lortet-Tieulent J.
      • Laversanne M.
      • Jemal A.
      • Bray F.
      International variations and trends in renal cell carcinoma incidence and mortality.
      About one-third of the patients present with locally advanced or metastatic RCC (mRCC) at initial diagnosis,
      • Posadas E.M.
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      Targeted therapies for renal cell carcinoma.
      • Pal S.K.
      • Ghate S.R.
      • Li N.
      • et al.
      Real-world survival outcomes and prognostic factors among patients receiving first targeted therapy for advanced renal cell carcinoma: a SEER–Medicare Database Analysis.
      usually requiring systemic treatment.
      • Posadas E.M.
      • Limvorasak S.
      • Figlin R.A.
      Targeted therapies for renal cell carcinoma.
      Until 2005, cytokine-based immunotherapies with agents such as interferon-alpha and interleukin-2 have been the standard of care for mRCC treatment
      • Posadas E.M.
      • Limvorasak S.
      • Figlin R.A.
      Targeted therapies for renal cell carcinoma.
      • Escudier B.
      • Albiges L.
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      Optimal management of metastatic renal cell carcinoma: current status.
      ; however, they are associated with significant toxicity and relatively low response rates.
      • Posadas E.M.
      • Limvorasak S.
      • Figlin R.A.
      Targeted therapies for renal cell carcinoma.
      Over the past decade, the treatment of mRCC has evolved dramatically and has undergone a paradigm shift. The introduction of molecularly targeted agents blocking the vascular endothelial growth factor (VEGF) and the mechanistic target of rapamycin (mTOR) signalling pathways
      • Posadas E.M.
      • Limvorasak S.
      • Figlin R.A.
      Targeted therapies for renal cell carcinoma.
      • Auclin E.
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      • et al.
      Prediction of everolimus toxicity and prognostic value of skeletal muscle index in patients with metastatic renal cell carcinoma.
      • Stukalin I.
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      Contemporary treatment of metastatic renal cell carcinoma.
      • Unverzagt S.
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      Immunotherapy for metastatic renal cell carcinoma.
      • Porta C.
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      • Czarnecka A.M.
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      Immuno-oncology for renal cell carcinoma treatment: future perspectives for combinations and sequences with molecularly targeted agents.
      has significantly improved the outcomes of patients with mRCC in clinical trials.
      • Posadas E.M.
      • Limvorasak S.
      • Figlin R.A.
      Targeted therapies for renal cell carcinoma.
      • Coppin C.
      • Kollmannsberger C.
      • Le L.
      • Porzsolt F.
      • Wilt T.J.
      Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials.
      It also improved overall outcome in the United States, although treatment-specific data are missing.
      • Vaishampayan U.
      • Vankayala H.
      • Vigneau F.D.
      • et al.
      The effect of targeted therapy on overall survival in advanced renal cancer: a study of the National Surveillance Epidemiology and End Results registry database.
      To date, several tyrosine kinase inhibitors (TKIs) have been approved for the treatment of mRCC: sorafenib and sunitinib in 2006, followed by pazopanib (2010), axitinib (2012), and lenvatinib (in combination with everolimus) in 2016. In addition, the mTOR inhibitors temsirolimus and everolimus were approved in 2007 and 2009, and the anti-VEGF antibody bevacizumab (in combination with interferon-alpha) was approved in 2009. Recently, novel targeted agents have broadened the therapeutic spectrum, such as the programmed cell death-1 immune checkpoint inhibitor (CPI) nivolumab, which was approved in 2015, whereas the role of additional tumor growth factor receptors such as the protein kinase MET and drug resistance genes such as the AXL oncogene are about to be further explored in RCC.
      • Posadas E.M.
      • Limvorasak S.
      • Figlin R.A.
      Targeted therapies for renal cell carcinoma.
      • Pal S.K.
      • Ghate S.R.
      • Li N.
      • et al.
      Real-world survival outcomes and prognostic factors among patients receiving first targeted therapy for advanced renal cell carcinoma: a SEER–Medicare Database Analysis.
      The insight into VEGF-receptor pathway resistance has already led to the development of a dual inhibition approach, with cabozantinib approved for the treatment of mRCC in 2016.
      • Choueiri T.K.
      • Pal S.K.
      • McDermott D.F.
      • et al.
      A phase I study of cabozantinib (XL184) in patients with renal cell cancer.
      Most recently, the United States Food and Drug Administration approved the combination of nivolumab and ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen 4 antibody, for patients with intermediate- or poor-risk mRCC in first-line.
      The rapid evolution of the treatment landscape for mRCC in recent years raises the question of how the choice of first- and second-line treatment has been changing over time, and how effective treatment is adapted outside of clinical trials. In contrast to the often highly selected patients included in randomized clinical trials, the general patient population treated in routine practice is more heterogeneous and likely to be less healthy and elderly, thus limiting the general translation of results from clinical trials into daily practice. Previously published data by us suggest that at least 60% of the patients with mRCC in German routine care would be ineligible for participation in clinical trials.
      • Marschner N.
      • Staehler M.
      • Müller L.
      • et al.
      Survival of patients with advanced or metastatic renal cell carcinoma in routine practice differs from that in clinical trials-analyses from the German Clinical RCC Registry.
      These trial-ineligible patients had overall inferior outcome compared with potentially trial-eligible routine patients. Hence, data on the treatment reality and on patients' outcome in routine practice are increasingly valuable but still scarce, especially from prospective longitudinal cohort studies.
      In this article, we present comprehensive data on the choice of first-line and second-line treatment, number and sequences of treatment lines between 2007 and 2017, and on best response, progression-free survival (PFS) and overall survival (OS) in patients with clear cell mRCC from the prospective clinical cohort study on mRCC (Tumour Registry of Advanced Renal Cell Carcinoma, RCC-Registry).

      Materials and Methods

      Data Source

      The Tumour Registry of Advanced Renal Cell Carcinoma (RCC-Registry) is an ongoing, open, longitudinal, multicenter, observational, prospective cohort study collecting data on the treatment of patients with documented locally advanced or metastatic RCC (mRCC). The registry, which started in December 2007, was approved by the responsible ethics committee and is registered at ClinicalTrials.gov (NCT00610012). At the time of preparing this manuscript, 122 sites (clinics and outpatient centers) located across Germany have been actively participating, and more than 1500 patients have been enrolled so far. Since 2013, the presence of prognostic factors has been documented, not only according to the Memorial Sloan Kettering Cancer Center (MSKCC),
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      • Motzer R.J.
      • Mazumdar M.
      • Bacik J.
      • Berg W.
      • Amsterdam A.
      • Ferrara J.
      Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
      but also according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)
      • Heng D.Y.C.
      • Xie W.
      • Regan M.M.
      • et al.
      Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.
      model. Further details on the methodology of the RCC-Registry have been previously described.
      • Marschner N.
      • Staehler M.
      • Müller L.
      • et al.
      Survival of patients with advanced or metastatic renal cell carcinoma in routine practice differs from that in clinical trials-analyses from the German Clinical RCC Registry.

      Cohort Definition

      At data cutoff, a total of 1443 patients with mRCC were recruited from December 20, 2007 to May 15, 2017 (Figure 1). For 1427 of these patients, at least the start of first-line treatment was documented. All patients with documented clear cell mRCC were included into this analysis (n = 1085; total cohort). Of these patients, prospectively enrolled patients who had started their first-line treatment until May 15, 2015 and had provided written informed consent no longer than 6 weeks after the beginning of the first-line treatment were included into the outcome analyses (n = 636; outcome cohort). The outcome cohort was split into trial-ineligible patients (Karnofsky Performance Status < 80% and/or hemoglobin level less than the lower limit of normal; n = 291; 46%) and potentially trial-eligible patients (n = 345; 54%) as described previously.
      • Marschner N.
      • Staehler M.
      • Müller L.
      • et al.
      Survival of patients with advanced or metastatic renal cell carcinoma in routine practice differs from that in clinical trials-analyses from the German Clinical RCC Registry.
      Figure thumbnail gr1
      Figure 1Cohort Definition. Number of Patients Enrolled in the RCC-Registry From December 2007 Until May 2017, Split up According to the Histologic Subtypes of mRCC. Patients With Clear Cell mRCC Constituted the Total Cohort (n = 1085). All Patients Who Had Started Their First-line Treatment Until May 15, 2015 and Had Provided Written Informed Consent < 6 Weeks After the Start of First-line Treatment Were Included Into the Outcome Analyses (n = 636; Outcome Cohort). The Outcome Cohort Was Split Into Trial-ineligible Patients (n = 291), Who Met Common Exclusion Criteria of Clinical Trials, and Potentially Trial-eligible Patients (n = 345) as Described Previously
      • Marschner N.
      • Staehler M.
      • Müller L.
      • et al.
      Survival of patients with advanced or metastatic renal cell carcinoma in routine practice differs from that in clinical trials-analyses from the German Clinical RCC Registry.
      ; Exclusion Criteria Included a Karnofsky Performance Status < 80% and/or a Hemoglobin Level Less Than the Lower Limit of Normal
      Abbreviation: mRCC = locally advanced/metastatic renal cell carcinoma.

      Statistical Analysis

      All analyses were performed using Dell, Inc. (Dell Statistica, Software-System für Datenanalyse), version 13, and SAS software, version 9.4 of the SAS System for Windows (SAS Institute Inc, Cary, NC). Time to events was analyzed using Kaplan-Meier estimates. First-line OS was defined as the time between the start of first-line treatment until death from any cause. Second-line OS was defined as the time between the beginning of second-line treatment until death from any cause. Data of patients alive or lost to follow-up were censored at the last documented contact. First-line PFS was defined as the interval between the first administration of any systemic treatment and the date of progression or death prior to the start of second-line treatment. Second-line PFS was defined as the interval between the beginning of systemic second-line treatment and the date of progression or death prior to the start of third-line treatment. Patients without such an event were censored at either the start of the next line treatment or, if no further line treatment had been documented, at the last documented contact.

      Results

      Patient and Tumor Characteristics

      Patient and tumor characteristics of the total cohort (n = 1085) are presented in Table 1, and key characteristics of the outcome cohort (n = 636) in Supplemental Table 1.1 (in the online version). The median age of the total cohort, predominantly consisting of men (68%), was 69 years at start of first-line treatment (Table 1). 83% of the patients experienced at least 1 concomitant disease at start of therapy, with hypertension documented most frequently (62%). One-third of the patients presented with comorbidities considered for the Charlson Comorbidity Index (CCI) (33% CCI ≥ 1). At the start of first-line treatment, lung metastases were documented most frequently, followed by bone or lymph node metastases. According to the MSKCC score,
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      22% of the patients were classified as having favorable (low) risk at the start of treatment, 55% were assigned to the intermediate risk group, and 11% to the poor (high) risk group, with 12% missing allocation to either one of the subgroups. Patients for whom risk factors for both MSKCC and IMDC scores have been collected (recruited since 2013; n = 350) were classified into 23%/13% favorable (low), 50%/39% intermediate, and 13%/16% poor (high) risk (13%/33% missing), according to the MSKCC/IMDC risk model, respectively.
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      • Heng D.Y.C.
      • Xie W.
      • Regan M.M.
      • et al.
      Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.
      Table 1Patient and Tumor Characteristics at the Start of Palliative First-line Treatment
      CharacteristicTotal Cohort (n = 1085)
      N (%)
      Median age, y (Min-Max)69.3 (35.3-90.6)
      Mean BMI, kg/m2 (SD)27.1 (4.8)
       Obese (BMI ≥ 30)221 (20.4)
       Missing132 (12.2)
      Gender
       Female353 (32.5)
       Male732 (67.5)
      Patients with comorbidity
       Any comorbidity
      At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      895 (82.5)
       CCI = 0
      CCI according to Quan et al.18,19
      729 (67.2)
       CCI ≥ 1
      CCI according to Quan et al.18,19
      356 (32.8)
       Hypertension670 (61.8)
       Diabetes mellitus247 (22.8)
       Additional renal disease135 (12.4)
       Congestive heart failure80 (7.4)
      MSKCC risk factors
      MSKCC risk factors according to Motzer et al, 2002.15
       (0) low risk241 (22.2)
       (1-2) intermediate risk594 (54.7)
       (3-5) high risk120 (11.1)
       Missing130 (12.0)
      Number of metastatic sites
       1288 (26.5)
       2229 (21.1)
       3110 (10.1)
       >349 (4.5)
       Unknown409 (37.7)
      Location of metastases
      As for some patients, more than 1 organ system was affected, the total number exceeds the number of patients.
       Lung437 (40.3)
       Lymph nodes205 (18.9)
       Bone203 (18.7)
       Liver138 (12.7)
       Unknown383 (35.3)
      (Partial) nephrectomy
      Prior to systemic first-line treatment.
       None148 (13.6)
       Unknown1 (0.1)
      Prior radiotherapy
      Prior to systemic first-line treatment.
      180 (16.6)
      Abbreviations: BMI = body mass index; CCI = Charlson Comorbidity Index; MSKCC = Memorial Sloan-Kettering Cancer Center; SD = standard deviation.
      Some percentages do not add up to 100% due to rounding.
      a At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      b CCI according to Quan et al.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      • Quan H.
      • Li B.
      • Couris C.M.
      • et al.
      Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.
      c MSKCC risk factors according to Motzer et al, 2002.
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      d As for some patients, more than 1 organ system was affected, the total number exceeds the number of patients.
      e Prior to systemic first-line treatment.

      Choice of Systemic Treatment

      Figure 2 shows the most frequently used first-line (Figure 2A) and second-line (Figure 2B) treatments between 2007 and 2017. Some care should be taken in interpreting percentage values of treatments used over time, because the proportion of patients in some time periods (eg, received 2 lines of treatment in 2016-2017) was rather small, and few patients could cause a relatively big change in percentages.
      Figure thumbnail gr2
      Figure 2Choice of Systemic Treatment Over Time in Patients With Clear Cell mRCC. A, First-line Treatments From 2007 to 2017 Sorted by Relative Frequency (n = 1085). B, Second-line Treatments From 2007 to 2017 Sorted by Relative Frequency (n = 615)
      Abbreviation: mRCC = locally advanced/metastatic renal cell carcinoma.

      First-line Treatment

      In total, about 70% of the patients received either the TKI sunitinib or the TKI pazopanib, whereas the remainder were treated with one of the other options (especially bevacizumab + interferon-alpha, temsirolimus, or sorafenib) (Figure 2A). Overall, about one-half of the patients received the TKI sunitinib, the most frequently used first-line treatment during the entire observation period. Although sunitinib was the targeted agent of choice in 2007 to 2009, there was a decline of sunitinib treatment over time in favor of pazopanib, which was approved in 2010.
      • Sternberg C.N.
      • Davis I.D.
      • Mardiak J.
      • et al.
      Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.

      Second-line Treatment

      A large variety of regimens were used for second-line treatment (Figure 2B). In 2007 to 2009, the most frequently used second-line treatments were sorafenib, temsirolimus, and sunitinib. The proportion of patients treated with either sorafenib or temsirolimus declined steadily. From 2010 to 2011 through 2014 to 2015, most patients were treated with the mTOR inhibitor everolimus, followed by sunitinib and pazopanib. After its approval in 2012,
      • Rini B.I.
      • Escudier B.
      • Tomczak P.
      • et al.
      Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
      second-line treatment with the TKI axitinib ranked second (together with sunitinib in 2014-2015 after everolimus). The newly approved immune CPI nivolumab
      • Motzer R.J.
      • Rini B.I.
      • McDermott D.F.
      • et al.
      Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial.
      was applied to almost one-half of the patients in 2016 to 2017 (database cutoff May 15, 2017). At the time of database cutoff, 1 treatment with the newly approved combination of lenvatinib and everolimus and no treatment with cabozantinib had been documented yet; however, only a very small number of patients had started second-line treatment between approval and database cutoff for this analysis.

      Sequential Treatment Strategies

      The most frequently used sequential treatment strategies and their change over time are presented in Figure 3, split into 3 observation periods (Figure 3A-C) that reflect the approval of the different targeted second-line treatment strategies (TKI, mTOR, CPI) and their introduction into routine clinical practice. The most frequently applied first-line → second-line sequence over the entire observation period was TKI → TKI. The most common TKI → TKI sequences were sunitinib → sorafenib in 2007 to 2011 (n = 75), sunitinib → pazopanib in 2012 to 2014 (n = 17), and pazopanib → sunitinib in 2015 to 2017 (n = 11). The frequency of the sequence TKI → mTOR slightly decreased. The most frequently used TKI → mTOR sequences included sunitinib → temsirolimus in 2007 to 2011 (n = 48), sunitinib → everolimus in 2007 to 2011 and 2012 to 2014 (n = 44 and n = 41, respectively), and pazopanib → everolimus in 2015 to 2017 (n = 15). About one-fifth of all patients starting treatment in 2015 to 2017 (n = 20) received the sequence TKI → CPI (approval of nivolumab in June 2015) (Figure 3C). This percentage would have increased if 2016 to 2017 had been analyzed solely, but this would have been at the expense of a markedly reduced sample size and thus lower accuracy for this period of time.
      Figure thumbnail gr3
      Figure 3Sequential Treatment Strategies Over Time in Patients With Clear Cell mRCC. Sequential Treatment Pattern is Presented for All Patients With Documented First- and Second-line Treatment at the Time of Database Cutoff (n = 615). Bevacizumab ± Interferon Is Included in “Other” Strategies. A, Start of Second-line Treatment Between March 15, 2007 and December 21, 2011 (n = 327). B, Start of Second-line Treatment Between January 15, 2012 and December 23, 2014 (n = 187). C, Start of Second-line Treatment Between January 15, 2015 and April 11, 2017 (n = 101). Percentages Might Not Add up to 100% Owing to Rounding
      Abbreviations: CPI = checkpoint inhibitor; mRCC = locally advanced/metastatic renal cell carcinoma; mTOR = mechanistic target of rapamycin; TKI = tyrosine-kinase inhibitor.

      Subsequent Systemic Lines of Treatment

      Figure 4 shows the percentage of patients of the outcome cohort receiving several subsequent lines of systemic treatment. Overall, at least 56% of the patients received a second-line treatment and 29% a third-line treatment. 13% of the patients were treated for 4 lines of treatment and 5% for 5 lines of treatment, whereas at least 25% of the patients died prior to a second-line and 42% prior to a third-line treatment. For patients marked as “potential” who had either not completed the current treatment line or had finished the current line but had not started a new one and for patients who were lost to follow-up at database cutoff, it is unknown if further treatment lines were given. If all these patients had received a further treatment line, 75% of patients would have received a second-line treatment; for example, if all had died, a maximum of 56% of patients would have been treated in a second-line setting.
      Figure thumbnail gr4
      Figure 4Subsequent Systemic Lines of Treatment (Outcome Cohort). Proportion of Patients Having Received a Systemic Palliative Second-, Third-, Fourth-, and Fifth-line Treatment and Proportion of Patients Who Died Prior to Receiving a Subsequent Line of Treatment. All Prospectively Enrolled Patients Who Started First-line Treatment Until May 15, 2015 (n = 636). Potential: Further Treatment Possible (Current Line Ongoing, Therapy Paused, or Documentation Finished)

      Best Response, PFS, and OS

      Median first-line PFS and OS for patients grouped by the MSKCC score are presented in Figure 5. Best response and supplemental outcome data for the entire outcome cohort and by type of first- or second-line treatment are shown in Supplemental Tables 1.1,1.2,1.3 and 2 (in the online version). Patient and tumor characteristics of the outcome cohort (see Supplemental Table 1.1 in the online version) and the total cohort (Table 1) were comparable. About one-half of the patients included in the outcome cohort could be considered as trial-ineligible patients (Figure 1). These patients were also slightly older than potentially trial-eligible patients (median age of 71 vs. 69 years) (see Supplemental Table 1.1 in the online version).
      Figure thumbnail gr5
      Figure 5PFS and OS by MSKCC Score
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      • Motzer R.J.
      • Mazumdar M.
      • Bacik J.
      • Berg W.
      • Amsterdam A.
      • Ferrara J.
      Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
      in Patients With Clear Cell mRCC (Outcome Cohort). Prospectively Enrolled Patients Who Started First-line Treatment Until May 15, 2015 (n = 636). A, PFS From Start of First-line Treatment. B, OS From Start of First-line Treatment
      Abbreviations: mRCC = locally advanced/metastatic renal cell carcinoma; MSKCC = Memorial Sloan Kettering Cancer center; OS = overall survival; PFS = progression-free survival.

      PFS and OS According to the MSKCC Score

      The median first-line PFS was 14.6 months (95% confidence interval [CI], 11.3-20.3 months) for low-risk, 8.1 months (95% CI, 6.9-9.9 months) for intermediate-risk, and 3.7 months (95% CI, 2.8-5.6 months) for high-risk patients (Figure 5A). The median first-line OS was 36.7 months (95% CI, 27.9-43.0 months) for patients in the low-risk, 18.7 months (95% CI, 16.0-20.8 months) for patients in the intermediate-risk, and 7.2 months (95% CI, 4.8-10.9 months) for patients in the high-risk group (Figure 5B).

      Best Response, Treatment Duration, and Further Outcome Data

      Overall, the median duration of first-line treatment was 5.1 months (interquartile range [IQR], 2.2-11.3 months) (see Supplemental Table 1.1 in the online version). The median duration of first-line treatment was longer for trial-eligible than for trial-ineligible patients (7.5 months; IQR, 2.8-13.6 months vs. 3.4 months; IQR, 1.6-8.3 months). With a disease control rate (DCR), covering complete/partial response and stable disease, of 53% (30% were unknown/missing; in patients with known best response: 76% DCR), more than one-half of all first-line treatments were successful. Overall, the median first-line PFS was 9.2 months (95% CI, 7.9-10.2 months), and the median first-line OS was 20.4 months (95% CI, 18.0-22.2 months). Potentially trial-eligible patients had a longer median first-line PFS (11.0 months; 95% CI, 9.7-12.9 months) and OS (26.2 months; 95% CI, 22.1-31.5 months) compared with trial-ineligible patients with a PFS of 6.5 months (95% CI, 4.9-7.3 months) and a OS of 14.6 months (95% CI, 11.5-18.0 months).
      The median duration of second-line treatment was 3.3 months (IQR, 1.6-7.0 months) (see Supplemental Table 2 in the online version). The DCR of second-line treatment was 39% (35% were unknown/missing; in patients with known best response: 60% DCR). Overall, the median second-line PFS was 5.0 months (95% CI, 4.2-5.9 months), and the median second-line OS was 14.3 months (95% CI, 11.4-16.7 months).

      Discussion

      The treatment landscape for mRCC has evolved rapidly in recent years, and the range of therapeutic options has broadened. There is a call for studies investigating how these new treatments affect choice of treatment and outcome of patients with mRCC in routine practice, because the evidence included in our guidelines and recommendations is mainly based on randomized clinical trials and thus trial-eligible patient populations.
      To our knowledge, this is the first comprehensive overview of the changes in treatment reality and the survival of patients with clear cell mRCC from a large longitudinal, prospective cohort study. We show the choice of first- and second-line treatment strategy reflecting the broad range of approved targeted agents including TKIs, mTOR inhibitors, and a CPI. Newly licensed agents have been quickly implemented into routine practice, which has led to a change in treatment reality during the past decade. Despite these very promising changes for the vast majority of patients, it has to be of note that those patients with unfavorable prognosis, including trial-ineligible patients, still have inferior outcomes – comparable to the times prior to the availability of these new therapeutic options. For potentially trial-eligible patients, median first-line PFS and OS were similar to the survival times reported from pivotal clinical trials.
      Despite the prospective data collection and the thorough design of the RCC-Registry data collection, the interpretation of data from cohort studies like ours remains limited by the observational design. There is no randomization of treatment or study sites, and homogeneity of the patient population cannot be assumed. Thus, causal relations cannot be drawn. Some care should be taken in interpreting percentage values of treatments used over time, because the proportion of patients in some time periods (eg, received 2 lines of treatment in 2016-2017) was rather small and few patients could cause a relatively pronounced change in percentages. The tumor assessment in routine care is not performed according to the Response Evaluation Criteria In Solid Tumors (RECIST) used in clinical trials, and thus, the PFS data presented here should be considered as the best clinical approximation and might not be identical to the PFS determined in clinical trials. On the other hand, the clear strengths of this study are the prospective, longitudinal design and the participation of physicians from all over Germany continuously recruiting a large study cohort.
      Since their approval, various targeted agents have been recommended as standard treatment for mRCC based on the evidence provided in randomized clinical trials and have been implemented in guidelines and recommendations that have been continuously updated reflecting the changing treatment landscape over time.
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Powles T.
      • Albiges L.
      • Staehler M.
      • et al.
      Updated European Association of Urology guidelines recommendations for the treatment of first-line metastatic clear cell renal cancer.
      • Powles T.
      • Staehler M.
      • Ljungberg B.
      • et al.
      Updated EAU Guidelines for clear cell renal cancer patients who fail VEGF targeted therapy.
      Our data confirm that first- and second-line treatment including sequential treatment strategies in clear cell mRCC in routine care mirror the wide range of approved agents for mRCC treatment and allow us to track these strategy changes throughout various time periods. In addition, we further show a change in treatment reality over time as a result of the rapid implementation of newly approved targeted agents in daily practice, reflecting adherence to new guidelines and evolving evidence. Since the start of the RCC-Registry to the database cutoff in May 2017, the number of sequential treatment strategies used has increased from mono-TKIs mainly (2006-2009), to the sequential use of TKIs and mTOR inhibitors (2009-2015), to now mostly 3-line strategies based on TKIs, mTOR inhibitors, and a CPI (since 2015).
      Our findings that TKIs accounted for the most frequently used first-line treatment in Germany are, in general, consistent with the results of previously published retrospective observational studies from other countries.
      • Geynisman D.M.
      • Hu J.C.
      • Liu L.
      • Tina Shih Y.-C.
      Treatment patterns and costs for metastatic renal cell carcinoma patients with private insurance in the United States.
      • Lindskog M.
      • Wahlgren T.
      • Sandin R.
      • et al.
      Overall survival in Swedish patients with renal cell carcinoma treated in the period 2002 to 2012: update of the RENCOMP study with subgroup analysis of the synchronous metastatic and elderly populations.
      • Maroun R.
      • Fleury L.
      • Nachbaur G.
      • Maunoury F.
      • Vanhille J.-L.
      • Durand-Zaleski I.
      Real-world costs and outcomes in metastatic renal cell carcinoma patients treated with targeted therapies: a cohort study from the French health insurance database.
      • Wagstaff J.
      • Jones R.
      • Hawkins R.
      • et al.
      Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry.
      We also present the treatment reality of recent years, whereas existing literature has often covered a shorter observation period than ours.
      • Geynisman D.M.
      • Hu J.C.
      • Liu L.
      • Tina Shih Y.-C.
      Treatment patterns and costs for metastatic renal cell carcinoma patients with private insurance in the United States.
      • Maroun R.
      • Fleury L.
      • Nachbaur G.
      • Maunoury F.
      • Vanhille J.-L.
      • Durand-Zaleski I.
      Real-world costs and outcomes in metastatic renal cell carcinoma patients treated with targeted therapies: a cohort study from the French health insurance database.
      • Tsimafeyeu I.
      • Zolotareva T.
      • Varlamov S.
      • et al.
      Five-year survival of patients with metastatic renal cell carcinoma in the Russian Federation: results from the RENSUR5 registry.
      • Harrison M.R.
      • Hirsch B.R.
      • George D.J.
      • et al.
      Real-world outcomes in metastatic renal cell carcinoma: insights from a Joint Community-Academic Registry.
      Over time, our data show a decline of sunitinib treatment in favor of pazopanib, following European marketing approval. The British RECCORD (Renal Cell Carcinoma Outcomes Research Dataset) registry also reported a shift from sunitinib to pazopanib between 2009 and 2012, with sunitinib remaining the most common first-line treatment.
      • Wagstaff J.
      • Jones R.
      • Hawkins R.
      • et al.
      Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry.
      Similar changes were seen in the Swedish RENCOMP (Renal Comparison) study that covered the time period 2002 to 2012.
      • Lindskog M.
      • Wahlgren T.
      • Sandin R.
      • et al.
      Overall survival in Swedish patients with renal cell carcinoma treated in the period 2002 to 2012: update of the RENCOMP study with subgroup analysis of the synchronous metastatic and elderly populations.
      Current guidelines recommend both sunitinib and pazopanib as one of the therapeutic options of first-line treatment for mRCC independent of the patient's prognostic score.
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Powles T.
      • Albiges L.
      • Staehler M.
      • et al.
      Updated European Association of Urology guidelines recommendations for the treatment of first-line metastatic clear cell renal cancer.
      Our data show that patients with a poor prognostic risk were most frequently treated with temsirolimus, which has been in accordance with guideline recommendation for this patient population until recently.
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Ljungberg B.
      • Albiges L.
      • Bensalah K.
      • et al.
      European Association of Urology Guidelines on Renal Cell Carcinoma: 2017.
      The Updated European Association of Urology Guidelines, however, newly recommend a combination of ipilimumab and nivolumab in intermediate- and poor-risk patients with mRCC in first-line treatment,
      • Powles T.
      • Albiges L.
      • Staehler M.
      • et al.
      Updated European Association of Urology guidelines recommendations for the treatment of first-line metastatic clear cell renal cancer.
      which was just recently approved by the United States Food and Drug Administration. Because VEGF-targeted therapy has become the first-line standard of care, the use of cytokine-based immunotherapies has decreased over time, which is in line with our data and was also shown by others.
      • Geynisman D.M.
      • Hu J.C.
      • Liu L.
      • Tina Shih Y.-C.
      Treatment patterns and costs for metastatic renal cell carcinoma patients with private insurance in the United States.
      • Ko J.J.
      • Choueiri T.K.
      • Rini B.I.
      • et al.
      First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.
      Second-line treatment which was received by more than one-half of all prospectively enrolled patients has changed during the course of the RCC-Registry. The TKI sorafenib, approved in 2006 after cytokines in first-line,
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib in advanced clear-cell renal-cell carcinoma.
      was the most common second-line treatment in 2007 to 2009, but has decreased substantially during the observation period. A similar trend has been reported previously.
      • Geynisman D.M.
      • Hu J.C.
      • Liu L.
      • Tina Shih Y.-C.
      Treatment patterns and costs for metastatic renal cell carcinoma patients with private insurance in the United States.
      In the later targeted period from 2012 on, sorafenib has been replaced by other TKIs including axitinib. With the approval of the mTOR inhibitor everolimus in 2009,
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors.
      guidelines have recommended its use after TKIs in first-line treatment,
      • Ljungberg B.
      • Hanbury D.C.
      • Kuczyk M.A.
      • et al.
      European Association of Urology Guidelines on Renal Cell Carcinoma.
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      which was followed in routine care as reflected by our data with everolimus ranged first from 2010 to 2011 through 2014 to 2015. In the British RECCORD registry, everolimus was also the most frequently used second-line treatment between 2009 and 2012.
      • Wagstaff J.
      • Jones R.
      • Hawkins R.
      • et al.
      Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry.
      Recommendations for second-line treatment in mRCC have recently changed again after the report of 2 phase III trials showing improvement in OS with the CPI nivolumab
      • Motzer R.J.
      • Rini B.I.
      • McDermott D.F.
      • et al.
      Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial.
      and the dual pathway inhibiting TKI cabozantinib
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      over everolimus. Both trials showed significant improvement in OS and response rate, whereas PFS was improved in the cabozantinib trial only.
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      The data presented here show that nivolumab has been rapidly implemented in routine practice as it was the most common second-line treatment in the most recent period from 2016 to 2017. However, the number of patients with documented second-line treatment in 2016 to 2017 was still rather small at the time of database cutoff in May 2017, limiting the interpretation of the results. Because cabozantinib was approved in September 2016, it is hardly surprising that our data cannot yet reflect the frequency of cabozantinib use in second-line treatment.
      The majority of the patients in the RCC-Registry received multiple systemic treatment lines, with almost one-half of the patients being given 3 or more treatment lines. The increasing number of available treatment options across multiple lines of treatment increases the number of potential sequences for using these therapies. However, the optimal sequential treatment strategy is an ongoing matter of debate and changes over time.
      • Fischer S.
      • Gillessen S.
      • Rothermundt C.
      Sequence of treatment in locally advanced and metastatic renal cell carcinoma.
      Some clinical trials have attempted to identify optimal sequential treatment strategies, for example Renal Cell Cancer Treatment With Oral RAD001 Given Daily; sunitinib → everolimus or vice versa
      • Motzer R.J.
      • Barrios C.H.
      • Kim T.M.
      • et al.
      Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma.
      and Sequential Study to Treat Renal Cell Carcinoma; sunitinib → sorafenib or vice versa.
      • Eichelberg C.
      • Vervenne W.L.
      • De Santis M.
      • et al.
      SWITCH: a randomised, sequential, open-label study to evaluate the efficacy and safety of sorafenib-sunitinib versus sunitinib-sorafenib in the treatment of metastatic renal cell cancer.
      • Bhavsar N.A.
      • Harrison M.R.
      • Hirsch B.R.
      • et al.
      Design and rationale of the Metastatic Renal Cell Carcinoma (MaRCC) Registry: a prospective academic and community-based study of patients with metastatic renal cell cancer.
      Although clinical trials usually recruit highly selected patients, clinical registries may represent all patients and all lines of treatment, allowing the analysis of sequential treatments in routine care. Our work is the first showing the sequential mRCC treatment strategies in a routine practice setting and their change over time as a result of the implementation of newly approved targeted agents. The large variety of the sequential treatments most likely mirrors individual treatment strategies adjusted to patient's comorbidities, tumor burden, response to previous treatments, or duration of remission. Access to these data is of high value to the community, because randomized clinical trials or prospective clinical evaluations with the focus on the investigation of sequences of treatment lines will remain rare. The few existing randomized clinical trials did not provide insight beyond the second-line treatment or were designed only to investigate second-line treatment options, and only a few combinations or sequences have been tested in a preplanned/randomized fashion.
      • Rini B.I.
      • Escudier B.
      • Tomczak P.
      • et al.
      Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      • Eichelberg C.
      • Vervenne W.L.
      • De Santis M.
      • et al.
      SWITCH: a randomised, sequential, open-label study to evaluate the efficacy and safety of sorafenib-sunitinib versus sunitinib-sorafenib in the treatment of metastatic renal cell cancer.
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • et al.
      Nivolumab versus everolimus in advanced renal-cell carcinoma.
      A large number of prognostic factors in mRCC have been identified that are associated with patients' response to treatment.
      • Sun M.
      • Shariat S.F.
      • Cheng C.
      • et al.
      Prognostic factors and predictive models in renal cell carcinoma: a contemporary review.
      Our data show that the outcome of patients with clear cell mRCC can be predicted by the MSKCC score, because the median first-line OS was 36.7 months for favorable (low) risk, 18.7 months for intermediate risk, and 7.2 months for poor (high) risk patients. In the initial publication of the MSKCC risk model, the median OS of patients with mRCC (Motzer's study population) with low risk was 30 months, with intermediate risk 14 months, and with high risk 5 months.
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      Assuming that patient characteristics of our RCC-Registry and the Motzer's study population are comparable, these data indicate that the outcome of patients with low and intermediate risk has been improved by the use of targeted agents. Although the MSKCC criteria have been developed during the era of cytokines, its applicability to targeted agents could also be demonstrated.
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • et al.
      Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Motzer R.J.
      • Escudier B.
      • Bukowski R.
      • et al.
      Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma.
      The IMDC risk model has been established for patients treated in the era of targeted therapy and has added neutrophilia and thrombocytosis to the list of MSKCC risk factors, whereas lactate dehydrogenase measures have been removed.
      • Heng D.Y.C.
      • Xie W.
      • Regan M.M.
      • et al.
      Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.
      According to the IMDC risk model, the OS in the population studied (Heng's study population) ranged from 43.2 months in low-risk patients with mRCC to 7.8 months in those with high risk.
      • Heng D.Y.C.
      • Xie W.
      • Regan M.M.
      • et al.
      External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study.
      The IMDC and the MSKCC risk model are reported as highly concordant, with 83% of patients classified into the same risk group by each model; however, still more than 10% of the population was upgraded to a less favorable risk group by the IMDC risk model.
      • Heng D.Y.C.
      • Xie W.
      • Regan M.M.
      • et al.
      External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study.
      In the current analyses, we cannot show outcome data according to the IMDC risk model as the proportion of patients with documented IMDC score was still too small and the duration of follow-up too short. This will be subject to further analyses of the RCC-Registry.
      Patients in routine practice differ from patients treated in clinical trials mainly owing to lower performance status and a higher number of impairing comorbidities.
      • Marschner N.
      • Staehler M.
      • Müller L.
      • et al.
      Survival of patients with advanced or metastatic renal cell carcinoma in routine practice differs from that in clinical trials-analyses from the German Clinical RCC Registry.
      • Mitchell A.P.
      • Harrison M.R.
      • Walker M.S.
      • George D.J.
      • Abernethy A.P.
      • Hirsch B.R.
      Clinical trial participants with metastatic renal cell carcinoma differ from patients treated in real-world practice.
      • Heng D.Y.C.
      • Choueiri T.K.
      • Rini B.I.
      • et al.
      Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials.
      We have previously shown that at least 60% of the patients with mRCC in German routine practice would have been ineligible for participation in clinical trials.
      • Marschner N.
      • Staehler M.
      • Müller L.
      • et al.
      Survival of patients with advanced or metastatic renal cell carcinoma in routine practice differs from that in clinical trials-analyses from the German Clinical RCC Registry.
      In the present analysis, almost one-half of the patients were classified as trial-ineligible, because only patients with clear cell histology were included.
      For the potentially trial-eligible patients included in the present analysis, the median first-line PFS of 11.0 months and OS of 26.2 months were similar to the survival times reported from phase III clinical trials, with a median first-line PFS of 5.5 to 11.0 months
      • Sternberg C.N.
      • Davis I.D.
      • Mardiak J.
      • et al.
      Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib in advanced clear-cell renal-cell carcinoma.
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
      • Motzer R.J.
      • Hutson T.E.
      • Cella D.
      • et al.
      Pazopanib versus sunitinib in metastatic renal-cell carcinoma.
      and a median OS of 17.8 to 29.3 months.
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
      • Motzer R.J.
      • Hutson T.E.
      • Cella D.
      • et al.
      Pazopanib versus sunitinib in metastatic renal-cell carcinoma.
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • et al.
      Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206.
      • Escudier B.
      • Bellmunt J.
      • Négrier S.
      • et al.
      Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival.
      • Sternberg C.N.
      • Hawkins R.E.
      • Wagstaff J.
      • et al.
      A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update.
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial.
      We also show, for the most frequently applied first-line treatments (sunitinib, pazopanib, bevacizumab + interferon, temsirolimus, and sorafenib), that trial-eligible patients had survival times comparable to those of the above-mentioned pivotal clinical trials. This may be used to model randomized clinical scenarios in a routine patient population, given that the criteria used are carefully chosen. For sorafenib, the number of patients was low and thus limits the interpretation of the data. Besides median PFS and OS, median duration of treatment also differed according to trial-eligibility. Median duration of first-line treatment of patients treated with targeted agents was also comparable with that reported from the respective phase III clinical trials.
      • Sternberg C.N.
      • Davis I.D.
      • Mardiak J.
      • et al.
      Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.
      • Hudes G.
      • Carducci M.
      • Tomczak P.
      • et al.
      Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
      Notably, despite similar outcomes, potentially trial-eligible patients had more comorbidities and were older than patients included in large clinical trials (median age of 69 years vs. 59-62 years
      • Sternberg C.N.
      • Davis I.D.
      • Mardiak J.
      • et al.
      Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
      • Escudier B.
      • Bellmunt J.
      • Négrier S.
      • et al.
      Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival.
      ). The median age of 69 years is representative for patients with mRCC in Germany.

      Robert Koch-Institut, Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., eds. Krebs in Deutschland 2011/2012. Häufigkeiten und Trends. 10. Ausgabe. Berlin; 2015.

      Conclusion

      To our knowledge, this is the first prospective longitudinal cohort study showing the changes in treatment reality during the past decade and the effectiveness of treatment in unselected patients with clear cell mRCC treated in Germany. We show that treatment options have increased over the past decade with newly approved treatments quickly being applied in routine care. Patients with unfavorable prognosis, including trial-ineligible patients, still have inferior outcomes. Despite higher age and more comorbidities, median first-line PFS and OS of potentially trial-eligible patients are similar to the survival times reported from clinical trials.
      Our data highlight the importance of population-based cohort studies to complement the results from clinical trials and improve the standard of care. We show that further research should focus on improving outcome for trial-ineligible patients or patients at high prognostic risk.

      Clinical Practice Points

      • The treatment landscape for mRCC has evolved rapidly in the past decade, and the range of therapeutic options has broadened substantially.
      • In contrast to the often highly selected patients included in clinical trials, the general patient population treated in routine practice is more heterogeneous and likely to be elderly and less healthy.
      • Cohort studies on treatment reality and on patients' outcomes are needed to further investigate the impact of new targeted treatments on patients in routine care. Such studies are still scarce, especially prospective, longitudinal studies.
      • To our knowledge, this is the first prospective, longitudinal cohort study showing the changes in treatment reality during the past decade and the effectiveness of treatment in unselected patients with clear cell mRCC treated in Germany.
      • The choice of first- and second-line treatment and its change from 2007 to 2017 reflect the chronological approval of different targeted agents; from mainly TKIs, to TKIs/mTOR inhibitors, to now TKIs/mTOR inhibitors/CPI.
      • Patients with unfavorable prognosis, including trial-ineligible patients who meet common exclusion criteria of clinical trials, have inferior outcomes.
      • Despite higher age and a considerable proportion of comorbidities, median first-line PFS and OS of potentially trial-eligible patients are similar to the survival times reported from clinical trials.
      • Our data are a valuable resource to understand the impact of treatment choices in mRCC and patient outcomes in routine practice setting, to complement the results from clinical trials and to improve the standard of care.
      • Further research should focus on improving outcome for trial-ineligible patients or patients at high prognostic risk.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Acknowledgments

      The authors thank all patients, physicians, and study teams participating in the RCC-Registry. They also thank the Arbeitskreis Klinische Studien in Onkologischen und Hämatologischen Praxen e.V. as well as the Bund der Urologen e.G. for supporting this registry.
      The authors thank Melanie Frank and Dr. Med Leonora Houet, (iOMEDICO) for critical comments on the manuscript. The authors would like to thank Dr. Anja Kaiser-Osterhues (iOMEDICO) for her support in preparing the manuscript.
      The RCC is designed, managed, and analyzed by iOMEDICO and has received continuous financial support from Novartis Pharma GmbH and temporary financial support from Bayer Vital GmbH, GlaxoSmithKline GmbH & Co. KG, Pfizer Pharma GmbH, and Roche Pharma AG. None of the funders had any role in study design, data collection and analysis, interpretation of results, decision to publish, or preparation of the manuscript.

      Supplemental Data

      Supplemental Table 1.1Patient Characteristics, Best Response, OS, and PFS of Patients in the Palliative First-line Setting (Outcome Cohort)
      Total Outcome CohortSunitinib
      Total (n = 636)Potentially Trial-eligible (n = 345)Trial-ineligible (n = 291)Total (n = 305)Potentially Trial-eligible (n = 184)Trial-ineligible (n = 121)
      Median age,
      At the start of first-line treatment.
      y (Min-Max)
      69.8 (36.5-88.5)68.9 (36.5-88.5)71.0 (38.2-86.6)69.3 (38.2-86.6)68.4 (38.6-85.9)71.7 (38.2-86.6)
      Patients with comorbidity
      At the start of first-line treatment.
      N (%)N (%)N (%)N (%)N (%)N (%)
       Any comorbidity
      At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      517 (81.3)265 (76.8)252 (86.6)245 (80.3)143 (77.7)102 (84.3)
       CCI ≥ 1
      CCI according to Quan et al.18,19
      215 (33.8)94 (27.2)121 (41.6)99 (32.5)49 (26.6)50 (41.3)
      MSKCC risk factors
      At the start of first-line treatment.
      ,
      MSKCC risk factors according to Motzer et al, 2002.15
       (0) low risk145 (22.8)145 (42.0)0 (0.0)74 (24.3)74 (40.2)0 (0.0)
       (1-2) intermediate risk336 (52.8)154 (44.6)182 (62.5)163 (53.4)82 (44.6)81 (66.9)
       (3-5) high risk86 (13.5)0 (0.0)86 (29.6)30 (9.8)0 (0.0)30 (24.8)
       Missing69 (10.8)46 (13.3)23 (7.9)38 (12.5)28 (15.2)10 (8.3)
      Best response
       CR/PR147 (23.1)97 (28.1)50 (17.2)75 (24.6)55 (29.9)20 (16.5)
       SD193 (30.3)104 (30.1)89 (30.6)79 (25.9)50 (27.2)29 (24.0)
       PD105 (16.5)53 (15.4)52 (17.9)55 (18.0)29 (15.8)26 (21.5)
       Unknown172 (27.0)80 (23.2)92 (31.6)87 (28.5)44 (23.9)43 (35.5)
       Missing19 (3.0)11 (3.2)8 (2.7)9 (3.0)6 (3.3)3 (2.5)
      Patients with completed treatment587 (92.3)316 (91.6)271 (93.1)280 (91.8)169 (91.8)111 (91.7)
       Median duration of treatment, mo (IQR)5.1 (2.2-11.3)7.5 (2.8-13.6)3.4 (1.6-8.3)5.4 (2.4-11.6)7.9 (3.0-14.3)3.2 (1.5-7.5)
      Progression-free survival
       Events441 (69.3)236 (68.4)205 (70.4)203 (66.6)126 (68.5)77 (63.6)
       Median PFS, mo (95% CI)9.2 (7.9-10.2)11.0 (9.7-12.9)6.5 (4.9-7.3)10.7 (8.1-12.1)11.3 (9.7-14.6)7.2 (4.8-11.8)
      Overall survival
       Events386 (60.7)199 (57.7)187 (64.3)179 (58.7)105 (57.1)74 (61.2)
       Median OS, mo (95% CI)20.4 (18.0-22.2)26.2 (22.1-31.5)14.6 (11.5-18.0)21.2 (16.6-27.9)29.6 (21.2-37.6)12.5 (9.9-20.3)
      Some percentages do not add up to 100% owing to rounding.
      Abbreviations: CCI = Charlson Comorbidity Index; CI = confidence interval; CR = complete response; IQR = interquartile range; MSKCC = Memorial Sloan-Kettering Cancer Center; OS = overall survival; PD = progression; PFS = progression-free survival; PR = partial response; SD = stable disease.
      a At the start of first-line treatment.
      b At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      c CCI according to Quan et al.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      • Quan H.
      • Li B.
      • Couris C.M.
      • et al.
      Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.
      d MSKCC risk factors according to Motzer et al, 2002.
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      Supplemental Table 1.2Patient Characteristics, Best Response, OS, and PFS of Patients in the Palliative First-line Setting (Outcome Cohort)
      PazopanibBevacizumab ± Interferon
      Total (n = 116)Potentially Trial-eligible (n = 56)Trial-ineligible (n = 60)Total (n = 84)Potentially Trial-eligible (n = 47)Trial-ineligible (n = 37)
      Median age, y (Min-Max)
      At the start of first-line treatment.
      70.1 (36.5-84.5)67.8 (36.5-79.7)71.4 (40.3-84.5)69.5 (44.3-83.7)69.3 (44.3-83.7)70.4 (49.4-83.4)
      Patients with comorbidity
      At the start of first-line treatment.
      N (%)N (%)N (%)N (%)N (%)N (%)
       Any comorbidity
      At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      96 (82.8)44 (78.6)52 (86.7)68 (81.0)35 (74.5)33 (89.2)
       CCI ≥ 1
      CCI according to Quan et al.18,19
      45 (38.8)17 (30.4)28 (46.7)26 (31.0)12 (25.5)14 (37.8)
      MSKCC risk factors
      At the start of first-line treatment.
      ,
      MSKCC risk factors according to Motzer et al, 2002.15
       (0) low risk25 (21.6)25 (44.6)0 (0.0)18 (21.4)18 (38.3)0 (0.0)
       (1-2) intermediate risk60 (51.7)26 (46.4)34 (56.7)48 (57.1)22 (46.8)26 (70.3)
       (3-5) high risk23 (19.8)0 (0.0)23 (38.3)7 (8.3)0 (0.0)7 (18.9)
       Missing8 (6.9)5 (8.9)3 (5.0)11 (13.1)7 (14.9)4 (10.8)
      Best response
       CR/PR33 (28.4)23 (41.1)10 (16.7)17 (20.2)10 (21.3)7 (18.9)
       SD37 (31.9)13 (23.2)24 (40.0)34 (40.5)22 (46.8)12 (32.4)
       PD12 (10.3)5 (8.9)7 (11.7)16 (19.0)8 (17.0)8 (21.6)
       Unknown27 (23.3)13 (23.2)14 (23.3)15 (17.9)5 (10.6)10 (27.0)
       Missing7 (6.0)2 (3.6)5 (8.3)2 (2.4)2 (4.3)0 (0.0)
      Patients with completed treatment99 (85.3)49 (87.5)50 (83.3)81 (96.4)44 (93.6)37 (100.0)
       Median duration of treatment, mo (IQR)7.6 (2.9-14.3)8.8 (3.6-16.1)5.8 (2.8-10.9)5.1 (2.4-12.3)7.8 (3.4-12.9)3.2 (2.0-7.9)
      Progression-free survival
       Events80 (69.0)39 (69.6)41 (68.3)56 (66.7)31 (66.0)25 (67.6)
       Median PFS, mo (95% CI)9.9 (8.3-13.5)10.8 (8.7-15.9)8.3 (4.9-12.4)9.6 (6.4-15.3)12.5 (6.9-16.4)6.5 (4.0-17.9)
      Overall survival
       Events67 (57.8)32 (57.1)35 (58.3)55 (65.5)31 (66.0)24 (64.9)
       Median OS, mo (95% CI)22.1 (17.0-31.8)26.5 (16.6-40.7)18.7 (13.4-32.3)21.1 (15.9-26.1)22.8 (19.0-29.7)17.9 (7.7-24.5)
      Some percentages do not add up to 100% owing to rounding.
      Abbreviations: CI = Confidence interval; CCI = Charlson Comorbidity Index; CR = complete response; IQR = interquartile range; MSKCC = Memorial Sloan-Kettering Cancer Center; OS = overall survival; PD = progression; PFS = progression-free survival; PR = partial response; SD = stable disease.
      a At the start of first-line treatment.
      b At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      c CCI according to Quan et al.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      • Quan H.
      • Li B.
      • Couris C.M.
      • et al.
      Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.
      d MSKCC risk factors according to Motzer et al, 2002.
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      Supplemental Table 1.3Patient Characteristics, Best Response, OS, and PFS of Patients in the Palliative First-line Setting (Outcome Cohort)
      TemsirolimusSorafenib
      Total (n = 76)Potentially Trial-eligible (n = 31)Trial-ineligible (n = 45)Total (n = 35)Potentially Trial-eligible (n = 16)Trial-ineligible (n = 19)
      Median age, y (Min-Max)
      At the start of first-line treatment.
      72.5 (46.5-86.5)73.7 (47.1-84.3)71.9 (46.5-86.5)70.6 (48.4-85.0)67.3 (48.4-85.0)70.7 (52.8-80.4)
      Patients with comorbidity
      At the start of first-line treatment.
      N (%)N (%)N (%)N (%)N (%)N (%)
       Any comorbidity
      At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      62 (81.6)23 (74.2)39 (86.7)29 (82.9)12 (75.0)17 (89.5)
       CCI ≥ 1
      CCI according to Quan et al.18,19
      25 (32.9)8 (25.8)17 (37.8)10 (28.6)4 (25.0)6 (31.6)
      MSKCC risk factors
      At the start of first-line treatment.
      ,
      MSKCC risk factors according to Motzer et al, 2002.15
       (0) low risk17 (22.4)17 (54.8)0 (0.0)7 (20.0)7 (43.8)0 (0.0)
       (1-2) intermediate risk34 (44.7)11 (35.5)23 (51.1)18 (51.4)7 (43.8)11 (57.9)
       (3-5) high risk19 (25.0)0 (0.0)19 (42.2)6 (17.1)0 (0.0)6 (31.6)
       Missing6 (7.9)3 (9.7)3 (6.7)4 (11.4)2 (12.5)2 (10.5)
      Best response
       CR/PR8 (10.5)2 (6.5)6 (13.3)9 (25.7)5 (31.3)4 (21.1)
       SD28 (36.8)12 (38.7)16 (35.6)8 (22.9)4 (25.0)4 (21.1)
       PD14 (18.4)6 (19.4)8 (17.8)3 (8.6)1 (6.3)2 (10.5)
       Unknown25 (32.9)10 (32.3)15 (33.3)15 (42.9)6 (37.5)9 (47.4)
       Missing1 (1.3)1 (3.2)0 (0.0)0 (0.0)0 (0.0)0 (0.0)
      Patients with completed treatment75 (98.7)30 (96.8)45 (100.0)33 (94.3)14 (87.5)19 (100.0)
       Median duration of treatment, mo (IQR)3.1 (1.0-6.7)4.5 (1.0-9.5)3.0 (1.3-5.1)2.2 (1.0-9.5)5.1 (1.2-9.5)1.4 (0.8-11.0)
      Progression-free survival
       Events65 (85.5)25 (80.6)40 (88.9)22 (62.9)6 (37.5)16 (84.2)
       Median PFS, mo (95% CI)4.4 (3.4-6.1)7.9 (3.5-11.9)3.7 (2.9-5.6)5.3 (3.8-13.8)10.5 (3.6-NA)3.8 (1.3-11.6)
      Overall survival
       Events52 (68.4)16 (51.6)36 (80.0)24 (68.8)9 (56.3)15 (78.9)
       Median OS, mo (95% CI)13.0 (6.3-15.5)14.3 (12.1-41.5)6.9 (4.0-14.9)16.0 (7.0-28.6)28.6 (11.5-54.4)7.0 (2.2-18.6)
      Some percentages do not add up to 100% owing to rounding.
      Abbreviations: CI = confidence interval; CCI = Charlson Comorbidity Index; CR = complete response; IQR = interquartile range; MSKCC = Memorial Sloan-Kettering Cancer Center; NA = not applicable; OS = overall survival; PD = progression; PFS = progression-free survival; PR = partial response; SD = stable disease.
      a At the start of first-line treatment.
      b At least 1 comorbidity according to Charlson and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      c CCI according to Quan et al.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      • Quan H.
      • Li B.
      • Couris C.M.
      • et al.
      Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.
      d MSKCC risk factors according to Motzer et al, 2002.
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
      Supplemental Table 2Patient Characteristics, Best Response, OS, and PFS of Patients in the Palliative Second-line Setting (Outcome Cohort)
      Total (n = 354)Everolimus (n = 100)Sunitinib (n = 65)Sorafenib (n = 47)Temsirolimus (n = 45)Pazopanib (n = 39)
      Median age,
      At the start of second-line treatment.
      y (Min-Max)
      69.5 (37.1-86.6)70.4 (39.0-86.6)67.6 (50.0-83.5)69.1 (37.8-84.7)67.5 (37.1-83.7)73.8 (46.0-83.5)
      Patients with comorbidity
      At the start of second-line treatment.
      N (%)N (%)N (%)N (%)N (%)N (%)
       Any comorbidity
      At least 1 comorbidity according to CCI and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      283 (79.9)82 (82.0)51 (78.5)38 (80.9)32 (71.1)34 (87.2)
       CCI ≥ 1
      CCI according to Quan et al.18,19
      120 (33.9)34 (34.0)16 (24.6)14 (29.8)21 (46.7)14 (35.9)
      MSKCC risk factors
      At the start of second-line treatment.
      ,
      MSKCC risk factors according to Motzer et al, 2002.15
       (0) low risk52 (14.7)14 (14.0)7 (10.8)7 (14.9)2 (4.4)5 (12.8)
       (1-2) intermediate risk177 (50.0)55 (55.0)29 (44.6)26 (55.3)19 (42.2)20 (51.3)
       (3-5) high risk66 (18.6)19 (19.0)10 (15.4)9 (19.1)14 (31.1)7 (17.9)
       Missing59 (16.7)12 (12.0)19 (29.2)5 (10.6)10 (22.2)7 (17.9)
      Best response
       CR/PR38 (10.7)6 (6.0)7 (10.8)3 (6.4)4 (8.9)6 (15.4)
       SD100 (28.2)29 (29.0)19 (29.2)13 (27.7)12 (26.7)11 (28.2)
       PD93 (26.3)36 (36.0)13 (20.0)11 (23.4)13 (28.9)5 (12.8)
       Unknown116 (32.8)28 (28.0)22 (33.8)19 (40.4)16 (35.6)17 (43.6)
       Missing7 (2.0)1 (1.0)4 (6.2)1 (2.1)0 (0.0)0 (0.0)
      Patients with completed treatment329 (92.9)93 (93.0)56 (86.2)46 (97.9)45 (100.0)32 (82.1)
       Median duration of treatment, mo (IQR)3.3 (1.6-7.0)3.7 (2.0-6.9)3.7 (1.6-7.4)3.8 (2.0-7.1)2.1 (0.5-3.3)2.5 (0.6-9.2)
      Progression-free survival
       Events262 (74.0)77 (77.0)43 (66.2)40 (85.1)40 (88.9)21 (53.8)
       Median PFS, mo (95% CI)5.0 (4.2-5.9)4.2 (3.3-5.3)5.6 (3.8-8.8)6.1 (4.1-7.7)2.3 (1.5-3.3)9.5 (5.9-21.5)
      Overall survival
       Events228 (64.4)69 (69.0)40 (61.5)36 (76.6)35 (77.8)17 (43.6)
       Median OS, mo (95% CI)14.3 (11.4-16.7)14.2 (9.5-19.5)15.5 (9.0-27.8)12.5 (10.1-17.0)5.7 (2.6-10.6)19.4 (12.1-NA)
      Abbreviations: CCI = Charlson Comorbidity Index; CI = confidence interval; CR = complete response; IQR = interquartile range; MSKCC = Memorial Sloan-Kettering Cancer Center; NA = not applicable; OS = overall survival; PD = progression; PFS = progression-free survival; PR = partial response; SD = stable disease.
      Some percentages do not add up to 100% due to rounding.
      a At the start of second-line treatment.
      b At least 1 comorbidity according to CCI and/or additional concomitant diseases; metastatic renal cell carcinoma (6 points) was not counted as a comorbidity.
      c CCI according to Quan et al.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      • Quan H.
      • Li B.
      • Couris C.M.
      • et al.
      Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.
      d MSKCC risk factors according to Motzer et al, 2002.
      • Motzer R.J.
      • Bacik J.
      • Murphy B.A.
      • Russo P.
      • Mazumdar M.
      Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.

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