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Transition to Targeted Therapies Improved the Prognosis and Increased the Utilization of Medical Treatments among Patients with Synchronous Metastatic Renal Cell Cancer

Transition to Targeted Therapies Improved the Prognosis and Increased the Utilization of Medical... Hindawi International Journal of Surgical Oncology Volume 2021, Article ID 5237695, 7 pages https://doi.org/10.1155/2021/5237695 Research Article Transition to Targeted Therapies Improved the Prognosis and Increased the Utilization of Medical Treatments among Patients with Synchronous Metastatic Renal Cell Cancer Lauri Laru, Hanna Ronkainen, and Markku H. Vaarala Department of Surgery, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, P.O. Box 21, 90029 OYS, Oulu, Finland Correspondence should be addressed to Markku H. Vaarala; markku.vaarala@oulu.fi Received 15 May 2021; Accepted 3 August 2021; Published 13 August 2021 Academic Editor: Arcangelo Picciariello Copyright © 2021 Lauri Laru et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Since the introduction of targeted therapies (TTs) for metastatic renal cell cancer (mRCC) in 2005, a limited amount of epi- demiological data on efficacy of modern drug therapies for synchronous mRCC has been published. We present a comprehensive nationwide cohort including all cases of primarily metastasized renal cell cancer among adults diagnosed between 2005 and 2010, based on data from the Finnish Cancer Registry and patient records from treating hospitals. Applied treatment protocols and survival outcomes were analyzed. A total of 977 patients were included in the analysis; 499 patients were diagnosed between 2005 and 2007 and 478 patients were diagnosed between 2008 and 2010. )e median overall survival (OS) was 8.80 months (95% confidence interval (CI): 7.60–10.02). )e median OS of the patients diagnosed at the latter era was significantly better (11.1; 95% CI: 8.8–13.4 vs. 7.0; 95% CI: 5.7–8.3 months, p≤ 0.001). A total number of 524 (53.8%) patients received drug therapy. Altogether, TTs including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTORi), and vascular endothelial growth factor inhibitor covered 331 (63.2%) of first-line treatments, whereas interferon and its combinations with chemotherapy were used for 186 (35.5%) patients. )e median OS rates for TT and interferon as first-line therapy groups were 19.9 (16.9–22.8) and 14.9 (12.3–17.4) months, respectively. )e OS for patients who did not receive drug therapy after cytoreductive nephrectomy was dismal. We found that the OS estimate of mRCC patients in Finland has improved since the introduction of tyrosine kinase inhibitors. However, the prognosis remains poor for frail, elderly patients with an impaired performance status. mRCC population is reported in these studies. Moreover, 1. Introduction synchronous and metachronous metastases are shown to Approximately 20–30% of renal cell cancer (RCC) patients have different prognoses, with synchronous metastatic have distant metastases at the time of initial diagnosis [1], disease tending to be of a more aggressive phenotype [7, 8]. thus being diagnosed with synchronous metastatic renal cell Whereas the role of cytoreductive nephrectomy remains carcinoma (mRCC). A limited amount of epidemiologic controversial, clear advances in drug therapy have been made during the last 2 decades [9–11]. data on mRCC has been published, and although the safety and efficacy of modern drug therapies have been shown in Until 2005, cytokine-based treatment with interferon randomized controlled trials, there is a scarcity of evidence alpha-2b (IFN-α), or less frequently interleukin-2, was on the effect of advances in medical therapy on the mRCC considered the cornerstone of drug therapy but has been population. Population-based registry studies from Norway, subsequentially replaced with targeted therapy (TT) such as Denmark, Sweden, Estonia, and Czech Republic [2–6] have vascular endothelial growth factor (VEGF) monoclonal been published during the last decade, and according to antibodies and VEGF receptor tyrosine kinase inhibitors these studies, the prognosis remains relatively poor, as (TKIs). Since phase three trials showed the superiority of overall survival (OS) of only 9–14 months for the entire sunitinib compared to IFN-α with tolerable side effects, TKIs 2 International Journal of Surgical Oncology have rapidly become the standard of care in treatment-na¨ıve 2.1. Statistical Analysis. )e main outcome, OS, was defined clear cell mRCC, surpassing cytokine treatment [12, 13]. )e as the time from diagnosis to death, otherwise censored at last follow-up contact. )e survival distribution and median efficacy of TKIs has been confirmed in multiple studies, showing improved OS times from 18.8 up to 52 months in survival were assessed with Kaplan–Meier estimates. Sig- selected patient populations [14, 15]. nificance was taken at p≤ 0.05. Log-rank tests were used to Lately, novel immunooncologic treatments with im- test the influence of treatments on OS. Comparing baseline mune checkpoint inhibitors have shown promising results characteristics between diagnostic period groups, Pearson and are currently gaining a robust position as an option to Chi-square test, Mann–Whitney U test, and Student’s t test TKIs in first-line treatment of mRCC [16]. However, owing were used for categorical, ordinal, and continuous variables, to the substantial cost of checkpoint inhibitors and wide respectively. Statistical analysis was performed using IBM clinical experience and evidence regarding TKIs, sunitinib, SPSS version 26 (Chicago, IL, USA). pazopanib, and cabozantinib still remain as the frequently used first-line treatments in Finland. 3. Results In this study, we present the patient characteristics, 3.1. Patient Characteristics and Biochemical and Pathological applied treatment protocols, and outcomes of a nationwide Features. Baseline characteristics are shown in Table 1. A cohort of 977 patients with synchronous mRCC diagnosed total of 977 patients were included in the analysis: 564 (57.7%) between 2005 and 2010. Furthermore, as a rapid transition in male and 413 (42.3%) female. Mean age was 68.4 years the standard drug treatment of these patients occurred from (standard deviation (SD): 11.8 years). Mean follow-up was 2007, we aimed to investigate the impact of the diagnostic 22.8 months. From the 656 patients with available histological time period to the survival estimate, performing separate diagnosis, 584 (89.0%) presented with clear cell histology and analysis for patients diagnosed in the cytokine (2005–2007) 72 (11.0%) with other histology. Sarcomatoid changes were and targeted therapy era (2008–2010). found in 56 (8.6%) of these patients. For 321 patients, his- tological diagnosis was not available. Patients identified with a 2. Materials and Methods local tumor stage: T1, 182 (20.3%); T2, 151 (16.9%); T3, 401 (44.8%); and T4, 162 (18.1%). Additionally, T staging was not Data from all patients with synchronous mRCC or RCC with reliably defined for 81 (8.3%) patients. Median primary tumor unknown metastatic status diagnosed between 2005 and 2010 maximum diameter was 9.0 (range: 1.0–25.0) cm. Nephrec- were identified from the Finnish Cancer Registry, which tomy was performed for 518 patients. Owing to the retro- includes all new cancer cases in Finland. Based on these data, spective nature of this study, serum calcium, neutrophil, and patient records of 2,169 consecutively diagnosed patients were lactate dehydrogenase levels were not available for analysis for requested from the according hospitals. )e following all patients; therefore, International Metastatic RCC Database numbers of patients were excluded from the analysis: 410, 500, Consortium (IMDC) or Memorial Sloan Kettering Cancer 20, and 57 patients were diagnosed outside the defined Center (MSKCC) risk criteria were not evaluated. However, timeframe, had no evidence of metastasis at the time of di- serum hemoglobin and CRP levels were retrieved for most of agnosis, were under 18 years of age, and had other cancers the patients. with advanced stage, respectively. Further, 31 posthumously diagnosed cases were excluded. Also, 166 patients with in- sufficient data on the time of diagnosis, end of surveillance, 3.2. Drug *erapies for mRCC and Respective Outcomes. received treatments, or metastatic stage were ruled out. In Median OS was 8.80 (95% confidence interval (CI): 7.60–10.02) addition, due to nonrenal cell cancer histology, 2 cases of months. A total number of 524 (53.8%) patients received drug poorly differentiated urothelial carcinoma, 3 neuroendocrine/ therapy. In first-line treatment, sunitinib was the most fre- small cell carcinomas, 1 malignant epithelioid angiomyoli- quently used and administered to 278 (53.1%) patients. IFN-α poma, 1 Wilms’ tumor, and 1 leiomyosarcoma were ruled out, was the second most frequently used drug in a first-line setting resulting in a total number of 977 patients included in the final (114 patients, 21.4%), followed by a combination of interferon analysis. )e following clinicopathologic variables were col- and vinblastine (58 patients, 11.1%). All first-line treatments lected: sex, age at the time of diagnosis, primary cancer and respective median overall survivals are listed in Table 2. characteristics (T stage, Fuhrman grade, and histology), Altogether, TTs including tyrosine kinase inhibitors (TKIs: metastasis details (location of metastasis and number of sunitinib, sorafenib, pazopanib, and regorafenib); mTORis metastatic sites), Eastern Cooperative Oncology Group (temsirolimus and everolimus); and VEGF inhibitor (VEGFi; (ECOG) performance status, laboratory results (serum he- bevacizumab) covered 331 (63.2%) of first-line treatments, moglobin and C-reactive protein (CRP)), nephrectomy status, whereas interferon and its combinations with chemotherapy and cause of death. T stage was reassigned according to the (i.e., vinblastine and capecitabine) were used for 186 patients 2017 TNM classification [17] and ECOG performance status (35.5%). Other first-line drug therapies were single or a at the time of diagnosis was evaluated retrospectively by the combination of cytotoxic chemotherapies. author if not clearly specified in the patient records. Treatment protocols, follow-up frequency, and modality were at the discretion of the treating physician. At least one 3.3. Cytoreductive Nephrectomy among Patients without Drug dose of the drug therapy for RCC was required to include the *erapies for mRCC. As cytoreductive nephrectomy was a patient in the analyses for drug therapies. recommended treatment during the study period, the effect International Journal of Surgical Oncology 3 Table 1: Baseline characteristics of patient population according to diagnostic period. Number of patients (%) Baseline characteristics Diagnostic period p-value Total 2005–2007 2008–2010 Total number of patients 499 478 977 Gender 0.094 M 301 (60.3%) 263 (55.0%) 564 (57.7%) F 198 (39.7%) 215 (45.0%) 413 (42.3%) Mean age at diagnosis (years) 68.6 68.8 68.4 0.619 ECOG <0.001 0 23 (5.5%) 40 (8.6%) 63 (7.2%) 1 202 (48.6%) 233 (50.3%) 435 (49.5%) 2 103 (24.8%) 124 (26.8%) 227 (25.8%) 3 61 (14.7%) 59 (12.7%) 120 (13.7%) 4 27 (6.5%) 7 (1.5%) 34 (3.9%) T stage 0.567 T1 95 (21.7%) 87 (19.0%) 182 (20.3%) T2 69 (15.8%) 82 (17.9%) 151 (16.9%) T3 191 (43.6%) 210 (45.9%) 401 (44.8%) T4 83 (18.9%) 79 (17.2%) 162 (18.1%) N stage 0.507 N0 305 (61.1%) 302 (63.2%) 607 (62.1%) N1 194 (38.9%) 176 (36.8%) 370 (37.9%) Number of metastatic sites 0.823 1 150 (30.1%) 135 (28.2%) 285 (29.2%) 2 159 (31.9%) 156 (32.6%) 315 (32.2%) ≥3 190 (38.1%) 187 (39.1%) 377 (38.6%) Metastatic sites Distant lymph nodes 112 (22.4%) 133 (27.8%) 245 (25.1%) 0.052 Lungs 297 (59.5%) 302 (63.2%) 599 (61.3%) 0.240 Bone 154 (30.9%) 159 (33.3%) 313 (32.0%) 0.421 Adrenal gland 101 (20.2%) 87 (18.2%) 188 (19.2%) 0.419 Liver 102 (20.4%) 96 (20.1%) 198 (20.3%) 0.890 Cerebral 30 (21.0%) 25 (24.0) 55 (22.3%) 0.568 Histology tumor type 0.800 Clear cell carcinoma 285 (89.3%) 299 (88.7%) 584 (89.0%) Other 34 (10.7%) 38 (11.3%) 72 (11.0%) Nephrectomy 246 (49.3%) 272 (56.9%) 518 (53.0%) 0.017 Hemoglobin< LLN 193 (60.5%) 207 (60.5%) 400 (60.5%) 0.995 CRP> ULN 211 (82.1%) 216 (74.7%) 427 (78.2%) 0.038 Histological diagnosis was missing for 318 patients: Tstage for 78, hemoglobin for 313, CRP for 428, and ECOG status for 95 patients. )e percentages in the second column were calculated only for the group of patients for whom data on these variables were available. Abbreviations: IQR � interquartile range; LLN � lower limit of normal; ULN � upper limit of normal. of this major surgery on median OS was separately explained by the fact that 43 patients died during 90 days evaluated among patients who did not receive drug after nephrectomy. therapies for mRCC. Only patients with primary tumor histology available were analyzed. Cytoreductive ne- 3.4. Time of Diagnosis as a Prognostic Factor. As the para- phrectomy, or nephrectomy and metastasectomy with curative intent, was performed for 89 and 31 patients who digm shift from interferon to TTs in standard drug therapy followed the deployment of sunitinib in 2007, we chose to did not receive drug therapies for mRCC, respectively. Ninety patients were not treated with either nephrectomy separately examine cases diagnosed between 2005 and 2007, or drug therapies. )ough four patients were alive at the compared to 2008–2010. A total of 499 patients were di- end of the follow-up after cytoreductive nephrectomy agnosed between 2005 and 2007 and 478 patients between only, the median OS after cytoreductive nephrectomy was 2008 and 2010. )e median OS of the patients diagnosed at the latter era was significantly better (11.1; 95% CI: 8.8–13.4 poor: 3.88 (95% CI 2.80–4.96) months (Figure 1). )e OS for patients with no surgical or drug therapies for mRCC months vs. 7.0; 95% CI: 5.7–8.3 months, p≤ 0.001) (Fig- ure 2). )e proportions of patients treated with interferon was 2.60 (95% CI 1.79–3.40) months. )e dismal prog- nosis of cytoreductive nephrectomy is at least partly and TTs and those without drug therapies for mRCC, with 4 International Journal of Surgical Oncology Table 2: First-line drug therapies and median overall survival (OS) times with respective 95% confidence intervals (CIs). Drug No. of patients (%) Median OS (95% CI) (months) No drug therapy 453 (46.4%) 3.0 (2.6–3.4) Sunitinib 278 (28.5%) 20.1 (15.7–24.5) Interferon single 112 (11.5%) 14.5 (8.5–20.6) Interferon + vinblastine 58 (5.9%) 15.6 (12.6–18.7) Interferon + capecitabine 16 (1.6%) 13.4 (1.8–25.0) Temsirolimus 16 (1.6%) 10.8 (8.5–13.1) Sorafenib 15 (1.5%) 19.9 (0.0–44.5) Pazopanib 7 (0.7%) 19.7 (16.0–23.5) Bevacizumab 7 (0.7%) 15.4 (8.9–22.0) Bevacizumab + interferon 3 (0.3%) 54.5 (4.1–104.8) Regorafenib 3 (0.3%) 51.3 (0.0–125.9) Vinblastine 2 (0.2%) 1.5 Everolimus 1 (0.1%) 8.5 Vinblastine + bevacizumab 1 (0.1%) 9.2 Etoposide 1 (0.1%) 3.3 Ifosfamide + doxorubicin 1 (0.1%) 18.3 Capecitabine 1 (0.1%) 6.4 Erlotinib 1 (0.1%) 10.3 Ifosfamide and mesna + adriamycin 1 (0.1%) 6.1 Overall 977 (100.0%) 8.7 (7.5–9.9) 60 60 40 40 0 20 40 60 80 100 120 0 10 20 30 40 50 60 Follow-up (months) Follow-up (months) Patients at risk Patients at risk Diagnosed 2005-2007 499 123 64 41 33 27 25 No Nephrectomy91 20 92111 Diagnosed 2008-2010 478 165 104 74 50 37 7 Cytoreductive 89 21 11 9 8 7 5 Curative 31 26 20 20 19 18 15 Diagnostic Time Period Diagnosed 2005-2007 Nephrectomy status Diagnosed 2008-2010 No nephrectomy Cytoreductive nephrectomy Figure 2: Kaplan–Meier analysis comparing overall survival of Operation with curative intent patients according to their diagnostic period (2005–2007 vs. 2008–2010). Figure 1: Kaplan–Meier analysis of overall survival in patients who did not receive drug therapies for histologically confirmed renal cell cancer. For this analysis, the follow-up time was limited to 60 months due to low number of patients surviving longer. from a Norwegian population-based study, which reported a median OS of 9.0 (95% CI 7.9–10.1) months for all respective OS rates, are presented in Table 3. )e OS tended primary mRCC patients diagnosed between 2002 and 2011 to improve among patients treated with TTs as first-line drug [2]. A Swedish population-based study reported an OS of therapy. 12.4 (95% CI 11.3–13.8) for mRCC patients diagnosed between 2006 and 2008, but only 31% of these patients presented with metastatic disease at initial diagnosis, which 4. Discussion makes the data not directly comparable to ours [4]. Median OS for mRCC patients receiving drug therapies in the In this study, we present a nationwide real-life cohort in- Danish population increased from 11.5 to 17.2 months cluding all clinically diagnosed primarily metastasized renal from 2006 to 2010, but OS for untreated patients remained cell cancers among adults from a six-year period. at 3.0 months for the same period, which is identical to our )e estimated overall survival of all patients was 8.8 results [3]. (95% CI 7.6–10.0) months. )is correlates closely to results Cumulative probability of OS (%) Cumulative probability of OS (%) International Journal of Surgical Oncology 5 Table 3: First-line drug therapies according to time of diagnosis. Number of patients and overall survival (OS) rates with 95% confidence intervals (CIs) are presented. Seven patients received only chemotherapy and were excluded from data presented in this table. Time of diagnosis Total First-line drug therapy 2005–2007 (N � 494) 2008–2010 (N � 476) N � 970 n (%) OS (95% CI) n (%) OS (95% CI) n (%) No medical treatment 260 (52.1) 2.86 (2.22–3.50) 193 (40.4) 3.38 (2.77–4.00) 453 (46.4) Interferon± chemotherapy 169 (33.9) 15.3 (12.5–18.1) 17 (3.6) 13.2 (4.74–21.6) 186 (19.0) TT 65 (13.0) 14.8 (11.9–17.6) 266 (55.6) 20.2 (16.3–24.1) 331 (33.9) respectively) was observed; however, this remains statisti- A significant proportion of cases represented a frail elderly population with reduced overall health status and limited cally insignificant. We found that the overall survival prognosis of mRCC tolerance of surgical treatment or drug therapies for mRCC. Although an age ≥75 years has not been proven as an inde- improved significantly during the observed period, which pendent prognostic factor for mRCC patients [18], it explains upholds the similar findings from other population-based the relatively poor overall survival compared to various mRCC studies [2–6]. We found a significant difference in the studies devoted to histologically confirmed clear cell tumors in baseline factors ECOG and increased CRP value between patients with relatively good (ECOG 0–1) performance status. diagnostic time groups in favour of the latter era, but no Cytoreductive nephrectomy as the only treatment resulted in statistically significant difference in the number or location no OS advantage. Almost half of the patients, who did not of metastatic sites or other baseline factors (Table 1). )us, receive drug therapies for mRCC, deceased during 90 days after the data suggests that the overall treatment of the more recently diagnosed patient population has been more ef- nephrectomy. However, single patients had excellent prognosis after cytoreductive nephrectomy only, which may be explained fective. )e transition of primary first-line drug therapy from interferon-based regimes to TT and simultaneous by spontaneous regression of the metastases [19–21], or in- correct radiological diagnosis of mRCC. Cytoreductive ne- improvement of OS can be observed in Table 3 and Figure 2, phrectomy is major surgery especially in locally advanced cases, respectively. and the patients should fit well for surgery. )e greatest strength of our study is that it is based on the )e OS observed in the first-line sunitinib group in our data from the Finnish Cancer Registry, which receives a unselected patient population was 20.1; 95% CI: 15.7–24.5 notification of every suspected or diagnosed cancer in months, which is comparable to median OS of 18.4 months Finland directly from the treating hospital [23]. Based on this information, complementary patient record acquisitions reported in an expanded-access sunitinib trial published in 2009, including 7% patients with brain metastases, 13% with from the hospitals were made to form a comprehensive review of the available patient data, describing the national an ECOG performance status of 2 or worse, and 13% nonclear cell RCC, presenting a more diverse patient pop- situation as accurately as possible. )e patient records were thoroughly examined by the author, collecting all the ulation [22]. In comparison, a median OS of 28.6 months was reported in a recent retrospective analysis including planned information that was available. In addition to the clear cell mRCC patients from all IMDC risk groups treated effects of drug therapies in a large real-life cohort, this study with first-line sunitinib, noting a prominent difference in the brings forth valuable and reliable information on the natural median OS of IMDC favorable (52.1, 95%CI: 43.4–61.2 history of synchronous mRCC, which is not a widely covered months) vs. combined IMDC intermediate and poor (23.2, subject in the current epidemiologic literature. 95% CI: 21.0–25.8 months) groups [15]. However, our study has obvious limitations. It is a retrospective study, and there are some proportions of Among the patients with a poorer performance status, histological diagnosis was also frequently missing. )is missing data. Particularly, laboratory results were not comprehensively available in many cases, probably because resulted mostly from the fact that acquiring histology was not judged to be essential in cases with absence of effective they were not included in the clinical practice at that time. We were not able to retrieve the original diagnostic imaging surgical or drug therapy options for mRCC, due to the poor general health of the patient. However, a proportion of material for reevaluation but relied on the local radiology patients received drug therapies for mRCC despite lacking reports on assessing the diagnostic stage and radiologic histological diagnosis (data not shown). progression or treatment response. In the present study, if In the pivotal phase three sunitinib vs. interferon trial by ECOG performance status was not assessed and recorded at Motzer et al. [12], the median progression-free survival was diagnosis, it was assigned retrospectively by the author, significantly longer in the sunitinib group compared to the when judged possible based on the available information. It would be of great interest to evaluate the effect of novel interferon group (11 vs. 5 months, respectively). Subse- quently, a significant OS benefit for the sunitinib group (26.4 immunooncological therapies among this patients pop- ulation, but due to financial issues, the use of this treatment vs. 21.8 months) compared to the IFN-α group was reported [13]. In our investigation, a similar trend of OS difference in modality is just expanding in Finland at the moment. So the perfect time for this analysis is yet to come. sunitinib and IFN-α groups (20.1 and 14.5 months, 6 International Journal of Surgical Oncology 5. Conclusion References [1] B. Ljungberg, S. C. Campbell, H. Y. 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Blumenstein et al., “Ne- phrectomy followed by interferon alfa-2b compared with Authors’ Contributions interferon alfa-2b alone for metastatic renal-cell cancer,” New England Journal of Medicine, vol. 345, no. 23, pp. 1655–1659, All the authors contributed to the study conception and design. Material preparation and data collection were per- [11] A. Mejean, ´ A. Ravaud, S. )ezenas et al., “Sunitinib alone or formed by Lauri Laru and analyses were performed by Lauri after nephrectomy in metastatic renal-cell carcinoma,” New Laru and Markku Vaarala. )e first draft of the manuscript England Journal of Medicine, vol. 379, no. 5, pp. 417–427, was written by Lauri Laru and all authors commented on previous versions of the manuscript. All authors read and [12] R. J. Motzer, T. E. Hutson, P. Tomczak et al., “Sunitinib versus approved the final manuscript. interferon alfa in metastatic renal-cell carcinoma,” New En- gland Journal of Medicine, vol. 356, no. 2, pp. 115–124, 2007. [13] R. J. 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Transition to Targeted Therapies Improved the Prognosis and Increased the Utilization of Medical Treatments among Patients with Synchronous Metastatic Renal Cell Cancer

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Copyright © 2021 Lauri Laru et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi International Journal of Surgical Oncology Volume 2021, Article ID 5237695, 7 pages https://doi.org/10.1155/2021/5237695 Research Article Transition to Targeted Therapies Improved the Prognosis and Increased the Utilization of Medical Treatments among Patients with Synchronous Metastatic Renal Cell Cancer Lauri Laru, Hanna Ronkainen, and Markku H. Vaarala Department of Surgery, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, P.O. Box 21, 90029 OYS, Oulu, Finland Correspondence should be addressed to Markku H. Vaarala; markku.vaarala@oulu.fi Received 15 May 2021; Accepted 3 August 2021; Published 13 August 2021 Academic Editor: Arcangelo Picciariello Copyright © 2021 Lauri Laru et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Since the introduction of targeted therapies (TTs) for metastatic renal cell cancer (mRCC) in 2005, a limited amount of epi- demiological data on efficacy of modern drug therapies for synchronous mRCC has been published. We present a comprehensive nationwide cohort including all cases of primarily metastasized renal cell cancer among adults diagnosed between 2005 and 2010, based on data from the Finnish Cancer Registry and patient records from treating hospitals. Applied treatment protocols and survival outcomes were analyzed. A total of 977 patients were included in the analysis; 499 patients were diagnosed between 2005 and 2007 and 478 patients were diagnosed between 2008 and 2010. )e median overall survival (OS) was 8.80 months (95% confidence interval (CI): 7.60–10.02). )e median OS of the patients diagnosed at the latter era was significantly better (11.1; 95% CI: 8.8–13.4 vs. 7.0; 95% CI: 5.7–8.3 months, p≤ 0.001). A total number of 524 (53.8%) patients received drug therapy. Altogether, TTs including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTORi), and vascular endothelial growth factor inhibitor covered 331 (63.2%) of first-line treatments, whereas interferon and its combinations with chemotherapy were used for 186 (35.5%) patients. )e median OS rates for TT and interferon as first-line therapy groups were 19.9 (16.9–22.8) and 14.9 (12.3–17.4) months, respectively. )e OS for patients who did not receive drug therapy after cytoreductive nephrectomy was dismal. We found that the OS estimate of mRCC patients in Finland has improved since the introduction of tyrosine kinase inhibitors. However, the prognosis remains poor for frail, elderly patients with an impaired performance status. mRCC population is reported in these studies. Moreover, 1. Introduction synchronous and metachronous metastases are shown to Approximately 20–30% of renal cell cancer (RCC) patients have different prognoses, with synchronous metastatic have distant metastases at the time of initial diagnosis [1], disease tending to be of a more aggressive phenotype [7, 8]. thus being diagnosed with synchronous metastatic renal cell Whereas the role of cytoreductive nephrectomy remains carcinoma (mRCC). A limited amount of epidemiologic controversial, clear advances in drug therapy have been made during the last 2 decades [9–11]. data on mRCC has been published, and although the safety and efficacy of modern drug therapies have been shown in Until 2005, cytokine-based treatment with interferon randomized controlled trials, there is a scarcity of evidence alpha-2b (IFN-α), or less frequently interleukin-2, was on the effect of advances in medical therapy on the mRCC considered the cornerstone of drug therapy but has been population. Population-based registry studies from Norway, subsequentially replaced with targeted therapy (TT) such as Denmark, Sweden, Estonia, and Czech Republic [2–6] have vascular endothelial growth factor (VEGF) monoclonal been published during the last decade, and according to antibodies and VEGF receptor tyrosine kinase inhibitors these studies, the prognosis remains relatively poor, as (TKIs). Since phase three trials showed the superiority of overall survival (OS) of only 9–14 months for the entire sunitinib compared to IFN-α with tolerable side effects, TKIs 2 International Journal of Surgical Oncology have rapidly become the standard of care in treatment-na¨ıve 2.1. Statistical Analysis. )e main outcome, OS, was defined clear cell mRCC, surpassing cytokine treatment [12, 13]. )e as the time from diagnosis to death, otherwise censored at last follow-up contact. )e survival distribution and median efficacy of TKIs has been confirmed in multiple studies, showing improved OS times from 18.8 up to 52 months in survival were assessed with Kaplan–Meier estimates. Sig- selected patient populations [14, 15]. nificance was taken at p≤ 0.05. Log-rank tests were used to Lately, novel immunooncologic treatments with im- test the influence of treatments on OS. Comparing baseline mune checkpoint inhibitors have shown promising results characteristics between diagnostic period groups, Pearson and are currently gaining a robust position as an option to Chi-square test, Mann–Whitney U test, and Student’s t test TKIs in first-line treatment of mRCC [16]. However, owing were used for categorical, ordinal, and continuous variables, to the substantial cost of checkpoint inhibitors and wide respectively. Statistical analysis was performed using IBM clinical experience and evidence regarding TKIs, sunitinib, SPSS version 26 (Chicago, IL, USA). pazopanib, and cabozantinib still remain as the frequently used first-line treatments in Finland. 3. Results In this study, we present the patient characteristics, 3.1. Patient Characteristics and Biochemical and Pathological applied treatment protocols, and outcomes of a nationwide Features. Baseline characteristics are shown in Table 1. A cohort of 977 patients with synchronous mRCC diagnosed total of 977 patients were included in the analysis: 564 (57.7%) between 2005 and 2010. Furthermore, as a rapid transition in male and 413 (42.3%) female. Mean age was 68.4 years the standard drug treatment of these patients occurred from (standard deviation (SD): 11.8 years). Mean follow-up was 2007, we aimed to investigate the impact of the diagnostic 22.8 months. From the 656 patients with available histological time period to the survival estimate, performing separate diagnosis, 584 (89.0%) presented with clear cell histology and analysis for patients diagnosed in the cytokine (2005–2007) 72 (11.0%) with other histology. Sarcomatoid changes were and targeted therapy era (2008–2010). found in 56 (8.6%) of these patients. For 321 patients, his- tological diagnosis was not available. Patients identified with a 2. Materials and Methods local tumor stage: T1, 182 (20.3%); T2, 151 (16.9%); T3, 401 (44.8%); and T4, 162 (18.1%). Additionally, T staging was not Data from all patients with synchronous mRCC or RCC with reliably defined for 81 (8.3%) patients. Median primary tumor unknown metastatic status diagnosed between 2005 and 2010 maximum diameter was 9.0 (range: 1.0–25.0) cm. Nephrec- were identified from the Finnish Cancer Registry, which tomy was performed for 518 patients. Owing to the retro- includes all new cancer cases in Finland. Based on these data, spective nature of this study, serum calcium, neutrophil, and patient records of 2,169 consecutively diagnosed patients were lactate dehydrogenase levels were not available for analysis for requested from the according hospitals. )e following all patients; therefore, International Metastatic RCC Database numbers of patients were excluded from the analysis: 410, 500, Consortium (IMDC) or Memorial Sloan Kettering Cancer 20, and 57 patients were diagnosed outside the defined Center (MSKCC) risk criteria were not evaluated. However, timeframe, had no evidence of metastasis at the time of di- serum hemoglobin and CRP levels were retrieved for most of agnosis, were under 18 years of age, and had other cancers the patients. with advanced stage, respectively. Further, 31 posthumously diagnosed cases were excluded. Also, 166 patients with in- sufficient data on the time of diagnosis, end of surveillance, 3.2. Drug *erapies for mRCC and Respective Outcomes. received treatments, or metastatic stage were ruled out. In Median OS was 8.80 (95% confidence interval (CI): 7.60–10.02) addition, due to nonrenal cell cancer histology, 2 cases of months. A total number of 524 (53.8%) patients received drug poorly differentiated urothelial carcinoma, 3 neuroendocrine/ therapy. In first-line treatment, sunitinib was the most fre- small cell carcinomas, 1 malignant epithelioid angiomyoli- quently used and administered to 278 (53.1%) patients. IFN-α poma, 1 Wilms’ tumor, and 1 leiomyosarcoma were ruled out, was the second most frequently used drug in a first-line setting resulting in a total number of 977 patients included in the final (114 patients, 21.4%), followed by a combination of interferon analysis. )e following clinicopathologic variables were col- and vinblastine (58 patients, 11.1%). All first-line treatments lected: sex, age at the time of diagnosis, primary cancer and respective median overall survivals are listed in Table 2. characteristics (T stage, Fuhrman grade, and histology), Altogether, TTs including tyrosine kinase inhibitors (TKIs: metastasis details (location of metastasis and number of sunitinib, sorafenib, pazopanib, and regorafenib); mTORis metastatic sites), Eastern Cooperative Oncology Group (temsirolimus and everolimus); and VEGF inhibitor (VEGFi; (ECOG) performance status, laboratory results (serum he- bevacizumab) covered 331 (63.2%) of first-line treatments, moglobin and C-reactive protein (CRP)), nephrectomy status, whereas interferon and its combinations with chemotherapy and cause of death. T stage was reassigned according to the (i.e., vinblastine and capecitabine) were used for 186 patients 2017 TNM classification [17] and ECOG performance status (35.5%). Other first-line drug therapies were single or a at the time of diagnosis was evaluated retrospectively by the combination of cytotoxic chemotherapies. author if not clearly specified in the patient records. Treatment protocols, follow-up frequency, and modality were at the discretion of the treating physician. At least one 3.3. Cytoreductive Nephrectomy among Patients without Drug dose of the drug therapy for RCC was required to include the *erapies for mRCC. As cytoreductive nephrectomy was a patient in the analyses for drug therapies. recommended treatment during the study period, the effect International Journal of Surgical Oncology 3 Table 1: Baseline characteristics of patient population according to diagnostic period. Number of patients (%) Baseline characteristics Diagnostic period p-value Total 2005–2007 2008–2010 Total number of patients 499 478 977 Gender 0.094 M 301 (60.3%) 263 (55.0%) 564 (57.7%) F 198 (39.7%) 215 (45.0%) 413 (42.3%) Mean age at diagnosis (years) 68.6 68.8 68.4 0.619 ECOG <0.001 0 23 (5.5%) 40 (8.6%) 63 (7.2%) 1 202 (48.6%) 233 (50.3%) 435 (49.5%) 2 103 (24.8%) 124 (26.8%) 227 (25.8%) 3 61 (14.7%) 59 (12.7%) 120 (13.7%) 4 27 (6.5%) 7 (1.5%) 34 (3.9%) T stage 0.567 T1 95 (21.7%) 87 (19.0%) 182 (20.3%) T2 69 (15.8%) 82 (17.9%) 151 (16.9%) T3 191 (43.6%) 210 (45.9%) 401 (44.8%) T4 83 (18.9%) 79 (17.2%) 162 (18.1%) N stage 0.507 N0 305 (61.1%) 302 (63.2%) 607 (62.1%) N1 194 (38.9%) 176 (36.8%) 370 (37.9%) Number of metastatic sites 0.823 1 150 (30.1%) 135 (28.2%) 285 (29.2%) 2 159 (31.9%) 156 (32.6%) 315 (32.2%) ≥3 190 (38.1%) 187 (39.1%) 377 (38.6%) Metastatic sites Distant lymph nodes 112 (22.4%) 133 (27.8%) 245 (25.1%) 0.052 Lungs 297 (59.5%) 302 (63.2%) 599 (61.3%) 0.240 Bone 154 (30.9%) 159 (33.3%) 313 (32.0%) 0.421 Adrenal gland 101 (20.2%) 87 (18.2%) 188 (19.2%) 0.419 Liver 102 (20.4%) 96 (20.1%) 198 (20.3%) 0.890 Cerebral 30 (21.0%) 25 (24.0) 55 (22.3%) 0.568 Histology tumor type 0.800 Clear cell carcinoma 285 (89.3%) 299 (88.7%) 584 (89.0%) Other 34 (10.7%) 38 (11.3%) 72 (11.0%) Nephrectomy 246 (49.3%) 272 (56.9%) 518 (53.0%) 0.017 Hemoglobin< LLN 193 (60.5%) 207 (60.5%) 400 (60.5%) 0.995 CRP> ULN 211 (82.1%) 216 (74.7%) 427 (78.2%) 0.038 Histological diagnosis was missing for 318 patients: Tstage for 78, hemoglobin for 313, CRP for 428, and ECOG status for 95 patients. )e percentages in the second column were calculated only for the group of patients for whom data on these variables were available. Abbreviations: IQR � interquartile range; LLN � lower limit of normal; ULN � upper limit of normal. of this major surgery on median OS was separately explained by the fact that 43 patients died during 90 days evaluated among patients who did not receive drug after nephrectomy. therapies for mRCC. Only patients with primary tumor histology available were analyzed. Cytoreductive ne- 3.4. Time of Diagnosis as a Prognostic Factor. As the para- phrectomy, or nephrectomy and metastasectomy with curative intent, was performed for 89 and 31 patients who digm shift from interferon to TTs in standard drug therapy followed the deployment of sunitinib in 2007, we chose to did not receive drug therapies for mRCC, respectively. Ninety patients were not treated with either nephrectomy separately examine cases diagnosed between 2005 and 2007, or drug therapies. )ough four patients were alive at the compared to 2008–2010. A total of 499 patients were di- end of the follow-up after cytoreductive nephrectomy agnosed between 2005 and 2007 and 478 patients between only, the median OS after cytoreductive nephrectomy was 2008 and 2010. )e median OS of the patients diagnosed at the latter era was significantly better (11.1; 95% CI: 8.8–13.4 poor: 3.88 (95% CI 2.80–4.96) months (Figure 1). )e OS for patients with no surgical or drug therapies for mRCC months vs. 7.0; 95% CI: 5.7–8.3 months, p≤ 0.001) (Fig- ure 2). )e proportions of patients treated with interferon was 2.60 (95% CI 1.79–3.40) months. )e dismal prog- nosis of cytoreductive nephrectomy is at least partly and TTs and those without drug therapies for mRCC, with 4 International Journal of Surgical Oncology Table 2: First-line drug therapies and median overall survival (OS) times with respective 95% confidence intervals (CIs). Drug No. of patients (%) Median OS (95% CI) (months) No drug therapy 453 (46.4%) 3.0 (2.6–3.4) Sunitinib 278 (28.5%) 20.1 (15.7–24.5) Interferon single 112 (11.5%) 14.5 (8.5–20.6) Interferon + vinblastine 58 (5.9%) 15.6 (12.6–18.7) Interferon + capecitabine 16 (1.6%) 13.4 (1.8–25.0) Temsirolimus 16 (1.6%) 10.8 (8.5–13.1) Sorafenib 15 (1.5%) 19.9 (0.0–44.5) Pazopanib 7 (0.7%) 19.7 (16.0–23.5) Bevacizumab 7 (0.7%) 15.4 (8.9–22.0) Bevacizumab + interferon 3 (0.3%) 54.5 (4.1–104.8) Regorafenib 3 (0.3%) 51.3 (0.0–125.9) Vinblastine 2 (0.2%) 1.5 Everolimus 1 (0.1%) 8.5 Vinblastine + bevacizumab 1 (0.1%) 9.2 Etoposide 1 (0.1%) 3.3 Ifosfamide + doxorubicin 1 (0.1%) 18.3 Capecitabine 1 (0.1%) 6.4 Erlotinib 1 (0.1%) 10.3 Ifosfamide and mesna + adriamycin 1 (0.1%) 6.1 Overall 977 (100.0%) 8.7 (7.5–9.9) 60 60 40 40 0 20 40 60 80 100 120 0 10 20 30 40 50 60 Follow-up (months) Follow-up (months) Patients at risk Patients at risk Diagnosed 2005-2007 499 123 64 41 33 27 25 No Nephrectomy91 20 92111 Diagnosed 2008-2010 478 165 104 74 50 37 7 Cytoreductive 89 21 11 9 8 7 5 Curative 31 26 20 20 19 18 15 Diagnostic Time Period Diagnosed 2005-2007 Nephrectomy status Diagnosed 2008-2010 No nephrectomy Cytoreductive nephrectomy Figure 2: Kaplan–Meier analysis comparing overall survival of Operation with curative intent patients according to their diagnostic period (2005–2007 vs. 2008–2010). Figure 1: Kaplan–Meier analysis of overall survival in patients who did not receive drug therapies for histologically confirmed renal cell cancer. For this analysis, the follow-up time was limited to 60 months due to low number of patients surviving longer. from a Norwegian population-based study, which reported a median OS of 9.0 (95% CI 7.9–10.1) months for all respective OS rates, are presented in Table 3. )e OS tended primary mRCC patients diagnosed between 2002 and 2011 to improve among patients treated with TTs as first-line drug [2]. A Swedish population-based study reported an OS of therapy. 12.4 (95% CI 11.3–13.8) for mRCC patients diagnosed between 2006 and 2008, but only 31% of these patients presented with metastatic disease at initial diagnosis, which 4. Discussion makes the data not directly comparable to ours [4]. Median OS for mRCC patients receiving drug therapies in the In this study, we present a nationwide real-life cohort in- Danish population increased from 11.5 to 17.2 months cluding all clinically diagnosed primarily metastasized renal from 2006 to 2010, but OS for untreated patients remained cell cancers among adults from a six-year period. at 3.0 months for the same period, which is identical to our )e estimated overall survival of all patients was 8.8 results [3]. (95% CI 7.6–10.0) months. )is correlates closely to results Cumulative probability of OS (%) Cumulative probability of OS (%) International Journal of Surgical Oncology 5 Table 3: First-line drug therapies according to time of diagnosis. Number of patients and overall survival (OS) rates with 95% confidence intervals (CIs) are presented. Seven patients received only chemotherapy and were excluded from data presented in this table. Time of diagnosis Total First-line drug therapy 2005–2007 (N � 494) 2008–2010 (N � 476) N � 970 n (%) OS (95% CI) n (%) OS (95% CI) n (%) No medical treatment 260 (52.1) 2.86 (2.22–3.50) 193 (40.4) 3.38 (2.77–4.00) 453 (46.4) Interferon± chemotherapy 169 (33.9) 15.3 (12.5–18.1) 17 (3.6) 13.2 (4.74–21.6) 186 (19.0) TT 65 (13.0) 14.8 (11.9–17.6) 266 (55.6) 20.2 (16.3–24.1) 331 (33.9) respectively) was observed; however, this remains statisti- A significant proportion of cases represented a frail elderly population with reduced overall health status and limited cally insignificant. We found that the overall survival prognosis of mRCC tolerance of surgical treatment or drug therapies for mRCC. Although an age ≥75 years has not been proven as an inde- improved significantly during the observed period, which pendent prognostic factor for mRCC patients [18], it explains upholds the similar findings from other population-based the relatively poor overall survival compared to various mRCC studies [2–6]. We found a significant difference in the studies devoted to histologically confirmed clear cell tumors in baseline factors ECOG and increased CRP value between patients with relatively good (ECOG 0–1) performance status. diagnostic time groups in favour of the latter era, but no Cytoreductive nephrectomy as the only treatment resulted in statistically significant difference in the number or location no OS advantage. Almost half of the patients, who did not of metastatic sites or other baseline factors (Table 1). )us, receive drug therapies for mRCC, deceased during 90 days after the data suggests that the overall treatment of the more recently diagnosed patient population has been more ef- nephrectomy. However, single patients had excellent prognosis after cytoreductive nephrectomy only, which may be explained fective. )e transition of primary first-line drug therapy from interferon-based regimes to TT and simultaneous by spontaneous regression of the metastases [19–21], or in- correct radiological diagnosis of mRCC. Cytoreductive ne- improvement of OS can be observed in Table 3 and Figure 2, phrectomy is major surgery especially in locally advanced cases, respectively. and the patients should fit well for surgery. )e greatest strength of our study is that it is based on the )e OS observed in the first-line sunitinib group in our data from the Finnish Cancer Registry, which receives a unselected patient population was 20.1; 95% CI: 15.7–24.5 notification of every suspected or diagnosed cancer in months, which is comparable to median OS of 18.4 months Finland directly from the treating hospital [23]. Based on this information, complementary patient record acquisitions reported in an expanded-access sunitinib trial published in 2009, including 7% patients with brain metastases, 13% with from the hospitals were made to form a comprehensive review of the available patient data, describing the national an ECOG performance status of 2 or worse, and 13% nonclear cell RCC, presenting a more diverse patient pop- situation as accurately as possible. )e patient records were thoroughly examined by the author, collecting all the ulation [22]. In comparison, a median OS of 28.6 months was reported in a recent retrospective analysis including planned information that was available. In addition to the clear cell mRCC patients from all IMDC risk groups treated effects of drug therapies in a large real-life cohort, this study with first-line sunitinib, noting a prominent difference in the brings forth valuable and reliable information on the natural median OS of IMDC favorable (52.1, 95%CI: 43.4–61.2 history of synchronous mRCC, which is not a widely covered months) vs. combined IMDC intermediate and poor (23.2, subject in the current epidemiologic literature. 95% CI: 21.0–25.8 months) groups [15]. However, our study has obvious limitations. It is a retrospective study, and there are some proportions of Among the patients with a poorer performance status, histological diagnosis was also frequently missing. )is missing data. Particularly, laboratory results were not comprehensively available in many cases, probably because resulted mostly from the fact that acquiring histology was not judged to be essential in cases with absence of effective they were not included in the clinical practice at that time. We were not able to retrieve the original diagnostic imaging surgical or drug therapy options for mRCC, due to the poor general health of the patient. However, a proportion of material for reevaluation but relied on the local radiology patients received drug therapies for mRCC despite lacking reports on assessing the diagnostic stage and radiologic histological diagnosis (data not shown). progression or treatment response. In the present study, if In the pivotal phase three sunitinib vs. interferon trial by ECOG performance status was not assessed and recorded at Motzer et al. [12], the median progression-free survival was diagnosis, it was assigned retrospectively by the author, significantly longer in the sunitinib group compared to the when judged possible based on the available information. It would be of great interest to evaluate the effect of novel interferon group (11 vs. 5 months, respectively). Subse- quently, a significant OS benefit for the sunitinib group (26.4 immunooncological therapies among this patients pop- ulation, but due to financial issues, the use of this treatment vs. 21.8 months) compared to the IFN-α group was reported [13]. In our investigation, a similar trend of OS difference in modality is just expanding in Finland at the moment. So the perfect time for this analysis is yet to come. sunitinib and IFN-α groups (20.1 and 14.5 months, 6 International Journal of Surgical Oncology 5. Conclusion References [1] B. Ljungberg, S. C. Campbell, H. Y. 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Published: Aug 13, 2021

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