- Email: [email protected]
The Necessity of Cytoreductive Nephrectomy in Patients With Metastatic Renal Cell Carcinoma Using Antiangiogenic Targeted Therapy After Interferon Alfa-2b
Accepted Manuscript The Necessity of Cytoreductive Nephrectomy in Patients with Metastatic Renal Cell Carcinoma Using Antiangiogenic Targeted Therapy After Interferone Alfa-2b Hasan Mutlu , MD, MD Şeyda Gündüz , MD Abdullah Büyükçelik , MD Özcan Yıldız , MD Mükremin Uysal , MD Deniz Tural , MD, MD Hakan Bozcuk , MD Hasan Şenol Coşkun , MD PII:
S1558-7673(14)00109-8
DOI:
10.1016/j.clgc.2014.06.006
Reference:
CLGC 279
To appear in:
Clinical Genitourinary Cancer
Received Date: 14 February 2014 Revised Date:
3 May 2014
Accepted Date: 3 June 2014
Please cite this article as: Mutlu H, Gündüz Ş, Büyükçelik A, Yıldız Ö, Uysal M, Tural D, Bozcuk H, Coşkun HŞ, The Necessity of Cytoreductive Nephrectomy in Patients with Metastatic Renal Cell Carcinoma Using Antiangiogenic Targeted Therapy After Interferone Alfa-2b, Clinical Genitourinary Cancer (2014), doi: 10.1016/j.clgc.2014.06.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TITLE PAGE THE NECESSITY OF CYTOREDUCTIVE NEPHRECTOMY IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA USING ANTIANGIOGENIC TARGETED
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THERAPY AFTER INTERFERONE ALFA-2B
Hasan Mutlu, Şeyda Gündüz, Abdullah Büyükçelik, Özcan Yıldız, Mükremin Uysal, Deniz Tural, Hakan Bozcuk, Hasan Şenol Coşkun
1. Hasan Mutlu, MD, MD, Department of Medical Oncology, Akdeniz University School of
SC
Medicine, Antalya, Turkey
2. Şeyda Gündüz, MD, Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey
Medicine, Istanbul, Turkey
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3. Abdullah Büyükçelik, MD, Department of Internal Medicine, Acıbadem University School of
4. Özcan Yıldız, MD, Department of Medical Oncology, Medipol University, Istanbul, Turkey 5. Mükremin Uysal, MD, Department of Medical Oncology, Kocatepe University School of Medicine, Afyon, Turkey
6. Deniz Tural, MD, MD, Department of Medical Oncology, Akdeniz University School of
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Medicine, Antalya, Turkey
7. Hakan Bozcuk, MD, Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey
8. Hasan Şenol Coşkun, MD, Department of Medical Oncology, Akdeniz University School of
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Medicine, Antalya, Turkey
The contact information of corresponding author: Hasan Mutlu, MD
Akdeniz Üniversitesi, Tıp Fakültesi, Tıbbi Onkoloji Bölümü, Konyaaltı, Antalya, Turkey. Tel: +905326958357, Fax: +902422491274, E-mail:[email protected].
ACCEPTED MANUSCRIPT Abstract The effects of cytoreductive nephrectomy (CRN) on prognosis of patients with metastatic Renal Cell Cancer (RCC) using antiangiogenic targeted agents were evaluated. The median overall survival were significantly higher in group with CRN (p=0.034). We speculate that CRN is still an important part of
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treatment modalities in patients with metastatic RCC in modern era used targeted therapy which is currently best systemic therapy.
Background: The targeted therapy has improved the survival of patients with metastatic renal cell cancer (RCC). In presented study, we evaluated whether there is an effect of cytoreductive surgery on
SC
prognosis of patients with metastatic RCC using antiangiogenic tyrosine kinase inhibitory (TKI) agents.
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Patients: A total of 52 patients with metastatic RCC from Akdeniz University, Afyon Kocatepe University and Medipol University. All the patients have received targeted antiangiogenic therapy after interferon alfa 2b (IFN). According to prior cytoreductive nephrectomy (CRN), the patients were divided into two groups as CRN (+) and CRN (-).
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Results: The CRN (+) group was very younger other CRN (-) group (p<0.001) and the hemoglobin levels were significantly higher in CRN (+) group (p=0.023). The median progression free survival time from the date of starting TKI were 8.5 and 3.0 months for CRN (+) and CRN (-) groups,
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respectively (p=0.104). The median overall survival were 15.1 and 5.4 months for CRN (+) and CRN (-) groups, respectively, (p=0.034).
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Conclusions: We speculate that CRN is still an important part of treatment modalities in patients with metastatic RCC in modern era used targeted therapy which is currently best systemic therapy. But the indications of CRN may be limited to good risk patients with metastatic RCC. The further randomized studies are warranted to clarify the necessity of CRN in patients with metastatic RCC. Keywords: Renal cell cancer, Survival, Cytoreductive Nephrectomy, Targeted Therapy, Angiogenesis
ACCEPTED MANUSCRIPT 1. Introduction Renal cell cancer (RCC) originates from renal cortex and comprises 2-3% of all cancer whilst it is responsible for approximately 85% of all primary renal cancer.1,2 Generally the patients with metastatic RCC have a poor prognosis and their five-year survival rates are approximately 11%.3
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After the using of new treatment agents the survival rates of patients with RCC have been increasing over time. After immunotherapy with interleukin or interferon, antiangiogenic agents (bevacizumab, sunitinib, sorafenib, pazopanib and axitinib) and mTOR inhibitory (temsirolimus and everolimus) are widely using to treat the patients with metastatic RCC in modern era.
SC
Due to there is no evidence regarding survival advantage of adjuvant therapy for non-metastatic renal cell cancer, surgery is only curative treatment schedule. In the patients with metastatic RCC, the
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performing of cytoreductive or debulking surgery is still controversial. There are case reports those had a spontaneously regression of metastases after cytoreductive nephrectomy (CRN) but the rate of regression is 1% or less in patients with metastatic RCC performing CRN [4].4 Although the CRN is an important part of the current combined treatment modalities in patients with metastatic RCC, the
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CRN rates are very low.5
In presented study, we aim to evaluate whether there is an effect of cytoreductive surgery on prognosis of patients with metastatic RCC using antiangiogenic agents.
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2. Patients and methods
A total of 52 patients with metastatic RCC at the time of diagnosis from Akdeniz University, Afyon
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Kocatepe University and Medipol University were analyzed. In all patients, the radical nephrectomy procedure has been performed as open surgery. All patients have received interferon alfa 2b (IFN) and they have progressed under the treatment of IFN. The patients were divided into two groups as CRN (+) and CRN (-) according to prior (CRN). The factors those nephrectomy (yes or no), age, sex, the type of tyrosine kinase inhibitory (TKI) agent, Karnofsky performance status (KPS), serum lactate dehydrogenase (LDH), corrected calcium and hemoglobin (Hgb) levels were recorded into the Statistical Package for the Social Sciences version 16.0 (SPSS 16.0) from the medical archives retrospectively. And also the time of diagnosis, the start time of IFN, the date of progression under IFN, the start time of TKI, the date of progression under TKI agents and the date of death (if yes) were
ACCEPTED MANUSCRIPT recorded into SPSS 16.0. To determine the characteristics of groups (CRN (+) or (-)), descriptive statistics (mean, frequency analysis and crosstabs, independent samples T tests) were performed. To evaluate the progression free survival (PFS) and the overall survival (OS), Kaplan-Meier statistical methods using log rank test were used. P <0.05 was considered to be statistically significant.
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3. Results The patients were divided into two groups as CRN (+) (n:28) and CRN (-) (n:24). The clinicopathological properties of the groups were given in Table 1. The mean ages of CRN (+) and CRN (-) groups were 53,6±9,8 and 67,5±10,5 years, respectively (p<0.001). We did not find any
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significant differences regarding sex and TKI types. In both groups, the patients have mostly used sunitinib rather than sorafenib or pazopanib. The Hgb levels were significantly higher in nephrectomy
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(+) group (11,4±1,9 vs 9,9±2,1gr/dl for CRN (+) and CRN (-) groups, respectively, (p=0.023). It was not found any significant difference regarding corrected calcium and LDH values (p=0.253 and p=0.107, respectively). When comparing two groups regarding Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic model including factors those KPS (<80%), serum LDH level (>1.5
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times the upper limit of normal), corrected serum calcium level (>10mg/dl), Hgb level (less than the lower limit of normal) and absence of nephrectomy, the ratio of patients with 0, 1-2, >2 risk factors was 28,6%, 57,1%, 14,3% and 0%, 41,7%, 58,3% for CRN (+) and CRN (-) groups, respectively
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(p=0.001).
The median PFS time from the date of starting TKI were 8.5 [95% CI: 1.3-15.8] and 3.0 [95% CI: 2.4-
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3.6] months for CRN (+) and CRN (-) groups, respectively (p=0.104). The median OS from the date of starting TKI were 15.1 [95% CI: 1.3-15.8] and 5.4 [95% CI: 1.3-15.8] months for CRN (+) and CRN (-) groups, respectively, this difference was significant (p=0.034). These PFS and OS curves were shown in Figure 1 and Figure 2. Additionally, the groups were evaluated in terms of PFS for IFN using. The median PFS time from the date of starting IFN were 6.4 [95% CI: 4.5-8.3] and 3.1 [95% CI: 2.4-3.9] months for CRN (+) and CRN (-) groups, respectively (p=0.049) (Figure 3). When all patients were evaluated in terms of OS from diagnosis, the median OS values were 21.5 [95% CI: 2.1-40.9] and 9.3 [95% CI: 3.5-15.1] months for CRN (+) and CRN (-) groups, respectively (p=0.008) (Figure 4).
ACCEPTED MANUSCRIPT 4. Discussion In patients with RCC, the CRN is one of the important parts of treatment. However, in modern therapeutic era, due to the discovery of targeted agents, an argue has been started whether the CRN is necessary in patients with metastatic RCC recently.
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Before the using of targeted therapy, especially TKI, two randomized trials have investigated the role of CRN in patients with metastatic RCC.6,7 In both of them, the patients have received interferon alfa based immunotherapy. Both of two studies have reported significant OS advantage for the patients performing CRN compared to CRN (-) patients. In addition Flanigan and Mickisch have reported a
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median survival advantage of 13.6 months for nephrectomy plus interferon vs 7.8 months for interferon alone basing on the combined analysis of these 2 trials and they have found a 31% decrease
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in the risk of death (p = 0.002).8 Having evaluated the response to IFN therapy before TKI using in presented study, we found that the median PFS were 6.4 and 3.1 months for CRN (+) and CRN (-) groups, respectively (p=0.049). Mickisch et al. have reported that a median PFS of 5 and 3 months for CRN (+) and (-) groups in patients with metastatic RCC who using IFN7 .
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The mechanisms of the benefit related to CRN have not been fully understood. It was speculated that immunotherapy might be more effective after CRN and CRN might prevent the seeding of cancer cells in primary lesion.9 Additionally, immunosuppressive compounds related to primary tumors perhaps
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might decrease the efficacy of immunotherapy.9
Recently, some studies have investigated the effectiveness of the CRN in combination with molecular
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targeted therapy in patients with metastatic RCC.10-12 In studies evaluating targeted therapy in metastatic RCC, the rate of CRN is between 90%-100% approximately.13 This rate was 67% in the poor risk patients with metastatic RCC.14 Choueiri et al. have reported that CRN was associated with a median overall survival of 19.8 months compared to 9.4 months for CRN (-) group in patients receiving targeted therapy with metastatic RCC (p<0.01),15 and they said that CRN was independently associated with a prolonged overall survival. But this advantage was no significant in poor risk patients (p=0.06). In contrast to this study, You et al. have reported no significant difference for mPFS and median OS in CRN (+) and CRN (-) groups in patients receiving targeted therapy with metastatic RCC (mPFS was 11.7 and 9.0 months in the CRN and non-CRN groups (p = 0.270), and mOS was
ACCEPTED MANUSCRIPT 21.6 and 13.9 months, respectively (p = 0.128)).16 In another study, it was found that the median OS were 20.6 and 9.5 months for CRN(+) and CRN(-) groups in patients who received targeted therapy, respectively (p<0.0001).17 According to our results, there was a significant difference between CRN (+) and CRN (-) groups in
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terms of OS. CRN (+) group had a median OS of 11 months advantage. But in our study, CRN (+) group was significantly younger than CRN (-) group and their mean hgb value which is a prognostic factor in RCC was significantly higher. Additionally, the ratio of patients with >2 risk factors according to MSKCC prognostic model was higher in CRN (-) group. These reasons may impact the
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significant survival difference. Due to these factors (age and MSKCC risk factors), CRN may probably not perform because CRN is a risk for post-op mortality and morbidity in poor risk patients
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with metastatic RCC. 5. Conclusion
We speculate that CRN is still an important part of treatment modalities in patients with metastatic RCC in targeted therapy which is currently the best systemic therapy era. But the indications of CRN
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may be limited to good risk patients with metastatic RCC. In this targeted therapy era, the results of ongoing studies such as CARMENA or SURTIME will be important for CRN decision in future. The argue about the necessity of nephrectomy may be especially resolved by CARMENA study evaluating
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the effect of nephrectomy on prognosis in metastatic RCC patients who have been receiving sunitinib in first-line setting. Also, the further randomized studies are warranted to clarify the necessity of CRN
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in patients with metastatic RCC.
Disclosure: There are no potential conflicts of interest.
References
1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta GACS, 2012. 2. Karumanchi SA, Merchan J, Sukhatme VP. Renal cancer: molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens. 2002; 11: 37-42. 3. http://seer.cancer.gov/statfacts/html/kidrp.html
ACCEPTED MANUSCRIPT 4. Marcus SG, Choyke PL, Reiter R et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. J Urol. 1993; 150: 463-6. 5. Bromwich E, Hendry D, Aitchison M. Cytoreductive nephrectomy: is it a realistic option in patients with renal cancer? BJU Int. 2002; 89:523-5.
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6. Flanigan RC, Salmon SE, Blumenstein BA et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001; 345: 1655-9
7. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; European Organisation for
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Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-
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cell carcinoma: a randomised trial. Lancet. 2001; 358: 966-70.
8. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004; 171: 1071-6
nephrectomy for metastatic
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9. Pantuck AJ, Belldegrun AS, Figlin RA. Cytoreductive
renal cell carcinoma: is it still imperative in the era of targeted therapy? Clin Cancer Res. 2007 15;13:693-6. Review
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10. Sakai I, Miyake H, Hinata N, Fujisawa M.Improved survival in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy in the era of targeted therapy. Int J
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Clin Oncol. 2013 Aug 30. [Epub ahead of print] 11. Stroup SP, Raheem OA, Palazzi KL et al. Does timing of cytoreductive nephrectomy impact patient survival with metastatic renal cellcarcinoma in the tyrosine kinase inhibitor era? A multi-institutional study. Urology. 2013; 81:805-11 12. Tsao CK, Small AC, Kates M et al. Cytoreductive nephrectomy
for
metastatic
renal cell carcinoma in the era of targeted therapyin the United States: a SEER analysis. World J Urol. 2013; 31: 1535-9 13. Margulis V, Matin SF, Wood CG. Cytoreductive nephrectomy in metastatic renal cell carcinoma. Curr Opin Urol. 2008; 18: 474-80.
ACCEPTED MANUSCRIPT 14. Hudes G, Carducci M, Tomczak P et al; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007; 356: 2271-81. 15. Choueiri TK, Xie W, Kollmannsberger C et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth
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factor targeted therapy. J Urol. 2011;185:60-6. 16. You D, Jeong IG, Ahn JH et al. The value of cytoreductive nephrectomy for metastatic renal cell carcinoma in the era oftargeted therapy. J Urol. 2011; 185: 54-9.
17. Heng DYC, Rini BI, Beuselinck B, et al: Cytoreductive nephrectomy (CN) in patients with
Renal
Cell
Carcinoma
Database
Consortium
(IMDC).
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Symposium. Abstract 396. Presented February 1, 2014.
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synchronous metastases from renal cell carcinoma: Results from the International Metastatatic Genitourinary
Cancers
ACCEPTED MANUSCRIPT Table 1. Properties of groups (Abb.: KPS:Karnofsky performance status, TKI: Tyrosine kinase inhibitory, LDH: Lactate dehydrogenase, Hgb: Hemoglobin)
22(78,6%) 6(21,4%)
16(66,7%) 8(33,3%)
23(82,1%) 4(14,3%) 1(3,6%) 0
19(79,2%) 2(8,3%) 3(12,5%) 0
13(54,2%) 11(45,8%) 241±98 9,7±0,8 11,4±1,9
21(75%) 7(25%) 369±329 9,5±0,7 9,9±2,1
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8(28,6%) 16(57,1%) 4(14,3%)
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P value <0.001 0.335
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Nephrectomy No (n:24) 67,5±10,5
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Yes (n:28) 53,6±9,8
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Parameters Age Sex Male Female TKI type Sunitinib Sorafenib Pazopanib Axitinib KPS ≥80% <80% LDH (IU/L) Corrected Calcium (mg/dl) Hgb (g/dl) MSKCC risk factors 0 risk factor 1-2 risk factors >2 risk factors
0 10(41,7%) 14(58,3%)
0.417
0.108
0.107 0.253 0.023 0.001
ACCEPTED MANUSCRIPT Figure 1. Progression free survival curves from the date of starting TKI for CRN (+) and (-) groups (Abb.: CRN: Cytoreductive neprectomy, TKI: Tyrosine kinase inhibitory) (p=0.104). Figure 2. Overall survival curves from the date of starting TKI for CRN (+) and (-) groups (p=0.034) (Abb.: CRN: Cytoreductive neprectomy, TKI: Tyrosine kinase inhibitory) Figure 3. Progression free survival curves from the date of starting IFN for CRN (+) and (-) groups (p=0.049) (Abb.: CRN: Cytoreductive neprectomy, IFN: Interferon alfa 2b ).
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Figure 4. Overall survival curves from diagnosis for CRN (+) and (-) groups (p=0.008) (Abb.: CRN: cytoreductive neprectomy).
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ACCEPTED MANUSCRIPT
S1558-7673(14)00109-8
DOI:
10.1016/j.clgc.2014.06.006
Reference:
CLGC 279
To appear in:
Clinical Genitourinary Cancer
Received Date: 14 February 2014 Revised Date:
3 May 2014
Accepted Date: 3 June 2014
Please cite this article as: Mutlu H, Gündüz Ş, Büyükçelik A, Yıldız Ö, Uysal M, Tural D, Bozcuk H, Coşkun HŞ, The Necessity of Cytoreductive Nephrectomy in Patients with Metastatic Renal Cell Carcinoma Using Antiangiogenic Targeted Therapy After Interferone Alfa-2b, Clinical Genitourinary Cancer (2014), doi: 10.1016/j.clgc.2014.06.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TITLE PAGE THE NECESSITY OF CYTOREDUCTIVE NEPHRECTOMY IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA USING ANTIANGIOGENIC TARGETED
RI PT
THERAPY AFTER INTERFERONE ALFA-2B
Hasan Mutlu, Şeyda Gündüz, Abdullah Büyükçelik, Özcan Yıldız, Mükremin Uysal, Deniz Tural, Hakan Bozcuk, Hasan Şenol Coşkun
1. Hasan Mutlu, MD, MD, Department of Medical Oncology, Akdeniz University School of
SC
Medicine, Antalya, Turkey
2. Şeyda Gündüz, MD, Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey
Medicine, Istanbul, Turkey
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3. Abdullah Büyükçelik, MD, Department of Internal Medicine, Acıbadem University School of
4. Özcan Yıldız, MD, Department of Medical Oncology, Medipol University, Istanbul, Turkey 5. Mükremin Uysal, MD, Department of Medical Oncology, Kocatepe University School of Medicine, Afyon, Turkey
6. Deniz Tural, MD, MD, Department of Medical Oncology, Akdeniz University School of
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Medicine, Antalya, Turkey
7. Hakan Bozcuk, MD, Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey
8. Hasan Şenol Coşkun, MD, Department of Medical Oncology, Akdeniz University School of
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Medicine, Antalya, Turkey
The contact information of corresponding author: Hasan Mutlu, MD
Akdeniz Üniversitesi, Tıp Fakültesi, Tıbbi Onkoloji Bölümü, Konyaaltı, Antalya, Turkey. Tel: +905326958357, Fax: +902422491274, E-mail:[email protected].
ACCEPTED MANUSCRIPT Abstract The effects of cytoreductive nephrectomy (CRN) on prognosis of patients with metastatic Renal Cell Cancer (RCC) using antiangiogenic targeted agents were evaluated. The median overall survival were significantly higher in group with CRN (p=0.034). We speculate that CRN is still an important part of
RI PT
treatment modalities in patients with metastatic RCC in modern era used targeted therapy which is currently best systemic therapy.
Background: The targeted therapy has improved the survival of patients with metastatic renal cell cancer (RCC). In presented study, we evaluated whether there is an effect of cytoreductive surgery on
SC
prognosis of patients with metastatic RCC using antiangiogenic tyrosine kinase inhibitory (TKI) agents.
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Patients: A total of 52 patients with metastatic RCC from Akdeniz University, Afyon Kocatepe University and Medipol University. All the patients have received targeted antiangiogenic therapy after interferon alfa 2b (IFN). According to prior cytoreductive nephrectomy (CRN), the patients were divided into two groups as CRN (+) and CRN (-).
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Results: The CRN (+) group was very younger other CRN (-) group (p<0.001) and the hemoglobin levels were significantly higher in CRN (+) group (p=0.023). The median progression free survival time from the date of starting TKI were 8.5 and 3.0 months for CRN (+) and CRN (-) groups,
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respectively (p=0.104). The median overall survival were 15.1 and 5.4 months for CRN (+) and CRN (-) groups, respectively, (p=0.034).
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Conclusions: We speculate that CRN is still an important part of treatment modalities in patients with metastatic RCC in modern era used targeted therapy which is currently best systemic therapy. But the indications of CRN may be limited to good risk patients with metastatic RCC. The further randomized studies are warranted to clarify the necessity of CRN in patients with metastatic RCC. Keywords: Renal cell cancer, Survival, Cytoreductive Nephrectomy, Targeted Therapy, Angiogenesis
ACCEPTED MANUSCRIPT 1. Introduction Renal cell cancer (RCC) originates from renal cortex and comprises 2-3% of all cancer whilst it is responsible for approximately 85% of all primary renal cancer.1,2 Generally the patients with metastatic RCC have a poor prognosis and their five-year survival rates are approximately 11%.3
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After the using of new treatment agents the survival rates of patients with RCC have been increasing over time. After immunotherapy with interleukin or interferon, antiangiogenic agents (bevacizumab, sunitinib, sorafenib, pazopanib and axitinib) and mTOR inhibitory (temsirolimus and everolimus) are widely using to treat the patients with metastatic RCC in modern era.
SC
Due to there is no evidence regarding survival advantage of adjuvant therapy for non-metastatic renal cell cancer, surgery is only curative treatment schedule. In the patients with metastatic RCC, the
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performing of cytoreductive or debulking surgery is still controversial. There are case reports those had a spontaneously regression of metastases after cytoreductive nephrectomy (CRN) but the rate of regression is 1% or less in patients with metastatic RCC performing CRN [4].4 Although the CRN is an important part of the current combined treatment modalities in patients with metastatic RCC, the
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CRN rates are very low.5
In presented study, we aim to evaluate whether there is an effect of cytoreductive surgery on prognosis of patients with metastatic RCC using antiangiogenic agents.
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2. Patients and methods
A total of 52 patients with metastatic RCC at the time of diagnosis from Akdeniz University, Afyon
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Kocatepe University and Medipol University were analyzed. In all patients, the radical nephrectomy procedure has been performed as open surgery. All patients have received interferon alfa 2b (IFN) and they have progressed under the treatment of IFN. The patients were divided into two groups as CRN (+) and CRN (-) according to prior (CRN). The factors those nephrectomy (yes or no), age, sex, the type of tyrosine kinase inhibitory (TKI) agent, Karnofsky performance status (KPS), serum lactate dehydrogenase (LDH), corrected calcium and hemoglobin (Hgb) levels were recorded into the Statistical Package for the Social Sciences version 16.0 (SPSS 16.0) from the medical archives retrospectively. And also the time of diagnosis, the start time of IFN, the date of progression under IFN, the start time of TKI, the date of progression under TKI agents and the date of death (if yes) were
ACCEPTED MANUSCRIPT recorded into SPSS 16.0. To determine the characteristics of groups (CRN (+) or (-)), descriptive statistics (mean, frequency analysis and crosstabs, independent samples T tests) were performed. To evaluate the progression free survival (PFS) and the overall survival (OS), Kaplan-Meier statistical methods using log rank test were used. P <0.05 was considered to be statistically significant.
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3. Results The patients were divided into two groups as CRN (+) (n:28) and CRN (-) (n:24). The clinicopathological properties of the groups were given in Table 1. The mean ages of CRN (+) and CRN (-) groups were 53,6±9,8 and 67,5±10,5 years, respectively (p<0.001). We did not find any
SC
significant differences regarding sex and TKI types. In both groups, the patients have mostly used sunitinib rather than sorafenib or pazopanib. The Hgb levels were significantly higher in nephrectomy
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(+) group (11,4±1,9 vs 9,9±2,1gr/dl for CRN (+) and CRN (-) groups, respectively, (p=0.023). It was not found any significant difference regarding corrected calcium and LDH values (p=0.253 and p=0.107, respectively). When comparing two groups regarding Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic model including factors those KPS (<80%), serum LDH level (>1.5
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times the upper limit of normal), corrected serum calcium level (>10mg/dl), Hgb level (less than the lower limit of normal) and absence of nephrectomy, the ratio of patients with 0, 1-2, >2 risk factors was 28,6%, 57,1%, 14,3% and 0%, 41,7%, 58,3% for CRN (+) and CRN (-) groups, respectively
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(p=0.001).
The median PFS time from the date of starting TKI were 8.5 [95% CI: 1.3-15.8] and 3.0 [95% CI: 2.4-
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3.6] months for CRN (+) and CRN (-) groups, respectively (p=0.104). The median OS from the date of starting TKI were 15.1 [95% CI: 1.3-15.8] and 5.4 [95% CI: 1.3-15.8] months for CRN (+) and CRN (-) groups, respectively, this difference was significant (p=0.034). These PFS and OS curves were shown in Figure 1 and Figure 2. Additionally, the groups were evaluated in terms of PFS for IFN using. The median PFS time from the date of starting IFN were 6.4 [95% CI: 4.5-8.3] and 3.1 [95% CI: 2.4-3.9] months for CRN (+) and CRN (-) groups, respectively (p=0.049) (Figure 3). When all patients were evaluated in terms of OS from diagnosis, the median OS values were 21.5 [95% CI: 2.1-40.9] and 9.3 [95% CI: 3.5-15.1] months for CRN (+) and CRN (-) groups, respectively (p=0.008) (Figure 4).
ACCEPTED MANUSCRIPT 4. Discussion In patients with RCC, the CRN is one of the important parts of treatment. However, in modern therapeutic era, due to the discovery of targeted agents, an argue has been started whether the CRN is necessary in patients with metastatic RCC recently.
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Before the using of targeted therapy, especially TKI, two randomized trials have investigated the role of CRN in patients with metastatic RCC.6,7 In both of them, the patients have received interferon alfa based immunotherapy. Both of two studies have reported significant OS advantage for the patients performing CRN compared to CRN (-) patients. In addition Flanigan and Mickisch have reported a
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median survival advantage of 13.6 months for nephrectomy plus interferon vs 7.8 months for interferon alone basing on the combined analysis of these 2 trials and they have found a 31% decrease
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in the risk of death (p = 0.002).8 Having evaluated the response to IFN therapy before TKI using in presented study, we found that the median PFS were 6.4 and 3.1 months for CRN (+) and CRN (-) groups, respectively (p=0.049). Mickisch et al. have reported that a median PFS of 5 and 3 months for CRN (+) and (-) groups in patients with metastatic RCC who using IFN7 .
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The mechanisms of the benefit related to CRN have not been fully understood. It was speculated that immunotherapy might be more effective after CRN and CRN might prevent the seeding of cancer cells in primary lesion.9 Additionally, immunosuppressive compounds related to primary tumors perhaps
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might decrease the efficacy of immunotherapy.9
Recently, some studies have investigated the effectiveness of the CRN in combination with molecular
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targeted therapy in patients with metastatic RCC.10-12 In studies evaluating targeted therapy in metastatic RCC, the rate of CRN is between 90%-100% approximately.13 This rate was 67% in the poor risk patients with metastatic RCC.14 Choueiri et al. have reported that CRN was associated with a median overall survival of 19.8 months compared to 9.4 months for CRN (-) group in patients receiving targeted therapy with metastatic RCC (p<0.01),15 and they said that CRN was independently associated with a prolonged overall survival. But this advantage was no significant in poor risk patients (p=0.06). In contrast to this study, You et al. have reported no significant difference for mPFS and median OS in CRN (+) and CRN (-) groups in patients receiving targeted therapy with metastatic RCC (mPFS was 11.7 and 9.0 months in the CRN and non-CRN groups (p = 0.270), and mOS was
ACCEPTED MANUSCRIPT 21.6 and 13.9 months, respectively (p = 0.128)).16 In another study, it was found that the median OS were 20.6 and 9.5 months for CRN(+) and CRN(-) groups in patients who received targeted therapy, respectively (p<0.0001).17 According to our results, there was a significant difference between CRN (+) and CRN (-) groups in
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terms of OS. CRN (+) group had a median OS of 11 months advantage. But in our study, CRN (+) group was significantly younger than CRN (-) group and their mean hgb value which is a prognostic factor in RCC was significantly higher. Additionally, the ratio of patients with >2 risk factors according to MSKCC prognostic model was higher in CRN (-) group. These reasons may impact the
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significant survival difference. Due to these factors (age and MSKCC risk factors), CRN may probably not perform because CRN is a risk for post-op mortality and morbidity in poor risk patients
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with metastatic RCC. 5. Conclusion
We speculate that CRN is still an important part of treatment modalities in patients with metastatic RCC in targeted therapy which is currently the best systemic therapy era. But the indications of CRN
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may be limited to good risk patients with metastatic RCC. In this targeted therapy era, the results of ongoing studies such as CARMENA or SURTIME will be important for CRN decision in future. The argue about the necessity of nephrectomy may be especially resolved by CARMENA study evaluating
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the effect of nephrectomy on prognosis in metastatic RCC patients who have been receiving sunitinib in first-line setting. Also, the further randomized studies are warranted to clarify the necessity of CRN
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in patients with metastatic RCC.
Disclosure: There are no potential conflicts of interest.
References
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ACCEPTED MANUSCRIPT 4. Marcus SG, Choyke PL, Reiter R et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. J Urol. 1993; 150: 463-6. 5. Bromwich E, Hendry D, Aitchison M. Cytoreductive nephrectomy: is it a realistic option in patients with renal cancer? BJU Int. 2002; 89:523-5.
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6. Flanigan RC, Salmon SE, Blumenstein BA et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001; 345: 1655-9
7. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; European Organisation for
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Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-
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cell carcinoma: a randomised trial. Lancet. 2001; 358: 966-70.
8. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004; 171: 1071-6
nephrectomy for metastatic
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9. Pantuck AJ, Belldegrun AS, Figlin RA. Cytoreductive
renal cell carcinoma: is it still imperative in the era of targeted therapy? Clin Cancer Res. 2007 15;13:693-6. Review
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10. Sakai I, Miyake H, Hinata N, Fujisawa M.Improved survival in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy in the era of targeted therapy. Int J
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Clin Oncol. 2013 Aug 30. [Epub ahead of print] 11. Stroup SP, Raheem OA, Palazzi KL et al. Does timing of cytoreductive nephrectomy impact patient survival with metastatic renal cellcarcinoma in the tyrosine kinase inhibitor era? A multi-institutional study. Urology. 2013; 81:805-11 12. Tsao CK, Small AC, Kates M et al. Cytoreductive nephrectomy
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renal cell carcinoma in the era of targeted therapyin the United States: a SEER analysis. World J Urol. 2013; 31: 1535-9 13. Margulis V, Matin SF, Wood CG. Cytoreductive nephrectomy in metastatic renal cell carcinoma. Curr Opin Urol. 2008; 18: 474-80.
ACCEPTED MANUSCRIPT 14. Hudes G, Carducci M, Tomczak P et al; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007; 356: 2271-81. 15. Choueiri TK, Xie W, Kollmannsberger C et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth
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factor targeted therapy. J Urol. 2011;185:60-6. 16. You D, Jeong IG, Ahn JH et al. The value of cytoreductive nephrectomy for metastatic renal cell carcinoma in the era oftargeted therapy. J Urol. 2011; 185: 54-9.
17. Heng DYC, Rini BI, Beuselinck B, et al: Cytoreductive nephrectomy (CN) in patients with
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Symposium. Abstract 396. Presented February 1, 2014.
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synchronous metastases from renal cell carcinoma: Results from the International Metastatatic Genitourinary
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ACCEPTED MANUSCRIPT Table 1. Properties of groups (Abb.: KPS:Karnofsky performance status, TKI: Tyrosine kinase inhibitory, LDH: Lactate dehydrogenase, Hgb: Hemoglobin)
22(78,6%) 6(21,4%)
16(66,7%) 8(33,3%)
23(82,1%) 4(14,3%) 1(3,6%) 0
19(79,2%) 2(8,3%) 3(12,5%) 0
13(54,2%) 11(45,8%) 241±98 9,7±0,8 11,4±1,9
21(75%) 7(25%) 369±329 9,5±0,7 9,9±2,1
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8(28,6%) 16(57,1%) 4(14,3%)
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P value <0.001 0.335
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Nephrectomy No (n:24) 67,5±10,5
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Yes (n:28) 53,6±9,8
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Parameters Age Sex Male Female TKI type Sunitinib Sorafenib Pazopanib Axitinib KPS ≥80% <80% LDH (IU/L) Corrected Calcium (mg/dl) Hgb (g/dl) MSKCC risk factors 0 risk factor 1-2 risk factors >2 risk factors
0 10(41,7%) 14(58,3%)
0.417
0.108
0.107 0.253 0.023 0.001
ACCEPTED MANUSCRIPT Figure 1. Progression free survival curves from the date of starting TKI for CRN (+) and (-) groups (Abb.: CRN: Cytoreductive neprectomy, TKI: Tyrosine kinase inhibitory) (p=0.104). Figure 2. Overall survival curves from the date of starting TKI for CRN (+) and (-) groups (p=0.034) (Abb.: CRN: Cytoreductive neprectomy, TKI: Tyrosine kinase inhibitory) Figure 3. Progression free survival curves from the date of starting IFN for CRN (+) and (-) groups (p=0.049) (Abb.: CRN: Cytoreductive neprectomy, IFN: Interferon alfa 2b ).
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Figure 4. Overall survival curves from diagnosis for CRN (+) and (-) groups (p=0.008) (Abb.: CRN: cytoreductive neprectomy).
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