The impact of primary region resection on the therapeutic outcome of combination regimens for metastatic renal cell carcinoma
- Authors:
- Published online on: September 20, 2023 https://doi.org/10.3892/ol.2023.14057
- Article Number: 470
Abstract
Introduction
Renal cell carcinoma (RCC) accounts for 3–5% of all cancer cases worldwide, and while improved screening has increased the detection of early stage disease, a total of 20–30% of patients with RCC are diagnosed with metastases at the initial presentation (1). Although in the past, there was no systemic therapy regimen that could be expected to be effective enough for patients with advanced RCC, the advent of molecular-targeted agents, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), has changed the treatment of metastatic RCC (mRCC) (2,3). Furthermore, combination regimens of the aforementioned drugs have been introduced over several years, and the prognosis of patients with mRCC has improved (4–8). The combination regimens approved by the health insurance system in Japan can be broadly classified into two types: Regimens combining two ICIs (ipilimumab and nivolumab; ICI–ICI) and regimens combining a TKI with an ICI (ICI-TKI). Four ICI-TKI regimens have been introduced: Avelumab + axitinib, pembrolizumab + axitinib, nivolumab + cabozantinib, and pembrolizumab + lenvatinib. All regimens have been shown to improve treatment efficacy and prognosis through randomized control trials (RCTs) (4–8). While the introduction of multiple effective systemic treatment options has been encouraging, nephrectomy as a treatment approach has been controversial (9–14). A number of retrospective studies have demonstrated the benefit of upfront cytoreductive nephrectomy (CN) in mRCC treated with TKIs (9,10) and ICIs (11,12); however, several RCTs have shown negative data for upfront CN in mRCC treated with TKIs (13,14). It is important to clarify the association between treatment efficacy and surgical therapy to select the optimal systemic treatment regimen. The present study aimed to determine the relationship between the therapeutic outcome of combination regimens, including ICIs and/or TKIs, and CN for mRCC.
Materials and methods
Patients
Inclusion criteria for the present study included: i) Treatment of mRCC between January 2018 and June 2022 at Kobe University Hospital or affiliated institutes: Hyogo Prefectural Amagasaki General Medical Center (Amagasaki, Japan), Hyogo Cancer Center (Akashi, Japan), Japanese Red Cross Society Himeji Hospital (Himeji, Japan), Kobe City Medical Center West Hospital (Kobe, Japan), Hyogo Prefectural Kakogawa Medical Center (Kakogawa, Japan), Kansai Rosai Hospital (Amagasaki, Japan), Kita-harima Medical Center (Himeji, Japan) and Yodogawa Christian Hospital (Osaka, Japan), from January 2018 to June 2022; ii) treatment with a combination regimen including TKI or ICI as first-line therapy; and iii) mRCC classified as intermediate or poor risk by the International mRCC Database Consortium (IMDC) (15). Exclusion criteria included: i) Treatment with a combination regimen as presurgical therapy; and ii) unknown pathology. A total of 8/172 patients with mRCC whose pathological diagnosis was not determined, and a total of 13/172 patients who were categorized as favorable risk, were excluded. As a result, 151 patients were included in the current study, and were retrospectively studied by reviewing the relevant clinicopathological data. Ethics approval was granted by the Ethics Committee of Kobe University (approval no. B230087).
Patients treated with ipilimumab + nivolumab, and those treated with either avelumab + axitinib, pembrolizumab + axitinib, nivolumab + cabozantinib or pembrolizumab + lenvatinib, were divided into the ICI–ICI and ICI-TKI groups, respectively. Clinicopathological data, including age, sex, pathological findings, Karnofsky performance status (KPS) score (16), metastasis status, choice of first-line regimen and IMDC risk, were evaluated for all patients, and the distribution of these parameters in each group was compared. The objective response (OR), OR rate (ORR), and the progression-free survival (PFS) and overall survival (OS) times for each group were determined. These analyses were performed for all patients, and patients were further classified into three patterns: Recurrence after primary tumor resection diagnosed as RCC (pattern A), mRCC at initial diagnosis with upfront CN (pattern B) and mRCC at initial diagnosis without upfront CN (pattern C).
Statistical analysis
The differences in the distribution of categorical variables between the groups were analyzed using a χ2 test, and when >20% of expected counts were ≤5, they were analyzed using Fisher's exact test. Tumor responses were determined by investigator assessment on the basis of RECIST version 1.1 (17). The PFS and OS times were determined using the Kaplan-Meier method, and the differences between the two groups were analyzed using log-rank test. All statistical analyses were conducted using Statview (version 5.0; Abacus Concepts, Inc.), and P<0.05 was considered to indicate a statistically significant difference.
Results
All patients
The median age of the patients was 71 years (range, 30–86 years). The median observation period was 16.6 months (range, 1–93.8 months). The first-line regimens were the ICI–ICI and ICI-TKI regimens in 98 and 53 cases, respectively. The number of patients with lymph node metastasis in the ICI–ICI group was significantly higher than that in the ICI-TKI group (Table IA). There was no statistically significant difference in either PFS or OS between the two regimen groups when all patients were assessed (Fig. 1).
 | Table I.Comparison of characteristics of patients between the ICI–ICI (n=98) and ICI-TKI (n=53) groups. |
Patients' characteristics in each pattern
Patterns A, B and C consisted of 62, 38 and 51 patients, respectively. The frequency of patients with non-clear histology, low KPS, multiple metastatic organs, bone metastasis, lymph node metastasis and poor IMDC risk was significantly lower in pattern A than in the other two patterns (Table II). The frequency of patients with poor IMDC risk in pattern B was significantly lower than that in pattern C (Table II). There was no significant difference in the background of patients between the ICI–ICI and the ICI-TKI groups in every pattern, except for a higher number of patients with lymph node metastasis in the ICI–ICI group in pattern B and C, and a higher number of patients with liver metastasis in the ICI-TKI group in pattern C (Table IB-D).
Treatment outcomes in each pattern
In the ICI-TKI group of pattern C and in that of all patients, the ORR [the frequency of patients with complete response (CR) or partial response (PR) as the best OR] was significantly higher, while the frequency of patients with CR and that with progressive disease (PD) as the best OR were significantly lower than that in the ICI–ICI group (Table III). In pattern A, the 50% PFS times of the ICI–ICI and the ICI-TKI groups were 33.6 months and not reached (NR) (Fig. 2A), respectively, and the 50% OS times were 53.7 months and NR, respectively (Fig. 2B). In pattern B, the 50% PFS times of the ICI–ICI and ICI-TKI groups were 10.5 and 8.2 months (Fig. 3A), respectively, and the 50% OS times were NR and 15.8 months, respectively (Fig. 3B). In pattern C, the 50% PFS time in the ICI-TKI group was significantly better than that in the ICI–ICI group (4.1 months and NR, respectively; Fig. 4A), and the 50% OS time was 29.8 months and NR, respectively (Fig. 4B).
| Table III.OR of first-line therapy in all patients (n=151), and patterns A (n=58), B (n=38) and C (n=42). |
Discussion
The introduction of molecular-targeted agents and ICIs has changed the therapeutic strategy of systemic therapy for mRCC in recent years. The use of various combination regimens with these agents has notably contributed to improved efficacy of treatment for patients with mRCC (4–8). The increase in therapeutic options has enabled the selection of treatment approaches that are expected to be effective for patients with diverse backgrounds (18,19). While the number of treatment options has increased, selecting the most appropriate therapy can be challenging. A previous study attempted to characterize every regimen by comparing results from multiple RCTs using network meta-analysis (20). To the best of our knowledge, no RCTs that directly compare first-line combination regimen options for mRCC have been performed; therefore, analyses derived from real-world data will be important in making treatment selections.
ORR was significantly higher in the ICI-TKI group than that in the ICI–ICI group, whereas there was no significant difference in either PFS or OS times when comparing all patients. However, the backgrounds of patients who had postoperative recurrence after radical surgery for low-stage RCC, and those who had metastasis from the initial diagnosis as high-stage RCC were considered to be different. In addition, since the physician decides whether to perform upfront CN on the basis of a comprehensive evaluation of the patient's condition, the pathophysiology of mRCC may notably vary between those cases where upfront CN was performed and those where it was not performed. In particular, the IMDC classification has been reported to be useful in the prognostic stratification of patients treated with combined regimens (21). The notable difference in the distribution of IMDC classification among the three patterns suggests that they should be separately examined.
First, in patients with recurrence after radical surgery (pattern A), satisfactory PFS and OS times, and ORR were obtained regardless of the selection of the first-line regimen, and no patient in the ICI-TKI group had PD as the best response. The proportion of patients with parameters that seemed to represent a poor prognosis, including non-clear histology, poor KPS and poor IMDC risk classification, was significantly lower in pattern A than in other patients with mRCC at initial diagnosis. Additionally, since recurrence was detected during regular follow-up, the frequency of patients with multiple sites of metastatic disease was also significantly lower. These characteristics of metastatic status were considered to be one of the reasons for the difference of treatment efficacy and prognosis of patients in pattern B compared with those in pattern C. The treatment outcome trends in ORR and PFS differed significantly between patients with and without upfront CN in patients with mRCC. Patients in pattern B, i.e. those with mRCC who underwent upfront CN, showed no difference in ORR, or PFS or OS times between the ICI–ICI and the ICI-TKI groups.
Second, the frequency of poor IMDC risk cases was significantly lower in pattern B compared with that in pattern C, indicating a tendency to choose upfront CN when the overall condition of the patient was good. A total of ~40% of patients in the ICI–ICI group had no recurrence, reflecting a trend towards improved OS in the ICI–ICI group. The results of the current study suggested that treatment with ICI–ICI may be more likely to be effective in such cases with relatively improved conditions (22). These results are consistent with a previously reported sub-analysis of an RCT showing the efficacy of ipilimumab + nivolumab therapy for mRCC by the number of IMDC risk factors (23).
In contrast to pattern B, in patients with mRCC who did not undergo upfront CN (pattern C), PFS times and ORR in the ICI-TKI group were significantly higher than those in the ICI–ICI group. Patients in pattern C had more advanced disease with multiple metastases than those patients in pattern B, and it was hypothesized that for many of these patients in pattern C they would not exhibit a durable response, which is an important feature of the effect of ICI–ICI therapy. Despite significant differences in ORR and PFS times, there was no significant difference in OS times between the two groups. It is biologically reasonable to assume that TKI-naïve patients who receive ICI–ICI as first-line therapy will have an improved response when they receive TKI in the second line or later, and that the ICI-TKI group will have fewer options for substantial therapy. A previous study also reported that even though ORR was higher in the ICI-TKI group, there was no difference in OS times between these regimens because there were fewer post-treatment options, and since the ICI–ICI group did not receive TKIs in first-line therapy, better efficacy of TKIs in subsequent therapy after failure of first-line therapy can be expected (24). However, patients in the ICI-TKI group, which offers good PFS times and ORR even in patients with poor IMDC risk, are more likely to choose surgical and radiotherapeutic options, including deferred CN and metastasectomy, for shrinking primary tumors and metastases, compared with the ICI–ICI group. These options are likely to become further available with increasing proficiency in the use of various systemic combination regimens and collaboration with other departments. In the current study, patients who were administered for the purpose of presurgical therapy were excluded, and deferred CN was performed in only one patient. The OS times may be further improved by multidisciplinary treatment with these aggressive interventions in the future.
The present study has several limitations. It is based on the analysis of real-world data and is a retrospective study with a relatively small sample size. Additionally, different regimens are included within the ICI-TKI group. The choice of regimen and whether to perform upfront CN depend on patient background, as the decision is made by the physician, taking into account the patient's overall medical condition, thus leading to potential selection bias in each regimen. Further analyses with a larger volume and longer follow-up period are warranted to confirm the findings of the present study.
In conclusion, the outcomes following treatment with ICI–ICI and ICI-TKI regimens were detected in patients with mRCC, including in those who exhibited recurrence after radical surgery, and those who did and did not undergo upfront CN before systemic therapy. Therapeutic efficacy could be achieved with any regimen in patients with recurrence after radical surgery, whereas improved results of PFS and ORR were archived with ICI-TKI in patients without upfront CN. The efficacy of systemic treatment is more promising than in the past decade; to further improve the effectiveness of treatment it is necessary to understand the characteristics of each regimen, and work towards multidisciplinary treatment with surgery and radiation therapy.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
ToT, JH, HU, NW, KH, YN, YO and MF contributed to the conception and design of the study, providing supervision and drafting the manuscript. JF, TaT, YB and TH contributed to the conception and design of the study, acquisition of data and drafting the manuscript. JT and YS contributed to the conception and design of the study, acquisition of data, drafting and critical revision of the manuscript, and clinical analysis. YS and YO confirm the authenticity of the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The protocol of the current study was approved by the Ethics Committee of Kobe University (approval no. B190010 and B230087), and was carried out according to the approved guidelines. No informed consent was obtained due to data anonymization as no identifying information associated with the participants was included.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2022. CA Cancer J Clin. 72:7–33. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Rini BI, Battle D, Figlin RA, George DJ, Hammers H, Hutson T, Jonasch E, Joseph RW, McDermott DF, Motzer RJ, et al: The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J Immunother Cancer. 7:3542019. View Article : Google Scholar : PubMed/NCBI | |
|
Pal SK, Ghate SR, Li N, Swallow E, Peeples M, Zichlin ML, Perez JR, Agarwal N and Vogelzang NJ: Real-world survival outcomes and prognostic factors among patients receiving first targeted therapy for advanced renal cell carcinoma: A SEER-medicare database analysis. Clin Genitourin Cancer. 15:e573–e582. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 378:1277–1290. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 380:1103–1115. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 380:1116–1127. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, et al: Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 384:829–841. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, et al: Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 384:1289–1300. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Choueiri TK, Xie W, Kollmannsberger C, North S, Knox JJ, Lampard JG, McDermott DF, Rini BI and Heng DY: The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 185:60–66. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Bhindi B, Abel EJ, Albiges L, Bensalah K, Boorjian SA, Daneshmand S, Karam JA, Mason RJ, Powles T and Bex A: Systematic review of the role of cytoreductive nephrectomy in the targeted therapy era and beyond: An individualized approach to metastatic renal cell carcinoma. Eur Urol. 75:111–128. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Singla N, Hutchinson RC, Ghandour RA, Freifeld Y, Fang D, Sagalowsky AI, Lotan Y, Bagrodia A, Margulis V, Hammers HJ and Woldu SL: Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: An analysis of the national cancer database. Urol Oncol. 38:604.e9–604.e17. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Hall ME, Bhindi B, Luckenbaugh AN, Laviana AA, Moses KA, Satkunasivam R, Rini B, Klaassen Z and Wallis CJD: Association between cytoreductive nephrectomy and survival among patients with metastatic renal cell carcinoma receiving modern therapies: A systematic review and meta-analysis examining effect modification according to systemic therapy approach. Cancer Causes Control. 32:675–680. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Bex A, Mulders P, Jewett M, Wagstaff J, van Thienen JV, Blank CU, van Velthoven R, Del Pilar Laguna M, Wood L, van Melick HHE, et al: Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: The SURTIME randomized clinical trial. JAMA Oncol. 5:164–170. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, et al: Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 379:417–427. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Heng DYC, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, 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. J Clin Oncol. 27:5794–5799. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Yates JW, Chalmer B and McKegney FP: Evaluation of patients with advanced cancer using the Karnofsky performance status. Cancer. 45:2220–2224. 1980. View Article : Google Scholar : PubMed/NCBI | |
|
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Stühler V, Herrmann L, Rausch S, Stenzl A and Bedke J: Real world data on IO-based therapy for metastatic renal cell carcinoma. J Cancer Res Clin Oncol. 149:3249–3258. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Iinuma K, Yamada T, Kameyama K, Taniguchi T, Kawada K, Ishida T, Nagai S, Enomoto T, Ueda S, Takagi K, et al: The efficacy and safety of immune checkpoint inhibitor and tyrosine kinase inhibitor combination therapy for advanced or metastatic renal cell carcinoma: A multicenter retrospective real-world cohort study. Cancers (Basel). 15:9472023. View Article : Google Scholar : PubMed/NCBI | |
|
Bosma NA, Warkentin MT, Gan CL, Karim S, Heng DYC, Brenner DR and Lee-Ying RM: Efficacy and safety of first-line systemic therapy for metastatic renal cell carcinoma: A systematic review and network meta-analysis. Eur Urol Open Sci. 37:14–26. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Ernst MS, Navani V, Wells JC, Donskov F, Basappa N, Labaki C, Pal SK, Meza L, Wood LA, Ernst DS, et al: Outcomes for international metastatic renal cell carcinoma database consortium prognostic groups in contemporary first-line combination therapies for metastatic renal cell carcinoma. Eur Urol. 84:109–116. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Hara T, Furukawa J, Shiraishi Y, Okamura Y, Bando Y, Terakawa T, Harada K, Nakano Y and Fujisawa M: Impact of cytoreductive nephrectomy prior to combination therapy of ipilimumab plus nivolumab in metastatic renal cell carcinoma. Int J Urol. May 2–2023.(Epub ahead of print). View Article : Google Scholar | |
|
Escudier B, Motzer RJ, Tannir NM, Porta C, Tomita Y, Maurer MA, McHenry MB and Rini BI: Efficacy of nivolumab plus ipilimumab according to number of IMDC risk factors in CheckMate 214. Eur Urol. 77:449–453. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Dudani S, Graham J, Wells JC, Bakouny Z, Pal SK, Dizman N, Donskov F, Porta C, de Velasco G, Hansen A, et al: First-line immuno-oncology combination therapies in metastatic renal-cell carcinoma: Results from the international metastatic renal-cell carcinoma database consortium. Eur Urol. 76:861–867. 2019. View Article : Google Scholar : PubMed/NCBI |
