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Carthon BC, Kim SE, McDermott DF, Dutcher JP, Puligandla M, Manola J, Pins M, Carducci MA, Plimack ER, Appleman LJ, MacVicar GR, Kohli M, Kuzel TM, DiPaola RS, Haas NB. Results From a Randomized Phase II Trial of Sunitinib and Gemcitabine or Sunitinib in Advanced Renal Cell Carcinoma with Sarcomatoid Features: ECOG-ACRIN E1808. Clin Genitourin Cancer 2023; 21:546-554. [PMID: 37455214 PMCID: PMC10543556 DOI: 10.1016/j.clgc.2023.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 06/23/2023] [Indexed: 07/18/2023]
Abstract
INTRODUCTION Sarcomatoid renal cancer (sRCC) patients have poor outcomes. EA1808 evaluated sunitinib and gemcitabine (SG) and sunitinib alone (S) in sRCC in a randomized cooperative group phase II trial (NCT01164228). PATIENTS AND METHODS Pts were aggregated 1:1 to SG (45 pts) or S (40 pts) using a 2-stage design. sRCC pts with ≤ 1 prior nonvascular endothelial growth factor tyrosine kinase inhibitor were stratified into prognostic groups: good (clear cell, < 20% sarcomatoid, PS 0), intermediate (20%-50% sarcomatoid, PS 0), and poor (nonclear cell or > 50% sarcomatoid or PS 1). The primary endpoint was response rate (RR). For SG, the null RR was 15% and a 30% RR was of interest. For S, a 20% RR was of interest vs. a 5% null rate. Secondary endpoints were progression-free survival, overall survival, and safety. RESULTS Both arms met protocol criteria for stage 2 of accrual. A total of 47 pts were randomized to SG and 40 to S. The SG arm had 9 of 45 evaluable patient responses (RR of 20%; CI = [13%-31%]) not meeting the predetermined threshold for success. The sunitinib arm met its endpoint with 6/37 (RR of 16%; CI = [9%-27%]) evaluable responses. Grade ≥ 3 events were experienced by 36 in the SG arm and 17 in the sunitinib arm CONCLUSIONS: EA1808 was the largest and first randomized cytotoxic trial for sarcomatoid RCC. Sunitinib alone but not the SG met the preset threshold of success. Cytotoxic chemotherapy is only useful in limited clinical scenarios for sRCC.
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Affiliation(s)
- Bradley C Carthon
- Department of Medicine, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Se Eun Kim
- Department of Statistics, Dana-Farber Cancer Institute, Boston, MA
| | - David F McDermott
- Division of Hematology/Oncology; Beth Israel Deaconess Medical Center, Boston, MA
| | | | | | - Judith Manola
- Department of Statistics, Dana-Farber Cancer Institute, Boston, MA
| | - Michael Pins
- Department of Pathology; Advocate Lutheran General Hospital, Park Ridge, IL
| | - Michael A Carducci
- Division of Hematology /Oncology; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | | | - Leonard J Appleman
- Department of Medicine; University of Pittsburgh Medical Center, Pittsburgh, PA
| | | | - Manish Kohli
- Department of Medicine; University of Utah, Salt Lake City, UT; Department of Medicine; Mayo Clinic, Rochester, MN
| | - Timothy M Kuzel
- Department of Medicine; Northwestern University, Chicago, IL
| | - Robert S DiPaola
- Department of Medicine; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
| | - Naomi B Haas
- Department of Medicine; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA.
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Buller DM, Antony M, Ristau BT. Adjuvant Therapy for High-Risk Localized Renal Cell Carcinoma: Current Landscape and Future Direction. Onco Targets Ther 2023; 16:49-64. [PMID: 36718243 PMCID: PMC9884052 DOI: 10.2147/ott.s393296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/15/2023] [Indexed: 01/25/2023] Open
Abstract
Locally and regionally advanced renal cell carcinoma (RCC) can recur at high rates even after visually complete resection of primary disease. Both targeted therapies and immunotherapies represent potential agents that might help reduce recurrence of RCC in these patients. This paper reviews the current body of evidence defining their potential impact and examines the large Phase III randomized clinical trials that have been performed to assess the safety and efficacy of these systemic therapies in the adjuvant setting. Given that the findings from these trials have been predominantly negative, this paper also explores the role of other potential adjuvant agents, including single and combination agent targeted therapies and immunotherapies, whose use is currently limited to metastatic RCC. Finally, the use of radiation therapy and the use of advanced imaging modalities in RCC are also considered.
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Affiliation(s)
| | - Maria Antony
- University of Connecticut School of Medicine, Farmington, CT, USA
| | - Benjamin T Ristau
- Division of Urology, UConn Health, Farmington, CT, USA,Correspondence: Benjamin T Ristau, Division of Urology, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030, Tel +1 860 679 3438, Fax +1 860 679 6109, Email
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Monteiro FSM, Soares A, Rizzo A, Santoni M, Mollica V, Grande E, Massari F. The role of immune checkpoint inhibitors (ICI) as adjuvant treatment in renal cell carcinoma (RCC): A systematic review and meta-analysis. Clin Genitourin Cancer 2023; 21:324-333. [PMID: 36823017 DOI: 10.1016/j.clgc.2023.01.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/14/2023] [Accepted: 01/15/2023] [Indexed: 01/21/2023]
Abstract
Pembrolizumab, a PD-1 ICI is approved for the adjuvant treatment of postnephrectomy patients with clear cell RCC in some countries worldwide. However, recent negative data from randomized clinical trials (RCT) with another ICIs makes the benefit of this treatment uncertain. A systematic review and study-level meta-analysis was performed to evaluate the benefit of disease-free survival (DFS) with adjuvant ICI treatment for patients with localized and/or metastatic resected RCC. Using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to September 15, 2022. The statistical analysis was performed by ProMeta 3 software in intention-to-treat (ITT) population and in predetermined subgroups. Four RCT totalizing 3407 patients were included in this analysis. Systemic immunotherapy was pembrolizumab, atezolizumab, nivolumab, and ipilimumab plus nivolumab in 496, 390, 404, and 405 patients, respectively. In the ITT population there was a nonstatistically significant DFS benefit with adjuvant ICI (HR: 0.85, 95% CI: 0.69-1.04). Regarding the subgroups, there was a DFS benefit for PD-L1 positive (HR: 0.72; 95% CI: 0.55-0.94), intermediate-high risk patients (HR: 0.77; 95% CI: 0.63-0.94), and patients with sarcomatoid component (HR: 0.66; 95% CI: 0.43-0.99). This meta-analysis did not demonstrate a statistically significant DFS benefit in overall population, however considering the heterogeneity between the RCTs the use of adjuvant ICI should be individualized.
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Affiliation(s)
- Fernando Sabino Marques Monteiro
- Latin American Cooperative Oncology Group - LACOG, Porto Alegre, RS, Brazil; Hospital Santa Lucia, Brasilia, DF, Brazil; Hospital Universitário de Brasília, Brasilia, DF, Brazil.
| | - Andrey Soares
- Latin American Cooperative Oncology Group - LACOG, Porto Alegre, RS, Brazil; Hospital Albert Einstein, São Paulo, SP, Brazil; Centro Paulista de Oncologia/Grupo Oncoclínicas, São Paulo, SP Brazil
| | - Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello", I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | | | - Veronica Mollica
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
| | | | - Francesco Massari
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
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Rebuzzi SE, Signori A, Stellato M, Santini D, Maruzzo M, De Giorgi U, Pedrazzoli P, Galli L, Zucali PA, Fantinel E, Carella C, Procopio G, Milella M, Boccardo F, Fratino L, Sabbatini R, Ricotta R, Panni S, Massari F, Sorarù M, Santoni M, Cortellini A, Prati V, Soto Parra H, Atzori F, Di Napoli M, Caffo O, Messina M, Morelli F, Prati G, Nolè F, Vignani F, Cavo A, Roviello G, Llaja Obispo MA, Porta C, Buti S, Fornarini G, Banna GL. The prognostic value of baseline and early variations of peripheral blood inflammatory ratios and their cellular components in patients with metastatic renal cell carcinoma treated with nivolumab: The Δ-Meet-URO analysis. Front Oncol 2022; 12:955501. [PMID: 36212433 PMCID: PMC9541611 DOI: 10.3389/fonc.2022.955501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/23/2022] [Indexed: 11/14/2022] Open
Abstract
Background Treatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors. Methods By a pre-specified analysis of the Meet-URO 15 multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs. Results The analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction <0.001), higher baseline IR values (NLR: p = 0.012, SII: p = 0.003, PLR: p = 0.003), increasing NLR and systemic immune-inflammatory index (SII) (i.e., NLR x platelets) Δ (p for interaction time-group = 0.0053 and 0.0435, respectively) were associated with disease progression. OS and PFS were significantly shorter in patients with baseline lower lymphocytes (p < 0.001 for both) and higher platelets (p = 0.004 and p < 0.001, respectively) alongside early neutrophils Δ (p = 0.046 and p = 0.033, respectively). Early neutrophils and NLR Δ were independent prognostic factors for both OS (p = 0.014 and p = 0.011, respectively) and PFS (p = 0.023 and p = 0.001, respectively), alongside baseline NLR (p < 0.001 for both) and other known prognostic variables. Conclusions Early neutrophils and NLR Δ may represent new dynamic prognostic factors with clinical utility for on-treatment decisions.
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Affiliation(s)
- Sara Elena Rebuzzi
- Medical Oncology Unit, Ospedale San Paolo, Savona, Italy
- Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, Genova, Italy
| | - Alessio Signori
- Department of Health Sciences, Section of Biostatistics, University of Genova, Genova, Italy
| | - Marco Stellato
- SS Oncologia Medica Genitourinaria, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Daniele Santini
- Department of Medical Oncology, Università Campus Bio-Medico of Roma, Rome, Italy
| | - Marco Maruzzo
- Oncology Unit 1, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Ugo De Giorgi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Paolo Pedrazzoli
- Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy
- Medical Oncology Unit, IRCCS Policlinico San Matteo, Pavia, Italy
| | - Luca Galli
- Medical Oncology Unit 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Paolo Andrea Zucali
- Department of Biomedical Sciences, Humanitas University, Milano, Italy
- Department of Oncology, IRCCS, Humanitas Clinical and Research Center, Milano, Italy
| | - Emanuela Fantinel
- Department of Oncology, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Verona, Italy
| | - Claudia Carella
- Division of Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Giuseppe Procopio
- SS Oncologia Medica Genitourinaria, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Michele Milella
- Department of Oncology, Azienda Ospedaliera Universitaria Integrata di Verona, University of Verona, Verona, Italy
| | - Francesco Boccardo
- Academic Unit of Medical Oncology, IRCCS Ospedale Policlinico San Martino of Genova, Genova, Italy
| | - Lucia Fratino
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano CRO-IRCCS, Aviano, Italy
| | - Roberto Sabbatini
- Medical Oncology Unit, Department of Oncology and Hemathology, University Hospital of Modena, Modena, Italy
| | | | - Stefano Panni
- Medical Oncology Unit, ASSTl– Istituti Ospitalieri Cremona Hospital, Cremona, Italy
| | - Francesco Massari
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy
| | | | | | - Alessio Cortellini
- Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, London, United Kingdom
- Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Veronica Prati
- Department of Medical Oncology, Ospedale Michele e Pietro Ferrero, Verduno, Italy
| | - Hector Josè Soto Parra
- Department of Oncology, Medical Oncology, University Hospital Policlinico-San Marco, Catania, Italy
| | - Francesco Atzori
- Medical Oncology Department, University Hospital, University of Cagliari, Cagliari, Italy
| | - Marilena Di Napoli
- Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
| | - Orazio Caffo
- Medical Oncology Department, Santa Chiara Hospital, Trento, Italy
| | - Marco Messina
- UOC Oncologia Medica, Istituto Fondazione G. Giglio, Cefalù, Italy
| | | | - Giuseppe Prati
- Department of Oncology and Advanced Technologies AUSL - IRCCS, Reggio Emilia, Italy
| | - Franco Nolè
- Medical Oncology Division of Urogenital and Head and Neck Tumors, IEO, European Institute of Oncology IRCCS, Milano, Italy
| | - Francesca Vignani
- Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
| | - Alessia Cavo
- Oncology Unit, Villa Scassi Hospital, Genova, Italy
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Firenze, Firenze, Italy
| | | | - Camillo Porta
- Interdisciplinary Department of Medicine, University of Bari “A. Moro”, Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- *Correspondence: Sebastiano Buti,
| | - Giuseppe Fornarini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Giuseppe Luigi Banna
- Department of Oncology, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
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Bersanelli M, Casartelli C, Buti S, Porta C. Renal cell carcinoma and viral infections: A dangerous relationship? World J Nephrol 2022; 11:1-12. [PMID: 35117975 PMCID: PMC8790307 DOI: 10.5527/wjn.v11.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/10/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Virus-related cancers in humans are widely recognized, but in the case of renal cancer, the link with the world of viruses is not clearly established in humans, despite being known in animal biology. In the present review, we aimed to explore the literature on renal cell carcinoma (RCC) for a possible role of viruses in human RCC tumorigenesis and immune homeostasis, hypothesizing the contribution of viruses to the immunogenicity of this tumor. A scientific literature search was conducted using the PubMed, Web of Science, and Google Scholar databases with the keywords “virus” or “viruses” or “viral infection” matched with (“AND”) “renal cell carcinoma” or “kidney cancer” or “renal cancer” or “renal carcinoma” or “renal tumor” or “RCC”. The retrieved findings evidenced two main aspects testifying to the relationship between RCC and viruses: The presence of viruses within the tumor, especially in non-clear cell RCC cases, and RCC occurrence in cases with pre-existing chronic viral infections. Some retrieved translational and clinical data suggest the possible contribution of viruses, particularly Epstein-Barr virus, to the marked immunogenicity of sarcomatoid RCC. In addition, it was revealed the possible role of endogenous retrovirus reactivation in RCC oncogenesis, introducing new fascinating hypotheses about this tumor’s immunogenicity and likeliness of response to immune checkpoint inhibitors.
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Affiliation(s)
- Melissa Bersanelli
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma 43126, Italy
| | - Chiara Casartelli
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma 43126, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
| | - Camillo Porta
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, Bari 70121, Italy
- Department of Medical Oncology, Policlinico Consorziale, Bari 70124, Italy
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