Articles

Stereotactic Ablative Radiation Therapy (SAbR) Used to Defer Systemic Therapy in Oligometastatic Renal Cell Cancer

Zhang Y, Schoenhals J, Christie A, et al.
Int J Radiat Oncol Biol Phys, Vol 105, 2, 367 – 375, October 2019
DOI: https://doi.org/10.1016/j.ijrobp.2019.07.023

Abstract

Purpose

Stereotactic ablative radiotherapy (SAbR) is a promising alternative for selected patients with renal cell carcinoma (RCC) with oligometastasis. The objective of this study was to evaluate the potential of SAbR for longitudinal control in patients with persistently oligometastatic RCC. We report the impact of SAbR on tumor control rates as well as its tolerability in systemic therapy–naïve patients with oligometastatic disease (without brain metastases) and assess the effect of SAbR on subsequent first line systemic therapy by comparison to historical controls.

Methods and Materials

We reviewed patients with metastatic RCC treated with front-line SAbR with a curative intent from 2007 to 2017 at UT Southwestern Kidney Cancer Program. We analyzed local control rates (LCR), toxicity, freedom from systemic therapy (FST), type and duration of first-line systemic therapy, and overall survival (OS). Cox regression and Kaplan-Meier analyses were used.

Results

We identified 47 patients with oligometastatic RCC treated with SAbR to 88 metastases; 11 patients had more than 1 SAbR course. The local control rate was 91.5% at 2 years with no reported grade ≥3 toxicity. With a median follow-up of 30 months (interquartile range, 13.7-40.9), median FST from first SAbR was 15.2 months (95% confidence interval [CI], 8.8-40.1). The most common systemic therapies initiated after SAbR were pazopanib (60.7%) and sunitinib (14.3%). The duration of first line systemic therapy appeared unaffected by SAbR. Improved FST was observed in patients with metachronous disease (hazard ratio, 2.67; P = .02), solitary metastasis (HR, 2.26; P = .05), and non-bone metastasis (HR, 2.21; P = .04). One-year and 2-year OS after SAbR were 93.1% (95% CI, 80.1-97.7) and 84.8% (95% CI, 69.1-92.9), respectively. Median OS was not reached.

Conclusions

SAbR is an effective and safe treatment for selected patients with oligometastatic RCC, can provide longitudinal disease control without systemic therapy for over a year, and does not appear to adversely affect the effectiveness of first-line systemic therapy once initiated. Prospective validation of these findings is being sought through a phase 2 trial.

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First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Results from the International Metastatic Renal-cell Carcinoma Database Consortium

Dudani S, Graham J, Wells JC, et al.
European Urology, Volume 0, Issue 0, Article in Press
DOI: https://doi.org/10.1016/j.eururo.2019.07.048

Abstract

Background

In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited.

Objective

To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies.

Design, setting, and participants

Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo.

Intervention

All patients received first-line IO combination therapies.

Outcome measurements and statistical analysis

First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors.

Results and limitations

In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] –8% to 22%, p =  0.4), TTF was 14.3 versus 10.2 mo (p =  0.2), TNT was 19.7 versus 17.9 mo (p =  0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46–1.12, p =  0.14), 0.65 (95% CI 0.38–1.11, p =  0.11), and 1.74 (95% CI 0.82–3.68, p =  0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3–57%, p =  0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p =  0.4; n = 55). Limitations include the study’s retrospective design and sample size.

Conclusions

There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially.

Patient summary

There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.

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Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights

Carlo M, Hakimi AA, Stewart GD, et al.
European Urology, Volume 0, Issue 0, Articles in Press
DOI: https://doi.org/10.1016/j.eururo.2019.06.015

Abstract

Context

Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years.

Objective

To review and summarise the recent preclinical and clinical literature in hereditary renal cancer.

Evidence acquisition

A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management.

Evidence synthesis

Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHLMETFHTSC1/TSC2FLCN, SDHA/B/C/DBAP1CDC73, and MITF. Clinical spectrum of SDHBAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy.

Conclusion

There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection.

Patient summary

This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.

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Adjuvant Therapy in High-Risk Renal Cell Cancer: A Systematic Review and Meta-analysis

Riaz I, Faridi W, Husnain M, et al.
Mayo Clinic Proceedings, Volume 94, Issue 8, 1524 – 1534, August 2019
DOI: https://doi.org/10.1016/j.mayocp.2019.01.045

Abstract

Objective

To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating risk-benefit for adjuvant postoperative treatments in high-risk renal cell carcinoma by assessing reported disease-free survival (DFS), overall survival (OS), toxicity, and quality of life.

Methods

A literature search was performed in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials to identify relevant RCTs (from database inception through May 15, 2018). The results of the ATLAS trial were published while writing this manuscript, and the manuscript was updated accordingly. A generic variance-weighted random effects model was used to derive estimates for efficacy and common adverse effects. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test.

Results

Adjuvant therapy with tyrosine kinase inhibitors compared with placebo was observed to have a DFS hazard ratio [HR] of 0.92 (95% CI, 0.83-1.01) and an OS HR of 1.01 (95% CI, 0.89-1.15) (4 RCTs; 4417 patients). Analysis of DFS for sunitinib compared with placebo (n=1909) in the adjuvant setting detected an HR of 0.90 (95% CI, 0.67-1.19). Increased risk of grade 3 or 4 adverse events (relative risk [RR]=2.6; 95% CI, 2.28-2.97), diarrhea (RR=9.89; 95% CI, 4.22-23.14), fatigue (RR=3.11; 95% CI, 1.86-5.18), hypertension (RR=3.63; 95% CI, 2.99-4.41), and palmar/plantar dysesthesia (RR=2.70; 95% CI, 2.47-2.96) was observed.

Conclusion

Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve OS or DFS, and there was a significant increased risk of toxicity in greater than half of the patients, leading to a decline in quality of life.

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Is cytoreductive nephrectomy relevant in the immunotherapy era?

Singla N, Ghandour R, Margulis V, et al.
Current Opinion in Urology. 29(5):526–530, September 2019
DOI: 10.1097/MOU.0000000000000659

Abstract

Purpose of review

The recent approval of immune checkpoint inhibitors (ICI) revolutionized the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, the role of cytoreductive nephrectomy is not well defined in this setting. Here, we review the contemporary role and timing of cytoreductive nephrectomy for advanced RCC in the era of immunotherapy.

Recent findings

Evidence concerning combination systemic therapy and cytoreductive nephrectomy in the multimodal management of mRCC is primarily limited to studies conducted in the targeted therapy era. The oncologic role of cytoreductive nephrectomy in the setting of ICI remains largely undefined and is supported primarily by case reports. Nonetheless, patient selection for cytoreductive nephrectomy is paramount, and appropriate candidacy in the ICI era will likely be refined as increasing evidence emerges. Until then, a cautious balance between perceived oncologic benefit and risks of intervention must be exercised. Several trials are ongoing to help shed light on patient selection, technical feasibility, and optimal timing of cytoreductive nephrectomy in the immunotherapy era.

Summary

Although the role and timing for cytoreductive nephrectomy remain to be further elucidated in the immunotherapy era, patient selection remains critical for treatment planning. Further studies are urgently needed to better define the role of cytoreductive nephrectomy in this setting.

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The evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma

Graham J, Bhindi B, Heng D.
Current Opinion in Urology. 29(5):507–512, September 2019
DOI: 10.1097/MOU.0000000000000657

Abstract

Purpose of review

To review the evidence related to cytoreductive nephrectomy in metastatic renal cell carcinoma (mRCC) treated in the targeted therapy era, with a focus on observational studies and randomized trials.

Recent findings

A number of retrospective observational studies exploring the role of cytoreductive nephrectomy have been reported. These have suggested an association between cytoreductive nephrectomy and survival, with hazard ratio estimates ranging from 0.39 to 0.68 in favour of cytoreductive nephrectomy. In contrast, the CARMENA randomized trial demonstrated that sunitinib alone was noninferior to cytoreductive nephrectomy followed by sunitinib in intermediate-risk and poor-risk patients. The results of the SURTIME trial suggest that initial sunitinib followed by a deferred cytoreductive nephrectomy may also be a reasonable approach in select patients.

Summary

On the basis of the evidence to date, there is still a role for cytoreductive nephrectomy in the multimodality treatment of mRCC. Careful patient selection is of paramount importance and discussion in multidisciplinary tumour boards is encouraged. As the treatment landscape of mRCC continues to change, the role of cytoreductive nephrectomy in the modern immuno-oncology era will need to be explored.

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Rapid Deep Responses With Nivolumab Plus Ipilimumab in Papillary Renal Cell Carcinoma With Sarcomatoid Dedifferentiation

Schvartsman G, Carneiro A, Filippi R, et al
Clinical Genitourinary Cancer, August 2019
DOI: 10.1016/j.clgc.2019.05.023

Clinical Practice Points

First-line treatment with nivolumab and ipilimumab for intermediate and high-risk patients with meta- static renal cell carcinoma (RCC) is standard-of- care.

The United States Food and Drug Administration extended approval to all RCC histologies, despite enrollment of clear-cell RCC only.

Sarcomatoid and rhabdoid dedifferentiation is associ- ated with significantly worse prognosis and may lead to increased programmed death-ligand 1 upregulation.

We present the first 2 cases, to our knowledge, of papillary RCC with sarcomatoid dedifferentiation with rapid and deep responses to the ipilimumab and nivolumab combination.

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Adjuvant Therapy in Patients With RCC

A Gul, BI Rini
Cancer, July 2019
DOI: 10.1002/cncr.32144

Abstract

Localized renal cell carcinoma (RCC) has an associated risk of recurrence after nephrectomy. Several clinical risk models attempt to predict oncologic outcomes based on clinical and pathologic features. In addition, novel gene signatures have been developed to refine risk prediction based on tumor biology. Systemic therapies targeting angiogenic pathways that are effective in metastatic RCC failed to show an improvement in overall survival in the adjuvant setting. Immune checkpoint inhibitors have shown significant antitumor activity with prolonged and durable responses in metastatic RCC, which led to an interest in evaluating these agents in the adjuvant setting. In this review, clinical risk predictive models, novel gene signatures, major clinical trials completed in the adjuvant setting, ongoing immune checkpoint inhibitor trials, and the perspective of adjuvant treatment in RCC are discussed.

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Surgical Safety of Cytoreductive Nephrectomy Following Sunitinib: Results from the Multicentre, Randomised Controlled Trial of Immediate Versus Deferred Nephrectomy (SURTIME)

Roderick Emile De Bruijna, Peter Muldersb, Michael A. Jewett, et al
European Urology, 2019
DOI: 10.1016/j.eururo.2019.06.006

Abstract

The European Organisation for Research and Treatment of Cancer SURTIME trial explored timing of sunitinib, a tyrosine kinase inhibitor (TKI), and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Previous retrospective studies suggest increased surgery-related adverse events (AEs) after presurgical TKI. We report surgical safety from a randomised comparison of CN before or after sunitinib. In-hospital mortality, 30-d readmission rate, and intraoperative and 30-d postoperative AEs according to Common Terminology Criteria for Adverse Events version 4 and Clavien-Dindo (CD) were analysed. Patients were randomised 1:1 to immediate CN followed by sunitinib versus sunitinib followed by deferred CN 24 h after the last dose of sunitinib. None of the tumours in the deferred arm became unresectable, and only two patients had a sunitinib-related delay of CN of >2 wk. AEs related to surgery (all grades) in the immediate and deferred arms occurred in 52% and 53% after CN, respectively, although the number of intraoperative surgery-related AEs was higher in the immediate arm. Postoperative AEs (CD ≥3), 30-d readmission, and in-hospital mortality rates were 6.5%, 13%, and 4.3% in the immediate arm and 2.5%, 7.5%, and 2.5% in the deferred arm, respectively. There were no differences in surgery time, blood loss, and hospital stay.

Patient summary:

Patients with metastatic kidney cancer do not have more surgical complications irrespective of whether they are treated with systemic therapy before or after surgery.

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Renal cell cancer treatment: an expert panel recommendation from the Latin American cooperative group-genitourinary and the Latin American renal cancer group: focus on surgery

Stênio de Cássio Zequi, Walter Henriques da Costa , Fernando Korkes, Rodolfo Borges dos Reis, Wilson Francisco Schreiner Busato, Wagner Eduardo Matheus, Deusdedit Cortez Vieira da Silva Neto, Felipe de Almeida e Paula, Gustavo Franco Carvalhal, Lucas Nogueira, Roni de Carvalho Fernandes, Adriano Gonçalves e Silva, André Deeke Sasse, André P. Fay, Denis Leonardo Jardim, Diogo Assed Bastos, Diogo Augusto Rodrigues da Rosa, Evanius Wierman, Fabio Kater, Fabio A. Schutz, Fernando Cotait Maluf, Fernando Nunes Galvão de Oliveira, Igor Alexandre Protzner Morbeck, José Augusto Rinck, Karine Martins da Trindade, Manuel Caitano Maia, Vinicius Carrera Souza, Fernando Sabino Marques Monteiro and Andrey Soares.

Abstract

Background:

Renal cell cancer (RCC) is one of the 10 most common cancers in the world, and its incidence is increasing, whereas mortality is declining only in developed countries. Therefore, two collaborative groups, The Latin American Oncology Cooperative GroupGenitourinary Section (LACOG-GU) and the Latin American Renal Cancer Group (LARCG), held a consensus meeting to develop this guideline.

Methods:

Issues (134) related to the treatment of RCC were previously formulated by a panel of experts. The voting panel comprised 26 specialists (urologists and medical oncologists) from the LACOG-GU/LARCG. A consensus was reached if 75% agreement was achieved. If there was less concordance, a new discussion was undertaken, and a consensus was determined by the most votes after a second voting session.

Results:

The expert meeting provided recommendations that were in line with the global literature; 75.0% of the recommendations made by the panel of experts were evidence-based level A, 22.5% of the recommendations were level B, and 2.5% of the recommendations were level D.

Conclusions:

This review suggests recommendations for the surgical treatment of RCC according to the LACOG-GU/LARCG experts.

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