Surgery in Metastatic RCC

Lee Lui ShiongSenior Consultant and Head of Department, Urology, Sengkang General Hospital

Senior Consultant, Department of Urology, Singapore General HospitalVisiting Consultant, National Cancer Centre

Lee.lui.shiong@singhealth.com.sg

Disclosures• Advisory board

– Janssen– Bayer– MSD– BMS– Astellas

• Clinical trial funding– Janssen

• Has CARMENA and SURTIME answered the question of CNx in TKI era?

• What is the role of CNx in the IO era?

Original Article

Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma

Arnaud Méjean, M.D., Ph.D., Alain Ravaud, M.D., Ph.D., Simon Thezenas, Ph.D., Sandra Colas, M.D., Jean-Baptiste Beauval, M.D., Karim Bensalah, M.D., Ph.D., Lionnel Geoffrois, M.D., Antoine Thiery-Vuillemin, M.D., Ph.D., Luc Cormier, M.D.,

Ph.D., Hervé Lang, M.D., Ph.D., Laurent Guy, M.D., Ph.D., Gwenaelle Gravis, M.D., Frederic Rolland, M.D., Claude Linassier, M.D., Ph.D., Eric Lechevallier, M.D., Ph.D.,

Christian Beisland, M.D., Ph.D., Michael Aitchison, M.D., Stephane Oudard, M.D., Ph.D., Jean-Jacques Patard, M.D., Ph.D., Christine Theodore, M.D., Christine Chevreau, M.D., Brigitte Laguerre, M.D., Jacques Hubert, M.D., Marine Gross-

Goupil, M.D., Ph.D., Jean-Christophe Bernhard, M.D., Ph.D., Laurence Albiges, M.D., Ph.D., Marc-Olivier Timsit, M.D., Ph.D., Thierry Lebret, M.D., Ph.D.,

and Bernard Escudier, M.D.

N Engl J MedVolume 379(5):417-427

August 2, 2018

Study Overview

• A randomized trial • overall survival • sunitinib alone was noninferior to sunitinib after nephrectomy • among patients with metastatic renal-cell carcinoma

• Patients had to be suitable candidates for nephrectomy….

Randomization, Treatment, and Follow-up of the Patients.

Méjean A et al. N Engl J Med 2018;379:417-427

Kaplan–Meier Estimates of Survival.

Demographic and Clinical Characteristics of the Patients at Baseline.

Tumor Response Outcomes.

Méjean A et al. N Engl J Med 2018;379:417-427

Méjean A et al. N Engl J Med 2018;379:417-427

Conclusions

• Sunitinib alone was not inferior to nephrectomy followed by sunitinib

• ….metastatic renal-cell carcinoma

• ….intermediate-risk or poor-risk disease.

Limitations of CARMENA

20%

10% No surgery

17% Had surgery

5%

• Recruitment of poor risk (almost half of cohort)

• Operating on poor risk – 16% Clavien III complications

• Using MSKCC criteria as risk stratification –what about overlaps with IMDC poor risk

• Lack of equipoise – no good risk recruited, recruitment took 9 years

What CARMENA taught us..

• Poor risk MSKCC – upfront CNx not indicated• Intermediate risk – select patients with low

metastatic burden

6 years 2010-2016

No CN CN

Median OS 43.2 mths (95%CI 31.4-50.1)

Median OS 22.5 mths (95%CI 18.7- 25.1)

Median OS 7.8 mths (95%CI 6.5- 9.7)

Poor risk have limited incremental OS benefit with CN

• Hence, in the TKI era….– CNx has a definite role in good risk– Possible role in intermediate risk– No role in poor risk

Lee LS et al. 2012 Nat. Rev. Urol. Predictive models for the practical management of renal cell carcinoma

• Patients can move between risk groups depending on the prognostic score one adopts

• Eg. MSKCC intermediate risk• Can be IMDC poor risk

Association of percentage of tumour burden removed with debulking nephrectomy and progression‐free survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth

factor‐targeted therapy

BJU InternationalVolume 106, Issue 9, pages 1266-1269, 23 MAR 2010 DOI: 10.1111/j.1464-410X.2010.09323.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2010.09323.x/full#f1

Outcome after cytoreductive nephrectomy for metastatic renal cell carcinoma is predicted by fractional percentage of tumour volume removed

BJU InternationalVolume 100, Issue 4, pages 755-759, 15 AUG 2007 DOI: 10.1111/j.1464-410X.2007.07108.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2007.07108.x/full#f1

• Hence, we will choose to do a CNx in those with predominant tumour burden in the kidney 70%

• What is the role of CNx in the era of IO?• (patient selection with IMDC)

Metastatectomy

J Urol

• Majority are pre-TKI era

• Selected cohort

• Solitary lung mets benefit most

• Indolent natural history after systemic therapy

• >1 mets site – some benefit but selection of patient not clear from this series

Making Cytoreductive surgery safer

Predicting surgical outcomes• n=294, complication 12%, Clavien 5%

– Liver mets, intra-op transfusion, pN1

• n=195, 8% Clavien 3 complications– age, Karnofsky status <80%

• n=279 patients, complication rate 22.6% Clavien 3 rate 8%. – age,tumor size >10 cm, WHO performance status >2

• Eur Urol 2015;69:84-91 • BJU Int 2012;110:1276–82• BJU lnt 2015; 116: 905‐910

• N=25• Sunitinib n=12, others n=13

• 84% stable thombi level• 4% (n=1) increase• 12 % (n=3) decrease, median 1.5 cm

Figure 1. OS following upfront surgery (M1 cohort)Clavien III and above (12%)

MVA -Atrial thrombus predictive of surgical complications

Reducing surgical morbidity

• Patient selection is the key!!!

• Minimally invasive techniques if possible

• Optimise the patient

• No “occasional go” surgeon

Alternatives to surgery

• Embolisation• Radiation therapy• Analgesia

Selecting patients in 2019• Cytoreductive surgery candidate• IMDC criteria / MSKCC

– Good risk– OS >12 months– symptomatic tumour– Bulk of burden in kidney– Limited metastatic sites (bone / brain mets)

• Selected intermediate risk• Not for poor risk

• Metastatectomy– Not upfront unless very straightforward– Systemic therapy as a screen– single site (lung), long natural history