The document discusses the role and implications of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC), highlighting its historical importance and evolving nature of treatment paradigms influenced by advancements in systemic therapies. Benefits of CN include alleviation of symptoms and potential enhancement of immune responses, while disadvantages encompass increased morbidity and delays in systemic treatment initiation. Recent clinical trials suggest that while CN may offer survival benefits in certain patient subsets, deferred approaches and the introduction of immunotherapies warrant further evaluation of its efficacy.

1. CYTOREDUCTIVE NEPHRECTOMY
Dr. Ankit Agarwal

2. INTRODUCTION
• RCC - 6th most common cancer in western world
• 15% of kidney cancers are metastatic at diagnosis
• 5-year survival drops from 93% to 12% when there is metastatic
cancer

3. CYTOREDUCTIVE NEPHRECTOMY
• Refers to removal of the kidney with primary tumor in patients
with synchronous metastatic RCC
• For several decades, CN was the cornerstone in newly diagnosed
metastatic RCC treatment
• Following advancements in systemic therapy, the role of CN has
become limited.

4. BENEFITS OF CN
• Symptoms caused by the local tumor are alleviated
• Pain
• Hematuria
• Distant paraneoplastic symptoms, including hypertension,
hypercalcemia, and hematopoietic disturbances
• Reduces Disease burden and potential for development of
aggressive biological clones capable of further metastases

5. BENEFITS OF CN • RCC is highly immunogenic tumor
• Immune system may be primed to target
renal cancer cells, but the response is
consumed by the primary tumor until it is
removed, possibly due –
• Volume of disease
• Immunosuppressive nature of the tumor
microenvironment, inhibiting T-cell function
• This could be relieved through resection of
the primary tumor, which also increase
efficacy of systemic therapy
Uzzo RG, Clark PE, Rayman P, et al. Alterations in NFkappaB activation in T
lymphocytes of patients with renal cell carcinoma. J Natl Cancer Inst

6. DISADVANTAGES OF CN
• Added Morbidity
• Upfront CN leads to delay in initiation of systemic treatment
• Not all patients who undergo CN may be able to receive systemic
therapy
• Upfront systemic therapy may identify patients with inherent resistant to
systemic therapy, who are then spared from CN (litmus test)

7. ROLE OF CN
• Cytokine based immunotherapy era - 2001
• VEGF-TKI targeted therapy era - 2010
• Immuno-oncology era

8. RISK STRATIFICATION
Two most widely adopted and validated risk stratification criteria utilized in
clinical trials.
• The Memorial Sloan Kettering Cancer Center (MSKCC) model/ Motzer
criteria - Immunotherapy era
• International Metastatic Renal Cell Carcinoma Database Consortium
(IMDC), or Heng criteria - Targeted therapy era

9. RISK STRATIFICATION
RISK GROUP MEDIAN SURVIVAL
GOOD (0 risk
factors)
20 MONTHS
INTERMEDIATE
(1-2 risk factors)
10 MONTHS
POOR (3 or more
risk factors)
4 MONTHS

10. THE SOUTHWEST ONCOLOGY GROUP
(SWOG)
EUROPEAN ORGANIZATION FOR
RESEARCH AND TREATMENT OF
CANCER (EORTC)
CYTOKINE BASED IMMUNOTHERAPY ERA
RCT, 2001

11. SWOG
• 245 pts
• CN followed by IFN-alpha vs IFN-
alpha
• OS – 11.1 v/s 8.1 month
• Time to progression not assessed
• 85 pts
• CN followed by IFN-alpha vs IFN-
alpha
• OS – 17 v/s 7 month
• Time to progression – 5 v/s 3 months
EORTC
Conclusion : CN followed by IFN-alpha results in longer
survival than IFN-alpha alone

12. SWOG EORTC
Time to progression
Overall survival

13. CYTOKINE TO TARGET THERAPY ERA

14. TARGET THERAPY ERA- VEGF-TKI
• Better than cytokine based immunotherapy
• Few cases with complete response with targeted therapy were noted
without nephrectomy
• Role of CN in targeted therapy era was still unclear

15. VEGF-TKI
• Retrospective studies
CN + Targeted therapy
(Median OS – months)
Targeted therapy alone
(Median OS – months)
Choueiri 19.8 9.4
SEER database 19 4

16. VEGF-TKI
Limitation of these Retrospective studies
• Inherent bias
• Patient selected for surgery tend to be healthier and with more
favorable disease
• When patients stratified by risk on sub group analyses,
• Favorable and intermediate risk – Benefit from CN
• Poor risk – No benefit from CN

17. • Retrospective study
• IMDC, 2014
• 1658 Pts
• Demonstrated that CN provided an OS
benefit in patients treated with targeted
therapy even after adjusting for
prognostic factors

18. Patients with 4 or more IMDC
criteria didn't derive benefit from
CN

19. TARGETED THERAPY
RCT, 2010
• CARMENA TRIAL (Clinical Trial to Assess the Importance of
Nephrectomy)
• SURTIME TRIAL (Surgery Time)

21. CARMENA TRIAL

23. RESULTS

24. RESULTS
Sunitinib Only Nephrectomy –
Sunitinib
Progressive free
survival
8.3 months 7.2 months
Objective response rate 29.1% 27.4%
Clinical Benefit 47% 36%
Adverse events 38% 42%
• Objective response rate was defined as the percentage of patients with a complete response or partial
response.
• Clinical benefit was defined as the percentage of patients with a complete response, partial response, or
stable disease for more than 12 weeks.
• Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version
3.0, of the National Cancer Institute

25. LIMITATIONS
• Enrolled patients were appropriate candidate for nephrectomy in the
opinion of the treating urologist, therefore the results could not be
generally applied to patients not suitable for nephrectomy
• The use of MSKCC risk groups, rather than IMDC, as it was in common
use at the time the trial was launched, was an unavoidable limitation.

26. LIMITATIONS
• Because this was a non inferiority trial , the results may underestimate
the benefits of nephrectomy.
• Another imitation of this trial is the recruitment of fewer patients than
planned (450 patients rather than 576), which reduced the statistical
power.
• However, the trend in longer overall survival and progression free
survival among patients who did not undergo nephrectomy suggests
that their conclusion is correct.

27. CONCLUSION
• Sunitinib alone was not inferior to nephrectomy followed by sunitinib in
patients with mRCC who were in the MSKCC intermediate or poor risk
group.

28. SURTIME

29. SURTIME

30. RESULTS
• 5.7 years
• Sample size – 99
• Systemic progression before planned CN in the deferred CN arm resulted in
deferred nephrectomy in 14 patients (29%)
Immediate DEFERRED CN
PFR 42% 43%
OS 15 32.4
Systemic
therapy
40/50 48/49
• Progression-free survival (PFS) is the interval from randomization to first progression (local or distant) or
death from any cause.
• Overall survival was counted from randomization to death from any cause
• The 28-week progression-free rate (PFR) was calculated as the binomial proportion of cases of disease
progression documented before or at week 28

31. RESULTS

32. LIMITATIONS
• Study has poor accrual
• 18% of patients were ineligible, although reasons were unrelated to
performance, surgical risk factors, or oncologic eligibility criteria.
• With hindsight, PFS and PFR end points required complex timing, and OS as
the primary end point would have been preferable.
• Finally, the superiority of nivolumab and ipilimumab over sunitinib in terms of
survival and quality of life changes first-line treatment for patients with
intermediate and poor-risk mRCC

33. CONCLUSION
• Deferred CN did not improve the 28-week PFR.
• With the deferred approach, more patients received sunitinib and OS
was higher (although this finding was not statistically significant).
• Pretreatment with sunitinib may identify patients with inherent
resistance to systemic therapy before planned CN.

34. CURRENT INDICATION

35. IMMUNO-ONCOLOGY
• Check Point Inhibitors
• CheckMate 214 trial

36. CHECKMATE 214

37. IOVE
• Combinations of IO and VEGF-targeted therapy

38. In comparing IOVE to ipi-nivo, a recent retrospective review found
• No significant differences in first-line outcomes, such as time to
treatment failure,
• But suggested a greater response to second-line VEGF based therapy
when ipi-nivo was used as the first-line treatment
Further trials are needed to re-evaluate the role of CN with these more
potent therapies.

39. CN ROLE IN METASTATIC NON –CLEAR
RCC
• Majority studies excluded Non clear RCC
• Some retrospective studies have been done
• All have shown median overall survival advantage in CN group
• Rigorous RCT still not done

40. EUA

41. EUA

42. CONCLUSION
CN may still be beneficial
• Good performance status, low volume, favourable risk
• Don’t require urgent systemic therapy
• Favourable or intermediate risk who respond to systemic therapy
• Symptomatic patients
CN in IO/IOVE era require further evaluation

43. THANKS