Management Guidelines with evidence for management of Renal cell carcinoma Various Trials included Guidelines included

1. Management of Renal Cell
Carcinoma
Dr Atul Gupta
DM Resident
Radiotherapy & Oncology
AIIMS Jodhpur

2.  Renal cell carcinoma (RCC) accounts for approximately 4% of adult malignancies, including approximately 90% of primary
renal tumors.
 Male Predominance (M:F= 1.5:1)
 Most Common in 6th-8th decade
 Metastatic disease in 30% at diagnosis, eventually in 50% (lung, liver, bone, distant nodes, adrenal, brain, opposite kidney)
 Most sporadic RCCs are U/L and unifocal
 Predominant histological type- Adenocarcinoma arising from tubular epithelium
 Adenocarcinoma subtypes- Clear Cell (75-85%), Papillary (10-15%), Chromophobe (5-10%), Sarcomatoid (1-6%, poor
prognosis)
Introduction -

4. Management of Localized Renal Cell
Carcinoma

5. 1. Radical Nephrectomy
2. Partial Nephrectomy
3. Thermal Ablation
4. Active Surveillance
* Each option has associated benefits and risks. None approach is best in all circumstances
Treatment Options Available for localized RCC-

6. Radical Nephrectomy-
Original RN - includes extra-fascial nephrectomy, I/L adrenalectomy and extended lymphadenectomy
* I/L Adrenalectomy- no longer recommended unless there is suspicion of direct invasion of gland by
tumor/radiographically invasion present (Similar propensity of RCC to metastasize to I/L and C/L adrenal gland)
* No therapeutic benefit of extended lymphadenectomy for patients with clinically localized RCC (risk of cN0- pN+
<5%)
(Role in high risk – controversial)

7.  When performing LND, the para-caval and
inter-aortocaval lymph nodes be removed
in patients with right-sided tumors and the
para-aortic and inter-aortocaval lymph
nodes be removed in patients with left-
sided tumors from the crus of the
diaphragm to the common iliac artery.
 No Level 1 evidence for RPLND.

8. Advantages Disadvantages Main Indications
Open Radical
Nephrectomy (ORN)
Traditional surgical approach
for renal cancer, effective in
removing tumor with
surrounding structures and
lymph nodes when indicated
 Morbidity of surgical incision
(flank, subcostal, midline,
thoracoabdominal)
 Renal functional implications of
removing entire kidney (average
35% decrease in GFR)
 Large tumor (>12 cm)
 Locally advanced tumor
 Tumor thrombus
 Bulky adenopathy
Minimal Invasive Radical
Nephrectomy (MIRN)
Reproducible and effective
surgery for most localized
renal tumors MIS, with
decreased pain, morbidity, and
convalescence compared to
ORN
 Some tumors (up to 7 cm or
larger) can be treated with PN
 Renal functional implications of
removing entire kidney (average
35% decrease in GFR)
 Medium to large tumor
(up to 10 to 12 cm)
 High tumor complexity

9. Partial Nephrectomy -
 Kidney sparing surgery –compete local resection of tumor while leaving largest possible amount of normal functioning
parenchyma in involved kidney
 Indicated in conditions that impose a threat to future renal function as HTN , DM, CAD, PAD, Nephrolithiasis,
Abnormal C/L kidney, multifocal/familial RCC
 Generally considered feasible for masses <5cm
 Leads to improve functional outcome even for complicated situation
 Temporary/Permanent RRT needed in <5% patients with solitary kidney (Rarely with C/L functioning kidney)
 Cancer specific survival post PN- T1a - >98% , T1b – 90%, T2- 86% ¹
1. Campbell S, Uzzo RG, Allaf ME, et al. Renal mass and localized renal cancer: AUA guideline

10. Advantages Disadvantages Main Indications
Open Partial Nephrectomy
(OPN)
 Oncologic outcomes
appear similar to RN,
although selection biases
limit this conclusion
 Maximizes renal functional
preservation when
performed with precise
tumor excision and
judicious use of regional
hypothermia
 Morbidity of flank incision
(bulge, longer recovery
than with MIS)
 Potential for local
recurrence due to
incomplete excision or de
novo tumors in the renal
remnant
 Small to medium tumors
(up to 7 cm and
occasionally larger)
 Moderate to high-
complexity tumors
Minimal Invasive Partial
Nephrectomy
(MIPN)
 Kidney-sparing surgery,
with maximal preservation
of renal function when
warm ischemia kept to
limited duration
 Higher complication rate
for high complexity tumors
and in less-experienced
hands
 Positive surgical margins
and local recurrence rates
may be higher than with
OPN in such situations
 Small renal masses (up to 5
cm and occasionally larger)
 Low to moderate (and
selected high) complexity
tumors

11. Is there a functional advantage of PN ?-
Risk of CKD –
Radical vs Partial Nephrectomy -
At 5 years -15% vs 0%
(McKernion et al, Urology, 59:816,2002)
At 10 years – 22.4% vs 11.6%
(Leu et al, Mayo Clin.Proc., 75:1236,2000)
Huang et al, a retrospective cohort study. Lancet Oncol. 2006
Sep;7(9):735-40. doi: 10.1016/S1470-2045(06)70803-8. PMID:
16945768; PMCID: PMC2239298.

12. Thermal Ablation -
 Thermal Ablation includes- Renal Cryosurgery and RFA (for small tumors <= 3cm)
 Long term efficacy – not well established
 A contemporary series from the Mayo Clinic recently reported the largest experience of thermal ablation with a median
follow-up greater than 5 years, noting no significant differences in oncological outcomes for cT1a renal masses when TA
was compared to PN. ¹
Ideal Candidate for TA-
• Advanced age and/or significant comorbidities who prefer a proactive approach (over surveillance) but are not optimal
candidates for conventional surgery,
• Patients with local recurrence after previous kidney-sparing treatments (PN or TA), and
• Patients with hereditary renal cancer who present with multifocal lesions for which multiple PNs might be place their
renal unit and therefore function at risk
1. Andrews JR, Atwell T, Schmit G, et al. Oncologic outcomes following partial nephrectomy and percutaneous
ablation for cT1 renal masses. Eur Urol 2019;76(2):244–251

13.  Tumor size and location are important factors in patient selection because the current technology does not allow for
reliable treatment of lesions >4 cm and those that are very anterior. Success rates appear to be highest for posterior
tumors
 Both ASCO and AUA guidelines (2020) recommends that TA is an alternate approach for the management of cT1a renal
masses .

14. Active Surveillance -
 Data have emerged to suggest that radiographically localized small renal masses, most of which are RCC exhibit slow
linear/volumetric growth (0.3 cm/year on average) with a low metastatic potential (1.1% to 1.4%) over the first 24 to 36
months following diagnosis.
 Moreover, in patients with localized small renal tumors at diagnosis, the risk of metastases appears to be related to both
the size of the primary tumor and perhaps more importantly the growth kinetics of the lesion.
 Interestingly, as many as 20% to 30% of small renal tumors exhibit zero radiographic growth over the initial 24 months
following their incidental detection.
 Given these data, AS with delayed intervention has been endorsed by existing practice guidelines for the management
of patients with lesions (Bosniak 3/4), and in those where the competing risks of death outweigh the benefit of active
oncological treatment.
 This practice is a calculated risk accepted by the patient and managed by the physician, utilizing serial imaging (every 3
to 6 months) where the oncological safety of AS is continuously re-evaluated.

15. Recommendation Strength
Perform a renal tumor biopsy before ablative therapy and systemic therapy without previous
pathology
Strong
Offer surgery to achieve cure in localized RCC Strong
Offer PN to patients with T1 tumours Strong
Offer PN to patients with T2 tumours and a solitary kidney or chronic kidney disease, if technically
feasible
Weak
Do not perform ipsilateral adrenalectomy if there is no clinical evidence of invasion of the adrenal
gland
Strong
Do not offer systematic lymph node dissection to patients with organ-confined disease Weak
Offer laparoscopic RN to patients with T2 tumors and localized masses not treatable with PN Strong
During nephrectomy remove clinically enlarged lymph nodes for staging, prognosis, and follow-up
implications
Weak
Remove the renal tumour and thrombus in cases of venous involvement in nonmetastatic disease Strong

16. Management of Locally Advanced RCC

17.  Renal tumors – unique in their ability to form tumor thrombus that can propagate from I/L Renal Vein to IVC to right Atrium
 ˜4-10% patients who present with RCC – have a concomitant tumor thrombus
 Tumor thrombus should be suspected in patients with – 1. New Onset Lower Limb Edema
2. Isolated right side varicocele
3. Dilated superficial abdominal veins
4. Proteinuria
5. Pulmonary Embolism
 5 year Cancer specific survival for patients with RCC and venous extension- 45-70%
 Patients with N0M0 and tumor thrombus at any level- may be cured with surgical resection
 Clinical Variables a/w survival following surgery in patients with tumor thrombus –
1.Level of thrombus- Level 1 & 2- better outcome
2. Papillary Histology and fat invasion- independent poor CSS indicators
 Peri-operative mortality rate s/w RN and IVC thrombectomy- 5-10%
 SBRT can be considered in symptom palliation in patients with intractable edema, ascites and cardiac/liver dysfunction
Surgery for Tumor Thrombus in IVC-

18.  Predictors of complex vascular reconstruction- (Psutka et al)-
1. Right sided tumor thrombus
2. AP diameter of IVC at renal ostium >34mm
3. Radiographic evidence of complete IVC occlusion
 In an effort to downsize the tumor thrombus and lessen the surgical morbidity, neoadjuvant treatment with
targeted agents has been studied with inconsistent and disappointing results.
 In the largest study, which included 25 patients with level III/IV thrombi, use of targeted agents had a
minimal effect in downsizing the tumor thrombi in any surgically meaningful measure.¹
1. Cost NG, Delacroix SE Jr., Sleeper JP, et al. The impact of targeted molecular therapies on the level of
renal cell carcinoma vena caval tumor thrombus. Eur Urol 2011;59(6):912–918.

20. Adjuvant Therapy in RCC -
 Localized RCC after surgical resection- 20-35% risk of distant mets & 2-5% risk of local recurrence
 Locally advanced RCC with high risk features- greatest risk of recurrence
 Prior trial evaluated hormonal therapy, RT , immunotherapy and tumor vaccines- negative results

21. Trial Name Study Population Treatment
Duration
Inclusion Criteria Results
ASSURE: Adjuvant Sorafenib
or Sunitinib for Unfavorable
Renal Cell Carcinoma
Sunitinib vs sorafenib vs
placebo
1 y Clear cell and non–clear cell RCC eligible
pT1b and G3-4; pT2/pT3/pT4; N1 if
complete dissection performed
No difference in DFS: Sunitinib (1.02 [CI
0.85-1.23], P = 0.80); Sorafenib (0.97 [CI
0.80-1.23], P = 0.72)
Median DFS: Sunitinib (5.8 yrs) vs
Sorafenib (6.1 yrs) vs placebo (6.6 yrs)
No difference in OS Median OS:
Sunitinib (77.9%) vs Sorafenib (80.5%)
vs placebo (80.3%)
SORCE: Sorafenib for Patients
with Resected Primary Renal
Cell Carcinoma
Sorafenib (for 1 or 3 y) vs
placebo
3 y Clear cell and non–clear cell RCC eligible
Mayo Clinic progression score 3–11
No difference is DFS: (1.01 [CI 0.83 to
1.23], P = 0.95. More than half of
participants stopped treatment by 12
months due to adverse side effects.
S-TRAC: Sunitinib vs. Placebo
for the Treatment of Patients
at high risk for Recurrent Renal
Cell Cancer
Sunitinib vs placebo 1 y Clear cell predominant histology eligible
High-risk RCC according to UISS
Modest Improvement in DFS: Sunitinib
(0.76, [CI 0.59–0.98] P = 0.03) Median
DFS: Sunitinib (6.8 yrs) vs placebo (5.6
year
EVEREST: Everolimus for
Renal Cancer Ensuing Surgical
Therapy
Everolimus vs placebo 1 y Clear cell and non–clear cell RCC eligible
pT1b and G3-4; pT2/pT3/pT4; N1 if
complete dissection performed
Not reported
ATLAS: Adjuvant Axitinib
Treatment of Renal Cancer
Axitinib vs placebo 3 y Clear cell predominant (>50%) eligible pT2
and G3-4; pT3a and >4 cm;
pT3b/pT3c/pT4; N1
No difference in DFS (0.87 [CI 0.66–
1.15], p = 0.32)
No difference DFS in the high-risk
population (0.735, [CI 0.525–1.028], P =
0.070)

22. PROTECT: Pazopanib as an
Adjuvant Treatment for Locally
Advanced Renal Cell
Carcinoma
Pazopanib vs placebo 1 y Clear cell predominant
(>50%) eligible pT2 and
G3-4; pT3/pT4; N1
Study broken in two groups due to toxicity: 600 mg group
(74%): No difference in DFS (HR 0.94 [CI 0.77- 1.14] P = 0.51).
Median DFS: Not reached in either arm 800 mg group (26%):
Improvement in DFS (HR 0.69 [CI 0.51- 0.94] P = 0.02), but at
the expense of increased toxicity. Median DFS: Not reached in
treatment group and 54 months in placebo
PROSPER:
Neoadjuvant/Adjuvant
nivolumab (antiPD-L1)
Arm 1: nivolumab →
nephrectomy → nivolumab
Arm 2: Nephrectomy alone
6
month
s
All RCC Histologies
including sarcomatoid;
T2NxM0 or TanyN+
disease; ECOG 0–1
Not reported
Keynote 564: Adjuvant
prembrolizumab (anti-PD-1), in
high-risk patients
Pembrolizumab vs placebo 1 y RCC with clear cell or
sarcomatoid
component; Leibovich
progression score 4–11
(pT2 Grade
4/sarcomatoid, pT3-
4N0, pTanyN+M0;
pTanyM1) M1*
Completely Resected
Significant improvement in DFS (0.68 [0.53 to 0.87], P = 0.002)
at 2-year follow-up. Grade 3 or greater AEs was observed in
32.4% of patients.
CHECKMATE 914:
Adjuvant nivolumab (anti-PD-
1) plus ipilimumab (anti-CTLA-
4)
Nivolumab +ipilimumab vs Pla 24
weeks
RCC with clear cell or
sarcomatoid
component; Leibovich
progression score 3–11
(pT2a Grade 3/4 only; ≥
pT2b Grade any;
pTanyN+)
Recruiting

23. Management of Advanced RCC

24. Surgical Management -
 Surgical Management Includes- Cytoreductive Nephrectomy
 Prior to introduction of targeted therapy- CN was recommended for M1 disease
 Current trend- decreasing in favor of CN
 Recent Recommendation – Trial of systemic therapy as a litmus test for CN may aid in patient selection
Risk of surgery should be weighed against disease biology before proceeding with surgery
 CARMENA Trial (2018)- Upfront CN f/b sunitinib vs Sunitinib alone in M1 RCC
Result- Sunitinib alone was non-inferior to the CN-sunitinib group (HR 0.89; 95% CI [0.71 to 1.10])
 SURTIME Trial (2010)- Sunitinib f/b CN vs CN f/b sunitinib
Result- Sequence of targeted therapy has no effect on DFS

25. Role of Metastatectomy in mRCC -
 The surgical resection of a solitary metastasis can be associated with long-term survival in selected patients
with mRCC.
 Retrospective, single-institution analysis of patients at the MSKCC analyzed role of metastatectomy in mRCC-
The 5-year OS rate of patients who underwent curative intent resection for the first recurrence was
44% (n = 141), compared with 14% for those who received noncurative intent resection (n = 70), and 11% for those who were
treated non-surgically (n = 67).
• Favorable predictors of survival by multivariate analysis included a single site of first recurrence, curative intent resection,
and a disease-free interval of more than 12 months.
• The site of metastatic disease also has implications for survival.
• Resection of metastasis to soft tissue (75%) > Resection of glandular tissue (thyroid, salivary gland, pancreas, adrenal,
ovary) (63%) > resection of isolated lung metastases (54%) > Resection of solitary brain metastases (18%)
 Currently, surveillance is recommended after complete resection of metastatic disease in RCC; systemic therapy should be
reserved for patients with residual measurable disease.

26. Role of bone-modifying agents for patients with skeletal metastases -
 Bone-modifying agents can be considered for patients with bone metastases to decrease skeletal-related
events (SRE).
 In a phase 3 trial of zoledronic acid (ZA) vs. placebo, a subset analysis of 74 mRCC patients showed that
administration of ZA compared to placebo resulted in a significant decrease in SREs in the ZA group . Thus,
monthly administration of ZA is a reasonable option. Careful monitoring of renal function is required. ¹
 Denosumab is an inhibitor of the receptor activator of nuclear factor kappa-B (RANK) ligand. In a phase 3 trial of
denosumab vs. ZA for treatment of malignancy with bone metastases (excluding breast or prostate cancer
patients), a subset of patients enrolled in this trial had mRCC. This trial demonstrated non-inferiority for
denosumab compared to ZA in terms of SRE reduction for the group overall, although no subgroup analysis for RCC
patients was done. Thus, denosumab could also be considered a reasonable option for this population of patients,
particularly those with impaired renal function obviating bisphosphonate use. ²
1. Lipton A, Colombo-Berra A, Bukowski RM, et al. Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic
acid. Clin Cancer Res. 2004;10:S6397–403. doi: 10.1158/1078-0432.CCR-040030
2. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab vs. zoledronic acid in the treatment of bone metastases in patients with advanced
cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125–32. doi: 10.1200/JCO.2010.31.3304.

27. Role of local therapy in oligo-progression :-
 Local therapy may be considered in the setting of oligo-progression.
 There are no randomized trials for the management of metastatic RCC patients with sites of oligo-progression.
 Treatment with local therapy (surgery, SBRT, cryotherapy, and/or radiofrequency ablation [RFA]) can be
considered, with the goal of delaying the need to start or change systemic therapy. Such an approach has
previously been studied primarily in metastatic non-small-cell lung cancer patients who developed oligo-
progression while on TKIs.¹
1. Cheung P, Patel S, North SA, et al. A phase 2 multicenter study of stereotactic radiotherapy (SRT) for oligoprogression in metastatic renal cell
cancer (mRCC) patients receiving tyrosine kinase inhibitor (TKI) therapy. J Clin Oncol. 2020;38 Abstract 5065. ASCO 2020.

28. Role of Neo-Adjuvant Therapy in LA RCC/mRCC -
 Neoadjuvant use of VEGF-targeted therapy has been tested in multicenter studies before cytoreductive nephrectomy to
assess the response to antiangiogenic therapy and to improve local resect-ability
 Of greatest concern for this approach is the increased risk of perioperative complications.
 Powles and colleagues reported a 13% rate of delayed wound complications from two phase II trials of neoadjuvant
sunitinib in the metastatic setting. ¹
 In the neoadjuvant pazopanib study, none of the patients experienced wound healing complications, supporting the safe
use of these agents in the perioperative setting.²
 Although the safety in these studies was deemed acceptable, the efficacy was much less clear. Review of several studies
revealed that 50% to 90% of patients demonstrated some degree of tumor regression in the primary lesion; however, the
degree of regression varied from 9% to 26% from baseline, which is of unclear clinical significance.
 At this time, a neoadjuvant therapeutic approach should be considered only in a clinical trial setting or when patients are
not initially deemed surgical candidates.
1. Powles T, et al. Safety and efficacy of pazopanib therapy prior to planned nephrectomy in metastatic clear cell renal cancer. JAMA Oncol. 2016;2(10): 1303–1309.
2. Rini BI, et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol. 2015;194:297–303.

29. Systemic Therapy for Advanced RCC-
Schema Factors
MSKCC ■ KPS <80
■ High lactate dehydrogenase >1.5 times of ULN
■ Low serum hemoglobin
■ High corrected serum calcium
■ Time from initial RCC diagnosis to start of therapy <1yr
IMDC
International
Metastatic
Renal Cell
Carcinoma
Database
Consortium
(IMDC) Criteria
■ KPS <80
■ Low serum hemoglobin
■ High corrected serum calcium
■ Time from initial RCC diagnosis to start of therapy < 1 yr
■Elevated Neutrophils
■Elevated Platelets
Prognostic Systems in Metastatic Renal Cell Carcinoma : -
Prognostic Risk Groups
• Low-risk group: no prognostic factors
• Intermediate-risk group: one or two
prognostic factors
• Poor-risk group: three or more prognostic
factors
• Favorable-risk group: no prognostic factors
• Intermediate-risk group: one or two
prognostic factors
• Poor-risk group: three to six prognostic factors

31. Current First Line Therapy options for mRCC -
 Front Line Therapy – Doublet Therapy (anti-PDL1 Ab + Anti- CTLA-4 Ab or VEGF TKI)
 VEGF TKI options – Sunitinib
Pazopanib
Axitinib
Cabozantinib
Lenvatinib
 TKI containing regimen – a/w more tumor shrinkage
 Ipi/Nivo combination – a/w more durable response
Not compared with each other
Choice depends on toxicity, cost ,com-
morbidities etc

32. Second Line Therapy options-
 After Failure of 1st line IO containing regimen – either single agent VEGF TKI or Lenvatinib + Everolimus
 Cabozantinib – multi-kinase inhibitor targeted at VEGFR, MET, AXL (very commonly used in refractory setting)
 Cabozantinib vs Everolimus – Better OS/PFS/ORR with Cabozantinib¹
 Role of Axitinib – (Phase III AXIS Trial)- in metastatic RCC refractory to Sunitinib, Cytokines, Bev ,
Temsirolimus
1. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell
carcinoma. N Engl J Med 2015;373(19):1814–1823.
Axitinib vs Sorafenib
Good PFS with Axitinib
FDA Approval for previously treated mRCC

33.  Role of Everolimus – Phase III Study¹
mRCC treated with Sorafenib/Sunitinib both
Everolimus vs Placebo
Median PFS better with Everolimus
 mRCC with progression on/within 9 months of stopping VEGF targeted therapy – Lenvatinib vs Everolimus vs Lenva +
Everolimus
Significantly improved PFS with Lenvatinib with Everolimus as compared to Everolimus alone
1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med
2015;373(19):1803–1813.

36.  In patients with advanced or metastatic sarcomatoid or poorly differentiated RCC, strong preference is
to use immunotherapy-based therapies. In patients who are not candidates for immunotherapy,
sunitinib can be considered.

39. First line treatment of metastatic clear-cell RCC.
Second line treatment of metastatic clear-cell
RCC.

42. What’s New in mRCC ?-

43.  In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib
provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile.
(18 months vs 9.9months)(HR=0.61)
 An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92).

44. The Hypoxia-Inducible Factor (HIF) pathway is central to the pathophysiology of ccRCC and von Hippel-Lindau (VHL) disease.
Belzutifan, a model of bench to bedside development, is a first-in-class oral HIF-2a inhibitor that block heterodimerization
with HIF-1B and downstream oncogenic pathways.
Belzutifan demonstrated a statistically significant improvement in progression-free survival and objective response rate
survival and objective response rate versus everolimus
There appears to be a 25% reduction in risk for progression or death with belzutifan versus everolimus

45. Thanks