EARLY Renal Cell Cancer Management

1. *HIGHLIGHTS FOR RENAL CELL CANCER*

2. -RCC:
-More common in:
 Men
 African Americans,
 American Indian populations.
https://seer.cancer.gov/statfacts/html/kidrp.ht
-JORDANIAN VALUES 2020:
INCIDENCE:226 – RANK:15
TH-%:2
DEATH NUMBER:109-
RANK:15TH-%:2

3. -PER STAGE:

4. -PATHOLOGY
• Clear cell carcinoma (75-85%)
Most common RCC
Arise from proximal tubules
Majority are sporadic
90% associated with Loss of chromosome 3p
Worse prognosis is associated with higher nuclear grade
or the presence of a sarcomatoid pattern
• Papillary carcinoma (10-15%)
Type I (favorable prognosis, early stage at presentation)
Type II (poor prognosis, advanced stage at presentation)

5. PATHOLOGY
– Chromophobe carcinoma (5-10%, favorable prognosis, early
stage at presentation)
• Oncocytoma (3-7%, benign, rarely metastatic, 10-
30% synchronous RCC)
Single / unilateral tumors: sporadic
Multiple / bilateral tumors: familial (TSC and BHD syndrome)
• Collecting duct tumors (rare, aggressive, advanced
stage at presentation, medullary variant is
associated with sickle cell disease)
• Translocation renal cell carcinoma (rare, median age
is 24 and advanced stage at presentation, associated
with previous chemotherapy exposure, associated
with TFE3 gene fusions)

6. -RISK FACTORS:
• Smoking
• Hypertension
• Obesity
• Chemotherapy
• Sickle cell disease
• Chronic Hepatitis C infection
• CKD and acquired polycystic disease
• Occupational exposure: cadmium, asbestos, and
petroleum byproducts
• Genetic predisposition

7. -FAMILIAL SYNDROMES:
• VHL disease:
Autosomal dominant inheritance
Associated with clear cell RCC, pancreatic neuroendocrine tumors,
pheochromocytomas, CNS hemangioblastomas, retinal angiomas ---
Germline mutation in VHL tumor suppressor gene on Chromosome 3p
• Hereditary papillary RCC:
Autosomal dominant inheritance
Associated with bilateral and multifocal Type I papillary RCC
Germline mutation in MET proto-oncogene, located on long arm of chrom. 7
• Hereditary leiomyomatosis and RCC (Reed’s syndrome):
Autosomal dominant inheritance
Associated with Type II papillary RCC, cutaneous and uterus leiomyomas
Germline mutation in Fumarate Hydratase (FH) tumor suppressor gene

8. -FAMILIAL SYNDROMES:
• Birt-Hogg-Dube syndrome:
Autosomal dominant inheritance
Associated with cutaneous fibrofolliculomas, most commonly located
on the head and neck, pulmonary cysts and spontaneous
pneumothorax
Wide range of tumor histologies, most commonly chromophobe tumors
and hybrid chromophobe/oncocytoma tumors
Germline pathogenic variants in the folliculin (FLCN) gene, located on
chromosome 17
• Succinate dehydrogenase deficiency (SDH) associated RCC
Autosomal dominant inheritance
Associated with pheochromocytoma, paragangliomas, and variant
histologies of RCC

9. -CLINICAL PRESENTATION:
• 10% present with the classic triad of flank pain,
hematuria, and a palpable abdominal renal mass
• Paraneoplastic symptoms include:
Anemia AND Erythrocytosis - Thrombocytosis
Cachexia
Fever in 20% of patients
Reversible hepatic dysfunction in the absence of
liver mets (stauffer’s syndrome)
Hypercalcemia (lytic bone mets, PTHrP ectopic
overproduction)

10. -INITIAL STAGING:
• Abdomen-Pelvis CT scan
• Chest x-ray, chest CT scan only if symptoms or
abnormal chest x-ray (NCCN)
Chest CT (ESMO)
• Bone scan if :symptoms, hypercalcemia,
elevated ALP
• Brain MRI if symptoms
• PET/CT is not routinely used (sensitivity of CT
vs PET for detection of RCC is 91.7% vs. 60%)
• Genetic testing : if age at diagnosis is ≤ 46,
bilateral or multifocal tumors, ≥1 first or second
degree relatives with RCC (NCCN)

11. . ..
.

14. -RISK ASSESSMENT IN METASTATIC
DISEASE:

15. -
TREATMENT
:
A.LOCALIZED
B.METASTATIC

16. A-LOCALIZED RCC TREATMENT:
• Partial nephrectomy preferred if ≤7cm tumors OR at
high risk for renal impairment
• Radical nephrectomy preferred if >7cm tumors
Partial vs radical nephrectomy (11204
patients)
Better post-op renal function
More blood loss and post-op
complications
Better all-cause mortality in
tumors ≤ 7cm
Same all-cause mortality in
tumors > 7cm

17. -Thermal ablation:
Cryoablation or RFA for ≤4cm
tumors
Associated with higher local
recurrences compared
-Active surveillance:
For ≤4cm tumors
Same cancer-specific mortality
rate compared to surgery
Higher all-cause mortality rate
compared to surgery
(5-year OS: 75% vs 92)%)

18. ADJUVANT?

19. LOCALIZED RCC
TREATMENT: ADJUVANT?
• Adjuvant Axitinib - phase III Atlas trial
• Adjuvant Sorafinib - phase III Sorce trial
• Adjuvant Pazopanib - phase III Protect trial
• * * * * * * *
• Adjuvant Sunitinib -Phase III S-TRAC
. ADJUVANT PEMBROLIZUMAB- KEYNTOE 564

20. -Adjuvant Pazopanib - phase III Protect trial

22. Adjuvant Axitinib - phase III Atlas trial

24. -Adjuvant Sorafinib - phase III Sorce

26. A. Phase III (S-TRAC trial ) :ADJUVANT
SUNITINIB
B.Phase III (KEYNTOE-564) :
ADJUVANT PEMBROLIZUMAB

30. MEDIAN DFS 6.8 YRS VS 5.6

31. -KEYNTOE 564 – ADJUVANT
PEMBROLIZUMAB:
Primary endpoint: PFS
-Clear cell RCC + high risk of
recurrence
(N = 994) (1:1
randomization)
Pembrolizumab
200mg IV Q3w for 1 year
Placebo
High risk of recurrence definition:
• T2 + tumor grade IV or sarcomatoid
differentiation
• T3, T4
• Regional LN involvement
• Oligometastatic disease [metastectomy
within 1 year of nephrectomy] 5% of trial

32. -LOCALIZED RCC TREATMENT – ADJUVANT
PEMBROLIZUMAB:
24-m DFS
77.3% vs
68.1%

33. -LOCALIZED RCC TREATMENT – ADJUVANT
PEMBROLIZUMAB:
Immature OS
Data
-Grade 3 or higher adverse events:
19% vs 1%

34. -CONCLUSION FOR ADJUVANT TTT IN HIGH
RISK- RCC:
1-S-TRAC TRIAL : SHOWED THAT MEDIAN DFS 6.8
YRS VS 5.6 FOR ADJUVANT SUNITINIB VS.
OBSERVATION – ANYWAY No OS benefit AND
Increased Toxicity (Dose interruptions 46.4% vs
13.2% & Discontinuations 28.1% vs 5.6%)
FDA approved – category 3 in NCCN (50mg PO
daily, 4 weeks on/2 weeks off for 1 year)
2. KEYNTOE 564 :SHOWED THAT 24-m DFS 77.3% vs
68.1% FOR ADJUVANT PEMBROLIZUMAB VS.
OBSERVATION

35. B.METASTATIC RCC MANAGEMENT:
1- Active Surveillance :
2- Oligometastatic Disease Management
3- Role of Cytoreductive Nephrectomy(CN)
4- First line treatment options:
– Immune checkpoint inhibitors
combinations
– TKIs
– Active surveillance
5- Subsequent line treatment options

36. -ACTIVE SURVEILLANCE:
Active surveillance is an acceptable treatment approach
for selected treatment-naive patients who have
favorable-risk disease & are asymptomatic with limited
disease burden.
CAP CT Q3m for the first year, Q4m for the second
year, and Q6m thereafter.
Phase II multinational prospective
trial, 48 patients
median time on surveillance until
initiation of systemic therapy was
longer for those with favorable-risk
disease relative to those with
intermediate- or poor-risk disease (22
versus 9 months)

37. -OLIGOMETASTATIC DISEASE:
• Retrospective study – 278 patients
• 51% curative metastectomy, 25% partial resection of
mets and 24% treated without surgery
• 5-year OS: 44% vs 14% vs 11%
• Favorable predictors for prolonged OS:
-DFS after nephrectomy>1 year [5-year OS:
55% vs 9% ]
-single site mets [5-year OS: 54% vs 29% ]

38. -OLIGOMETASTATIC DISEASE
-Adjuvant therapy AFTER Metastectomy:
• Sorafinib – phase II Resort trial
• Pazopanib – phase III ECOG-ACRIN research
group trial
• Pembrolizumab
KEYNOTE-564 : FDA approved for oligometastatic
disease [metastectomy within 1 year of
nephrectomy]

39. -LOCALIZED RCC TREATMENT –
ADJUVANT PEMBROLIZUMAB:
Primary endpoint: PFS
Clear cell RCC + high risk of
recurrence
(N = 994) (1:1 randomization)
Pembrolizumab
200mg IV Q3w for 1 year
Placebo
High risk of recurrence definition:
• T2 + tumor grade IV or sarcomatoid differentiation
• T3, T4
• Regional LN involvement
• Oligometastatic disease [metastectomy within 1
year of nephrectomy] 5% of trial population
KEYNTOE-564

40. ROLE OF
RADIOTHERAPY IN
OLIGOMETASTASIS
NOT CANDIDATE FOR
SRUGICAL
METASTECTOMY?

41. -OLIGOMETASTATIC DISEASE: RTX
Future treatment options
• Single-arm phase II trial at MD
Anderson cancer center 30
patients
• Eligibility: 1-5 oligomets ccRCC +
ECOG PS 0-2 + prior
nephrectomy
• Intervention: SBRT (≤5 Fx with
≥7 Gy per Fx)
• Median PFS: 22 months

42. -OLIGOMETASTATIC DISEASE:RTX
Future treatment options
• Single-arm multi-institutional phase
I/II trial (30 patients)
• Eligiblity: 1-5 oligomets ccRCC
• Intervention: 20 Gy/1Fx SABR,
followed by Pembrolizumab 200 mg
Q3W for eight cycles
• 44% intermediate-risk + 56%
favorable-risk disease
• ORR : 63% and DCR: 83%
• Estimated 1- and 2-yr PFS: 60% and

43. -CONCLUSION FOR OLIGOMETASIS
MANAGEMENT:
SEVERAL RETROSPECTIVE TRIALS
SHOWED CONFIRMED BENEFITS OF
OLIGOMETASTECTOMY ESPECIALLY
IN THE FOLLOWING SITUATIONS:
1-DFS after nephrectomy>1 year
[5-year OS: 55% vs 9% ]
2-single site mets [5-year OS: 54% vs
29% ]
-ONLY PEMBROLIZUMAB (KEYNTOE-
564 )SHOWED INCREASED DFS IN :
[metastectomy within 1 year of
nephrectomy] 5% of trial population

45. -Esmo guidleines for
oligometastsis:

46. CYTOREDUCTI
VE
NEPHRECTOMY
?

52. CYTOREDUCTIVE
NEPHRECTOMY 1
IMDC RF
METASTATIC
SITE