mrcc

1. METASTATIC RENAL CELL
CARCINOMA

2. Introduction
 Metastatic renal cell carcinoma (mRCC) is one of the most
treatment-resistant malignancies; outcomes are generally
poor and median survival after diagnosis is less than one
year.
 Surgery and chemotherapy have limited or no effect, leaving
mRCC patients underserved in the realm of cancer treatment.
 RCC is the most common cancer of the kidney, accounting
for 85% of renal tumours

3. Introduction
 According to the American Cancer Society estimates, RCC is
the seventh most common cancer and is the tenth leading
cause for cancer-specific deaths.
 As the world’s population ages and the prevalence of risk
factors (obesity, hypertension) increases, the burden of
mRCC is predicted to increase significantly.
 With a shift in treatment of mRCC to novel therapies, such as
molecularly targeted therapies (MTTs) (e.g., sorafenib and
sunitinib), clinicians, payers, and other healthcare decision-
makers must re-evaluate the optimal role for new treatments

4. Introduction
RCC is made up of number of different types of cancers with
different histology, different clinical courses and caused by
different gene
Clear cell
75%
Type
Incidence (%)
Associated
mutations
VHL
Papillary type 1
5%
c-Met
Papillary type 2
10%
FH
Chromophobe
5%
BHD
Oncocytoma
5%
BHD
A sarcomatoid variant represents1% to 6% of renal cell
carcinoma and these tumours are associated with a significantly
poorer prognosis

5. Pathophysiology
 The tissue of origin for RCC is the proximal renal tubular
epithelium.
 Renal cancer occurs in a sporadic (nonhereditary) and a
hereditary form, and both forms are associated with structural
alterations of the short arm of chromosome 3 (3p).
 Genetic studies of the families at high risk for developing
renal cancer led to the cloning of genes whose alteration
results in tumour formation.
 These genes are either tumour suppressors (VHL, TSC) or
oncogenes (MET)

6. Pathophysiology
 At least four hereditary syndromes associated with renal cell
carcinoma are recognized, as follows:
 Von Hippel-Lindau (VHL) syndrome
 Hereditary papillary renal carcinoma (HPRC)
 Familial renal oncocytoma (FRO) associated with Birt-
Hogg-Dube syndrome (BHDS)
 Hereditary renal carcinoma (HRC)

7. Pathophysiology
Hereditary renal cancer

8. Aetiology
 The aetiology of RCC is still largely unknown
 In addition to obesity and hypertension, known risk factors for
RCC include cigarette smoking, diet, diabetes, male gender
(RCC is twice as common in men as in women) and, among
women, oophorectomy and parity
 Occupational exposures to petroleum products, heavy
metals, solvents, coke-oven emissions, or asbestos are
believed to be contributors, but no definite carcinogens have
been identified

9. TNM Staging

10. Diagnosis
 General: History, Physical examination
 Laboratory studies:
 CBC, Serum Calcium, liver function tests, alkaline
phosphatase, BUN, creatinine, urinalysis
 Radiographic studies: Use of imaging increased the
detection of renal lesions most of which are simple cysts
 X-Ray KUB region
 Ultrasonography: Excellent in distinguishing cystic from
solid masses
 Intravenous Urography: Starting point for hematuria
evaluations and function of contralateral kidney

11. Diagnosis
 Computed tomography: Provides an excellent
assessment of the parenchyma and nodal status
 Magnetic Resonance Imaging: Excellent
demonstration of solid renal masses and is image test
of choice to demonstrate extent of vena caval
involvement with tumour. Useful in patients with renal
insufficiency. CECT thorax. Bone scan. MRI brain if
symptomatic

12. Diagnosis
Figure : Computed
tomography demonstrates a
right renal carcinoma (m) with
a large contralateral adrenal
metastasis (a).
Figure: CT scan shows large
left renal mass with
calcification (m) invading the
left renal vein (arrow).

13. Management
Metastatic
Disease
Surgery
Radio
Therapy
Chemo
Therapy
Targeted
Therapy
Immuno
Therapy
Management of Metastatic Disease

15. Cytoreductive nephrectomy-
Integration of Targeted therapy
 Surgery is the mainstay in localised RCC, however in metastatic RCC
surgery is curative if all metastatic deposits are removed.
 TKI, VEGF antibodies and mTOR are the mainstay of systemic
treatment for RCC.
 Evidence for efficacy of CN was demonstrated by SWOG and EORTC
trials.
 The benefit of CN integrated with Targeted therapy has been explained
by several theories.

16. Advantages of Cytoreductive
Nephrectomy
 Presurgical targeted therapy has been shown to benefit
patients of metastatic RCC by improving disease free
survival and overall survival.
 Many unresectable tumours were downsized and
deemed to be resectable post Targeted therapy.
 Several trials are underway to also demonstrate and
establish the role of cytoreductive nephrectomy followed
by targeted therapy( Few studies have demonstrated
Median OS to be better when CN is undertaken prior to
targeted therapy.

17. Disadvantages
 Although SWOG and EORTC trials have proven the
role of Cytoreductive nephrectomy, these trials were
conducted in the era of Immunotherapy.
 No definitive trials have proven the benefit of CN with
Targeted therapy. CARMENA trial was initiated to
prove the role of CN + targeted therapy but the trial
concluded prematurely with a lot of bias , hence the
results haven’t been validated.
 Another Trial SURTIME has been initiated to evaluate
the role of cytoreductive nephrectomy with targeted
therapy, the results are awaited.

18. MSKCC model
 MSKCC is used as the prognostic model to
identify which patients benefit from CN.
 Parameters include :
1. Hemoglobin levels
2. Karnofsky performance status
3. LDH
4. Corrected serum Calcium
5. Prior nephrectomy

19. Risk stratification

20. IMDC MODEL-International
Metastatic RCC Database
Consortium
IMDC has been validated in the targeted therapy era
hence more accurate for assessment of Poor risk
 Karofsky performance status <80%.
 Time from diagnosis to treatment < 1yr.
 Anaemia.
 Hypercalcemia.
 Neutrophilia.
 Thrombocytosis.
Score 0 – Favourable ; 1-2- Intermediate; >3-poor
risk

21. Management
Surgery:
 Palliative Nephrectomy: Indicated in patients with
 Severe hemorrhage
 Severe pain
 Para-neoplastic syndrome
 Compression of adjacent viscera
 Solitary metastasis can be resected and may show some
survival advantage

22. Metastasectomy
 Resection of isolated metastatic lesions is
appropriate in selected patients.
 Retrospective studies have indicated patients
undergoing complete resection of isolated
metastatic foci may experience long disease
free intervals with median OS rate of 35 to 50
%.

23.  Factors associated with improved outcome
after metastasectomy:
1. Complete resection.
2. Presence of solitary metastatic lesion.
3. Age<60yrs.
4. Smaller tumor size.
5. Presence of pulmonary mets.

24. Management
Radiotherapy:
 Palliation
 Used for local or symptomatic metastatic disease, such as
painful osseous lesions or brain metastasis
 Treatment field encompasses metastatic deposit (or local
recurrence) with 2-3cm margins
 Higher doses (up to 35-40Gy) may be required to
overcome radio-resistance
 Symptomatic relief in 64-84% of patients

25. Management
Chemotherapy:
 RCC is a chemo resistant tumour. Phenomenon due to
presence of multi drug resistant glycoprotein (MDR) in tumour
cell - causes extrusion of the drug
 Conventional therapy has little to offer
 5-FU alone has a response rate of 10%
 On-going clinical trials of combination chemotherapy
including Gemcitabine and 5-FU + Doxorubicin ( Sarcomatoid
Ca)
 Limited data reveals some response in non-clear cell RCC to
Carboplatin, Cisplatin plus Gemcitabine ( collecting Duct Ca)

26. Targeted Therapy
 Based on advances in the understanding of
the molecular biology of RCC
- Highly vascularlized tumor with increased
VEGF and EGFR expression
- Tumor growth mediated via VEGF pathway
and mammalian target of rapamycin (mTOR)
pathway

27. VEGF Pathway Inhibition
 Tyrosine kinase (TK) inhibitors block the
intracellular domain of the VEGF receptor
- Sunitinib (Sutent)
- Sorafenib (Nexavar)
 Monoclonal antibody that binds circulating
VEGF preventing the activation of the VEGF
receptor
- Bevacizumab (Avastin)

28. Sunitinib
 Oral receptor kinase inhibitor with activity against
VEGF-R, PDGF-R, C-kit and fms-like tyrosine
kinase 3.
 Dose is 50mg OD 28/7 or 14/7 days.
 It leads to inhibition of vascular endothelial
development, proliferation and inhibition of
vascular pericyte function.
 Side effects include fatigue, HTN, nausea,
diarrhea, Hand-foot syndrome, hypothyroidism
and bone marrow suppression.
 First line FDA approved agent with significantly
longer PFS and OS.

29. Sorafenib
 Oral receptor kinase inhibitor with activity against
VEGF-R, PDGF-R and raf-1
 Dose is 400mg OD 5days on/2days off
 Side effects include HTN, fatigue, rash, hand-foot
syndrome, diarrhea, nausea.
 Currently infrequently used as first line.
 Other agents include Pazopanib, Axitinib,
Cabozanitinib and Tivozanib.

30. Humanised monoclonal antibody against VEGF-R
that blocks angiogenesis.
Not FDA approved, but can be used as second-
line therapy
AVOREN trial :
- INF alpha plus Bevacizumab or placebo
- Avastin group resulted in PFS of 10.2 vs. 5.4 m.
- Unclear activity as single agent however as a
second line agent showed benefits.
Bevacizumab

31. mTOR Pathway Inhibition
 Temsirolimus (TMSR) is an intravenous
rapamycin analog that inhibits mTOR kinase.
 Approved by FDA for poor risk patients.
 Benefit greater in non-clear cell RCC.
 Side Effects include Mucositis, fatigue, rash,
hyperglycemia, hypercholesterolemia and
hypophosphatemia.

32.  Everolimus is an orally active drug
 Used in the treatment of VEGF refractory
disease.
 It is a 2nd line FDA approved Drug.

33. Immunotherapy
 Immunotherapy with IL-2 activates immune
response against RCC resulting in tumor
remission rates 10-20% with median duration of
19-91 months
 Severe toxicity including hypotension, capillary
leak syndrome, MI, renal insufficiency,
pulmonary edema, hepatic dysfunction, CNS
dysfunction
 Treatment requires ICU monitoring
 Used for patients that can tolerate side effects

34. Allogenic hematopoietic stem cell transplant
 Allows the replacement of host or recipient
immune and hematopoietic systems with those
of a healthy HLA compatible donor.
 Still an experimental approach.

35. Immune check point inhibitors
 Iplimumab a monoclonal antibody targeting CTLA -4 and Nivolumab
an anti PD1 antibody.
 Goal of this therapy is to restore tumor specific T cell immunity by
releasing brakes on immune system.
 These drugs block the synthesis of certain proteins made by cells of
the immune system.
 These proteins keep immune responses in check and can keep T
cells from killing cancer cells.
 When these proteins are blocked the brakes on the immune system
are released and T cells are able to kill cancer cells better.