MANAGEMENT OF METASTASIS RENAL CELL CARCINOMA

1. MANAGEMENT OF METASTATIC
RENAL CANCER
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai

2. Professors:
▪ Prof. Dr. G. Sivasankar, M.S., M.Ch.,
▪ Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
▪ Dr. J. Sivabalan, M.S., M.Ch.,
▪ Dr. R. Bhargavi, M.S., M.Ch.,
▪ Dr. S. Raju, M.S., M.Ch.,
▪ Dr. K. Muthurathinam, M.S., M.Ch.,
▪ Dr. D.Tamilselvan, M.S., M.Ch.,
▪ Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

3. ▪ Approximately 1/3rd of all newly diagnosed → synchronous metastatic
disease
▪ 20-40% of clinically localized disease at diagnosis → develop metastases
▪ Metastatic RCC is almost always fatal with 10 year survival rates of less than
5%
▪ Patients with metastatic disease account for majority of deaths related to
RCC
3
Dept of Urology, GRH and KMC, Chennai.

4. • Haematogenously via renal sinus veins, renal veins,
and venae cavae → pulmonary metastases
• Renal vein → lumbar veins → paravertebral venous
plexus → dural venous sinuses & pelvic veins →
CNS & osseous mets
• Lymphatic metastases can involve hilar, aortic, and
caval lymph nodes, and can enter the thoracic duct
or involve thoracic nodes directly.
4
Dept of Urology, GRH and KMC, Chennai.

5. LOCAL
THERAPY
SYSTEMIC
THERAPY
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Dept of Urology, GRH and KMC, Chennai.

6. LOCAL THERAPY
• Cytoreductive
nephrectomy
• Embolisation of primary
tumor
Primary tumor
• Metastasectomy
• Radiotherapy
• Embolisation
Metastases
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Dept of Urology, GRH and KMC, Chennai.

7. SYSTEMIC
THERAPY
▪Immunotherapy
▪Targeted therapy
▪Chemotherapy
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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

9. 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
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Dept of Urology, GRH and KMC, Chennai.

10. ▪ CURATIVE
▪ Tumor resection is curative only if all tumors are resected
▪ Primary tumor with single or oligo metastatic resectable disease
▪ PALLIATIVE
▪ For most patients to control sever local & systemic symptoms
▪ Requires systemic therapy
10
Dept of Urology, GRH and KMC, Chennai.

11. ▪ In immunotherapy era with cytokines
▪ Increased long term survival with CN
▪ SWOG/EORTC Trial – OS improved by 11.1 months with CN+IFN alpha
▪ Targetted therapy era
▪ Doubtful benefit
▪ CARMENA TRIAL / SURTIME TRIAL
11
Dept of Urology, GRH and KMC, Chennai.

12. ▪ Eliminate the primary source of immunosuppressive & growth promoting factors
▪ Removal of large primary tumors may provide clinical benefit
▪ Reports of spontaneous regression of metastatic lesions after nephrectomy
▪ Inhibition of Tcell function with large primary tumors → inability of systemic
agents (cytokines) to induce meaningful responses
▪ Prevents potential bleeding & pain from metastases during systemic therapy
▪ Accurate histologic subtyping
▪ Highly symptomatic tumor removed for symptom palliation 12
Dept of Urology, GRH and KMC, Chennai.

13. ▪ OS (11.1 vs 8.1 months)
improved in CN+IFN alpha
13
Dept of Urology, GRH and KMC, Chennai.

14. ▪ Good performance status (ECOG 0/1)
▪ Resectable primary tumor
▪ As palliative in
▪ Intractable pain, hematuria
▪ Constitutional symptoms
▪ Paraneoplastic manifestations
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Dept of Urology, GRH and KMC, Chennai.

15. ▪ Poor PS
▪ IMDC poor risk
▪ Small primaries & high metastatic volume
▪ Sarcomatoid tumor
▪ Confirmed by CARMENA
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Dept of Urology, GRH and KMC, Chennai.

16. ▪ Delay the start of systemic targeted therapy
▪ Perioperative complications coupled with disease progression
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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

20. ▪ Sequence of CN and sunitinib did not affect the progression free rate
at 28 weeks
▪ 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.
20
Dept of Urology, GRH and KMC, Chennai.

21. ▪ Cytoreductive surgery should be offered to favorable risk group
▪ Metastatic RCC at presentation + good performance status + Resectable primary
+ low tumor burden outside the kidney → upfront CN is preferred
▪ For patients with limited tumor burden – metastasectomy rather than immediate
systemic therapy → associated with prolonged disease free survival in selected
patients
21
Dept of Urology, GRH and KMC, Chennai.

22. ▪ Palliative
▪ Massive hematuria
▪ Flank pain
Unfit for surgery
Non resectable disease
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Dept of Urology, GRH and KMC, Chennai.

23. EAU GUIDELINES
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Dept of Urology, GRH and KMC, Chennai.

24. EAU GUIDELINES
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Dept of Urology, GRH and KMC, Chennai.

25. EAU GUIDELINES
Offer embolization to patients unfit for surgery presenting
with massive hematuria or flank pain
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Dept of Urology, GRH and KMC, Chennai.

26. ▪ Higher OS & PFS for metastasectomy in Pulmonary, Liver & Pancreas
▪ Bone Metastases – Single dose IGRT 24 Gy/SBRT/EBRT
▪ Brain metastases – SRS / SRS+WBRT (better OS for SRS+WBRT)
▪ Embolisation
▪ Prior to resection of hypervascular bone or spinal mets – reduce
blood loss
▪ Palliative in painful bone mets
26
Dept of Urology, GRH and KMC, Chennai.

27. ▪ Solitary metastatic lesion
▪ Age < 60 years
▪ Disease free interval of more than 1 year
▪ Pulmonary metastases (<4cm)
▪ Metachronous lesions
27
Dept of Urology, GRH and KMC, Chennai.

28. ▪ Solitary brain metastases
▪ Metastatic lesions in weight bearing joints/bones
▪ Vertebral metastases with impending spinal cord compression
Surgical resection often combined with radiation and/or systemic
therapy
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Dept of Urology, GRH and KMC, Chennai.

29. EAU GUIDELINES
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Dept of Urology, GRH and KMC, Chennai.

30. EAU GUIDELINES
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Dept of Urology, GRH and KMC, Chennai.

31. SYSTEMIC
THERAPY
Immunotherapy
Targeted therapy
Chemotherapy
31
Dept of Urology, GRH and KMC, Chennai.

32. ▪ Interferon alpha
▪ Interleukin 2
▪ Immune check point inhibitors
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Dept of Urology, GRH and KMC, Chennai.

33. • Spontaneous remissions have been documented.
• Increased risk of cancer in immunodeficient states
• Tumor infiltrating lymphocytes (TILs)
• Lymphocytes have been found within tumors.
• Isolated and expanded TILs have been the focus of experimental therapies.
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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

35. ▪ Was commonly the agent of choice in the initial treatment of
metastatic RCC until the advent of VEGF pathway antagonists
▪ Response rate – 6-15%
▪ Decrease in tumor progression risk 25%
35
Dept of Urology, GRH and KMC, Chennai.

36. ▪ Effective only in some patient subgroups
▪ ccRCC with favourable risk criteria
▪ Lung metastases only
▪ Bevacizumab + IFNalpha
▪ Increased response rates & PFS
36
Dept of Urology, GRH and KMC, Chennai.

37. 5 MIU sc 3 days a week for 4 weeks
Wait for 4 weeks
Re-imaging
Response /
stable
Further course
Standard : 12 weeks
Maximum: 36 weeks
Progression Alternate systemic treatment
37
Dept of Urology, GRH and KMC, Chennai.

38. Acute toxicity
▪ ‘Flu like syndrome’
▪ Hypotension
▪ Renal abnormalities
Chronic toxicity
▪ Neuropathy
▪ Depression
▪ Hematological abnormalities
▪ Dermatological
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Dept of Urology, GRH and KMC, Chennai.

39. ▪ Recombinant human IL-2
▪ Patients with clear cell RCC appear most likely to benefit from IL-2
therapy.
▪ Lyophilized powder : 5 MU /vial
▪ Reconstituted with 1 ml of saline
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Dept of Urology, GRH and KMC, Chennai.

40. ▪ Response rate : 15-20%
▪ Complete regression of all metastatic tumor – 7-9% with high dose
IL2
▪ >80% of complete responder → disease free on long term follow up
▪ Unacceptably high treatment related mortality rate : 2-5%
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Dept of Urology, GRH and KMC, Chennai.

41. ▪ Only high dose IL2 regimens being considered for cytokine therapy
▪ Good performance status
▪ Limited metastases
▪ Time from nephrectomy to systemic therapy > 1 year
▪ Over expression of CAIX
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Dept of Urology, GRH and KMC, Chennai.

42. ▪ High dose - 6- 7.2 MU/kg q8h x 5 days IV bolus
▪ 2.5 MU/day S.C / 5 days a week for 4 weeks
▪ Dose same as for INF alpha
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Dept of Urology, GRH and KMC, Chennai.

43. ▪ Hypotension
▪ Capillary leak syndrome
▪ Respiratory distress syndrome
▪ Neurologic (depression, confusion)
▪ Hepatic and renal abnormalities
▪ Cardiac (arrhythmias)
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Dept of Urology, GRH and KMC, Chennai.

44. Death with IL-2 : 4%
Death with interferon : 0.74%
▪ Interferon is preferred over interleukin
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Dept of Urology, GRH and KMC, Chennai.

45. ▪ Combination of IL-2 and interferon resulted
▪ Higher response rate (18.6%)
▪ Higher 1-year event-free survival (efs; 20%)
▪ COMBINATION OF BOTH ARE NOT USED
▪ Due to toxicity
▪ No significant difference in survival
45
Dept of Urology, GRH and KMC, Chennai.

46. ▪ The role of cytokine therapy in the current management of kidney cancer has changed with
the availability of novel inhibitors of VEGF and mTOR pathways, as well as immune
checkpoint inhibitors with activity in clear cell RCC.
▪ Single agent interferon, once the standard in many institutions, is no longer used in
the treatment of clear cell RCC.
▪ However, given the inability of newer targeted agents to induce durable responses, high-
dose intravenous IL-2 remains a reasonable option in most carefully selected patients
with metastatic clear cell RCC
46
Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

48. PD-L1/PD-1 & CTLA-4/B7
interaction inhibits immune
activation and reduces T-cell
cytotoxic activity
Maintains normal immune
responses and limits T-cell activity
to protect normal cells during
chronic inflammation
Tumor cells may circumvent T-cell–
mediated cytotoxicity by
expressing PD-L1
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Dept of Urology, GRH and KMC, Chennai.

49. ANTIBODY
AGAINST PD-1
ANTIBODY
AGAINST PDL-1
ANTIBODY
AGAINST CTLA-4
Pembrolizumab Atezolizumab Ipilimumab
Nivolumab Durvalumab
Avelumab
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Dept of Urology, GRH and KMC, Chennai.

50. DRUG DOSAGE DURATION
Pembrolizumab 200mg IV q3Wk Until disease progression or
unacceptable toxicity
Nivolumab 240mg IV q2wk or
480mg IV q4wk
Until disease progression or
unacceptable toxicity
Nivolumab + Ipilimumab 3mg/kg IV Nivolumab
immediately followed by
ipilimumab (1mg/kg IV) on
the same day every 3 weeks
Upto 4 doses or unacceptable
toxicity
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Dept of Urology, GRH and KMC, Chennai.

51. ▪ Severe autoimmunity
▪ Hypophysitis
▪ Vitiligo
▪ Diarrhoea
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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

54. ▪ Tyrosine kinase inhibitors
▪ VEGF inhibitors
▪ mTOR inhibitors
Sorafenib
Sunitinib
Pazopanib
Axitinib
Cabozantinib
Lenvatinib
Tivozanib
Bevacizumab
Everolimus
Temsirolimus
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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

56. ▪ Oral TKI
▪ Activity against – VEGFR, PDGFR, raf-1
▪ Dose – 400mg BD x 12 weeks
▪ Side effects – Hypertension, fatigue, rash, hand foot syndrome, diarrhoea
▪ Currently infrequently used in first line setting
▪ Patients whose disease has progressed on other VEGFR inhibitors may
respond favourably
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Dept of Urology, GRH and KMC, Chennai.

57. ▪ Oral TKI
▪ Inhibits – VEGFR, PDGFR, cKit, fms like tyrosine kinase 3
▪ Widely used in initial management of ccRCC
▪ Started after 14 days following CN
▪ Dose: 50 mg OD for 4 weeks followed by 2 weeks off (as long as
tolerable)
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Dept of Urology, GRH and KMC, Chennai.

58. ▪ SE: diarrhoea, rash, hand foot syndrome, fatigue, asthenia,
hypertension
▪ Bone marrow suppression & hypothyroidism – notable side effects
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Dept of Urology, GRH and KMC, Chennai.

59. ▪ Selective activity against VEGFR
▪ Also inhibits PDGFR & FGFR
▪ 800mg OD
▪ Decreased side effects
▪ Reasonable first line option
▪ Better tolerated
▪ Increased incidence of hepatotoxicity
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Dept of Urology, GRH and KMC, Chennai.

60. ▪ Highly selective oral TKI of VEGFR (1,2,3)
▪ Dose: 5mg BD
▪ MC side effects: diarrhoea, fatigue, hypertension
▪ FDA – second line setting in patients with advanced RCC
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Dept of Urology, GRH and KMC, Chennai.

61. ▪ Cabozantinib - Oral inhibitor of TK, MET,VEGR, AXL
▪ Lenvatinib – Oral inhibitor of VEGFR(1,2,3), FGFR(1,2,3), PDGFR, RET,
c-KIT
▪ Tivozanib – Highly selective inhibitor of VEGFR1,2,3
▪ Nintedanib – VEGFR1,2,3, PDGFR, FGFR1,2,3, RET, Flt-3
▪ Dovitinib – VEGFR, PDGFR, FGFR
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Dept of Urology, GRH and KMC, Chennai.

62. ▪ Monoclonal antibody against VEGF
▪ Dose: 10mg /kg iv every 2 weeks
▪ 4 weeks after CN
▪ SE: bleeding, hypertension, fatigue, proteinuria
▪ For improving efficacy – combined with IFNalpha
▪ Not used as single agent in initial therapy
▪ Role in patients who failed initial first line agents
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Dept of Urology, GRH and KMC, Chennai.

63. ▪ 25mg IV once weekly
▪ Not recommended in VEGF TKI refractory
disease
▪ Used in
▪ Poor risk disease
▪ Non clear cell RCC
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Dept of Urology, GRH and KMC, Chennai.

64. ▪ Oral agent – 10mg OD
▪ Established in treatment of
VEGF refractory disease
▪ Used in High risk disease
▪ Non clear cell RCC
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Dept of Urology, GRH and KMC, Chennai.

65. ▪ Rashes
▪ Mucositis
▪ Hepatic dysfunction
▪ Hyper-cholestrolemia
▪ Hyper-glycemia
▪ Hypophosphatemia
▪ Stomatitis
▪ Gastritis
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Dept of Urology, GRH and KMC, Chennai.

66. ▪ Conventional cytotoxic chemotherapy has been largely ineffective in the
management of clear cell RCC
▪ Overall response rate is 5.5% to 6.0%
▪ Response in Collecting duct carcinoma
▪ Sarcomatoid component
▪ A small case series has suggested promising activity for gemcitabine-
based chemotherapy
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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.

68. ▪ mTOR inhibitors
▪ VEGFR inhibitors – modest efficacy in papillary RCC
▪ Foretinib – TKI against MET & VEGFR2 – HPRCC
▪ Bevacizumab + Erlotinib – FH mutations (Type II Papillary RCC)
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Dept of Urology, GRH and KMC, Chennai.

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Dept of Urology, GRH and KMC, Chennai.