mRCC ppt with updates of newere EAU.pptx

mRCC ppt with updates of newere EAU guideliness

1. Metastatic Renal cell carcinoma -Dr. Kuppan C T

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.

3. Risk Stratification

4. Risk Stratification

5. Cytoreductive Nephrectomy Goal is to reduce tumour load to increase efficacy of systemic therapy . Several hypotheses have been proposed for beneficial effect like Removal of immunologic sink that is diminished production of growth factors and cytokines by tumour Post poned metastatic progression Cytoreductive Nephrectomy (IFN era) The most compelling evidence in support of cytoreductive nephrectomy with immunotherapy is provided by two RCT's conducted by the SWOG 8949 and the EORTC 30941. A pooled analysis of both trials by Flanigan et al. revealed an advantage of approximately half a year regarding OS among those who underwent cytoreductive nephrectomy

6. Cytoreductive Nephrectomy Cytoreductive Nephrectomy (Targeted Therapy era) Based on above two trials, CN was continued to be offered by default. To understand and investigate indications of CN combined with VEGF targeted therapy, two prospective RCTs were initiated in 2010 (SURTIME AND CARMENA) The results of CARMENA and SURTIME demonstrated that patients who require systemic therapy benefit from immediate drug treatment.

7. Cytoreductive Nephrectomy Cytoreductive Nephrectomy (Immune checkpoint inhibitors era) Currently, there is no randomized study to convincingly prove the beneficial role of cytoreductive nephrectomy in ICl era. Conclusion Poor risk — no immediate Good risk — immediate CN Intermediate risk — if metastatic burden is low and patient is having hematuria and symptomatic because of the tumor, immediate CN

8. Embolisation of Primary Tumour Unfit for surgery Non resectable disease Done for Palliative intent and/or to reduce Massive hematuria and Flank pain

9. Local Therapy for Metastasis Higher OS & PFS for metastasectomy in Pulmonary, Liver & Pancreas Bone Metastases - Single dose IGRT 24 Gy /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

10. Favourable factors for metastasectomy Solitary metastatic lesion Age < 60 years Disease free interval of more than I year Pulmonary metastases (<4cm) Metachronous lesions

11. Non Curative Resection Of Metastases 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

12. Systemic Therapy

13. Chemotherapy Chemotherapy has proven to be generally ineffective in the treatment of RCC but can be offered to patients with collecting duct or medullary carcinoma 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

14. Immunotherapy Interferon alpha Interleukin 2 Immune check point inhibitors

15. INF ALPHA 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% Effective only in some patient subgroups ccRCC with favourable risk criteria Lung metastases only

16. INF ALPHA

17. INF ALPHA Acute toxicity 'Flu like syndrome' Hypotension Renal abnormalities Chronic toxicity Neuropathy Depression Hematological abnormalities Dermatological abnormalities

18. IL 2 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

19. IL 2 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%

20. IL 2 Only high dose IL2 regimens being considered for cytokine therapy Good performance status Limited metastases Time from nephrectomy to systemic therapy > 1 year

21. IL 2 – Complications Hypotension Capillary leak syndrome Respiratory distress syndrome Neurologic (depression, confusion) Hepatic and renal abnormalities Cardiac (arrhythmias)

22. IL2 + INTERFERON Combination of IL-2 and interferon resulted Higher response rate (18.6%) Higher 1-year event-free survival COMBINATION OF BOTH ARE NOT USED Due to toxicity No significant difference in survival

23. Current Role Of Cytokine Therapy The role of cytokine therapy in the current management of kidney cancer has changed with he availability of novel inhibitors of VEGF and mTOR pathways, as well as immune heckpoint inhibitors with activity in clear cell RCC. Single agent interferon, once the standard in many institutions, is no longer used in he 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

24. Immune Checkpoint Inhibitors Immune checkpoint inhibitor with monoclonal antibodies targets and blocks the inhibitory T-cell receptor PD-1 or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-signalling to restore tumour-specific T-cell immunity

25. Immune Checkpoint Inhibitors

26. Immune Checkpoint Inhibitors

27. Drugs

28. Dose

29. Adverse Effects Severe autoimmunity Hypophysitis Vitiligo Diarrhoea

30. Targeted Therapy Tyrosine Kinase Inhibitor Monoclonal VEGF antibody mTOR inhibitors

31. Sunitinib Oral TKI Inhibits VEGFR, PDGFR, cKit 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) SE: diarrhea, rash, hand foot syndrome, fatigue, asthenia, hypertension

32. Pazopanib Selective activity against VEGFR Also inhibits PDGFR & FGFR 800mg OD Decreased side effects Reasonable first line option Better tolerated Increased incidence of hepatotoxicity

33. Axitinib Highly selective oral TKI of VEGFR (1,2,3) Dose: 5 mg BD MC side effects: diarrhoea, fatigue, hypertension FDA second line setting in patients with advanced RCC

34. Other TKIs 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 VEGFR 1,2,3

35. Bevacizumab 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 IFN alpha Not used as single agent in initial therapy Role in patients who failed initial first line agents

36. Temsirolimus 25mg IV once weekly Not recommended in VEGF TKI refractory disease Used in Poor risk disease Non clear cell RCC

37. Everolimus Oral agent 10 mg OD Established in treatment of VEGF refractory disease Used in High risk disease Non clear cell RCC

38. MTOR Inhibitors – Adverse Effects Rashes Mucositis Hepatic dysfunction Hyper cholestrolemia Hyper glycemia Hypophosphatemia Stomatitis Gastritis

39. Evolution of Treatment of mRCC

40. Current Role of IO in RCC (Algorithm) Non- mRCC mRCC

41. Treatment choice of mRCC 2 initial things to establish: IMDC score and treatment naïve or not Treatment choice to be individualized Apart from guidelines/standard Of care, due consideration to be given for: Availability of IO agent Tolerability with IO Expertise to manage IO related toxicities Cost/affordability

42. EAU Guideliness 2024

43. Thank You