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Renal Cell Carcinoma
..going beyond Targeted therapies
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Renal Cell Carcinoma
Incidence
There are approximately 30,000 new cases per year
and 12,000 cancer related deaths
Incidence is rising 6.1 to 9.3 per 100,000 over 20 years
Third most common genitourinary cancer after
prostate and bladder
5-year survival has improved for Advanced disease
7.3% during 1992-1995 to 11.1% during 2002-2008
25% of tumors present with advanced disease RCC
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PREVALENCE IN INDIA
cases prev1yr prev5yr mort
M 4738 2685 9783 3425F 2129 1247 4685 1459
Incidence is on the increase
Rare in young, it usually affects adults (50 - 70 yrs)
Male to female ratio is 2:1
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Risk factors
1. Diet high in fat2. Tobacco smoking
3. Obesity / Hypertension
4. Being on long term dialysis
5. Taking pain killers
6. Exposure to cadmium or asbestos
7. Inherited gene mutation: Von Hippel-Lindau
syndrome
8. Tuberous sclerosis
Autosomal dominant disorder with
patients developing:
Adenoma sebaceum,
Distinctive skin lesions, Epilepsy,
Mental retardation, Renal cysts,
Angiomyolipoma
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mTOR Downstream Signalling
..for tumor growth
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Targeted Therapies:
The Revolution
Immunotherapy : IL-2 and IFN have shown promising results for
Asymptomatic pts with Good performance status, Had a prior
nephrectomy, Non bulky pulmonary or soft tissue metastasis
Targeted Therapies
1. Sunitinib for first-line treatment of patients with favorable
or intermediate outlooks
2. Sorafenibfor second-line treatment of patients
previously treated with biological therapy
3. Temsirolimus or mTOR Inhibitors for first-line treatment of
patients with a poor outlook
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Targeted Therapy: Drawbacks
1. Activity is robust, but there are few, if any,complete responses
2. Continued treatment appears required to maintainefficacy
3. Disease resistance usually develops within 6-12months for VEGF inhibitors
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Potential Mechanisms of RCC Treatment Resistance
Rini BI and Atkins M. Lancet Oncol 2010.
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Everolimus
Benefits
1. Acts on novel sitemTOR & HIF pathway
2. Inhibits Cell growth, Angiogenesis, Proliferation
3. Tackles upregulated mTOR pathway due to VEGF
inhibitors use including Sunitinib, Sorafenib
4. Relatively low side effect profile that requires
nodosage modification - this preventunderdosing and therefore therapeutic
resistance
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EverolimusmTOR inhibitor
Cancer Treat Rev (2012), doi:10.1016/j.ctrv.2011.12.009
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Everolimus and mRCC..better tolerability profile
mRCC commonly observed with increased age
associated with comorbid conditions and poor PS
Discontinuation or dose reduction for Sunitib often
associated with increasing age
Grade 3 events (Hypertension, Hand-foot syndrome) more common with
Elderly
Fatigue and Rash/desquamation more common with
Sorafenib use
Age has little impact on the incidence of Grade 3/4 AEswith mTOR inhibitors
Everolimus is structurally and functionally similar to
Temsirolimus offering oral convenience compared to
weekly injections (IV) Porta C. Eur Urology 2012;826-833
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Phase 3 trial of everolimus in patients with mRCC progressing on VEGFR-TKIs
Cancer Volume 116 Issue 18 a es 4256-4265 19 AUG 2010 DOI: 10.1002 cncr.25219
Everolimus for RCC pts with Prior TKIs: (RECORD 1)
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Everolimus for RCC pts with Prior TKIs: (RECORD 1 Results)
Everolimus offers Significant improvement in PFS rates (4.9 mths vs. 1.9 mths)
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mRCC Guideline based approach - ESMO 2012
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ESMO 2012