Renal Cell Cancer Flashcards
Why is the vHL protein instrumental in the development of RCC?
VHL protein combines with hydroxyproline. This activates Hypoxia-inducible factor alpha, which is then degraded by a proteasome.
Withy hypoxic environments (as in a tumor), or in patients with abnormal vHL protein (as in ccRCC), HIFalpha is activated, inducing hypoxia-inducible genes.
- eg. VEGF and PDGF
How does the MSKCC Criteria 2002 correlate with survival?
0 risk factors = 30 months
1 or 2 = 14 months
3 or more = 5 months
What is the Heng index?
By Daniel Heng 2009
Validated components of the MSKCC score, and serves as a prognostic score for OS in patients tx with VEGF agents
6 components:
- Hb ULN
- Neutrophils > ULN
- PS ULN
3 risk categories:
- 0 = Favorable = mOS not reached, 2y OS 75%
- 1 or 2 = intermediate = mOS 27m, 2y OS 53%
- 3 or more = poor = mOS 9m, 2y OS 7%
What is the limitation of MSKCC?
Derived from the era of immunotherapy and are limited to a population of patients eligible for participation in immunotherapy clinical trials.
Unclear if the same prognostic factors are relevant to those with VEGF-targeted therapy.
What is the only curative modality of mRCC?
High-dose IL-2
JCO 1995 Gwendolyn Fyfe
N=255, phase II
Met RCC
Proleukin (Aldesleukin), 600 000 or 720 000 IU/kg q8H x 14 doses (over 15min infusion) over 5 days
Supportive measures
2nd cycle after 5-9 days of rest
Courses could be repeated every 6-12 weeks in stable or responding patients
Results:
- ORR 14% , 5% CR, 9% PR
- med Duration of response for CR 80m, 20m in PR pts
- 4% mortality secondary to treatment
What is the evidence for using Sunitinib over Alpha-Interferon?
Motzer 2007, 2009
Aim: Prove in RCT that Sunitinib is efficacious in met RCC
N=750, prep untreated, mRCC, phase III
2 arms:
A) Sunitinib 50mg OM x4weeks, q6Weeks
B) Subcut Alpha IF 9MU 3x/week
Results:
- PFS 11m vs 5m HR 0.42
- ORR 30% vs 6%
- Fatigue more in Alpha IF, diarrhea more in SUnitinib
- Better QoL with Sunitinib
Updated 2009:
- mOS 26m vs 22m HR 0.8
- med PFS 11m vs 5m (primary endpoint)
- ORR 50% vs 10%
- most common S/E with Sunitinib = fatigue, HTN, diarrhea, HFS
What is the evidence for Temsirolimus?
Gary Hudes NEJM 2007
RCT phase III, n= 600
Prev Untx poor-prognosis mRCC
3 arms:
- IV Temsirolimus 25mg weekly
- Alpha IFN 3 million U SC 3x/week (with increase up to 18million)
- Temsirolimus 15mg weekly + IFN 6million U 3x /week
Results:
- Temsirolimus = longer OS HR 0.73 and longer PFS
- OS in combi group = IFN group
- Med OS:
» 7m (IFN) vs 11m (Tem) vs 8m (Combi)
- S/e Tem: rash, peripheral edema, hyperglycemia, hyperlipemia
Tell me about the AVOREN trial
Aim :whether combination of Bev + IFN will be more efficacious
RCT phase 3, n=650, prep untreated mRCC
2 arms:
- IFN 9MIU SC 3x/week + Bev 10mg/kg q2W
- placebo and IFN alpha 2a
Results:
- mPFS 10m (Combi) vs 5m HR 0.63
What is the evidence of Pazopanib?
Sternberg JCO 2010
Aim: to evaluate efficacy + Safety in Tx-naive and cytokines-pretreated adv RCC
N=400
2arms (2:1)
Pazopanib vs placebo
Results:
PFS: 9m vs 4m HR 0.5
- Tx naive: med PFS 11m vs 3m HR 0.4
- cytokines-pretx: med PFS 7m vs 4m HR 0.5
ORR: 30% with Pazopanib and 3% with placebo
Tell me about the COMPARZ study
Aim :
Non-inferiority study to compare Pazopanib against Sunitnib in 1st line setting
N=1100 , ccRCC, met RCC
2 arms:
- Pazopanib 800 mg OM
- Sunitnib 50 mg Q4w Q6w
Results:
- PFS and OS similar
- Sunitnib had higher incidence of fatigue, HFS, thrombocytopenia
- Pazopanib had higher incidence of raised ALT
Result: similar efficacy. Safety and QoL favor Pazopanib
Tell me about the TARGET Trial
N=900
2 arms:
Sorafenib vs Placebo
Cross-over allowed when PFS benefit was shown
Results:
Final OS: 18m vs 15m
Evidence for Everolimus?
Motzer
Met RCC patients who had PD on Sunitnib, Sorafenib or both.
2 arms:
Everolimus 10 mg OM or placebo
Results:
Med PFS 4m (Everolimus) vs 2m
8% pneumonia is rate with Everolimus
Tell me about the AXIS trial
Aim= Compare Axitinib vs Sorafenib as 2nd line Tx for met RCC
N=700
2nd line tx
1st line= Sunitnib, Bev+IFN, Temsirolimus, cytokines
2 arms:
A) Axitinib 5mg BD
- can increase to 7mg, then 10mg BD in those who can tolerate
B) Sorafenib 400 mg BD
Results:
Med PFS 7m vs 5m HR 0.7
Txt discontinuation in 8% (Sorafenib) vs 4%
What about the INTORSECT study ?
Hutson et al
Aim: To investigate efficacy of Temsirolimus vs Sorafenib as 2nd line after Sunitnib
N=500
PD on Sunitinib
2 arms:
- IV Temsirolimus 25mg once a week
- Oral Sorafenib 400mg BD
Results:
- med PFS 4.3m (Tem) vs 3.9 (Sorafenib)
- med OS 12.3m (Tem) vs 16.6 (Sorafenib)
Conclusion:
- 2nd line Tem did not show a PFS advantage as compared to Sorafenib
- OS advantage with Sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC
Which is better? Pazopanib or Sunitnib and why?
PISCES study
N=110
No prior therapy
2 arms:
- Pazopanib 800 mg OM x 10weeks –> Sunitinib
- Sunitnib 50mg 4/2 x 10 weeks –> Pazopanib
- 2-week washout in between
- off study after 22 weeks, (10weeks –>2w–>10w), off study, put choice of tx to PD
Results:
- Preference:
»Pazopanib–>Sunitnib 80% preferred Pazopanib
»Sunitinib –> Pazopanib: 60% preferred Pazopanib
What do you know about sequencing of treatment in mRCC?
RECORD-3 Motzer JCO 2014
Aim: Wanted to assess if 1st line Everolimus–> Sunitinib was the same as Sunitinib–> Everolimus
N=470
Results: Med PFS: - 8m 1st line Everolimus - 11m 1st line Sunitinib Med Combined PFS: - 21m 1st line Everolimus - 26m 1st line Sunitinib Med OS: - 22m 1st line Everolimus - 32m 1st line Sunitinib
Results:
Still Sunitinib –> Everolimus
What do you know about Sequential TKIs in Adv RCC?
Sablin et al 2007
Retrospective studies suggest activity to 2nd agent
No obvious correlation of response to first TKI with response to second TKI
What do you know about using Cabozantinib ?
Choueiri NEJM 2015
Cabozantinib = oral, small-molecule TKI that targets VEGFR, MET and AXL
RCT aim to compare Cabozantib vs Everolimus in mRCC who had PD after VEGFR-targeted therapy
- but no previous mTOR inhibitors
N=650
2 arms:
- Cabozantinib
- Everolimus
Results:
- med PFS 7m with Cabo and 4m with Everolimus
- ORR 20% with Cabo and 5% with Everolimus
- OS longer with Cabo HR 0.7
- Dose reduction rate higher with Cabo, but discontinuation of study treatment similar at rate of 10%
Name the common side-effects of Sunitinib?
Fatigue GI disorders Dysgeusia LOA HTN HFS Skin discoloration Mucosal inflammation Rash
Name the side effects with Sorafenib
Diarrhea
Rash
Alopecia
Name the side effects with Temsirolimus
Asthenia Anemia Rash GI disorders Oedema Metabolic disorders Displeasure Pain Cough Bacterial infections
Name the side-effects of Bev/IFN-alpha
Anorexia Fatigue/Asthenia Hemorrhage HTN Influenza-like illness Headaches Diarrhea
Explain re: Sunitinib and cardiotoxicity
All-grade LVEF decrease 15%, G3-4 3%
Sunitinib discontinuation in presence of clinical manifestations of CHF
Interrupt dose or dose reduce in those without clinical evidence of CHF but with LVEF 20% decrease below baseline
Tell me about the checkmate 025 study for met RCC
Phase 3, RCT n = 800 Adv ccRCC Previous 1 or 2 regimens of antiangiogenic therapy 2 arms: A) IV Nivolumab 3mg/kg q2weekly B) PO Everolimus 10mg OM
Primary endpoint = OS
Results:
- Med OS 25m vs 20m
- ORR 25% vs 5%
- med PFS similar 4m
- G3/4 tx-related adverse events 20% v 40%
How do you manage HFSR?
Grade 0 = prophylactic care
- avoid excessive friction, vigorous exercise
- thick cotton socks/gloves
Grade 1 = numbness, parenthesis, dysaesthesia, painless swelling, erythema
- avoid hot water
- moisturize
- Urea 20-40%
- thick cotton socks/gloves
Grade 2 = Painful erythema, swelling, interferes with ADLs
- as above
- dose reduce 50% for 7-28days
- potent topical steroids ointment
- pain relief with oral painkiller eg codeine
Grade 3 = moist desquamation, ulceration, blistering, severe pain, interferes with ADLs
- Dose interruption at least 7 days, till improvement to grade 0 or 1
- further dose reduce by one dose level
For Grades 2 and 3, require 2 weekly review
Describe ccRCC
75-90% incidence
Genetic features:
-3p deletion, -6q,-8p,-9p,-14q
+5q insertion
VHL
VEGFR and mTOR-directed therapy
Describe papillary RCC
10-15% incidence
Genetics:
- cMET (Type I)
- Fumarate hydratase (Type II)
- -Y
Sunitinib, Sorafenib, Temsirolimus, +/- Everolimus and Bev, MET-directed therapy
Describe chromophobe RCC
4-5%,
Birt-Hogg-Dube syndrome
Tend o present with lower stage and grade than ccRCC with very low incidence of mets
Overall prognosis may be no different to ccRCC
Sunitinib, Sorafenib, Temsirolimus, Everolimus, Pazopanib,
What are the components of MSKCC Criteria (2002)?
KPS 2.5 mmoL/L
Time from Dx to treatment with IFN
Talk about collecting ducts of Bellini RCC
What is the T1 and T2 for Kidney cancer?
T1 = Tumor 7cm or less, limited to kidney
T1a T4cm or less
T1b Tumor 4-7cm
T2= Tumor limited to kidney, >7cm T2a = Tumor >7cm, up to10cm T2b = Tumor >10cm, but limited to kidney
What is T3 and T4 of kidney cancer staging?
T3 = tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota's fascia T3a = tumor grossly extends into renal vein or its segmental branches, or tumor invades perirenal and/or renal sinus fat but not beyond Gerota's fascia T3b = Tumor grossly extends into vena cava below diaphragm T3c = Tumor extends into vena cava above diaphragm or invades wall of vena cava
T4 = Tumor invades beyond Gerota’s fascia (including contiguous extension into ipsilateral adrenal gland)
Tell me about the staging of RCC
Stage I - T10N0M0
Stage II - T2N0M0
Stage III - T3N0-1 or T1-2N1M0
Stage IV - as long as T4 or M1
What is the triad of RCC symptoms?
Hematuria
Flank mass
Flank pain
What does a radical nephrectomy consists of?
Perifascial resection of:
- the kidney
- perirenal fat
- regional LN
- ipsilateral adrenal gland
Preferred treatment if the tumor extends into the inferior IVC
What are the methods of radical nephrectomy?
Open
Laparoscopic
Robotic surgical
Long-term outcomes indicate lap and open equivalent cancer-free survival rates
What does Sunitinib target?
Multi kinase inhibitor
Several receptor tyrosine kinases
- PDGFR-alpha and beta
- VEGFR 1, 2 and 3
- stem cell factor receptor (c-kit)
- FMS-like tyrosine insane (FLT-3)
- colony-stimulating factor (CSF-1R)
- Neuotrophic factor receptor (RET)
Tell me about the bio markers in RCC
None validated for general use in the prognostic/predictive assessment of RCC
PBRM1 mutations confer a favorable prognosis
BAP1 confer poor prognosis
Small proportion with PBRM1 + BAP1 mutations = worst survival
Options for T1 tumors (I.e.
Partial nephrectomy Laparoscopic radical nephrectomy RFA Cryoablative treatments (3cm or less) Active surveillance
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
What are the components of the MSKCC Criteria (2002)
LDH > 1.5 ULN
C.Ca > 2.5
Hb
