Renal Cell Cancer Flashcards by Eileen Poon

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 well did you know this?

Not at all

Perfectly

How does the MSKCC Criteria 2002 correlate with survival?

0 risk factors = 30 months
1 or 2 = 14 months
3 or more = 5 months

How well did you know this?

Not at all

Perfectly

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%

How well did you know this?

Not at all

Perfectly

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.

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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%

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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%

How well did you know this?

Not at all

Perfectly

Name the common side-effects of Sunitinib?

Fatigue
GI disorders
Dysgeusia
LOA
HTN
HFS
Skin discoloration
Mucosal inflammation 
Rash

How well did you know this?

Not at all

Perfectly

Name the side effects with Sorafenib

Diarrhea
Rash
Alopecia

How well did you know this?

Not at all

Perfectly

Name the side effects with Temsirolimus

Asthenia
Anemia
Rash
GI disorders
Oedema
Metabolic disorders
Displeasure
Pain
Cough
Bacterial infections

How well did you know this?

Not at all

Perfectly

Name the side-effects of Bev/IFN-alpha

Anorexia
Fatigue/Asthenia
Hemorrhage
HTN
Influenza-like illness
Headaches
Diarrhea

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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 well did you know this?

Not at all

Perfectly

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 ```