4 - RCC - radical / locally advanced / metastatic

Question 1

Pros and Cons of radical nephrectomy over partial

Answer 1

➔ For cT2 or locally advanced RCC, or when partial is not feasible

Pros
1) Better oncological control for higher stage tumour

2) Less Technically demanding esp for minimal invasive

3) Lower complication rate compared to PN
- Van Poppel EORTC 30904: PN (3% haemorrhage, 4% urinary leakage, 4% re-operation) vs RN (1% haemorrhage, 0% urine leak, 2% re-op)

4) Lower positive surgical margins

5) Renal function preservation is worse than PN, but no definite evidence on poor OS
- Brian Lane / Campbell JU 2013 showed surgical CKD (eGFR <60) has better renal function stability / all cause mortality compared to medical CKD, and does not increase risk of CVD

Cons
1) Worse RFT
- EORTC 30904: PN has 21% absolute risk reduction in moderate or severe CKD (eGFR<60); however risk of eGFR<30 or <15 was similar

Question 2

What structures are removed in radical nephrectomy?

Answer 2

• En-bloc removal of kidney, peri-renal fat, and Gerota’s fascia
• Ureter transected at iliac fossa

Question 3

What are the attachments of Gerota fascia?

Answer 3

Anterior: passes anterior to great vessels, and fuse with contralateral Gerota’s fascia

Posterior: fuse with psoas fascia, lateral to side of vertebral body

Superior: fuse at kidney upper pole, split to enclose the adrenal, then fuse up again to form suspensory ligament of adrenal gland, and fuse with diaphragm

Inferior: Does not fuse together; posterior layer descends downwards and fuse with iliac fascia, while anterior layer blends with connective tissue of iliac fascia

Question 4

Steps in right radical nephrectomy

Answer 4

(Usual pre-op, antibiotics etc)

Lap right radical ➔ left lateral position
Also need additional liver retraction port

1) White line of Toldt is incised, and hepatic flexure and ascending colon is medially reflected, in a plane anterior to Gerota Fascia

2) Kocher maneuvre (incision at lateral peritoneal reflection of duodenum, and medially reflect the duodenum to expose IVC and aorta)

3) Right ureter is identified and ligated at the iliac fossa level
- trace up to identify the renal hilum

4) Right renal vein isolated

5) Ligation of right gonadal veins (enters directly to IVC, ligated to avoid bleeding)

6) Right reanl artery isolated to right of IVC

7) Two large hemoloc and 0-silk suture ligature are used to secure main renal artery first, then vein

Question 5

Steps in left radical nephrectomy

Answer 5

(Usual pre-op, antibiotics etc)

Lap approach ➔ right lateral position

1) White line of Toldt is incised, and splenic flexure and descending colon is medially reflected, in a plane anterior to Gerota Fascia

2) Spleno-colic ligament is divided

3) left ureter identified and ligated at iliac fossa
- trace up to identify hilum

4) Left renal vein isolated (which receives left gonadal, adrenal, and lumbar tributaries)

5) Left renal artery isolated from posterior approach (avoid inadvertent ligation of SMA)

6) Two large hemoloc and 0-silk suture ligature are used to secure main renal artery first, then vein

Question 6

Would you perform an ipsilateral adrenalectomy concurrently with a radical nephrectomy (RN)?

What is the rationale?

Answer 6

Routine adrenalectomy is not needed, because:
1) No survival benefit proven by Brian Lane’s prospective study JU 2009
2) Chance of adrenal involvement is low, usually <5%
3) CT is highly accurate, with <2% micro-metastasis in radiologically normal adrenal
4) Even if CT positive or intra-op suspected involvement, 90% still benign as per Brian Lane (JU 2009)

Ipsilateral adrenalectomy is only needed if:
i) pre-operative imaging suggests adrenal involvement
ii) intra-op noted the tumour to involve the adrenal in contiguity

Question 7

When would you perform LN dissection during nephrectomy?

Is routine LN dissection needed? Explain the reasons.

Answer 7

Only consider LN dissection if:
1) Visible or palpable LNs during surgery
2) clinically N+ (e.g. radiologically)
➔ for staging, prognosis, adjuvant therapy and follow-up implications
+) Cytoreductive nephrectomy

Routine is not needed:
1) Blom EORTC 30881 (for cN0) and Thompson’s international study (for cN+) showed that there is no survival benefits or oncological benefits
2) RCC metastasise through bloodstream and lymphatic system with equal frequency
3) Lymphatic drainage is also variable, with even extensive LN dissection cannot be expected to remove all possible sites of LN metastasis

Question 8

What is the template for LN dissection for RCC

Answer 8

➔ only perform if cN+ or visible/palpable LN for staging purposes, not routine

Proposed by Blom/Van Poppel for extended LND:
- LNs surrounding the ipsilateral great vessel and the inter-aortocaval region
- from the crus of the diaphragm to the common iliac artery.

Question 9

Transperitoneal or retroperitoneal approach for radical Nx?

Answer 9

Depends on the tumour factor (location of tumour), patient factor (obese, Hx of surgery, CAPD), surgeon factor (any expertise)

RCT by Gill (2005) showed there is no difference in blood loss, peri-op complications or hospital stay
(evidence for PNx = RECORD2)

Question 10

What are the pros and cons of retroperitoneal approach for radical nephrectomy?

Answer 10

Pros and Cons of retro
+) Easy access to renal artery
+) Avoid peritoneum entry, suitable for those with adhesions / CAPD / obese
+) Minimise post-op ileus
+) Minimise risk of spleen injury

-) Exposure to renal pedicle not as good as transperitoneal
-) Not possible for lymphadenectomy or venous thrombectomy
-) No examination of peritoneum
-) Unsuitable for patients with severe scoliosis or cardio-pulmonary problems
-) Need to divide large muscles (LD, serratus posterior inferior, ext and int oblique muscles, transversus abdomens)
-) Risk of pleural injury
-) Risk of injury to peripheral nerve

Question 11

What are the pros and cons of transperitoneal approach for radical nephrectomy?

Answer 11

Pros and Cons of transperitoneal
+) Better and rapid exposure to renal hilum
+) Possible for lymphadenectomy or venous thrombectomy
+) Examination of peritoneum for metastasis
+) Suitable for patients with severe scoliosis or cardio-pulmonary problems where retro is not possible
+) Lower risk of pleural injury or injury to peripheral nerve

-) Access to renal artery not as good as retroperitoneal
-) Difficult or not suitable for those with adhesions / CAPD / obese
-) More post-op ileus
-) Higher risk of spleen injury

Question 12

Open or lap or robotic radical nephrectomy?

Answer 12

No evidence showing oncological outcome is different between different approaches

Laparoscopic is shown to be superior to open in a retrospective study by Hemal:
+) Shorter hospital stay
+) Less blood loss
+) Less analgesics use
-) Longer OT time

Robotic vs Lap is shown to be similar in retrospective study by Jeong:
- Similar complication rates
- But longer operating time and higher hospital costs

Question 13

Physical examinations that may suggest venous thrombus in RCC

Answer 13

• LL oedema
• Non compressible varicocele (usually left side)
• Caput medusae

Question 14

Classification for locally advanced RCC

Answer 14

Neves or Novick

Neves
0 - renal vein
1 - <2cm from renal vein ostium
2 - >2cm from renal vein osmium, below hepatic vein
3 - above hepatic vein, below diaphragm
4 - above diaphragm

Novick
1 - renal vein
2 - IVC below hepatic vein
3 - above hepatic vein, below diaphragm
4 - above diaphragm
————————–
T3a:
i) renal veins or segmental branches
ii) pelvicalyceal system
iii) peri-renal or renal sinus fat

T3b: extends into vena cava below diaphragm

T3c:
i) extends into vena cava above diaphragm
ii) invades wall of vena cava

Question 15

Does IVC thrombus extent affects survival?

Answer 15

Based on International RCC - venous thrombus consortium (IRCC-VTC) largest cohort:

5-year survival:
- 45%: renal vein thrombus
- 40%: IVC below diaphragm
- 20% IVC above diaphragm

Question 16

Additional workup of RCC with IVC thrombus

Answer 16

In addition to usual Ix like contrast CT with angiogram phase, additional Ix can help to determine the superior extent of tumour thrombus to guide surgical approach:

1) MRI scan
- Slightly higher sensitivity and specificity for tumor thrombus
- T2W provides a superior delineation of uppermost tumor thrombus

2) Venous cavography
- when MRI or CT is equivocal, or contra-indicated for CT or MRI

3) TEE
- evaluation of tumour extension
- monitor embolism if any
- assessment of pre-load and after-load during IVC clamping

Question 17

Mortality of IVC thrombectomy

Answer 17

Neves I = 1%
Neves II = 20%
Neves III = 26%
Neves IV = 47%

Question 18

How to remove Neves type 0 thrombus

Answer 18

Neves 0 = renal vein
aka Novick I / T3a

• Perform radical nephrectomy as usual
• Confirm extent of thrombus with gentle palpation and USG
• Two Satinsky clamp applied at junction between renal vein and IVC
• transect the renal vein proximal to Satinsky clamp
• Caval defect closed with 4-O prolene

Question 19

How to perform IVC thrombectomy for Neves 1-2 thrombus

Answer 19

i.e. infrahepatic
Neves 1 = <2cm from renal vein ostium
Neves 2 = >2cm from renal vein ostium, but below hepatic vein

1) TEE to evaluate cephalic extent of thrombus

2) Chevron incision
- or thoraco-abdominal incision if large upper pole tumour

3) Confirm thrombus level by gentle palpation and USG

4) Vessel control by Successive clamping with Rummel Tourniquet:
i) Ipsilateral renal artery
ii) IVC below thrombus
iii) Contra-lateral renal vein (+/- right renal artery if left sided tumour because lack of collateral venous drainage, so would cause congestion if only right renal vein clamped but not artery)
iv) IVC above thrombus
v) Accessory hepatic veins are ligated to caudate lobe - to gain 2-3cm extra infra-hepatic IVC exposure

5) IVC cavotomy with Potts scissors

6) Thrombus and kidney removed en-bloc

7) IVC closed with 4-O Prolene

Question 20

Any difference in surgery for right vs left Neves 1-2 RCC?

(also: Why does left RCC with IVC thrombectomy more difficult?)

Answer 20

• Right renal vein has no collateral drainage
• Whereas left renal vein has collateral drainage by gonadal / lumbar / adrenal veins

Therefore for surgery for left RCC with Neves 1-2 IVC thrombus, need to perform additional clamping of right renal artery, otherwise only clamping right renal vein would cause congestion

This is not needed for right RCC, as clamping of left renal vein will not cause congestion, therefore left renal artery does not need to be clamped

Question 21

How to approach if there is caval wall invasion noted during IVC thrombectomy?

Answer 21

1) IVC lumen can be safely narrowed by half

2) Reconstruction with PTFE graft if needed

3) Resection of infra-renal IVC without reconstruction is possible, due to extensive venous collateral network esp lumbar

4) For right side RCC, resection of supra-renal IVC (below hepatic vein) without reconstruction is possible, as long as intact left gonadal / lumbar / adrenal veins for drainage of left side kidney

5) For left side RCC, resection of supra-renal IVC (below hepatic vein) also require:
- auto-transplantation of right kidney
- saphenous venous graft of right renal vein to splenic / portal / or inferior mesenteric vein

Question 22

How to perform IVC thrombectomy for Neves 3 to 4

Answer 22

Neves 3 = above hepatic vein, infra-diaphragmatic
Neves 4 = supra-diaphragmatic

MDT approach with HBP, CTS, Anaes

1) TEE to evaluate cephalic extent of thrombus

2) Chevron incision + Median sternotomy

3) Liver mobilised by Langenbeck maneuvre to allow exposure to retro-hepatic IVC

4) Ligate renal artery and ureter

5) Circulatory control
- Veno-venous bypass (for III, and selected IV thrombus)
- CPB+DHCA (cardiopulmonary bypass + deep hypothermic circulatory arrest)

6) Thrombus and kidney removed en-bloc

7) IVC closed with 4-O Prolene

Question 23

Explain veno-venous bypass for Neves 3-4 RCC

What are the pros and cons

Answer 23

Clamping at
- infra-renal IVC
- IVC above hepatic vein but below right atrium

Cannulate at femoral vein
➔ bypass pump
Back at subclavian vein to SVC

Pros and Cons:
+) No need heparinisation
+) Less blood loss
+) Shorter OT time
-) Not suitable if thrombus up to right atrium
-) Still bleeding from lumbar veins, azygous and hemiazygous vein

Question 24

Explain CPB-DHCA for Neves 3-4 RCC

What are the pros and cons

Answer 24

Cardiopulmonary bypass
Deep hypothermic circulatory arrest

Rationale:
- Put on bypass, systemic cooling to 18’C using bypass machine
- Stop bypass pump ➔ Start of DHCA: 30-45 minutes duration allowed where patient is in state of hibernation with no breathing, heartbeat or brain activity
- Start bypass pump again afterwards

Pros and Cons
+) Bloodless field for careful dissection and thrombus removal
-) Hypocoagulable state on reversal
-) Longer OT time
-) More complications including stroke 6%, AMI

Question 25

What is the role of neoadjuvant systematic therapy before surgery for RCC?

Answer 25

I would not offer neoadjuvant therapy, because there is no high quality evidence supporting its efficacy.

Current evidence suggests that:
1) Rarely leads to significant primary tumour size reduction (<20%)
- by Thomas JU 2009
- neoadjuvant sunitinib

2) Minimal effect in reducing IVC thrombus level
- by Cost EU 2011
- Only 10% reduction in thrombus level
- 30% increase in thrombus height and 4% increase in thrombus
level

3) 20-30% would progress, making initially resectable primary tumor unresectable

4) PROSPER RCC
- showed no RFS or OS benefit even with IO
- neoadjuvant nivolumab + adjuvant nivolumab

5) May leads to poor wound healing rendering surgery more difficult

Question 26

What is the role of adjuvant therapy after nephrectomy for RCC?

Answer 26

Based on KEYNOTE 564, I would discuss for the use of adjuvant Pembrolizumab for patients with high risk RCC:

1) pT2 with ISUP G4 or sarcomatoid
2) pT3-4
3) N+
4) M1NED (i.e. no evidence of recurrence after metastatectomy)

Because it can lead to:
- 10% improvement in 2-year DFS (78% vs 68%)
- Latest update noted improvement in OS

I would not recommend adjuvant targeted therapy

Question 27

Would you recommend adjuvant targeted therapy for RCC?

Answer 27

I would not suggest the use of adjuvant targeted therapy for RCC because:
1) Questionable efficacy:
- only 1 in 3 trials is positive
- meta-analysis showed no DFS / OS benefit
2) High toxicity and discontinuation rate
3) Over-treatment

Current evidence:
1) S-TRAC trial
- positive trial, showed adjuvant sunitinib can increase DFS
- however has high drop-out rate and more G3 or above adverse events
2) The positive results was not replicated with ASSURE:
- sunitinib and sorafenib vs. placebo
- no DFS / OS benefit
- high toxicity
3) PROTECT trial also negative with Pazopanib

Question 28

Tell me the evidence on adjuvant immune checkpoint inhibitors for RCC

Answer 28

1) KEYNOTE 564
- The only positive trial, with Pembrolizumab
- 10% improvement in 2-year DFS (78% vs 68%)
- Latest update noted improvement in OS

** the rest are all negative trials **:
2) PROSPER (neoadj + adj Nivolumab)
3) Checkmate 914 (Nivolumab + Ipilimumab)
4) IMmotion 010 (Atezolizumab)

Question 29

What post-op nomogram for localised RCC?

Answer 29

1) Mayo Leibovich
- based on T stage, size, N stage, necrosis
- for 5-year metastasis
- 2003: for ccRCC
- 2018: expanded for ccRCC, pRCC, chRCC

2) UCLA Integrated Staging System
- T stage, Fuhrman grade, ECOG status
- for 5-year CSS and OS
- for all subtypes

3) Mayo Clinic SSIGN (Stage, Size, Grade, Necrosis) stage

Question 30

Tell me about Mayo Leibovich nomogram

Answer 30

Mayo Leibovich 2003:
- concordance 0.83
- only for ccRCC
- for 5-year risk of metastasis

Based on:
1) T stage (0 if T1a, 2 if T1b, 3 if T2, 4 if T3+)
2) Tumour size (1 if >10cm)
3) Nodal status (2 if N+)
4) Necrosis (1 if +ve)

Low risk = 0-2 (5%)
Intermediate risk = 3-5 (25%)
High risk = 6 or above (70%)

Question 31

Tell me about UCLA integrated staging system

Answer 31

UCLA integrated staging system- concordance 0.68
- for all RCC subtypes
- for 5-year risk of CSS and OS

Based on:
1) T stage
2) Fuhrman grade
3) ECOG

Low risk = T1 + G1-2 + ECOG 0 (90% 5-year CSS)
Intermediate risk (80% 5-year CSS)
High risk = T4 or T3 + G2-4 + ECOG1 (50% 5-year CSS)

Question 32

Why do we need regular FU for RCC?

Answer 32

Based on RECUR consortium

1) Proven OS benefits for patients under surveillance

2) Oncologically benefits:
- Late recurrence with metastasis is possible
- Early detection of local recurrence or distant metastasis allows early curative surgery or treatment

3) Prevent renal and cardiovascular deterioration

Question 33

How to follow-up after radical nephrectomy?

Answer 33

Follow-up protocol based on risk of recurrence from nomogram
- 2003 Mayo Leibovich system for ccRCC
- UCLA integrated staging system for non-ccRCC
- Intensify FU if PNx for T2 disease, or PSM +ve

FU with:
- Clinical history, Sx
- Physical examination
- Blood pressure
- RFT
- Proteinuria
- CT thorax + abdomen

For low-risk profiles at > 3 years and intermediate-risk at > 5 years of follow-up respectively, consider counselling patients about terminating oncological follow-up imaging based on assessment of comorbidities, age, life expectancy and/or patient wishes

Question 34

What risk nomogram is used for metastatic RCC?

Answer 34

IMDC Nomogram
(international mRCC Database Consortium)

1) Karnofsky performance status <80
2) Time from diagnosis to systematic treatment <12m
3) Corrected Ca >ULN
4) Hb <LLN
5) Neutrophil >ULN
6) Platelet >ULN

0 = good risk
1-2 = intermediate risk
>2 = poor risk

Median survival = 43m / 23m / 8m

================
In pre-targeted therapy era, used MSKCC nomogram, instead use LDH (no neutrophilia or thrombocytophilia)

Question 35

Overview of treatment algorithm for mRCC

Answer 35

Review in MDT
Based on disease factor (IMDC risk), patient factor, symptom factor

1) Poor risk
- immediate systematic therapy, not for CN (CARMENA)

2) Intermediate risk
- immediate systematic therapy (by CARMENA)
- consider delayed CN if responsive (by SURTIME)
- can consider CN first if local Sx with low metastatic burden

3) Good risk
- immediate CN in patients with a good performance status who do not require systemic therapy (Heng IMDC review)

4) Oligometastatic disease with feasible complete local control
- immediate CN + Metastatectomy (by Dabestani)

Question 36

Patient presented with RCC + multiple metastasis, how would you approach him?

Answer 36

I would see patient in multi-disciplinary team clinic setting with oncologist

Clarify symptom first to see if asymptomatic
Take bloods including CBC LRFT Calcium

Review contrast CT T+A+P to assess the extent of metastasis, and consider histological diagnosis by Bx

Treatment options would be systematic therapy by combination immuno checkpoint inhibitors, with or without cytoreductive nephrectomy, depending on the IMDC risk stratification as well as

1) Patient factos
- life expectancy
- fitness for operation and Tx

2) Disease factor
- resectability of tumour and metastasis

3) Symptom factors

Question 37

Aim of cytoreductive nephrectomy

Answer 37

Palliative in nature, with aims to
1) Reduce tumour load
- potential source of immunosuppression or tumour promoting growth factors
- hopefully reduce disease burden and new metastasis

2) Palliation of symptoms and reduce Cx
- loin pain
- haematuria
- paraneoplastic Sx e.g. HTN, refractory hyperCa

3) Improve survival
- Heng’s IMDC retrospective review (good risk), immediate -> 20m vs 9m OS
- SURTIME (intermediate), delayed ➔ 32m vs 15m OS

Question 38

Indications of cytoreductive nephrectomy

Answer 38

1) IMDC good risk ➔ immediate CN
- Heng’s IMDC retrospective review: 11.1m median OS benefit (20m vs 9m)

2) IMDC intermediate risk ➔ delayed CN if good response to systematic therapy
- SURTIME: 32m vs 15m

3) When complete resection can be achieved by metastatectomy (Dabastani)

±4) Symptomatic for palliation

Question 39

What are the key evidence for cytoreductive nephrectomy?

Answer 39

20,9,18,14,32,15

1) Heng’s IMDC database retrospective review
- CN + targeted vs targeted only
- 1600 patients
- 11.1m median OS benefit (20m vs 9m)
- 3.1m PFS benefit (7 vs 4m)

2) CARMENA
- MSKCC intermediate to poor risk group
- Immediate CN + Sunitinib vs Sunitinib
- non-inferiority RCT
- no difference in PFS
- i.e. Sunitinib alone is non-inferior to, or even better, than immediate cytoreductive CN + sunitinib (18m vs 14m)
- esp in poor risk

3) SURTIME
- All receives Sunitinib
- deferred CN vs immediate CN
- 88% intermediate risk
- retrospective study
- same PFS
- OS HR 0.57 in deferred CN (32m vs 15m)
- Immediate CN may delay or cause patients ineligible for Sunitinib

Question 40

Should we perform metastatectomy for mRCC?

What are the advantages?

Answer 40

If complete metastatectomy if possible, then it should be done

Dabestani’s systematic review on Lancet Oncology:
- complete metastatectomy has survival benefit 40m vs 14m

Advantages:
1) Improve DFS and OS
2) Local symptom control
3) Acceptable surgical morbidity
4) Delay systematic therapy

Question 41

Modalities for local therapy for RCC metastasis

Answer 41

Metastatectomy is the most appropriate treatment if possible, esp for:
1) lung
2) liver
3) pancreas

Except for brain or bone metastasis ➔ treat with stereotactic RT (bone can consider metastatectomy or curettage based on case series)

Question 42

Should we give adjuvant therapy after complete metastatectomy?

Answer 42

No benefit for targeted therapy, but controversial for immunotherapy

1) RESORT study
- adj Sorafenib
- negative trial with no difference in RFS

2) KEYNOTE-564
- adj Pembrolizumab
- subgroup of M1 NED showed improvement of DFS
➔ however no study has compared adj immuno vs. active surveillance and upfront dual-IO upon progression

Active surveillance trials (e.g. MaRCC trial) for oligometastatic RCC showed that can be observed for up to 16 months before systemic therapy is required due to progression, therefore it is reasonable to observe too

Question 43

What is the role of chemotherapy for mRCC? Why?

Answer 43

No role, because RCC is chemo-resistant.

This is because RCC arises from proximal tubules, which has high expression of multi-drug resistant P-glycoprotein

Question 44

What are the first and second line systematic therapy for mRCC?

Answer 44

Depends on IMDC risk class

First line “ALCI”
IMDC favourable risk:
1) Pembro + Axitinib (KEYNOTE 426)

2) Pembro + Len-va-tinib (CLEAR)

3) Nivo-lumab + Cabo-zan-tinib (CHECKMATE 9ER)

IMDC intermediate or poor risk
All of the above
+4) Nivo-lumab + Ipilimumab (CHECKMATE 214)

==================
SECOND LINE “SPC” if cannot tolerate IO
Favourable risk
1) Sunitinib (Molzer)
2) Pazo-panib (COMPARZ)
Intermediate or poor
3) Cabo-zan-tinib (METEOR)

Question 45

Explain targeted therapy for mRCC

Answer 45

It is a form of systematic therapy using molecular agents to block cancer cell growth by targeting specific molecules needed for carcinogenesis and tumour growth

Currently used as combination with immune checkpoint inhibitor as first line, and as second line

e.g. TKO against VEGF-receptor
1) Axitinib (+PDGF-R)
2) Lenvatinib (+FGFR)
3) Carbozantinib (+c-MET + AXL)
4) Sunitinib (+PDGF-R)
5) Pazopanib (+PDGF-R)

Question 46

How are TKI metabolised?

Answer 46

Metabolised in liver completely, therefore dose not require renal dose adjustment

Question 47

What are the TKI toxicity?

Answer 47

1) Constitutional esp Fatigue (50%)
- weight loss
- GI upset with nausea and diarrhoea

2) Hand-foot skin reaction (20%)

3) Endocrine:
- Hypothyroidism (14%)
- DM / Hyperlipidemia (pazopanib)

4) Cardiovascular
- HTN
- Thromboembolism

5) Pneumonitis

6) Nephrotoxicity if sunitinib

7) Hepatotoxicity

8) Myelosuppression

Question 48

Compare the second line TKI for mRCC

Answer 48

“SPC”

1. Sunitinib
Targets VEGFR-R and PDGF-R
Based on Motzer JCO: superior than IFN-α
+) Well known side effect
-) More AEs e.g. fatigue, hand-foot syndrome, thrombocytopenia than pazopanib
-) Less QoL than pazopanib
-) Less preferred by patients

2. Pazopanib
Targets VEGF and PDGF R
Based on COMPARZ trial:
+) Oncology similar PFS and OS with sunitinib
+) Better QoL, less side effects
-) More hepatotoxicity

3. Carbozantinib
Targets VEGF-R + C-MET + AXL (escape mechanism for resistance)
METEOR study showed:
+) Good PFS and OS
-) More dose discontinuation

Question 49

What are immune checkpoint inhibitors? Explain the mechanism

Answer 49

Immune checkpoint inhibitors are monoclonal antibidies

That targets and blocks inhibitory T-cell receptors (e.g. PD1 CTLA-4) or inhibitory PD-L1 on tumour cell

Thus avoids T-cell deactivation, restore its immunity, and allow to kill tumour cell

Question 50

What are the first line immune checkpoint inhibitors for mRCC?

What are the evidence?

Answer 50

PD-1 inhibitor
- Pembrolizumab
- Nivolumab

CTLA-4 inhibitor
- Ipilimumab

First line “ALCI”

IMDC favourable risk:
1) Pembro + Axitinib (KEYNOTE 426)
- vs. Sunitinib
- OS HR 0.68
- Benefits observed in all risk groups, also regardless of PD-L1 expression

2) Pembro + Len-va-tinib (CLEAR)
- vs. LEN + everolimus + sunitinib
- OS HR 0.66

3) Nivo-lumab + Cabo-zan-tinib (CHECKMATE 9ER)
- vs. Sunitinib
- OS HR 0.60
- Efficacy observed in all risk groups and independent of PD-L1 status

IMDC intermediate or poor risk
+4) Nivo-lumab + Ipilimumab (CHECKMATE 214)
- vs. Sunitinib
- OS HR 0.65 in intermediate and poor risk group
- OS not reached in favourable risk

Question 51

Why is IO combined with TKI in first line of mRCC?

Answer 51

• Different pathway / mechanism
• Different complication profile
• Can be used irrespective of PD-1 expression

Question 52

Contraindications for IO

Answer 52

Exclusion criteria for CHECKMATE 214 (Nivo+Ipi):
- CNS metastasis
- Autoimmune disease
- Steroid
- Immunosuppressant

Question 53

Side effects of PD-1 inhibitor

Answer 53

1) Fatigue (50%)
2) Nausea
3) Immune mediated pneumonitis
4) Immune mediated enterocolitis & hepatitis
5) Pancreatitis
6) Immune mediate endocrinopathies
7) Immune mediate skin reaction