Ca kidney [edmond]

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Ca Kidney

Dr. Edmond WongEAU GL 2010

UCNA 2008Other’s PPT

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Epidemiology and etiology

• RCC: 9th most common malignancy in EU• Annual incidence increase of 2%• Mortality: increase until 1990 , then decrease• Male : Female : 1.5: 1• Peak incidence: 60-70 yo• Etiology factors:

– Smoking– Obesity– HT– 1st degree relative with RCC

• Recommended prophylaxis : Avoid smoking and obesity

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Hereditary tumors:

1. VHL syndrome (clear cell)

2. Hereditary papillary RCC (pRCC)

3. Birt-Hogg-Dube syndrome (chromophobe RCC) 4. Hereditary Leiomyomatosis RCC (HLRCC)

5. Tuberous sclerosis complex

6. Constitutional chromosome 3 translocation

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VHL Disease• Rare, autosomal dominant, familial cancer syndrome• VHL tumor suppressor gene at chromosome 3• One VHL allele is inherited with a mutation inactivation of the other allele

loss of VHL protein and VBC complex decrease destruction of HIF-alfa (transcription factor) accumulate over expression of many genes related to angiogenesis VEGF & PDGF

• Renal-cell carcinoma, arise from the inactivation or silencing of the remaining normal (wild-type) VHL allele

• Manifestation (benign & malignant tumor or cyst):1. CNS hemangioblastomas2. Retinal angiomas / hemangioblastomas3. Pancreatic cyst and endocrine tumor 4. Pheochromocytomas5. ccRCC6. Epididymal cystadenomas7. Endolymphatic sac tumor : located in the posterior area of petrous bone and

frequently involve the dura (present with hearing loss)• Defective VHL gene account for 60% of sporadic RCC

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Mx of VHL

• Multiple RCC in kidney after 20yo• If lesion > 2-3cm increase risk of malignancy• FU if see lesion > 2cm :

– Annual USG– CT/MRI when cyst > 2cm (6-12monthly)

• Mx: – NSS is the aim– Cryo, RFA or HIFU for small lesion < 3cm– PN for lesion > 3cm – RRT if anephric

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Other familial condition

• Birt-Hogg-Dube syndrome: – Autosomal dominant– Associated with chromophobe RCC / oncocytoma– Mutation in Chromosome 17– Features:

1. Fibrofolliculomas (neoplastic proliferation of the fibrous sheath of the hair follicle)

2. Pulmonary cysts 3. Colonic lesion4. Oncocytomas5. Chromophobe RCC

• Familial renal oncocytomatosis– Multi-centric , bilateral tumor– Early stage of onset– Genetic basis unknonw

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• Hereditary papillary renal carcinoma syndrome– The causative gene is the proto-oncogene c-MET

(chromosome 7, for hepatocyte growth factor)– Autosomal dominant– Associated with type 1 papillary renal cell carcinoma

• Hereditary leiomyomatosis and renal cell cancer syndrome– Associated with type 2 papillary renal cell carcinoma– Cutaneous and uterine leiomyoma– Fumarate hydratase gene (chromosome 1)

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Histology and grading

• RCC: 90% of renal malignancies• Arise from proximal convoluted tubule• Fuhrman grading (1982)

– 4-point scale based solely on nuclear features—size, shape, chromasia,and nucleolar prominence

– Most powerful prognostic factor [Novara JU07]– Problem with interobserver reproducibility– 2 tiered scheme (low and high) improve interobserver

agreement (Lang Cancer 2005)

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• Histology:– Clear cell RCC (80%)

• Proximal tubule• Highly vascular • Clear cell (glycogen & cholesterol) or glandular

(eosinophillic , mitochondria)– Papillary RCC (15%) :

• Type 1 : low grade , chromophilic cytoplasm• Type 2 : eosinophilic cytoplasm (worse prognosis) [Pignot Uro

2007]

– Chromophobe RCC (5%)• Arises from cortical portion of collecting duct• Perinuclear halo of microvesicles

– Collecting duct (Bellini) : rare, young , poor prognosis– Medullary cell: rare , from calyceal epithelium, sickle-

cell pt, poor prognosis– Sarcomatoid : infiltrative poorly diff variant of any type

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UCNA 2008

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Steps in development of RCC

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Symptom and Diagnosis

• Most RCC detected incidentally (50%)• Symptom: Flank pain (40%), gross hematuria

(40%), palpable abdominal mass (25%) , all 3 (<10%)

• Constitutional symptoms :Weight loss (33%) Fever (20%) Night sweats Malaise

• Paraneoplastic syndromes (30% on presentation) • 30% present as metastasis • Symptom due to metastastic disease: bone pain ,

cough

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Paraneoplastic syndrome

• 30% on presentation– PTH-like hormone hyper Ca– Renin hypertension– Erythropoietin polycythaemia– Anemia (30%)

• Stauffer’s syndrome: (5%)– Non metastatic hepatic dysfunction– Fever, weight loss– Thrombocytopenia, neutorpenia – Discrete region of hepatic necrosis– Liver fxn normalized in majority of case after

nephrectomy

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Paraneoplastic symptoms

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Important physical finding

• Cervical LN

• Palpable abdominal mass

• Non reducing varicocele

• Bilateral LL edema (venous involvement)

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Lab test

• CBP: Anemia , Plt , neutropenia

• Serum Cr / GFR (esp bil tumors)

• CRP/ ESR

• ALP

• Corrected serum Ca

• Isotope scan

• 24 hr urine

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Separate renal fxn

• When solitary kidney or bilateral tumors

• When RFT compromised

• Patient with co-morbid disorder with risk of future renal impairment (DM, chronic pyelonephritis, renovascular disease , stone, renal polycystic disease)

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Radi Investigation

• USG as screening• Doppler USG: venous extension• CT: Primary tumor extension, LN , adrenal extension ,

morphology of contralateral kidney, metastasis (liver) • MRI: Local growth, IVC involvement• Contrast enhance USG: tumor thrombus• CT angiogram: vascular anatomy• PET: remain to be determine• To differentiate solid or cystic

– If cystic : Bosnik Classification– If solid : presence of enhancement

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CT• Enhancement in renal mass: change in >20 HU strong evidence

of enhancement• But poorer enhancement than surrounding parenchyma• Absence of fat content (vs AML) • CT phase:

1. *Pre-contrast phase: 3-5mm slide with overlap to reduce partial volume effect

2. Iodinated contrast (50-100ml @ 150-300mg/ml Iodine rapid IV)3. Cortico-medullary phase (30-70s): good for vessels4. *Nephrographic phase (70-180s) : optimum depiction of renal mass

that do not enhance to the same degree as renal parenchyma5. Excretory phase (10-20min): for collecting system

• Isodense but enhancing: Pseudotumor hypertrophied cortical column (of Bertin) or dysmorphic segment

• Provide information on: 1. Function & morphology of contralateral kidney2. Primary tumor extension + extrarenal spread3. Venous involvement4. Local LN enlargement5. Adrenal gland and liver

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Precautions before CT

• Drugs-particularly metformin/nephrotoxic drugs

• issue of contrast nephropathy

• address contrast allergy

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Metformin• Guideline from European Society of Urogenital

Radiology1. if serum creatinine: normal

• stop metformin (at the time of exam until 48 hours passed and serum Cr remain normal)

2. if serum creatinine: impaired• stop metformin 48 hours before exam, resume

metformin 48 hours later if serum Cr remained at pre-exam level

3. if contrast given to patient taking metformin• metformin stopped immediately• hydration to ensure U/O 100ml/hr x 24 hours• monitor serum Cr, lactic acid and blood gas

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Lactic acidosis

• symptoms:–Vomiting, anorexia, hyperpnea, lethargy,

diarrhea, thirst

• Lab results–blood pH <7.25, lactic acid> 5mmol/L

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Contrast nephropathy• Definition:

– 25% increase in serum Cr , or at least 44umol/L– During 3 days after contrast administration

• Mechanism: – Direct toxic effect on tubular cells– Vasoconstriction:

• High osmolar content induce marked natriuresis and diuresis• Trigger tubulo-glomerular feedback response with constriction of glomerular

afferent arterioles• Resulting in decrease in GFR

• Risk factor: 1. Age > 702. Renal impairment3. DM4. Dehydration5. Congestive heart failure6. Concurrent treatment with nephrotoxic drugs

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• To minimize risk:– Stop nephrotoxic drugs if any– Adequate hydration– Adminstration of N-acetylcesteine: 600mg BD

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Contrast allergy

• Really allergy?• Anaphalactoid reaction:

– Idiosyncratic reaction unpredictably and independently of dosage and concentration of the contrast media

• Related to ionic and high osmolar content of the contrast• Leading to release of different mediators

• Chemotoxic– Severity related to dosage/concentration of contrast media– Also related to characteristics of the agent

• Prevention:– use low molecular non-ionic contrast medium– Corticosteroid

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Metastatic workup

• Chest CT most accurate for chest staging

• At least CXR

• Bone scan/ CT brain: only if symptom

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PET in RCC: primary diagnosis

• Diagnosis– FDG

• Increased background activity of healthy renal tissue and normal FDG excretion in urine can make visualization of primary renal cancers by PET difficult

• Not useful in primary diagnosis• Low sensitivity as compared to CT (60% vs. 91.7%)

Kang et al 2004

– FMISO (fluoromisonidazole)• 18F-FMISO, recognized non invasive method for detecting hypoxia in

tumours– RCC is regarded as resistant to treatment with radiation and

chemotherapy– May be due to malignant hypoxic areas in the tumour.

• Mildly increased uptake in some but not all histologically confirmed RCCLawrentschuk et al (2005)

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PET in RCC: nodal staging and metastasis

• Nodal status– Highly specific for retroperitoneal lymph node metastasis by

using 18F-FDG• PET was 75% sensitive and 100% specific• (92.6% sensitivity and 98.1% specificity for abdominal CT)

Kang et al (2005)

• Distant metastasis– Bone

• High sensitivity and specificity for bone metastasis• Diagnostic sensitivity and accuracy of FDG-PET were 100% and 100%• (bone scan sensitivity and accuracy were 77.5% and 59.6%, respectively)

Wu et al (2002)

• 100% specificity for 18F-FDG PET for differentiating between benign lesions and bone metastases

Kang et al (2004)

– Soft tissue• PPV for metastases to soft tissue was 98.4%

Kang et al (2004)

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PET in RCC: Summary

• 18F-FDG– Not useful for primary diagnosis because of urinary excretion– Certain role in staging and restaging disease when evaluating

especially visceral, lymph node and bony disease• As a complementary problem solving tool when conventional scans are

suspicious for metastatic RCC but equivocalKang et al (2004)

• Positive FDG-PET is predictive for the presence of metastatic RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations

Majhail et al (2003)

– Superior value of 18F-FDG PET over CT in the evaluation of patients with suspected recurrent RCC

Ramdave et al (2001)

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Bosnik Classification

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Bosnik classification

• Type I: Benign, smooth margin, no septation , calcification or contrast enhancement (no FU)

• Type II: Benign, hyperdense cyst < 3cm , smooth margin ,simple septation , minimal calcification , no contrast enhancement (no FU)

• Type II F: Small risk of malignancy, hyperdense cyst > 3cm , mild thickening wall, hairline septae with minimal enhancement ,nodular and thick calcification , no contrast enhancement (FU)

• Type III: 50% malignant, thick irregular wall & septa with contrast enhancement (surgery or FU)

• Type IV: clearly malignant cystic lesion with contrast enhance soft tissue component (Surgery)

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Proposed screening population

1. ESRF on dialysis– Those with relative long life expectancy with no major co

morbidities(Screening should start from the 3rd yr of dialysis)

2. VHL disease– Biannual CT / USG from 11 yrs of age – Periodic screening for extra renal manifestations

• Regular urinary catecholamines• Regular ophthalmic exam• Regular MRI CNS• Regular auditory exam

– Should also consider genetic analysis in other family members• 3. Other familial forms of RCC• 4. Patients with tuberous sclerosis

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TNM staging

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TNM Staging

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TNM 2009 Change

• Size stratification in T2:– T2a : >7cm , <10cm– T2b : >10cm

• T3a: tumor thrombus extend into renal vein only (RV previous T3b)

• Adrenal invasion: pT4 (very poor prognosis)

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Issues on Renal sinus fat

• RSF invasion carries a worse prognosis then perinephric fat invasion

• Should be not be T3a

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Adrenal invasion

• Adrenal invasion has very poor prognostic value • CSS of pT3a/b with ipsilateral adrenal involvement worse

compare with pT3a/b that did not invade the adrenal gland (p<0.001)

• No difference of pT3a/b + adrenal compare with T4• RCC with adrenal invasion more aggressive then tumor

involve perinephric or renal sinus fat

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Prognostic Factors• Anatomical: TNM stage: size, venous invasion, capsule, adrenal, LN ,

Distance Met • Histological:

– Fuhrman grade– RCC subtype (chRCC >> pRCC >> ccRCC) [Patard JCO05]– Sacromatoid features– Microvascular invasion– Tumor necrosis– Invasion into collecting system

• Clinical: – Pt performance status– Localized symptoms– Cachexia, anemia , Plt count

• Molecular : Carbonic anhydrase IX, VEGF, HIF, Ki67, p53, Phosphatase and tensin homologue, E-cadherin , CD44

• No molecular markers can improve predictive accuracy of current prognostic system, not for routine practice

• prognostic information provided by the RCC subtype is lost when stratified to tumor stage

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Cephalic extent of venous thrombus

• Cephalic extent controversial• Some reports suggest cephalad extent not of prognostic

value as long as tumor is otherwise confined• Others reckon incidence of systemic / locoregional

progression higher with level III-IV VTT• Novick and Glazer 1996

– 5yCSS 56% in 18 patients with thrombus up to RA– All dealt with CPB + DHCA (the gold standard)

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Nomogram

• Nomograms are statistical models specifically designed to maximize predictive accuracy

• Based on a combination of variables that allow for a more individualized prediction of outcome

• Superiority of more complex predictive modeling in providing improved accuracy compared with risk group assignment techniques (TNM, stage)

• A precise and punctual instrument to estimate the prognosis of a single patient

• Concordance index (c-index) : a measure of the predictive accuracy of prognostic algorithms

• CI = 1 (perfect accuracy), CI =0.5 (random chance)

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Pre-op Prognostic model

• Pooled MKSCC and Mayo clinic (2517pt)• Predict outcome of pt treated with nephrectomy• Factors:

1. Size2. Mode of presentation3. LN 4. Necrosis on imaging – Significantly associated with metastastic recurrence after nephrectomy

• Condrodance index of 0.8 [JU 2008]

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Pre-op normogram

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•Accuracy: 84-88%

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Poor prognostic indicator

• MSKCC 1. Low Karnofsky performance status (<70)

2. Elevated LDH

3. Low Hb

4. Elevated corrected Ca

5. Time from initial dx to start of therapy > 1 year

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Post-op predictive models

• MSKCC (Kattan) post-op prognostic nomogram

• UCLA-ISS (Integrated staging system) score

• Mayo Clinic SSIGN (stage, size, grade, necrosis) score

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MSKCC (Kattan)

• 2001(all RCC): TNM, size, Histology, symptoms at presentation Predict 5 yr PFS

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MSKCC (Kattan 2005 )

• ccRCC1. TNM (stage)2. Size3. Fuhrman (grade)4. Necrosis 5. Vascular invasion 6. Symptom at

presentation• Predict 5yr

recurrence • Accuracy : 74%JU 2005

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UCLA- UISS (2001)

• Divided pt into 5 risk group• Statistically significant difference in disease-specific

survival• Base on tumor stage , nuclear grade , ECOG PS• 82-86% accuracy

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UCLA- UISS 2002• Stratified pt into: low, intermediate , high risk group for disease progression• Predict 1-5 CSS & OS• For non metastasis and metastasis disease• Does not predict probability for individual, group instead• Fully validated : accuracy 73%

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Mayo SSIGN score (2002)

• Pt with cRCC (>1800)

• Score based on: TNM, size, nuclear grade, presence of necrosis

• Estimate cancer specific survival (1-10yr)

• Has not yet been validated internally or externally against additional database

• CI: 0.833

Frank , JU 2002

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Which one is most accurate?

• 2404 record, 6 countries• Compare : Kattan, UCLA-UISS, Yaycioglu (pre-op), Cindolo (pre-op) model• Discriminating ability by Harrel c-index• Result:

– All model discriminated well (p<0.0001)– CI : Kattan (0.7), UCLA (0.68), Yaycioglu (0.59), Cindolo (0.615)

• Conclusion: post-op predictive model better then pre-op• Kattan model was most accurate, follow by UCLA• Katten model can be useful in UISS intermediate risk patients

Cindolo , Cancer 2005

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Molecular prognostic model

• CA-IX: marker for response to systemic therapy (high CA-IX high response to IL-2), but dose not predict response to temsirolimus

• B7-H1: expression asso with 4.5x risk of CS mortality• B7-H1 + Survivin: 2.8x CS death• Fxn as inhibitor of T cell mediate antitumoral immunity blockade

with monoclonal antibody result in therapeutic response

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• Poor prognostic factors: – Tumor size > 7cm (i.e >T2)– Fuhrman Grade III or IV– Perinephric/ renal sinus fat invasion – Level of thrombus: RV >> Level I >> Level 2/3– N+ , M+ status

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Impact of level of thrombus on CSS

• Any N, any M: – T3a (RV) vs T3b (level 1): significant (p=0.002)– T3b (level I) vs T3c (level 2+3): Significant

(p=0.002)

• N0M0: – T3a (RV) vs T3b (level 1) : not signi (p=0.725)– T3b (level1) vs T3c (level 2+3) : significant

(p=0.000)

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Other renal Tumor

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Bellini duct carcinoma (collecting duct carcinoma)

• Very rare type of RCC• 40% have metastatic at

initial presentation • Most patients die within 1–

3 years from dx• Largest case series (n =

81) outcome: – At diagnosis : Regional

lymph node metastases (44%) distance metastases (32%).

– Survival rate : 48% (5 yrs) & 14% (10 yrs)

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• Sarcomatoid RCC: – High-grade transformation in different RCC types,

without being a distinct histological entity. Worse prognosis

• Renal medullary carcinoma: – Devastating malignancy, extremely rare – Young men with sickle cell trait. – 2% of all primary renal tumors in 10-20yo– 95 % present with Metastatic disease

• Unclassified RCC: – Diagnostic category for RCC that cannot be assigned

to any other category of RCC-type carcinoma• Papillary adenoma:

– Tumors with papillary or tubular architecture – Low nuclear grade and < 5 mm in diameter– only found incidentally in a nephrectomy specimen

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Multilocular cRCC (multilocular cystic RCC):

– There are no strict histopathological criteria – In the WHO 2004 classification , multilocular cRCC is an

independent entity, but it is essentially a well-differentiated cRCC.

– 3.5% of surgically treated kidney tumors – Metastases of this tumour have not been described – Bosniak classification, presents as a Bosniak type II or III cystic

lesion – This type of Bosniak lesion can also be due to a mixed epithelial

and stromal tumour of the kidney (MESTK), a cystic nephroma, or a multilocular cyst, all benign lesions.

– Pre-operative biopsy and intra-operative frozen-section analysis does not lead to a correct diagnosis.

– All these tumours are treated with the same operative strategy.– If technically feasible, a nephron-sparing procedure is the

procedure of choice for a complex multicystic renal mass with enhanced density is observed

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• Translocation carcinoma– uncommon tumours, children & young adults. – 90% involve the transcription factor E3 (TFE3) located on Xp11.2– At an advanced stage at presentation , but relatively indolent course– Another rare group of RCCs : translocation (t (6; 11) (p21; q12)) has

also been reported

• Mucinous tubular and spindle cell carcinoma– Associated with the loop of Henle. – behave in a low-grade fashion

• Metanephric tumours– 3 types: 1) metanephric adenoma,2) adenofibroma, and 3)metanephric

stromal tumour. – Very rare benign tumours and surgical excision is sufficient

• Renal epithelial and stromal tumours (REST)– a new concept that brings together two benign mixed mesenchymal and

epithelial tumours: 1) cystic nephroma and 2) mixed epithelial and stromal tumours

– Imaging REST cystic lesions : Bosniak type III – Consider to be benign and surgical excision as curative

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Carcinoma associated with ESRF• Cystic degenerative changes (acquired cystic kidney disease [ACKD]) and a higher

incidence of RCC are typical features of ESKD (end-stage kidney disease). • Incidence of ACKD : 50% in patients undergoing dialysis, but also depends

– on the duration of dialysis– gender (3x more common in men) – diagnostic criteria of the method of evaluation.

• RCCs of native end-stage kidneys : 4% of patients. • Lifetime risk of developing RCCs : > 10 times higher than general population. • RCC in ACKD is characterized by :

– multicentricity and bilaterality– found in younger patients (mostly male)– less aggressive behavior.

• It is usually quite aggressive in transplanted patients (immunosuppression) • Histological spectrum similar

– Predominant form is pRCC, 41-71% of ACKD-associated RCC vs 10% in sporadic RCC.

– The remaining tumours are mostly cRCC • 2 new renal tumor associated with ESKD: [Tickoo et al]

– 1)acquired cystic disease-associated RCC‘ and – 2)‘clear-cell pRCC‘. – These entities have not generally been accepted..

• Patients with ESKD should undergo an annual ultrasound evaluation of the kidneys

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Other benign renal tumor

• Renal cortical adenoma

• AML

• Oncocytoma

• Metanephric adenoma

• Cystic nephroma

• Renal leiomyoma

• Mixed epithelial stromal tumor

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Oncocytoma• Benign tumors• 3-7% of all renal tumors • Presentation: incidental , rarely loin pain or hematuria• Imaging appearance:

– Imaging characteristics alone are unreliable to differentiate from RCC

– Central stellate scar in CT or MRI– Spoke-wheel pattern of feeding arteries on MRA

• Gross: – Well –circumscribed, homogenous, tan color lesion– Central stellate scar (entrapped tumor cells exhibiting focal

cytoplasmic clearing• Histology:

– cells with deeply eosinophilic cytoplasm packed with mitochondria originate from intercalated cell of the collecting ducts

– EM: cytoplasm loaded with mitochondria (cytoplasmic eosinophilia, brown)

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• Genetics: – loss of chromosomes Y and 1, – Translocation of chromosome 11– Heterozygosity on C 14q

• Pre –op percutaneous biopsy : low specificity , oncocytotic cells are also found in – cRCC (granular-cell variant of RCC)– Eosinophilic variant of chromophobe RCC

• ‘Watchful waiting’ : selected cases of histologically verified oncocytoma (level of evidence: 3)

• After nephrectomy: no need to FU as benign

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AML• 1% of surgically removed tumor • benign mesenchymal tumor composed

1. Adipose tissue2. spindle and epitheloid smooth muscle cells, 3. abnormal thick-walled blood vessels.

• Sporadically (80%)– 4x more likely in women, middle age– 80% Rt side– Growth rate 5% per year

• In tuberous sclerosis (20%)– F: M = 2:1 , 30yo– multiple, bilateral, larger– Growth rate 20% per year– likely to cause spontaneous hemorrhage

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• Presentation: incidental (50%), loin pain , mass , hematuria• Massive retroperitoneal bleeding (10%): Wunderlich’s syndrome• Dx

– USG: bright echo- pattern without acoustic shadow (vs stone)– CT and MR imaging: presence of adipose tissue (low HU -20 to 0)– Biopsy is rarely useful. Difficult to differentiate between tumours

composed predominantly of smooth muscle cells and epithelial tumours. • Epitheloid AML is a potentially malignant variant of AML• Complications:

– retroperitoneal bleeding – bleeding into the urinary collection system– Bleeding tendency : irregular and aneurysmatic blood vessels

• The major risk factors for bleeding : – tumour size (>4cm) – the grade of angiogenic component of the tumour– Presence of tuberous sclerosis

AML

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• Primary indications for intervention – Symptoms such as pain, bleeding or suspected

malignancy. • Prophylactic intervention is justifiable for:

1. large tumors (the recommended threshold is≥ 4 cm)2. Females of childbearing age3. Patients in whom follow-up or access to emergency

care may be inadequate • Surgery: Most cases NSS, some RN• Others: selective arterial embolisation (SAE)

and radiofrequency ablation (RFA)• Although SAE is effective at controlling

haemorrhage in the acute setting, it has limited value in the longer-term management of AML

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Angiomyolipoma

• “Oesterling and coworkers (1986) reported that 82% of patients with AMLs larger than 4 cm in diameter were symptomatic, with 9% in hemorrhagic shock at the time of presentation; in contrast, patients with smaller tumors were symptomatic 23% of the time”

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Tuberosis Sclerosis• Genetic multisystem disorder characterized by widespread

hamartomas in several organs: brain, heart, skin, eyes, kidney, lung, and liver

• Bilateral, multifocal AML; 1-3% had RCC• AD with incomplete penetrance; 1 in 5,800-10,000• Features:

– adenoma sebaceum / ungual or periungual fibroma / shagreen patch / hypomelanotic macule

– retinal hamartoma / cortical tuber / subpendymal nodule or astrocytoma– cardiac rhabdomyoma / lymphangiomyomatosis

• Affected genes TSC1 (9p34) and TSC2 (16p13.3) code for hamartin and tuberin.

• TSC2 mutations more common than TSC1, esp in sporadic cases (70-80%)

• The hamartin-tuberin complex inhibitis the mTOR pathway, thus affecting cell proliferation and growth

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• Diagnostic criteria : 2 major or 1 major + 1minor clinical feature

• CNS complications occur in 85% of TS patients :– Mental retardation– autism, behavioral problems– epilepsy

•• Cortical tuber,

subependymal nodule, subependymal giant cell astrocytoma

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• Renal complications in TS– Commonest cause of TS-related death– AML occurs in 70-90% of TS

• 20% to 30% of all AMLs are found in patients with TS• AML in TS patients (c.f. sporadic AML) :

– Mean age at presentation is 30 years– Female-to-male predominance of 2:1 – Bilateral and multicentric– Accelerated growth rates and symptomatic presentation

• Massive retroperitoneal hemorrhage from AML : Wunderlich's syndrome

• Ref : Campbell v9 Chapter 47, Curatolo et al Lancet 2008; 372 : 657-68

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New histological entities

• Thyroid-like follicular tumour/carcinoma of the kidney

• RCC associated with neuroblastoma• Renal angiomyoadenomatous tumour• Tubulocystic carcinoma• Clear cell pRCC• Oncocytic pRCC• Follicular renal carcinoma• Leiomyomatous RCC

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Treatment of Localized RCC

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Small renal mass

• Growth rate

• Chance of being malignant

• Chance of metastasis

• Any predictor of benign of malignant tumor

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Natural History

• Bosniak and associate in 1996–72 small renal tumors (<3.5cm) in 68 pt–FU interval 2-10 years (mean 3.3 years)–Tumor characteristics:

well marginated, homogenous solid tumors

–Tumor growth rate:• median growth rate 0.36cm/year• no metastasis

–32 tumors >3cm excised• all were stage I RCC

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Natural History-Results from Meta-analysis

• 234 renal lesions from 9 institutions undergo a period of active surveillance–overall combined mean size 2.6cm (1.73-

4.08cm)–mean Fu duration 34 months–mean growth rate 0.28cm/year (0-1.76cm)

• Chawla SN, Uzzo RG.The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006

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Pathology of Active Surveillance Series

• In Chawla meta-analysis• 46% of pathology was available• 92% were malignant (reflect selection bias)

– clear cell (>90%)– 9% (papillary)

• grading available in 76%– low grade more common (again reflect selection bias)

• Lesion size at presentation did not predict the overall growth rate• Progression to met disease was identified in only 1% of lesions• Conclusion : surgery remain standard of care

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Predictor of Malignancy: size related

Analysis of 2935 nephrectomy specimens in Mayo Clinic Frank , et al: Solid renal tumors: an analysis of pathological features related to

tumor size. J Urol 170. 2217-2220.2003;

<1cm 1-2cm 2-3cm 3-4cm

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Correlation of growth rate and malignancy

• Most series confirmed lack of growth does not correlate with benign pathology

• Largest one from ‘zero growth’ study: Uzzo Ju2007– 106 enhancing renal mass observed for 29 months– 33% had zero net growth– likelihood of pathologically confirmed RCC were identical

in ‘zero growth’ and ‘active growth’ groups.– no difference in

• Age• Solid /Cystic appearance

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Growth rate of Benign and Malignant lesions

• No difference in Growth rate –comparing benign lesions (oncocytomas) and

RCC

• Chawla SN, Uzzo RG.The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006

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Predictors for Malignancy

Size X cystic or solid component

X Growth rate

X Age of patient

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Any Predictors of Progression?

• symptoms?

• size of lesion?

• cystic or solid components?

• Pathology grading?

• Histological subtype?

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Clinical Predicators of progression

• Symptomatic tumors tend to have more rapid growth in a series of 22 patients–45ml/year v.s 16ml/year

• but no comparision of initial tumor size• Sowery RD, Siemens DR.Growth characteristics of

renal cortical tumors in patients managed by watchful waiting. Can J Urol 2004.

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Symptom developmentcorrelate with worse outcome

• Tumor related symptoms–only 2 series in literature commented on

symptoms development–most were haematuria–onset of symptoms warrant consideration of

surgical removal• associated with high grade/stage• lower 10 year cancer specific survival

– Tsui KH,etal Renal cell carcinoma: prognostic significance ofincidentally detected tumors. J Urol 2000

– Ou YC, Yang CR, Ho HC et al. The symptoms of renal cell carcinoma related to patients’ survival. J Chin Med Assoc2003

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Radiological Predictor• Lesion size

–not correlate with growth rate in multiple studies/meta-analysis

• Cystic and solid components–cystic component tend to have better prognosis

• but not consistently predict a slower growth rate

• Still no reliable radiographic variable to predict growth

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Pathological predictors• Nuclear grade

–association between nuclear grade and tumor growth is not consistent

• Histological subtypes–disease progression appeared to related to tumor

histology• More favourable in chromophobe and papillary RCC

–but no study has investigated the kinetics of different histological variant

• Molecular markers –still at the stage of experiment

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Any Predictors of Progression?

symptoms

?Histological subtype (may be)

X size of lesion

X cystic or solid components

X Pathology grading

108

How common is tumor metastasis for small renal tumor?

109

Morbidity of observation-metastasis

• progression into metastasis is very rare–in pooled analysis of 286 patients, only 3

progressed to metastasis (~1%)–baseline size and growth rate were not predictive–all were symptomatic at progression (haematuria)

• Chawla S.N, et al: The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 175. 425-431.2006;

• Sowery R.D., Siemens D.R.: Growth characteristics of renal cortical tumors in patients managed by watchful waiting. Can J Urol 11. 2407-2410.2004; Abstract

• Lamb G.W, et al: Management of renal masses in patients medically unsuitable for nephrectomy—natural history, complications, and outcome. Urology 64. 909-913.2004;

• Crispen P.L., Uzzo R.G.: The natural history of untreated renal masses. BJU Int 99. 1203-1207.2007

http://80-www.mdconsult.com.ez.ekg.org.hk/das/journal/view/N/15238326?PAGE=1.html&source=MI&ANCHOR=abs

110

Reasons of apparently low rate of metastasis

• relatively short duration of Follow up (~2-3 yrs)

• presence of benign disease because of selection bias (small homogenous tumors)

• treatment of growing lesions

111

Limitations & Pitfall• most were small retrospective series from single

institutions • significant selection bias

– tend to include small, well marginated and homogenous renal mass • significant proportion of these tumors are benign

• pathological evaluation not available in all patients under observation

• series usually contained subpopulation of patients with aggressive tumors– e.g. 25% of masses doubled in size in 12 months in

Volpe’s Series 2004.

112

Active Surveillance• Delaying treatment for evidence of

progression• Rationale:

–significant proportion were benign disease ~20%–even for RCC

• slow growth rate in short-medium term• low potential to metastasize• delayed management does not appear to compromise

survival or increase surgical morbidity

–many RCC occurred in mainly elderly• risk of peri-operative morbidity is higher than

progression of tumor

113

Common Indicationsfor surveillance

• multiple co-morbidities

• patient’s choice

• fear of the potential need of renal replacement

• tumor in solitary functioning kidney /bilateral renal tumors

114

Concerns

• results from literature are subject to selection bias–application in young fit patients can be

dangerous

• awaiting studies to confirm the safe use of active surveillance

• factors that trigger discontinuation of surveillance remains to be established

115

small renal mass in elderly

• FU on 537 patients >75 and renal tumor <7cm for ~ mean 3.9 years– examine overall survival

• Death rate 28%– cardiovascular mortality most common (28%)– death from tumor progression 4% only

• Multivariate analysis (predictor of survival)– age, comorbidity but not management type

• predictor of cardiovascular mortality– renal function and comorbidity– nephrectomy is associated with greater loss of function

Lane Br etal. Cleveland clinic.Active treatment of localized renal tumors may not impact overall survival in patients aged 75

years or older.Cancer. 2010 Jul 1;116(13):3119-26.

116

Active surveillance--Messages• Most lesion dx nowadays are < 3cm (80%)• > 80% of SRM are malignancy [Chawla]• Most lesions grow slowly (0.3cm/year) [Chawla , Bosniak]• Morbidity and progression to metastasis appeared low (1%) [Chawla]• And death due to tumor progression for pt on surveillance is low (4%) [Lane

2010]• It seems that AS may be acceptable• Still, there is no reliable predictors whether tumor is malignant or tumor will

progress– Only size correlated to chance of malignancy (but not growth rate, age or features)– Only symptoms correlated to progression (but not size, features or grade)

• Thus even for SRM : treatment is justified (don’t know how to monitor)• However, AS is still advocated in certain situation (see above)• Surgical intervention can be safely deferred in short and medium term.• Active Surveillance is safe in elder patients with multiple co morbidity and short

lifespan– should be initiated with caution, particularly in young/fit patients

• Triggering point for surgery is still at the discretion of urologist.

117

Campbell 9th ed

• Patient with small, solid, enhancing, well-marginated, homogeneous renal lesions, who are elderly or poor surgical risks, can safely be managed with observation and serial renal imaging at 6 months and 1 year interval

• BUT this approach is not appropriate for patients with larger (>3cm), poorly marginated, or nonhomogeneous solid renal lesions.

• Observation is not advisable in younger otherwise healthy patients with small, solid tumors that have radiological characteristics of RCC

• follow up data of natural history of small renal masses is limited and imaging can not predict the behavior of renal mass. Generally, AS is only suitable for elderly or short life expectancy patient

118

Role of renal biopsy

• Aim: to determine malignant and type• Not routinely done because: PPV of imaging is

so high that a –ve bx result dose not alter management

• Indication: only when it can avoid operation1. Renal abscess 2. Lymphoma3. Before ablative therapy 4. Before Systemic therapy without previous histology 5. Surveillance

119

• Advantage: – Confirm dx– Tumor subtype and grading (70% correct) – Impact on change of management (60%)

• Disadvantage: – Difficult to diff benign from low grade malignant disease – Chromophobic RCC may mimic oncocytoma – Chance of False negative due to sampling error (24%)

• Core biopsy: Higher sensitivity and specificity (>90%) than FNAC series

• 10-20% insufficient sampling (sampling error) • Both FNA and bx are safe• Cx: seeding (< 0.01%), bleeding (2%), penumothorax

(1%), AV fistula , visceral injury• Not recommended for larger renal mass scheduled for

nephrectomy

120

Treatment Options: Treatment Options: Factors Driving DecisionsFactors Driving Decisions

1.1. Patient factorsPatient factors– Age, comorbidity, critical anticoagulation, other

cancers

2.2. Kidney factorsKidney factors– Renal function, status of contralateral kidney,

prior renal surgery

3.3. Tumor factorsTumor factors– Size and number of tumors, location, symptoms

4.4. Physician factors?Physician factors?– Experience, support personnel, available

technology

121

Choice of operation localized RCC

• 1st must decide Radical nephrectomy vs NSS ?• Then : Open vs Lap ?• Result of ORN ?• Role of LRN ?• Therefore:

– ORN vs OPN (role of NSS)– ORN vs LRN (role of LRN) – OPN vs LPN (role of LPN) – Robotic

• Ablative surgery: Cryotherapy , RFA

122

Txn of Localized RCC

• Surgery is the only curative approach for RCC

• RN +/- adrenalectomy +/- LND is the reference standard for curative treatment for localized RCC with normal fxn contralateral kidney [Lam EU04]

123

Adrenalectomy• Incidence of adrenal involvement is low & related to stage [UCLA

series]– T1-2: 0.6%, T3-4: 8%, overall : 4%– All adrenal metastases occurred in

• Upper pole (all low stage and 60% of high stage)• High stage • Multifocal tumors (30% of high stage RCC adrenal mets)

– CT is >90% in SP and SV in detecting these metastases• Not indicated in:

– Pre-op staging (CT/MRI) show normal adrenal – Intra-Op: no suspicious metastasis– No direct invasion by a large upper pole tumor

• Indicated: 1. Pre-op CT show suspicious adrenal involvement 2. Tumor at upper pole3. Tumor of high stage T3/44. Intra-op:

• Nodule within the adrenal gland• Direct invasion of the adrenal gland by large upper pole tumor

124

LN dissection• Reasons why routine LN dissection is not required:

1. Tumors metastasize through bloodstream and lymphatic system with equal frequency.

2. Lymphatic drainage is variable3. Even extensive dissection cannot be expected to remove all

possible site of metastasis.4. RLND doest not improve long term survival5. In modern series eg. UCLA Pantuck 2004 : no difference in

local recurrence rate (~3%) with or without LND

• When LND is required: – LND limited to hilar region or palpable or CT detected for

staging purposes– During cytoreductive nephrectomy: survival was longer who

underwent LND than those without [Vasselli (NCI)]

125

LN dissection

• There is no RCT with mature results published for this area

• I would not separately perform LND because I believe the staging accuracy is unlikely to be improved further by a LND if the preop CT is negative

• However I would perform LND when– There are obviously grossly enlarged LN – this is mainly for

staging purposes– The patient is having cytoreductive nephrectomy in preparation

for systemic immunotherapy because retrospective series has shown survival benefit (5 months longer)

126

Embolization

• No benefit before routine nephrectomy

• For symptom controlled in pt: – Unfit for surgery– Present with non-resectable disease

• Reduce inta-op blood loss before resection of bone or vascular met

• Relieve pain in bone or paravertebral met

128

Radical nephrectomy: Robson

• Radical nephrectomy consists of– Early ligation of renal artery and vein– Removal of kidney outside the Gerota’a fascia

(25% of localized RCCs manifest perinephric fat involvement)

– Excision of the ipsilateral adrenal gland– Performance of a complete regional

lymphadenectomy from crus of diaphragm to the aortic bifurcation

129

Contemporary Indications for Open Nephrectomy

• Clinical T3b-c / T4 disease

• Size > 13 cm (T2b >10cm)

• Hilar / interaortocaval adenopathy

Hilar Encasement by Adenopathy Tumor = 16 cm

130

Approach: Transperitoneal• Advantages

– rapid and excellent exposure of renal pedicle that allow early pedicle control

– minimize chance of tumor thrombi from entering systemic circulation

– able to inspect peritoneal cavity for evidence of metastasis– able to deal with concurrent extra-renal disease that require

operation. (e.g Gallstone)– kyphoscoliosis/severe pulmonary disease where retroperitoneal

approach is not suitable

• Disadvantages: – not suitable in patients with prior history of multiple abdominal

operation– difficulty in patients with obesity– higher incidence of postoperative ileus and possible long term

intra-abdominal adhesion formation

131

Retroperitoneal Approach

• Advantages– avoid contamination of peritoneal cavity, drainage is limited at

retroperitoneal space– suitable in obese patient– panniculus falls forward

• Disadvantages: – exposure of renal pedicle is not as good as transperitoneal

approach– unsuitable for patient with severe scoliosis– unsuitable for patients with cardiopulmonary problems– lateral position with flexion of table would decrease venous

return due to compression on IVC and dependent leg position

132

Lap Radical Nephrectomy• Established surgical procedure

• 1st by Clayman in 1991

• Same retroperitoneal or intraperitoneal

• 10 yr LRN result: Gill

• 7yr LRN vs ORN: Gill

133

Lap Radical Nephrectomy• Laparoscopic is the new standard of care for low-intermediate stage

RCC and select stage 4 (metastatic) disease• Indications

– Renal mass not amenable to partial nephrectomy (T1b or T2 +/- T3a)– Normal renal function– Normal contralateral kidney

• Lap RN vs ORN– equivalent cancer free survival rates– same tumor control rate – lower morbidity rate (blood loss)– Shorter length of stay – Less analgesic requirement– Early return to normal activity

Colombo JR Urology 2008; Permpongkosol S J Urol 2005; Gill IS Cancer 2001

134

Lap radical nephrectomy

• Berger & Gill, J Uro 2009

– Long term result of LRN (mean FU 11yrs)

– 73 patients, 85% T1-2 RCC

– 10yrs OS 65%, CSS 92% and RFS 86%

– 14% metastasis at mean FU 67months

– Conclusion

• Long term oncological outcome of Lap radical nephrectomy are excellent and comparable to those of open surgery

135

Lap RN vs ORN

• Colombo, J Urol 2008• Cleveland Clinic, Gill

LRN ORN• 7yr OS 72% 84%• CCS 91% 93%• RFS 91% 93%

• No port site recurrence• Literature review showed

– port site recurrence is very rare (< 10 cases reported)• most did not use entrapment bag or spillage of urine

– incidence port site metastasis comparable to Abdominal wound scar metastasis (0.4%)

136

5 year Cancer specific survival

• T1a 100%• T1b 90%• T2 70-80%• T3a 50-60% RSF ~25%• T3b 40-60%• T3c 30-50% vein wall invasion ~25%• T4 0-20%• N+ 5-30%• M+ 0-10%

137

Survival of patient is mainly stage dependent

Stage Cancer Specific Survival

T1a 90-100%

T1b ~90%

T2 70-80%

T3a 60-80%

Venous Thrombosis 40-60%

138

LRN vs ORN (1)

• Colombo , Cleveland clinic , Clinic 2007 – 88 pt (LRN 45, ORN 43) – T1 and T2 tumor– Similar oncological outcome– 5 yr OS for LRN: 81% – 6 yr OS for ORN: 79%– CSS similar (90% vs 92%)

139

LRN vs ORN (2)

• Hemal, JU 2007– LRN (41) vs ORN (71) , 5 yr result– T2 with mean size 10cm– No local or port site metastasis– CS equivalent for both group

• Hemal , WJU 2007, result of LRN

T1a T1b T2

5 yr DFS 97% 84% 82%

CSS 97% 86% 82%

140

LRN vs ORN (3)

• Permpongkosol, JU 2005, 10 yr series

10 yr DFS CSS OS

LRN 94% 97% 85%

ORN 87% 89% 72%

T1 98% 98% 75%

T2 84% 95% 81%

141

Complication of LRN

• Intra/early post-op:– Bleeding– Wound infection– Convert to open– Damage to adjacent organ– Chest infection , MI , CVA– Cx of penumoperitoneum (gas embolism , impair

venous return thrombosis & resp)

• Catheter and drain complication• Need of monitoring of recurrence and RFT

142

Nephron Sparing Surgery (NSS)• WHY?

1. NSS has similar oncological outcome to Radical surgery and is recommend for T1 (up to 7cm)

2. Less incidence of renal failure in the long term• NSS not suitable for:

– >T2 (locally advance)– Unfavorable location– Significant deterioration of general health

• Shall have Lap /open RN• Open is still consider as the GOLD standard for PN

143

What consist of NSS

• OPN & LPN

• Thermal ablation– Cryoablation– RFA– HIFU

144

Partial Nephrectomy

• Indications and contraindications

• Oncological control (as compared with radical nephrectomy)–survival data–recurrence

• Complications

145

Why the role of RN is challenged?

1. Stage & size migration : more < 4cm mass

2. Renal preservation is critical even in normal contralateral kidney

3. Higher risk of CKD after RN for RCC increased risk of cardiac events, hospitalization and death [population study]

4. Possible late recurrence in contralateral kidney limited options of salvage surg

146

Then what is the role of RN?

1. Primary tumor > 7cm

2. Replace too much renal parenchyma

3. Location not suitable for NSS (central)

4. Older pt whom risk of complex PN may not be acceptable

147

Indication for NSS

• Absolute: – Anatomic/fxn solitary kidney

• 8% temp dialysis, 4% permanent dialysis

– Bilateral synchronous RCC

• Relative: – Unilateral RCC with reduce fxn of contralateral kidney– Opposite kidney fxn affected by condition that may impair renal

fxn in the future (e.g Hereditary RCC, DM, HT, RVD)– Pt with increase risk of second malignancy (VHL)

• Elective: – healthy contralateral kidney with favorable anatomy– Small tumor< 4cm , Peripheral exophytic , non hilar tumor

148

Contraindication for PN

• Size: only up to 7cm (EAU)

• Tumor control is unable to be achieved– Multifocal disease– Locally advanced disease (>T3/ N+)

• Unfavorable position (relative)

• Too much parenchyma replaced by tumor (relative)

149

Why Preserve Nephrons?• Possibly benign diagnosis (20% in SRM)

– Women 2x more likely to have a benign dx• Better preservation of renal function after PN than RN (even in pt

with normal pre-op renal fxn) [Lau , Mayo Clinic 2000]• Renal tumor patient are prone to have underlying KD:

– Older male : > 60– Medical co-morbidities affecting renal fxn– 90% have intrinsic kidney disease [Path study from Harvard Med

School]• Morbidity of dialysis and chronic renal disease

– Radical nephrectomy is a major cause of CKD in elderly patients– Progression to ESRF after nephrectomy– CKD Increase incidences of CVD , Hospitalization and lead to death

(related to severity of CKD) HR 1-6 [Go AS, NEJM 2004]– Up to 50% yearly mortality in elderly diabetics undergoing HD– 5yr survival in severe CKD (Grade 4-5) only 30%

• Thus renal preserving strategies is most important in RCC patient

150

Evidence that PN preserves renal function

• Mayo Clinic study from Lau 2000.–patients undergoing radical nephrectomy more

likely as compare to PN• proteinuria• serum Cr >2ng/ml

151


• MSKCC data by Mckiernan– study patients matched for associated risk factors, e.g. DM/HT– serum creatinine in PN group significantly better than RN

group• 1.0mg/dL v.s 1.5mg/dL (statistically significant)

• Huang/Levy from MSKCC– 3 yr probablity of freedom from new onset of chronic

kidney disease (GFR less than 60ml/min) • 35% for radical nephrectomy• 80% for Partial nephrectomy

– Multivariate analysis: radical nephrectomy is an independent factor for new onset CKD

152


• Mayo clinic study by Thompson 2008–query in nephrectomy registry

• RN or PN for organ confined tumor less than 4cm• overall survival evaluated in patient <65• RN was associated with increased risk of death

– after adjusting for tumor histology and medical comorbidities

153

Benefit of NSS vs RN

1. Equivalent oncologic outcomes in those with tumors <4 cm, and probably some up to 7 cm

2. Avoid over treatment of benign lesion (20% of SRM)3. Concerns of lateral contralateral kidney recurrence4. Equivalent cost effectiveness 5. Better QOL 6. Peri-op morbidity similar to RN 7. Decrease overall mortality8. No difference in survival

154

Who will benefit most from PN

• For those who need to preserve renal fxn most– Increase serum Cr– Proteinuria , HT – Low tumor burden (< 4cm , low stage,

solitary)

• Pre-op normogram to predict post-nephrectomy renal insufficiency

155

Complication of OPN• Higher than RN but still tolerable (Van Poppel, Eur Uro 2007 RCT)• Renal failure (6%) and need of dialysis (3%)

– Tumor > 7cm– Excision of > 50% parenchyma– Ischemic time > 60min

• Urinary fistula : (7%)– Risk decrease in elective indication and small lesion– Risk increase in central or hilar location

• Bleeding: 2%– Reactive – Secondary

• Renal infection / abscess: 3%• Re-operation 2%• Mortality 2%• NSS for ABSOLUTE rather than elective carries an increase complication rate and a

higher risk of developing locally recurrent disease, probably due to the larger tumour size

• Risk of local recurrence after PN– General literature: 0-10%– Tumor <4cm: 1-3% [Cleveland clinic Uzzo 2001]

157

• Only 1 RCT (level 1b)• Van Poppel, Eur Urol 2011• EORTC 30904, clinically <=5cm, T1-2

NSS RN 268 vs 273

• OS same for RCC patient• 10yr OS : 75 = 80%• 10yr no progression > 95%• Both method provide excellent oncological

result i.e. no recurrence / met

Radical vs partial nephrectomy

158

ORN vs OPN

• Lau et al , Mayo clinic 2000• Matched comparison: 164 pt• FU 10 years• ORN vs OPN• Results: No significant differences in

– OS – CSS : 96% (RN) vs 92% (PN)– Complication rate– Metastastic disease

• PN have decrease incidence of CKD and proteinuria

159

Oncological efficacy: OPN series• Largest report from Hafez , Cleveland clinic , JU 1999

– 485 pt with sporadic RCC , review– 91% for absolute indication– 5-year OS: 81%, 5-yr CSS : 92%– 10-year OS: 53% , 10-yr CSS: 80%– Enduring oncologic efficacy– CSS is better with pt with tumor <4cm (100%)

• Fergany, JU 2000 [Novick’s 10year series]– 107 OPN, 90% for absolute indication – 5yr CSS: 88% 10-yr CSS : 73%– Preservation of Renal fxn : 93%– Local /distant recurrence: 10%/ 28%

• Herr , JU 1999 [10 year series]– Unilateral tumor, normal contrlateral kidney– 10-yr OS: 93%– 10-yr Metastasis free survival : 97%

160

NSS for ELECTIVE indications

• MSKCC Herr 1999– 10yrCSS 97%

• Mainz group (25yr fu)– 5yr CSS 99%– 5yr CSS 97%

• Novick’s TNM series (Hafez 1999)– Subgroup of elective NSS (N=45)– All <4cm– 5YCSS 100%

161

Predictors of better outcome

• Careful patient selection: – Lower tumor burden: < 4cm , low stage,

solitary lesion

• 5 year CSS of patient fitting these criteria is 100% – Cleveland clinic series (Licht, 1994)

162

Open Partial Nephrectomy: Why is 4 cm the cutoff?

• 185 PN vs. 205 RN: – No difference in CSS between groups with tumors

≤ 4 cm– < 5% local recurrence in the PN group

• 252 patients with renal tumors ≤ 4.0 cm underwent PN vs RN– No local recurrence after either procedure, – no difference in disease specific, disease-free or

overall survival

Lerner et al. J Urol 1996; Lee et al 2000

163

Open Partial Nephrectomy: Can it be done for 4-7 cm (T1b)?

• Patard , multicenter, JU 2004• CSS or tumor recurrence: no difference between

patients treated with RN vs PN for tumors 4-7 cm• Leibovich , JU 2004

• Comparable CSS and distant metastases free Survival for PN vs RN for T1b tumor

• Thompson, J Urol 2009– MSKCC & Mayo clinic, 5yr Fu– 873 RN vs 286 PN, 4-7cm– No difference in 5yr and 10 yr OS / CCS

79%/92% 57%/86%

• Probably can expand elective partial nephrectomy to tumors up to 7 cm

• Favourable result only in high volume center [Mayo, MSKCC, UCLA]

164

OPN: impact of +ve surgical margin

• Kwon , BJU 2007– 777 OPN– Recurrence: 4% for PSM vs 0.5% for NSM

• What happen if we survillence PSM– 1/7 die of metastasis, 6/7 DF at 32 months

• Study with longer FU needed to determine true significant of PSM

• Cleveland FU protocol: – FU CT 3 months 6 monthly for 5 year

165

What is the current status of LPN?

• Clamping of the renal vasculature to provide bloodless field

• Careful resection of mass with rim of normal parenchyma

• Intracorporeal suturing to close the collective system and repair of capsular defect

166

Lap PN

• Altrenative to OPN in experienced hands and selected pt• Depend on experience and comfort of surgery than

on oncoligcal guidelines• Optimal indication: small and peripheral tumor• Long term RFT depends on warm ischemic time• LPN vs OPN:

– Longer Ischemic time [Godoy JU09]– Higher Complication rate– Higher need of temp/perm dialysis– Less costly (reduce LOS)– Similar 5 yr oncological outcome: LPN = OPN

• RaLPN : still undergoing evaluation

167

• LPN (771) vs OPN (1029) [Gill from Cleveland clinic, 2007]• Multicenter study , Single renal tumor, <7cm• Similar:

– CSS (99.3 % vs 99.2% at 3 yrs)– Post-op RFT (97.9% vs 99.6% at 3mo)

• Compare to OPN , LPN has:– Decrease OT time– Decrease blood loss– Shorter hospital stay– Longer warm ischemic time (30min vs 20min)– More post-op complication require additional intervention– More Urological complications (9.2% vs 5% p=0.0006)– 3x More postoperative hemorrhage (4.2% vs 1.6% p=0.0002)

• Note: OPN is a higher risk group , more malignant bias

168

LPN long term oncological outcome

• Lane , Cleveland clinic, JU 2007– 56 pt, 5 year FU,86% T1a– OS : 86%– CSS : 100%– On case of local recurrence (2.7%), no metastasis

• Permpongkosol , JU 2006– OPN (58) vs LPN (85)– 5-yr DFS : 91.4%– Actuarail Survival rate: 93.8%

169

JU Feb 2010

• 2246pt , cT1 tumor , < 7cm • Txn with OPN or LPN• In patient complete 7 year FU

– LPN OPN– T1a CSS: 95% 95%– T1b CSS: 82% 96%– Metastasis free Survival: 97.5% 97.3%

• Conclusion: – LPN and OPN provide similar long term OS and CSS

in pt undergoing PN for T1 RCC– Oncological outcome are excellence with 97%

metastatic free survival in both group

170

When will you chose OPN

• Centrally located tumor

• Tumor in a solitary kidney

• Predominatly cystic tumor

• Multifocal disease

171

• Benway , EU 2010• Largest retrospective review, 4 center , 2006-2008• 183 pt, mean FU 28m• Result:

– Mean ischemic time: 24min– PSM: 2.7%– Major complication : 8%– No recurrence , no derange RFT

• Conclusion: – RaLPN is safe and efficacious approach for PN with advantage

of short ischemic time– Similar morbidity to other approach

172

Renal ischaemic injury

• What is the upper limit of warm ischaemic time for full renal recovery?– up to 30min can be sustained with eventual full

recovery of renal function [Ward]– > 30min , generally significant renal fxn loss (necrosis

in proximal tubular cells)

• Who are more likely to sustain longer warm ischaemic time?– Solitary functioning kidney– Kidney with extensive collateral vascular supply (renal

arterial occlusive disease)

173

Renal ischaemic injury

• How to prevent?1. Preoperative and intraoperation hydration2. Avoidance of nephrotoxic drugs3. Avoidance of hypotension during anesthesia4. Avoid unnecessary manipulation or traction on

the renal artery5. Mannitol before arterial clamping6. Clamping of artery alone instead of both

artery and vein7. Cold ischaemia if required

174

Cold ischaemia

• When is cold ischaemic required? Prolong procedure

• Mechanism?– Reduce energy dependent metabolic activity of

cortical cells– Decrease breakdown of adenosine phosphate– Optimal intra-renal temp according to canine study is

15 degree.– In reality, 20-25 degree is a reasonable and practical

compromise.– Animal and human studies showed that this level of

hypothermia can provide complete renal protection up to 3 hours

175

What are the methods of Cold ischemia?

• Surface cooling– Usually with ice slush– Keep kidney covered with ice for 10-15 mins

after renal artery occlusion• To achieve adequate core cooling

• Intra-arterial cooling via renal artery

176

Solid Renal MassSolid Renal Mass

Open radical Open radical nephrectomynephrectomy

•IVC tumor thrombusIVC tumor thrombus

•Extensive adenopathyExtensive adenopathy

•T4 diseaseT4 disease

•Extensive prior renal Extensive prior renal surgerysurgery

Laparoscopic Laparoscopic radical radical

nephrectomynephrectomy

•No imperative No imperative indication for NSSindication for NSS

•No indication for No indication for open nephrectomyopen nephrectomy

Nephron-Sparing Nephron-Sparing TherapyTherapy

•Imperative Imperative indications for NSSindications for NSS

•Elective Elective indicationsindications

NEXTNEXT

177

Nephron-Sparing TherapyNephron-Sparing Therapy

Expectant Expectant ManagementManagement

•Elderly

•High comorbidity

•Small, asymptomatic tumor

•Established slow growth

Partial nephrectomyPartial nephrectomy

Open Laparoscopic

Ablative therapyAblative therapy

Perc. Lap.

•1 or >1 tumor, cystic

•Location (intrarenal or central)

•Ischemia time >30-45m

•Prior renal surgery

•Technology and personnel available

•Age, comorbidities

•Critical anticoagulation

•Prior renal surgery

178

Fu after nephrectomy• Aim :

– assess complication and renal fxn– Monitor for local recurrence (5%), contralateral tumor (5%) &

metastasis• Risk of local or distant recurrence:

– T1 7%– T2 20%– T3 40%

• Individual protocol of FU according to Leibovich Score (Mayo clinic)– According to: T stage, N stage, size, nuclear grade , necrosis– To assess the risk of metastasis up to 10 year– Low risk: USG kidney + CXR– Intermediate & high risk:

• Abd + pelvis CT for 5yr• CXR for 5 yr

181

Alternative to surgery

• Active surveillance: – No correlation btw local tumor progression and risk of

metastasis– If progression offer treatment

• Embolization:– No benefit before routine nephrectomy– Control gross hematuria and flank pain in

nonresectable disease or unfit pt– Reduce intra-op blood loss in resection of bone or

paravertebral met

182

Ablative therapy• Percu: RFA, Cryo, Microwave, laser, HIFU• Adv: reduce morbidity , outpatient therapy, for high surgical risk pt• Indication: small , incidental , exophytic elderly, genetic predisposition ,

solitary kidney with high risk of renal failure after NSS• Not for percutaneous: >3cm , hilum, near ureter or collecting system• Absolute CI: coagulapathies, severe sepsis• RFA and cryo mostly study with medium FU data• Preparation: bx for histology (but pathology unknown in 40% RFA and 25%

cryo pt)• Cryoablation vs RFA: [Uzzo Meta-analysis Cancer 2008]

– More likely to be Lap approach but with higher complication rate– Better local tumor control rate– Less recurrent tumor – Less require repeat ablation– Both recurrence rate are higher then NSS (4.6 , 7.9 vs 2.7%) [Weld 05)– Similar cancer specific survival rate but poorer than surgery

183

Cryotherapy• Mechanism:

– As low as -190 degree– Exploiting Joule Thompson principle :

• Rapid gas expansion of compressed argon leading to ultracold condition• Cellular damage through:

1. Ice formation initially at extracellular space2. Extracellular fluid become hyper-osmotic3. Fluid shift lead to intracellular dehydration (Desiccation trauma)4. Continue rapid super-cooling lead to intracellular ice formation5. Intracellular ice disrupts cell organelles and cell membrane

– Delay Microcirculation stagnation– Occur at slow thawing phase– Circulation arrest and cellular anoxia – chronic inflammation and necrosis

• Approach: Open , Lap, Percu• Lap: Anterior & lateral tumors, Percu: posterior /post-medial tumor• Method:

– rapid freeze (Argon) and slow thaw (Helium) (extend ice ball 1cm beyond visible tumor edge under USG)

– Double Free-thaw cycle (larger necrotic area)

184

• Indication;– Small tumor< 3cm– Non-hilar tumor/ exophytic cases

• Contraindication: – Poor life expectancy < 1 year– Tumor> 3cm– Located in hilum or proximal ureter or central collecting system

• Adv:– No need hilar clamping or renal warm ischemia– Relative low complication rate, rapid recovery– Able to monitor & target the area by real time USG

• Complications:– hemorrhage (1%) – vascular thrombosis– ureteral stricture, urinary fistula (consider stenting in solitary kidney or central

tumor)• Effect on renal function: minimal• Monitor: MRI (day 1, at 3,6 and 12 months then annual)

– Decrease in cryolesion size (89% by 5 year, complete disappear in 73%)– Hallmark of success: absent of enhancement in cryolesion on gadolinium

enhanced MRI• Outcome inferior to PN because: old pt with morbidity, initial experience

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Oncological outcome

• Cleveland clinic experience of Lap cryotherapy in 56 patients (with minimum 3 yr FU: Hegarty, JU 2006– 75% decrease in cryolesion– OS: 81% , CSS 98%

• RFA : Park , Cancer Control 2007– Mean Fu 20 months– CSS: 83-100%

186

• 80 Lap Cryo, minimum 5-yr FU• 69% bx proven RCC • MRI : day 1 , 3,6 &12 months than annual• Bx at 6 months• T1 tumor, mean size 2.3cm• 5 local , 2 local + met , 4 metastasis• 5-yr RF: 78% CSS: 95% ,OS: 83%• 10-yr DSS 83%, OS: 84% (in bx proven RCC) • Previous RN significant predictor for DFS and

DSS JU March , 2010

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Lap Cryo vs PN Systemic review [EU2011]

• Both PN and LCA procedures are viable options for management of patients with SRMs.

• Compared with PN, LCA results in a– higher risk of local tumor progression– Lower risk of perioperative complications (strongly influenced by

selection bias) and thus limited conclusions can be made regarding true differences in complications between both procedures.

• PN is therefore the gold standard for SRMs,but LCA may be indicated in selected patients with significant comorbidity.

• Balancing cancer control and patient morbidity will be crucial for counseling the patient.

188Cancer July 2010

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Radiofrequency

• Mechanism–Monopolar alternating current of 400-500kHz–High frequency alternating current flows from

needle electrode to target tissue• Ionic agitation• Heat related molecular friction• Denature of cellular protein• Melting of cellular membrane

• Goal: maintain target tissue at 50-100° C–Adequacy of ablation is assessed by

temperature or impedance from RF generators

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Radiofrequency• suitable cases:

–small renal tumor less than 3cm–Non hilar exophytic cases

• Advantages:–No need for hilar clamping–no renal warm ischaemia–low complication rate, rapid recovery

• Disadvantages:–The process of RFA itself cannot be actively

monitored in real time imaging • though impedance can be measured.

191

RFA: result

• Levinson etal from Johns Hopkins: 5 yr• reported outcome for 31 patients undergone RFA for RCTs

(mean 2 cm)• mean follow-up of 61.6 months. • Only 18 had pathologically confirmed RCC • overall recurrence free survival rate was 90.3%. • However, the overall survival rate was 71%

– most died of non-RCC comorbidities• Complication rate: 21%

• 3 case series : 300pt– Average FU 2yr– Tumor control rate (no lesion in MRI) : 90%

• Long term data is need to confirm efficacy

192

HIFU

• Not FDA approved• Adv

– No puncture to tumor– Transcutaneous ablation of tumor– No risk of haemorrhage or tumor spillage

• Disadv (Extracorporeal HIFU)– Inadequate eradication due to acoustic complexity of

intervening structures and respiratory movements of kidneys

– Inability to monitor treatment progression in real time• Transducer is brought directly to the target by

laparoscopic HIFU (Klingler Phase I trial)

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Problems with ablative therapy

• Lack of enhancement on MRI not equal to no viable cancer

• Lack of pathologic dx after txn

• Inability to confirm complete tumor clearance

• Salvage surgery after ablation is challenging

• Success rate fall for tumor > 3.5cm

194

Comparing Thermal ablation with PN

• Meta-analysis by Weld/Landman 2005– higher local recurrence with cryoablation and RFA

• 4.6% and 7.9%, compared with 2.7% by PN

• Disadvantages:– inferior oncological control– poor definition of post ablation success– lack of pathology diagnosis following treatment– inability to confirm complete tumor kill– salvage nephron sparing surgery after ablation can be

very challenging

196

Mx of local recurrence

• Mechanisms of local recurrence – Incomplete resection in the first operation– Occult multicentric disease

• Novick : overall mean rate of multifocality in RCC 15.2%• Novick : in tumors <4cm the risk is ~5%

– Genuine recurrence of new focus in the renal remnant

• Surgical excision if not metastasis• For post PN recurrence;

– Either further PN or RN

197

Special scenario

• Bilateral tumor

• Hereditary RCC

• Tumor in solitary kidney

• Centrally located tumor

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Bilateral tumor

• Aim: maximum renal preservation NSS• Bilateral staged operation• Operate 1st on kidney with less complicated

tumor base on size and location (Cleveland clinic) 1st PN then RN

• Exception : Larger tumor is locally advanced• Advantage:

– Provide flexibility in planning contralateral operation– Abrogated need for temp dialysis

• Other options: simultaneous op, ablation

199

When bilateral RCCs encountered and one side must be removed with a

radical nephrectomy, what would you do?

200

• Bilateral RCC is an absolute indication for NSS.• If NSS is precluded on one side, I would perform

the partial nephrectomy first followed by contralateral radical nephrectomy in a staged manner

• This sequence obviates the need for temporary dialysis in the immediate postop period (if ATN develops after NSS)

• Also provides flexibility when planning the procedure on the opposite side (?)

201

Hereditary RCC• Younger age, higher tumor burden, bilateral and multifocal disease ,

may harbour hundred microscopic tumor , local recurrence is common after NSS

• NSS vs RN vs surveillance• NSS: 1st line

– Give pathology information– High local recurrence rate – 5-yr CSS for VHL : 70-100% – ESRF : 23% require RRT

• RN: eliminate risk of recurrence, overtreatment, hasten ESRF• If bilateral RN consider subsequent renal tranplantation• Ablation: for hx of NSS, impaired RFT (not for further hilar clamping)

,significant multifocal disease • For recurrence disease:

– <3cm surveillance– > 3cm NSS– Do not monitor hereditary leiomyomatosis because aggressive

202

Tumor in Solitary kidney• At least 20% of normal kidney must be spared to avoid ESRF

[Campbell 07]• Still some require RRT : temporary (8%), permanent (4%)• >20min of warm ischemic time lead to higher rate of renal failure &

dialysis [Thompson JU07]• Lane ,Cleveland clinic , JU2008

– OPN (169) vs LPN (30) in solitary kidney– Equivalent 3 mo RFT– LPN has:

• Longer warm ischemic time (9min P<0.001)• 2.54x higher post-op complication (p < 0.05)• Higher rate of post-op dialysis (P=0.01)

• Conclusion: – OPN is a better treatment approach for localized tumor in solitary

kidney who have high risk of renal failure– Ablation is an alternative

203

Centrally located renal tumor• Margin size has no effect on risk of recurrence as along as the final margin

is negative• Hafez , JU 1998

– Solitary , unilateral , < 4cm tumor, txn with PN or RN– No significant difference between central and peripheral tumor in terms of :

survival , tumor recurrence or long term RFT– PN is more challenging for central tumor than for peripheral tumor (longer

ischemic time, more entering into collecting system) • Frank, JU 2006:

– LPN for Central vs peripheral tumor– Similar peri-op complication and median blood loss– Central tumor has:

• Longer ischmia time• Longer OT time• Longer hospital stay

• LPN can be expanded to include central tumors• OPN is still the better approach in most patients• RN is a viable options if PN cannot achieved –ve margin, reconstruction not

feasible , expertise with PN not available

204

Adjuvant therapy

• Tumor vaccination might improve PFS of patients undergoing nephrectomy for T3 renal carcinomas

• Need confirmation about the impact on OS (level of evidence: 1b)

• No role of adj therapy post nephrectomy other than clinical trial (Grade A)

• Cytokines and vaccines: no improvement in survival

205

Mx of Locally advance T3b/c RCC

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Introduction

• Prevalence of RCC with venous thrombus: 4-10%

• Presentation: 95% symptomatic– Hematuria (35%)– Incidental (23%)– Flank or abd pain (17%)– Abdominal mass (2%)

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• Physical examination: – Bilateral LL edema– Varicocele of recent onset (Rt side) – Dilated superficial abd wall veins– Caput medusae– Pulmonary embolus– Proteinuria

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Imaging

• To determine superior extent of tumor thrombus to determine surgical approach

• MDCT: 75-100% accuracy– Vascular enhancement on angiogram in 35-40% (Preop embolisation

helpful in these cases)

• MRI– Non invasive– 80% accuracy– MRI can differentiate bland from tumor thrombus with gadolinium

contrast enhancement– Reconstructed image: caval wall invasion & relationship to HV

• Vena cavography• TEE• Should be done 1 week before OT

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Pre-op embolization

• Adv: – Decrease tumor size – Facilitate surgical dissection (direct assess RV

without isolating RA)• Dis:

– Pain and risk of embolization• Complication:5%

– Angioinfarction syndrome: pain , fever, leukocytosis & vomiting

• Use: palliative procedure in poor surgical candidate

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Pre-op TKI

• Sunitinib: decrease tumor size up to 36%

• Shrink level IV tumor thrombus [Karakiewicz EU2008]

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Other pre-op preparation

• Cardiac consultation: CPBP

• Coronary angiography

• CT & MRI of brain : exclude brain met that could bleed

• Bx + Neo-adj systemic therapy in case of high burden of metastatic disease

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Thrombus staging

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Prognostic staging system

• TNM classification– pT3b : below diaphragm– pT3c: above diaphragm

• Robson staging system: – All tumor extending into the IVC or renal vein

are classified as stage III disease

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Neves and Zincke [BJU 1987]

• Level 0: thrombus in RV

• Level I (renal): Thrombus < 2cm from RV

• Level II (Infrahepatic) : > 2cm from RV

• Level III (Intrahepatic): involved HV but infradiaphragmatic

• Level IV (atrial) : involve supradiaphragmatic vena cava or atrium

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Incision

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Incision• Midline + sternotomy

– For level III & IV thrombus– Single incision with good access to IVC , Renal pedicel and

contralateral kidney– Div: no good exposure to liver and retrohepatic IVC

• Subcoastal (Chevron)– For any thrombus level– Exposure to both renal pedicles– Can extend to include sternotomy (CPB)– Posterolateral exposure to kidney– Div: significant post-op pain

• Thracoabdominal: – Ideal exposure to retrohepatic IVC (excellent for level III)– Div: throacic cx (hernia, phrenic n injury , pneumothroax)

• Frank: – Limited access to IVC– Only for level 0 right IVTT without IVC extension

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Operative approach

• Level I: Transabd approach– Cause partial vena caval obstruction– Satinsky clamping of renal vein / infrahepatic vena

cava proximal and distal to thrombus and contralateral renal vein before venotomy to remove thrombus

– May need caval reconstruction with pericardial graft / PTFE graft.

• Level II: Transabd approach– Extensive vena caval dissection– Lumbar vein ligation– Ligation of small hepatic vein to caudate liver lobe

220

Operative approach

• Level III:– Transesophageal echocardiography (TEE)– Transabdominal / thoraco-abdominal– Liver transplant techniques to expose the retrohepatic veins – Application of suprahepatic clamping and Pringle’s maneuver to

avoid hepatic congestion and back bleeding (20mins)– Veno-venous bypass or CPB + DHCA in selected cases

• Level IV: – TEE– Gold standard is CPB + DHCA– Combined median sternotomy and abdominal incision– Useful technique is cavo-atrial shunt (to ?avoid CPB) but may

require Pringle’s maneuver

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General principle

1) Renal hilar exposure2) Ligation of the renal artery3) Successive occlusion of the IVC above the thrombus

first, then of the contralateral renal vein and, finally, of the IVC under the thrombus

4) Opening of the vena cava5) Nephrectomy and thrombectomy6) Verification that no residual thrombus is attached to the

IVC7) Fushing of the occluded segment with blood and

heparin during the vena cava closure, keeping the cephalad vascular clamp in place to avoid emboli

8) Release of the vascular clamps.

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CPBP

• Approach for level III & IV IVTT

• Continuous venous return & arterial output during IVC occlusion

• Combine with DHCA for complete bloodless field

• Risk: – Stroke (6%)– Peri-op mortality (22%)

224

Venovenous bypass (VVBP)

• For II, most III & select IV thrombus

• Adv: – No need

heparinization– Decrease blood

loss– Short OT Time

225

Oncological outome

• Non metastatic disease: T3b/c– Median survival : 38-116m– Overall 5yr DSS: 40-65% (Norvick series 60%)

• Metastatic disease: T4/N1– Median survival: 10-20m– Overall 5yr DSS: 6-28%

• Problem: – Lack of data on tumor and pt ECOG status– Choice of systemic txn or metastasectomy

227

Prognostic factors

• ECOG performance status• positive lymph nodes • distant metastasis• sarcomatoid features• perinephric fat invasion • Tumor histology: unclassified RCC & collecting

duct carcinomas• NO prognostic value:

– CC, Chrmophobe or papillary– Level of thrombus – Nuclear Fuhrman grade

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Complications

• Peri-op death: 2-10%• Increase with tumor level:

– 0 : 12%, I: 1%, II : 20%, III: 26%, IV: 47%• Overall complication rate: 12%

– Intra-op tumor thrombus embolization (1.5%) 75% mortality rate

– Hemorrhage, Transfusion– Need for reoperation– Sepsis– ARF, MI, PE, Pneumothroax– Pancreatic injury /Pancreatitis

230

Mx of mRCC

Dr. Edmond Wong

9/4/2011

231

Outline

• Cytoreductive nephrectomy

• Metastatectomy

• Systemic therapy– Immunotherapy– Targeted therapy

232

Surgical Txn for mRCC• Cytoreductive nephrectomy:

– Palliative intend require complementary systemic therapy (INF-a)

– From a combine analysis by Flanigan in JU 2004 (of 2 RCT SWOG & EORTC in 2001):

• Increase overall survival (13.6m vs 7.8m) compare to immunotherapy alone (INF-a)

• Overall survival advantage is 6 months • 31% decrease in risk of death (p=0.002)

– Indication : • fit pt with good performance status or• pulmonary only metastasis

– Limited data on value combine with targeting agents, although in the series of Sunitanib , > 90% of pt has CN

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Rationale for Cytoreductive Nephrectomy

1. Palliation• Pain• Bleeding• Paraneoplastic syndrome

2. Improve performance status

3. Primary tumor rarely responds to systemic

immune therapy; response to targeted

therapy is incomplete and temporary4. Enhance response to systemic therapy5. Improved survival

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1. Surgical morbidity/mortality significant2. Spend majority of time left recovering

from surgery3. Significant disease progression during

post-operative recovery period may preclude systemic therapy

4. Delays initiation of systemic therapy to treat metastatic disease

Argument Against Cytoreductive Nephrectomy

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SWOG 8949 NEJM 2001

EORTC 30947 Lancet 2001

Flanigan JU 2004

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Indirect evidence: Cytoreductive nephrectomy prior to target therapy

• Benefit of sunitinib primarily demonstrated in nephrectomized population

• 90% of phase 3 trial patients had nephrectomy– prolonged median progression free survival and overall

survival largely applied to patient without primary insitu

• limited data from subgroup analysis favoured CN• multiple retrospective series reported advantage

underdoing CN• awaiting CARMENA trial (NCT00930033)

– Sunitanib alone vs Sunitanib + CN

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Role for Laparoscopic Cytoreductive Nephrectomy

• Technical elements similar to a radical nephrectomy, except it is done in the metastatic setting (=noncurative)

• Offers better QOL: more rapid recovery, less pain

• Earlier initiation of systemic therapy? Maybe (but

timing probably makes little difference)

Martin SF et al 2006

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Metastases resection

• Lung (67%) metastasis consist of majority after curative nephrectomy

• Synchronous metastatic spread: metastasectomy if resectable and good performance status

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• Complete resection of all meastastic lesion is of importance for long term survival

• Number of lesions removed does correlate with survival

• Resection of pulmonary lesions resulted in longer survival compared to resection of lesion elsewhere

• Initial nephrectomy seems to be a prerequisit for the outcome after metastasectomy

• Outcome prognosis depends on organ site of metastatic lesions although long term DFI observed after resection of brain metastases (glandular sites favourable)

• Disease free interval is of prognostic importance• Recurrence of metastasectomy are still suitable

for surgical management

241

RT for mRCC

• For symptomatic pt with– Nonresectable brain metastasis– Nonresectable ossesos lesion– Do not respond to systemic treatment

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Systemic therapy for mRCC

• RCC develop from the proximal tubules, high levels of expression of the multiple-drug resistance protein (P-glycoprotein)

• Resistant to chemotherapies.

• TF : Chemotherapy monotherapy : NO

• Moderately effective only if 5-fluorouracil (5FU) is combined with immunotherapeutic agents

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Immnunotherapy: INF-a

• Cytokine that activate natural killer (NK) cells• Enhance antigen expression by cancer cell and

antiproliferative• IV IFN-a 3-5 days per week• Result:

– Onset of response slow – Overall response rate: 15%– Median response duration : 6m– Complete response : rare

• Cx: “Flu-like” symptom, fatigue, nausea, diarrhea, rash , pruritus and depression

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Immnunotherapy: INF-a• INF-a vs Placebo:

– Response rate: 6-15%– 25% decrease in the risk for tumor progression– Modest survival benefit: 3-5m– equivalence in efficacy to the combination IFN-alpha + IL2 +

5FU– Superior for survival over: hormonal , placebo

• bevacizumab + INF-alpha vs INF monotherapy: – Increase RR and PFS

• INF vs [sunitinib, bevacizumab + IFN-alpha or temsirolimus]– Worse at 1st line setting

• Conclusion: – INF has limited response rate (15%)and modest survival benefit

(3m)– INF montherapy not recommended as 1st line therapy for mRCC– Role in selected case : good Motzer risk , ccRCC, lung met only

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Interleukin-2

• Strongly induce lymphocyte cytotoxicity• Response rate: 7-27%• Durable complete response: 5%• Long term complete response (10yr): high dose bolus IL-

2, only in ccRCC• Toxicity higher then INF-a: require ICU monitor

– Severe hypotension – Vascular leak syndrome– Neuropsychiatric toxicity

• Only ccRCC response to immunotherapy• Not validated in RCT compare with best supportive

care

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What Motzar says

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Immunotherapy general

• Partial or complete remission: 12.4%• Median survival : 13months (modest adv)• No dose-response relations • No correlation btw response rate and OS• Small proportion with long lasting response• Can be considered curative in some patient• Only in selected patient with: good risk profile &

ccRCC show benefit from IL-2

248

Karnofsky <80: Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed.

249

Targeted therapy

• In ccRCC, HIF accumulation due to VHL inactivation over expression of VEGF and platelet-derived growth factor (PDGF), both of which promote neo-angiogenesis

• no data to indicate that the new agents have a curative effect; rather, they appear to stabilize mRCC

250

Targeting Drug

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Sunitinib

• Oxindol tyrosine kinase (TK) inhibitor• Selectively inhibits PDGFR, VEGFR, c-KIT and FLT-3

and has anti-tumour and anti-angiogenic activity• Motzer , NEJM 2007• Phase 3, first line mono RCT : Sunitinib vs INF

– Response rate: 39% vs 8%– Longer PFS : 11m vs 5m (p < 0.000001)– OS : 26.4 vs 21.8m (borderline significant) – No post study txn: 28.1 vs 14.1m (p=0.003)– Restricted to lower/intermediate risk group

253

Sorafenib (TARGET)

• Oral multiple tyrosine kinase (TK) inhibitor• Act against:

– VEGFR-2, PDGFR – Raf-1 serine/threonine kinase, B-Raf– FMS-like tyrosine kinase 3 (FLT-3) and c-KIT

• Escudier NEJM 2007 RCT: Sorafenib vs Placebo – Failed or unfit for immunotherapy, low – intermediate risk – Objective response rate: 10% – PFS: 3m improvement (6 vs 3m)– Median OS: 17m vs 14m

• Survival: improve in pt cross over from placebo to Sorafenib txn

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Pazopanib

• Oral angiogenesis inhibitor

• Targeting VEGF receptor, PDGF receptor, and c-KIT.

• 1st line / cytokine treated RCT: – pazopanib vs placebo – significant improvement in PFS & tumour

response (9.2 vs 4.2 mo)

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Bevacizumab

• Humanized monoclonal antibody that binds isoforms of VEGF-A

• Bevacizumab (10mg/kg/2weeks) vs Placebo– Overall response: increase 10%– Increase PFS

• Toxicity:– Hypertension– Proteinuria (nephrotic syndrome)– Bleeding at tumor site– Thromboses

256

Bevacizumab (AVOREN)

• 1st line bevacizumab (10 mg/kg every 2 weeks) + IFN-a (9 MIU subcutaneously 3x weekly) vs IFN-a monotherapy – Median OR : 31% vs 13% for IFN-a only ( p < 0.0001)– Median PFS: 10.2m vs 5.4mo with IFN-a only (p <

0.0001) – But only in low-risk and intermediate-risk group– No benefit was seen in high-risk patients– No mature data on OS

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Bevacizumab (CALGB 90206)

• JCO 2008• Untreated, ccRCC• Bevacizumab (10mg/kg IV every 2weeks) + IFN

(9 MIU SC 3x/week) vs IFN• Median PFS: 8.5m vs 5.2m (P<0.001)• ORR: 25.5% vs 13.1 % (P<0.001)• Overall toxicity more in combine gp:

– Grade 3 HT (9% vs 0)– Anorexia (17% vs 8 %)– Fatigue (35% vs 28%) – Proteinuria (13% vs 0)

258

Temsirolimus (Global ARCC)• Specific mammalian target of rapamycin (mTOR)

inhibitor • High-risk mRCC , RCT, 1st line• Temsirolimus vs IFN-a monotherapy vs temsirolimus +

IFN-a– Greater objective response– PFS (3.8mo vs 1.9mo; p < 0.001) – OS :10.9 mo (Temsirolimus ) vs 7.3 mo (IFN-a) ( p < 0.0069). – Median OS : no signi difference

• Combined temsirolimus plus IFN-a, OS was not significantly improved

• The only agent with OS benefit in poor risk patient group

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• Common side effect: more frequently in the temsirolimus group than in the IFN-a group1. asthaenia (11%)

2. rash (4%)

3. nausea (2%).

4. anaemia (20%)

5. Thrombocytopaenia (14% vs 8%)

6. Stomatitis (20% vs 4%),

7. Peripheral oedema (27% vs 8%)

8. Infection (27% vs 14%)

9. Hyperglycaemia (26% vs 11%)

10.Hyperlipidaemia (27% vs 14%) &hypercholesterolaemia (24% vs 4%)

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Everolimus (RECORD-1)

• Oral mTOR inhibitor. • Phase 3 study : everolimus versus placebo (with

best supportive care)• Who had failed previous targeting treatment. • Median PFS : 4 mo (everolimus) vs 1.9 mo

(placebo) ( p < 0.001)

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Target therapy

• General recommendation for targeted therapy in mRCC

• Substantial improvement in PFS & OS• Noted: only provide partial response but NOT

COMPLETE RESPONSE • 1st and 2nd line as recommended• Sequential therapy is still in research

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Evidence of Clinical Efficacy

Sunitinib v.s IFN

Sorafenib v.s placebo (TARGET)

Temsirolimus vs IFN (ARCC)

Bevacizumab+IFN vs placebo+ IFN(AVOREN)Bevacizumab + IFN vs IFN(CALGB 90206)Everolimus vs placebo (RECORD-1)

Pazopanib vs placebo

26.4 v.s. 21.8

17.8 v.s.14.3

10.9 v.s 7.3

NA

NA

NA

NA

Overall Survival (months)

Progression Free Survival (months)

11 v.s. 5.1 (6m)

5.5 v.s. 2.8 (3m)

5.5 v.s. 3.1 (3m)

10.4 v.s 5.5 (5m)

8.4 v.s 4.9 (4m)

4 v.s. 1.9 (2m)

9.2 v.s. 4.2 (5m)

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TARGET

AVOREN

ARCC

RECORD-1

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Target therapy: Toxicity• Constitutional toxicity

– fatigue, asthenia, fever, weight loss, flu like illness• sorafenib (muscle loss)

• Immunosuppression (lymphopenia)– particularly mTOR inhibitors– HBV/HCV antibody titre should be assessed

before starting mTOR inhibitors– HBV carrier should receive prophylactic antiviral

treatment• HBV DNA should be monitored

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• Endocrine and metabolic toxicity– Hypothyroidism (sunitinib, 14%, pazopanib

<10%)• need to monitor thyroid function

– Hyperglycemia, hyperlipidemia and hypercholesterolemia• common with mTOR inhibitors

• Cardiovascular toxicity– HT (sunitinib, sorafenib and bevacizumab, grade

3-4 HT 6-8.5%)– LVH dysfunction– arterial and venous thromboembolism, bleeding

tendency (bevacizumab, sorafenib or sunitinib)

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• Respiratory Toxicity–noninfectious pneumonitis (everolimus

and temsirolimus mainly, also in sorafenib and sunitinib)

• Bone marrow toxicity–anemai/neutropenia/thrombocytopenia

• GI–anorexia/nausea/diarrhoea

• Kidney toxicity–sunitinib/everolimus: impaired renal

function, proteinuria

• Skin/mucoal toxicity–hand-foot skin reaction

(sorafenib/sunitinib)

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Role of Bisphosphates

• Skeletal complications occurs in 25% of patients with metastatic RCC

• What does bisphosphates do?–decrease bony resorption by direct

inhibition of osteoclastic activity and proliferation

–Zoledronate, most powerful bisphosphanate• 100x more powerful than pamidronate

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Evidence• RCT comparing zoledronic acid versus

placebo in patients with RCC– significantly reduced the proportion of patients

who experienced any SRE (41% vs. 79%)– prolonged the time to 1st SRE – reduced the risk of development of 2nd SRE by

58%

• Side Effects– Flu like symptoms– Elevation of serum creatinine– Osteonecrosis of jaw– Reaction at injection site

-Rosen LS,, et al. J Clin Oncol 2003.

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Medication for mRCC

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1st line therapy

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2nd line therapy

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Surveillance post nephrectomy or ablative therapy

• Monitor or identified complication

• Renal function

• Local recurrence

• Recurrence in contralateral kidney

• Development of metastasis

• No evidence that early vs late dx of recurrence improve survival

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FU

• Repeated long-term monitoring of eGFR is indicated if there is impaired renal function before surgery or a post-operative deterioration

• Tumour-bed recurrence is rare (2.9%), but early diagnosis is useful because the most effective treatment is cytoreductive surgery

• Recurrence in the contralateral kidney is also rare (1.2%) and is related to positive margins, multifocality and grade

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Fu Plan• Stratified FU base on risk of progression• Several scoring system and nomogram

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Wilms’ tumor (Nephroblastoma)• Rare but most common childhood tumor (1 in 10,000)• 80% of all child GU tumor• M:F = 1:1, familial (20%) , bilateral (5%)• Gross: soft pale grey tumor• Micro: contain blastema, epithelial and connective tissue component• Genetic:

– mutation of deletion of both copies of WT-1 tumor suppressor gene (Ch11p) tumor genesis

– Autosomal dominant inheritance, recessive at cellular level• Presentation:

– mass (90%) – abd+ loin pain (33%)– hematuria (30%) – HT (50%) – hemihypertrophy , aniridia , cryptorchidism (15%)

• Investigation: USG , CT (abd + chest)• Txn: Staging nephrectomy +/- neo-adj or adj chemo• Chemo: Actinomycin D, vincristine , doxorubicin• Survival: OS > 90%

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Neuroblastoma• Most common extra cranial solid tumor in child• 80% <4yo• Neural crest origin : 50% adrenal , 50% along sympathetic trunks• Presentation:

– Fever– Abd pain / distension/ Mass– Weight loss– Anemia– Bone– Retro-orbital metastases

• Investigation: – CT Chest + abd: Calcification of tumor (diff from Wilms’ tumor)– MIBG scan: very sensitive

• Stage: – I : confined to organ of origin , complete resection – II: Unilateral tumor, residual disease post resection or LN– III : Bilateral tumor or contralateral LN– IV : Met beyond regional LN , survival (6%)

IVS: Unilateral tumor with Met limited to Skin, Liver or Bone marrow (survival 70%)• Txn: excision , RT, combine chemo , autologous BMT, • Prognosis : poor except for Stage I and IVS

Ca kidney [edmond]

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