kidney cancer – rcc & tcc

Kidney Cancer – RCC & TCC

Julian Mander RPH Urology

Upper Tract RCC vs TCC

Both upper renal tract tumours

RCC = Renal cell carcinoma Renal parenchymal cancer, arising from renal tubular cells (proximal convoluted tubule). Most common upper tract malignancy.

• TCC = Transitional cell carcinoma Arising from “urothelium” lining the urinary collecting system, (which was original called transitional epithelium). Relatively uncommon, usually in heavy smokers.

Renal Parenchyma and RCC Histology

Renal Parenchyma Clear Cell Renal Cell Carcinoma

RCC Macroscopic

Transitional Epithelium and TCC Histology

Transitional Epitheium

Transitional Cell Carcinoma Low Grade

Papillary TCC Macroscopic

Epidemiology Renal Cell Carcinoma

2.4% of all cancers in Australia.

2,586 cases diagnosed in Australia in 2008 = 2.2% increase in diagnoses from 2003.

Diagnosis twice as common in men.

855 deaths in Australia in 2007 – 539 male 316 female (13% of these TCC).

Mortality fallen 2.1% from 2004 to 2007.

5 year survival has improved 47% 1982 – 1987 vs 76% 2006 – 2010 Source: AHIW Australian Cancer Database

Public Health - Screening

Formal screening for renal cell carcinoma is not advocated

In effect we now have “non systematic partial screening” of the population through increased use of ultrasound and CT scanning for diagnostic imaging

“Partial screening” reflected in transient peak in incidence in 1994 in USA

“Partial screening” reflected in stage migration Memorial Sloan Kettering 1989 – 1998 decrease mean tumour size 7.8cm to 5.3cm increase organ confined tumours 47% to 78%

Pantuck et al The Changing Natural History of Renal Cell Carcinoma J Urology, 166, 1611, 2001

Increase in Diagnosis of Small Solid Renal Masses

Increased use of diagnostic imaging, both ultrasound and CT scanning, has resulted in a significant increase in the diagnosis of small solid renal masses.

61% of renal masses incidental finding in 1998 (Chow et al JAMA 281:1628–1631, 1999)

13% of renal masses incidental finding in 1973

• Stage migration is associated with the increase in incidentally detected RCCs, with more small solid renal masses now being diagnosed at a lower stage.

• Greatly increased scope for nephron sparing partial nephrectomy (or minimally invasive ablative techniques – RFA and Cryotherapy) with stage migration.

Etiology Renal Cell Carcinoma

Smoking thought to account for around 50% of RCC

Genetic predisposition syndromes 1) Von Hippel-Lindau syndrome and HIF (Hypoxia Inducible Factor) pathways: Associated with multiple bilateral clear cell RCC starting at a young age Autosomal dominant Results from a mutation in the Von Hippel-Lindau tumour suppressor gene on chromosome 3p25.3. Incidence of one in 36,000 births. There is over 90% penetrance by the age of 65. Associated with retinal angioma, haemangioblastoma, pheochromocytoma, pancreatic serous cystadenoma, endolymphatic sac tumour and bilateral papillary cystadenomas of the epididymis in men or broad ligament of the uterus in women. VHL gene has a mutation and produces a faulty VHL protein (pVHL). VHL gene protein product binds 2 proteins, called Elongin C and B. These belong to family of proteins that are critical to transcriptional

regulation. VHLprotein-Elongin C/B complex binds to Cul-2, a member of the multigene cullin family

VHLprotein-ElonginC/B-Cul-2 complex targets a protein called HIF1-alpha = hypoxia inducible factor leading to ubiquitin mediated degradation of HIF1-alpha.

In kidney cancer, mutant VHL gene product does not degrade HIF1-alpha and HIF accumulates, stimulating VEGF, GLUT 1, PDGF, TGF-alpha and

erythropoietin

HIF1-alpha is a protein that accumulate under hypoxic stress and controls the transcription of a number of downstream genes: VEGF – vascular endothelial growth factor, GLUT 1 – glucose transporter, PDGF - platelet derived growth factor, TGF-alpha – transforming growth factor alpha and Erythropoietin i.e. genes theoretically important to tumourogenesis

Approximately 20% of cases of VHL disease are found in individuals without a family history, known as de novo mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.


• Genetic predisposition syndromes

2) Papillary Type 1 RCC and c-MET Oncogene

Papillary RCC is associated with loss of Y chromosome, trisomies 7 and 17, and a specific translocation between chromosome X and chromosome 1 t(X;1)(p11.2;q21.2) Some Papillary RCC shown to be caused by activating mutations in the c-MET proto-oncogene in chromosome 7q = Hereditary renal cell carcinoma

Hereditary papillary renal carcinoma type 1 (HPRC) Autosomal dominant and highly penetrant Gene responsible is located at chromosome 7q31.1-34 Missense mutations found in the tyrosine kinase domain of the MET gene – product is cell surface receptor for ligand hepatocyte growth factor

HGF(A) Three mutations in MET gene found located in codons homologous to those in the c-KIT and RET oncogenes “These findings suggest that the missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein in papillary renal

carcinomas.” Mutations in MET gene also found in some sporadic noninherited type I papillary renal carcinomas


Genetic predisposition syndromes 3) Papillary Type 2 RCC, HLRCC/MCL and FH Gene:

HLRCC Hereditary leiomatosis renal cell carcinoma / MCL Multiple cutaneous leiomyoma HLRCC/MCL is a disease complex with multiple cutaneous leiomyomas, uterine leiomyoma, uterine leiomyosarcoma and papillary type 2 RCC

FH Fumarate hydratase gene for HLRCC/MCL is the gene that codes for Krebs cycle enzyme fumarate hydratase

Tumourogenesis mechanisms as yet undetermined

(Papillary Type 2 RCC is aggressive and treatment surgical)

Linehan et al The Genetic Basis of Cancer of the Kidney J Urology 170, 2163 2003


Genetic predisposition syndromes

4) Hereditary Chromophobe RCC and BHD Gene

BHD Birt Hogg Dube syndrome described in 1977 Inherited autosomal dominant syndrome with cutaneous hair follicle tumours involving face and neck, and pulmonary cysts associated spont pneumothorax 25%

Linked to chromophobe bilateral, multifocal chromophobe RCC by Roth in 1993

Genetic linkage analysis in 2002 found BHD gene at 4cM area on short arm of chromosome 17

Mutations of the BHD gene found in germline of those with BHD syndrome characteristics of tumour suppressor gene

Current work on BHD gene in sporadic chromophobe RCC and oncocytoma

Linehan et al The Genetic Basis of Cancer of the Kidney J Urology 170, 2163 2003

Staging of Renal Cell Carcinoma

Staging improvements evolved to reflect improvements in imaging and appreciation of natural history of the cancer, ultimately leading to UICC 1997 TNM staging and subsequent AJCC modification of 1997 UICC staging

Staging of Renal Cell Carcinoma and Prognosis

Staging is the most important prognostic indicator for renal cell carcinoma

Pantuck et al The Changing History of Renal Cell Carcinoma J Urology 166,1611, 2001

Grading of Clear Cell Renal Cell Carcinoma

Tumour grading is the second most important independent prognostic indicator Fuhrman grading accepted in 1982 for clear cell carcinoma incidence Grade 1 10% Grade 2 35% Grade 3 35% Grade 4 20%

Fuhrman Grade 1 Fuhrman Grade 2 Fuhrman Grade 3

Grading of Clear Cell Renal Cell Carcinoma and Prognosis

Tsui et al Prognostic Indicators For Renal Cell Carcinoma: A Multivariate Analysis of 643 Patients Using The Revised 1997 TNM Staging Criteria J Urology 163, 1090 2000

Histological Subtyping – Vital to Understanding Molecular Biology and New Therapies

Clear cell carcinoma 70% (Von Hippel-Lindau syndrome and HIF pathways)

Papillary carcinoma 15% Type 1 and Type 2 – histological typing Multifocal 41% important for consideration partial nephrectomy Bilateral 8% “ “ “ “ Type 1 papillary RCC better prognosis than clear cell Type 1: small basophilic cells lower grade and stage, better prognosis (c-Met oncogene association) Type 2: large eosinophilic cells poorer prognosis 66% 5 year survival c/f 95% for type 1 (HLRCC/MCL FHgene) Familial predisposition documented but rare 0.03%. Association bladder TCC standardised incidence ratio 23.88 Chromophobe carcinoma 5% Similar appearance to benign oncocytoma Similar prognosis as clear cell RCC, stage for stage (Birt Hogg Dube syndrome chromosome 17 (17p11)) Unclassified carcinoma 2.8% Large aggressive tumours with early metastasis and poor prognosis 90% present with metastases. Includes “sarcomatoid” tumours, with spindle cell appearance – median survival 3.8 to 6.8 months. Surgery alone does not improve survival. Surgery + immunotherapy (IL-2) does improve survival. Immunotherapy alone (IL-2) does improve survival - but months only. Collecting duct carcinoma 1% Aggressive tumours, commonly present with symptoms. Currently not curable. Average survival 11.5 months. Very rare subtypes: Epithelioid angiomyolipoma Clear cell variant of epithelioid angiomyolipoma

Histological Subtyping and Genetic Associations

Linehan et al The Genetic Basis of Cancer of the Kidney J Urology 170, 2163, 2003

Investigation of Renal Mass Lesion – Blood and Urine tests

Blood tests: U&E creatinine required for CT scan and decision making for treatment Calcium – hypercalcemia as a paraneoplastic or metastatic phenomenon LFTs occasionally abnormal as paraneoplastic phenomenon – Stauffer’s syndrome poorer prognosis as liver metastases - relatively rare FBP polycythemia as paraneoplastic syndrome Coagulation profile required if pending biopsy or RFA in particular

• Urine Tests: MSU occasionally diff diagnosis “nephronia” (focal pyelonephritis)

Cytology if differential diagnosis includes TCC

Paraneoplastic syndromes and RCC

Constitutional symptoms: PUO, cachexia and weight loss Specific metabolic and biochemical abnormalities: Hypercalcemia 13 – 20% of cases (when not from bone metastases) Hypertension double the hypertension rate of age matched controls – renin elevation in 37% RCC Hepatic dysfunction 3 – 20% of cases Stauffer’s syndrome (when not from liver metastases) Polycythemia 1 – 8% of cases thought due paraneoplastic EPO, though 66% have elevated EPO Amyloidosis 3 – 8% of cases (nonendocrine paraneoplastic syndrome)

Investigation of Renal Mass Lesion – Abdominal Imaging

Solid renal mass lesions

Renal cell carcinoma malignant with no specific identifying features on imaging

Oncocytoma benign “with theoretical malignant potential” with no specific identifying features on imaging

Angiomyolipoma benign and generally containing fat, heperechoic on U/S and fat density on non contrast CT

• Complex cystic renal masses

Simple cysts containing dense or hyperechoic material – haemorrhagic cysts, proteinaceous cysts, infected cysts

Cystic renal cell carcinoma – generally contain contrast enhancing components

Bosniak Score Bosniak 1 simple cyst, imperceptible wall, generally round 0% malignant Bosniak 2 minimally complex, a few thin (< 1mm) septa, thin Ca++; non-enhancing high-attenuation (due to to proteinaceous or

haemorrhagic fluid) renal lesions of less than 3 cm are also included in this category; these lesions are generally well marginated.

Bosniak 2F minimally complex but requiring follow up. Increased number of septa, minimally thickened or enhancing septa or wall, thick Ca++, hyperdense cyst that is: > 3 cm diameter, mostly intrarenal (less than 25% of wall visible); no enhancement. Needs ultrasound / CT follow up

~ 25 % malignant

Bosniak 3 indeterminate, thick or multiple septations, mural nodule, hyperdense on CT. Treatment is necessary - partial nephrectomy or RF ablation in elderly / poor surgical risk ~ 54% malignant

Bosniak 4 clearly malignant, solid mass with large cystic or necrotic component . Treatment: partial / total nephrectomy or RFA ~100% malignant

Diagnosis of Renal Mass Lesion – Abdominal Imaging

• Generally U/S followed by 3 phase contrast CT scan non contrast, arterial and portal venous phase, with pyelographic

phase added if concerns about transitional cell carcinoma (= 4 phase CT scan)

Very limited place for MRI, mainly in assessing renal vein involvement (4 – 9% of cases)

Very limited place for PET scan – sensitivity 75% with PPV 92.3% - not useful if negative

Small right RCC non con CT Small right RCC arterial phase CT Small right RCC portal venous phase CT Left RCC with IVC involved CT

Large right RCC CT Large left RCC U/S Complex right renal cyst right kidney U/S Renal Angiomyolipoma U/S

Diagnosis of Renal Mass Lesion – Chest Imaging

CT scan chest problematic

Invariably one or two small peripheral lung lesions ?tumour ?benign granuloma with respiratory referral and long term F/U with 6 monthly CT chest, most commonly do not turn out to be metastases.

• CXR preferred option

Will demonstrate cannonball metastases, which are obviously important from a management perspective.

(Lung metastases are relatively rare, more common in large poorly differentiated RCC).

InvestigationCore Needle Biopsy for Histopathological Diagnosis

6% - 20% of solid renal masses benign (more commonly benign if < 4cm diameter)

Angiomyolipomas usually but not always identifiable from RCC radiologically with U/S + CT

Oncocytomas not radiologically identifiable as different from RCC

Complex cystic masses problematic with imaging and biopsy – Bosniak classification

Fine needle biopsy abandoned as largely considered inaccurate

Core biopsy developed as spring loaded 18G “Biopty” guns became available histopathology more accurate than FNA cytology

Advances in CT scanning – more accurate needle placement in select cases U/S guided core biopsy still used in many cases, but targeting remains a theoretical concern – negative biopsy becomes a problem

Core Needle Biopsy for Histopathological Diagnosis

Neuzillet Accuracy and Clinical Role of Fine Needle Percutaneous Biopsy with Computerized Tomography Guidance of Small (Less Than 4.0cm) Renal Masses J Urology 171,1802 2004

Solid Renal Mass Biopsy

Mean tumour size 3.3 cm 20 % benign 21% inconclusive

Percutaneous Core Biopsy for Renal Masses Lebret et al J Urology 178,1184 October 2007

Solid Renal Mass Biopsy

Median tumour size 2.9 cm, average less than 5 cm 19% benign 18% non diagnostic

The Value of Preoperative Needle Core Biopsy for Diagnosing Benign Lesions Among Small, Incidentally Detected Renal Masses Shannon et al J Urology 180, 1257 2008

Treatment of Renal Cell Carcinoma

Curative RCC does not respond to standard chemotherapy and radiotherapy regimes

Surgery Radical nephrectomy - open Radical nephrectomy - laparoscopic Partial nephrecomy open Partial nephrectomy laparoscopic

Minimally invasive ablative techniques RFA Radiofrequency Ablation

Cryotherapy – percutaneous and laparoscopic

HIFU

Cyberknife radiotherapy

Radical Nephrectomy - Open

First description by Mortenson in 1948 via thoracoabdominal incision Popularised by Robson 1960’s

“The results of radical nephrectomy for renal cell carcinoma.” Robson et al J Urol 1969 Mar;101(3):297-301.

Substantial improvements in cancer survival once radical nephrectomy was widely adopted

Various open surgical approaches: loin incision – 12 th , 11th , 10th rib incisions and thoracoabdominal

Radical Nephrectomy - Laparoscopic

First laparoscopic radical nephrectomy performed in 1990 at Washington University, St Louis, Missouri by Clayman in an 85 year old woman with 3cm solid renal mass. The operation took 6 hours 45 minutes and the kidney was removed by morcellation with port site extraction extraction. Turned out to be a benign oncocytoma (luckily).

• Became standard of care after 2000 and the specimen is now removed intact (seeding occurred with morcellation).

• Now 3 – 4 hours surgical time, using 3 ports on the left and 4 ports on the right, with 3” incision for extraction site

• Transperitoneal and retroperitoneal approaches, with patient positioning same as open (open conversion 2%)

• Oncological outcome are now the same as open surgery

• Slightly higher complication rate than with open surgery

Partial Nephrectomy

Developed in USA through the 1990’s at Cleveland Clinic, Mao Clinic and Memorial Sloan Kettering as curative therapy for renal cell carcinoma while preserving renal fn.

Open partial nephrectomy initially, now extended to laparoscopic partial nephrectomy.

Can be technically demanding, with slow uptake by the urologists outside these centres.

Ultimately, cancer outcomes the same for T1 tumours whilst preserving renal function.

Should now be standard therapy for T1A RCC.

Recent evidence for lower cardiovascular death risk with nephron sparing surgery.

Partial Nephrectomy and Cancer Outcomes

Long Term Results of Nephron Sparing Surgery For Localised Renal Cell Carcinoma: A Ten Year Review Novick et al J Urology 163, 442 Feb 2000

Partial Nephrectomy for Unilateral Renal Cell Carcinoma and a Normal Contralateral Kidney: 10 Year Followup Herr J Urology 161, 33 January 1999

70 patients with median follow up 10 years 1979 – 1997

98.5% no local recurrence 97% no metastases

Mean tumour size 3 cm

107 patients before 1988 with ~ 10 year follow up

Mean tumour size 4.7 cm

40% T1a 94.5 % 10 year CSS20% T1b 67% “4% T2 100% “20% T3a 74% “16% T3b 23.5% “

Partial Nephrectomy and Cancer Outcomes

Safety and Efficacy of Partial Nephrectomy for all T1 Tumours Based on an International Multicenter Experience Patard et al J Urology 171, 2181 2004

Nephron Sparing Surgery for Renal Tumours: Indications, Techniques and Outcomes Novick et al J Urology 166, 6 2001

Partial Nephrectomy for Renal Tumours 4 - 7 cm Diameter

Cancer specific survival in 704 patients treated with RN ….… and 239 treated with PN _____(p 0.039), tumour size 4 – 7 cm.

Partial Versus Radical Nephrectomy for 4 to 7 cm Renal Cortical Tumors Russo, Blute et al J Urology 182, 2601 Dec 2009

Partial nephrectomy

Radical nephrectomy

• Expansion of partial nephrectomy into larger RCCs - study on 1,159 patients with sporadic RCC at 2 centres Mayo Clinic and Sloan Kettering between 1986 and 2006.

• 10% solitary kidney and 15% chronic kidney disease in partial nephrectomy group.

Slow Urologist Upskilling in Partial Nephrectomy

SEER Data patients > 66 years old 2340 cases where tumour ≤ 4 cm diameter (up to 2002)

Diffusion of Surgical Innovation Among Patients With Kidney Cancer Miller et al Cancer 112, 1708 April 2008

Partial Nephrectomy - Open

Larger tumours and centrally located tumours require vascular control with renal arterial and venous cross clamping.

Acceptable warm ischaemic time has traditionally been 30 minutes, so “clamp and cool” necessary in many circumstances.

Small arteries and veins underrun.

Collecting system closure is important.

“Bolsters” commonly used to fill defect.

Partial Nephrectomy - Laparoscopic

Specific laparoscopic skill set required, generally in the bigger centres in USA – Cleveland Clinic, Mayo and MSK.

Robotic surgery probably advantageous here.

“Clamp and cool” problematic still.

Floseal haemostatic agent appears to be important.

Minimally Invasive Ablative Techniques

Radiofrequency Ablation of Renal Cell Carcinoma

Using techniques developed for management liver metastases Early experience with those unsuitable or refusing surgery Recent sloughed upper ureter in Brisbane

McDougal et al Long Term Follow Up of Renal Cell Carcinoma After Radiofrequency Ablation J Urology 174, 61 2005

16 patients, minimum 4 year followup - No patient died of metastatic disease - 5 patients died of other causesImaging showed 64% reduction in average mass size - One mass incresed in size considered failureBut no followup histopathology

Cryoablation of Renal Cell Carcinoma

Early experience – percutaneous vs laparoscopic Potential vascular complications with splitting ice ball and torrential haemorrhage

Gill et al Renal Cryoablation: Outcome at 3 Years J Urology 173, 1903 2005

Laparoscopic approach – visual and laparoscopic U/S observation of ice ball - 56 patients37.8% cryolesions completely disappeared on MRI at 5 years2/39 biopsied lesions showed RCC 6 months after cryo

High Intensity Focussed Ultrasound HIFU

Experimental

Kohrmann et al High Intensity Focussed Ultrasound as Nononvasive Therapy for Multifocal Renal Cell Carcinoma: Case Study and Review of The Literature J Urology 167 2397 2002

High Intensity Focussed Ultrasound HIFU

Results of Percutaneous Ablative therapy

Problem with histopathology on both initial diagnosis and proof of cure with cryo and RFA – few biopsies done on these patients. “Incomplete treatment” defined as contrast enhancement of lesion on CT scan.

• Local recurrence rates

Partial nephrectomy 2.6% of 5,037 cases

Cryotherapy 4.6% of 496 cases

RFA 11.7% of 607 cases

AUA Guidelines for Management of T1a RCC

For Index Patient No. 1: A healthy patient with a clinical T1a (≤4.0 cm) enhancing renal mass Standard: Complete surgical excision by partial nephrectomy is a standard of care and should be strongly considered. [Based on review of the data and Panel consensus.] Both open and laparoscopic approaches to PN can be considered, dependent on tumor size, location and the surgeon's expertise. LPN can provide more

rapid recovery, although this approach has been associated with increased warm ischemic times and an increased risk of urological complications including postoperative hemorrhage and urinary fistula. Most patients with a solitary kidney, preexisting renal dysfunction, hilar tumor, multiple tumors or predominantly cystic tumor are best managed with an open surgical technique. With improved laparoscopic instrumentation and greater dissemination of expertise, improved outcomes and more widespread application of LPN is anticipated in the future.

Standard: Radical nephrectomy should be discussed as an alternate standard of care which can be performed if a partial nephrectomy is not technically feasible as determined by the urologic surgeon.

[Based on review of the data and Panel consensus.] Radical nephrectomy can lead to an increased risk of CKD, which is associated with increased risks of morbid cardiac events and death according to

population-based studies. Management should focus on optimizing renal function rather than merely precluding the need for dialysis. PN is a greatly underutilized procedure that is often feasible even for central or hilar tumors, given adequate surgeon expertise. Nevertheless, occasional localized renal tumors in this size range are not amenable to PN, and RN should be considered an alternative standard of care. A laparoscopic approach can provide reduced blood loss and more rapid recovery and should be considered, presuming adequate surgeon expertise.

Option: Thermal ablation, such as cryoablation or radio frequency ablation, should be discussed as a less-invasive treatment option, but local tumor recurrence is more likely than with surgical excision, measures of success are not well defined, and surgical salvage may be difficult.

[Based on review of the data and Panel consensus.] Thermal ablation is associated with a substantially increased risk of local recurrence, the majority of which can be managed with a second attempt at

thermal ablation. However, some local recurrences are not amenable to this approach and require surgical salvage. In this setting laparoscopic surgery and PN are often not possible due to extensive reactive fibrosis within the perinephric space. In addition, measures of success for thermal ablation have come into question with some studies demonstrating apparently viable cancer cells despite loss of contrast enhancement. It is possible that outcomes associated with ablative modalities will improve with further advances in technology and application; however, judicious patient selection and counseling remain of paramount importance for these less-invasive technologies.

Option: Active surveillance with delayed intervention should be discussed as an option for patients wishing to avoid treatment and willing to assume oncologic risk.

[Based on review of the data and Panel consensus.] Approximately 80% of all clinical T1a renal masses are malignant, and of these, about 20% to 30% demonstrate potentially aggressive histologic features.

The risk of tumor progression that could preclude NSS or lead to unsalvageable systemic metastases is not well defined in the current literature. Enhanced renal mass biopsy (incorporating molecular analyses) holds promise for assessing aggressive potential; however, further research will be required to define the utility and limitations of this approach. Healthy patients considering AS must be willing to assume a calculated risk of tumor progression.

Guideline for Management of the Clinical T1 Renal Mass Campbell et al J Urology 182:4 1271 October 2009

AUA Guidelines Meta-analysis – Local Recurrence-Free SurvivalResults of Percutaneous Ablation vs Partial vs Radical Nephrectomy

Study Type # of Studies Survival Rate (%)1 95% Confidence Interval2

Mean/Median Patient Age

(yrs)3

Mean/Median Tumor Size

(cm)3

Mean/Median Follow-Up

(mos)3

Lower Limit (%)

Upper Limit (%)

Cryo 10 90.6 83.8 94.7 67.0/67.0 2.5/2.6 19.5/18.2

RFA 10 87.0 83.2 90.0 67.6/70.0 2.8/2.7 22.9/19.4

LPN 17 98.4 97.1 99.1 61.2/61.0 2.6/2.6 20.8/15.0

OPN 21 98.0 97.4 98.5 60.5/60.0 3.3/3.1 55.5/46.9

LRN 8 99.2 98.2 99.7 60.7/61.0 4.6/4.6 30.2/17.7

ORN 10 98.1 97.3 98.6 62.6/63.0 4.6/4.8 59.3/58.3

Cryo = cryotherapy RFA = radiofrequency ablation LPN = laparoscopic partial nephrectomy OPN = open partial nephrectomy LRN = laparoscopic radical nephrectomy ORN = open radical nephrectomy

Local Recurrence-Free Survival

AUA Guidelines Meta-analysis – Complication RatesPercutaneous Ablation vs Partial vs Radical Nephrectomy

Study Type # of Studies Complication Rate (%)1 95% Confidence Interval2

Mean/Median Patient Age

(yrs)3

Mean/Median Tumor Size

(cm)3

Lower Limit (%)

Upper Limit (%)

Cryo 15 4.9 3.3 7.4 67.0/66.7 2.6/2.6

RFA 20 6.0 4.4 8.2 68.5/70.0 2.7/2.7

LPN 22 9.0 7.7 10.6 60.4/59.9 2.6/2.6

OPN 15 6.3 4.5 8.7 59.5/59.0 3.2/3.0

LRN 13 3.4 2.0 5.5 60.7/61.0 4.8/5.1

ORN 6 1.3 0.6 2.8 62.7/62.3 4.9/5.2

Major Urological Complications

Cryo = cryotherapy RFA = radiofrequency ablation LPN = laparoscopic partial nephrectomy OPN = open partial nephrectomyLRN = laparoascopic radical nephrectomy ORN = open radical nephrectomy

Worse Survival For Radical Nephrectomy vs Partial Nephrectomy

“Compared with partial nephrectomy, radical nephrectomy increases the risk of chronic kidney disease, which is a significant risk factor for cardiovascular events and death. Given equivalent oncological efficacy in patients withsmall renal tumors, radical nephrectomy may result in overtreatment.”

A total of 2,547 patients (81%) underwent radical nephrectomy and 556 (19%) underwent partial nephrectomy. During a median followup of 4 years 609 patients experienced a cardiovascular event and 892 died. When adjusting forpreoperative demographic and comorbid variables, radical nephrectomy was associated with an increased risk of overall mortality (HR 1.38, p 0.01) and a 1.4 times greater number of cardiovascular events after surgery (p 0.05). However,radical nephrectomy was not significantly associated with time to first cardiovascular event (HR 1.21, p 0.10) or with cardiovascular death (HR 0.95, p 0.84).

SEER data used, 2991 patients, all > 66 years old

Renal tumours ≤ 4 cm diameter

Surgery between 1995 and 2002

Partial Nephrectomy Versus Radical Nephrectomy in Patients With Small Renal Tumors—Is There a Difference in Mortality and Cardiovascular Outcomes? Russo et al J Urology 181, 55 January 2009


OS = Overall Survival

Nephrectomy Induced Chronic Renal Insufficiency is Associated With Increased Risk of Cardiovascular Death and Death From AnyCause in Patients With Localized cT1b Renal Masses Novick et al J Urology 183, 1317 April 2010

From 1999 to 2006, 1,004 patients with renal masses between 4 and 7 cm underwent extirpative surgery, partial nephrectomy (524) or radical nephrectomy (480) = T2 b tumours.

On multivariate analysis cancer specific survival was equivalent for patients treated with partial nephrectomy or radical nephrectomy.

Those patients undergoing radical nephrectomy lost significantly more renal function than those undergoing partial nephrectomy.

The average excess loss of renal function observed with radical nephrectomy was associated with a 25% (95% CI 3–73) increased risk of cardiac death and 17% (95% CI 12–27) increased risk of death from any cause on multivariate analysis.


Renal function vs survival in entire surgical group of 1004 patients

Nephrectomy Induced Chronic Renal Insufficiency is Associated With Increased Risk of Cardiovascular Death and Death From AnyCause in Patients With Localized cT1b Renal Masses Novick et al J Urology 183, 1317 April 2010

Palliative Treatment for Renal Cell Carcinoma

Targeted therapy: medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for

carcinogenesis and tumour growth.

Following on from the identification of HIF pathways in Von Hippel-Lindau syndrome, “pathways” identified that are open to manipulation by various molecules.

Currently in Australia two targeted therapies are available on PBS: Sunitinib and Pazaponib, both tyrosine kinase inhibitors.

Bevacizumab (VEG-F monoclonal antibody) has been used and does work in some cases, but not on PBS.

Thalidomide is being trialled for treatment of RCC.

• Immunotherapy originally great hope because of anecdotes of resolution of metastatic RCC after tumour nephrectomy

Interfereron initially used but subsequently proven not to be effective.

Interleukin 2 (IL2) used in the 1990’s but proven ineffective.

IL2 – LAK therapy (lymphokine activated killer cells) with exposure to tumour used NCI shown possible cure in a few cases.

Clear Cell Renal Cancer and Molecular Therapies

Lam et al Renal Cell Carcinoma 2005: New Frontiers in Staging, Prognosticationand Targeted Molecular Therapy.

J Urology 173,1853 2005

Targeted Therapy for Metastatic Renal cell Carcinoma

At present, in Europe and/or the USA, six targeted agents are approved for first and second-line treatment of clear cell metastatic RCC: sunitinib sorafenib temsirolimus everolimus bevacizumab (in combination with interferon) pazopanib

In addition, several new targeted agents, are also currently in development for the treatment of metastatic RCC:

axitinib tivozanib

Targeted Therapy for Metastatic Renal cell Carcinoma

Therapy % Prior nephrectomy Median survival (months) Overall survival (months)

Sunitinib 91% 11.0 26.4

Pazopanib 11.1 (overall survival similar to sutent with ~ 50% less foot-mouth (NEJM 2013 369)

Bevacizimab 100% 10.2 23.3

Sorafanib 94% 5.5 17.8 Recent Advances in the Treatment of Advanced Renal Cell Carcinoma: Toward Multidisciplinary Personal Care Bex et al BJUI 2012 110; 1289-1300

Sunitinib listed on PBS for Stage IV Renal Cell Carcinoma (RCC), patient must meet the Memorial Sloan Kettering Cancer Centre (MSKCC) low to intermediate risk group criteria, patient must have a WHO performance status of 2 or less, the treatment must be the sole PBS-subsidised tyrosine kinase inhibitor therapy for this condition. Patients who have developed progressive disease on pazopanib are not eligible to receive PBS-subsidised sunitinib

Pazopanib listed on PBS for Stage IV clear cell variant renal cell carcinoma (RCC) Treatment Phase: Initial treatment, Patient must meet the Memorial Sloan Kettering Cancer Centre (MSKCC) low to intermediate risk group criteria, patient must have a WHO performance status of 2 or less, the treatment must be the sole PBS-subsidised tyrosine kinase inhibitor therapy for this condition. Patients who have progressive disease on sunitinib are not eligible to receive PBS-subsidised pazopanib.

Bevacizimab listed on PBS for treatment in combination with first-line chemotherapy, of a patient with previously untreated metastatic colorectal

cancer with a WHO performance status of 0 or 1. Sorafenib listed on PBS for Stage C hepatocellular carcinoma

Upper Tract TCC Clinical Management

Relatively uncommon, more common in smokers and in the old days in those exposed to APC analgesics.

3% of patients with bladder TCC get upper tract TCC – more common in high grade bladder TCC.

Lynch syndrome – colorectal cancer and TCC, more commonly ureteric.

Macroscopic haematuria with loin pain and no stone.

CT pyelogram +/- urine cytology useful in diagnostic workup.

Modern diagnosis with flexible ureteroscopy and biopsy.

Traditional management with nephroureterectomy including a 1 cm cuff of bladder adjacent to ureteric orifice.

Laparoscopic radical nephrectomy with open approach to lower ureter and UO with 1 cm bladder cuff now common.

Ureteroscopy and diathermy of small renal pelvic TCC now possible +/- intrarenal Mitomicin to reduce recurrence.

Segmental distal ureteric resection with renal preservation for distal ureteric tumour best option.

Endoscopic resection of UO with “pluck” of ureter (after Semple) for large renal pelvic TCC removed with laparoscopic nephrectomy is appropriate management.

kidney cancer – rcc & tcc

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