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134 Challenging Concepts in Urological Surgery
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8. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol.
2000;18(17):3068– 3077.
9. Loehrer PJ, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in
combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic
urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10(7):1066– 1073.
10. Logothetis CJ, Dexeus FH, Finn L, et al. A prospective randomized trial comparing MVAC
and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol.
1990;8(6):1050– 1055.
11. Galsky MD, Chen GJ, Oh WK, et al. Comparative effectiveness of cisplatin- based and
carboplatin- based chemotherapy for treatment of advanced urothelial carcinoma. Ann
Oncol. 2012;23(2):406– 410.
12. Dreicer R, Manola J, Roth BJ, et al. Phase III trial of methotrexate, vinblastine, doxorubicin,
and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the
urothelium. Cancer. 2004;100(8):1639– 1645.
13. Dogliotti L, Cartenì G, Siena S, et al. Gemcitabine plus cisplatin versus gemcitabine plus
carboplatin as first- line chemotherapy in advanced transitional cell carcinoma of the
urothelium: results of a randomized phase 2 trial. Eur Urol. 2007;52(1):134– 141.
14. Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin- based chemotherapy. Lancet Oncol.
2011;12(3):211– 214.
15. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first- line treatment in cisplatinineligible patients with locally advanced and metastatic urothelial carcinoma: a single- arm,
multicentre, phase 2 trial. Lancet. 2017;389(10064):67– 76.
16. Balar AV, Castellano D, O’Donnell PH, et al. First- line pembrolizumab in cisplatin- ineligible
patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-
052): a multicentre, single- arm, phase 2 study. Lancet Oncol. 2017;18(11):1483– 1492.
17. Bellmunt J, Théodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive
care compared with best supportive care alone after a platinum- containing regimen in
patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol.
2009;27(27):4454– 4461.
18. McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional- cell carcinoma. J Clin Oncol. 1997;15(5):1853– 1857.
19. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly
paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol.
2002;20(4):937– 940.
20. Jones RJ, Hussain SA, Protheroe AS, et al. Randomized phase II study investigating
pazopanib versus weekly paclitaxel in relapsed or progressive urothelial cancer. J Clin
Oncol. 2017;35(16):1770– 1777.
21. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti- PD- L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558– 562.
22. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second- line therapy for advanced
urothelial carcinoma. N Engl J Med. 2017;376(11):1015– 1026.
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SECTION 6
Upper urinary
tract cancer
Case 14 Localized renal cancer with inferior
vena cava tumour thrombus
Case 15 Metastatic renal cancer
Case 16 Upper urinary tract urothelial carcinoma
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14
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CASE
Localized renal cancer with
inferior vena cava
tumour thrombus
Tobias Klatte, Antony C.P. Riddick,
and Grant D. Stewart
Expert commentary Jose A. Karam
Case history
A 61- year- old patient is referred by his general practitioner with a 4- week history of
intermittent right loin pain. He does not report haematuria or systemic symptoms. His
current World Health Organization performance status is 0. Except for a right inguinal
hernia repair 20 years ago, he has not had any previous surgeries. He is not on any
regular medications but takes paracetamol when he has pain. The clinical examination
is unremarkable. Routine blood tests and the urine dipstick are normal. He undergoes an ultrasound study, which shows a large right renal tumour. The subsequent
computed tomography (CT) scan of the chest, abdomen, and pelvis confirms a large,
heterogeneous, enhancing right renal mass with a tumour thrombus extending into
the infrahepatic inferior vena cava (IVC, Mayo level II) (Figure 14.1).1 There is no
evidence of metastatic disease in the chest, abdomen, or pelvis. The clinical stage is
T3bN0M0.
Figure 14.1 Contrast- enhanced CT scan demonstrating heterogeneous right renal tumour with
extension into the infrahepatic IVC. (a) Axial; (b) coronal.
Reproduced with permission.
1
138 Challenging Concepts in Urological Surgery
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Learning point Diagnostic imaging
CT scans of the chest, abdomen, and pelvis are usually performed initially and subsequently
supplemented by magnetic resonance imaging (MRI) scans at many centres (Figure 14.2). Data
established decades ago2 suggested that MRI scans may be superior to CT in delineating the cephalad
extent of the venous tumour thrombus (VTT) and may be able to distinguish a bland thrombus
(non- enhancing, benign) from a tumour thrombus (enhancing, malignant). However, more recent
studies suggest that there are no clinically meaningful differences between MRI and contemporary CT
technology
date imaging must be obtained within 7– 10 days of the scheduled date for optimal surgical planning.
This imaging strategy excludes rapid tumour progression that would change management.
3– 5
and that a CT scan alone may be sufficient.6 It cannot be overemphasized that up- to-
Expert comment Cavotomy
and haemostasis
Ligation of the right gonadal vein
and the right adrenal vein, in
addition to the lumbar veins, is
crucial for excellent haemostasis
during cavotomy.
Figure 14.2 Axial water LAVA- Flex (GE Medical) gradient echo MRI demonstrating right renal
tumour extending and distending the renal vein and IVC.
Reproduced with permission.
1
Learning point Vascular anatomy on imaging
In surgical candidates, several additional vascular features warrant attention while reviewing the
scan. Arterial anatomy is crucial, as early arterial control is desired; this lowers blood loss and leads
to thrombus ‘shrinkage’ by decreasing venous back pressure. In right- sided cases, arterial control can
be achieved by identifying the renal artery in the inter- aorto- caval space if there are no bulky lymph
nodes. The anatomy of lumbar veins should be studied, as ligation is essential to achieve a bloodless
field during cavotomy. The gonadal vein and adrenal vein are often prominent as they may provide a
collateral circulation for the kidney with an obstructed renal vein.
Learning point Anteroposterior diameter of the IVC
An important feature is the anteroposterior diameter of the IVC at the level of the renal vein ostium.
An increasing diameter is associated with an increased risk of IVC wall invasion,7 which generally
necessitates IVC resection and possibly reconstruction to achieve negative resection margins. An
anteroposterior diameter of ≥24 mm (odds ratio (OR) 4.4), right- sided tumour location (OR 3.3),
and radiographic complete occlusion of the IVC at the renal vein ostium (OR 4.9) are all significant
predictors of the need for IVC resection and should be assessed.
8
Learning point Venacavography
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Invasive venacavography is reserved for surgical candidates in whom both contrast CT and MRI are
contraindicated, or if findings are equivocal. Transabdominal ultrasound may be used as an adjunct
modality in select cases, but requires highly trained personnel and is often indeterminate.9 Finally,
initial (i.e. preoperative) transoesophageal echocardiography is highly accurate for staging of VTT, but
does not provide additional information to CT/ MRI.10 Rather, it is used as a baseline investigation
for cardiac anatomy and function. Intraoperative continuous echocardiography can assist both
surgeons and anaesthetists during the operation, as it provides real- time imaging during surgery while
monitoring cardiovascular and fluid status.
11
Learning point Clinical, surgical, and pathological staging
Clinical staging of localized renal cell carcinoma (RCC) is based on imaging and physical examination.
The most commonly used clinical classification system is the tumour, node, and metastasis (TNM)
system, which is supplemented by a surgical VTT classification (Table 14.1).
Based on imaging, the tumour is classified clinically according to TNM. The eighth edition of the
TNM classification was implemented for all new cancer diagnoses from 1 January 2018. For tumours
with IVC- VTT, the primary clinical tumour (cT) stage is always T3b, T3c, or T4. Pathological tumour
(pT) stage needs to be guided by the operating surgeon as the pathologist will not be able to discern
between pT3b and pT3c based on the appearance of the tumour thrombus.
Clinical N stage refers to regional retroperitoneal lymph nodes and is based on the short- axis
diameter on cross- sectional imaging. The short- axis diameter is the longest perpendicular diameter
to the longest (i.e. long- axis) lymph node diameter.12 The historical cut- off for retroperitoneal
nodes is ≥10 mm,12 although this remains controversial. The risk of positive lymph nodes is 20% in
nodes ≥7 mm, 29% in nodes ≥10 mm, 47% in nodes ≥15 mm, and 66% in nodes ≥20 mm.13 Adding
additional imaging parameters to multivariable models does not improve the net benefit over
measurement of the short- axis diameter alone.13 Finally, M stage refers to distant or non- regional
lymph node metastases and is assessed clinically. pM1 can be assigned in rare circumstances in which
a metastatic deposit is sent for pathology, that is, after surgical removal (most commonly an ipsilateral
adrenal metastasis) or biopsy of a metastasis.
14
A variety of surgical VTT classifications have been published, all of which are directly related to surgical
management. The authors use the Mayo classification according to Neves and Zincke,15 which is
shown in Table 14.1.
Table 14.1 Clinical and surgical classification of VTT
Classification Class Description
14
TNM
T3b Tumour grossly extends into IVC below diaphragm
T3c Tumour grossly extends into IVC above diaphragm or invades
wall of the vena cava
T4 Tumour invades beyond Gerota’s fascia (including contiguous
extension into ipsilateral adrenal gland)
Mayo classification15I Tumour extends into IVC <2 cm from renal vein ostium
II Tumour extends into IVC >2 cm from renal vein ostium but
under the major hepatic veins
III Tumour extends into IVC at or above major hepatic veins
IV Tumour extends into IVC above diaphragm
Source data from: Brierley JD, Gospodarowicz MK, Wittekind C. Union for International Cancer Control (UICC)
TNM Classification of Malignant Tumours. 8th ed. Chichester, West Sussex, UK: Wiley Blackwell; 2017 and Neves
RJ, Zincke H. Surgical treatment of renal cancer with vena cava extension. Br J Urol. 1987 May;59(5):390– 395.
139Case 14 Localized renal cancer with inferior vena cava tumour thrombus
Expert comment Correct
staging
One way to facilitate the correct
staging is by having the urological
surgeon include the tumour
thrombus level with the specimen
details sent to pathology.
140 Challenging Concepts in Urological Surgery
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The scans were reviewed in the multidisciplinary team (MDT) meeting. This confirmed the presence of probable right renal cancer with extension into the IVC well
below the major hepatic veins, equalling a VTT level of II according to the Mayo
classification. There were no features suggestive of IVC wall involvement. A single
right renal artery was present. There was no intra- abdominal lymphadenopathy. The
MDT panel discussed presurgical systemic therapy (as part of a clinical trial) versus
immediate surgery and recommended offering immediate surgical resection. The patient was brought back to clinic and the outcome of the MDT meeting was discussed.
The patient agreed to undergo surgery. He was thoroughly consented to understand
the indication, complications, and all possible outcomes of the disease and procedure.
Expert comment Planning for VTT surgery
Aim to schedule surgery as soon as possible, ideally within 2 weeks, to avoid tumour extension or
embolization. We generally use prophylactic doses of anticoagulation between presentation to
clinic and time of surgery. However, there are no prospective data to support the use of therapeutic
anticoagulation in patients with IVC thrombus prior to surgery, in the absence of bland tumour
thrombus, deep vein thrombosis, or pulmonary embolism. Presurgical IVC filter placement
cranial to the IVC tumour thrombus should not be performed. Similarly, presurgical renal artery
embolization is generally not needed. The only clinical scenario when we perform renal artery
embolization is in patients who present with Budd– Chiari syndrome. In these patients, we reassess
for surgical candidacy around 2 months after renal artery embolization, to check if Budd– Chiari
syndrome has resolved. For tumour thrombus level III or higher, the surgery will ideally take place in
a thoracic/ cardiac operating room, in the presence of a cardiac anaesthesiologist, a thoracic/ cardiac
surgeon (in addition to a urological surgeon), transoesophageal echocardiography machine, and
cardiac pump on standby.
Learning point Presurgical systemic therapy
Downstaging of locally advanced or initially unresectable primary RCC is the aim of presurgical
systemic approaches with tyrosine kinase inhibitors (TKIs) and often discussed as a potential
option in MDT meetings. At present, there are no published case series with immune checkpoint
inhibitors alone or in combination with TKIs. Several retrospective case series evaluated the
impact of targeted therapy in patients with VTT. For this case, we performed a quantitative data
synthesis of eight retrospective case series with a total of 109 patients using standard random
effects models (Publication cut- off: 4 January 2019) (Figure 14.3). Four studies focused on
mixed groups of targeted therapies,
pazopanib.23 The median number of treatment cycles was two. Overall, 65.1% of patients (95%
confidence interval (CI) 47.9– 79.1) showed a measurable decrease in VTT height with a mean
reduction of 2.0 cm (95% CI 1.8– 2.5), while 19.4% (95% CI 12.5– 28.8) showed an increase in
VTT height. The VTT level decreased in 22.6% (95% CI 14.9– 32.9), remained stable in 73.6% (95%
CI 64.1– 81.4), and increased in 7.2% (95% CI 3.4– 14.3). (Note: these proportions are derived
from separate random effects models and therefore do not add up to 100%.) Results were most
favourable for sunitinib and axitinib.
There is only one ongoing prospective trial in this setting. NAXIVA (Neoadjuvant study of AXItinib
for reducing extent of venous tumour thrombus in clear cell renal cell cancer with Venous invAsion;
NCT0349481) is a single- arm phase II feasibility trial of neoadjuvant axitinib on 20 patients with clear
cell RCC and VTT. The primary endpoint is change in VTT level.
In summary, the effect of targeted therapies on tumour thrombi is variable although it may alter
surgical management in select patients. Current guidelines do not recommend presurgical systemic
therapy outside of clinical trials.
16– 19
two on sunitinib,
16,18,22
20,21
one on axitinib,22 and one on
141Case 14 Localized renal cancer with inferior vena cava tumour thrombus
Decrease thr
% of patients
Decrease thr
Increase thr
Increase thr
0102030405060708090 100
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ombus height
ombus level
ombus height
ombus level
Figure 14.3 Graphical abstract summarizing quantitative analyses of studies on presurgical
TKI therapy in patients with IVC- VTT. No significant heterogeneity was observed (each p for
heterogeneity >0.35).
65.1%
22.6%
19.4%
7.2%
The patient was placed in the supine position. Antibiotic prophylaxis with 160
mg of gentamicin was given. Laparotomy was performed using a rooftop incision.
A Thompson retractor was placed. The right hemicolon and hepatic flexure were
mobilized off Gerota’s fascia. The small bowel was mobilized and the duodenum
Kocherized. Hepatic ligaments and adhesions between the lower margin of the liver
and Gerota’s fascia were then divided. The supra- and infrarenal vena cava and the
left renal vein were then fully exposed, and slings were passed around these structures
(Figure 14.4a). The renal artery was identified in the inter- aortocaval groove and divided between polyglactin 1 ties. Lumbar veins were divided between polyglactin 4- 0
ties. The kidney was then fully mobilized. Intraoperative ultrasound was applied, confirming infrahepatic tumour thrombus. A tourniquet was applied around the proximal
and distal cava and the left renal vein. An elliptic incision was made around the right
renal vein ostium and extended 4 cm cephalad using Potts scissors. The right kidney,
right renal vein, and the IVC thrombus were then removed en bloc (Figure 14.4b,c).
The lumen of the cava was irrigated using heparinized saline and subsequently closed
with a running Prolene® 4- 0 suture. The tourniquets were released and no bleeding
encountered. The wound was closed in 2 layers using running polydioxanone 1. The
intraoperative blood loss was 400 mL, and the operating time was 210 minutes.
Figure 14.4 Intraoperative images. (a) Control of the infrarenal and suprarenal vena cava and left renal
vein with slings, which will be used as tourniquet. All lumbar veins have been divided at this stage. (b) After
cavotomy, the tumour thrombus is removed. (c) The renal tumour was excised in continuity with the thrombus.
Reproduced with permission.
1
142 Challenging Concepts in Urological Surgery
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Expert comment Approach to VTT surgery
● We usually provide venous thromboembolism prophylaxis prior to surgery using heparin.
● A midline incision is my preferred approach, it provides quick entry and closure, as well as excellent
access to the retroperitoneum, especially when coupled with a Thompson retractor. In rare cases
where more cranial extension is needed, the skin can be opened for another 5 cm and the xiphoid
process can be resected, which allows for even more retraction and exposure.
● It is important to control and divide all short hepatic veins for level II thrombi in order to allow full
mobilization of the IVC as cranial as possible caudal to the major hepatic veins.
● I fully mobilize the IVC after the right renal artery has been controlled. This can be achieved early
in the surgery after identifying the left renal vein, cleaning the preaortic nodes, lifting the left renal
vein anteriorly with a vein retractor, then finding the right renal artery posterior to the left renal vein,
which is the safest location for control in IVC thrombectomy surgeries. After the right renal artery is
controlled and divided, the IVC is isolated cranially and caudally, and so is the left renal vein, with
vessel loops or umbilical tapes placed loosely placed around these structures.
● We generally leave the kidney in situ without any mobilization in order to minimize the risk of
tumour thrombus embolization, which could occur during handling of the kidney.
● For cranial IVC control, we generally use a clamp instead of a tourniquet as sometimes we need to
resect more IVC wall cranially that planned for/ expected, and this would be more stable compared
to a tourniquet which could become loose if the IVC is opened too close to it. This can be used for
caudal IVC control as well.
● I generally use a 15- blade to perform the cavotomy as it is less likely to violate the tumour thrombus when
opening the IVC wall, given the blade’s convex shape (in contradistinction to an 11- blade, for example).
● It is helpful to have in the surgical set reverse Potts scissors in addition to regular Potts scissors to
allow for more versatility in the resection of IVC wall. It is very important to resect the renal vein
ostium. A bovine pericardium patch should be available on standby in these types of surgeries in
case the IVC wall is resected more than expected preoperatively.
● It is helpful to have a No. 1 Penfield dissector available for this surgery, as it is a very useful tool to
dissect an adherent thrombus away from IVC wall.
● My preference for caval closure is to use two separate Prolene® sutures, one starting from each
corner of the cavotomy and then tied together. Some additional manoeuvres that can be used is
to put the table in Trendelenburg position and opening the clamps temporarily prior to tying the
Prolene® sutures in order to minimize the risk of embolism. If already in use, transoesophageal
echocardiography can be used to check the heart for air when this is done.
Pathology showed a clear cell RCC with invasion of the perirenal fat, renal sinus
fat, and the collecting system. As the thrombus extended into the infra- diaphragmatic
cava but not the caval wall, the final T classification was 3b. The maximum size of the
primary tumour was 9 cm. There were areas of coagulative tumour necrosis. Tumour
cell nucleoli were eosinophilic and clearly visible at 100× magnification. There was no
sarcomatoid or rhabdoid dedifferentiation. The final International Society of Urological
Pathology (ISUP) grade was 3. The tumour did not reach the perirenal resection
margin. There were ten negative lymph nodes. The final stage was T3bN0M0, and the
Leibovich score was 6 (‘high risk’).
Learning point Risk stratification
An accurate prediction of the individual probability of recurrence based on multivariable prognostic
models is essential to counsel patients, individualize surveillance, and select patients for adjuvant
clinical trials. The Leibovich prognostic score24 and the University of California Integrated Staging
System (UISS)25 are the most commonly used postoperative prognostic models and can be assigned
from routine clinicopathological data (Table 14.2).26 The Leibovich score does include patients with
N+ disease, while UISS treats those as metastatic. While the Leibovich score was developed for clear
cell RCC, UISS includes all RCC subtypes.
Table 14.2 The Leibovich score and UISS for postoperative risk stratification of clinically
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localized renal cell carcinoma
Name Feature Points
Leibovich Score
(T1– 4N any M0)
UISS
(T1– 4N0M0)
ECOG, Eastern Cooperative Oncology Group; PS, performance status.
Adapted from reference26.
T classification T1a
T1b
T2
T3 or T4
N classification pNx or pN0
pN+
Tumour size <10 cm
≥10 cm
Nuclear grade G1 or G2
G3
G4
Tumour necrosis Absent
Present
Stratification based on total points 0– 2
3– 5
6– 11
T1, grade 1– 2, ECOG PS 0 Low risk
T1, grade 1– 2, ECOG PS ≥1
T1, grade 3– 4, any ECOG PS
T2, any grade, any ECOG PS
T3, grade 1, any ECOG PS
T3, grade 2– 4, ECOG PS 0
T3, grade 2– 4, ECOG PS ≥1
T4, any grade, any ECOG PS
0
2
3
4
0
2
0
1
0
1
3
0
1
Low risk
Intermediate risk
High risk
Intermediate risk
Intermediate risk
Intermediate risk
Intermediate risk
Intermediate risk
High risk
High risk
143Case 14 Localized renal cancer with inferior vena cava tumour thrombus
The postoperative course was uneventful and the patient was discharged home on
postoperative day 5. He completed a 28- day course of subcutaneous low- molecularweight heparin injections. Following release of the pathology report, the case was
re- discussed at the MDT meeting. The panel recommended ‘high- risk follow- up’ and
offered participation in an adjuvant clinical trial. The patient was counselled that the
risk of disease recurrence is approximately 50%.
Learning point Surveillance and adjuvant therapy
At present, postoperative surveillance remains the standard of care for patients with completely
resected non- metastatic RCC. There is little evidence in this field and therefore little agreement among
professional bodies regarding the optimal surveillance regimen. The authors of this case follow the
EAU schedule (Table 14.3).
Adjuvant trials are typically superiority placebo- controlled clinical phase III trials, which are initiated
following successful drug testing in the metastatic setting. There have been numerous investigations
over the past decades on a range of interventions, including radiotherapy, hormone therapy, cytokines,
and vaccines. Many of these trials were underpowered and, with the exception of one vaccine trial,28
none produced convincing data of benefit. Several trials investigating the use of TKIs and mammalian
target of rapamycin inhibitors are now published or currently in follow- up (Table 14.4).
trial (S- TRAC29) showed an improvement in disease- free survival (of 1.2- year delay in progression
for 1 year of sunitinib therapy), adjuvant therapy with TKI is therefore not recommended by the
European Association of Urology guidelines panel.27 Recently, adjuvant pembrolizumab at a dose of
200 mg once every 3 weeks for up to 17 cycles (approximately 1 year) improved disease- free survival
27
29– 32
Only one
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