Recent Advances in Diagnosis
Saturday, May 17, 2008
6:00- 8:00 p.m.
COURSE 08 EC
W. Marston Linehan, M.D., Ph.D.
Peter A. Pinto, M.D.
Jeffrey A. Sosman, M.D.
American Urological Association
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2008 Annual Meeting, Orlando, FL
May 17-22, 2008
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2008 AUA Annual Meeting
08 EC Kidney Cancer: Recent Advances in Diagnosis and Management
5/17/2008 6:00 - 8:00 p.m.
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Recent Advances in Diagnosis and Management
of Kidney Cancer
W. Marston Linehan, M.D.
Chief, Urologic Oncology Branch
National Cancer Institute
Bldg 10 Rm 1-5942
Bethesda, Maryland 20892-1107
Tel: (301) 496-6353
Fax: (301) 402-0922
Peter Pinto, M.D.
Senior Investigator, Urologic Oncology Branch
National Cancer Institute
Bldg 10 Rm 2-5940
Bethesda, Maryland 20892-1107
Tel: (301) 496-6353
Fax: (301) 402-0922
Email : firstname.lastname@example.org
Jeffrey A. Sosman, M.D.
Professor of Medicine (Hematology/Oncology)
777 Preston Building
Nashville, TN 27232-6307
Office (615) 343-7602
RECENT ADVANCES IN DIAGNOSES AND MANAGEMENT
OF KIDNEY CANCER
Saturday, May 17, 2008
6:00PM - 8:00PM
From To Speaker Topic
6:00 PM - 6:20 PM W. Marston Linehan, M.D. I. Molecular Genetics of Renal Carcinoma:
Implications for the Urologic Surgeon
II. Hereditary Forms of Renal Cancers
6:20 PM - 7:00 PM Peter A. Pinto, M.D. III. Techniques and Indications
A) Laparoscopic Nephrectomy
B) Laparoscopic Partial Nephrectomy
IV. Robotic Assisted Nephrectomy and
7:00 PM - 7:40 PM Jeffrey A. Sosman, M.D. V. Role of Targeted Systemic Therapy
In the Management of Advanced Clear Cell
And Non-Clear Cell Kidney Cancer
7:40 PM - 8:00 PM W. Marston Linehan, M.D. VI. A) Management of Patients Who Present with
Peter A. Pinto, M.D. Advanced Disease with Kidney In Place
Jeffrey A. Sosman, M.D. B) Role of Adjuvant Therapy in the
Management of Patients with High Risk
Kidney cancer affects over 39,000 Americans annually and it is estimated that nearly
13,000 will die of this disease in the United States each year. Patients who are found to have the
disease when it is localized to the kidney can have up to a 95% 5 and 10 year survival rate.
Patients who present to their urologic surgeon with locally advanced disease have up to a 65%
chance of surviving 5 years. Those who present with advanced disease have an 18% 2 year
The advent of laparoscopic surgery has provided new and significantly less morbid
surgical strategies for the management of patients with localized, locally advanced and even
advanced renal carcinoma. There have been exciting advances in the development of new
minimally invasive strategies for the management of patients with localized kidney cancer
involving radio frequency ablation therapy as well as cryotherapy. Recent advances in
immunologic and molecular targeted forms of therapy have provided new hope for patients with
advanced renal cell carcinoma.3,4
1. Molecular Genetics of Renal Carcinoma: Implications for the
Urologic Surgeon (W. Marston Linehan, M.D.)
Kidney cancer is not a single disease, it is made up of a number of different types of
cancer that occur in the kidney; each with a different histology, having a different clinical course,
responding differently to therapy and caused by different genes.
Figure 1 Kidney cancer is made up of a number of different types of cancer, each with a
different histology, with a different clinical course, responding differently to therapy and
caused by different genes. From Linehan, et al.5
This section of the course will update you on current studies of the molecular genetics of
sporadic and familial renal cancer, background on kidney cancer tumor suppressor genes and
oncogenes, data for why we conclude that the von Hippel Lindau disease gene and the Met genes
are critical genes for both hereditary and non-familial, sporadic kidney cancers, for how these
genes fit the definitions of cancer genes and how these types of findings could lead to better
methods for early diagnosis, prevention and, potentially, therapy of renal cancers will be
2. Tumor Suppressor Genes and Oncogenes
A. Tumor Suppressor Genes
The pioneering studies of Dr. Alfred Knudson led to the development of a hypothesis that
the most basic aspect of cancer would involve what is called a tumor suppressor gene. Instead of
cancer being the result of activation of a gene such as an oncogene, which drives the abnormal
proliferation that we know of as cancer, Knudson hypothesized that, instead, cancer could be the
result of inactivation of a gene, a so called tumor suppressor gene, whose normal function was to
regulate or control cellular growth.
We each have two copies of each gene, one maternal and the other paternal. If both
copies of a tumor suppressor gene were inactivated (Knudson “two-hit” hypothesis) by either
loss of DNA (DNA sequence deletion), or another mechanism such as mutation, transformation
Knudson hypothesized that if this were the case in a sporadic, non-hereditary cancer, and
there were a hereditary variant of the same malignancy, that the same gene might be involved in
the origin of both. This is the case in retinoblastoma, where both copies of the retinoblastoma
gene are inactivated in both the sporadic and hereditary form of the disease. Abnormalities of
tumor suppressor genes have been found in a number of solid human tumors, including breast,
bladder and, as we shall see, kidney cancer. The VHL kidney cancer tumor suppressor gene,
the gene for clear cell renal carcinoma, is a classic tumor suppressor gene located on
An oncogene is a “gain of function gene”; i.e., a gene in which a mutation of the gene
results in activation of the gene, resulting in the unregulated growth that we know of as cancer.
Often an oncogene may be “duplicated” in a cancer, resulting in three copies of the gene (instead
of two copies). This is called trisomy. The c-Met oncogene, the gene for Hereditary
Papillary Renal Carcinoma (HPRC), is a classic oncogene located on chromosome 7.
II. Hereditary Forms of Renal Cancers
Kidney cancer is like retinoblastoma and colon cancer in that there is both a sporadic and
a familial form. Familial kidney cancer is far more prevalent than had been previously imagined.
It is estimated that 5% of kidney cancer is familial (hereditary). There are four types of
hereditary kidney cancer. The well described is clear cell renal cancer associated with von
Hippel Lindau (VHL); there is a hereditary form of type 1 papillary renal carcinoma (HPRC); the
third type is hereditary chromophobe renal carcinoma associated with Birt Hogg Dubé (BHD)
and the fourth is a hereditary type of papillary type 2 renal carcinoma associated with Hereditary
Leiomyomatosis Renal Carcinoma (HLRCC).
Table 1 Inherited Forms of Renal Carcinoma
1. Von Hippel Lindau (VHL)
Clear Cell RCC
2. Hereditary Papillary Renal Carcinoma (HPRC)
Papillary Type 1 RCC
3. Birt Hogg Dubé (BHD)
4. Hereditary Leiomyomatosis RCC (HLRCC)
Papillary Type 2 RCC
These familial forms of kidney cancer are different from sporadic, non-familial kidney
cancer in that they tend to be multifocal, bilateral and occur at a younger age, suggesting a genetic
predisposition to develop these cancers.
1. Von Hippel Lindau (VHL)
A. Renal Carcinoma Gene Localization Studies: Inherited Renal Cancer
To identify the disease gene for clear cell kidney cancer the familial form of renal cell
carcinoma associated with von Hippel Lindau (VHL) was studied. Von Hippel Lindau is an
autosomal dominant hereditary cancer syndrome in which affected individuals are at risk to develop
tumors in a number of organs, including the kidneys.
VHL patients are at risk to develop multiple, bilateral renal carcinomas and cysts, cerebellar
and spinal hemangioblastomas, pheochromocytomas, retinal angiomas, epididymal cystadenomas,
pancreatic cysts and islet cell tumors and tumors in the inner ear, endolymphatic sac tumors.
Table 2 Clinical Features of VHL
h Kidney tumors (clear cell RCC)
h Adrenal tumors (pheochromocytoma)
h Pancreatic tumors (islet tumors)
h CNS tumors (hemangioblastoma)
h Retinal tumors (angioma)
h Endolymphatic sac tumors (inner ear)
h Epididymal cystadenoma
B. VHL: Clinical Evaluation
Clinical evaluation of VHL patients involves MRI of the brain and spine (for CNS
hemangioblastomas), abdominal CT and ultrasound (for evaluation of renal, adrenal and
pancreatic manifestations of VHL), ophthalmologic evaluation (for evaluation for retinal
hemangiomas), audiometric and ENT evaluation (to search for presence of ELST tumors),
testicular ultrasound (to evaluate epididymal cystadenomas).
Table 3 Clinical Evaluation-VHL
• VHL gene germline mutation testing
• MRI of the brain and spine
• Abdominal CT and ultrasound
• Ophthalmologic evaluation
• Audiometric and ENT evaluation
• Testicular Ultrasound
• Metabolic evaluation (catechols)
C. VHL: Surgical Management
Surgical management of the renal manifestations of VHL patients involves nephron
sparing surgery whenever possible. Patients with small renal tumors, generally under 2.5 cm, are
often managed with expectant management. When the tumors reach 3 cm, surgery is often
recommended. As it has been estimated that there can be up to 600 tumors per kidney in VHL
patients, surgical resection of renal lesions is not considered “curative.” Rather, it is considered
that surgical management will hopefully “set back the clock”; i.e. help prevent metastasis.
Historically 35 to 45% of VHL patients have died of complications of metastatic renal cell
carcinoma. The decision to recommend surgery must balance the risk of metastasis with the
morbidity of surgery. This is often a complex issue in VHL patients with multisystem
manifestations. When surgery is performed, thorough evaluation of the kidney with
intraoperative ultrasound is considered a valuable adjunct to the surgical procedure. This allows
the surgeon to localize renal tumors and cysts and to perform as thorough and safe a procedure as
Renal Lesions in VHL Patient Microscopic VHL RCC Focus
It is important that VHL patients undergo a complete screening and metabolic evaluation prior to
a surgical procedure, to rule out such unsuspected manifestations as a CNS hemangioblastoma or
D. The VHL gene is on Chromosome 3
In order to identify the gene associated with VHL we evaluated affected and at risk
individuals for VHL. DNA was extracted from blood of over 4,000 individuals. 450 patients
were screened at the NIH for the presence of von Hippel Lindau. In order to localize this kidney
cancer disease gene genetic linkage analysis was utilized, which narrowed the area of the VHL
gene to a small region on chromosome 3, which is the same region where we showed
abnormalities in tumor tissue from patients with non-familial, clear cell kidney cancer.
Mutations of the VHL Gene in the Germline of VHL Patients From Chen et al.6
E. The VHL gene is the gene for sporadic, non-inherited clear cell RCC
Mutations of the VHL gene is tumors from patients with sporadic, non-
hereditary clear cell kidney cancer. From Gnarra, et al. 7
VHL mutations have been identified in a high percentage of tumors from patients with
sporadic, clear cell renal carcinomas. VHL somatic mutations have been detected in the earliest,
localized clear cell tumors. No mutations have been found in papillary, chromophobe, collecting
duct or other types of renal tumors.
F. Molecular Targeting the VHL gene in clear cell kidney cancer
It is hoped that understanding the pathways for the genes that cause kidney cancer will
lead to the development of more effective forms of therapy for patients with this disease. The
VHL clear cell kidney cancer gene was identified in 1993 and since that time an intensive effort
has been underway to identify how damage to this gene leads to kidney cancer. The VHL gene
product has been found to be important regulator of Hypoxia Inducible Factor (HIF). HIF is a
transcription factor which regulates a number of downstream genes known to be important in
cancer, such as vascular endothelial growth factor (VEGF), platelet derived growth factor
(PDGF), erythropoietin, etc. Scientists are currently evaluating the role of small molecules that
block this pathway as potential strategies for therapy.
VHL Kidney Cancer Gene Pathway RCC Molecular targeting: anti-VEGF antibody.
Adapted from Linehan, et al.5
The FDA recently approved three new agents, sunitinib, sorafenib and temsirolimus for the
treatment of patients with advanced kidney cancer.
Targeting VHL/HIF in Clear Cell RCC
VEGF PDGF TGF-α
VEGFR PDGFR EGFR
Sunitinib The partial response rate in patients with advanced renal carcinoma
treated with sunitinib has been reported to be 31% and there was an increase in
progression free survival in patients treated with sunitinib versus interferon.8 The
most commonly reported side effects with sunitinib involve diarrhea, skin
discoloration, mouth irritation, weakness, and altered taste. Patients treated with
sunitinib may also experience, high blood pressure, fatigue, bleeding, and
Targeting VHL/HIF in Clear Cell RCC
VEGF PDGF TGF-α
VEGFR PDGFR EGFR
Sorafenib The partial response rate in patients with advanced renal carcinoma
treated with sorafenib has been reported to be 10% and the progression free
survival was 5.5 months versus 2.8 months for patients treated with placebo.9
Targeting VHL/HIF in Clear Cell RCC
VEGF PDGF TGF-α
VEGFR PDGFR EGFR
Temsirolimus (inhibitor of mammalian target of rapamycin-MTOR)
Temsirolimus, the MTOR-inhibiting agent, has been found to have activity in
patients with advanced, poor prognosis kidney cancer. In a recent report of a
randomized three-arm phase 3 trial, temsirolimus was found to have an overall
statistically significant survival benefit versus treatment with interferon alone
(10.9 versus 7.3 months). This study confirmed MTOR as a valid target in kidney
cancer and that temsirolimus monotherapy prolongs survival in patients with poor
prognosis kidney cancer. 10
G. Adjuvant Treatment
The role of agents such as sunitinib and sorafenib in the adjuvant setting are not known. To
address this question, a randomized phase 3 trial involving 1332 patients, supported by the
Eastern Cooperative Oncology Group (ECOG), the Cancer Trials Support Unit CTSU), the
Southwest Oncology Group (SWOG), the Cancer and Leukemia Group B (CALGB) and the
National Cancer Institute of Canada (NCIC). In this trial, patients with T1B, T2 or T4 (N0-N2)
will be randomized to receive one year of sunitinib, sorafenib or placebo after nephrectomy.11
Information about the trial can be found at the Kidney Cancer Association web site.
2. Hereditary Papillary Renal Cell Carcinoma: HPRC
A. HPRC: Clinical Features
Hereditary Papillary Renal Carcinoma is a hereditary cancer syndrome in which affected
individuals are at risk for the development of bilateral, multifocal, type 1 papillary renal
carcinoma.12 HPRC patients are at risk for the development of up to 3,000 tumors per kidney,
which are uniformly of type 1 papillary histologic type.13
Figure 2 Hereditary Papillary Renal Carcinoma (HPRC) is a hereditary cancer
syndrome where affected individuals are at risk for the development of bilateral,
multifocal, type 1 papillary renal carcinoma. From Linehan, et al.5
Table 4 Hereditary Papillary Renal Carcinoma
h Clinical Features
h Bilateral, multifocal papillary renal cell carcinoma
h Type I papillary renal carcinoma
h Clinical Evaluation
– C-Met gene germline mutation testing
– Abdominal CT and ultrasound
B. Met is the Hereditary Papillary Renal Carcinoma gene
The gene for type 1 papillary renal carcinoma associated with Hereditary Papillary Renal
Carcinoma is the Met proto-oncogene on chromosome 7.14,15 Met is a normal gene (a proto-
oncogene) that codes for Met, the cell surface receptor for the ligand hepatocyte growth factor.
Met becomes an oncogene when activating mutations occur in the tyrosine kinase domain of this
gene in the germline of HPRC patients. A simple blood test is available to determine if the at-
risk individual carries the germline Met mutation.
Figure 3 Met, the cell surface receptor for the ligand, hepatocyte growth factor, is the gene
for Hereditary Papillary Renal Carcinoma. Germline mutations of Met are found in
affected individuals in HPRC kindreds. From Linehan, et al 5
3. Birt Hogg Dubé (BHD): Chromophobe Kidney Cancer
Birt Hogg Dubé is a hereditary syndrome in which affected individuals are at risk for the
development of kidney cancer, cutaneous lesions and pulmonary cysts.
Figure 4 Birt Hogg Dubé (BHD) is a hereditary cancer syndrome in which patients
are at-risk for the development of cutaneous lesions (fibrofolliculoma), pulmonary
cysts and kidney cancer. From Linehan et al.5
The kidney tumors can be chromophobe, hybrid/oncocytic, papillary or clear cell RCC.16 The
BHD gene was recently identified on chromosome 1717 and a blood test is now available for
determination of whether at-risk individuals are affected with BHD.18
Table 5 Clinical Features of Birt Hogg Dubé
h Cutaneous nodules (hair follicle tumors,
fibrofolliculoma) on the face and neck
h Pulmonary cysts
h Renal tumors
h Chromophobe RCC
h Oncocytic hybrid RCC
h Clear cell RCC
Figure 5 BHD associated kidney cancer can be chromophobe, hybrid/oncocytic
RCC or oncocytoma. From Linehan, et al.5
Table 6 Clinical Evaluation-BHD
• BHD gene germline mutation testing
• Dermatologic evaluation-skin biopsy
• Lung CT
• Abdominal CT/ultrasound
4. Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC)
A. HLRCC: Clinical Features
Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is a hereditary cancer
syndrome in which affected individuals are at risk for the development of cutaneous and
uterine leiomyomas (fibroids) and an aggressive form of type 2 papillary kidney cancer.19
Figure 6 HLRCC is a hereditary cancer syndrome in which affected individuals are
at-risk for the development of cutaneous and uterine leiomyomas and type 2
papillary renal carcinoma. From Linehan, et al.5
Table 7 Clinical Features of Hereditary
Leiomyomatosis Renal Cell Carcinoma (HLRCC)
h Cutaneous nodules (leiomyomas)
h Uterine leiomyoma (fibroids)
h Uterine leiomyosarcoma
h Renal tumor (type 2 papillary RCC)
h Often solitary
h Aggressive, early to metastasize
B. Fumarate Hydratase (FH) is the gene for HLRCC
The Krebs cycle enzyme, fumarate hydratase (FH) is the gene for the hereditary form of Type II
papillary renal carcinoma associated with Hereditary Leiomyomatosis Renal Carcinoma
(HLRCC) and there is a blood test available to determine whether or not a patient is affected
with HLRCC.20 These tumors can be very aggressive21 and partial nephrectomy is often not
recommended for these patients. Early intervention with nephrectomy is recommended as these
aggressive tumors may spread early.
Table 8 Clinical Evaluation-HLRCC
• Fumarate hydratase (FH) gene germline
• Dermatologic evaluation-skin biopsy
• Abdominal CT/ultrasound
• Pelvic CT/uterine ultrasound
5. Familial Renal Carcinoma (FRC)
Recently scientists in Iceland have performed studies suggesting that genetic
susceptibility may be a major component in the development of ordinary, “sporadic” renal
carcinoma. In their initial study, 68% of individuals in Iceland who had kidney cancer had up to
a second degree relative (a second cousin) with kidney cancer. This work suggests that it is
important to ask all patients with renal carcinoma whether any other family member also was
affected with renal carcinoma. Urologic surgeons at the NCI are currently studying families in
which multiple members are affected with kidney cancer (FRC) in order to identify the genetic
basis of this form of kidney cancer.22
Figure 7 Studies have shown that there may be a strong hereditary
component to “sporadic” kidney cancers. Investigators are currently
intensively studying families in which more than one family member has
kidney cancer in order to determine the gene(s) for familial renal
carcinoma. From Linehan, et al.5
III. Techniques and Indications (Peter Pinto, M.D.)
A) Laparoscopic Nephrectomy
Surgical Technique: Transperitoneal Approach
The following will describe the operative technique for a transperitoneal left laparoscopic
nephrectomy. The patient undergoes general endotracheal anesthesia, prophylactic antibiotics
and placement of an orogastric tube and urinary catheter. While supine the lower midline
incision is marked with an indelible pen. This is done prior to positioning to allow the incision
for possible specimen extraction to be symmetric in reference to the midline. This is difficult to
judge after the patient is positioned. The patient is then placed in a modified left flank position
with a bump under their left side. The right arm is tucked and the left arm is folded over
cushions across the chest. (Picture 1)
Picture 1) Positioning for transperitoneal left laparoscopic renal surgery.
From Pinto, et al.23
All pressure points are checked and padded. The patient is secured to the table with 3
inch wide silk tape. In order to confirm that the patient is adequately secured, the table is
maximally tilted prior to draping.
The operating table is returned to a neutral position and the patient is prepped and draped
in the standard fashion. The surgeon and assistant stand on the patient’s right side and the scrub
nurse on the left side by the legs. In cases where a robotic camera holder is used, it is secured to
the table at the level of the patient’s right shoulder prior to draping. With the aid of a Veress
needle, pneumoperitoneum is established at a pressure of 20 mmHg. Four trocars are
subsequently placed: a 10mm periumbilical port for the camera, a 12mm port in the left
midaxillary line at the level of the umbilicus, a 12mm port in the midline of the premarked
pfannensteil incision, and a 5mm trocar in the midline, halfway between the umbilicus and
xyphoid. (Picture 2) In obese patients, the port placement is altered slightly. In these cases, the
ports are shifted laterally, with the camera port at the level of the umbilicus, but lateral to the
rectus muscle. (Figure 1)
Picture 2) Port placement for left laparoscopic nephrectomy/partial nephrectomy.
Lower midline port can be extended for specimen retrieval.
Figure 1) Port placement shifted laterally for obese patient. From Williams et al.24
A visualizing trocar is used to place the first port, allowing the remaining three to be
placed under vision. Even in the setting of previous abdominal surgery, initial entry with a
veress and visualizing trocar has been shown to be safe. ( J Urol 170, 61–63, July 2003)
All trocars are secured to the skin with suture to avoid inadvertent removal during surgery.
The table is then tilted maximally to the right to help the bowel fall medially. This can be
facilitated by an assistant using a paddle retractor through the low midline port. The
retroperitoneal space is entered by incising the line of Toldt sharply from the spleen to the iliac
vessels. (Figure 2)
Figure 2) Entering the retroperitoneal space
As the descending colon is reflected medially care must be taken to develop the plane
between the mesocolon and anterior gerota’s fascia. If not, a common mistake is to dissect
lateral to the kidney. This divides the renal attachments laterally and makes future hilar
dissection more difficult. In order to obtain proper exposure to the renal hilum and especially for
upper pole tumors, the splenophrenic ligament must be incised. Take care to avoid inadvertent
injury to the stomach and diaphragm as the spleen is being mobilized. Once completely
mobilized, the spleen, tail of pancreas and splenic flexure will fall medially out of the operative
Upper pole dissection is then carried out. The lienorenal ligaments are divided sharply in
order to avoid inadvertent splenic lacerations. This dissection is carried out toward the renal
hilum in order to separate the adrenal gland and expose the adrenal vein as it enter the renal vein.
In cases where the tumor location does not necessitate taking the adrenal gland, the renal vein
may be transected lateral, preserving the adrenal vein’s entry into the renal vein. Alternatively,
the adrenal vein can be clipped and divided. (Figure 3)
Figure 3) Upper pole mobilization when needed
With the upper pole of the kidney mobilized, attention is turned to the lower pole of the kidney,
ureter, gonadal and renal hilum. Dividing the colorenal ligaments allows the colon to fall
medially and exposes the lower pole, gonadal vessels and ureter. (Figure 4)
Figure 4) Lower pole, ureteral and gonadal dissection
A plane is developed between the psoas muscle and the gonadal/ureteral packet. If the
ureter is difficult to identify, or obscured by a large lower pole mass, the dissection can be started
distally at the level of the iliac vessels and continued proximally to the renal vein. At the level of
the renal hilum lumbar vessels are ligated and divided as necessary. The neuro-lymphatic and
fibrofatty tissue surrounding the renal artery and vein is ligated and divided isolating the artery
down to its take off from the aorta. This dissection also allows for a hilar lymphadenectomy to be
performed if indicated. The renal artery and vein can be controlled with titanium or polymer
clips (leaving 3 on the patient side) or an endoscopic linear cutter stapler with a vascular staple
load (Figure 5).
Figure 5) Ligation of the renal vessels
With the vessels divided, the ureter is ligated and the remaining lateral, posterior and
superior attachments are freed with cauterized scissors.
If intact specimen extraction is to be performed, the lower midline trocar is then
exchanged for an entrapment sac device (15mm Endo Catch II, US Surgical, Norwalk, CT). The
specimen can then be placed into the deployed entrapment sac and delivered through a low
midline incision which incorporates the lower midline trocar. The extraction incision is then
closed and pneumoperitoneum is re-established to ensure that adequate hemostasis was obtained.
This is done at a pressure of 5mmHg to reveal bleeding that might be present at normal
insufflation pressures. Alternatively, the specimen can be morcellated. In these cases the
specimen must be placed in an impermeable entrapment sac (Lapsac® Cook, Bloomington, IN)
prior to morcellation. The 12mm trocar sites are then closed with the aid of a needle-point suture
passer after the pneumoperitoneum has been evacuated.
Indications for laparoscopic radical nephrectomy include organ confined tumors (stage Tl
or T2) not amenable to nephron-sparing surgery. Some investigators have demonstrated that
even large masses (12cm) can be removed laparoscopically. Tumors spreading beyond Gerota's
fascia or involving the renal vein are technically challenging, but have been performed.
Laparoscopy has also provided a benefit to patients in the setting of metastatic disease.
Surgical Technique: Retroperitoneal Approach
The patient is placed on the operating table in the standard flank position with the side of
pathology facing up. The top arm is draped over a padded Mayo stand or multiple pillows. An
axillary roll is placed. The bottom leg is flexed and bent while the top leg is straight. The kidney
rest is elevated and the table is flexed in order to maximize the working space between the ribs
and iliac crest (Picture 3).
Picture 3) The patient is placed in a full flank position with the kidney rest elevated and the table flexed.
This increases the distance between the costal margin and iliac crest, thus maximizing the working space.
The skin between the iliac crest and the ribs should be taut on palpation. All pressure
points are padded and the patient is then secured to the table with tape at the shoulders, hips, and
legs. The table is rotated left and right to make sure the patient does not shift during the
procedure. The surgeon and camera assistant are positioned facing the patient's back. The scrub
nurse stands on the opposite side at the end of the table. (Fig 6)
Fig 6) Operating room setup for laparoscopic retroperitoneal renal surgery.
From Pinto et al.25
Two monitors are used to provide all personnel with an unobstructed view. Alternatively,
the camera assistant can be replaced by a mechanical or robotic arm which can be fixed to the
operating table to hold the camera. The robotic arm is controlled by the surgeon through voice
commands, a hand control or a foot pedal.
Access and Port Placement
Three trocars are positioned in the anterior, mid, and posterior axillary lines.(Picture 4)
Picture 4) Trocar placement. The laparoscope is positioned in the mid-axillary line. A 12-mm port is placed
in the posterior axillary line. A 5-mm port is placed in the anterior axillary line.
Initial entry into the retroperitoneal space is established off the tip of the 12th rib via the
open Hassan technique. A 1.5 cm transverse incision is made just anterior and inferior to the tip
of the 12th rib. The incision is carried down sharply through the posterior thoracolumbar fascia,
flank muscles and anterior thoracolumbar fascia.
Upon entering the retroperitoneal space, the index finger is used to sweep the peritoneum
anteriorly and medially, developing a space between the psoas muscle anteriorly and Gerota’s
fascia posteriorly. (Fig 7)
Fig 7) The surgeon's finger is used to start the retroperitoneal dissection.
A space behind the kidney is created to place the balloon dissector. See Pinto et al.25
The retroperitoneal space can then be created with balloon dissection (Fig 8A) and the balloon
tipped 10mm trocar (Fig 8B) provides a seal to establish the pneumoretropertioneum.
Fig 8 A) The working space is created by balloon dissection. The kidney and peritoneum are
displaced anteriorly exposing the renal hilum. B) Blunt-tipped trocar. The collar on the port
slides down against the balloon tip to prevent loss of pneumoretroperitoneum. See Pinto et al.25
Alternatively, retroperitoneal access can be obtained directly with a 12 mm laparoscopic
visualizing trocar. Once the characteristic fat of the retroperitoneum is seen, insufflation is
begun. The laparoscope is used to bluntly develop the working space.
Renal dissection is carried out as was described previously, but without the need to
manipulate the peritoneal organs. The psoas muscle and ureter are the initial structures for
orientation, since the intraperitoneal structures are not seen. Maintaining orientation is important
throughout the procedure. This helps identify landmarks such as the psoas muscle, peritoneal
reflection, ureter, gonadal vein, and pulsations of the renal artery. Initial dissection is carried out
posteriorly to isolate the ureter and mobilize the lower pole.
The peritoneal attachments anterior to the kidney are not divided in order to prevent the
kidney from falling into the working space. Blunt dissection along the ureter reveals the gonadal
vein. Theses structures are traced cephalad to the renal hilum. Dissection along the aorta or vena
cava will quickly bring the renal vessels into view. The renal artery is encountered first as it lies
posterior to the vein. Hilar ligation is performed as was described in the transperitoneal
approach. Once the vessels have been controlled, the anterior surface of the kidney is mobilized
from its peritoneal attachments. Care is taken not to enter the peritoneum and injure the adjacent
bowel and mesentery.
Prior to extubation the orogastric tube is removed. After routine observation in a post
anesthesia care unit, the patients are transferred to a non-monitored floor bed. In the morning of
the first post operative day, the urinary catheter is removed, routine blood work is performed,
ambulation is encouraged and oral liquids are started. The diet is then advanced as tolerated
throughout the day. Routine discharge is in the morning of post-operative day # 2 if blood work
and vital signs are stable, the patient is able to ambulate and tolerate oral diet.
III. Techniques and Indications:
B) Laparoscopic Partial Nephrectomy
Surgical Technique: Transperitoneal / Retroperitoneal Approach
Positioning and Port Placement
Same as for laparoscopic nephrectomy. Additional instruments needed for laparoscopic
partial nephrectomy include: laparoscopic vascular clamps (Picture 5- bulldogs, Picture 6-
Statinksy), ultrasound with a laparoscopic transducer and topical hemostatic sealant.
Picture 5) Laparoscopic bulldog clamps
Picture 6) Laparoscopic Statinsky clamp
When the renal mass is abutting the collecting system, and entry into a calyx is expected,
cystoscopy and placement of an open ended 5 French ureteral catheter is performed before
positioning. This aids in reconstructing the collecting system by retrograde injection of dilute
methylene blue. As in open surgery, dissection of the kidney is performed leaving a “cap”of fat
overlying the renal tumor. Intraoperative ultrasound aids in determining the tumor’s depth and
also to rule out any additional tumors.
Exophytic masses that are attached by a narrow base and peripherally located can be
excised without the need for vascular occlusion. The capsule around the tumor is scored with
cautery, and the mass is removed with the aid of laparoscopic scissors or an ultrasonic scalpel.
Hemostasis is obtained with the aid of an argon beam coagulator and hemostatic sealants.
Large, more broad-based or deeper tumors require interruption of renal blood flow. Prior
to clamping the renal hilum, a brisk diuresis is initiated with the use intravenous fluids and
osmotic diuretics. Mannitol (25 grams) is given when the surgeon begins to free up the renal
hilum allowing for increased perfusion of the renal parenchyma along with protection from free
radical deposition. The capsule around the mass is scored, and a laparoscopic bulldog clamp is
placed on the renal artery. Alternatively, a laparoscopic Statinsky vascular clamp can be used,
but this requires the placement of an additional trocar. Hilar clamping is performed to allow for a
bloodless field and therefore better visualization when resecting the tumor. The tumor is excised
with cold scissors to allow pathological assessment of the tumor’s margins. The tumor is excised
ensuring a rim of normal parenchyma around it. Any suspicious areas in the renal bed can be
biopsied and sent for frozen section analysis.
Retrograde instillation of methylene blue via the ureteral catheter ensues that the
collecting system has not been entered. If it has, repair is performed with 2-O polyglactin suture.
Open vessels seen in the renal bed are suture ligated with 2-O polyglactin suture. A gelatin
matrix hemostatic sealant is applied and the kidney is reconstructed by reapproximating the renal
defect over surgicel bolsters (Picture 7) using O polyglactin sutures through the renal capsule.
Picture 7) Surgicel pledgets, approximately 1 cm wide and 4 cm
long, are prepared prior to tumor excision.
The clamps on the renal vessels are removed and the kidney is observed to confirm it is
being well perfused and there is no active bleeding. Prior to exiting the abdomen, a closed
suction drain is left in the retroperitoneum behind the kidney.
Cold ischemia is technically feasible laparoscopically, but not practical. Therefore when
operating under the time constraints of warm ischemia, it is important to be expeditious in your
approach to resection and reconstruction of the kidney.
Indications for laparoscopic partial nephrectomy are as described for the open procedure.
Although initially indicated for tumors involving a solitary kidney or bilateral disease, nephron-
sparing surgery is now performed for tumors smaller than 4cm in the presence of a normal
IV. Techniques and Indications:
Robotic Assisted Nephrectomy and Partial Nephrectomy
Nephron sparing surgery for complex renal tumors, such as multiple, endophytic, or hilar
tumors, may further preclude a laparoscopic approach for most urologists and may pose
challenges for even experienced laparoscopic surgeons. A renal mass with tumor thrombus may
require vascular suturing, which is also challenging for laparoscopic techniques. It is in these
cases that robotic renal surgery may be of assistance.
Potential advantages include 3-dimensional stereoscopic vision, articulating instruments,
and scaled-down movements reducing tremor. The articulating instruments and increased
freedom of movement may also allow the surgeon to replicate well established open surgical
maneuvers more readily. This technique emulates both open and laparoscopic techniques of renal
cancer surgery. (Rogers et al. 2008)
Surgical Technique: Transperitoneal Approach
Positioning, Ports, and Docking:
After intubation, orogastric tube placement and bladder catheterization, the patient is
positioned in modified lateral position. Full flank position may also be used. Following
abdominal insufflation with a Veress needle. Ports are placed as demonstrated in Picture 8. A
12mm periumbilical port is placed for the camera. Two robotic instrument ports are placed
approximately 8 cm from the camera in a wide “V” configuration centered on the renal tumor.
These ports may be shifted laterally and/or superiorly for patients with a large body habitus or
upper pole tumor location. A 12 mm assistant port is placed inferior to the camera port. An
optional 5mm assistant port may be placed above the camera port if needed. For docking (as
seen in Picture 9), the robot is brought in posteriorly at approximately a 20 degree angle toward
the head of the patient.
Picture 8) Port placement for left sided robotic renal surgery
Picture 9) daVinci robot is docked against the patient’s back at
approximately a 20 degree angle toward the head of the patient.
A zero degree lens is used initially, but a 30 degree downward lens may also be utilized
as needed. Robotic instruments used include a Bipolar Maryland forceps, monopolar cautery
scissors, and needle drivers. The peritoneum is incised sharply along the Line of Toldt and the
bowel is mobilized medially using sharp and blunt dissection, developing the plane between the
anterior Gerota’s fascia and the posterior mesocolon. The bedside assistant maintains medial
counter-traction. Dissection is continued along the upper pole of the kidney to mobilize the
spleen or liver. We utilize robotic assistance from the beginning of bowel mobilization unlike
some reports of a “hybrid technique”, initially utilizing conventional laparoscopy to reflect the
Anatomical Landmarks and Hilar Dissection:
Continued medial reflection of the bowel allows for exposure of the gonadal vessels and
the ureter. These structures are retracted anteriorly, exposing the underlying psoas muscle. Care
is taken not to strip the fascia from the psoas muscle. Dissection then proceeds towards the renal
hilum. The Maryland bipolar forceps are used to place the kidney on stretch and the renal hilar
vessels are dissected to allow access for clamp placement. Lateral renal attachments are left in
place to aid in countertraction. Venous branches can be ligated as needed for exposure
Ultrasound and Tumor Exposure:
A laparoscopic ultrasound probe is used to map the location and size of renal tumor(s)
and to confirm resection margins and depth during partial nephrectomy. Gerota’s fascia is
opened and the fat is cleaned off the renal capsule to expose the tumor(s). The use of color
Doppler may be used to identify adjacent vessels. The margin of resection is scored
circumferentially using monopolar cautery. In cases of nephrectomy and tumor thrombectomy, it
is used to determine the extent of tumor thrombus.
Hilar Clamping, Tumor Excision and Renal Reconstruction during Partial
For tumors that are endophytic or adjacent to the renal hilum, resection is done under
warm ischemia. The assistant clamps the renal hilar vessel(s) using laparoscopic bulldog
clamp(s) through the primary 12mm assistant port. Mannitol (12.5 gm) may be administered
intravenously prior to clamping. The tumor is resected along the previously scored margin using
cold resection with the robotic monopolar scissors. The Maryland bipolar forceps are used to
manipulate the tumor for exposure and to aid in dissection. The assistant uses suction to expose
and maintain visualization of the resection plane of the tumor. After excision, the tumor can be
placed beside the kidney or on top of the liver for later retrieval. If the status of the surgical
margin is in question, a biopsy and frozen section analysis may be performed.
Hemostasis is achieved using a combination of cautery, hemostatic agents, and suturing.
A pre-placed ureteral catheter may be used to inject methylene blue to identify entry into the
collecting system. The robotic instruments are exchanged for needle drivers. A 3-0 Vicryl suture
on an RB-1 needle is used to achieve hemostasis and repair any previously identified entry into
the collecting system (a SH needle may also be used). Sutures may be secured with either
absorbable suture clips or by tying knots. Renal parenchymal defects are approximated over
surgicel bolsters using 2-0 Vicryl sutures on an SH needle (a 0-Vicry suture on a CT-1 needle
may also be used). A hemostatic agent is applied. Preplacing surgicel bolsters and sutures in the
abdomen may reduce warm ischemia time during earlier experience. The kidney is placed back
on stretch using the robotic needle driver and the hilar clamp is removed by the assistant.
Hemostasis is confirmed. A pre-placed lap pad may be used to apply pressure to the resection
The specimen is placed in a retrieval bag and removed through the primary assistant 12
mm port, enlarging the port site if needed. Gerota’s fascia is approximated over the defect using
a running 3-0 Vicryl suture on an SH needle. A drain is placed in the perinephric space. 26-54
V. Role of Targeted Systemic Therapy in Management of Advanced Clear
Cell and non-Clear Cell Kidney Cancer (Jeffrey A. Sosman, M.D.)
Therapy of advanced Renal Cell Carcinoma (RCC) has gone through a major evolution over the
past few years. Previously, patients with RCC were considered for high dose Interleukin-2
therapy, if young and healthy and IFN-alpha for the less robust or elderly patient. A relatively
small subset of patients did benefit from cytokine therapy, but far too few to effect median
progression-free (PFS) or overall survival (OS)55,56. The great majority of patients only suffered
the toxicity of treatment. This all began to change following the remarkable work of Drs. Kaelin,
Maxwell, Linehan and others who helped define the role of the VHL gene and the consequence
of loss of its function.57 The generation of an antibody to the vascular endothelial growth factor,
VEGF (anti-VEGF; Bevacizumab) molecule provided an initial tool to interrupt the downstream
effects of VHL (Von Hippel Lindau) loss. The stabilization of the HIF-1a and HIF-2a molecules
with the subsequent over expression of VEGF, PDGF, EGFR, CAIX, EPO, Glut1 etc was key to
the malignant phenotype of clear cell RCC. This is a critical pathway not simply in genetic
syndromes with Von Hippel Lindau, but in at least the majority of patients with sporadic clear
In the initial report by Yang et al., anti-VEGF was shown to increase PFS >2 fold in a cytokine
(IL-2) refractory population even though its objective response rate was only 10%.58 However,
it was clear that even those without objective clinical responses had a far different clinical course
than those on placebo with many having prolonged stable disease or small degrees of regression
not meeting the 30% RECIST threshold of an objective response. A reassessment of meaningful
clinical responses needed to be performed the first time there may have been convincing data
that stable disease was an indication of benefit in RCC. In the interim, a number of multi-
targeted tyrosine kinase inhibitors (TKI) that targeted the VEGFR2 tyrosine kinase as well as a
variety of other receptor signaling pathways, have been evaluated and some approved for therapy
of advanced RCC. These orally administered drugs were also able to inhibit other receptors
including VEGFR1, VEGFR3, PDGF, c-kit, and RAF to name a few. The initial two agents
receiving the most attention and most rapidly approved by the FDA were BAY43-9006
(Sorafenib) Nexavar and SU011248 (Sunitinib) Sutent.59 While their spectrum of kinase targets
was overlapping, there were some key differences. Sorafenib inhibited RAF, while Sunitinib was
a more potent and effective inhibitor of VEGFR2. (See Table 1)
Table 1: Phase II/III Trials of Targeted Agents in Untreated RCC patients
Pt Response Median Median
Drug of Risk factors Nephrectomy
Number Rate PFS OS
375 Favorable(34%) 39% 11 mos NA
Sunitinib vs IFN III 90%
375 Intermediate(56%) 8% 5.1 mos NA
Bevacizumab + 327 Favorable (28%) 31% 10.2mos NA
IFN vs IFN 322 Intermediate(56%) 12% 5.4 mos NA
Temsirolimus 209 8.6% 5.5mos 10.9mo
Temsirolimus+IFN III 210 67% 8.1% 4.7mos 8.4 mo
Vs IFN 207 4.8% 3.1mos 7.3 mo
Sorafenib 97 Favorable NA(68%)* 5.7mos NA
Vs IFN 92 Intermediate NA(39%)* 5.6mos NA
Number in parenthesis represents % of patients with some degree of tumor shrinkage, not an objective
Initially, Sorafenib demonstrated prolonged progression-free survival in cytokine
refractory patients in a phase II randomized trial where stable disease patients at 12 weeks were
randomized to continue Sorafenib or switched to placebo (randomized discontinuation).59 Those
patients having switched to placebo had a significantly less PFS than those on Sorafenib, when
the placebo patients who progressed were rechallenged with Sorafenib, stable disease could be
re-established. This was confirmed and proven in a large phase III trial of Sorafenib versus
placebo in cytokine-refractory patients where again as in the phase II trial there was a doubling
in progression-free survival from 2.8 to 5.5 months9. Unfortunately this study was then
unblinded (per recommendations of the FDA) and overall survival results were confounded by
the significant cross-over of patients from placebo to Sorafenib. It is worth pointing out that in
both of these studies the objective response rate of Sorafenib was < 10% while many patients had
smaller degrees of regression and prolonged stable disease.
Later after its approval a relatively small, 189 patient, randomized phase II trial of
Sorafenib or IFN in therapy-naïve patients was conducted. Surprisingly, there was no advantage
to the Sorafenib arm.60 This was unexpected based on the second line results with Sorafenib in
cytokine-refractory patients. While a low objective response rate could have been expected, the
lack of any improvement in patients’ PFS with a median of 5.7 months, was a surprise. The trial
also examined the effect of cross over to Sorafenib and dose escalation of Sorafenib in patients
who progressed on their initial therapy. Patients progressing on IFN, could receive Sorafenib at
standard doses of 400mg BID. This group of patients did exhibit some stabilization of their
disease for 5.7 months and some degree of tumor shrinkage in 75% of patients. Those who
progressed on Sorafenib could be dose escalated to 600mg BID and among these 44 patients, a
4.1 months median PFS and tumor shrinkage in 44% were observed. For all practical purposes,
this large randomized phase II trial signaled the end of Sorafenib as a front line therapy in the
majority of patients. Larger, single agent, upfront trials with Sorafenib at standard doses, are
unlikely to be explored further.
The pathway to Sunitinib approval was quite different. Initial phase II studies did
demonstrate a high response rate of 35-45% in cytokine-refractory patients, as well as prolonged
progression-free survival. Following this result, Sunitinib was directly compared to IFN-alpha in
therapy naïve patients. This large 750 patient trial demonstrated a remarkable objective response
rate for Sunitinib that remained very high at 40%, while IFN's response rate was <10%8.
Furthermore, the median progression-free survival was 11 months, more than double that of
IFNα. The difference in overall survival did not meet significance due to the lack of events at the
time of the analysis. Again the survival analysis is confounded by patient crossover from IFN to
Sunitinib as allowed in the protocol once Sunitinib was approved by the FDA.
Following the approval of both MTKI, the results of several phase III trials featuring
Bevacizumab (anti-VEGF) have been reported. In a large study now published in Lancet by
Escudier, et al., IFN alone was compared to IFN with anti-VEGF in a population of therapy-
naïve RCC patients.61 The results showed a striking improvement in response rate (31% vs 7%)
and progression-free survival (10.2 mos vs 5.4 mos). The response rate was better than seen in
both the initial Yang trial in cytokine refractory patients (10%) and the 13% in the randomized
phase II trial of anti-VEGF +/- erlotinib (EGFR TKI). It is possible that the addition of IFNα to
anti-VEGF led to a better response rate and improved the progression-free survival of anti-
VEGF. But there are no more definitive results to either support or counter this argument.
Finally, limited release results from a trial conducted by CALGB show there were further
supporting data to the benefit of Bevacizumab plus IFN. The trial represented another phase III
trial of IFN +/- anti-VEGF. The combined arm (anti-VEGF + IFN) demonstrated an improved
response rate and progression-free survival compared to IFN alone. Final results are still
Issues with phase III trials in front line therapy
When reviewing the important trials with Sorafenib, Sunitinib, and Bevacizumab, there
are several important issues needing to be addressed. First, patients on all of these studies were
either intermediate or low-risk based on the MSKCC criteria62. They had 0-2 of (anemia,
hypercalcemia, high LDH, lower performance status (<70% Karnofsky criteria) or either
within 1 year of diagnosis of RCC or without nephrectomy) the five criteria. Three or more
of these criteria were indicative of poor prognosis. In previously evaluated patients at MSKCC,
this criteria could separate patients with a 20 month median (low risk, favorable prognosis)
overall survival to as low as a 4 month median survival for those high risk (poor prognosis)
patients. The entry criteria for all of the above studies also required clear cell histology. All
patients on the Bevacizumab plus IFN trial had nephrectomy (as per entry criteria), while over
90% had prior resection of their primary on the Sunitinib trial. There were a small number of
poor prognosis patients entered on both trials, 6% on the Sunitinib trial and 8% on the
Bevacizumab + IFN trial. Both the front and second line trials with Sorafenib enrolled patients
with intermediate to low risk and nearly 90% had nephrectomy. The results in the poor
prognostic patients were dismal but PFS may have been improved from 1.2 months to 3.7
months in those receiving Sunitinib. Not even this small effect was seen in the Bevacizumab+
IFN trial where poor prognosis patients had a 2.1-2.2 median progression free survival regardless
which arm they were enrolled on.
In phase I and II clinical trials, RCC patients appeared to derive a benefit of CCI-779,
Temsirolimus, even though the response rates were less than 10%. Patients improved with less
bone pain, improved appetite and weight gain. Temsirolimus is a mTOR (mammalian target of
rapamycin) inhibitor. mTOR is downstream from PI-3/Kinase/ Akt. It represents a pathway that
can modulate protein synthesis (translation) including that of HIF-1a and HIF-2a. The phase II
trial demonstrated that patients with poor prognostic factors had the greatest benefit. Benefit was
based on a major extension in progression-free and overall survival in the poor prognosis
group.63 Overall survival was much better than expected for this poor prognosis patient group.
This led to a phase III trial comparing Temsirolimus versus IFN in poor prognostic patients (3 or
more of 5 criteria in MSKCC). The trial did get slightly modified to increase poor accrual by
adding one more poor prognostic factor, multiple disease sites (by organ involvement). Patients
needed 3 or more of the 6 risk factors for entry. There were no restrictions on histology and
requirements for nephrectomy. About 20% had non-clear cell histology and about 33% had their
primary in place and were enrolled within their first year of diagnosis. The trial was an ambitious
effort in a poor prognostic group of patients who in the past would likely not have been treated
with cytokines due to their overall performance status. The trial included 3 arms; one with IFN
alone; one with Temsirolimus; and the other a combination of both IFNa plus Temsirolimus 64.
The doses of Temsirolimus were attenuated to allow concomitant IFNa therapy. The trial’s
primary endpoint was overall survival, with progression-free survival only a secondary endpoint.
Overall survival was increased from a median of 7.3 to 10.9 months with an overall hazard ratio
of .73 and the p value=0.0069. PFS was improved in both the Temsirolimus arm and the IFN
plus Temsirolimus arm, but those in the combined arm did not get any improvement in overall
survival. This may have to do to the extensive dose modification of when IFN and Temsirolimus
were given together. This result clearly established Temsirolimus as the standard therapy for
poor prognostic patients. Overall response rates in all three arms were under 10%, further
evidence that objective responses were a poor indicator of treatment benefit from drugs in RCC.
Several additional analyses were done retrospectively on pre-treatment patient characteristics and
clinical outcome. For those 74% of the overall enrollment who did qualify under the MSKCC
model as a poor prognostic group (3 or more of 5 MSKCC criteria) the benefit from
Temsirolimus was most prominent. Most of the benefit was apparently concentrated within this
group of patients. Furthermore, about 20% of patients had histology of their tumor different from
the typical clear cell. Papillary renal cancer makes up the bulk of these non-clear cell cancers.
Others include chromophobe and sarcomatoid (high grade IV) that make up a small number of
cases. In those patients with non-clear cell histology the benefit was especially prominent as is
described below in non-clear cell RCC. This was unique to this trial of Temsirolimus since the
other upfront trials excluded these patients and were restricted to clear cell RCC alone.
Toxicities from the targeted agents (See Table 2)
In addition to overall survival, progression-free survival, and objective response rate,
toxicity, and patient tolerance is of critical importance when considering treatment with this class
of agents. This is especially true, since the nature of these agents is to continue their
administration indefinitely or until progression. Complete responses are very rare and much of
therapy is administered with the intent to maintain disease control. Both Sunitinib and Sorafenib
have the most overlapping spectrum of toxicities as might be expected based on the targets of
Table 2: Toxicities from Targeted Agents
Toxicities HTN Proteinuria Vascular Stomatitis HFS Rash Diarrhea Fatigue
Sunitinib X X X x X X
Sorafenib X x X X X X
Temsirolimus x X X
Bevacizumab X X X
X Common and significant problem
x Less common and/or infrequent problem
Sunitinib can cause fatigue, hypertension, a functional (symptomatic with minimal
findings on examination) stomatitis, diarrhea, and some hand-foot syndrome. Most common
grade 3 or 4 toxicities have been due to fatigue and hypertension, though hypertension in general
can be well controlled with medications. At times multiple anti-hypertensive agents are required
for adequate blood pressure control. Hypothyroidism is becoming more appreciated as a
frequently associated side effect. Thyroid functions should be followed throughout treatment.
Sometimes the fatigue from Sunitinib is due to thyroid dysfunction and this can be easily
addressed with hormone replacement. A less frequent but increasingly recognized toxicity is a
decline in cardiac ejection-fraction. While declines below normal range or greater than 10% of
baseline are relatively common at 10-15%, symptoms of congestive heart failure is seen in less
than 5% of patients. Obtaining baseline ejection fraction and subsequent follow-up cardiac
evaluations are now recommended even in the absence of symptoms.
Sorafenib toxicities include many of those seen with Sunitinib but there is a slight but
recognizable change in the spectrum of them. Hypertension is common as with Sunitinib, but
fatigue is infrequently a dose limiting toxicity. Diarrhea is experienced in up to 40% of patients
but is grade 3 or 4 in only several percent. Most bothersome has been the hand foot syndrome
that is observed in up to 30% of patients. While severe desquamation of the hands and feet is
uncommon, symptomatic callus formation with neuropathic pain is frequently observed. Patients
can have trouble with walking and use of their hands. This toxicity is readily reversible upon
suspending drug administration, but if the symptoms worsen while drug continues to be given
then recovery can be quite slow. Sorafenib can also induce a number of different rashes from a
diffuse macular, papular, pruritic rash to a localized acneform rash similar to that associated with
EGFR tyrosine kinase inhibitors or antibodies. It can also cause multiple furuncles and
carbuncles in and around the axillas or the inguinal regions. These can become secondarily
infected and required drainage and antibiotics.
Bevacizumab is very well tolerated on a daily basis. Minor fatigue and myalgias can be
associated with intravenous administration for 24-48 hours afterwards. Patients frequently
experience hypertension and proteinuria. Blood pressure control is important since lack of
control can lead to hypertensive crisis. Proteinuria must be monitored closely and in general is
very reversible. Recommendations have become more lax in terms of the threshold for
proteinuria in deciding to hold Bevacizumab. At the present time, 3.5 gm of protein in a 24 hour
urine is the limit for continuing Bevacizumab dosing. Otherwise the dose is held until protein in
urine has dropped below the threshold. Bevacizumab is generally safe and well tolerated. It must
be recognized that Bevacizumab can significantly slow wound healing and even lead to wound
dehiscence. This must be considered around procedure and any major surgery. In general
Bevacizumab should be held two weeks prior to surgery and at least 4 weeks following surgery
to allow healing to take place optimally. However there are much more infrequent toxicities of a
very serious nature. These include vascular events, especially arterial thrombotic and venous
thromboembolic , hemorrhage, multifocal leukoencephalopathy associated with poorly
controlled hypertension, gastrointestinal perforation, and fistula formation.
Finally, Temsirolimus is tolerated quite well. Some degree of asthenia (fatigue) is
relatively common. However, this can be difficult to attribute to either disease or therapy.
Additionally, patients have some degree of pancytopenia with anemia being most prominent.
Secondary infection or bleeding is very rare. Some mouth ulcerations and rashes can also be
seen. An untoward toxicity relatively unique to this agent is hyperglycemia, hypertriglyceremia,
and hyperlipidemia. Pancreatitis may occur secondary to the elevated tryglycerides. While
therapy can be cumbersome with its weekly intravenous schedule, its overall toxicity is mild
even in the overall more debilitated patients who have been studied.
Alternate Doses and Schedules
For two of the agents, alternative dosing and scheduling have been attempted. Sunitinib
can be given continuously at 37.5mg po daily. This schedule avoids the break in treatment for 2
weeks where conditions may favor regrowth. However, the lower dose, continuous schedule was
not superior and the overall response rate appeared lower than the standard 50mg daily for 4 of 6
weeks. This schedule was not directly compared to the standard schedule in a randomized trial.
Additionally, toxicity was similar with the continuous dosing schedule. Attempts have been
made at dose escalation of Sorafenib. There was some evidence from the randomized phase II
trial of Sorafenib that those who progressed on 400mg BID could be dose escalated to 600 mg
BID. Amato and his colleague have attempted to follow a very aggressive dose escalation in
treatment naïve patients. In 44 patients, 41 were able to be escalated to 600mg BID after 1 month
and then 32 of these patients were able to be increased to 800mg BID after 2 months65. There
was a very high response rate of 55% with 16% complete responses. Though the median PFS
was just 8+ months and overall survival was at 11.5 months. This is surprisingly short
considering the high response rate and suggests that these are short clinical responses that may
be limited by toxicities. This must be reproduced in a multi-center phase II study, but if positive
it would be quite significant and ways to ameliorate Sorafenib toxicities would take on even
more importance. Until then these results should be looked at with great caution and only
considered in a trial setting.
Therapy in Patients Who Have Failed Front Line Anti-angiogenesis Therapy
There is little information to guide therapy in patients failing their initial treatment. One
study has provided some direction in patients who have failed Bevacizumab66. These patients
with progressive disease while on Bevacizumab were then treated with Sunitinib. Therapy had to
be initiated within several months of stopping Bevaciumab treatment. Of 61 patients there was
an objective response rate of 23% with a median progression-free survival of 30.4 weeks (7.4
mos) and overall survival of 47.1 weeks (10.9 months). Of the 57 patients with post-treatment
tumor evaluations 51 (84%) demonstrated some degree of tumor regression. Patients who had
failed to have any prior response to Bevacizumab were among those who demonstrated objective
responses to Sunitinib (11/14 patients with PR). To date, this represents the most mature study of
second line therapy.
Rini, et al. reported on a cohort of 62 patients who had failed Sorafenib and were
subsequently treated with another multi-targeted kinase inhibitor, Axitinib with potent activity
against all three VEGFR1, 2,and 3.67 Many of these patients had not only failed Sorafenib, but
also Sunitinib, cytokines, and chemotherapy. Of 62 patients, 21% experienced a partial clinical
response and 34% had stable disease for at least 3 months. Hypertension as was previously
observed in frontline studies was the most problematic side effect from Axitinib.
Finally, Escudier has reported on 90 patients from France who had previously received
Sorafenib and following progression were switched to Sunitinib (68 patients) and 22 patients
who had failed Sunitinib and were then switched to Sorafenib therapy. Among those 68 patients
who were switched to Sunitinib there was a 15% objective response rate with an additional 51%
with stable disease. The median PFS was 25 weeks. For the 22 patients who had failed Sunitinib
and switched to Sorafenib, there was a 9% response rate with stable disease in 55% and median
PFS of 17 weeks. While this was only a retrospective study it does support the lack of complete
cross resistance for these two drugs even with their similar target profile.
Combination Targeted Therapy in Advanced RCC
A number of studies have been reported combining several of the active targeted agents
including Sorafenib or Sunitinib with Bevacizumab and Temsirolimus with either Bevacizumab,
Sorafenib or Sunitinib. While most of these studies enrolled small numbers of patients and
included several dose levels, there have been some common findings. In general toxicity of the
two agents appears to be exacerbated. There has been an increase in known toxicities such as
hand-foot syndrome, hypertension, or proteinuria. In some cases, new toxicities have occurred
such as a microangiopathy associated with hemolysis, thrombocytopenia, renal insufficiency and
mental status changes. That has been recently observed with Sunitinib and Bevacizumab
combination. While some combinations appear to allow full doses of both agents (Bevacizumab
and Temsirolimus) most of the combinations required dose reduction of either one or both of the
agents. Combinations of Sorafenib and Bevacizumab have required significant dose reductions
of both agents. Activity in many cases appears to be preserved but still no formal phase II studies
have been undertaken with any of the combinations. A recently opened randomized phase II trial
will explore three of the combinations of Sorafenib with Bevaciumab, Sorafenib with
Temsirolimus, Bevacizumab with Temsirolimus, and as a control, Bevacizumab alone.
Additionally, another phase III trial is being planned to compare Bevacizumab with
Temsirolimus or with IFN. In general, there remains many questions about combination therapy,
especially in the face of toxicity and requirements for lower doses of the agents when they are
combined. So far complete responses have been as rare as with single agents. It may be in the
future that sequential therapy will be considered the best approach to treatment as it is frequently
done today. Only through well performed trials will we gain this information.
Use of Targeted agents in the treatment of Papillary Renal Cell Carcinoma (See Table 3)
The role of HIF and its hypoxia induced gene expression program in papillary RCC is not
understood. In the past most medical urologists, believed these malignancies responded to
chemotherapy based regimens. This was never adequately studied to draw any conclusions.
Probably the most convincing information about treatment efficacy in papillary RCC comes from
the front line Temsirolimus trial as described above. In this trial out of 626 patients about 19%
had non-clear cell histology. Of those where histology was better described 75% had papillary
RCC as would be expected. In the two arms of Temsirolimus versus IFN there were 73 patients
with non-clear cell histology. In a striking result, the progression-free survival was 7.0 versus
1.4 months favoring the Temsirolimus arm and overall survival was more than doubled in those
receiving Temsirolimus with OS of 11.6 months versus 4.3 months for IFN–treated patients. This
data has a number of problems; the number of patients is small and the actual with papillary
RCC is not definite, but assuming the arms are balanced and most are papillary cancers, these
results suggest Temsirolimus is an active drug in papillary RCC.
Finally, in a retrospective report recently published from 5 centers in the US and France,
the clinical outcomes of Sorafenib and Sunitinib in patients with papillary RCC was reported.
Forty-one of the 53 patients had papillary RCC and the response rate was only 4.8% (2/41) and
both received Sunitinib. The median PFS for papillary RCC treated with Sunitinib was 11.9
months (13 patients) while for the other 28 patients treated with Sorafenib the median PFS was
5.1 months. Few patients had central pathology review. While the data on Sunitinib is limited
with only 13 patients, there appears to be some activity (2/13 patients with PR) and PFS was
11.9 months. On the other hand, therapy with Sorafenib had only a median PFS of 5.1 months
and no clinical responses in the 28 patients. It is obvious further information is needed to make
any definite decisions on therapy with either Sunitinib, Sorafenib or even Temsirolimus. It is
critical to perform large enough multicenter studies with only papillary RCC to better gauge
effects of any of the above agents.
Table 3: Experience with Targeted Agents in Papillary Renal Cell Carcinoma
Drug Histology Patient Response Median PFS Median OS
Sorafenib Papillary 28 0/28 5.1 mos NA
Sunitinib Papillary 13 2/13 11.9 mos NA
Temsirolimus Non-clear cell# 37 NA 7.0 mos 11.6 mos
Vs IFN 75% Papillary 36 NA 1.4 mos 4.3 mos
# Patients all had poor prognostic factors based on MSKCC and Multiple Organ Sites (>3/6 risk factors)
Summary (See Table 4)
Great progress has been made in a few years as shown in Table 4. Frontline data supports
the use of either Sunitinib alone or Bevacizumab with IFN in patients with favorable or
intermediate prognostic factors. The role of nephrectomy is not known, but almost all patients
enrolled onto previous studies did have nephrectomies. Those patients with poor prognostic
factors should probably receive Temsirolimus. Data on Sunitinib is simply not very convincing
at this point but there very well could be activity comparable to Temsirolimus. Second line
cytokine failures would be appropriate candidates for Sorafenib based on its prolongation in
median PFS. Finally those who have failed front line targeted therapy have very little guidance
about what treatment should be given next. Bevacizumab failures can receive a significant
benefit from Sunitinib and patients who fail one of the MTKI, Sorafenib or Sunitinib can respond
with objective clinical responses or stable disease from the other agent. However, this is an area
which still requires extensive study. Lastly, patients who are young, healthy, have good organ
function, an excellent performance status, and access to an experienced IL-2 center may be
considered for high dose Interleukin-255 . It is the only treatment which offers a chance for cure
and very prolonged disease free periods. While this number is less than 10%, because of its
impact on these patients is so great, some may consider it for frontline therapy and targeted
agents after failing IL-2. We have impacted on many more patients that any of the cytokines ever
did. While few studies show an overall benefit except for Temsirolimus, those of us taking care
of patients have experienced living for a number of years with disease control where in the past
their survival was measure in months to a year. This impact will become more clear with time.
Hopefully over that time we will gain further insight how to use these agents.
Table 4: Potential Standards for Advanced Stage Clear Cell RCC
First-Line Good or intermediate Sunitinib High-dose IL-2
Therapy risk* Bevacizumab? With IFN?
Poor risk* Temsirolimus/ Sunitinib
Second- Prior cytokine Sorafenib
Line Prior VEGFR Temsirolimus??
Prior mTOR inhibitor No data available
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