NEWER TECHNIQUES OF RENAL CARCINOMA MANAGEMENT

1. CURRENT TRENDS IN MANAGEMENT
OF
RENAL CELL CARCINOMA
Moderator:-Prof.P.K.Puri, HOD
DEPTT. OF UROLOGY
 Presented by:-Dr.VIKAS KUMAR
IGMC,SHIMLA

2. Renal Cell Carcinoma
 Commonest malignant lesion of kidney
 most lethal of the urologic cancers
 accounts for 2% to 3% of all adult
malignant neoplasms
 male: female= 3;2
 Majority are sporadic and 4% familial
 sixth and seventh decades of life
 ~ 1/2 discovered incidentally
 5 fold increase in small (< 3 cm) tumors
in last 20 years
 Slow growing

3.  Classification
 Mode of presentation
 Sporadic
 Familial
 VHL- von Hippel Lindau symdrome
 Hereditary papillary RCC
 Others
 Histological
 Conventional (70-80%)
 Clear cell
 Granular
 Mixed
 Chromophillic (10-15%)
 Chromophobic
 Collecting duct

4. Clinical features
 Majority asymptomatic
 50% incidentally detected
 Dull flank pain
 hematuria
 Abdominal mass
 anorexia
 Hypertension
 Anaemia
 Triad- flank pain, gross hematuria, palpable abdominal
mass – now rare
 Features of paraneoplastic syndrome

5. Investigations
 Ultrasonography
 CT- Scan (plain & contrast
enhanced)
 IVU
 MRI
 Angiography, venocavography
 FNAB

7. Robson’s staging

8. Staging and Prognosis
Cohen HT, McGovern FJ. NEJM. 2005;353:2477.

9. Treatment options
 Surgery
 Rad. Nephrectomy
 Partial nephrectomy
 Nephron sparing surgery
 Minimal invasive methods (thermal ablative therapy)
 Immunotherapy
 Chemotherapy
 radiotherapy
 Vaccines & cytokines
 Targated agents
 Hormone therapy

10. Surgical
modalities
Rad.Neph
Open
Lap
N.S.S
Open
Lap
Minimally
invasive
approach
Cryoablation
open
P.C
LapR.F.A open
P.C
LAP
Noninvasive HIFU
ablation

11.  No Prospective & randomized trials have been
performed to compare elective partial
nephrectomies with Rad. Neph. or to compare
evolving techniques of minimally invasive surgery
with Std. Open Surgical tech.

12. Localized RCC Treatment
 Surgery is the only curative therapy for stage I-III
 Radical nephrectomy is gold standard
 Partial nephrectomy in selected patients
 No role for adjuvant therapy except under
investigational protocol
 20-30% of patients relapse within 2-3 years
- Metastases to the lung most common 50%
- Local recurrence is rare 2-3%

13. Management of localised RCC

14. Rad. Nephrectomy
 ORN was the gold std. for localized RCC
 Surgical approach for R.N is determined by size/location
of tumor & pt related factors.
 Disadvantage ofTransperitoneal approach is longer post
op. ileus & intra abd. Adhesions.
 R. Nephrectomy consists of early control of vasculature
and removing kidney outside G.F with removal of ipsilat
Adr. Gland .
 Adrenalectomy should be part of R.N for RCC of > 5 cm.
as risk of unexpected microscopic invasion of Adr. has
been shown to be as high as 7.5%.
 Therapeutic value of lymph adenectomy remains
controversial.

15. Lap.Rad.Nephrectomy
 L.R.N :- (a)Transperitoneal
(b) R.Peritoneal
becoming std.T/t for localizedT1-2 tumors that
are not amenable to NSS.
 Benefits of LRN :- (1) Decreased P.O pain
(2) Shortened hospital stay.
(3) Quick convalescence & improved
cosmesis.
 5Yrs ds free rates for Lap R.N & ORN are comparable..
 C/I :- Rad. Neph. shdn’t be done for small < 4 cm size tumor that is
amenable to PN.

16.  Lap R.N shdn’t be done in large vol. tumor i.e. of > 8 cm /
locally advanced RCC/RCC with R.V or I.V.C involvement.
 R.Neph. Shdn’t be done if at all possible in a functionally or
anatomically solitary kidney thus forcing the pt into Chr.
Dialysis.
 Complications – include vascular injury ,splenic injury, bowel
perforation; pneumothorax, port site metastasis & rupture /
morcellation of bagged kidney that could obliterate tumor
margin.

17. NephronSparingSurgery(NSS)
 OPEN N.S.S- (a) simple enucleation
(b) wedge resection
(c) polar segmentalnephrectomy
(d) transverse resection
(e) Ext.corp.neph.with
auto transplantation

18.  Results of open P.N in term of long term cancer free survival
with unilat, unifocal ds of < 4 cm is equivalent to open R.N.
 3 D volume rendered CT is must before P.N.
 Indication (1) Absolute
(2) Relative or Elective
 Absolute – B/L synchr. tumor ; tumor in solitary kidney or
significant renal failure.
N.S.S

19.  Relative – Contralat kidney has preexisting renal ds.
 Elective– tumor of < 4cm in presence of
N-Contralat kidney.
 Intra op. tumor free status is assessed by USG/Frozen-
section analysis for surgical margin.
 C/I – Large tumor, where –ve tumor free margin can’t be
achieved and large tumor with R.V / IVC involv.
 Complications --- Haemorrhage
Urinary fistula
Renal insufficiency
R.I is common b/c ofARF seen in pt undergoing N.S.S with
tumor > 7 cm or when >50% of parenchyma is excised or b/c
of > 60 min. of Ischemia time.
 Major disadvantage is LTR (10%).

20. Cryotherapy
 Kidney is favoured site b/c it can readily be dissected from
adjacent organs & usually gives rise to unifocal malig.
 Can be used in P.C / Open/ Lap approach
 Temp. of -20 degree C induces cell necrosis.
 Rapid freezing causes crystal form in microvasculature & E.C
spaces and within cells , this results in failure of oxid.phosph.
and failure of microvasculature.
 Adequate cryodestruction requires Intraop. monitoring of
resultant ice ball with U.S.G.
 COMPLICATIONS --- Ur. Fistula formation
--- PostT/t haemorrhage
--- Injury to adjacent structure
 Criticism ---- Histological documentation of complete tumor
destruction is not currently available.

21. RFA & HIFU
 Pr. Mech of tissue destruction by both is thermonecrosis.
 R.F energy can be used PC/Lap/ in open surgery .
 R.F energy of 10-90W are applied to raise the temp.>60
degree C to induce coagulative necrosis.
 Probe carries an A.C of high freq. radiowaves that causes
the local ions to vibrate ,resistance in the tissue creates
heat thus causing thermal caugalation.
 U.S.G, Fluroscopy, CT & MRT is used for P.C placement of
probe; but none of these is reliable for monitoring R.F
lesions & completness of cancer call death.

22.  HIFU aims to completely ablate renal tumor in a non –
invasive manner.
 Indications :-
-- small exophytic tumor most suitable ; success rate
decrease with increase in size of tumor & as the
location becomes central.
-- patient withVHL ds & patient with multiple renal tumor.
 Complications – risk of ureteral / calyceal injury in
cases of centrally located lesions.
---- Perinephric haemotoma
---- Skin metastasis

23. Conclusions
 Lap. RN is rapidly replacing the ORN withT1-2
tumor.
 ORN is mainly reserved forT3 tumor/tumor of >8
cm / tumor with R.V or IVC involv.
 NSS will play a major role in small < 4 cm
peripheral tumor.
 Open PN is still the std. form of NSS but with
refined tech. Lap PN may be soon coming.

24. OBSERVATION
 Bosniaks data suggests observation policy for
small; solid enhancing; well marginated
homogenous renal lesions (i.e RCC of < 3 cm) in
elderly poor risk cases & follow up with serial
renal imaging at 6mth/1 yr.
 Tumor growth rate in these subset of pt. is 1.3
cm/yr & incidence of metastasis is quite low i.e.
1-3%.

25. Advanced RCC Treatment
 Primary treatments are systemic therapy
with molecularly targeted therapy or
immunotherapy
 Surgery is palliative therapy
Solitary recurrence following nephrectomy
- Symptoms related to bulkiness of disease
including pain, nausea, or GI obstruction

26. Laparoscopic ablation Percutaneous ablation
Open partial
Laparoscopic nephrectomy Laparoscopic partial
Changing trends in surgical
management
 Trend towards less invasive options
Radical nephrectomyRadical nephrectomy Open partial

27. Thermal ablative therapy
a. cryotherapy
b. radiofrequency ablation
 Cryotherapy
 Advanced age
 Co morbidity not fit for surgery
 Local recurrence after NSS
 Hereditary renal cancer
 Tumour size- <3.5cm
 Disadvantage- no tissue for histology
 Lethal temp. to be achieve -20degree C
 Causes ischaemic necrosis by repeated freeze-thaw cycle
 Rapid freezing causes crystal form in microvasculature &
E.C spaces and within cells failure of oxidative
phosphorylation and failure of microvasculature.
 Complication- urinary fistula, hemorrhage,

28. Cryoablation
 Needle (cryoprobe)
 Argon gas

29. Cryoablation technology
(Joule-Thompson principle)
Cryoprobe
High pressure
argon
Expansion chamberatmosphere
-160° C

30. Laparoscopic Renal
Cryoablation
 Anterior or posterior approach
 Mobilize colon, or other vulnerable structures
away from ablation zone
 Cryoprobes positioned percutaneously,
utilizing laparoscopic ultrasound guidance
 Can be difficult to control blood loss
(Surgicel/Gelfoam)

31. Laparoscopic Renal
Cryoablation

32. Percutaneous Renal
Cryoablation
 Smaller cryoprobes (1.7 mm diameter ~15
gauge)
 US and/or CT guidance
 Faster
 Easier than laparoscopic
 Significant bleeding is rare

33. RFA (Radiofrequency
ablation)
 Pri. Mechanism of tissue
destruction by -
thermonecrosis.
 R.F energy can be used in-
 PC
 Lap
 in open surgery.
 R.F energy = 10-90W

34. Contd..
 Indications :-
-- small exophytic tumor most suitable ; success rate
decrease with increase in size of tumor & as the
location becomes central.
-- patient withVHL ds & patient with multiple renal tumor.
 Mech. - denaturation of intra cellular protein and melting of cell
membrane
 Less reliable than cryotherpy
 Complications-
 Uncommon, ARF, UPJ stricture, necrotising pancreatitis, lumbar
radiculopathy

35. Contd…
 temp. is raised = >60 degree C to induce
coagulative necrosis.
 Probe carries an A.C of high freq. radio waves
that causes the local ions to vibrate ,resistance in
the tissue creates heat thus causing thermal
coagulation.
 U.S.G, Fluroscopy, CT & MRT is used for P.C
placement of probe; but none of these is reliable
for monitoring R.F lesions & completness of
cancer call death.

36. New technology- (HIFU) high intensity focusedUSG,
image guided radio surgical treatment
 Under development
 May be used as extracorporeal approach
 HIFU aims to completely ablate renal tumor in a
non –invasive manner

37. Targeted Therapy
 Based on advances in the understanding of
the molecular biology of RCC
- Highly vascularlized tumor with increased
VEGF and EGFR expression
- Tumor growth mediated viaVEGF pathway
and mammalian target of rapamycin (mTOR)
pathway

39. VEGF Pathway Inhibition
 Tyrosine kinase (TK) inhibitors block the
intracellular domain of theVEGF receptor
- Sunitinib (Sutent)
- Sorafenib (Nexavar)
 Monoclonal antibody that binds circulating
VEGF preventing the activation of theVEGF
receptor
- Bevacizumab (Avastin)

40. Sunitinib
 Two phase II trials evaluating activity and
safety in previously treated advanced RCC
- 25-36% of patients had an objective response
- Progression free survival (PFS) 8.3-8.7
months
- Median survival 16.4 months
 Side effects include fatigue, HTN, nausea,
diarrhea, mucositis, and hypothyroidism

41. Sunitinib
 Phase III trial 750 pts
with untreated stage
IV RCC Sunitinib vs.
INFa
 Sunitinib showed
prolonged median
PFS 11 vs. 5m and
higher response rate
of 31% vs. 6%
Motzer RJ, et al. NEJM. 2007;356:115-124

42. Sorafenib
 Phase II and phase III trials in advanced RCC
 Phase IIITARGET study of 903 previously tx
pts w/ stage IV RCC randomized to Sorafenib
vs. placebo
- Sorafenib improved median PFS 5.5 vs. 2.8m
- No statistically significant survival benefit,
median survival of 17.8 vs. 15.2 m
 Side effects include HTN, fatigue, rash, hand-
foot syndrome, diarrhea, nausea

43.  Phase II trial of 116 pts, Bevacizumab shows
-No difference in median survival
 Phase III AVOREN trial of 648 untreated pts
- INFa plus Avastin or placebo
- Avastin group resulted in PFS of 10.2 vs. 5.4 m.
- Unclear activity as single agent however
 Not FDA approved, but can be used as second-
line therapy
Bevacizumab

44. mTOR Pathway Inhibition
 Temsirolimus (TMSR) is a rapamycin analog
that inhibits mTOR kinase
 Phase III trial 626 untreated poor-prognosis
pts with stage IV RCC tx w/TMSR,TMSR
+INFa, or INFa.
-TMSR prolonged survival compared to INFa
(10.9 vs. 7.3m) and prolonged PFS (3.8 vs.
1.9m)
- Benefit greater in non-clear cell RCC

45. Evidence of an
Immunological Role
in Combating RCC
immunotherapy

46. • Spontaneous remissions have been documented.
• Increased risk of cancer in immunodeficient states
• Tumor infiltrating lymphocytes (TILs)
• Lymphocytes have been found within tumors.
• Isolated and expanded TILs have been the focus of experimental therapies.
• Interleukin 2 (IL-2)
• The only FDA-approved adjuvant therapy for metastatic RCC
• Interferons
• Being tested as a therapy for metastatic RCC
Role of Immunological Responses in Kidney Cancer

47. Cytokines and cytokine
regimen used in renal cell
carcinoma
 Interferon alfa
 Interleukin -2
 Interferon alfa + interleukin -2
 Interferon alfa + vinblastin
 Interferon alfa + cis- retinoic acid
 Interferon alfa + interleukin -2+ 5- fluorouracil

48. Immunotherapy
 Interferon alpha
 Approx 15% resp rate
 Median time to response 4 mo
 Often short-lived and/or partial responses
 Largest study to evaluate long-term outcome
(Motzer et al, JCO 2002)
 Retrospective review of 463 pts on 6 trials
 Median OS 13 mo
 14% 2yr PFS

49. Immunotherapy – IL-2
 High dose bolus IL-2 + LAK cells
 In mid-1980s
 Dramatic and durable responses in some pts
 Later, IL-2 alone shown to be equivalent
 High-dose IL-2
 1992: FDA approval based on 7 phase II trials (255 pts)
 Treatment schedule-600,000 – 720,000 IU/kg q8h up to 14
doses. Repeat q 12 weeks, up to 3 cycles
 Pts with excellent organ function.
 May need ICU monitoring

50. Immunotherapy – IL-2
 Cont infusion IL-2
 Slight decrease in resp rate
 No improvement in toxicity
 Inhalational Rx
 Results confusing, as it was given with SC doses as
well
 Out pt. S/C admin
 6% PR rate in one study
 22% PR rate in another (incomplete f/u in this study –
Sleijfer, JCO 1992)

51. Immunotherapy – IL-2
 Lower dose IL-2 IV therapy
 Only 4% resp rate c/w 16% for std dosing and 11%
for SC dosing.
 Low dose IL-2 and SC dosing had less toxicity
 Repeat IL-2 treatement
 For pts who respond and then relapse, only 2%
will respond to the same IL-2 regimen

52. Adverse effects of IL-2
capillary leak syndrome
Capillary permeability
fluid retention
interstitial edema
hypotension
intrarenal vasocon. (reversible)
acute renal insufficiency

53. Immunotherapy – IL-2
 Minimizing toxicity of IL-2
 IL-2 stimulates IL-1,TNF alpha, IFN gamma, NO
 Co-admin of L-NMMA (NO inhibitor) led to
improvement in hypotension in all patients with
IL-2 induced hypotension

54. Intratumoral therapy
 Leuvectin {plasmid DNA/lipid) expression of
sustained level of IL2
tumour regression
 Repeated administration --safe & well
tolerated---phase1 study
 Systemic toxicities can be avoided
 Phase III-study using leuvectin going on

55. Chemotherapy
 RCC is only minimally responsive to
chemotherapy
 83 clinic trials involving over 4000 pts, overall
response rate is only 6%
 On-going clinical trials of combination
chemotherapy including Gemcitabine and 5-
FU
 Limited data reveals some response in non-
clear cell RCC to Carboplatin, Cisplatin plus
Gemcitabine

56. Systemic chemotherapy
 Single agent
 Vinblastine: 2.5 – 25% resp rate
 Floxuridine: 10-20% resp rates in small studies
 Review of 72 diff regimens (mainly single agent),
found resp rate of 5.6%
 Mostly limited responses, rare to see increased
survival

57. Chemotherapy
 Combination chemo Rx
 Gemcitabine / 5FU (Rini et al, JCO 2000)
 17% resp rate
 PFS 29 weeks
 Unclear if superior to single agent Rx
 Overall, RCC is considered chemo Rx
resistant, and no regimen can be considered
standard of care at this time.

58. Reasons for chemo resistance of RCC
 Proximal tubule cells (source of most RCC), have
high expression of P-glycoprotein (MDR) mRNA
 In one study 6/8 RCC’s and 4/4 RCC cell lines
overexpressed MDR
 Another study: if 1% or > cells (+) for MDR, PFS
4mo vs 27 mo

59. Radiation Therapy
 RCC relatively radioresistant
 XRT has limited use in metastatic disease
- Painful bone or recurrent abdominal
metastases
- Brain metastases

60. vaccines
 HSPs have been extensively investigated in preclinical
cancer models:
 Efficacy demonstrated in the prevention or treatment of
many different cancer types (>12 models)
 4 species: Mouse, rat, hamster, frog
 Multiple cancers:
Lung, skin, colon, liver, prostate, thymus, melanoma, lymphoma, leukemia
 Cancers arising by different mechanisms:
Spontaneous, chemically-induced, UV-induced
 HSP vaccine technology has been validated by more
than 27 independent laboratories

61. To immunise RCC patients in post op. setting.
Using simple purification techniques, HSPs and their associated
peptides are isolated from the tumor tissue, filtered and vialed as
an injectable vaccine.
Vaccine is shipped frozen to the physician.
Autologous irradiated tumour cells mixed with BCG
Oncophage® (HSPPC-96)
Investigational Autologous Vaccine (Wood et.al.-2004)

62. Oncophage
Administration Schedule
 Oncophage: HSP (gp96) - peptide complex
 Individually prepared from surgically resected cancer
specimens and formulated for s.c. or i.d. injection
1 2 3
1st
Dose
2nd
Dose
3rd
Dose
4
4th
Dose
Weeks
5 6
5th
Dose
Then every 2 weeks
until completely
used

63. Nonablative stem cell
transplantation
 Since RCC is very sensitive to immunomodulation,
graft versus tumor effect would be possible for RCC
 Childs et al (NEJM 2000):
 19 pts with refractory RCC
 Cytoxan / fludarabine conditioning
 HLA-ident or mismatched sib alloTx
 Reponse delayed – only seen after 100% donor cells in
marrow
 GVHD grade 2-4  90% chance of response
 Overall 47% resp rate

64. Nonablative stem cell
transplantation
 Rini et al (JCO 2002)
 15 pts, conditioned with fludara / cytoxan
Tacrolimus + mycophenolate
 GVHD seen only in 8 pts
 33% resp rate (44% in those with persistent
engraftment)

65. Ongoing trials
 CALGB 69901: A phase II randomized trial of carboxyaminoimidazole
 May work as an angiogenesis inhibitor
 A Multi-center, Randomized Phase III Study of Adjuvant Oncophage
Versus Observation
 a vaccine made from the patient’s tumor
 Gemcitabine (weekly x 3 weeks)+ capecitabine (qd x 3 weeks), 2 cycles
 UCN-01, a protein kinase C inhibitor
 Stereotactic XRT to 1-3 brain mets
 CCI-779 (mTOR inhibitor) plus IFN
 IL-12 + IFN alpha
 IL-12 + IL-2
 Thalidomide +Taxol
 Nonablative stem cellTx protocols

66. Summary
 RCC is relatively rare but increasing incidence
 Associated with tobacco and inherited disorders
 Surgery is the only curative modality for Stage I, II,
and III
 Stage IV disease holds poor prognosis despite
advancements in molecular understanding
 IL-2, Sorafenib, Sunitinib, andTemsirolimus are FDA
approved treatments for advanced RCC