CURRENT TRENDS IN MANAGEMENT OF RENAL CELL CARCINOMA
Moderator:-Prof.P.K.Puri, HOD DEPTT. OF UROLOGY
Presented by:-Dr. VIKAS KUMAR IGMC,SHIMLA
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
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
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
Investigations
Ultrasonography CT- Scan (plain & contrast
enhanced) IVU MRI Angiography,
venocavography FNAB
Robson’s staging
Staging and Prognosis
Cohen HT, McGovern FJ. NEJM. 2005;353:2477.
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
Surgical
modalities
Rad.Neph
Open
Lap
N.S.S Open
Lap
Minimally
invasive approach
Cryoablation
open
P.C
Lap
R.F.A open
P.CLAP
Noninvasive HIFU ablation
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.
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%
Management of localised RCC
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 of Transperitoneal 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.
Lap.Rad.Nephrectomy
L.R.N :- (a) Transperitoneal (b) R.Peritoneal becoming std. T/t for localized T1-2 tumors that are not amenable to NSS. Benefits of LRN :- (1) Decreased P.O pain (2) Shortened hospital stay. (3) Quick convalescence & improved
cosmesis. 5 Yrs 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.
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.
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
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
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 of ARF 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%).
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 --- Post T/t haemorrhage --- Injury to adjacent structure Criticism ---- Histological documentation of complete
tumor destruction is not currently available.
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 10-90 W 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.
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 with VHL ds & patient with multiple
renal tumor. Complications – risk of ureteral / calyceal injury
in cases of centrally located lesions.
---- Perinephric haemotoma ---- Skin metastasis
Conclusions
Lap. RN is rapidly replacing the ORN with T1-2 tumor.
ORN is mainly reserved for T3 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.
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%.
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
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
Thermal ablative therapya. cryotherapyb. 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,
Cryoablation
Needle (cryoprobe) Argon gas
Cryoablation technology (Joule-Thompson principle)
CryoprobeHigh pressure argon
Expansion chamberatmosphere
-160° C
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)
Laparoscopic Renal Cryoablation
Percutaneous Renal Cryoablation Smaller cryoprobes (1.7 mm
diameter ~15 gauge) US and/or CT guidance Faster Easier than laparoscopic Significant bleeding is rare
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 = 10-90 W
Contd..
Indications :- -- small exophytic tumor most suitable ; success
rate decrease with increase in size of tumor & as
the location becomes central. -- patient with VHL 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
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.
New technology- (HIFU) high intensity focused USG, 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
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 via VEGF pathway and mammalian target of rapamycin (mTOR) pathway
VEGF Pathway Inhibition
Tyrosine kinase (TK) inhibitors block the intracellular domain of the VEGF receptor
Sunitinib (Sutent) Sorafenib (Nexavar) Monoclonal antibody that binds
circulating VEGF preventing the activation of the VEGF receptor
- Bevacizumab (Avastin)
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
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
Sorafenib
Phase II and phase III trials in advanced RCC
Phase III TARGET 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
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
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
Evidence of an Immunological Role in Combating RCC
immunotherapy
• 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
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
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
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
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)
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
Adverse effects of IL-2capillary leak syndrome
Capillary permeability
fluid retention
interstitial edema
hypotension
intrarenal vasocon. (reversible)
acute renal insufficiency
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
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
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
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
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.
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
Radiation Therapy
RCC relatively radioresistant
XRT has limited use in metastatic disease
Painful bone or recurrent abdominal metastases
Brain metastases
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
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)
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
1stDose
2ndDose
3rdDose
4
4thDose
Weeks
5 6
5thDose
Then every 2 weeks until completely used
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 allo Tx Reponse delayed – only seen after 100% donor
cells in marrow GVHD grade 2-4 90% chance of response Overall 47% resp rate
Nonablative stem cell transplantation
Rini et al (JCO 2002) 15 pts, conditioned with fludara /
cytoxanTacrolimus + mycophenolate
GVHD seen only in 8 pts 33% resp rate (44% in those with
persistent engraftment)
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 cell Tx protocols
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, and Temsirolimus are FDA approved treatments for advanced RCC
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