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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