BSJ

Renal Cell Carcinoma

Diagnosis & ManagementRaúl H. Morales - Borges, MD, FICPS, FIACATH

Chairman of the Board of Trustees and Lecturer of Pathology, Immunology & Genetics

San Juan Bautista School of Medicine

Medical Director of The Ashford Institute of Hematology & Oncology

Attending Physician and Consultant

Ashford Presbyterian Community Hospital

BSJ

Disclosures

• Investments: None

• Speaker Bureau:– Pfizer Caribbean– Sanofi Aventis– Astra Zeneca

• Consultant:– Astra Zeneca Glaxo SmithKline– Sanofi Aventis Merck

TOPICS TO BE DISCUSSED

• Overview: Epidemiology, Pathology, and Pathogenesis of Rena Cell Carcinoma (RCC)

• Clinical manifestations, evaluation, and staging of RCC

• Prognosis and Treatment of RCC

• Targeted therapies for RCC

INTRODUCTION• Renal cell carcinoma (RCC) has increased its incidence at a rate

of 2% per year on the last 65 years as well as its mortality on the last 2 decades.

• Partial Surgery is the new option for localized tumors. 20% to 40% of the operated tumors will develop metastases in a future and will require additional therapy.

• RCC are resistant to chemotherapy and radiotherapy. Hormones doesn’t work too.

• New target therapy agents are available with great responses & survival benefits.

Overview of RCC

EpidemiologyPathology

Pathogenesis

Epidemiology• RCC is the responsible of 2% - 3% of all malignancies

in the adults.• The incidence peak age is: 60 – 80 years old.• Men : Women ratio of 2:1• Incidence & Mortality are rising in African Americans.• 51190 new cases & 12890 deaths on 2007 with

54390 cases and 13010 deaths on 2008 in USA.• 5-year survival rate of 65% by 1995-2000..

• RCC affects more than 150,000 people annually worldwide, resulting in 78,000 deaths each year.

• An individual with positive family history of RCC have a 2.5-fold greater chance for developing renal cancer during their life time.

• Patients with a family history comprise about 4% of all cases of RCC.

Pathology

Clear cell (non-papillary) carcinoma is the most common.

Pathogenesis

A number of environmental, hormonal, A number of environmental, hormonal, cellular, and genetic factors have been cellular, and genetic factors have been studied as possible causes of RCC. studied as possible causes of RCC.

Etiology• Tobacco• Obesity• Chronic arterial

hypertension• Diabetes mellitus• End-Stage Renal Disease on

hemodialysis• High fat, high protein diet,

fried food, red meat

• Use of phenacetin chronically as analgesics

• Amphetamines• Petroleum products• Cadmiun• Asbestos• Aromatic hydrocarbons

• Smoking: 30% in men, 24% in women.

• Obesity: Increased BMI is related with RCC, but more favorable prognosis.

Familiar type RCC & von Hippel Lindau

• Suppressor gene in the short arm of chromosome 3 as autosomic dominant.

• 1 in 30,000 births.• Age of early symptoms: 26.3 years old.• Penetrance age of 60 years old.• RCC: bilateral low staging.• Associated features: retinal angiomas, cerebelar &

spinal cord hemagioblastomas, cysts and/or angiomas of solid organs, pheochromocytomas.

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Birt-Hogg-Dubé Syndrome • Rare autosomal dominant• Gene located at the short arm of the

chromosome 17• Chromophobe RCC with low metastatic

potential• Fibrofolliculomas trichodiscomas (benign

hamartomas of the hair follicule), pulmonary cysts, spontaneous pneumothorax

Clinical Manifestations

Evaluation and StagingOf RCC

Clinical Presentation• Small tumors as

incidental findings• Hematuria• Abdominal pain• Palpable abdominal

mass

• Paraneoplastic syndrome:– Bone pain– Hypercalcemia– Fever– Weight loss– Polycythemia– Neuromyopathy– Amyloidosis

• 30% presented with metastatic disease, 25% with locally advanced disease, and 45% with localized disease.

• 75% of metastatic disease presents with pulmonary lesions, 36% to soft tissues, 20% to the bones, 18% to the liver, 8% to the skin, and 8% to the CNS.

Diagnostic tests

• History & Physical Exam• Laboratory: CBC, CMP, LDH, ESR, U/A• CXR, Abdomino-pelvic CT Scan• MRI if IVC thrombosis suspected• Bone scan if bone metastases suspected• PET/CT is controversial

Prognosis and Treatment of RCC

Prognostic factors

• Symptomatic presentation• Weight loss• Poor performance status• ESR > 30 mm/hr• Anemia• Elevated alkaline phosphatase• Tumor size, positive margins, liver & lung

metastases, Sarcomatoid tumors

Surgery in RCC• We are moving from Radical nephrectomy to partial

nephrectomy using laparoscopy.

• We can minimize positive margins in partial nephrectomy using:– Intraoperative sonography– Use of cold scissors for parenchymal transection– Hilum control to avoid vascular leak (bleeding).

• The first nephrectomy was performed on June 4th of 1861. Since then, there have been significant advances in surgical techniques.

• The most common procedure today for treatment of localized renal carcinoma > 4 cm is radical nephrectomy.

• Laparoscopic nephrectomy has become the standard of care for management of most renal tumors not amenable to nephron-sparing surgery.

• At present, lymphadenectomy is a safe adjunct to radical nephrectomy and is primarily used for staging.

• Cytoreductive nephrectomy in metastatic RCC is controversial, but depends on the selection of the patient due to insignificant benefit and short term survival.

Angioinfarction

• Embolization of the renal artery: only for palliation. No definitive benefit.

Chemotherapy

• NO ROLE !!!!!

• Combination of Vinblatine + Toremifene/ Verapamil/ Nifedipime/ Cyclosporin ????? Due to inhibition of p-glycoprotein which is the responsible for chemo-resistance.

• 4% SPONTANEOUS REGRESSION RATE.• IL-2 & IFN-alpha 2a and 2b alone or in

combinations: poor response rates.• TIL’s, LAK cells, and Dendritic cell therapies:

very complex and expensive with low response rates.

IMMUNOTHERAPY

Targeted Therapies for RCC

New Class of Agents Used in RCC: Tyrosine Kinase Inhibitors (TKI’s)

• Sorafenib : Approved by FDA in Dec. 2005

• Sunitinib : Approved by FDA in Jan. 2006

• Temsirolimus : Approved in May 2007

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47

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Long-term toxicity of TKI’s• HYPOTHYROIDISM

• MYELOSUPPRESSION

• FATIGUE

•B.k Vakkalanka et al: Abstract 16045; ASCO 2008

Adjuvant Therapy

Adjuvant Therapy: Rationale

• Patients with recurrent disease following nephrectomy have micrometastatic disease at the time of surgery

• There is a 35%-65% recurrence rate* with locally aggressive tumors

• Use of effective therapy may reduce the risk of relapse

Lam JS, et al. BJU Int. 2005;96:483-488.

*Depending on pathologic stage.

Adjuvant Therapy• To date, all adjuvant therapy trials have failed to

demonstrate DFS or OS advantage– High-dose (HD) IL-2– Interferon– Autologous tumor cells +

BCG vaccine– Vitespen (HSPPC-96) vaccine

• Given the risk/benefit profile, no adjuvant treatment is appropriate outside clinical trial

• VHL mutation (and thus VEGF production) is an early oncogenic event in RCC

– Radiation therapy– Megestrol acetate

ASSURE Trial (Intergroup Sponsored by ECOG)

• Eligibility: nonmetastatic kidney cancer– Disease T1b N any (resectable) M0 by

radiologic criteria

• Primary endpoint: DFS

Nephrectomy

Patients with nonmetastatic kidney

cancer

Disease stage II-IV

(N = 1332)

Stratification by UISS stage (II-V) and histologic subtype (clear cell or nonclear cell) Sunitinib 50 mg daily

for 4 of 6 wks

Sorafenib 800 mg daily continuously

Placebo daily continuously

Available through www.CTSU.org

1 year

SORCE (MRC Adjuvant trial)

• Eligibility– No evidence of residual disease after RCC resection– Leibovich prognostic score 3-8 (high or intermediate

risk of metastatic RCC or death) postsurgery– ≥ 4 weeks and ≤ 4 months since surgery

• Endpoints– Primary: metastasis-free survival– Secondary: DFS, toxicity, genomics

Patients with high- and intermediate-risk resected RCC

(Planned N = 1420)

Placebo

3 years

Sorafenib

Sorafenib

Placebo

1 year

ARISER Study

cG250 (WX-G250) IV over 15 minutes

once weekly

Placebo IV over 15 minutes once weekly

Patients with clear-cell nonmetastatic RCC

(N = 600+)

• Eligibility– Clear-cell RCC, no metastasis, ECOG status 0– RCC patients at high-risk of recurrence*

• Primary endpoints: DFS, OS

* T3b/T3c/T4 N0/XM0; All T stages N+M0; T1b/T2 N0/XM0 with G ≥ 3 and MVI or T3a N0/XM0 with G ≥ 3

Nephrectomy

24 weeks

Neoadjuvant Trials• Phase II

– Neoadjuvant sunitinib: Cleveland Clinic Foundation• For patients with “unresectable” primary renal tumors

(with or without metastases)– Neoadjuvant RAD-001 (mTOR inhibitor): UCLA

Metastatic RCC: Frontline/Monotherapy

CALGB 90206: Interferon alfa-2b ± Bevacizumab in Advanced RCC

• Endpoints– Primary: OS– Secondary: TTP, ORR, toxicity

• Follow-up– Every 3 months for 2 years– Annual thereafter (up to 10 years from

study entry)

Interferon alfa-2b 9 MU SC 3 times weekly

(n = 350)

Interferon alfa-2b 9 MU SC 3 times weekly + Bevacizumab 10 mg/kg IV

Days 1 and 15, every 28 days(n = 350)

Patients with untreated, metastatic or unresectable

clear-cell RCC

(N = 700)

Stratified for nephrectomy status

and MSKCC risk group

Patients with metastatic clear cell RCC, status post

nephrectomy

(N = 638)

• Primary endpoint– OS (improvement from 13-17 months)

European Phase III Trial of IFN/Bevacizumab in RCC (BO17705)

Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks +

Placebo every 2 weeks until disease progression

Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks + Bevacizumab 10

mg/kg every 2 weeks until disease progression

• Randomized, open-label, multicenter trial

– 100 Sites (US, Canada, Europe, Australia, Brazil)

Phase III Trial of Sunitinib vs Interferon alfa in Metastatic RCC

Patients with metastatic clear cell RCC

(N = 690)

Sunitinib orally administered daily (4 of every 6 weeks)

(n = 345)

Interferon alfa administered 3 times weekly

(n = 345)

• Endpoints– Primary: PFS

– Secondary: TTP, OS, RR, QoL, safety, cost-effectiveness

ASK1

Phase II trial• 111 patients

• RR: 7%

• TTP: 5.8 months

• OS: 15 months

• Toxicity: rash, fatigue, mucositis, nausea

CCI-779: mTOR inhibitor

Cap-dependent translation

02

Schematic from Bjornsti and Houghton Nat Rev Cancer 4L335-348 (2004) Atkins J, et al. J Clin Oncol. 2004;22:909-918.

ATPAmino acids

Protein stability

Phosphatidic acidTOR

Mitochondria

Transcription-factor translocation

Apoptosis

S6K1

Translation ribosomal proteins

eIF4E

Ribosome biogenesis

Nutritional-stress response

Growth/survival factors

Nucleus

4E-BP1

Plasma membrane

Cytoplasm

• International phase III randomized trial• Endpoints

– Primary: OS

– Secondary: Safety, PFS, RR, health outcomes

Temsirolimus (CCI-779) + Interferon alfa in Advanced RCC

1. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296.

CCI-779 IV25 mg weekly

CCI-779 15 mg IV weekly +Interferon alfa 6 MU SC TIW

Interferon alfa SC up to 18 MU TIW as tolerated

Patients with previously untreated advanced RCC

Poor risk criteria[1]

(Planned N = 600)

Outcome UCLA, %(N = 83)

Boston, %(N = 66)

No of metastatic pts with > 85% CA IX

77 62

Response in high CA IX 27* 51Response in low CA IX 14 24Responders with high CA IX 91 78Nonresponders with high CA IX 80 51

*Including all CRs.

Bui MH, et al. Clin Cancer Res. 2003;9:802-811.Atkins M, et al. Clin Cancer Res. 2005;11:3714-3721.

CA IX and Response to Interleukin-2 (IL-2) Therapy in RCC

rIL-2 600,000 IU/kg

q8h by15-min infusion

rIL-2 600,000 or

q8h by15-min infusion

Rest

9 days5 days 5 days

• Eligibility – Measurable metastatic RCC; all histologic subtypes– Consented to provide tumor blocks– No prior systemic therapy – Candidate for HD IL-2– ECOG PS 0-1 and good organ function

Maximum 3 courses per patient.Responses independently audited.

HD IL-2 “Select” Trial: Study Design

Metastatic RCC: Determining Clinical Cross-Resistance to VEGF-

Targeted Agents

KDR

HIF

VEGF

mTOR inhibitor (temsirolimus, CCI-779)

Bevacizumab

Sorafenib, sunitinib, AG13736

O2

Approach to Tyrosine Kinase Inhibitor (TKI)–Resistant Disease

• Hypothesis– Resistance to 1 TKI will be mediated by pathways sensitive

to inhibition by another TKI– Varying response rates and toxicity profiles suggest some differences

between TKIs

• Sunitinib in bevacizumab-refractory RCC – VEGF-R (and other targets like PDGF) after VEGF ligand

inhibition– ASCO 2006: definite activity, data to be presented– Sorafenib in sunitinib or bevacizumab-refractory RCC

• Multitargeted agent, plus Raf kinase inhibition

• AG013736 in sorafenib-refractory RCC– More potent VEGFR inhibition

• All 3 are standard clinical trials– No insights into mechanisms of resistance, etc, are possible

A B Trials

6-Arm Randomized Phase II Trial (E9805): Sunitinib Failures

Patients failing sunitinib

Sunitinib daily

Arm A

Arm B

Sunitinib + Bevacizumab

Arm C

Change to Sorafenib

Patients failing sorafenib

6-Arm Randomized Phase II Trial (E9805): Sorafenib Failures

Increase Sorafenib dose

Sorafenib + Bevacizumab

Arm D

Arm E

Arm F

Change to Sunitinib

Arm DArm D

Arm E

Metastatic RCC: Combinations

Phase I and II Combination Studies

• Sorafenib + bevacizumab• Sunitinib + bevacizumab• CCI-779 + bevacizumab• CCI-779 + sorafenib• AMG386 (anti-Ang2/Tie2) + bevacizumab, TKI• HD IL-2 + bevacizumab (Phase II CWG study)

Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15)

Patients with advanced RCC

(N = 360*) Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15)

Sorafenib 400 mg PO twice daily

*Accrual goal.†Arm to be added when phase II doses are available from ongoing phase I trials.

Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) and Temsirolimus 25 mg IV

weekly (Days 1, 8, 15 and 22)

Sorafenib PO twice daily and Temsirolimus IV weekly (Days 1, 8, 15 and 22)†

• Randomized phase II study• Endpoints

– Primary: PFS– Secondary: ORR, OS, correlates (DCE-MRI, biomarkers)

ECOG “BEST” Trial

Stratified by prior therapy (prior cytokine/vaccine or no prior

cytokine) and Motzer risk category (low, intermediate, or high)

Patients with clear cell RCC(N = 499)*

1 year

Phase III Renal EFFECT Trial

*Initial, nonrandomized dose-finding study for sunitinib and interferon-alfa2b in first 25 patients at 4 sites

Primary endpoint: improvement in TTP from 8-12 months; 85% power (hazard ratio = 0.67); 222 events required.

1 year of follow-up after end of treatment

Sunitinib, 50 mg/d orally, 4 weeks on 2 weeks off

(n = 149)

Sunitinib, daily, 4 weeks on 2 weeks off, plus Interferon alfa-2b every 3 weeks

(n = 149)

Sunitinib 35 mg/d orally for 6 weeks (n = 149)

Conclusions

• VEGF and other targeted therapies – Robust activity in metastatic RCC– Cornerstone of future therapy

• Currently under investigation– Value in earlier stages of disease– Clinical cross-resistance– Optimal sequencing/combination

• Clinical trials – Participation mandatory for benefit of all

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