Giuseppe Tonini [email protected] Oncologia Medica Universita’ Campus Bio-Medico, Roma...

Giuseppe ToniniGiuseppe Tonini [email protected]@unicampus.it

Oncologia MedicaOncologia MedicaUniversita’ Campus Bio-Medico, RomaUniversita’ Campus Bio-Medico, Roma

Mediterranean School of Oncology:Highlights in the management of Kidney Cancer

Roma, 7-8 Novembre 2008Establishing the role of cytokine Establishing the role of cytokine

therapy intherapy inadvanced renal cell carcinomaadvanced renal cell carcinoma

http://intranet/FotoGallery/Giornata%20della%20Ricerca%202007%20-%2018%20Maggio%202007/pages/Pubblico%20della%20Giornata.htm

EpidemiologyEpidemiology

3% of all adult malignancies

Third most frequent urological malignancy after prostate and bladder cancer.

In 2004, almost 60.000 individuals in the European Union were diagnosed with RCC, and almost 30 000 individuals died from the disease.

De Mulder PH et al, Ann Onc 2004

Boyle P et al, Ann Oncol 2005

Incidence and Mortality of Kidney Incidence and Mortality of Kidney Cancer in Selected EU Countries Cancer in Selected EU Countries

(2002)(2002)

GLOBOCAN Database 2002.

IncidenceIncidenceAge-standardised rate (per Age-standardised rate (per

100,000)100,000)

MortalityMortalityAge-standardised rate (per Age-standardised rate (per

100,000)100,000)

MalesMales FemalesFemales MalesMales FemalesFemales

AustriaAustria 12.212.2 6.86.8 5.05.0 2.92.9

BelgiumBelgium 9.99.9 5.15.1 4.74.7 2.52.5

FinlandFinland 10.810.8 6.76.7 4.84.8 2.72.7

FranceFrance 10.410.4 4.64.6 4.74.7 2.02.0

GermanyGermany 12.312.3 5.85.8 5.65.6 2.72.7

GreeceGreece 7.37.3 3.73.7 3.03.0 1.31.3

IrelandIreland 8.28.2 4.34.3 3.83.8 2.02.0

ItalyItaly 11.511.5 4.64.6 4.04.0 1.51.5

NetherlandsNetherlands 9.89.8 4.94.9 5.55.5 2.72.7

SpainSpain 9.29.2 3.73.7 3.23.2 1.41.4

SwedenSweden 8.98.9 5.35.3 4.94.9 3.13.1

SwitzerlandSwitzerland 10.210.2 5.35.3 4.14.1 2.02.0

UKUK 8.68.6 4.44.4 4.24.2 1.91.9• Worldwide incidence of RCC is increasing at an annual rate of approximately 2%• Worldwide mortality >100,000 per year

Rationale for immunotherapy in Rationale for immunotherapy in kidney cancerkidney cancer

Late relapses after radical nephrectomyLate relapses after radical nephrectomy

Long disease stabilization without systemic Long disease stabilization without systemic therapytherapy

Spontaneous remissions after nephrectomy, probably as a result of immune responses.

Responses to cytotoxic chemotherapy < 10%

Reis LAG, et al. Seer Cancer Statistics Review, 1975–2003.

Immunotherapy for Advanced RCCImmunotherapy for Advanced RCC

IFN alfa and IL-2 have low level of IFN alfa and IL-2 have low level of antitumor activityantitumor activity

Ineffective as adjuvant therapies after Ineffective as adjuvant therapies after complete resection of locally advanced complete resection of locally advanced diseasedisease

Muss HB. Semin Oncol. 1988;15(5 suppl 5):30-34.Clark JI, et al. J Clin Oncol. 2003;21:3133-3140.

Progress in the Treatment of RCCProgress in the Treatment of RCC

Increased understanding of the molecular Increased understanding of the molecular changeschanges1,21,2 Identification of cellular pathways relevant in RCCIdentification of cellular pathways relevant in RCC VEGF, PDGF, RAS, mTORVEGF, PDGF, RAS, mTOR

New approaches to treat RCC by targeting New approaches to treat RCC by targeting pathwayspathways22

SorafenibSorafenib Sunitinib Sunitinib TemsirolimusTemsirolimus IFN-a + bevacizumabIFN-a + bevacizumab

1Kaelin WG Jr. Nat Rev Cancer. 2002;2:673-682. 2Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353:2477-2490.1

Today what is the role Today what is the role

of cytokine therapy in of cytokine therapy in

advanced RCC?advanced RCC?

IFN-α in advanced RCCIFN-α in advanced RCC

Biological effects of IFN-αBiological effects of IFN-α

• Tumoral growth inhibition

• Increase of tumor antigenicity

• Inhibition of c-myc and c-fos

• Inhibition of p450 cytochrome

•Activation of oncosuppressor genes

• Induction of cell differentiation

• Stimulation of antibodies activity

• Stimulation of T-cytotoxic lymphocytes

IFN-α in advanced RCCIFN-α in advanced RCC

IFN-α is widely used for treating advanced RCC

The first responses to IFN-α in patients with metastatic RCC were reported in 1985.

Kirkwood JM et al, Cancer Res 1985

Cochrane meta-analysis: OS in Cochrane meta-analysis: OS in patients treated with IFN- αpatients treated with IFN- α

Coppin C, et al. Cochrane Database of Systematic Reviews 2004.

6117 patients treated in 53 randomized studies

ORR: 12.5% vs 1.5% for non-immunotherapy controls (95% CI 3.0–19.2)

Reduction of 1-year mortality (HR= 0.56, 95%CI=0.40–0.77, P=0.0005)

Improvement in median survival of 3.8 months (11.4 vs 7.6 months, P < 0.001)

Cochrane meta-analysis: ResultsCochrane meta-analysis: Results


.

Interferon-α provides a modest survival benefit compared to other commonly used treatments. In patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-α gives the best survival strategy.

Cochrane meta-analysis: Cochrane meta-analysis: ConclusionsConclusions


IFN-α: dose, schedule and IFN-α: dose, schedule and durationduration

At low doses, there is a dose–response relationship, the minimum effective dose is 20–40 MU/week. Higher doses: greater toxicity with no concomitant improvement in response rates.

Dosing schedules vary among studies, no definitive conclusion has been established.

Treatment duration varies across the major trials, it is difficult translate study treatment protocols into clinical practice.

De Mulder PH et al, Ann Onc 2004

Anaemia Altered taste Depression Elevated liver function tests Flu-like symptoms: fever, fatigue,

headache, myalgia Leukopenia Nausea Vomiting Weight loss Hypotyroidism

IFN-α: toxicitiesIFN-α: toxicities

Jonasch E et al, Oncologist 2001

Efficacy of IFN-α + various agentsEfficacy of IFN-α + various agents

Association with cimetidine, coumarin plus cimetidine and vinblastine: no benefit in survival compared with IFN-α alone [1, 2, 3].

One study showed an improvement in median OS with IFN-α + 13-cis-retinoic acid (17.3 months) VS IFN-α alone (13.2 months; P =0.048); the combination was associated with increased toxicity [4].

The most effective combination regimen was IFN-α + 5-FU+ IL-2 with RR of 39%, with a median OS of 24 months [5].

1. Fossa SD, et al Ann Onc 1992 2. Kinouchi T, J Cancer Res Clin Oncol 20063. Sagaster P, et al, Ann Oncol 1995 4. Aass N, Ann Onc 2005 5. Atzpodien J, Br J Cancer 2001

Lack of compelling data on IFN-α and the increasing availability of alternative targeted treatments has led the National Comprehensive Cancer Network (NCCN) to remove its recommendation for use of IFN-α as a first-line treatment option for patients with stage IV RCC in their latest guidelines.

IFN-α in metastatic RCC: IFN-α in metastatic RCC: conclusionsconclusions

National Comprehensive Guidelines Network. Kidney cancer 2007

IL-2 in advanced RCCIL-2 in advanced RCC

TheScientificWorldJOURNAL (2007) 7, 837–849

Biological Effects of IL-2Biological Effects of IL-2

Negrier S, et al. N Engl J Med. 1998;338:1272-1278.Yang JC, et al. J Clin Oncol. 2003;21:3127-3132.McDermott D, et al. J Clin Oncol. 2005;23:133-141.

StudyStudy RegimenRegimen NN RRRR PP-value-value NotesNotes

Negrier et al. Negrier et al. (1998)(1998)

IL-2IL-2 147147 8%8% No OS differenceNo OS difference Combination arm Combination arm

had severe had severe toxicitytoxicity

Best response in Best response in patients with good patients with good prognosis (only prognosis (only one metastatic one metastatic site)site)

IFNIFN 138138 7%7%

IL-2 + IFNIL-2 + IFN 140140 19%19% <0.01<0.01

Yang et al. Yang et al. (2003)(2003)

HD IL-2 (iv)HD IL-2 (iv) 156156 21%21% 0.050.05 No OS differenceNo OS difference Higher RR with HD Higher RR with HD

IL-2IL-2LD IL-2 (iv)LD IL-2 (iv) 150150 13%13%

McDermott et McDermott et al. (2005)al. (2005)

HD IL-2 (iv)HD IL-2 (iv) 9595 23%23% 0.020.02No OS differenceNo OS differenceIL-2 (sc) + IL-2 (sc) +

IFNIFN 9191 10%10%

Key IL-2 Studies in RCCKey IL-2 Studies in RCC

“Interleukin 2 (IL-2) is the only systemic treatment currently available that is capable of curing patients with metastatic RCC. Over 80% of all patients who obtain a CR following HD IL-2 never experience disease recurrence and seem to be cured of their disease”.

Steven A Rosenberg, NCPO, 2007Herbert T. Cohen , NEJM 2005

In the “Targeted Therapies In the “Targeted Therapies Era”……..Era”……..

Iv IL-2 ToxicitiesIv IL-2 Toxicities

Vascular leak syndromeVascular leak syndrome Hypotension Hypotension Respiratory distress syndromeRespiratory distress syndrome Neurologic (depression, confusion)Neurologic (depression, confusion) Hepatic and renal abnormalities as oliguria and Hepatic and renal abnormalities as oliguria and

increase in serum creatinine levels increase in serum creatinine levels Cardiac (arrhythmias, myocardial infarction)Cardiac (arrhythmias, myocardial infarction) Treatment related deaths (1% - 2%)Treatment related deaths (1% - 2%)

The potential for severe toxicity with high-dose IL-2 must be balanced identifyng patients who respond

completely to treatment!!!

Iv IL-2 is significantly more toxic!!Iv IL-2 is significantly more toxic!!

No differences in outcome!!!!

Negrier S. et al. Clin Cancer Res 2008

Selecting patients who Selecting patients who

benefit from cytokine benefit from cytokine

therapytherapy

Prognosis and response to IFN-Prognosis and response to IFN-αα

Retrospective study of 463 pts

P<0.001

PERCY Quattro study

• 492 patients with intermediate prognosis

• No survival benefit for IFN-α therapy (median OS: 15.2 months) VS MPA control (median OS 14.9 months)

“Good” prognosis is associated with response to IFN-α!!!

Motzer RJ, et al. J Clin Oncol, 2002Negrier S. Ann Oncol 2006

Prognosis and response to IL-2Prognosis and response to IL-2

“Good” prognosis is associated with response to IL-2!!!

Mc Dermott DF, et al. J Clin Oncol, 2005Negrier S. Ann Oncol 2006

PERCY Quattro study

• 492 patients with intermediate prognosis)

• No survival benefit for IL-2 based therapy (median OS: 15.3 months) VS MPA control (median OS 14.9 months)

PrognosisPrognosis Median OSMedian OS

GoodGood 30.9 months

IntermediateIntermediate 16.8 months

Intermediate/Intermediate/

PoorPoor3 months3 months

PoorPoor 1.6 months

Randomized Phase III trial with HD IL-2 therapy:

Clear cell with alveolar features Lack of granular or papillary features

Histological features predictive of response to Histological features predictive of response to IL-2IL-2

Immunological markers predictive of response Immunological markers predictive of response to IL-2to IL-2

Low neutrophil count Lack of intratumoral neutrophils High intratumoral CD57+ T-cells Low regulatory T-cell count after treatment

Gore ME et al, BJU Int 2008

CAIX (Carbonic anhydrase IX)CAIX (Carbonic anhydrase IX)and response to IL-2and response to IL-2

Transmembrane protein that is thought to play a role in the regulation of cell proliferation under hypoxic conditions.

CAIX is present in 94% of clear cell RCCs and low CAIX levels are associated with poor prognosis in patients with metastatic disease.

High CAIX levels are associated with better response to IL-2 (positive predictive factor)

Buy MH et al, Clin Cancer Res 2003

Relationship between CAIX staining and response: 78% of the responders (CRor PR) were high CAIX expressers compared with only 51% of the nonresponders.

Atkins M et al, Clin Cancer Res 2005

CAIX and response to IL-2CAIX and response to IL-2



Survival of >5 years was only seen in patients with high CAIX expressing tumors.



Survival for patients in good and poor predictive groups based on the refined model combining pathologic predictive group and CAIX staining.

Cytokine Versus Targeted Therapy: Cytokine Versus Targeted Therapy:

Evidences from Clinical TrialsEvidences from Clinical Trials

Sunitinib A6181034 Study DesignSunitinib A6181034 Study Design

Sunitib50 mg qdSunitib

50 mg qd

IFNa9 MU scx3/w

IFNa9 MU scx3/w

Major endpoints• Survival• PFS• RR

(1:1) Randomization

n~690

Eligibility criteria• Histologically/

cytologically confirmed, unresectable and/or metastatic disease

• Clear cell histology• Measurable disease• No prior systemic

therapy• ECOG PS 0 or 1• Good organ function• No brain metastasis

Motzer R et al NEJM 2007


Phase III Trial of Sunitinib vs. IFNaPhase III Trial of Sunitinib vs. IFNaBest Tumor ResponseBest Tumor Response

P<0.001

SunitinibMedian: 11 months(95% CI: 10-12)

IFN-Median: 5 months(95% CI: 4-6)

Hazard Ratio = 0.415(95% CI: 0.320-0.539)P < .000001

No. at Risk Sunitinib: 235 90 32 2No. at Risk IFN-: 152 42 18 0

Time (Months)

Pro

gre

ssio

n-F

ree S

urv

ival P

rob

ab

ilit

y

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Phase III Trial of Sunitinib vs. IFNa:Phase III Trial of Sunitinib vs. IFNa:Progression-Free SurvivalProgression-Free Survival


Randomized phase II trial of first-line Randomized phase II trial of first-line treatment with sorafenib versus interferon in treatment with sorafenib versus interferon in patients with advanced renal cell carcinomapatients with advanced renal cell carcinoma

Previously untreated patients (N: 189) with advanced RCC were randomized to continuous oral SOR 400 mg bid or IFN 9 million units tiw.

Primary endpoint: PFS Results:

- DCR: 79% (S) vs 64% (IFN) - Median PFS: 5.7 months (S) vs 5.6 months (IFN) - PFS: 90.0% vs 70.4%, 45.9% vs 46.5% and 11.5% vs 30.4% at 3, 6, and 12 months, respectively.

Conclusions: Even if no significant advantage in PFS, SOR showed activity in first-line treatment of RCC based on disease control rate.

Szczylik C. et al,ASCO 2007

Combination Strategies: Combination Strategies:

Evidences from Clinical TrialsEvidences from Clinical Trials

Global A.R.C.C Trial DesignGlobal A.R.C.C Trial Design

Stratification by:Stratification by:

Geographical Regions:Geographical Regions:EU + AU + CA (21%)EU + AU + CA (21%)

US (29%)US (29%)

Other (50%)Other (50%)

Nephrectomy:Nephrectomy:YesYes

NoNo Temsirolimus 15-mg IV Temsirolimus 15-mg IV once weekly plus IFN-once weekly plus IFN-αα

6 MU 6 MU 3 times weekly (n=210)3 times weekly (n=210)

RANDOMIZE

IFN-IFN-αα escalating to escalating to 18 MU SC18 MU SC

3 times weekly (n=207)3 times weekly (n=207)

TemsirolimusTemsirolimus 25-mg IV 25-mg IV once weekly (n=209)once weekly (n=209)

Hudes et al. N Engl J Med. 2007, 356;22:2271.

Main Inclusion Criteria: Main Inclusion Criteria: Poor Prognostic FactorsPoor Prognostic Factors

Karnofsky performance status 60 or 70Karnofsky performance status 60 or 70 More than 1 metastatic organ site of disease (sites More than 1 metastatic organ site of disease (sites

defined as different tissues with metastasis: lung, defined as different tissues with metastasis: lung, liver, bone, kidney, lymph node, etc.)liver, bone, kidney, lymph node, etc.)

Hemoglobin less than the lower limit of normal Hemoglobin less than the lower limit of normal (LLN)(LLN)

Less than 1 year from time of initial RCC diagnosis Less than 1 year from time of initial RCC diagnosis to randomizationto randomization

Corrected serum calcium > 10 mg/dLCorrected serum calcium > 10 mg/dL Lactate dehydrogenase > 1.5 times the upper limit Lactate dehydrogenase > 1.5 times the upper limit

of normal (ULN)of normal (ULN)

Patients had at least 3 of 6 “poor prognostic factors” for shortened survival listed below:


Adverse EventAdverse Event IFN n=203IFN n=203 TEMSR n=209TEMSR n=209 TEMSR + IFN TEMSR + IFN n=210n=210

All All Gr 3-4Gr 3-4 All All Gr 3-4Gr 3-4 AllAll Gr 3-4Gr 3-4

Asthenia Asthenia 6666 2727 5454 1212 6464 3030

NauseaNausea 4343 55 3737 44 4242 22

Rash Rash 55 00 3737 11 1616 22

DyspneaDyspnea 2828 88 3030 99 2626 1111

DiarrheaDiarrhea 2020 22 2828 11 2727 55

Peripheral edemaPeripheral edema 99 00 2727 00 1616 22

Vomiting Vomiting 2929 33 2121 33 3131 22

StomatitisStomatitis 33 00 2020 11 2121 55

HyperlipidemiaHyperlipidemia 1616 11 2828 77 3939 22

HyperglycemiaHyperglycemia 1111 11 2626 1010 1616 44

HypercholesteremiaHypercholesteremia 55 00 2424 11 2727 00

Creatinine increaseCreatinine increase 1212 11 1616 44 2222 22

ThrombocytopeniaThrombocytopenia 88 00 1313 11 3737 99

NeutropeniaNeutropenia 1212 88 77 33 2525 1414

ToxicitiesToxicities


Phase III Trial of Temsirolimus ± IFNaPhase III Trial of Temsirolimus ± IFNaOverall SurvivalOverall Survival

.6912.0069Log-rank Pvalue

0.950.73Hazard Ratio

15%49%Increase in median OS (vs. arm 1)

8.4 months10.9 months7.3 months

Median OS

152141149No. deaths

210209207No. patients

Temsirolimus+ IFN

TemsirolimusIFN

.6912.0069Log-rank Pvalue

0.950.73Hazard Ratio

15%49%Increase in median OS (vs. arm 1)

8.4 months10.9 months7.3 months

Median OS

152141149No. deaths

210209207No. patients

Temsirolimus+ IFN

TemsirolimusIFN

Treatment with Temsirolimus was associated with a 49% increase in median OS compared with IFN-α!!

CAVEAT:

High dose IFN-α have

been used!!!


Bevacizumab in RCC Bevacizumab in RCC Phase III Study Design (AVOREN)Phase III Study Design (AVOREN)

Escudier B, et al. Lancet 2007

RCC patients (n=649)

IFN α 2a + bevacizumab (n=327)

IFN α 2a + placebo(n=322)

PD

PD

• Bevacizumab/placebo 10 mg/kg IV q2w until progression• IFN-α2a 9 MIU sc three times/week

(maximum 52 weeks; dose reduction allowed)• Multinational ex-US study: 101 study sites in 18 countries• Primary endpoint: OS

IFN/PlaceboIFN/Placebo IFN/BEVIFN/BEV HRHR p-valuep-value

Response Rate: CRResponse Rate: CR

PRPR2%2%

11%11%1%1%

30%30%pp0.00010.0001

Duration of ResponseDuration of Response 11m11m 13m13m

Tumor ShrinkageTumor Shrinkage 39%39% 70%70%

PFSPFS 5.4m5.4m 10.2m10.2m 0.630.63 pp0.00010.0001

PFS: Good RiskPFS: Good Risk

Intermediate Intermediate RiskRisk

Poor RiskPoor Risk

7.6m7.6m

4.5m4.5m

2.1m2.1m

12.9m12.9m

10.2m10.2m

2.2m2.2m

pp=0.004=0.004

pp0.00010.0001

pp=0.457=0.457

OSOS 19.8m19.8m NRNR

Efficacy resultsEfficacy results

Escudier B, et al. Lancet 2007

Bevacizumab Plus IFN-Bevacizumab Plus IFN-αα VS IFN- VS IFN-αα in Patients With MRCC: CALGB in Patients With MRCC: CALGB

90206.90206. 732 patients enrolled. 732 patients enrolled.

Median PFS : 8.5 months (bev + IFN) VS 5.2 Median PFS : 8.5 months (bev + IFN) VS 5.2 months (IFN)months (IFN) P < .0001P < .0001

ORR: 25.5% (bev + IFN) VS 13.1% (IFN) ORR: 25.5% (bev + IFN) VS 13.1% (IFN) P < .0001.P < .0001.

Toxicity greater for bevacizumab plus IFN: Toxicity greater for bevacizumab plus IFN: more G 3 hypertension (9% v 0%), anorexia more G 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%). proteinuria (13% v 0%).

Rini BI et al. J Clin Oncol 2008

First-line bevacizumab combined with reduced First-line bevacizumab combined with reduced dosedose

IFN-a2a is active in patients with MRCCIFN-a2a is active in patients with MRCC 649 patients received IFN 9 MIU s.c. 3 times/w +

bevacizumab 10 mg/kg or placebo q2w until progression. The IFN dose was reduced to 6 or 3 MIU with the development of IFN-attributed toxicity.

Substantial decreases in the rate of adverse events following dose reduction without differences in PFS!!!

Melichar B et al, Ann Oncol 2008

First-line bevacizumab combined with reduced First-line bevacizumab combined with reduced dosedose

IFN-a2a is active in patients with MRCC:IFN-a2a is active in patients with MRCC:ConclusionsConclusions

Combined therapy induces antitumour immune Combined therapy induces antitumour immune responseresponse

In combination the complementary and In combination the complementary and sinergistic antiangiogenic and sinergistic antiangiogenic and immunotherapeutic effects are more immunotherapeutic effects are more pronouncedpronounced

The dose of IFN can be reduced to manage side effects while maintaining efficacy in patients with mRCC receiving bevacizumab + IFN.

Melichar B et al, Ann Oncol 2008

Randomized prospective phase II trial of two Randomized prospective phase II trial of two schedules of sorafenib daily and IFN -α2a in schedules of sorafenib daily and IFN -α2a in metastatic RCC (RAPSODY): GOIRC Study metastatic RCC (RAPSODY): GOIRC Study

0681.0681. 100 patients enrolled100 patients enrolled Arm A: Sorafenib 400mg BID plus sc IFN (9 MU 3 Arm A: Sorafenib 400mg BID plus sc IFN (9 MU 3

times a week)times a week) Arm B: Sorafenib 400mg BID plus sc IFN (3 MU 5 Arm B: Sorafenib 400mg BID plus sc IFN (3 MU 5

times a week)times a week) ORR (A vs B): 17,6% VS 34.7% (p=0.05)ORR (A vs B): 17,6% VS 34.7% (p=0.05)

Median PFS with a median FUP 8,5 months (A vs Median PFS with a median FUP 8,5 months (A vs B): 7,9+ months VS 8,5+ months (p=0.21)B): 7,9+ months VS 8,5+ months (p=0.21)

Sorafenib plus IFN (even low doses!!) can be Sorafenib plus IFN (even low doses!!) can be considered a promising regimen in MRCC. considered a promising regimen in MRCC.

Bracarda S, et al. ASCO 2008; abstract 357

Ongoing US Combination trials in RCCOngoing US Combination trials in RCC

EAU Guidelines 2007EAU Guidelines 2007

IFN-α is beneficial for mRCC patients with a good PS, a PFS following initial diagnosis of more than 1 year, and preferably lung metastasis as the only metastatic site Level of evidence: 1b

IL-2 has more side-effects than IFN- α. HD IL-2 gives durable complete responders in a limited number of patients. To date, no superiority has been seen for treatment with either IFN- α or IL-2 in mRCC patients. Level of evidence: 1b

Ljungberg B et al, European Association of Urology 2007

ConclusionsConclusions

Only few patients might benefit from exclusive cytokine therapy.

It is essential to define prognostic features to improve the accuracy of patient selection.

The toxicity associated with cytokine therapy can be considerable (Iv IL-2), so exposure to these drugs should be avoided in patients who are unlikely to gain benefit



The cytokine therapy could no be suitable for The cytokine therapy could no be suitable for patients with poor or intermediate prognostic patients with poor or intermediate prognostic featuresfeatures

Pathological features and immune status should Pathological features and immune status should be considered before starting cytokine therapybe considered before starting cytokine therapy

Other negative predictive factors include low CAIX expression and non clear-cell histology.

Further research to identify additional prognostic factors and efforts to combine these into workable clinical models are required for a more accurate selection of patients.


By contrast with cytokine therapy , targeted By contrast with cytokine therapy , targeted therapy have rarely resulted in complete and therapy have rarely resulted in complete and lasting remissionlasting remission

Targeted therapy require continuous Targeted therapy require continuous administration to induce periods of indolent administration to induce periods of indolent growthgrowth

Studies are underway to evaluate the potential of combining cytokines with targeted therapies.

The future role of cytokines for treating RCC will be ultimately determined by the results of large, randomized clinical trials comparing cytokines with targeted agents in good prognosis patients.

Further research is required to determine how cytokines can be added to targeted therapies, either in combination or as sequential therapy.


Oncologia Medica

Università Campus Bio-Medico, Roma

Giuseppe Tonini

Daniele Santini Francesco Pantano

Bruno Vincenzi Maria Elisabetta Fratto

Annalisa La Cesa Alice Calvieri

Claudia Grilli Olga Venditti

Sara Galluzzo Chiara Spoto

Simona Gasparro Salvatore Intagliata

Vladimir Virzì Calogero Gucciardino

Gaia Schiavon Laura Rocci

Valentina Leoni Federica Uzzalli

Marianna Silletta Marzia Mazzaroni

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Giuseppe Tonini [email protected] Oncologia Medica Universita’ Campus Bio-Medico, Roma...

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