Targeted Therapies in Renal Cell Carcinoma mammalian Target of Rapamycin (mtor) Inhibitors

(1)

 

Targeted Therapies in Renal

Cell Carcinoma

mammalian Target of Rapamycin (mTOR) Inhibitors

Kristen Hehr, Pharm.D.

PGY2 Oncology Pharmacy Resident

South Texas Veterans Health Care System

University of Texas Health Science Center at San Antonio

October 2, 2009 

Objectives:

1. Describe the pathophysiology of renal cell carcinoma

2. Discuss the various pathways that target newer therapies

3. Discuss the chemical structure, mechanism of action and toxicities associated with mTOR

inhibitors

4. Analyze the clinical evidence for the use of mTOR inhibitors in renal cell carcinoma

http://professional.cancerconsultants.com/images/renal_chart.jpg

(2)

I. Incidence

1

Figure 1 – Cancer Facts and Figures 2009

II. Renal Cell Carcinoma (RCC)

A. Clinical Manifestations

2

1. Classic Triad of RCC

a)

Flank pain

b)

Hematuria

c)

Palpable abdominal renal mass

2. Paraneoplastic syndrome

a)

Anemia – reported in 29 to 88% of RCC and can precede

diagnosis by several months

b)

Hypercalcemia – occurs in up to 15% of RCC with the cause

stemming from either lytic bone lesions, increased production of

parathyroid hormone-related protein or prostaglandin mediated

c)

Fever – occurs in about 20% of RCC and as with other

malignancies, intermittent and associated with night sweats, weight

loss, anorexia

d)

Cachexia

e)

Erythrocytosis – occurs 1 to 5 % of RCC

f)

Thrombocytosis – rare, but associated with poor prognosis

B. Pathology

2

(3)

b)

Tumor thrombus may form and may extend into the vena cava

and right atrium

4. Types of RCC

Table 1 - Types of RCC

2

Histologic Tumor Type Prevalence (%)

Clear Cell 70

Papillary 10

Chromophobe 5

Hereditary cancer syndromes 5

Multilocular cystic < 1

Collecting duct carcinoma < 1

Medullary carcinoma < 1

Mucinous tubular and spindle cell carcinoma < 1 Neuroblastoma-associated < 1 Xp11.2 translocation – TFE3 carcinoma < 1

Unclassified lesions 4

5. Genetics

Table 2 - Genetics

2

Hereditary Syndrome Chromosome Abnormality Histologic Type

von Hippel-Lindau 3p26 Clear cell

Hereditary Papillary 7q34 Type 1 papillary Hereditary leiomyoma 1q42-43 Type 2 papillary Birt-Hogg-Dube Syndrome 17p11.2 Chromophobe Medullary Carcinoma 11p Medullary carcinoma

C. Risk Factors

1. Risk Factors

2

a)

Cigarette smoking – 20%

b)

Obesity – 30%

c)

Hypertension

d)

Chronic dialysis/End-stage renal disease

e)

Genetic Factors (as previously mentioned)

2. Memorial Sloan-Kettering Cancer Center (MSKCC) Risk

Stratification

3

a)

Predictors of Short Survival – Risk Factors

(1)

Lactate levels > 1.5 times the upper limit of normal

(2)

Hemoglobin less than the lower limit of normal

(3)

Corrected serum calcium level > 10 mg/dl

(4)

Interval of less than a year from diagnosis to start of

systemic therapy

(5)

Karnofsky performance score of

≤

80 (see appendix)

(6)

≥

2 sites of organ metastasis

(4)

b)

Prognostic Stratification

Table 3 - MSKCC Risk Stratification

3

OS Percent Prognostic Factors Median PFS Median OS 1 yr 2 yr 3 yr 0 (low-risk) 8.3 months 30 months 83 55 45 1 – 2 (intermediate-risk) 5.1 months 14 months 58 31 17 3 – 5 (high-risk) 2.5 months 5 months 20 6 2

PFS = progression free survival; OS = overall survival

D. Goals of therapy

2

1. Delay progression of disease

2. Maximize quality of life

E. Options for therapy

1. Surgery

2

a)

Can undergo radical nephrectomy or renal-sparing approaches

b)

In metastatic disease, surgery can help prolong survival if done

prior to therapy

c)

Possible spontaneous remission

2. Cytokine Therapy

2

a)

Interferon alfa (INFA)/Interleukin-2 (IL-2)

b)

Induction of antitumor immunity involves direct killing of

tumor cells by activated T-cells and natural killer cells

c)

INFA – antiangiogenic effect

d)

Mechanism of action poorly understood

Table 4 - Cytokine Therapy Responses

4-6

Treatment ORR PFS OS CR

High-dose IL-2 20 – 23 % 3.1 months 19 months 5 – 7 % Low-dose IL-2

or IFNA

10 – 15 % 4.7 months 12 – 14 months na

ORR = objective response rate; PFS = progression free survival; OS = overall survival; CR = complete response; Adapted from

3. Targeted Therapy

a)

Bevacizumab

b)

Sunitinib/Sorafenib

c)

Temsirolimus/everolimus

(5)

III. Targeted Therapy

Figure 2 - Targeted Therapy Pathways

7

A. von Hippel Lindau (VHL) gene (refer to figure 2)

8-12

1. Normal VHL gene and Normoxic Conditions

a)

VHL gene encodes for VHL protein (pVHL)

b)

pVHL binds with E3 ligase and is a component of a ubiquitin

ligase complex

c)

The ligase complex brings substrates within the proximity of a

ubiquitin conjugating enzyme which then degrades the substrate

2. Abnormal VHL gene or Hypoxic Conditions

a)

Biallellic VHL inactivation

(1)

Defective VHL gene in germline places individuals at

risk for:

(a)

RCC

(b)

Vascular tumors of the retina, cerebellum and

spinal cord

(c)

Adrenal gland tumors

(2)

Remaining wild-type VHL allele can be inactivated by

either somatic mutation or hypermethylation

(6)

b)

pVHL is not produced



does not help to mobilize substrates

to enzyme



substrates do not undergo enzymatic degredation

B. Hypoxia Inducible Factor (HIF; refer to figure 2)

11-15

1. Most well documented substrate of pVHL ligase complex are

α

subunits

2. Normoxic Conditions

a)

HIF

α

becomes hydroxylated and generates a pVHL binding

site

b)

Binds with pVHL complex and is degraded

c)

In addition to oxygen, 2-oxoglutarate, vitamin C and iron are

other cofactors for the hydroxylation of HIF

α

3. Hypoxic Conditions or Loss of VHL gene

a)

HIF

α

is not degraded and begins to accumulate

b)

HIF

α

dimerizes with HIF

β

c)

This dimer binds to hypoxia response elements and activates

transcription of 100 – 200 genes that promote adaptation to acute

or chronic hypoxia (ex vascular endothelial growth factor [VEGF]

and platelet derived growth factor [PDGF])

4. HIF1

α

and HIF2

α

a)

HIF1

α

and HIF2

α

can activate transcription

b)

Clear cell renal carcinomas produce either HIF1

α

and HIF2

α

or

HIF2

α

alone

c)

Both in vitro and in vivo, HIF2

α

can override pVHL’s tumor

suppressor function, whereas HIF1

α

cannot

d)

HIF1

α

can undergo proteasomal degredation in the absence of

pVHL either because of alternative ubiquitin ligases or a direct

interaction with the proteasome

C. Vascular Endothelial Growth Factor (VEGF) Pathway

16,17

1. Overview

a)

Dimeric glycoprotein that is a member of the platelet-derived

growth factor (PDGF super family)

b)

Critical to angiogenesis (normal and tumor-associated)

through…

(1)

Increased microvascular permeability

(2)

Induction of endothelial cell division and migration

(3)

Promotion of endothelial cell survival through

protection from apoptosis

(4)

Reveral of endothelial cell senescence

c)

VEGF interacts with tyrosine kinase receptors present on the

cell surface that dimerize and autophosphorylates causing

activation of a cascade of downstream proteins

(7)

2. Bevacizumab

a)

Monoclonal antibody that binds and neutralizes VEGF

3. Small Molecule Tyrosine Kinase Inhibitors

a)

Sunitinib

(1)

Inhibits VEGF tyrosine kinase and other tyrosine

kinases associated with the PDGF receptor

b)

Sorafenib

(1)

Inhibits multiple tyrosine kinases (including VEGF-R)

as well as raf kinase

SURVIVAL

ras

PI3K

Akt

mTO

R

raf

Mek

ERK

Sorafenib Sunitinib VEGF-R VEGF _Bevacizumab Sorafenib

(8)

Table 5 - Targeted Therapy Responses

18-23 Treatment ORR PFS OS Sunitinib Treatment naïve Cytokine refractory 47% vs 12%(INFA) 44% 11 mo vs 5 mo(INFA) 8.4 months 26.4 mo vs 21.8 (INFA) Not reached Small Molecule inhibitors of VEGF Sorafenib Treatment naïve Cytokine refractory Not reported 57% vs 34% (placebo) 5.7 mo vs 5.6 mo (INFA) 5.5 mo vs 2.8 (placebo) Not reached 19.3 mo vs 15.9 mo (placebo) VEGF ligand-binding agent Bevacizumab Treatment naïve Cytokine refractory 31% (+INFA) vs 13% (INFA alone) 10% (10mg/kg) vs 0% (3 mg/kg and placebo) 10.2 mo (+INFA) vs 5.4 mo (INFA alone) 4.8 mo (10 mg/kg) vs 3 mo (3 mg/kg) vs 2.5 mo (placebo)

Not reached (+INFA) vs 19.8 mo (INFA alone)

Not evaluated

ORR = objective response rate; PFS = progression free survival; OS = overall survival; CR = complete response; Adapted from

D. mTOR Pathway (refer to figure 2)

13-15

1. Overview, Activation and Signaling

a)

Member of a group of structurally similar protein kinases that

share a domain that mediates protein-protein interaction

b)

For activation, growth factors trigger activation of PI3K, Akt

and eventually mTOR

(1)

TOR complex 1 (TORC1) – controls translation of

cyclin D, m-Myc and other proteins involved in cell

proliferation through the disassociation of 4E binding

protein-1 (4E-BP1) and eukaryotic initiation factor-4

subunit E (EIF-4E); also regulates expression and stability

of HIF1

α

(2)

TOR complex 2 (TORC2) – through protein kinase C

α

,

controls cell morphology and adhesion; also can

phosphorylate/activate Akt

(3)

TORC2 is relatively resistant to inhibition by

rapamycin in vitro



possible mechanism of resistance

2. Inhibiting mTOR

a)

Rapamycin first associates with FKBP12 (abundant

intracellular protein)

b)

Drug-FKBP12 complex binds to mTOR kinase at rapamycin

binding domain thus allosterically inhibiting the kinase

(9)

IV. mTOR Inhibitors

A. History

B. Structure

7

Figure 4 - Structure of current mTOR inhibitors

7

1. Differ from rapamycin at C43 to increase solubility and bioavailability

2. Share some similar properties

a)

Total clearance increases with dose

b)

Exposure increases less proportionally with dose (area under

the plasma concentration v time curve)

C. Mechanism of Action

7

1. Binds to FKBP12

2. Complex binds to rapamycin binding domain on mTOR kinase

causing allosteric inhibition

1960

1970

1980

1990

2000

1965

– rapamycin/sirolimus

Isolated from a microorganism

(

Streptomyces hygroscopicus

) in

soil from Easter Island

Immunosuppressant macrolide

antibiotic

₁₉₉₄

mTOR discovered by DM Sabatini

Late 1990s

mTOR inhibitor (rapamycin) finds

its way into cancer research

(10)

D. Specific Agents

24

1. Temsirolimus (CCI-779) indications

a)

Advanced RCC (poor risk) – 25 mg IV over 30 – 60 minutes

weekly

2. Everolimus (RAD001) indications

a)

Advanced RCC (after failure on sunitinib/sorafenib) – 10 mg

PO daily

3. Ridaforolimus (AP23573) seeking indication

a)

Sarcoma

b)

Endometrial cancer

c)

Prostate cancer

d)

Breast cancer

e)

Non-small cell lung cancer

V. Literature

Randomized Phase II Study of Multiple Dose Levels of CCI-779, a Novel Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Refractory Renal Cell Carcinoma

Atkins MB, Hidalgo M, Stadler WM, et al.25

Study Population Advanced renal-cell carcinoma (histologically confirmed) with either previous therapy for advanced disease or were not appropriate candidates for first-line IL-2 based therapy

Number of Patients 111 patients enrolled

• 36 received 25 mg • 38 received 75 mg • 37 received 250 mg

Objectives Primary Endpoints

• Determine dose

• Objective tumor response rate

Secondary Endpoints

• Time to tumor progression • Survival

Inclusion/Exclusion Criteria

Inclusion

• Bidimensionally measurable disease • Documented disease progression • ≥ 18 years of age

• Adequate bone marrow, renal and hepatic functions o Neutrophil ≥ 1500/mm3

o Platelets ≥ 100,000/mm3 o Hg ≥ 8.5 g/dl

o SCr ≤ 1.5 times upper limit of normal or CrCl ≥ 60 ml/min

o AST ≤ 3 times the upper limit of normal (≤ 5 times if liver metastases present)

o Total bilirubin ≤ 1.5 times upper limit of normal

o Fast total cholesterol ≤ 350 mg/dl and triglycerides ≤ 300 mg/dl

• ECOG PS of 0 or 1

• Life expectancy at least 12 weeks

Exclusion

• History of CNS metastases

(11)

• Active infection (including HIV) • Using immunosuppressive agents • Cardiovascular disease

• Hypersensitivity to macrolide antibiotics

• Women who are pregnant, nursing or have childbearing potential not using effective contraception

Study Design/Methods Treatment

• Randomly assigned to receive 25, 75 or 250 mg of temsirolimus weekly as

a 30 minute intravenous infusion

• Treatment continued until disease progression or unacceptable toxicity • Pretreated with 25 to 50 mg diphenhydramine approximately 30 minutes

prior to therapy

• Treatment was reduced for grade 3 (25% reduction) or 4 (50% reduction)

adverse events with two dose reductions allowed Evaluation

• Clinical evaluations at baseline and at 4-week intervals (tumor size

assessed at 8 week intervals) Results Efficacy

o CR + PR – 7% o MR – 26% o CR, PR, MR or SD ≥ 24 weeks – 51% • Time to progression o Median – 5.8 months o 25 mg – 6.3 months o 75 mg – 6.7 months o 250 mg – 5.2 months • Survival at 2 years o Overall – 29% o 25 mg – 24% o 75 mg – 26% o 250 mg – 36% Adverse Events

• Most common adverse events (all grades) were maculopapular rash

(76%), mucositis (70%), asthenia (50%) and nausea (43%)

• Grade 3/4 adverse events with an overall frequency ≥ 5% included hyperglycemia (17%), hypophosphatemia (13%), anemia (9%) and hypertriglyceridemia (6%)

• No significant differences seen in the percentage of patients in the

different dose groups who had either grade 1 to 4 or grade 3/4 adverse events

Conclusions • No standard second-line therapy for patients who disease does not respond

to, or progresses after, IL-2 and/or INFA based therapy

• Temsirolimus demonstrates encouraging activity considering the heavily

pretreated patient population studied (91% had received prior therapy; over half and received more than one previous treatment)

• Intermediate and poor prognosis populations had a 1.6 to 1.7 fold longer

median survival than those of INFA treated patients

• mTOR inhibitors may be relevant in patients with poor prognosis RCC (possible first-line alternative)

• Toxicities similar across all levels, however more dose reductions

occurred and discontinuations at the higher two dose levels suggesting that 25 mg should be optimum dose

Comments • Poorly designed phase II

• Created dosing recommendations for temsirolimus • Demonstrated effectiveness in previously treated RCC

(12)

Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma Hudes G, Carducci M, Tomczak P, et al.26

Study Population Advanced renal-cell carcinoma (histologically confirmed stage IV or recurrent disease) with a Karnofsky performance score of ≥ 60 and no previous systemic therapy

Number of Patients 626 patients enrolled

• 207 interferon alfa-2a (15 ineligible and 7 did not receive treatment) • 209 temsirolimus (17 ineligible and 1 did not receive treatment) • 210 combination (13 ineligible and 2 did not receive treatment)

Objectives Primary Endpoint

• Overall survival, calculated on an intention-to-treat basis

Secondary Endpoints

• Progression-free survival • Objective response rate

• Clinical benefit rate (defined as the proportion of patients with stable disease for at least 24 weeks or an objective response)

Inclusion/Exclusion Criteria

Inclusion

• Stage IV RCC or recurrent disease (histologically confirmed) • Karnofsky scale ≥ 60

• Tumor measureable according to the Response Evaluation Criteria in Solid Tumors (RECIST)

• Adequate bone marrow, renal and hepatic functions o Neutrophil ≥ 1500/mm3

o Platelets ≥ 100,000/mm3 o Hg ≥ 8 g/dl

o SCr ≤ 1.5 times upper limit of normal

o AST ≤ 3 times the upper limit of normal (≤ 5 times if liver metastases present)

o Total bilirubin ≤ 1.5 times upper limit of normal

o Fast total cholesterol ≤ 350 mg/dl and triglycerides ≤ 400 mg/dl

• Brain metastases were eligible if their condition was neurologically stable

and did not require corticosteroids after surgery

• At least 3 or the following predictors for short survival were required: o Serum lactate ≥ 1.5 times the upper limit of normal

o Hemoglobin below the lower limit of normal

o Correct serum calcium ≥ 10 mg/dl

o Time from initial diagnosis to randomization < 1 year

o Karnofsky performance score of 60 or 70

o Metastases in multiple organs

Study Design/Methods Treatment – randomly assigned to a group in equal proportions

• Group 1 – INFA alone

o Received interferon alfa-2a (Roche) starting at 3 million units three times per week for the first week; increased to 9 million units three times per week for the second week; increased to 18 million units three times per week for the third week (if tolerated)

o Patients who were unable to tolerate 9 million or 18 million units, received the highest tolerable dose (3 million units, 4.5 million units or 6 million units)

• Group 2 – Temsirolimus alone

(13)

temsirolimus infusion

• Group 3 – Combination

o Received temsirolimus 15 mg weekly in a 30 minute intravenous infusion and interferon alfa-2a starting at 3 million units three times weekly for one week and then 6 million units three times weekly thereafter

• Treatment continued until disease progression, symptomatic deterioration

or intolerable adverse events

• Treatment was held for grade 3 or 4 adverse events and restarted at a

reduced dose after recovery to grade 2 or less (for combination group – one or both agents were held, depending on adverse event)

• For poorly tolerated grade 2 adverse events, patients’ were dose reduced

without holding the agent(s) Evaluation

• Baseline CBC, fasting lipids, renal and hepatic function labs

• Adverse events, serum chemical analyses and CBC monitored weekly or

biweekly

• Imaging was performed at baseline and at 8-week intervals to evaluate

tumor size Results Efficacy

• Median overall survival

o Interferon – 7.3 months

o Temsirolimus – 10.9 months

o Combination – 8.4 months

• Median progression-free survival o Interferon – 1.9 months

o Temsirolimus – 3.8 months

o Combination – 3.7 months

• Objective response rates (not statistically different) o Interferon – 4.8%

o Temsirolimus – 8.6%

o Combination – 8.1%

• Stable disease for at least 6 months or objective response o Interferon – 15.5%

o Temsirolimus – 32.1% (p<0.001)

o Combination – 28.1 (p=0.002) Adverse Events

• Overall, grade 3/4 ADE was reported in 67% of temsirolimus group, as

compared with 78% of the interferon group (p= 0.02) and 87% in the combination group (p=0.02)

• Asthenia most common ADE (Grade 3/4 - temsirolimus: 11%; interferon:

26%; combination: 28%; p<0.001 for both)

• Anemia, neutropenia and thrombocytopenia were more common in the

combination group than the interferon group (p<0.001) or in the temsirolimus group (p<0.001 for neutropenia and thrombocytopenia; p=0.002 for anemia)

• Dyspnea, diarrhea, nausea or vomiting was similar in all three groups

• Dose reductions were less common in the temsirolimus group

Conclusions • Study involved patients with extensive metastatic disease and multiple

adverse prognostic factors that would be expected to have a shortened survival than those patients enrolled in studies of cytokine therapy or trials of sunitinib or sorafenib

• As compared with interferon alone, treatment with temsirolimus was

associated with a moderate prolongation of overall survival in advanced disease with poor prognosis

(14)

patients than interferon alone

• The combination did not improve overall survival and had the greatest

grade ¾ ADE that caused frequent delays and reductions in treatment likely explaining the failure of the combination to improve overall survival

• Moderate efficacy of temsirolimus in advanced disease suggests that the

drug might benefit patients with less extensive metastatic renal-cell carcinoma

• Results suggest the possibility of using temsirolimus as first-line treatment

for metastatic renal-cell carcinoma Comments • Compared temsirolimus to first-line agent

• Included limited patient population (poor risk) • Included clear cell and non-clear cell histologies

• Combination utilized decrease doses which possibly lead to a lack of

increased effectiveness

Efficacy of Everolimus in Advanced Renal Cell Carcinoma: a double-blind, randomized, placebo-controlled phase III trial

Motzer RJ, Escudier B, Oudard S, et al.27

Study Population Patients with metastatic renal cell carcinoma that showed a clear-cell

component, which had progressed on or within 6 months of stopping treatment with sunitinib or sorafenib or both drugs

Number of Patients 410 patients enrolled (6 patients did not receive treatment after randomization)

• 269 patients received everolimus • 135 patients received placebo Objectives Primary Endpoint

• Progression-free survival documented with RECIST by blinded,

independent review Secondary Endpoint

• Safety

• Overall survival • Disease-related symptoms • Quality of life Inclusion/Exclusion Criteria Inclusion • ≥ 18 years of age

• Presence of measurable disease per RECIST criteria • Karnofsky PS ≥ 70%

• Adequate bone marrow, hepatic and renal function

• Previous use of bevacizumab, IL-2 or INFA were permitted

Exclusion

• Previous use of mTOR inhibitor • Untreated CNS metastases

• Uncontrolled medical conditions (ex. HF, unstable angina, diabetes) Study Design/Methods Treatment

• Patients stratified based on MSKCC prognostic score and previous therapy • Randomly assigned in a two to one ratio to everolimus or placebo

• Patients received everolimus 10 mg once daily or placebo every 28 days along with best supportive care

o Patients to take two 5 mg tablets in fasting state or with light meal

(15)

• If patients progressed on placebo, they were unblinded and given the

option to crossover to open-label everolimus Assessment

• Safety assessed every 14 days for first three cycles and every 4 weeks

after that

o Monitoring and recording all adverse events

o Regular monitoring of hematology and chemistries, vital signs and physical examination

• Tumor measurements (CT or MRI) were done at baseline then every 8

weeks or when disease progression suspected

• Quality of life was assessed with European Organization for the Research

and Treatment of Cancer (EORTC) QLQ-30 and Functional Assessment of Cancer Therapy Kidney Symptom Index – Disease-related symptoms (FKSI-DRS) given before randomization, on day one of every cycle and discontinuation of study

Results Efficacy

• Progression Free Survival o Everolimus – 4 months

o Placebo – 1.9 months

o Probability of being progression free at 6 months  Everolimus – 26%

 Placebo – 2%

• Objective Tumor Response

o Everolimus – 1%

o Placebo – 0%

• Overall Survival

o Everolimus – not reached

o Placebo – 8.8 months

• No difference in QOL between the groups • Discontinuation

o Everolimus – 10%

o Placebo – 4%

• Death within 28 days of their last dose

o Everolimus – 5% all cause (1 case possibly attributed to drug)

o Placebo – 4% Adverse Events

• In the everolimus group, most common adverse events (all grades) were

stomatitis (40%), rash (25%), fatigue (20%), asthenia (18%) and diarrhea (17%)

• Also in the everolimus group, most common lab abnormalities (all grades)

were anemia (91%), hypercholesterolemia (76%), hypertriglyceridemia (71%), hyperglycemia (50%), elevated SCr (46%) and lymphopenia (42%)

• Grade ¾ adverse events in the everolimus group with an overall frequency

≥ 5% included hyperglycemia (12%), lymophopenia (15%) and anemia (9%)

• Significant difference was seen with Grade 3/4 events for stomatitis,

infections, hypercholesterolemia, hyperglycemia, lymphopenia and hypophosphatemia

Conclusions • Efficacy of everolimus is likely due to disease stabilization as minimal

objective tumor response seen

• Results suggest that clinical resistance to VEGF inhibitors does not imply

clinical resistance to mTOR inhibitors

Comments • Limited patient population to those who failed sunitinib/sorafenib • Demonstrated improved effectiveness over no intervention

(16)

VI. Conclusions

A. Temsirolimus

1. Useful in both clear cell and non-clear cell histologies

2. Demonstrated efficacy in both previously treated and untreated

patients

3. Only tested in poor risk patients

B. Everolimus

1. Limited to patients who failed sunitinib or sorafenib

2. Better than no intervention

C. mTOR inhibitors

1. mTOR is a novel target that occurs in a variety of malignancies, with

resistance to VEGF inhibitors not inferring resistance to mTOR inhibitors

2. Further research is being conducted on mTOR inhibitors in various

malignancies

3. We will likely see more indications for both, temsirolimus and

everolimus, as well as other mTOR inhibitors in the future

(17)

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28. Medina PJ and Fausel C. Cancer treatment and chemotherapy. Pharmacotherapy: a pathophysiologic approach. 7th_{ed. DiPiro JT. 2009.}

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Appendix

Karnofsky and ECOG performance scores

28

Description: Karnofsky Scale Karnofsky (%)

ECOG Description: ECOG

No complaints; no evidence of disease 100 0 Fully active; able to carry on all predisease activity

Able to carry on normal activity; minor signs or symptoms of disease

90 Cares for self; unable to carry on

normal activity or to do active work

80 1 Restricted in strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature

Requires occasional assistance by is able to care for most personal needs

70 Requires occasional assistance by is

able to care for most personal needs

60 2 Out of bed more than 50% of time; ambulatory and capable of self-care, but unable to carry out any work activities

Requires considerable assistance and frequent medical care

50 Disabled; requires special care and

assistance

40 3 In bed more than 50% of time; capable of only limited self-care

Severely disabled; hospitalization indicated, but death not imminent

30 Very sick; hospitalization required;

requires active supportive treatment

20 4 Bedridden; cannot carry out any self-care; completely disabled

Moribound; fatal processes progressing rapidly

10

Death 0 5 Death

ECOG = Eastern Cooperative Oncology Group

TNM staging RCC

24

Definition of American Joint Committee on Cancer TNM stage for RCC

Primary Tumor (T)

TX Primary tumor cannot be assessed T0 No evidence of primary tumor

T1 Tumor 7 cm or less in diameter and limited to the kidney T1a Tumor 4 cm or less in greatest dimension and limited to kidney T1b Tumor more than 4 cm but not more than 7 cm and limited to kidney T2 Tumor more than 7 cm in greatest dimension limited to the kidney

T3 Tumor extends into major veins or invades the adrenal gland or perinephric tissues, but not beyond Gerota’s fascia

T3a Tumor directly invades the adrenal gland or perinephric tissues but not beyond Gerota’s fascia T3b Tumor grossly extends into the renal vein or its segmental branches, or vena cava below the

diaphragm

T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava T4 Tumor invades beyond Gerota’s fascia

Regional Lymph Nodes (N)

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Distant Metastasis (M)

MX Distant metastasis cannot be assessed M0 No distant metastasis

M1 Distant metastasis

Stage grouping for RCC

Stage I T1 N0 M0 Stage II T2 N0 M0 T1 N1 M0 T2 N1 M0 T3a N0 M0 T3a N1 M0 T3b N0 M0 T3b N1 M0 T3c N0 M0 Stage III T3c N1 M0 T4 N0 M0 T4 N1 M0 Any T N2 M0 Stage IV Any T Any N M1