Understanding Renal Cell Carcinoma

Understanding Renal Cell Carcinoma Ronald M. Bukowski, MD Emeritus Staff, Consultant Cleveland Clinic Taussig Cancer Center Cleveland, Ohio

Overview

RCC Statistics
US estimates for 2007 1
51,190 individuals diagnosed with cancer of the kidney and renal pelvis
12,890 individuals died from cancer of the kidney and renal pelvis
3 rd most common genitourinary cancer after prostate cancer and bladder cancer 2
Median age at diagnosis: 65 years (2000-2004) 1
Median age at death: 71 years (2000-2004) 1
An estimated 240,266 US individuals with a history of kidney and renal pelvis cancer were alive in 2004 1
5-year survival has improved 3
50.9% in 1975-1977; 65.7% in 1996-2003
1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008. 2. Jemal A et al. CA Cancer J Clin . 2007;57:43. 3. Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

US Yearly Kidney and Renal Pelvis Cancer Incidence and Mortality
Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

US Kidney and Renal Pelvis Cancer in Comparison With Other Cancers
1. Jemal A et al. CA Cancer J Clin . 2007;57:43.
Accounts for 3.5% of all cancers in the US 1
7th most common cancer in men  9th most common cancer in women
NHL = non-Hodgkins lymphoma 100 678,060 All sites 100 766,860 All sites 3 19,440 Leukemia 2 18,830 Pancreas 3 19,600 Kidney & renal pelvis 3 24,180 Oral cavity & pharynx 3 22,430 Ovary 3 24,800 Leukemia 4 25,480 Thyroid 4 31,590 Kidney & renal pelvis 4 26,030 Melanoma 4 33,910 Melanoma 4 28,990 NHL 4 34,200 NHL 6 39,080 Uterine corpus 7 50,040 Urinary bladder 11 74,630 Colon & rectum 10 79,130 Colon & rectum 15 98,620 Lung & bronchus 15 114,760 Lung & Bronchus 26 178,480 Breast 29 218,890 Prostate % of all New Cases Cancers in Women % of all New Cases Cancers in Men

Historical Overview of Treatment

Surgery for Localized RCC
Nephrectomy
Radical: entire kidney removed
Partial: only the cancerous portion of the kidney removed along with a margin of healthy tissue
Potentially curative for patients with early-stage disease (ie, stage I, II, or III)
Ongoing surveillance in these individuals is critical, as 25-50% will develop disease recurrence 1
May be used for palliation or in combination with other treatment modalities in metastatic disease
1. Janzen N et al. Urol Clin North Am . 2003;30:843.

Advanced RCC
20-30% of patients present with metastatic disease 1
Another 25-50% of individuals treated for localized disease experience recurrence 2
Additional treatment options aside from surgery
Radiotherapy
Not an effective option
Chemotherapy
Not an effective option
Immunotherapy
Limited/some benefit
Targeted therapy
Clinical benefit; active area of research and further refinement
1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008. 2. Janzen N et al. Urol Clin North Am . 2003;30:843.

Radiotherapy
RCC characterized as radioresistant
No effect on survival when administered pre- or postsurgery
1. Finney R. Br J Urol . 1973;45:258. 2. Juusela H et al. Scand J Urol Nephrol. 1977; 11:277 . 3. Stein M et al. Radiother Oncol . 1992;24:41. 4. Janzen N et al. Urol Clin North Am . 2003;30:843.
Radiotherapy may have some benefit for 1
Painful bone metastases
Brain metastases
Painful recurrences in renal bed
* Radiotherapy administered postsurgery in Finney & Stein studies; administered presurgery in Juusela study 55% 40% 147 Stein et al. 1992 3 47% 63% 88 Juusela et al. 1977 2 36% 44% 100 Finney 1973 1 Surgery + Radiotherapy Surgery 5-Year Survival Number of Patients Study

Chemotherapy
RCC has intrinsic resistance to conventional chemotherapy
Literature review of 33 chemotherapy agents tested in 1347 patients in 51 phase II trials found no justification for using any drugs as single agents based on poor response rates 1
23 trials reported response rates of 0%
38 trials reported response rates ≤6%
Chemotherapy ineffective even when multidrug resistance modifiers (eg, cyclosporine A, tamoxifen) are used to try and sensitize tumors to therapy 1
Response rates ≤11% seen in all 15 trials assessing this approach
As such, chemotherapy is rarely used in RCC
1. Motzer RJ, Russo P. J Urol. 2000;163:408.

Immunotherapy
RCC considered to be an immunogenic disease
Spontaneous regression of metastatic lesions observed 1
Prolonged stabilization of disease without systemic treatment is seen 2,3
Tumor-infiltrating lymphocytes present at site of lesions 4-6
Durable responses can be elicited with cytokine therapy 7
As such, immunotherapy has long been the principal treatment modality for managing advanced RCC 8
1. de Reise W et al. Int Urol Nephrol . 1991;23:13. 2. Motzer RJ et al. N Engl J Med . 1996;335:865. 3. Whang, YE, Godley PA Curr Opin Oncol . 2003;15:213. 4. Schoof DD et al. Cell Immunol . 1993;150:114. 5. Kowalczyk D et al. Br J Urol . 1997;80:543. 6. van den Hove LE et al. Clin Ex Immunol. 1997;109:501. 7. Coppin C et al. Cochrane Database Syst Rev . 2005;(1):CD001425. 8. Bukowski RM. Oncology . 1999;13:801.

Immunotherapy
2 immunotherapies used, either alone or in combination
Recombinant human interleukin-2 (IL-2)
Recombinant human interferon  -2b (IFN-  )
IL-2
Stimulates growth of immune cells and activates them to destroy tumor cells
Common sides effects: flu-like symptoms, nausea, diarrhea, hypotension, decreased urine production
IFN- 
Increases antigen presentation on the surface of cancer cells, thereby increasing their susceptibility to attack by the immune system
Common side effects: flu-like symptoms, nausea, fatigue, depression

Immunotherapy
IL-2 and IFN-  have limited benefit in RCC
Meta-analysis of 58 randomized trials of immunotherapy conducted in 6880 patients with advanced RCC 1
ORR of immunotherapy vs active controls: 12.4% vs 2.4%
Mean OS with immunotherapy vs active controls: 13 vs 9.5 months
Efficacy of IFN-  vs controls: mean increase in OS of 3.8 months, 44% reduction in 1-year mortality, 26% reduction in 2-year mortality
Efficacy of high-dose IL-2 vs controls: RR as high as 23% observed, but this conferred no improvement in OS
Toxicity of these agents often outweighs the potential benefits
1. Coppin C et al. Cochrane Database Syst Rev . 2005;(1):CD001425. OS = overall survival RR = response rate

Unmet Treatment Needs
Prognosis for patients with metastatic RCC is dismal, with a 5-year survival rate of 9.5% 1
Surgery is generally not an option for cure
RCC resistant to radiotherapy and chemotherapy
Immunotherapy results in limited benefit with marked toxicity
Significant unmet treatment needs for patients with advanced RCC prompted research into biologic basis of renal oncogenesis to guide rational therapeutic approaches
1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2008.

Biologic Basis of Renal Oncogenesis

Angiogenesis
Angiogenesis is a key determinant in the pathophysiology of RCC 1
RCCs are the most vascularized of all solid tumors 2
1. Izawa JI, Dinney CP. CMAJ . 2001;164:662. 2. Cristofanilli M et al. Nat Rev Drug Discov . 2002;1:415. Map of Blood Flow to a Metastatic RCC Lesion

Growth Factors
Vascular endothelial growth factor (VEGF) is a key growth factor involved in angiogenesis 1,2
VEGF mRNA expression correlates with vascularization
VEGF is overexpressed in most clear-cell RCCs
Other growth factors that play a role in angiogenesis and oncogenesis include platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)
1. Cristofanilli M et al. Nat Rev Drug Discov . 2002;1:415. 2. De Mulder PH. Ann Oncol. 2007;18:ix98.

Role of VEGF in Angiogenesis 1. Cristofanilli M et al. Nat Rev Drug Discov . 2002;1:415.

Angiogenesis
Molecular mechanisms leading to angiogenesis 1-3
Disruption of von Hippel-Lindau (VHL) gene function
Disruption of mammalian target of rapamycin (mTOR) signal transduction pathway
1. Stadler WM. Cancer . 2005;104:2323. 2. Seeliger H et al. Cancer Metastasis Rev . 2007;26:611. 3. Faivre S et al. Nat Rev Drug Discov . 2006;5:671.

VHL and RCC
VHL is a tumor suppressor gene located on chromosome 3p25
Loss of heterozygosity of VHL gene locus detected in ~85-95% of clear-cell RCCs 1,2
VHL genetic abnormalities present in 60-90% of patients with sporadic RCC 1,2
VHL mutated in 52-71% of patients with sporadic RCC
VHL silenced by hypermethylation in an additional 5-20%
Inactivation of VHL thought to be a very early event in clear-cell RCC tumorigenesis
1. Shuin T et al. Cancer Res . 1994;54:2852. 2. Brauch H et al. Cancer Res . 2000;60:1942. 3. Yao M et al. J Natl Cancer Inst . 2002;94:1569. 4. Banks RE. Cancer Res . 2006;66:2000.

Normal VHL Function Stadler WM. Cancer . 2005;104:2323. O 2 VEC NEDD8 Degradation by proteasome
Hypoxia Response:
Angiogenesis
Glycolysis
Erythropoiesis
pH
Cell adhesion
ECM assembly
Cul2 VHL Rbx1 Elongin B Elongin C OH HIF-1  OH x Ub

Mutant VHL Stadler WM. Cancer . 2005;104:2323. O 2 VEC NEDD8 Degradation by proteasome X X X Mutant VHL mimics conditions of hypoxia HIF-1  mRNA transcription Cul2 Mutant VHL Rbx1 Elongin B Elongin C HIF-1  HIF-1  VEGF PDGF TGF-  EGFR Ub

Pathways Activated by HIF-1  1,2 1. Stadler WM. Cancer . 2005;104:2323. 2. Vignot S et al. Ann Oncol . 2005;16:525. Endothelial/ Tumor cells Angiogenesis/Cell proliferation Angiogenesis Cell survival Upregulation in response to HIF-1 transcription PDGF VEGF EGF Ras RAF MEK Erk PLC RAC P38MAPK Cell migration PKC Cell proliferation Cell survival PI3K AKT/PKB SRC JAK STAT Cell survival

mTOR Pathway Seeliger H et al. Cancer Metastasis Rev . 2007;26:611. PI3K Growth factors = insulin, IGF, VEGF, IL-2 Protein synthesis Upregulation in response to HIF-1 transcription Growth Factor AKT mTOR S6K1 PTEN HIF-1  eIF-4E

Rational Approaches to Treating RCC Based on Disease Biology

Targeting the Molecular Pathways of RCC Oncogenesis Stadler WM. Cancer . 2005;104:2323. Angiogenesis/Cell proliferation/Cell survival bevacizumab gefitinib, cetuximab, erlotinib, panitumumab Gene expression rapamycin, temsirolimus, everolimus, AP23573 CI-1040 sorafenib, ISIS-5132 Endothelial/ Tumor cells Upregulation in response to HIF-1 transcription sorafenib, sunitinib, PTK/ZK PDGF VEGF EGF Ras RAF PI3K AKT MEK ERK mTOR

Clinically Available Targeted Agents for Advanced RCC
4 targeted agents available for advanced RCC
1. Escudier B et al. Lancet . 2007;370:2103. 2. Rini BI et al. 2008 ASCO Genitourinary Cancers Symposium. Abstract 350. 3. Motzer RJ et al. N Engl J Med . 2007;356:115. 4. Escudier B et al. N Engl J Med. 2007;356:125. 5. Hudes G et al. N EngJ Med . 2007;356:2271. 8.5 vs 5.2; P < .0001 26% vs 13% 732 Bevacizumab + IFN-  vs IFN-  2 3.7 vs 1.9 (IFN-  ); P = .001 9% vs 7% vs 11% 626 Temsirolimus vs IFN-  vs both agents 5 mTOR Temsirolimus 5.5 vs 2.8; P = .000001 10% vs 2% 903 Sorafenib vs Placebo 4 VEGF receptor Sorafenib 11.1 vs 5; P = .00001 37% vs 9% 750 Sunitinib vs IFN-  3 VEGF receptor Sunitinib 10.2 vs 5.4; P = .0001 31% vs 13% 649 Bevacizumab + IFN-  vs Placebo + IFN-  1 VEGF Bevacizumab TTP (mos) ORR No. Treated Comparison Efficacy in Randomized Phase III Trials Target Agent

Summary
RCC accounts for 3.5% of all cancers in US
7th most common cancer in men
9th most common cancer in women
Incidence of RCC has steadily increased over past 30 years, likely due to increased rate of incidental detection
Treatment of RCC
Surgery potentially curative for early-stage RCC
RCC resistant to chemotherapy and radiotherapy
Immunotherapy produces limited benefit in advanced RCC
Targeted therapy proving to be a promising approach to treatment of advanced RCC

Summary
Insight into biologic basis of RCC has led to rational development of targeted therapies
RCC angiogenesis driven by loss of VHL function and disruption of mTOR pathway
Key growth factors involved in angiogenesis include VEGF, PDGF, and EGF
4 targeted agents available for advanced RCC
Bevacizumab, sunitinib, and sorafenib all target VEGF pathway
Temsirolimus targets mTOR pathway
Landscape of RCC treatment continues to evolve with more new targeted agents on the horizon

Understanding Renal Cell Carcinoma

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