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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


New Science and Therapeutic Advances in the Treatment of Renal Cell Carcinoma: A Case Study Review


GOAL
To provide genitourinary oncologists with up-to-date information on the treatment and management of patients with renal cell carcinoma.

TARGET AUDIENCE
This activity is designed for genitourinary oncologists. No prerequisites required.

LEARNING OBJECTIVES
At the conclusion of this activity, the participant should be able to:

  • Summarize the current treatment options available for patients with renal cell carcinoma (RCC) at different stages of disease.
  • Demonstrate how experimental biologic agents may be used to modulate appropriate signal transduction pathways associated with disease progression.
  • Describe how the new biologic agents will be integrated with existing treatment options in evolving clinical trials.
  • Apply knowledge based on the latest experimental and clinical data to case studies in order to improve the management and quality of life of patients with RCC.

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 1.5 hours.

After reading this monograph, participants may receive credit by completing the CME test, evaluation, and receiving a score of 70% or higher.

Release date: February 15, 2008. Expiration date: February 15, 2010.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Pfizer Inc.

Full Disclosure Policy Affecting CME Activities
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation.  The presenting faculty reported the following:

PROGRAM DIRECTOR

Roberto Pili, MD
Assistant Professor of Oncology and Urology
The Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins Hospital
Baltimore, Maryland
Dr Pili reports receiving grants/research support from Pfizer Inc; and serving as a consultant for Active Biotech and Locus.

PARTICIPATING FACULTY

Thomas E. Hutson, DO, PharmD
Director, Genitourinary Oncology  Program
Texas Oncology, PA
Baylor Sammons Cancer Center
Co-Chair, Genitourinary Research, US Oncology
Dallas, Texas
Dr Hutson reports receiving grants/research support from Bayer/Onyx, GlaxoSmithKline, Pfizer Inc, and Wyeth; and serving as a consultant for, receiving honoraria from, and serving on the speakersÕ bureau for Bayer/Onyx, Pfizer Inc, and Wyeth.

Eric Jonasch, MD
Assistant Professor
Genitourinary Medical Oncology
The University of Texas
MD Anderson Cancer Center
Houston, Texas
Dr Jonasch reports receiving grants/research support from Genentech, Inc; and serving as a consultant for, receiving honoraria from, and serving on the speakers' bureau for Bayer/Onyx, Pfizer Inc, and Wyeth.


Notice: The audience is advised that an article in this CME activity contains reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Jonasch—bevacizumab, sorafenib, and sunitinib.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

INTRODUCTION
Roberto Pili, MD*

Advances in the molecular and genetic understanding of renal cell carcinoma (RCC) have contributed to the development of novel targeted agents for disease treatment. Additionally, further insight into the molecular profiles of renal neoplasms may overcome existing limitations in traditional histologic diagnosis of RCC.1 Molecular profiles of defined histologic types of RCC, such as clear cell (or conventional), papillary, chromophobe, and oncocytoma, are more fully recognized, which may potentially allow for earlier diagnosis, typing, and medical intervention.

Tumor angiogenesis, or the proliferation of the blood vessel network essential for cancer cell growth and survival, can be triggered by genetic/epigenetic gene silencing (ie, von Hippel-Lindau in RCC), which initiate the overexpression of proangiogenic proteins, such as hypoxia-inducible factor (HIF)-1a, and downstream vascular endothelial growth factor (VEGF).2 Antiangiogenic mechanisms of targeted agents include the prevention of VEGF production through inhibition of HIF-1a (eg, mammalian target of rapamycin [mTOR] inhibitor or histone deacetylase inhibitor), VEGF neutralization (eg, monoclonal antibody [mAb] or soluble decoy receptor), or VEGF receptor blockade (eg, receptor tyrosine kinase inhibitor [RTKI] or mAb).

Chronic dosing of antiangiogenic therapies is relatively well tolerated, allowing for maximal tumor inhibition. However, optimal doses and schedules to overcome drug resistance, as well as final survival data, are still undetermined with many of these agents. Additionally, clinical research involving adjuvant therapies and combination strategies that enhance antiangiogenesis in RCC is ongoing. For example, the Adjuvant Sorafenib or Sunitinib in Unfavorable Renal Cell Carcinoma trial, a neoadjuvant trial, is examining the antitumor activities of the RTKIs sunitinib or sorafenib versus placebo in high-risk patients undergoing nephrectomy for localized RCC.3 Combination strategies involve concomitant use of targeted agents (eg, VEGF inhibitors and mTOR inhibitors), or immunotherapies (eg, interleukin-2 and VEGF inhibitors).

Because clinical information and therapeutic guidelines for RCC are constantly evolving, physicians can benefit through advanced knowledge garnered in ongoing research. Current clinical trials of antiangiogenic therapies are investigating not only optimal tumor response, but also mechanisms to avoid tumor drug resistance. In addition to tumor cell mutations (eg, tyrosine kinase mutations), resistance to antiangiogenic therapies may result through cellular adaptations. Induced hypoxia with a resulting increase in angiogenic factors, endothethial cell genetic instability, and VEGF pathway blockade may cause therapy resistance. 

This issue of Johns Hopkins Advanced Studies in Medicine includes the proceedings of a satellite symposium held on October 13, 2007, in Chicago, Illinois, at The Sixth International Kidney Cancer Symposium. After my brief introduction, Eric Jonasch, MD, Assistant Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, reviewed existing and promising pharmacotherapies for the treatment of RCC, with emphasis on relevant clinical trial results. He also addressed clinical trial approaches that could evolve future RCC therapy and extend progression-free survival. The final discussion by Thomas E. Hutson, DO, PharmD, Director of the Genitourinary Oncology Program at Baylor Sammons Cancer Center, summarized RCC treatment strategies through formal case presentation examples, one of which is reviewed in this monograph. Through panel interaction, the pros and cons of various treatment approaches are debated.

REFERENCES
1. Yang XJ, Sugimura J, Teh BT, et al. Classification of renal neoplasms based on molecular signatures. J Urol. 2006;175:2302-2306.
2. Folkman J. Angiogenesis inhibitors: a new class of drugs. Cancer Biol Ther. 2003;2:S127-S133.
3. Eisen T. Adjuvant therapy in renal cell carcinoma: where are we? Eur Urol. 2007;6:492-498.

*Assistant Professor of Oncology and Urology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland.
Address correspondence to: Roberto Pili, MD, Assistant Professor of Oncology and Urology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Bunting-Blaustein Cancer Research Building, IM52, 1650 Orleans Street, Baltimore MD, 21231. E-mail: piliro@jhmi.edu.

The content in this monograph was developed with the assistance of a medical writer. Each author had his/her final approval of his article and all its contents.





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