Bukowski, Ronald M.

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Ronald M. Bukowski

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www.frontiersin.org October 2011 | Volume 1 | Article 32 | 1
Specialty Grand challenGe article
published: 10 October 2011
doi: 10.3389/fonc.2011.00032
Genitourinary oncology: current status and future challenges
Ronald M. Bukowski*
Cleveland Clinic Foundation, Cleveland Clinic Taussig Cancer Center, Pepper Pike, OH, USA
*Correspondence: bukow464@sbcglobal.net
IntroductIon
Genitourinary oncology (GU Oncology) 
focuses on research and treatment of uri-
nary system cancers in both genders, as well 
as malignancies affecting the male sexual 
organs. Sites included are the kidneys, blad-
der, prostate, and testes. These malignancies 
represent approximately one fourth of all 
solid tumors, however, the field remains 
underrepresented in the basic science, epi-
demiologic, clinical research, and transla-
tional research literature. The Genitourinary 
Oncology Section of Frontiers in Oncology 
is a welcomed addition to the medical lit-
erature, and will provide an important 
mechanism for publication of reviews and 
research in this field. The purpose of this 
manuscript is to briefly review the field, and 
outline some of the challenges confronting 
GU Oncology clinical and basic researchers.
Since the 1970s, the advantages of a mul-
timodality approach in GU tumors has been 
recognized, and many of the advances rep-
resent the combined efforts of urologists, 
medical, and radiation oncologists, as well 
as basic research scientists. Among the 
early reports in this era was the develop-
ment of curative therapy for advanced non- 
seminomatous testicular cancer utilizing 
platinum based chemotherapy and surgical 
resection of residual disease (Hayes-Lattin 
and Nichols, 2009). Utilizing the treatment 
paradigm of combined modality therapy, 
therapeutic advances in renal cell, blad-
der, and prostate cancers (PC) have subse-
quently occurred.
Prostate cancer
Prostate cancer is the most common non-
cutaneous cancer in men and accounted for 
an estimated 217,000 new cases annually 
the USA in 2010 (Jemel et al., 2010). PC 
develops initially as an androgen depend-
ent disease that relies on the androgen 
receptor (AR) for growth and progression 
(Wilson, 2010), but then develops into a 
castration-resistant PC (CRPC) during 
androgen deprivation therapy (Antonarakis 
and Eisenberger, 2011). Understanding the 
molecular and genetic events occurring 
during progression and responsible for the 
acquisition of the castrate-resistant pheno-
type is needed. Clinically, significant pro-
gress in diagnosis and management of PC 
has been made, however, numerous issues 
remain controversial including screening, 
chemoprevention, active surveillance, and 
therapeutic approaches to localized disease. 
New treatment options for CRPC include 
the tumor vaccine Sipuleucel-T (Kantoff 
et al., 2010), various chemotherapy options, 
and novel agents such as the CYP17 inhibi-
tor abiraterone acetate (administered with 
prednisone; de Bono et al., 2011). Patient 
outcomes have improved, but the durations 
of progression-free and overall survival 
still remains relatively short and further 
improvement is needed. Areas such as the 
biology and treatment of bone disease and 
metastases should be active areas of investi-
gation. Finally, validated clinical, radiologic, 
biologic, and genomic response biomarkers 
are needed, which may then act as surro-
gates of clinical benefit.
renal cell carcInoma
Renal cell carcinoma (RCC) accounts for 
approximately 3% of all malignancies, and 
was formerly only treatable by surgery. Over 
the past 10 years there has been significant 
progress in the understanding and manage-
ment of this tumor, with new surgical and 
systemic therapy strategies revolutionizing 
its management. A recent major advance 
in RCC is the realization that this disease 
is not a single entity but rather a collection 
of different tumor types, each derived from 
the various parts of the nephron and pos-
sessing distinct genetic characteristics, his-
tologic features, and to some extent clinical 
phenotype. Clear cell carcinoma, the most 
common histologic subtype, has been exten-
sively studied, and investigations into the 
molecular, biologic, and clinical aspects of 
the non-clear cell subtypes are now needed.
A major advance in understanding RCC 
was the recognition that the Von Hippel–
Lindau (VHL) factor, a negative regulator of 
hypoxia-inducible factor (HIF), is encoded 
by a tumor suppressor gene which lost in 
>75% of clear cell RCCs (Kaelin, 2007). 
Inactivation of VHL results in increased 
HIF availability in tumor cells and subse-
quent transcriptional upregulation of vas-
cular endothelial growth factor (VEGF), 
platelet-derived growth factor (PDGF), 
and a variety of other targets (Kaelin, 
2007). Activation of the mammalian target 
of rapamycin (mTOR) pathway also leads to 
increases in HIF production (Thomas et al., 
2006). The VEGF and the mTOR pathways 
have been targeted for drug development 
and therapeutic approaches have focused 
on these targets. Current approaches for 
management of metastatic RCC (mRCC) 
utilize knowledge of histology, molecular 
abnormalities, clinical prognostic factors, 
and the efficacy/toxicity of available treat-
ments. Prior to 2006, immunotherapy was 
the standard of care, but its effects remain 
controversial. Agents blocking angiogenic 
pathways, including sunitinib, pazopanib, 
sorafenib, bevacizumab, everolimus, and 
temsirolimus, have demonstrated efficacy 
in mRCC (Brian, 2010). Investigations of 
additional genetic abnormalities (PBRM1, 
SETD2, UTX), mechanisms of resistance, 
and development of novel agents (axitinib, 
tivozanib) area priority. Additionally, 
the roles of immune therapy and immu-
noregulation in mRCC are again under 
study. Immune checkpoint inhibitors such 
as monoclonal antibodies recognizing 
CTLA-4 and PD-1 are in clinical trials, and 
the effects on tumor associated immuno-
suppression and immunoregulation of 
therapeutic agents are being evaluated. 
Vaccine development strategies and clini-
cal trials are again considerations.
Surgical developments during the last 
10–15 years include defining the role of 
minimally invasive surgery, active surveil-
lance for small (<4.0 cm) masses, and non-
surgical ablative techniques (cryoablation, 
radiofrequency ablation). Tumor staging 
and clinical features identify a population of 
RCC patients at high risk of recurrence after 
Frontiers in Oncology | Genitourinary Oncology  October 2011 | Volume 1 | Article 32 | 2
Bukowski Genitourinary oncology challenges
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Hayes-Lattin, B., and Nichols, C. R. (2009). Testicular 
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Kantoff, P. W., Higano, C. S., Shore, N. D., Berger, R. W., 
Small, E. J., Penson, D. F., Redfern, C. H., Ferrari, A. 
C., Dreicer, R., Sims, R. B., Xu, Y., Frohlich, M. W., 
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Received: 16 September 2011; accepted: 20 September 2011; 
published online: 10 October 2011.
Citation: Bukowski RM (2011) Genitourinary oncology: 
current status and future challenges. Front. Oncol. 1:32. 
doi: 10.3389/fonc.2011.00032
This article was submitted to Genitourinary Oncology, a 
specialty of Frontiers in Oncology.
Copyright © 2011 Bukowski. This is an open-access article 
subject to a non-exclusive license between the authors and 
Frontiers Media SA, which permits use, distribution and 
reproduction in other forums, provided the original authors 
and source are credited and other Frontiers conditions are 
complied with.
for muscle–invasive bladder cancer, but this 
approach has yet to receive wide acceptance 
(Bajorin and Herr, 2011). Further under-
standing the biology, molecular aspects, and 
metastatic potential of bladder cancer may 
permit tailoring therapy for the highest risk 
patients.
In patients with advanced and metastatic 
disease, combination chemotherapy with 
cisplatin-based combination chemotherapy 
is associated with improved outcomes, but 
most patients relapse and die of progressive 
disease (Ismalli et al., 2011). Current regi-
mens produce suboptimal outcomes in the 
frontline setting with no proven effective 
second-line regimen. Patients with meta-
static TCC in both the frontline and salvage 
chemotherapy settings should be consid-
ered candidates for clinical trials utilizing 
novel agents.
summary
Significant advances in therapeutic 
approaches to the various GU malignan-
cies have occurred over the past 10–15 years. 
Tools such as genomic analysis, various 
molecular biologic techniques, and bio-
chemistry, are providing additional insights. 
Personalized approaches to GU tumors are 
not yet a reality, but certainly are a likely 
outcome of current research.
references
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cancer. N. Engl. J. Med. 364, 2055–2058.
Bajorin, D. F., and Herr, H. W. (2011). Kuhn’s paradigms: 
are those closest to treating bladder cancer the last 
to appreciate the paradigm shift? J. Clin. Oncol. 29, 
2135–2137.
Brian, R. I. (2010). New strategies in kidney cancer: thera-
peutic advances through understanding the molecular 
basis of response and resistance. Clin. Caner Res. 16, 
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surgery. The TKI’s sunitinib, sorafenib, and 
pazopanib are being studies as postopera-
tive adjuvant therapy. Additionally, identi-
fication of biomarkers in high risk patients, 
and utilization gene expression patterns to 
define risk groups are under study.
Bladder cancer
Bladder cancer remains a common malig-
nancy in Western society, with global inci-
dence of over 356,000 new cases per year 
(Ploeg et al., 2009). Most tumors are tran-
sitional cell carcinomas (TCC). Diagnostic 
cystoscopy remains the gold standard for 
detecting lower urinary tract malignancies. 
Urine cytology remains the most specific 
adjunct to cystoscopy for detection and sur-
veillance of bladder tumors (Sexton et al., 
2010). Many biomarkers have been utilized 
for the diagnosis, surveillance, and manage-
ment of bladder cancer (Parker and Speiss, 
2011), however, the ideal marker has not yet 
been identified.
At diagnosis, >70% of bladder tumors 
will be non-muscle–invasive (stage Ta/T1) 
tumors, with the rest being muscle– invasive 
(stages T2-4). In non-muscle–invasive 
tumors, recurrence and progression to 
muscle–invasive disease are the critical steps 
that dictate therapy and are associated with 
worse survival rates. Additional biological 
and molecular insights into the pathogen-
esis of muscle–invasive bladder cancer are 
needed to permit adequate and appropri-
ate therapy and decrease the progression 
rates. The genetic and epigenetic changes 
responsible for tumor development, and the 
molecular pathways associated with these 
alterations should be a focus of investiga-
tion. An example is the recent report of 
whole-exome sequencing (Gui et al., 2011) 
of genomic DNA from TCC.
Radical cystectomy accompanied by pel-
vic lymph node dissection (PLND) remains 
the standard surgical treatment for mus-
cle–invasive bladder cancer. The roles of 
postoperative adjuvant chemotherapy and 
preoperative neoadjuvant chemotherapy 
have been evaluated. The available evidence 
therefore supports the integration of neo-
adjuvant chemotherapy with cystectomy 


Genitourinary Oncology: Current Status and Future Challenges

Ronald M Bukowski

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Genitourinary Oncology: Current Status and Future Challenges

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