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Penile Cancer: New Insights into the “Way Forward” for this Rare Disease
Penile Cancer: New Insights into the “Way Forward” for this Rare Disease PENILE cancer is a rare tumor, accounting for only 1,640 new cases diagnosed in the United States in 2014.1 Overall, although it is more common in developing countries, the incidence of penile cancer in the United States and Europe accounts for less than 1% of all malignant neoplasms. However, despite its rarity, the morbidity and mortality associated with penile cancer can be significant. Even for localized or regional disease, treatment can have substantial medical and psychosocial implications. The 5-year survival rates decrease with increased lymph node involvement (approximately 75% for 1 or 2 and approximately 25% for more than 2 involved inguinal lymph nodes), and are dismal for patients with more advanced disease (eg extranodal extension, pelvic nodal involvement) at less than 10%.2 Unfortunately, overall survival in patients with lymph node involvement has not changed appreciably during the last 2 decades, indicating that surgery alone is insufficient and multimodal strategies are needed to improve patient outcomes.3,4 The rarity of penile cancer precludes single institution large scale prospective or randomized studies. In addition, the marked variability in disease presentation and in patient socioeconomic differences makes the initiation of dedicated clinical trials in the management of the disease difficult. Although we have obtained much information regarding risk factors and the disease course through retrospective case series and population studies, enhancing our knowledge base is hindered due to limited patient and tissue resources at any one institution.5 Therefore, there is a strong need for international research collaboration to effectively maximize patient numbers and tissue resources to further knowledge in the field. During the last few years significant effort has been put forth to establish a multinational collaboration for penile cancer as a part of the International Rare Cancers Initiative, a joint venture sponsored by the National Cancer Institute in the United States and the European Organization for Research and Treatment of Cancer in the United
0022-5347/15/1932-0394/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
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j
www.jurology.com
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RESEARCH, INC.
Kingdom. Specifically the International Penile Advanced Cancer Trial (InPACT) was developed.6 This initiative, anticipated to open in 2015, involves investigators from Europe, the United States, South America and Canada, and represents multiple specialties including urology, medical oncology, pathology, radiology, biostatistics and radiation oncology. The main focus of InPACT will be to assess, in a randomized fashion, optimal methods to incorporate multimodal strategies such as neoadjuvant chemotherapy and chemoradiation into the management of advanced penile cancer to improve survival. A second goal will be to assess the roles of pelvic lymph node dissection and radiotherapy after inguinal dissection for those patients at risk for recurrence based on pathological staging. Another unique aspect of InPACT is the use of a Bayesian statistical model, which will enable investigators to analyze a number of therapeutic modalities combined with multiple randomizations and still arrive at meaningful study conclusions with an estimated accrual of about 400 patients.6 The need for improved collaborative molecular and translational research in penile cancer is great, especially given the limited amount of specimens available. With advancements in biomedical research and the anticipated formation of centralized tumor banks,6 we hope to gain an improved understanding of the primary pathways responsible for the development of penile cancer and its progression. Dissection of these pathways becomes especially important with respect to the design of chemotherapeutic and/or targeted therapy regimens for the management of advanced disease. Nonetheless, improved knowledge of penile cancer at the molecular level and identification of prognostic biomarkers can help guide treatment and surveillance decisions for all stages of the disease. In this issue of The Journal 2 studies are instructive in this regard, and can help to inform larger studies such as InPACT, which also has proposed correlative research surrounding human papillomavirus expression in penile cancer.6e8 This
http://dx.doi.org/10.1016/j.juro.2014.11.075 Vol. 193, 394-395, February 2015 Printed in U.S.A.
NEW INSIGHTS INTO PENILE CANCER
field is growing exponentially in terms of its implications in other squamous malignancies (eg cervical, oropharyngeal, vulvar and anal cancer) as well as the potential to prevent infection with effective vaccination.9,10 Using samples from the Netherlands Cancer Institute (2001 to 2009), Djajadiningrat et al (page 526) examined 212 invasive penile tumor specimens and found that high risk human papillomavirus (hrHPV) infection was present in a quarter of specimens, a prevalence similar to previous decades.7 After adjustment for age and other prognostic factors including stage, grade and lymphovascular invasion, the authors found that the presence of hrHPV was associated with improved disease specific survival (p¼0.03). Using the over expression of P16ink4a as a potentially more sensitive marker for hrHPV status, Tang et al (page 519) examined 119 consecutive patients with penile cancer.8 The authors found over expression of P16ink4a in 59 patients (49.5%). Unlike Djajadiningrat et al, this group did not find a significant association with survival based on P16ink4a status. However, this finding may be due to the smaller number of patients in the latter study and, therefore, decreased power to detect such an association. Importantly, P16ink4a negative tumors were more likely to recur (p¼0.04), especially if lymph node involvement was present at the time of diagnosis (p¼0.002). Therefore, Tang et al
395
concluded that patients with P16ink4a negative penile tumors may need closer surveillance after definitive surgery.8 If confirmed in other studies, P16ink4a could also be used to stratify patients with positive lymph nodes for subsequent adjuvant therapy. The future is becoming more promising for patients diagnosed with penile cancer. Insights gained in other squamous malignancies have served as a model to study penile cancer, thus potentially shortening time to discovery. Improved international and multi-institutional clinical trial collaboration, along with funding for basic research, will undoubtedly improve patient outcomes and reduce the morbidity associated with this potentially devastating disease. Stephen H. Culp Department of Urology University of Virginia Charlottesville, Virginia and
Curtis A. Pettaway* Department of Urology The University of Texas M.D. Anderson Cancer Center Houston, Texas *Financial interest and/or other relationship with Wolters Kluwer.
REFERENCES 1. American Cancer Society: Cancer Facts and Figures 2014. Available at http://www.cancer. org/research/cancerfactsstatistics/cancerfacts figures2014/. 2. Dickstein RJ, Munsell MF, Pagliaro LC et al: Prognostic factors influencing survival from regionally advanced squamous cell carcinoma of the penis after preoperative chemotherapy. BJU Int 2014; Epub ahead of print. 3. Kayes O, Lau D, Nigam R et al: Longitudinal analysis of outcomes for men with node positive penile cancer. J Urol, suppl., 2013; 191: e386, abstract 939. 4. Verhoeven RH, Janssen-Heijnen ML, Saum KU et al: Population-based survival of penile cancer
patients in Europe and the United States of America: no improvement since 1990. Eur J Cancer 2013; 49: 1414. 5. Daling JR, Madeleine MM, Johnson LG et al: Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 2005; 116: 606. 6. Nicholson S, Kayes O and Minhas S: Clinical trial strategy for penis cancer. BJU Int 2014; 113: 852. 7. Djajadiningrat RS, Jordanova ES, Kroon BK et al: Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol 2015; 193: 526.
8. Tang DH, Clark PE, Giannico G et al: Lack of P16ink4a over expression in penile squamous cell carcinoma is associated with recurrence after lymph node dissection. J Urol 2015; 193: 519.
9. De Vuyst H, Clifford GM, Nascimento MC et al: Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a metaanalysis. Int J Cancer 2009; 124: 1626.
10. O’Rorke MA, Ellison MV, Murray LJ et al: Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol 2012; 48: 1191.
0022-5347/15/1932-0394/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
394
j
www.jurology.com
AND
RESEARCH, INC.
Kingdom. Specifically the International Penile Advanced Cancer Trial (InPACT) was developed.6 This initiative, anticipated to open in 2015, involves investigators from Europe, the United States, South America and Canada, and represents multiple specialties including urology, medical oncology, pathology, radiology, biostatistics and radiation oncology. The main focus of InPACT will be to assess, in a randomized fashion, optimal methods to incorporate multimodal strategies such as neoadjuvant chemotherapy and chemoradiation into the management of advanced penile cancer to improve survival. A second goal will be to assess the roles of pelvic lymph node dissection and radiotherapy after inguinal dissection for those patients at risk for recurrence based on pathological staging. Another unique aspect of InPACT is the use of a Bayesian statistical model, which will enable investigators to analyze a number of therapeutic modalities combined with multiple randomizations and still arrive at meaningful study conclusions with an estimated accrual of about 400 patients.6 The need for improved collaborative molecular and translational research in penile cancer is great, especially given the limited amount of specimens available. With advancements in biomedical research and the anticipated formation of centralized tumor banks,6 we hope to gain an improved understanding of the primary pathways responsible for the development of penile cancer and its progression. Dissection of these pathways becomes especially important with respect to the design of chemotherapeutic and/or targeted therapy regimens for the management of advanced disease. Nonetheless, improved knowledge of penile cancer at the molecular level and identification of prognostic biomarkers can help guide treatment and surveillance decisions for all stages of the disease. In this issue of The Journal 2 studies are instructive in this regard, and can help to inform larger studies such as InPACT, which also has proposed correlative research surrounding human papillomavirus expression in penile cancer.6e8 This
http://dx.doi.org/10.1016/j.juro.2014.11.075 Vol. 193, 394-395, February 2015 Printed in U.S.A.
NEW INSIGHTS INTO PENILE CANCER
field is growing exponentially in terms of its implications in other squamous malignancies (eg cervical, oropharyngeal, vulvar and anal cancer) as well as the potential to prevent infection with effective vaccination.9,10 Using samples from the Netherlands Cancer Institute (2001 to 2009), Djajadiningrat et al (page 526) examined 212 invasive penile tumor specimens and found that high risk human papillomavirus (hrHPV) infection was present in a quarter of specimens, a prevalence similar to previous decades.7 After adjustment for age and other prognostic factors including stage, grade and lymphovascular invasion, the authors found that the presence of hrHPV was associated with improved disease specific survival (p¼0.03). Using the over expression of P16ink4a as a potentially more sensitive marker for hrHPV status, Tang et al (page 519) examined 119 consecutive patients with penile cancer.8 The authors found over expression of P16ink4a in 59 patients (49.5%). Unlike Djajadiningrat et al, this group did not find a significant association with survival based on P16ink4a status. However, this finding may be due to the smaller number of patients in the latter study and, therefore, decreased power to detect such an association. Importantly, P16ink4a negative tumors were more likely to recur (p¼0.04), especially if lymph node involvement was present at the time of diagnosis (p¼0.002). Therefore, Tang et al
395
concluded that patients with P16ink4a negative penile tumors may need closer surveillance after definitive surgery.8 If confirmed in other studies, P16ink4a could also be used to stratify patients with positive lymph nodes for subsequent adjuvant therapy. The future is becoming more promising for patients diagnosed with penile cancer. Insights gained in other squamous malignancies have served as a model to study penile cancer, thus potentially shortening time to discovery. Improved international and multi-institutional clinical trial collaboration, along with funding for basic research, will undoubtedly improve patient outcomes and reduce the morbidity associated with this potentially devastating disease. Stephen H. Culp Department of Urology University of Virginia Charlottesville, Virginia and
Curtis A. Pettaway* Department of Urology The University of Texas M.D. Anderson Cancer Center Houston, Texas *Financial interest and/or other relationship with Wolters Kluwer.
REFERENCES 1. American Cancer Society: Cancer Facts and Figures 2014. Available at http://www.cancer. org/research/cancerfactsstatistics/cancerfacts figures2014/. 2. Dickstein RJ, Munsell MF, Pagliaro LC et al: Prognostic factors influencing survival from regionally advanced squamous cell carcinoma of the penis after preoperative chemotherapy. BJU Int 2014; Epub ahead of print. 3. Kayes O, Lau D, Nigam R et al: Longitudinal analysis of outcomes for men with node positive penile cancer. J Urol, suppl., 2013; 191: e386, abstract 939. 4. Verhoeven RH, Janssen-Heijnen ML, Saum KU et al: Population-based survival of penile cancer
patients in Europe and the United States of America: no improvement since 1990. Eur J Cancer 2013; 49: 1414. 5. Daling JR, Madeleine MM, Johnson LG et al: Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 2005; 116: 606. 6. Nicholson S, Kayes O and Minhas S: Clinical trial strategy for penis cancer. BJU Int 2014; 113: 852. 7. Djajadiningrat RS, Jordanova ES, Kroon BK et al: Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol 2015; 193: 526.
8. Tang DH, Clark PE, Giannico G et al: Lack of P16ink4a over expression in penile squamous cell carcinoma is associated with recurrence after lymph node dissection. J Urol 2015; 193: 519.
9. De Vuyst H, Clifford GM, Nascimento MC et al: Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a metaanalysis. Int J Cancer 2009; 124: 1626.
10. O’Rorke MA, Ellison MV, Murray LJ et al: Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol 2012; 48: 1191.