A systematic review published in 2018 assessed the prevalence of HPV DNA and p16INK4a in penile cancer and penile intraepithelial neoplasia1. The pooled HPV DNA prevalence in penile cancer (52 studies; n=4199) was 50.8% (95%CI 44.8-56.7; I2=92.6%). A particularly high pooled HPV DNA prevalence was seen in basaloid squamous cell carcinomas (84.0%, 95%CI 71.0-93.6; I2=48.0%) and in Warty-basaloid carcinoma (75.7%, 95%CI 70.1-81.0; I2=0%).The pooled HPV DNA prevalence in penile intraepithelial neoplasia (19 studies; n=445) was 79.8% (95%CI 69.3-88.6; I2=83·2%). The pooled p16INK4a percent positivity in penile cancer (24 studies; n=2295) was 41.6% (95%CI 36.2-47.0; I2=80.6%), with a high pooled p16INK4a percent positivity in HPV-related squamous cell carcinoma of 85.8% (95%CI 72.1-95.4; I2=56.4%). According to Dr. Ayres, it may be time to further explore the benefits of HPV vaccination in men and boys, akin to what is already standard of care among females.
A study evaluating adherence to the EAU guidelines on penile cancer with regard to primary surgical treatment and management of lymph nodes treated at 12 European and American centers between 2010 and 2016 was published in the World Journal of Urology2. The EAU guidelines on the surgical treatment of the primary tumor and lymphadenectomy were respected in 74.8% and 73.7% of cases, respectively. Adherence to the guidelines on primary penile surgery was significantly associated with a good OS (HR 0.40, 95%CI 0.20-0.83). Similarly, the adherence to the guidelines on lymphadenectomy was statistically significantly associated with OS (HR 0.48, 95%CI 0.24-0.96).
There have also been tremendous advancements over the last decade regarding penile-sparing surgery. Among 332 patients treated with penile-sparing surgery at St. George’s Hospital London, 64% of the patients had a <5 mm clear deep surgical margin, while 16% were clear by <1 mm3. 4% of patients had a local recurrence, with a median time to recurrence of 6 months. There was a statistically significant relationship between cavernosal involvement (p = 0.014) and lymphovascular invasion (p = 0.001) and local recurrence. Furthermore, there was an increased risk of local recurrence in the clear margin cohort of <1 mm compared to those of >1 mm (p < 0.001).
An important systematic review published in 2018 assessed the evidence of adjuvant inguinal radiotherapy after radical inguinal lymphadenectomy among patients with high-risk features (node-positive)4. Among 7 studies including 1,605 men, the indications for adjuvant inguinal radiotherapy varied but were typically involvement of two or more inguinal nodes or extranodal extension. Regional recurrence rate following adjuvant inguinal radiotherapy was also quite variable and reported at 10-91.7%. Two studies compared recurrence and survival between men who received and who did not receive adjuvant inguinal radiotherapy, with no significant difference (p>0.05). As such, Dr. Ayres suggests that the evidence for use of radiotherapy is lacking.
Considering the dismal prognosis for patients with metastatic penile cancer, advances in systemic therapy are most welcome. To this extent, Necchi et al.5 assessed first-line dacomitinib (an irreversible, pan-epidermal growth factor receptor (HER) inhibitor) in a phase II study among 28 patients. Eight patients had visceral metastases, 14 had pelvic and 17 had clinically involved bilateral lymph nodes. There was one complete and eight partial responses obtained (ORR 32.1%, 80%CI 21.0-43.0%). The median follow-up duration was 19.8 months: 12-month PFS was 26.2% and 12-month OS was 54.9%. As such, dacomitinib may represent an option when combined chemotherapy cannot be administered.
Similar to organ sparing procedures for penile cancer, there continue to be advances in testis-sparing surgery for small testicular masses. Among 522 patients undergoing testis-sparing surgery in Cologne, Germany, 28 patients (5%) had a primary benign tumor after resection, including Leydig cell tumors in 9 (32%), epidermoid cysts in 9 (32%), adenomatoid tumors in 8 (29%) and Sertoli cell tumors in 2 (7%)6. Importantly, the median volume of benign tumors was significantly less than that of malignant tumors (0.75 cm3, range 0.1-2.1 vs 15 cm3, range 4.5-39.9, p ≤0.001). At a cutoff of 2.8 cm3 tumor volume most accurately differentiated between benign and malignant disease, and it was a predictor of malignancy with 83% sensitivity and 89% specificity (OR 1.389, 95%CI 1.035-1.864).
A very important study was published in 2018 reviewing non-risk-adapted surveillance for stage I testicular cancer7. A total of 68 studies were included in this critical review. The authors found that cancer-specific survival approaches 100% for men with CSI disease undergoing non-risk-adapted surveillance. Active treatment is limited to 20-30% of patients who will recur, of which these patients will require salvage chemotherapy and possibly an RPLND. Existing AS protocols include imaging and laboratory evaluations that are initially intensive but less frequent with increasing follow-up. This provides the strongest and conclusive evidence that we should be instituting non-risk-adapted surveillance for all stage I patients in an attempt to keep from overtreating patients who never needed therapy.
Dr. Ayres concluded his review of penile and testis cancer impactful papers published in 2018 by pitching and overviewing the eUROGEN EAU initiative. This is a multi-national European “virtual” online multidisciplinary meeting using a secure platform to discuss rare (ie. penile and testis cancer) and complex cases and to give recommendations to the referring clinician. The moto is Share (share knowledge) Care (improve patient care) Cure (better outcomes).8
Presented by: Benjamin Ayres, Urological surgeon, St. George’s Hospital, London, United Kingdom
Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 16th Meeting of the European Section of Oncological Urology, #ESOU19, January 18-20, 2019, Prague, Czech Republic
- Olesen TB, Sand FL, Rasmussen CL, et al. Prevalence of human papillomavirus DNA and p16INK4a in penile cancer and penile intraepithelial neoplasia: A systematic review and meta-analysis. Lancet Oncol 2019 Jan;20(1):145-158.
- Cindolo L, Spiess PE, Bada M, et al. Adherence to EAU guidelines on penile cancer translates into better outcomes: A multicenter international study. World J Urol 2018 Oct 30 [Epub ahead of print].
- Sri D, Sujenthiran A, Lam W, et al. A study into the association between local recurrence rates and surgical resection margins in organ-sparing surgery for penile squamous cell cancer. BJU Int 2018 Oct;122(4):576-582.
- Robinson R, Marconi L, MacPepple E, et al. Risks and benefits of adjuvant radiotherapy after inguinal lymphadenectomy in node-positive penile cancer: A systematic review by the European Association of Urology Penile Cancer Guidelines Panel. Eur Urol 2018 Jul;74(1):76-83.
- Necchi A, Lo Vullo S, Perrone F, et al. First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open-label, single-arm, single-center, phase 2 study. BJU Int 2018 Mar;121(3):348-356.
- Paffenholz P, Held L, Loosen SH, et al. Testis Sparing Surgery for Benign Testicular Masses: Diagnostics and Therapeutic Approaches. J Urol 2018 Aug;200(2):353-360.
- Pierorazio PM, Albers PC, Black PC, et al. Non-risk-adapted Surveillance for Stage I Testicular Cancer: Critical Review and Summary. Eur Urol 2018 Jun;73(6):899-907.
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