As we are all keenly aware, there is not a day that passes when our email inbox doesn’t include news of a genetic discovery that contributes to the ever-expanding body of knowledge in the prostate cancer world. The practicing urologist has to decipher this maelstrom of data, somehow gain a basic understanding of its significance, and determine its clinical utility. Clearly, the world of prostate cancer management has taken on degrees of complexity that none of us ever imagined. We are well past the days of bilateral orchiectomy.

Without question, the urology community is woefully deficient in identifying the patient with advanced prostate cancer who is at risk of developing metastatic disease. Prior to the introduction and commercialization of prostate-specific antigen (PSA) testing, patients with prostate cancer were typically monitored for pain evaluation, serum prostatic acid phosphatase testing, and interval imaging. The advent of PSA testing changed this schema. However, the failure of the urologist, as well as the medical oncologist, to understand the limitations and usefulness of PSA, especially in the setting of the patient on androgen deprivation therapy (ADT), has led to delays in identification of metastases and subsequent institution of superior therapies. There are several examples that highlight this disconnection, which continues to be prevalent.

It has been well documented in a number of trials that among patients who progress beyond ADT to what we now call castration- resistant prostate cancer (CRPC), nearly one-third, many of whom are completely asymptomatic, will actually harbor metastatic disease.

 The dependence on clinical symptomatology, one of the few determinants of the need for imaging and restaging in the setting of low or slowly accelerating PSA, has been a major challenge for physicians in their clinical practice. As a direct result, many patients are going untreated, despite the plethora of new agents currently available.

Many of us have used first-generation androgen receptor signaling inhibitors/antiandrogens for many years. However, in the setting of metastatic CRPC (mCRPC), these agents as monotherapies have not demonstrated a survival benefit compared with all of the newer therapies approved by the FDA since 2010. Despite this fact, the number of patients who get started on antiandrogens as first-line therapy remains high. Much of this revolves around the misguided notion that drops in PSA, usually very short-lived with these agents in the patient with CRPC, will result in better outcomes. This is far from the truth. Two FDA-approved agents for mCRPC, sipuleucel-T (Provenge) and radium-223 (Xofigo), have significant survival benefit but do not always result in a diminution of PSA.

 Sadly, many providers have refused to utilize these therapies due to this lack of PSA response. Again, there is a refusal to give up previously held beliefs.

Recently, 2 trials have been presented that utilize an intermediate endpoint, metastasis-free survival, to evaluate the efficacy of these newer agents in patients with nonmetastatic CRPC.

 Knowing that PSA was not a good surrogate marker to predict overall survival (OS) in CRPC and that OS has been the gold standard for mCRPC trials, this represents a significant step forward by the FDA in trial design, given the number of potential targeted therapies that are currently being investigated. Hopefully, this breakthrough will allow more oncolytics to enter the market faster as we gain an understanding of resistance mechanisms.

These scenarios highlight the need for clinicians to rethink and challenge their traditional ways of practice and educational needs. In particular, it is imperative that we gain a better understanding of the molecular drivers that result in progression of disease. We will continue to have a cascade of discovery and new information from the many scientists working in this field. To better serve our patients and avoid clinging to tradition, we, as clinical scientists, need to continue to evolve our thinking and approach to patient care.

Yu EY, Miller K, Nelson J, et al. Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. 

 2012;188(1):103-109. doi: 10.1016/j.juro.2012.03.008.

Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

2010;363(5):411- 422. doi: 10.1056/NEJMoa1001294.

Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.

. 2014;15(7):736-746. doi: 10.1016/S1470-2045(14)70183-4.

Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC).

2018;36(suppl 6S; abstr 3). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.3.

Smith MR, Saad F, Chowdhury S, Oudard S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. 

2018;378(15):1408-1418. doi: 10.1056/NEJMoa1715546.

Articles

Raoul S. Concepcion, MD, FACS, discusses how to sort through the massive amount of data in the urology space, gain a basic understanding of its significance, and determine its clinical utility.

Rethinking the Prostate Cancer Paradigm in the Urology Community

Penile cancer occurs rarely in the United States and Western Europe. In the United States, the incidence is 1 to 2 cases for every 100,000 individuals a year. In Western Europe, it is less than 1% of all male cancers. Risk factors include being uncircumcised, poor hygiene, history of human papillomavirus (HPV) infection, and smoking tobacco. HPV strains 16 and 18, in particular, put men at risk for penile cancer.

The presentation of penile cancer is variable. Patients may present with a penile mass or ulcer. In addition, some patients develop a red, velvety rash or foul-smelling discharge from beneath the foreskin.

Table 1. Stages and Grades of Penile Cancer

Clinicians should have a low threshold to biopsy penile lesions. This can usually be done under local anesthesia. No treatment should be undertaken without a confirmation of an unequivocal permanent section pathology diagnosis. Urologists should not depend on a frozen section diagnosis done at the same time as a partial or total penectomy.

It is important to stage the primary tumor (T), the regional lymph nodes (N), and the presence of distant metastases (M). Several staging systems have been used through the years, but currently, the TNM system is the most widely used.

 The grade of the primary lesion is also considered in determining prognosis (

Magnetic resonance imaging (MRI) has emerged as the imaging modality of choice for the primary lesion.

 MRI is superior to computed tomography (CT) scans in the evaluation of the primary lesion because MRI has excellent soft tissue and spatial resolution. T2-weighted and gadolinium-enhanced T1-weighted images are the most useful in determining the local extent of the penile cancer.

Determining lymph node status also is critical in establishing prognosis. Ravi reported that the 5-year survival rate declined from 95% for patients without nodal disease to 81% for patients with 1 to 3 positive nodes to 50% for patients with 4 or more positive nodes. CT, MRI, and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and CT have all been used for the evaluation of inguinal lymph nodes.

 Ultrasound with fine needle aspiration cytology (FNAC) can be useful when there are palpable nodes on physical exam. The European Association of Urology supports the use of FNAC in this circumstance, noting sensitivity of 93%.

CT imaging has been disappointing for the evaluation of inguinal lymph nodes. Horenblas et al reported a series of 14 patients and found that CT had a sensitivity of 36% and a specificity of 100%, but was unable to detect occult metastases in groins without palpable nodes.

 MRI results in evaluation of inguinal nodes have not been superior to CT.

Due to the limitations of standard CT and MRI imaging of the inguinal nodes, FDG PET/CT has gained increasing acceptance as the study of choice for inguinal node imaging. Schlenker et al reported a prospective study of 35 patients with penile cancer and found that the FDG PET/CT had a sensitivity of 88.2% and a specificity of 98.1%, with a positive predictive value of 93.8% and a negative predictive value of 96.3%.

 Graafland et al also utilized FDG PET/CT for penile cancer staging and reported a sensitivity of 91%, a specificity of 100%, and a diagnostic accuracy of 96% in identifying inguinal/pelvic node involvement.

The technique of sentinel node biopsy was introduced by Cabanas in 1977 in an attempt to sample the first landing site of inguinal node metastatic spread.

 His rationale was that this node or cluster of nodes located around the superficial epigastric vein was predictive of the status of the remainder of the inguinal nodes. However, the lymphatic drainage of the penis is variable and several authors have reported false negative rates of 10% to 25%.

 Therefore, this technique, although theoretically attractive, has fallen into disfavor.

To try to improve accuracy, dynamic sentinel lymph node biopsy (DSLNB) was introduced. This technique involves mapping the penile lymphatic drainage with blue dyes and/ or radiotracers.

 The results of DSLNB appear to be highly variable and user dependent; some results were no better than standard lymph node biopsy.

Newer techniques, such as single-photon emission computed tomography (SPECT)/CT have been evaluated in a few centers with encouraging results.

 In a series of 84 patients, plain lymphoscintigraphy identified sentinel lymph nodes in 87% of patients whereas SPECT/CT was able to identify at least 1 node in 100% of patients. However, Jakobsen et al reported a series of 129 patients where the results of SPECT/CT and standard lymphoscintigraphy were essentially equivalent.

 Imaging of the inguinal nodes in penile cancer continues to evolve. However, at the present time, FDG PET/CT is gaining increasing acceptance as the imaging modality of choice.

Carcinoma in situ and verrucous carcinoma of the penis involve the superficial layers of the skin and can usually be treated topically with laser therapy, Mohs surgery, fluorouracil, imiquimod, or cryotherapy.

This article will discuss primary stage II lesions that are best treated by either partial or total penectomy. The goals of therapy should be 2-fold: oncological cure and preservation of sexual function, when possible.

 The primary consideration of surgical planning for the urologist should be to achieve a clear surgical margin. For many years, the traditional dogma had been that a 2-cm margin was required to ensure cure; however, we reviewed our own series and found that all clear surgical margins were equivalent in terms of local control. This has practical implications in the management of the local lesion. A partial penectomy that does not provide enough phallic length for sexual stimulation and/or penetration and that does not afford the patient the ability to stand to void does not benefit the patient. A clear margin that enables sexual pleasure, even without penetration, and maintains the ability for the patient to stand to void is a desirable outcome.

Before either a partial or total penectomy is performed, a permanent pathologic biopsy should always be obtained. Proceeding with definitive extirpative surgery on the basis of a frozen section result represents an unnecessary risk that could result in unindicated disfiguring surgery. However, a frozen section should always be taken at the time of a partial penectomy to confirm a negative margin.

A potential complication of either a partial or total penectomy is stenosis or stricture of the neomeatus. We have published the “rosebud” technique that is based on similar surgical principles utilized in the maturation of an ileal conduit stoma.

The technique involves mobilization of the urethral stump after the completion of either a partial or total penectomy, which should provide a length of urethra of about 1 cm that can then be spatulated (

Figure 1. Urethral Mobilization for Creation of a Neomeatus

Figure 2. Maturation of the Urethral Stump for Creation of a Neomeatus

A total penectomy is preferable in larger or more proximal penile lesions when a partial penectomy would not reliably provide a clear surgical margin. The base of the penis is circumscribed and the corpora cavernosa and corpus spongiosum are dissected proximally. The base of the corpora cavernosa is controlled with mattress sutures, and the urethra is mobilized with attention to preserving its vascularity. A useful technical point is to place an infant feeding tube into the remaining urethral stump and secure it with a suture. The feeding tube can then be grasped with a forceps, which facilitates passage down to the perineum where a neomeatus is created.

The surgical management of the inguinal nodes has evolved. For many years, it was accepted practice to give patients with palpable inguinal nodes a 6-week course of antibiotics to see if the enlarged nodes would resolve before proceeding with a lymphadenectomy. Today, most surgeons proceed with the groin dissection without a course of antibiotics unless the primary lesion is grossly infected.

The management of nonpalpable nodes has also evolved. With more accurate imaging studies, most clinicians proceed with an inguinal dissection if there is radiographic suspicion of metastases. In addition, Tabatabaei has provided useful information regarding the risk of nodal metastases based on the stage and grade of the primary tumor (

The classic open lymphadenectomy is associated with significant morbidity including lower extremity lymphedema, lymphoceles, wound infection, and wound separation. The limits of the dissection are the apex of the femoral triangle distally, the sartorius muscle laterally, the adductor longus medially, and the inguinal ligament superiorally.

Table 2. Positive Node Rate Based on Primary Tumor Stage and Grade

In an attempt to decrease the morbidity of the surgery, Colberg introduced the concept of a modified inguinal lymphadenectomy.

 This technique is used primarily in nonpalpable disease or minimally palpable disease. This technique differs from the standard technique by (1) decreasing the extent of the node dissection by excluding the regions lateral to the femoral artery and caudal to the fossa ovalis, (2) saphenous vein preservation, (3) elimination of transfer of the sartorius muscle, and (4) preservation of the subcutaneous tissue superficial to Scarpa’s fascia. Regardless of whether a standard or modified lymphadenectomy is performed, careful handling of the skin edges is important to avoid postoperative wound complications. We have found the use of the Scott ring retractor useful to achieve this goal.

Modifications of surgical technique continue to be reported. Endoscopic inguinal node dissections (the VEIL procedure) are now being performed with reports of longterm efficacy.

 In addition there is a growing experience with robotic inguinal lymphadenectomy that suggests comparable results to the traditional open dissection.

The potential future advances in the management of penile cancer are exciting. Biomarkers may enable us to diagnose and monitor patients more accurately.

 There are also realistic options to replace the penis with either autologous tissue or with a penile transplant.

The next decade will undoubtedly provide clinicians with new challenges and opportunities for the treatment of patients with penile cancer.

TNM Staging System. Cancer.net website. Penile cancer: stages and grades. cancer.net/cancer-types/penile-cancer/stages-and-grades. Updated August 2017. Accessed May 1, 2018.

Suh Ch, Bahefi AD, Tirumani SH, et al. Multimodality imaging of penile cancer: what radiologists need to know. 

2015;40(2):424-435. doi: 10.1007/ s00261-014-0218-6.

Ravi R. Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the penis. 

Hakenberg OW, Compérat EM, Minhas S, et al. EAU guidelines on penile cancer: 2014 update. 

2015;67(1):142-150. doi: 10.1016/j.eururo.2014.10.017.

Horenblas, van Tinteren H, Delamarre JF, et al. Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and rate of lymphangiography, computerized tomography scan and fine needle aspiration cytology.

1991;146(5):1279-1283. doi: 10.1016/S0022-5347(17)38068-0.

Heyns CF, Fleshner N, Sanger V, et al. Management of lymph nodes in penile cancer. 

 2010;76(2 suppl 1):S43-57. doi: 10.1016/j.urology.2010.03.001.

Schlenker B, Scher B, Tilling R, et al. Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: a prospective single-center study. 

2012;30(1):55-59. doi: 10.1016/j.urolonc.2009.10.012.

Graafland NM, Leijte JA, Valdes Olmas RA, et al. Scanning with 18F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal node-positive carcinoma.

2009;56(2):339-345. doi: 10.1016/j.eururo.2009.05.016.

Cabanas RM. An approach for the treatment of penile carcinoma.

Fossa SD et al. Cancer of the penis. Experience at Norwegian Radium Hospital 1974-1985.

Cabanas RM. Anatomy and biopsy of sentinel lymph nodes. 

Pettaway CA, Pisters LL, Dinney CP, et al. Sentinel lymph node dissection for penile carcinoma: the M.D. Anderson Cancer Center experience. 

 1995;154(6):1999- 2003. doi: 10.1016/S0022-5347(01)66671-0.

Wespes E. The management of regional lymph nodes in patients with penile carcinoma and reliability of sentinel node biopsy.

2007;52(1):15-16. doi: 10.1016/j.eururo.2007.02.045.

Speiss PE, Izawa JI, Bassett R, et al. Preoperative lymphoscintigraphy and dynamic sentinel node biopsy for staging penile cancer: results with pathologic correlation. 

 2007;177(6):2157-2161. doi: 10.1016/j.juro.2007.01.125.

Sadeghi R, Gholami H, Zakavi SR, et al. Accuracy of sentinel lymph node biopsy after inguinal lymph node staging of penile squamous cell carcinoma: systematic review and metaanalysis of the literature.

 2012;187(1):25-31. doi: 10.1016/j.juro.2011.09.058.

Brouwer OR, van den Berg NS, Mathéron HM, et al. A hybrid radioactive and fluorescent tracer for sentinel node biopsy in penile carcinoma as a potential replacement for blue dye. 

 2014;65(3):600-609. doi: 10.1016/j.eururo.2013.11.014.

Jakobsen JK et al. DaPeCa-3: promising results of sentinel node biopsy combined with (18) F-fluorodeoxyglucose positron emission tomography/computed tomography in clinically lymph node-negative patients with penile cancer - a national study from Denmark.

. 2016;118(1):102-111. doi: 10.1111/bju.13243.

Treatment options for penile cancer, by stage. American Cancer Society website. cancer.org/cancer/penile-cancer/treating/by-stage.html. Accessed May 1, 2018.

Loughlin KR. Penile cancer sparing surgery: the balance between oncological cure and functional preservation. 

2018;36(4):153-155. doi: 10.1016/j. urolonc.2017.12.008.

Hoffman MA, Renshaw AA, Loughlin KR. Squamous cell carcinoma of the penis and microscopic pathologic margins: how much margin is needed for local cure?

Loughlin KR. The “rosebud” technique for creation of a neomeatus after partial or total penectomy. 

Tabatabaei S, McDougal WS. Positive node pathology based on primary tumor stage and grade. In: Richie JP, D’Amico AV, eds.

Philadelphia, PA: Elsevier/Sanders; 2005:710-722.

Colberg JW, Andriole GL, Catalona WJ. Long-term follow-up of men undergoing modified inguinal lymphadenectomy for carcinoma of the penis. 

Loughlin KR. Use of Scott ring surgical retractor for inguinal node dissection.

Loughlin KR. Surgical management of penile carcinoma: the inguinal nodes.

 2006;97(5):1125-1134. doi: 10.1111/j.1464-410X.2006.06178.x.

Tobias-Machado M, Tavares A, Molina WR Jr. et al. Video endoscopic inguinal lymphadenectomy (VEIL): minimally invasive resection of inguinal lymph nodes. 

Singh A, Jaipuria J, Goel A. Comparing outcomes of robotic and open inguinal lymph node dissection in patients with cancer of the penis. 

. 2018;199(6):1518- 1525. doi: 10.1016/j.juro.2017.12.061.

Vuichoud C, Klap J, Loughlin KR. The emerging role and promise of biomarkers in penile cancer. 

 2016;43(1):135-143. doi: 10.1016/j. ucl.2015.08.012.

Capelouto CC, Orgill DP, Loughlin KR. Complete phalloplasty with prelaminated osteocutaneous fibula flap. 

 1997;158(6):2238-2239. doi: 10.1016/S0022-5347(01)68213-2.

Bateman C. World’s first successful penis transplant at Tygerberg Hospital. 

 2015;105(4):251-252. doi: 10.7196/SAMJ.9602.

Thoma C. Surgery: first penis transplant in the USA. 

2017;14(8):452. doi: 10.1038/nrurol.2017.88. doi: 10.1038/nrurol.2017.88.

Kevin R. Loughlin, MD, MBA, discusses the diagnosis, staging, and management of penile cancer.

Surgical Challenges and Opportunities in Treating Penile Cancer

Providing comprehensive, compassionate, cost-effective care has been the guiding principle of Urology San Antonio (USA) from its beginning in 1996. Those same attributes have been integrated into the innovative cancer care program offered by this medical practice that treats all aspects of prostate cancer from diagnosis to end-of-life care, including an in-house pharmacy, catheter service, disease-specific nurse navigation, and clinical trials division.

With a team of 26 urologists, 8 advanced practice providers, and 2 pelvic floor physical therapists, the practice manages over 200,000 visits and establishes relationships with more than 22,000 new patients each year. Four additional urologists and the practice’s first urologic-oncologist will join the care team at USA later this year.

Coordinated care does not happen by accident. The practice offers a wide range of services along a continuum of care overseen by a team of subspecialists across 9 locations. From cutting-edge diagnostics including biomarkers to guided targeted biopsy services, genomic testing, and multiparametric MRI fusion biopsy services, the practice designed and follows clinical pathways for active surveillance and prostate and bladder cancer treatment. As a result, the physicians have attained a 58% positive biopsy rate with a healthy distribution across treatment modalities that meets or exceeds national averages: 35.2% of men in active surveillance, 27.3% in intensity-modulated radiation therapy (IMRT), and 23.5% selecting prostatectomy.

Robust data analytic tools managed by disease-specific nurse navigators help identify patients for life-saving treatment modalities and potential participation in clinical trials. Chronic care management of patients with prostate cancer continues to expand with over 100 patients in active management currently through the prostate cancer Chronic Care Management program.

“The Advanced Therapeutics Clinic opened in 2011 and currently manages more than 300 patients. Identifying who is appropriate for active treatment versus active surveillance has been crucial to our success,” Daniel Saltzstein, MD, explained. By using biomarkers and offering new diagnostic imaging modalities that might someday replace MRI, the practice individualizes advanced cancer therapies while offering companion therapies such as PARP inhibitors.

In-house pathology services enhance the consistency and timeliness of diagnosis and treatment. Patients have access to immunotherapy, secondary hormonal therapy, agents to manage bone health, and radiopharmaceuticals. Currently, physicians like Saltzstein, the practice champion for Advanced Prostate Cancer Care, are investigating the potential of new oral antagonists and considering incorporating FDA-approved adrenal biosynthesis inhibitors and second-generation androgen—receptor signaling inhibitors earlier in the prostate cancer treatment paradigm.

The Reyna Cancer Center was added in 2005 and provides IMRT to 80 men per day in addition to offering conventional radiation treatment for a variety of cancers.

Diagnostic and treatment services are augmented by an in-house retail pharmacy that allows USA to manage 80% of its patients started on all 3 oral agents for advanced prostate cancer care, as well as provide many medications for the patients’ other urologic needs. In fact, the pharmacy fills almost 1000 prescriptions per month for a variety of urologic issues.

USA’s robust clinical trials division, with 8 current prostate cancer trials in addition to its work in medical devices and other disease processes such as bladder cancer, allows USA’s caregivers to accompany the patient and his family along the cancer journey. USA is preparing to launch its end-of-life program now to support the patient and his family and caregivers in dignified, informed decision-making.

USA is governed by a board of 5 physicians who work with an executive director. The practice employs 288 individuals located in 7 clinics, a radiation cancer center, and a specialty ambulatory surgery center.

Providing comprehensive, compassionate, cost-effective care has been the guiding principle of Urology San Antonio. The practice manages over 200,000 visits and establishes relationships with more than 22,000 new patients each year.

August 2018 | Oncology Live Urologists in Cancer Care®

Rethinking the Prostate Cancer Paradigm in the Urology Community

Surgical Challenges and Opportunities in Treating Penile Cancer

Practice in South Texas Offers Vertically Integrated Cancer Care