PENILE CANCER Date Developed: January, 2011 Date Revised: February, 2012 The recommendations contained in this guideline are a consensus of the Alberta Provincial Genitourinary Tumour Team synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
BACKGROUND Penile cancer is rare in developed countries, occurring annually in approximately 1 in 100,000 men 1. This type of cancer occurs most often in older men (i.e. those 60 years of age and older). An association with human papilloma virus (HPV) has been suggested 2. There are several types of penile cancer, nearly all of which are of squamous cell origin, including verrucous carcinoma, basaloid carcinoma, warty carcinoma (verruciform), and neuroendocrine carcinomas 3-6. Staging of penile cancer is based on the 7 th edition of American Joint Committee on Cancer (AJCC) manual 7. A detailed description of staging can be found in the Appendix. In stage I disease, carcinoma in situ (CIS) of the penis that occurs on the glans is referred to as erythroplasia of Queyrat, whereas when CIS occurs on the penile shaft it is referred to as Bowen disease. The five year survival rate for CIS of the penis is over 90%. With lymph node involvement, the five year survival rate declines to 60%. The prognosis with stage IV disease is a five year survival rate of approximately 20% 8. GUIDELINE QUESTIONS What are the appropriate management and follow up strategies for penile cancer? DEVELOPMENT PANEL This guideline was reviewed and endorsed by the Alberta Provincial Genitourinary Tumour Team. Members of the Alberta Provincial Genitourinary Tumour Team include medical oncologists, radiation oncologists, urologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Genitourinary Tumour Team and a Knowledge Management Specialist from the Guideline Utilization Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Utilization Resource Unit Handbook. SEARCH STRATEGY Entries to Medline, EMBASE, and Cochrane (January 2000 to December 2011) and clinical practice guideline databases were searched for evidence relevant to this topic. Search terms included: penile cancer OR cancer of the penis OR carcinoma of the penis OR penile carcinoma, limited to studies published in English. TARGET POPULATION The recommendations outlined in this guideline apply to adults over the age of 18 years with penile cancer. Different principles may apply to pediatric patients. RECOMMENDATIONS These recommendations have been adapted from the European Association of Urology s Guidelines on Penile Cancer 9, the National Cancer Institute s Penile Cancer Treatment guidelines 10, and the BC Cancer Agency s Cancer Management Guidelines on cancer of the penis 11. Page 2 of 9
Institutional Approach A multi-disciplinary approach encompassing collaboration between the members of the clinical team, especially the surgeon and the radiation oncologist, is recommended for all patients undergoing treatment for penile cancer 12. Tis, Ta N0 M0 (Stage 0) Management Options 10 Surgical excision with an adequate margin. In order to minimize scarring, deformity, and impaired function, Mohs micrographic surgery is preferred. During Mohs procedure, successive horizontal layers of tissue are excised and examined microscopically. Brachytherapy. Laser therapy in selected cases, using Nd:YAG or CO2 lasers. Topical treatment with 5-fluorouracil cream in cases of erythroplasia of Queyrat and Bowen disease. Topical treatment with Imiquimod 5% cream, an immune response modifier. Cryosurgery in patients with erythroplasia of Queyrat and verrucous penile carcinoma. T1 N0 M0 (Stage I) Management Options 9-11 Circumcision is standard therapy. Wide local excision. Partial penectomy (1 cm proximal to the lesion) for infiltrating tumours of the glans. Brachytherapy for tumours that infiltrate the glans (T1, T2, and selected, well differentiated T3 tumours) 12.13 External beam radiotherapy for larger tumours or those extending onto the shaft. T2 N0 M0 (Stage II) and T3 N0 M0 (Early Stage III) Management Options 9,10 Partial penectomy or radical penectomy, depending on the extent and location of the neoplasm. Radiotherapy (external beam or brachytherapy). Patients should be referred for appropriate use of imaging and needle biopsy, assessment, and discussion of lymph node scintigraphy, and potential sentinel node biopsy prior to surgery. Prophylactic groin node dissection. T1-3 N1-2 (Stage III) Management Options 9-11 Partial penectomy or radical penectomy, depending on the extent and location of the neoplasm. Antibiotic therapy for a short period then reassessment at six weeks. Bilateral superficial inguinal dissection could be considered, upon direction by biopsy and imaging findings. Clinically evident regional lymph node metastasis without evidence of distant spread is an indication for groin node dissection. Page 3 of 9
Patients with positive lymph nodes in the specimen may be considered for radical radiation therapy. Surgery to inguinal lymph nodes and radiation therapy may only be considered as an alternative to radical surgery if patient declines. Post-operative adjuvant radiation therapy may be considered to decrease the risk of recurrence. Patients who are either not candidates for or who refuse surgery may be considered for radical radiation therapy to lymph nodes. T4 or N3 or M1 (Stage IV) Management Options 9,10 Exenterative surgery in select cases. Palliative radiotherapy and/or chemotherapy. Metastatic Disease and Adjuvant Therapy Chemotherapy has been largely ineffective in treating patients with large disease burden 13-20. Options that have been used in clinical trials include: bleomycin, vincristine, and methotrexate +/- radiotherapy and ifosfamide, paclitaxel, and cisplatin, followed by surgery. There is no established role for adjuvant chemotherapy in patients who have completely resected disease. Follow-Up Follow-up of patients who have completed treatment for penile carcinoma allows for the detection of a potential recurrence, which may be curable if the recurrence is regional or loco-regional, as well as the assessment of early or late complications from treatment 9. Follow-up also allows for the periodic review and improvement of current treatment policy. 11 Follow-up traditionally consists of inspection and physical evaluation. Diagnostic imaging with ultrasound and PET scan are also useful modalities 21. As approximately 92% of all recurrences occur within the first five years 23 after which recurrences tend to be local or new primaries, it is important to provide intensive follow-up for the first two years with less frequent follow-up thereafter 9. The following schedule of follow-up intervals is recommended 9 : For patients who have received penile-preserving treatment of primary tumour: o Years 1 and 2: every 3 months regular physician or self-examination. o Years 3, 4, and 5: every 6 months regular physician or self-examination. o Follow-up following penile brachytherapy will be more frequent initially and at the discretion of the treating physician. For patients who have received amputation as treatment of primary tumour: o Years 1 and 2: every 6 months regular physician or self-examination. o Years 3, 4, and 5: every 1 year regular physician or self-examination. For patients undergoing a wait-and-see approach with respect to the inguinal lymph nodes: Page 4 of 9
o Years 1 and 2: every 3 months regular physician or self-examination; ultrasound with fine-needle o Years 3, 4, and 5: every 6 months regular physician or self-examination; ultrasound with fineneedle For patients who are pn0 with respect to the inguinal lymph nodes: o Years 1 and 2: every 6 months regular physician or self-examination; ultrasound with fine-needle o Years 3, 4, and 5: every 1 year regular physician or self-examination; ultrasound with fine-needle For patients who are pn+ with respect to the inguinal lymph nodes: o Years 1 and 2: every 3 months regular physician or self-examination; ultrasound with fine-needle o Years 3, 4, and 5: every 6 months regular physician or self-examination; ultrasound with fineneedle DISCUSSION Management Strategies Based on evidence from well-designed comparative studies, correlation studies, and case reports, the choice to provide conservative surgical treatment is dependent largely upon the potential morbidity of the procedure and the surgeon s experience. Depending upon the size of the excised area, skin grafts can be used to improve cosmetic results in conservative procedures. For partial or radical penectomies, a spatulated repair is recommended in order to avoid stenosis 9. Radiotherapy can afford T1-2 patients a greater chance of penile preservation. This can be provided as external beam irradiation (EBRT; i.e. high-energy photons, 4-6 MV), using a CT scan to define the target volume and optimise dosage distribution, or as brachytherapy (BRT; i.e. external isotope, low dose rate BRT, pulse-dose rate BRT, or high-dose rate BRT). These modalities are considered equivalent, as there are no studies to date that suggest one is more effective than another. As compared with partial penectomy, radiotherapy results in higher local and regional failure rates. However, salvage surgery is an option 9. A recent study by Crook, et al. (2009) 22 demonstrated that in patients (n=74) with T1 (58%), T2 (32%), selected T3 (7%), and Tx (3%) tumors who were treated with brachytherapy (60 Gy as either pulse dose rate brachytherapy or Iridium192) for primary management, the five- and ten-year actuarial rates of penile preservation were 88% and 69%, respectively (eight local failures occurred). The actuarial ten-year overall survival rate for that study was 61%. The risks associated with radiotherapy include soft tissue necrosis and urethral stenosis, at rates of 10-20% and 20-35%, respectively 9,23. Differentiation (well differentiated versus moderately or poorly differentiated) was shown to be a positive predictive factor of failure free survival in T1, T2, and T3 patients 24. Palpable inguinal nodes should be examined with ultrasound and fine-needle Early bilateral lymphadenectomy should be performed 25-28. In contralateral non-palpable lymph nodes, surgical Page 5 of 9
staging is recommended either by dynamic sentinel node biopsy or lymph node dissection. Radiotherapy is not recommended in N0 patients, as this treatment does not prevent lymph node metastases, is associated with complications, and can cause fibrotic changes to occur, making follow-up more difficult 9. In addition, neoadjuvant therapy, such as radiotherapy, may be required for patients with inguinal masses prior to surgery 29. A variety of agents and treatment schedules have been used in treating patients with metastatic disease beyond the inguinal and pelvic nodes. The most commonly used agents include cisplatin, bleomycin, methotrexate, paclitaxel, and 5-fluorouracil 13-16. Response rates to single agent cisplatin ranges from 15-32% and is often of short duration 15. Overall, chemotherapy has been largely ineffective in treating patients with large disease burden. The largest prospective clinical trial (SWOG) in metastatic penile cancer, in which patients were treated with cisplatin, bleomycin, and methotrexate, demonstrated an overall response rate of 32.5% with a median survival time of 28 weeks; mortality from this trial was 13.9% 18. In another study, ten patients with inguinal and pelvic node metastases were treated with a combination of ifosfamide, paclitaxel, and cisplatin, followed by surgery. Clinical benefit was demonstrated in nine patients (three complete responses, one partial response, and five stable disease), with a median survival time of 26 months 19. Finally, a trial involving 30 patients with stage III or stage IV (N2 or N3) disease, but no distant metastasis, treated with four courses of paclitaxel, ifosfamide, and cisplatin on a three-week cycle, showed that among patients who went on to surgery (n=22), there were three complete responses. The overall response rate for the whole group (surgery or chemotherapy only) was 50% and the median time to progression and overall survival were 8.1 months and 17.1 months, respectively. No deaths were attributed to treatment, 17 deaths were attributed to progressive, metastatic disease 19. There is no data to support a role for adjuvant chemotherapy in patients who have completely resected disease. Institutional Approach A multi-disciplinary approach encompassing collaboration between the members of the clinical team, especially between the surgeon and the radiation oncologist, is recommended for all patients and is essential for patients with tumours classified as T2 or higher with nodal involvement (i.e. two or more involved lymph nodes, bilateral involvement, evidence of extranodal extension, and pelvic nodal metastases) 12. For these patients, adjuvant therapeutic strategies may be required. Given the relative rarity of penile cancer, there are limited clinical trials to test the efficacy of various therapies or combinations of therapies in patients. Furthermore, clinicians practicing at a given cancer centre may treat as few as one to two patients per year. Therefore, it is important to develop expertise within the cancer centre by centralizing the care of these patients to one or two designated surgeons and radiation oncologists who can then garner more extensive experience in treating the disease. Page 6 of 9
GLOSSARY OF ABBREVIATIONS Acronym AJCC BRT CIS ERT HPV MRI PET UICC Description American Joint Committee on Cancer brachytherapy carcinoma in situ external beam irradiation human papilloma virus magnetic resonance imaging positron emission tomography International Union Against Cancer DISSEMINATION Present the guideline at the local and provincial tumour team meetings and weekly rounds. Post the guideline on the Alberta Health Services website. Send an electronic notification of the new guideline to all members of Alberta Health Services, Cancer Care. MAINTENANCE A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2012. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. CONFLICT OF INTEREST Participation of members of the Alberta Provincial Genitourinary Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. Alberta Health Services Cancer Care recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial Genitourinary Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner. REFERENCES 1.Society AC. Cancer Facts and Figures 2009. American Cancer Society 2009. 2.Del Mistro A, Cheico Bianchi L. HPV-related neoplasias in HIV-infected individuals. Eur J Cancer 37 2001;37(10):1227-1235. 3.Bezerra AL, Lopes A, Landman G. Clinicopathologic features and human papillomavirus dna prevalence of warty and squamous cell carcinoma of the penis. Am J Surg Pathol 2001;25(5):673-678. 4.Cubilla AL, Reuter VE, Gregoire L. Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol 1998;66(6):755-781. 5.Schwartz RA. Verrucous carcinoma of the skin and mucosa. J Am Acad Dermatol 1995;32(1):1-21. Page 7 of 9
6.Vadmal MS, Steckel J, Teichberg S. Primary neuroendocrine carcinoma of the penile urethra. J Urol 1997;157(3):956-957. 7.Edge SB, Byrd DR, Compton CC. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 8.UK. CR. Statistics and Outlook for penile cancer. URL: http://www.cancerhelp.org.uk/help/ default.asp?page=22745#overall.retrieved on September 4 2009. 9.Pizzocaro G, Algaba F, Horenblas S, Solsona E, Tana S, Van Der Poel H, et al. Guidelines on Penile Cancer. Euro Association Urol 2009. 10.National Cancer Institute. Penile Cancer Treatment, PDQ Summary. 2009. 11.Agency BC. Cancer Management Guidelines: Genitourinary: Penis. URL: http://www.bccancer.bc.ca/hpi/cancermanagementguidelines/genitourinary/ {MiscellaneousGenitourinaryTumours}/Penis.htm.{Retrieved}: {September} 2009;4. 12.Lynch DF, Pettaway CA. Tumors of the penis. In: Walsh P, Retik A, Vaughan E, Wein A, editors. Campbell's Urology Philadelphia, PA: Saunders; 2002. p. 2945-2982. 13.Roth AD, Berney CR, Rohner S, Allal AS, Morel P, Marti MC, et al. Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential. Br J Cancer 2000 2000 Dec;83(12):1637-1642. 14.Sheen MC, Sheu HM, Huang CH, Wang YW, Chai CY, Wu CF. Penile verrucous carcinoma successfully treated by intra-aortic infusion with methotrexate. Urol 2003 2003 Jun;61(6):1216-1220. 15.Di Lorenzo G, Cartenì G, Autorino R, Gonnella A, Perdonà S, Ferro M, et al. Activity and toxicity of paclitaxel in pretreated metastatic penile cancer patients. Anticancer Drugs 2009;20(4):277-280. 16.Connell CF, Berger NA. Management of advanced squamous cell carcinoma of the penis. Urol Clin North Am 1994 1994 Nov;21(4):745-756. 17.Pettaway CA, Pagliaro LC, Theodore C, Haas G. Treatment of visceral, unresectable or bulky/unresectable regional metastases of penile cancer. Urol 2010 2010 Aug;76(Suppl 1):S58-S65. 18.Haas G, Blumenstein BA, Gagliano RG, Russell CA, Rivkin SE, Culkin DJ, et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol 1999;161(6):1823-1825. 19.Bermejo C, Busby JE, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol 2007 2007 Apr;177(4):1335-1338. 20.Pagliaro LC, Williams D, Daliani D, Williams MB, Osai W, Kincaid M, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Onco 2010;28(24):3851-3857. 21.Scardino E, Villa G, Bonomo G, Matei DV, Verweij F, Rocco B, et al. Magnetic resonance imaging combined with artificial erection for local staging of penile cancer. Urol 2004 2004 Jun;63(6):1158-1162. 22.Crook J, Fleshner N, Jewett M, Ma C, Jezioranski J, Esche B, et al. Squamous cell carcinoma of the penis: Results of brachytherapy as primary management for 74 patients over an 18-year period. ASCO GU Cancer Symposium 2009. 23.Crook JM, Jezioranski J, Grimard L, Esche B, Pond G. Penile brachytherapy: results for 49 patients. Int J Radiat Oncol Biol Phys 2005 Jun 1;62(2):460-467. 24.Crook J, Ma C, Grimard L. Radiation therapy in the management of the primary penile tumor: an update. World J Urol 2009;27(2):189-196. 25.Hungerhuber E, Schlenker B, Frimberger D, Linke R, Karl A, Stief CG, et al. Lymphoscintigraphy in penile cancer: limited value of sentinel node biopsy in patients with clinically suspicious lymph nodes. World J Urol 2006;24(3):319-324. 26.Harty JI, Catalona WJ. Carcinoma of the penis. In: Javadpour N, editor. Principles and Management of Urologic Cancer. 2nd ed. Baltimore, Md: Williams and Wilkins; 1983. p. 581-597. Page 8 of 9
27.Theodorescu D, Russo P, Zhang ZF. Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes. J Urol 1996;155(5):1626-1631. 28.Lindegaard JC, Nielsen OS, Lundbeck FA. A retrospective analysis of 82 cases of cancer of the penis. Br J Urol 1996;77(6):883-890. 29.Busby JE, Pettaway CA. What s new in the management of penile cancer? Curr Opin Urol 2009;15:350-357. APPENDIX The American Joint Committee on Cancer (AJCC) staging for penile cancer (7 th edition, 2010): Tumour Tx: Primary tumour cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ Ta: Noninvasive verrucous carcinoma T1a: Tumour invades subepithelial connective tissue without lymph vascular invasion and is not poorly differentiated (i.e., grade 3 4) T1b: Tumour invades subepithelial connective tissue with lymph vascular invasion or is poorly differentiated T2: Tumour invades corpus spongiosum or cavernosum T3: Tumour invades urethra T4: Tumour invades other adjacent structures Regional lymph nodes Nx: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in a single inguinal lymph node N2: Metastases in multiple or bilateral inguinal lymph nodes N3: Extranodal extension of lymph node metastasis or pelvic lymph node(s) unilateral or bilateral Distant Metastasis Mx: Metastasis can not be assessed M0: No distant metastasis M1: Distant metastasis Page 9 of 9