Editing EAU & ASCO: Penile Cancer 2023 (section)

=== Primary Tumour ===

* ''' <span style="color:#ff0000">Aims of primary tumour treatment (2)'''
*# '''<span style="color:#ff0000">Complete tumour removal with''' 
*# '''<span style="color:#ff0000">As much organ preservation as possible (without compromising oncological control)'''
* Fully functional penis is central to 
** Sexual functioning
** Urination
** Sense of wholeness, desirability and masculinity

==== Options ====
* '''<span style="color:#ff0000">Non-surgical (4)'''
*# '''<span style="color:#ff0000">Topical therapy (2)'''
*## '''<span style="color:#ff0000">Imiquimod'''
*## '''<span style="color:#ff0000">5-fluorouracil'''
*# '''<span style="color:#ff0000">Laser therapy'''
*# '''<span style="color:#ff0000">Radiation'''
*#* '''<span style="color:#ff0000">Brachytherapy'''
*#* '''<span style="color:#ff0000">External beam radiation'''
* '''<span style="color:#ff0000">Surgical'''
** '''<span style="color:#ff0000">Organ-sparing (3)'''
**# '''<span style="color:#ff0000">Circumcision'''
**# '''<span style="color:#ff0000">Wide local excision'''
**# '''<span style="color:#ff0000">Partial or total glansectomy, with or without reconstruction'''
** '''<span style="color:#ff0000">Amputative (2)''' 
**# '''<span style="color:#ff0000">Partial amputation'''
**# '''<span style="color:#ff0000">Radical amputation'''
*'''<span style="color:#ff0000">Organ-sparing approaches are considered to be the primary treatment method for localised penile cancer</span>''' 
**Generally, penile-preserving surgery preserves superior functional, erectile and cosmetic outcomes compared to partial or total penectomy (amputation)
***Glans sensation and orgasm can be affected in penile-preserving surgery
**'''Patients should be informed about the higher risk of local recurrence with organ-sparing treatments, compared to amputative surgery'''
*No RCTs or observational comparative studies for any of the treatment options for localised penile cancer

===== Non-surgical =====

====== Topical ======
* '''<span style="color:#ff0000">Indications'''
**'''<span style="color:#ff0000">Biopsy-confirmed PeIN'''
*'''Options'''
*#'''Imiquimod'''
*#'''5-fluorouracil'''
*Dosing
** Imiquimod
*** Commonly used 3 times per week for 12 weeks
** 5-fluorouracil
*** No standard protocol exists
*** 5-FU ointment on for 12 hours every 48 hours during a 4 to 6-week treatment course is often recommended
*Adverse events
**Discontinuation of topical agents due to side effects observed in 12% of cases

====== Laser ======
*'''Options'''
** '''Neodymium:Yttrium-Aluminium-Garnet (Nd:YAG''', penetration 4–6 mm, wavelength 1064 nm)
** '''Carbon dioxide (CO2''', penetration < 1 mm, wavelength 10600 nm)
* '''<span style="color:#ff0000"> Indications
** '''<span style="color:#ff0000"> Biopsy-confirmed PeIN, Ta, or T1 lesions

====== Radiation ======
*Efficacy
**5-year recurrence-free survival improved with brachytherapy compared to EBRT (≈80% vs. ≈55%)
*'''<span style="color:#ff0000">Indications
**'''<span style="color:#ff0000">Biopsy-confirmed T1 or T2 lesions

====== Moh’s micrographic surgery ======
*A surgical technique by which tissue is excised and processed with en face histological margins in real time to give a complete circumferential and deep margin
**Aims at maximal organ-preservation by adopting margin-guided excision
*'''Not routinely recommended as data are very limited'''
===== Surgical =====
* '''Pre-operative planning requires taking into consideration the''' 
** '''Size of the mass'''
** '''Involvement of surrounding structures'''
** '''Anticipated skin and soft tissue defects (as well as plastic surgical consultation (as appropriate))'''
* '''<span style="color:#ff0000">Organ-sparing'''
** '''<span style="color:#ff0000">Options (3)'''
**# '''<span style="color:#ff0000">Circumcision'''
**#* '''<span style="color:#ff0000">Standard treatment for foreskin/preputial penile cancer'''
**#* '''<span style="color:#ff0000">Facilitates follow-up in patients treated with topical treatment, laser therapy or brachytherapy, facilitates follow-up examinations'''
**# '''<span style="color:#ff0000">Wide local excision'''
**# '''<span style="color:#ff0000">Partial or total glansectomy, with or without reconstruction'''
**#* '''Glans resurfacing'''
**#** '''Consists of full thickness removal of the glandular epithelium followed by reconstruction with a graft'''
**'''<span style="color:#ff0000">Indications'''
***'''<span style="color:#ff0000">Lesions confined to the glans and prepuce (PeIN, Ta, T1–T2) and patient willing to comply with strict follow-up'''
* '''<span style="color:#ff0000">Amputative surgery (2)'''
*# '''<span style="color:#ff0000">Partial penectomy'''
*#* '''<span style="color:#ff0000">Indications'''
*#*# '''<span style="color:#ff0000">Invasion of the corpora cavernosa (T3)'''
*#*# '''<span style="color:#ff0000">Patient not willing to undergo organ-sparing surgery or not willing to comply with strict follow-up.'''
*#*Efficacy
*#**Risk of local recurrence ≈4–5%
*#'''<span style="color:#ff0000">Total penectomy with perineal urethrostomy'''
*#*'''<span style="color:#ff0000">Indications'''
*#**'''<span style="color:#ff0000">Large invasive tumours not amenable to partial amputation'''
* '''With surgical treatment, negative surgical margins for invasive carcinoma must be obtained.'''
** Width of negative surgical margin (macroscopic margins can indeed be minimal, specifically in smaller and less aggressive lesions)
*** Standard excision must include a margin of clinically normal-appearing skin around the tumour and surrounding erythema. However, for bulky or higher-grade lesions where local recurrence may have an impact on survival, adoption of a wider margin or partial penectomy may be prudent
** Perform intra-operative frozen section analysis of resection margins in cases of doubt on the completeness of resection.
*** Use of intra-operative frozen section assessment not routinely recommended
*** Helpful tool to achieve definitive tumour-free margin in cases of doubt on the radicality of the resection

==== Treatment of superficial non-invasive disease (PeIN, Ta) ====

*'''<span style="color:#ff0000">Options'''
** '''<span style="color:#ff0000">Non-surgical'''
*** '''<span style="color:#ff0000">Topical therapies'''
**** '''<span style="color:#ff0000">Imiquimod'''
**** '''<span style="color:#ff0000">5-fluorouracil'''
****'''Insufficient responses and recurrences may signify underlying invasive disease, hence, if topical treatment fails, it should not be repeated'''
***'''<span style="color:#ff0000">Laser ablation'''
**'''<span style="color:#ff0000">Surgical'''
***'''<span style="color:#ff0000">Circumcision''' 
****'''<span style="color:#ff0000">Should be the primary surgical option'''
***** Following circumcision, the glans mucosa keratinizes over a period of 3–6 months and any residual PeIN or lichen sclerosus may resolve. Close monitoring before starting additional therapy has been advocated
***'''<span style="color:#ff0000">Local excision'''
**** Extensive PeIN, residual PeIN in resection margins or recurrent disease after ablative or topical therapy, can be treated by surgical excision
**** Glans resurfacing
* '''<span style="color:#ff0000">Despite treatment, penile intra-epithelial neoplasia can progress to invasive lesions in 2.6–13% of patients'''

==== Treatment of invasive disease confined to the glans (cT1/T2) ====

* <span style="color:#ff0000">'''Treatment choice depends on tumour size, histology, stage and grade, localisation and patient preference.</span>
** <span style="color:#ff0000">'''When feasible, small and localised invasive lesions should receive organ-sparing treatment.'''</span>
*** <span style="color:#ff0000">'''Organ-sparing surgery associated with higher recurrence rates than amputative surgery''' </span>
* <span style="color:#ff0000">'''Foreskin tumours'''</span>
** <span style="color:#ff0000">'''Treated by ‘radical’ circumcision.''' </span>
* <span style="color:#ff0000">'''Glandular and coronal tumors'''</span>
** <span style="color:#ff0000">'''Non-surgical options'''</span>
*** <span style="color:#ff0000">'''External beam radiotherapy and brachytherapy'''</span>
**** Can be given as external radiotherapy with a minimum dose of 60 Gy combined with a brachytherapy boost or as brachytherapy alone
****Brachytherapy has been studied only for lesions < 4 cm hence its use should be limited to tumours not exceeding this size
****In the few studies comparing surgical treatment and radiotherapy, results of surgery were slightly better.
****Complications of radiotherapy for penile cancer
*****Meatal/urethral stenosis
*****Glans necrosis
*****Late fibrosis of the corpora cavernosa
*****Pain with sexual intercourse
*****Dysuria
****Local recurrence after radiotherapy can be salvaged by surgery
*** '''Laser ablation'''
**** '''Option for smaller invasive lesions (likely best limited to T1 tumours)'''
***** Laser therapy of small lesions has been reported but the risk of invasive disease must be recognized, and the recurrence risk is high, possibly as a result of the limited tissue penetration depth of laser ablation. 
**<span style="color:#ff0000">'''Surgical options</span>'''
*** <span style="color:#ff0000">'''Wide local excision (and circumcision)'''</span>
**** '''Lesions located on the corona or glans, limited in size, may be treated with wide local excision which should include a margin of clinically normal-appearing skin around the tumour and surrounding erythema</span>'''
****Additional circumcision is advised in glandular tumours.
*** <span style="color:#ff0000">'''Glansectomy (with or without reconstruction)'''</span>
**** '''Patients with tumours confined to the glans and prepuce that are not eligible for wide local excision or glans resurfacing are good candidates for glansectomy'''
****'''Split-thickness skin graft is commonly used to reconstruct a neo-glans'''
*****Poor candidates for graft application:
******Poor vascular function
******Diabetes
******Immunosuppression,
******Previous radiation to the groin area
*** <span style="color:#ff0000">'''Amputation'''
**** '''Reserved for more advanced disease'''

==== Locally advanced disease (T3–T4) ====

===== Resectable disease =====

* '''Pre-operative MRI or US can assist in surgical planning'''
* '''<span style="color:#ff0000">cT2 (corpus spongiosum): g<span style="color:#ff0000">Glansectomy (partial or total), with or without reconstruction'''
** If doubt of corporeal or tunica albuginea invasion, rather than continuing the dissection over Buck’s fascia to perform glansectomy combined with distal corporectomy, dissection superficial to the tunica albuginea can be adopted after dividing the neurovascular bundle.
*** Frozen sections of the corporeal tips and urethra may be helpful in assessing the radicality of the procedure peri-operatively.

* <span style="color:#ff0000">'''cT3 (corpus cavernosum): partial amputation</span>'''
** Reconstructive options can be offered, such as (2) 
**# Urethral centralisation and/or
**# Neo-glans formation with the use of a graft
**# Total phallic reconstruction in patients undergoing total/subtotal amputation
** In patients undergoing total/subtotal amputation, a total phallic reconstruction may be offered
** Patients should be informed that a wider resection provides a lower risk of local recurrence at the cost of functionality of the penis
** '''Radical amputation and diversion of urination with a perineal urethrostomy is reserved for those patients in whom a resection with a safe margin would result in the inability to void standing upright or without wetting the scrotum.'''
** In case of locally-advanced and ulcerated cases which are resectable, composite myocutaneous flaps or advancement flaps may be needed to cover the surgical defect

* Radiotherapy for locally-advanced penile lesions should be undertaken with concurrent chemotherapy.

===== Non-resectable disease =====

* '''Induction chemotherapy''' 
** '''Offers the ability to downstage disease and may enable surgical resection among responders'''
*** Several retrospective studies have evaluated combination regimens using paclitaxel or docetaxel with cisplatin and ifosfamide or 5-FU
* If inadequate response, consider palliative chemo-radiotherapy

==== Local recurrence after organ-sparing surgery ====

* If there is no corpus cavernosum invasion, a second organ-sparing procedure can be performed
* For large or high-stage recurrence (involving corpora cavernosa), partial or total amputation is required, unless unresectable or concurrent with nodal or distant metastatic recurrence