Editing EAU & ASCO: Penile Cancer 2023 (section)

== Management ==

* '''Patients should be referred to comprehensive referral centers for penile cancer'''

=== 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

=== Regional Lymph Nodes ===

*'''<span style="color:#ff0000">Penile cancer metastasizes in a stepwise manner from the primary tumor through the lymphatic system'''
**'''<span style="color:#ff0000">Initially to the superficial inguinal nodes  (which can occur on both or either side'''
***'''<span style="color:#ff0000">Superficial nodes are located under the subcutaneous fascia and above the fascia lata within Scarpa’s triangle'''
**'''<span style="color:#ff0000">Then to the deep inguinal nodes  (which can occur on both or either side)'''
***'''<span style="color:#ff0000">Deep nodes lie within the region of the fossa ovalis where the superficial saphenous veins anastomose with the femoral vein at the saphenofemoral junction.'''
***'''The Cloquet’s node (or Rosenmuller’s node) is located medial to the femoral vein around the entrance to the femoral canal and marks the transition between inguinal and pelvic regions.'''
**'''<span style="color:#ff0000">Then the pelvic nodes (which can only occur with ipsilateral inguinal LN metastasis)'''
***Crossover metastatic spread, from one groin to the contralateral pelvis, is rare
**'''<span style="color:#ff0000">And finally to distant nodes'''
***Lymphatic spread from the pelvic nodes to retroperitoneal nodes (para-aortic, para-caval) is classified as systemic metastatic disease
*'''<span style="color:#ff0000">Detecting lymphatic spread as early as possible is a crucial element in penile cancer management'''

==== Clinically node-negative patients (cN0) ====

* '''<span style="color:#ff0000">≈20-25% of cN0 patients may harbour occult metastases''' 
** '''<span style="color:#ff0000">Additional staging is warranted'''
** initial LN staging is focused on identifying (micro)metastatic disease in the inguinal LNs as early as possible

===== Staging in cN0 =====

====== Indications ======

*'''<span style="color:#ff0000">Recommended'''
** '''<span style="color:#ff0000">High-risk tumors: T1b or higher'''
* Optional for intermediate-risk (pT1a G2)
** Surveillance is an alternative to surgical staging in patients willing to comply with strict follow-up

====== Options ======

* '''<span style="color:#ff0000">Surgical staging'''
** '''Invasive/surgical staging remains indispensable to identify micro-metastasis before nodal metastases become palpable/visible.'''
** '''<span style="color:#ff0000">Approaches (2)'''
**# '''<span style="color:#ff0000">Dynamic sentinel node biopsy (DSNB) (preferred)'''
**#* '''A sentinel node (SN) is defined as the first LN on a direct drainage pathway from the primary tumour.'''
**#** Based on this concept, it is assumed that if the SN is negative, this indicates the absence of lymphatic tumour spread in the corresponding inguinal basin.
**#** If histopathology identifies SN (micro)metastasis, ipsilateral completion ILND is indicated
**#* Test characteristics
**#** Sensitivity 92–96% (in experienced centres)
**#** False negative rates 4–8% (in experienced centres)
**#* '''Technique'''
**#** '''Inguinal US is obtained prior to DSNB'''
**#*** If sonographically suspicious nodes are detected, fine needle aspiration cytology (FNAC) can easily be performed in the same session to confirm the diagnosis of inguinal LN metastasis
**#**** if US + FNAC is positive, it can reduce the need for DSNB and allow for additional staging and therapeutic LN dissection at an earlier stage
**#*Adverse events
**#**Complication rate 6–14% (in experienced centres)
**#***Developed to avoid resecting unnecessary LNs and thereby minimizing the morbidity of surgical staging
**#*'''If DSNB is not available, and referral to a centre with experience with DSNB is not feasible, or if the patient does not want to run the risk of a false-negative procedure, ILND (modified/superficial/video-endoscopic) can be considered after informing the patient of the inherent risk of higher morbidity associated with these procedures.'''
**# '''<span style="color:#ff0000">Inguinal lymph node dissection (ILND)'''
**#* '''Radical inguinal lymph node dissection (ILND)''' 
**#** Most accurate surgical staging method
**#** Associated with the highest complication rates
**#* '''Modified ILND'''
**#** Lowers morbidity 
**#** Maintains sufficient sensitivity
**#** Modifications in modified ILND
**#**# Shorter skin incision
**#**# No dissection lateral to the femoral artery
**#**# No dissection caudal to the fossa ovalis
**#**# Preservation of the saphenous vein
**#*'''Video-endoscopic/robot-assisted radical LND'''
**#**Introduced more recently
**#**Similar lymph node yield compared to open
**#**Reduces wound-related complications compared to open ILND, but no significant reduction in lymphatic complications
**#***Main predictor of lymphatic complications is the number of lymph nodes removed
* '''<span style="color:#ff0000">Non-surgical staging'''
** '''<span style="color:#ff0000">Imaging'''
*** '''<span style="color:#ff0000">Not reliable to evaluate clinically node-negative patients'''
**** Conventional imaging modalities such as US, computed tomography (CT) or MRI cannot detect micrometastases
****18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) does not detect LN metastases < 10 mm
****These imaging modalities can be of value to detect enlarged/abnormal nodes in patients when physical examination is challenging (e.g., due to obesity).

==== Clinically node-positive patients (cN+) ====

* '''Lymph node metastasis should preferably be histopathologically confirmed by image-guided biopsy (e.g., US or CT) before initiating treatment.'''
* Cure can be achieved in limited LN-disease confined to the regional LNs
* '''Complete surgical inguinal and pelvic nodal management within 3 months of diagnosis (unless the patient has undergone prior neoadjuvant chemotherapy).'''
** Delay in nodal management of more than three to six months may affect disease-free survival.

==== Options ====

===== Radical inguinal lymph node dissection =====
* '''Standard of care for patients with cN1–2 (or cN0 patients with a tumour positive sentinel node at DSNB)'''
* No widespread adoption of lymph node yield or density as quality marker
* '''Adverse events'''
** '''Significant morbidity due to impaired lymph drainage from the legs and scrotum'''
*** '''Overall complication rate: 21–55%'''
*** '''Most common complications''' 
**** '''Wound infections (2–43%)'''
**** '''Skin necrosis (3–50%)'''
**** '''Lmphoedema (3.1–30%)'''
**** '''Lymphocele formation (1.8–26%)'''
**** '''Seroma (2.4–60%)'''
* '''Approaches (2)'''
*# '''Open'''
*#* '''Standard for cN1–2 disease'''
*#** In patients with cN1 disease offer either ipsilateral:
*#*** Fascial-sparing inguinal lymph node dissection (ILND)
*#*** Open radical ILND; sparing the saphenous vein, if possible
*#** In patients with cN2 disease offer ipsilateral open radical ILND; sparing the saphenous vein, if possible
*# '''Minimally-invasive'''
*#* Offer minimally-invasive ILND to patients with cN1–2 disease only as part of a clinical trial.
*#* Although operative time is longer, LN yields can be similar to open ILND, length of hospital stay shorter in VEIL/RAVEIL and wound complications lower, though lymphocele and readmission rates were equivalent

===== Neoadjuvant chemotherapy =====
* '''Alternative approach to upfront surgery to selected patients who are candidates for cisplatin and taxane-based chemotherapy with (2):'''
*# '''Bulky mobile inguinal nodes or'''
*# '''Bilateral disease (cN2)''' 

====== Prophylactic pelvic lymph node dissection ======
* In most cases represents a staging procedure that can thus identify candidates for early adjuvant therapy, although in select patients may also provide a therapeutic benefit
* '''Indications (2)'''
*#'''≥3 inguinal nodes are involved on one side on pathological examination'''
*#'''Extranodal extension is reported on pathological examination'''

===== Clinical N3 Disease (fixed inguinal nodal pass or pelvic lymphadenopathy) =====
* '''Neoadjuvant chemotherapy (NAC) using a cisplatin- and taxane-based combination should be offered to chemotherapy-fit patients with pelvic lymph node involvement or those with extensive inguinal involvement (cN3), in preference to up front surgery.'''
** Bulky inguinal LN enlargement indicates extensive lymphatic metastatic disease for which few patients will benefit from surgery alone.
** Surgery as the initial treatment in patients with a fixed inguinal mass or clinically evident pelvic adenopathy (cN3) at presentation or recurrence is discouraged in routine management. 
*** Surgery alone will rarely cure patients with cN3 disease.
*** Even when technically feasible, upfront surgery often results in large skin/soft tissue defects, the need for myocutaneous flap reconstruction, prolonged hospital stays and is associated with high overall complication rates
** '''If responding to NAC and resection is feasible, offer surgery''' 
*** ≈50% with advanced (cN2–cN3) penile cancer respond to combination chemotherapy.
*** Responders that subsequently undergo consolidative inguinal/PLND have an OS chance of ≈50% at 5 years.
* If not candidate for conventional multi-agent chemotherapy, pre-operative chemo-radiation/radiation can be offered in an attempt to downsize tumours to improve resectability.
* Surgical resection 
** Timing
*** should proceed 5–8 weeks after completion of chemotherapy to provide time for haematologic recovery and other therapy related symptoms to improve.
** Technique
*** Inguinal LND in cN3 patients often requires resection of overlying skin to effectively remove a fixed bulky nodal mass
** Approach (1)
*** Open
**** Minimally-invasive techniques (i.e., robotic-, laparoscopic ILND) are considered inappropriate in cN3 inguinal metastases
** Pelvic lymph node dissection
*** Simultaneous PLND should be performed at the time of ILND if pelvic LN metastases were clinically evident at diagnosis.
*** Ipsilateral PLND should also be performed in a simultaneous (preferred) or delayed fashion in the setting of advanced bulky inguinal metastases without clinically evident pelvic metastases as well (i.e., prophylactic).

=== Multimodal Chemotherapy/Radiotherapy in the management of regional lymph nodes ===

==== Chemotherapy ====

* Adjuvant chemotherapy
** Have a balanced discussion of risks and benefits with high-risk patients with surgically resected disease, in particular with those with pathological pelvic LN involvement (pN3)

==== Radiotherapy ====

* '''Adjuvant radiation (with or without chemo sensitisation)'''
** '''Indications'''
*** '''pN2/N3 disease (including those who received prior neoadjuvant chemotherapy)'''
* '''Definitive radiotherapy (with or without chemo sensitisation)'''
** '''Indications'''
*** '''Patients unwilling or unable to undergo surgery'''
*** '''cN3 patients who are not candidates for multi-agent chemotherapy'''

=== Advanced disease ===

* Offer patients with distant metastatic disease, platinum-based chemotherapy as the preferred approach to first-line palliative systemic therapy.
* Offer radiotherapy for symptom control (palliation) in advanced disease.