Akshr Ptel ,Arsh O.Nghvi ,Peter A.Johnstone ,Philippe E.Spiess ,G.Dniel Grss ,＊

a University of South Florida Morsani College of Medicine,Tampa,FL,USA

b Department of Radiation Oncology,H.Lee Moffitt Cancer Center and Research Institute,Tampa,FL,USA

c Department of Genitourinary Oncology,H.Lee Moffitt Cancer Center and Research Institute,Tampa,FL,USA

KEYWORDS Brachytherapy;Chemoradiation;Radiation;Radiotherapy;Penile cancer;Squamous cell carcinoma of the penis;Penile-sparing;Penile metastase;Human papillomavirus

Abstract Objective: Penile cancer is a rare malignancy in most developed countries,but may represent a significant oncologic challenge in certain African,Asian,and South American regions.Various treatment approaches have been described in penile cancer,including radiotherapy.This review aimed to provide a synopsis of radiotherapy use in penile cancer management and the associated toxicities.In addition,we aimed to discuss palliative radiation for metastases to the penis and provide a brief overview of how tumor biology may assist with treatment decision-making.Methods: Peer-reviewed manuscripts related to the treatment of penile cancer with radiotherapy were evaluated by a PubMed search(1960-2021)in order to assess its role in the definitive and adjuvant settings.Selected manuscripts were also evaluated for descriptions of radiation-related toxicity.Results: Though surgical resection of the primary is an excellent option for tumor control,select patients may be treated with organ-sparing radiotherapy by either external beam radiation or brachytherapy.Data from randomized controlled trials comparing radiotherapy and surgery are lacking,and thus management is frequently determined by institutional practice patterns and available expertise.Similarly,this lack of clinical trial data leads to divergence in opinion regarding lymph node management.This is further complicated in that many cited studies evaluating lymph node radiotherapy used non-modern radiotherapy delivery techniques.Groin toxicity from either surgery or radiotherapy remains a challenging problem and further risk assessment is needed to guide intensification with multi-modal therapy.Intrinsic differences in tumor biology,based on human papillomavirus infection,may help aid future prognostic and predictive models in patient risk stratification or treatment approach.Conclusion:Penile cancer is a rare disease with limited clinical trial data driving the majority of treatment decisions.As a result,the goal of management is to effectively treat the disease while balancing the importance of quality of life through integrated multidisciplinary discussions.More international collaborations and interrogations of penile cancer biology are needed to better understand this disease and improve patient outcomes.

1.Introduction

Penile cancer mostly affects men past the age of 60 years old and has a prevalence between 0.1 and 1 per 100 000 men in developed countries;however,in certain Asian,African,and South American countries,this may comprise up to 10% of male malignancies [1].Approximately 2000 new cases occur in the United States [2] and about 26 000 globally per year [3].The variance in global incidence is related to multiple risk factors such as human papillomavirus (HPV) infection,tobacco exposure,chronic inflammation,and diverse circumcision practices [1].Due to diversity in socioeconomic and cultural practices,penile squamous cell carcinoma (PSCC) incidence can vary substantially within a single region or country [4].Most (95%)invasive penile cancers arise from mucosal cells of squamous origin and are termed PSCC.The most common site of tumor development is on the glans (35%-48%) [5,6] with approximately 40% being localized disease,which has a 5-year overall survival (OS) rate of approximately 90% [7].Many patients with localized disease may be treated with therapeutic circumcision,partial or total penectomy with urethrostomy.When organ-sparing surgery is not feasible,a penectomy has been associated with a detriment in quality of life,which encompasses urinary and sexual function as well as mental health [8].In patients with regional metastatic disease,the OS can range between 10% and 80%based on the burden of nodal disease despite aggressive inguinopelvic lymph node dissections,chemotherapy,and external beam radiotherapy (EBRT) [9].

Dating back to the early to mid-20th century,clinicians have debated on whether surgery,radiation therapy,or a combination of both should be used in the management of PSCC.An alternative definitive approach in select patients is penile-conserving radiotherapy,which may include EBRT or brachytherapy.These approaches may provide opportunity for organ preservation around 70%-90%and reserve surgery for salvage without a decrease in OS[10].The role of EBRT in more locoregionally advanced disease is controversial as the supporting data are heterogenous and sometimes conflicting.Many of the unanswered questions in multi-modality management are being addressed in the ongoing International Advanced Penile Cancer Trial (InPACT)[11].

High quality evidence is lacking for the management of PSCC and current treatment is commonly based on institutional practice patterns and available expertise.At present,there are no validated biomarkers to guide treatment recommendations,though emerging data suggest HPV infection status may be predictive of radiation response in some patients.

2.Methods

An extensive literature review was conducted within PubMed for all peer-reviewed manuscripts written in the English language between 1960 and 2021 related to the management of penile cancer with radiotherapy.Key search words included “penile cancer”,“penile squamous cell carcinoma”,“penile metastasis”,“radiotherapy”,and“brachytherapy”,independently and with Boolean queries.Given the limited number of articles on the topic,manual investigation of citations within identified articles was also performed.Clinicopathologic,treatment,outcome,and toxicity data were extracted from manuscripts where available for patients treated by radiotherapy with or without chemotherapy.

3.Radiotherapy as definitive management for primary penile cancer

The debate on whether to use radiotherapy,surgery,or both in PSCC management has been ongoing for more than 50 years [12,13].At present,data from randomized controlled trials comparing radiotherapy and surgery are lacking,and thus management is frequently determined by institutional practice patterns and available expertise.This is reflected in a recent National Cancer Database analysis evaluating local management trends in the United States for locally invasive cT1-T3 PSCC where radiation was utilized in 2%-3% of cases between 2004 and 2013 [14].Additional population-based studies noted less than 1% of patients with early stage disease are treated with radiotherapy [15] and less than 0.5% are treated with brachytherapy [16].Thus,definitive EBRT or brachytherapy is chosen infrequently for the management of localized PSCC.

Due to psychosocial consequences associated with deformative penile surgery,organ-sparing surgery or a preservation approach with EBRT or brachytherapy in patients with suitable tumor characteristics is advised;this view is supported by the European Association of Urology(EAU) guidelines [17].Though local recurrence rates with organ-sparing surgery range between 5% and 30%,cancer-specific survival (CSS) may not differ in early stage tumors following a local recurrence,but may be worse in patients with more aggressive disease presentations[18,19].Radiation has been used in patients who wish to avoid penectomy or are elderly and frail.The approach with definitive radiation depends on the size,location,and invasive characteristics of the tumor.Commonly selected tumor attributes suitable for preservation with radiation are superficial or exophytic lesions measuring less than 4 cm in size and localized to the glans or coronal sulcus.Although,tumors less than 4 cm and on the glans with less than 1 cm of invasion may also be suitable for definitive radiation.

3.1.External beam radiation

Localized PSCC may be treated with various penile-sparing techniques,topical therapy (e.g.5-fluorouracil and imiquimod) [20],or penile-sparing surgeries [21].EBRT may also provide the opportunity for functional preservation and adequate tumor control.A major advantage of EBRT is its wide availability and ease of implementation by a radiation oncologist,though a disadvantage is the protracted time required to achieve the desired tumor response over the course of treatment.There are several small heterogeneous cohort series described in the literature,which span a range of tumor staging systems and radiation approaches,reflecting the evolution of treatment approaches over the last several decades.Overall,an approach with EBRT may provide penile preservation rates between 36%and 66% at 5-year (Table 1).

A series from Princess Margaret Hospital demonstrated patients with Tis/T1a(n=11)achieved complete responses with no recurrences at a median follow-up of 7 years;this study used a variety of dose and fractionation schedules making conclusions on treatment approach difficult to interpret [22].As most superficial cases are treated with non-radiation approaches,more advanced disease presentation usually necessitates treating the full thickness of the penis.This requires positioning the penis in a manner to maintain daily reproducibility of target coverage while sparing surrounding normal tissues.A suitable method is to encase the penis in a tissue-equivalent block with a central cylinder.At present,it is recommended to use conventional fractionation to a total dose of 66-70 Gy with fraction sizes of at least 2 Gy.From the selected case series,dosing regimens range from 25 Gy to 74 Gy over a variable number of fractions [22-27] and poor tumor response has been associated with total dose less than 60 Gy [25,28,29].More hypofractionated approaches with 50-55 Gy in 16 fractions may be associated with worse long-term toxicity [24,26].Classically,EBRT yields a local control rate of 60% (range:41%-69%) with 5-year cause-specific survival of 60%[22,24-27].

3.1.1.Treatment set-up

In preparing a patient for definitive EBRT,a radical circumcision is recommended upfront to reduce risk of paraphimosis,foreskin contracture,or tissue necrosis.It is also important to address sperm preservation when necessary.Very localized and superficial lesions (e.g.,Tis,T1a)may be treated by orthovoltage (125 kilovoltage) or 9 MeV electrons with bolus and lead cut outs,similar to skin cancer set-ups.The electron energy should be chosen to ensure that the 90%isodose line achieves coverage at depth with 100% coverage at the surface.For more advanced disease,a block with tissue-equivalent electron density can house the penis and hold it in position to ensure coverage of the entire length and surface when needed.EBRT can be delivered with parallel opposed lateral fields using 4-6 MV energy.Care should be taken to shield the groin and testes with a lead block when needed.

In more advanced disease,radiation to the primary and nodal regions may warranted,but there should be consideration of concurrent chemotherapy.We refer readers to an excellent review on EBRT set-up for more details on positioning and target delineation [30].

3.2.Brachytherapy

Brachytherapy is also a suitable alternative to penectomy in patients with localized PSCC,though this approach is not as widely available due to the need for specific expertise.Patient selection for brachytherapy ideally includes disease limited to the glans,less than 4 cm in diameter,and less than 1 cm of invasion [31-33].With doses ranging from 38 Gy to 70 Gy,the use of brachytherapy offers 5-year local control and penile preservation rates ranging approximately from 70% to 90%,with 5-year OS rates of 63%-100%[10,34],which are comparable to surgical series [35].The 5-year local control rates vary between T1 (89%-91%),T2(75%-78%),and T3 (50%-71%) stage of disease [33,36].Crook et al.[28] also demonstrated no differences in local control with brachytherapy between well-differentiated and moderate/poorly-differentiated tumor histology,though more aggressive disease raises the risk of nodal metastases.Early series reported brachytherapy is associated with a higher penile preservation rate than EBRT(78%vs.64%) [37].In a meta-analysis by Hasan et al.[35],brachytherapy offered superior local control and penile preservation when compared to EBRT(5-year:50%and 49%,respectively),which translated to a significantly higher OS.In this analysis,brachytherapy offered a similar 5-year local control to penectomy (79%vs.84%) without a significant difference in OS (73%vs.76%).This suggests that even in those with a local recurrence after brachytherapy,surgical salvage with penectomy could be employed without an impact on OS.

All forms of brachytherapy offer similar disease control and toxicity (Table 2).Earlier studies predominantly utilized low dose rate (LDR) brachytherapy,with 50-70 Gy delivered continuously over 5 days with a classic dose rate of 50-60 cGy per hour [28,31-33,36,38-43].The use of high dose iridium-192 given in hourly pulses(50-60 cGy per pulse),or pulse dose rate brachytherapy,is treated with similar dosimetric parameters,but between pulses,offers less radiation exposure risk to healthcare staff and family[42,43].More common employment of high dose rate(HDR)brachytherapy offers a similar local control/penile preservation rate,but utilizing a hypofractionated regimen with comparable bioequivalent dosing with 30-54 Gy over 5-9 days using a twice daily (BID) regimen [10,44-49].Recently,HDR has come into favor due to patient convenience,less patient isolation due to lower risk of radiation exposure to staff,and adjustable source dwell time allowing for dose optimization of the target and normal tissue.

Figure 1 High dose rate interstitial penile brachytherapy.(A)Example of a mobile hybrid implantation with interstitial catheters,bolus with external catheters to supplement superficial dose and aid in homogeneity,along with a foley in place during the duration of the implant;(B-D) Treatment planning of a bilateral glans tumor.(B) Axial;(C) Sagittal;(D)Coronal.Note the catheter spacing and dosing,limiting the V150 (blue) and V200 (green) volume to mitigate stenosis/necrosis risk.Note the catheter spacing from the urethra/meatus and supplementing dose from outside of the bolus,allowing a homogenous plan and limiting urethral toxicity.Note the supplemental dose from outside the template contributing to the target volume.

Brachytherapy can either be delivered with interstitial therapy,surface mold,or a hybrid of the two.Interstitial LDR/pulse dose rate requires catheter spacing 12-18 mm between adjacent needles,whereas HDR requires 10-12 mm spacing to avoid hot-spots during dosimetry optimization.Surface mold or “plesiotherapy” can be utilized to treat tumors up to 5 mm in depth or can be used in conjunction with interstitial catheters to improve surface dose and dosing homogeneity (Fig.1).Additional technical details on penile brachytherapy can be found in the American Brachytherapy Society (ABS) and Groupe Européen de Curiethérapie/European Society for Therapeutic Radiation and Oncology(GEC-ESTRO)guidelines[50]as well the experience from Crook et al.[51] with their high-volume experience.Common toxicities with brachytherapy include acute radiodermatitis with a late presentation of soft tissue necrosis (0%-26%) and urethral stenosis(1%-45%)[32,33,36,37,39,41].With the use of dose optimization in HDR,an approach of 3 Gy BID fractionation to 42-54 Gy has been shown to provide local control and penile preservation rates of 86%-100%,with no necrosis or stenosis by limiting the volume receiving 125% and 150% of the prescription dose (i.e.,V125 and V150,respectively)[47,49].The ABS-GEC ESTRO guidelines for penile brachytherapy recommends V125 of less than 50%,V150 of less than 25%,limiting confluent areas of 125% to skin surface,as well as limiting urethral dosing to V115 of less than 10%and V90 of less than 95% [50].Rouscoff et al.[45] utilized HDR to 36-39 Gy in nine fractions with a 5-year local control of 92%and a stenosis and necrosis of 8%,by limiting the V150 of less than 25%,V200 of less than 10 mm,and avoiding confluent V200 isodose lines.Thus,with modern day treatment planning and utilization of HDR,previously seen toxicities can be minimized.Fig.1 demonstrates an example of HDR penile brachytherapy performed at our institution,which employed the volumetric constraints mentioned previously to minimize toxicity.

4.Adjuvant radiotherapy

4.1.Management of primary site

Commonly,adjuvant treatment to the primary site and nodal basins can be considered separately based on risk factors.The role of post-operative EBRT to the primary site is not clearly defined in the literature.Langsenlehner et al.[52] reported a 28.5% 5-year local recurrence rate in a subset of patients (n=14) following incomplete surgical resection who were treated with post-operative EBRT with 45-50 Gy with a boost to the surgical stump up to 60 Gy.Similarly,Zouhair et al.[27]reported a local relapse rate of 25% in patients with positive surgical margins treated with post-operative EBRT.Though the data are limited,post-operative EBRT in patients with positive margins may improve local control and prevent additional tumor-related morbidity.

4.2.Management of nodal sites

PSCC has a high propensity for spread to the inguinal lymph nodes (ILNs) and pelvic lymph nodes (PLNs),which is the most important prognostic factor for survival.PSCC follows a step-wise nodal echelon spread pattern with the most advanced regional disease culminating in the PLNs.Accordingly,survival substantially decreases with nodal burden and location [53],with PLN metastases having a 5-year OS less than 30% [54].A comprehensive description of the surgical management of lymph nodes is beyond the scope of this review;thus we refer readers to an excellent review on this topic by Leone et al.[55].

There are several important points to highlight for the treating radiation oncologist since surgical management of lymph nodes is important to consider when formulating EBRT nodal target volumes in either the definitive or adjuvant setting.First,the optimal management for patients with clinically node negative (cN0) disease is currently undefined and continues to evolve with“risk-adapted”staging approaches characterized by sentinel lymph node mapping or modified superficial lymphadenectomy [56].Even with a modified superficial inguinal lymphadenectomy,morbidity rates can be as high as 30%-40% [57].

If there are palpable or radiologically-evident inguinal nodes (clinically-positive [cN+]) or histologic confirmation on intra-operative assessment (pathologically-positive[pN+]),then a bilateral radical inguinal lymphadenectomy is often indicated.However,if these nodes are fixed or bulky,then neoadjuvant chemotherapy is commonly recommended followed by consolidative surgery [55].PLN dissection is usually advised if there is evidence of ≥2 ILNs,extranodal extension(ENE),or obvious pelvic nodal disease[17,58].Patients with positive ILN have an estimated pelvic node risk of 20%-65% [59].Due to the lack of nodal cross-over,bilateral PLN dissection is only considered if increased risk factors are appreciated in the bilateral ILNs or there is evidence of bilateral PLNs’ involvement;it should be noted that subjecting a patient to a PLN dissection is controversial as 5-year OS is less than 10%and risk of morbidity is substantial [60].

4.2.1.Management of cN0 inguinal node

The role of prophylactic groin EBRT in cN0 patients is unclear.The ILN occult metastasis rate in patients with aggressive primary tumor features (e.g.,>T2,poor differentiation,and perineural invasion) can be about 20%-30%[61].Data from the 1950s have demonstrated that elective groin EBRT using 30-40 Gy results in approximately a 5%risk of pathologic ILN metastases [12,62];these findings led some to believe groin EBRT cannot eradicate micrometastatic disease as this is a similar percentage seen with surgical evaluation in cN0 patients [63].Due to these data,a watch-and-wait approach has been advocated for patients with cN0,yet the EAU and National Comprehensive Cancer Network (NCCN) guidelines are conflicting on recommendations.The EAU guidelines only recommend groin radiation for palliation [17],whereas the NCCN guidelines suggest to consider prophylactic EBRT to ILNs in nonsurgical candidates or those who decline surgery [64].Some providers advised against elective EBRT to the groins because there are few gained benefits and the risk of radiation-related toxicity is high;this is a similar philosophy to early ILN dissection.

The study cited by the EAU guidelines to support no benefit to prophylactic groin EBRT is from Kulkarni and Kamat [65],which compared bilateral ILN dissection,bilateral ILN EBRT,or surveillance in 37 cN0 and 27 cN1-2a(palpable inguinal nodes,but not metastatic) patients within a prospective non-randomized trial from 1979 to 1982.Eighteen of these patients were treated with EBRT,in which 12(67%)were cN0 and 6(33%)were cN1-2a.Although this study identified increased 5-year OS in the surgical versus EBRT group (74%vs.66%),relapse occurred in only two patients(2/18;11%)with EBRT[65].In this study,EBRT was delivered to the inguino-femoral region using 50 Gy over a 5-6 week period,though no additional details of radiation fields and energies are described.Given the years of this study,it can be assumed two-dimensional (2D)planning was employed,possibly with cobalt-60,using opposed fields treated to midplane with or without supplemental electron fields to boost the groins.

The Gynecologic Oncology Group 88 trial evaluated ILN dissection versus prophylactic groin EBRT (50 Gy in 25 fractions prescribed to 3 cm depth in the groin) following resection of the primary cN0 vulvar cancer.This study was stopped early due to excessive groin recurrences in the EBRT arm,suggesting a lack of benefit for groin EBRT in cN0 patients [66].This EBRT approach in the Gynecologic Oncology Group 88 is similar to earlier PSCC studies,but Koh et al.[67] demonstrated that prescribing to this depth(3 cm)using computed tomography-based planning leads to inferior inguinal nodal coverage,as the median patient depth was approximately 6.0 cm(range:2.0-18.5 cm);this results in EBRT doses of less than 50 Gy,which may not be sufficient in patients with high-risk primary disease and occult ILN metastasis rates of about 20%-30%.

4.2.2.Management of ILN cN+or pN+

In patients with cN+or pN+ILNs,inguinal EBRT may provide improved locoregional control,though adjuvant inguinal lymph node EBRT(AIRT)has not been vigorously evaluated.For this reason,there currently is no level I evidence to define the role of AIRT in PSCC.The NCCN guidelines(version 2.2021) recommend adjuvant EBRT if any of the following high-risk features are present:positive surgical margins,≥2 pelvic nodal metastases,ENE,bilateral inguinal nodal involvement,or ≥4 cm tumor deposit in lymph nodes [64].Interestingly,Winters et al.[68]found that patients treated at academic centers were 50% less likely to receive AIRT compared to those treated at community cancer programs,which suggests academic physicians may prefer not to treat patients without level I evidence compared to non-academic practices.It should be noted that this is in contrast to the EAU guidelines,which indicate adjuvant EBRT should not be given due to the lack of prospective data[17].Select studies evaluating adjuvant ILN with or without PLN radiation and chemotherapy±PLN±chemotherapy are shown in Table 3.

Earlier studies,using antiquated EBRT delivery techniques (e.g.,no megavoltage energies,thus beam penetration to target region is of question) have demonstrated less than optimal tumor control in the groins[12,69,70]and have supported the view that EBRT to the groins does not provide substantial benefit[71].A study by Mistry et al.[26]describes 65 patients treated between 1993 and 2003,in which eight underwent ILN dissection with one treated with AIRT;the surgery alone group had a groin recurrence rate of 43% (3/7) versus 0% (0/1) with AIRT.In this study,four patients with cN+disease received EBRT alone with palliative intent using doses ranging from 12 Gy to 40 Gy in a hypofractionated manner,which resulted in 50% groin control rate [26].It is hard to draw conclusions from this study about ILN EBRT efficacy.

A systematic review by Robinson et al.[72]identified only seven studies suitable for evaluating AIRT following lymph node dissection,all of which were retrospective,highly heterogeneous,and limited by high selection bias.As this analysis is the most robust to date,it is important to highlight several aspects of the cohorts that form the basis of the authors conclusions,which recommend against AIRT.First,this analysis encompassed 1605 patients,of which only 114 had data available for AIRT-specific evaluation.The regional recurrence rate following AIRT ranged from 10% to 92%(derived from five studies).Three of the studies were from patients treated from the 1950s to late 1990s,and thus the majority of these patients were treated with 2D treatment planning.This is an important point as conventional EBRT fields were based on bony landmarks,and as subsequent studies in vulvar cancer have demonstrated,this 2D approach leads to inferior target coverage in the deep-seated inguinal-femoral nodal regions[67],though this has not been formally evaluated in the adjuvant setting for PSCC.

The largest cohort in the study by Djajadiningrat et al.[7] (n=944,1956-2012) provided no information on the number of men receiving AIRT nor the ILN recurrence rates following EBRT.They indicated that AIRT was given to patients with ≥2 ILN positive and/or ENE on pathology evaluation,which was delivered with 50 Gy/25 fractions.This dataset overlaps with the study by Graafland et al.[73],which described a cohort of 161 patients,of which 67 were treated with ipsilateral AIRT for similar indications as the former study using non-volumetric planning.The overall 5-year ILN recurrence rate was 16%,but the recurrence rates in all the patients treated with AIRT are not provided.It is noted that of the 26 patients that had an inguinal recurrence,42% received AIRT and three of these relapsed during treatment [73].

The 2nd largest cohort (n=285) by Ravi et al.[74] contains a subset of only 12 patients treated with adjuvant groin EBRT due to ENE,in which the 5-year disease-free survival (DFS) was 8% in those 12 patients.The AIRT in this study was delivered with 2D planning and dose to the groins was not defined.Interestingly,this study found that pre-operative groin EBRT for patients (n=38) with mobile nodes ≥4 cm reduced the rate of ENE to 8%and resulted in only 3%of patients having a post-operative groin recurrence[74].The study by Demkow [75] described a series of 64 men,of which about half underwent ILN dissection.The 12 patients that received AIRT had a 17% OS rate at a median follow-up of 33 months.No details on the radiation approach were provided [74].

Chen and Wu [76] reported a subset of 40 men with PSCC,of whom 14 underwent ILN dissection,and of these,nine received AIRT.The radiation included high energy 10-15 MV photons or a mixed field with 12 MeV electrons to boost the inguinal fields.The depth was prescribed to the deepest margin of the femoral vessels with CT-based planning,or 4-5 cm if non-volumetric planning was utilized.The median radiation dose was 54 Gy (range:40-70 Gy) using conventional fractionation,which was described to cover the primary site,areas of local extension,bilateral ILNs,and lower iliac lymph nodes.With this approach,only one(11%)patient had a regional recurrence with AIRT compared to 60% (3 of 5) of patients with ILN dissection alone.Franks et al.[77] described a series of 23 men,in which 14 were treated with adjuvant radiation to both the ILNs and PLNs between 2002 and 2008.All of these patients who underwent CT-based volumetric planning with coverage of the bilateral iliac,inguinal,obturator,and presacral nodes were treated with 45 Gy in 20 fractions with or without an additional 12 Gy boost to areas at risk.Six patients (43%) had locoregional recurrence at 3 years and ENE portended worse tumor control [77].These data form the basis of the EAU guidelines,which currently do not recommend AIRT.

An important point to consider when critically evaluating these data is the radiation approaches used in these studies.Mittal et al.[78] recently analyzed the location of greater than 200 ILNs in 33 patients with cN+PSCC and found that 99% of nodes were anterior (81% antero-medial and 18%antero-lateral) to the femoral vessels with 95% being superior to the pubic symphysis;with these data they proposed variable margin expansions off the vessels to encompass at least 95%of mapped ILNs.The implementation of intensitymodulated radiation therapy with daily image guidance now provides the opportunity for three-dimensional CT-based anatomic delineation coupled with highly conformal dose coverage,which can reduce dose to skin,bowel,bladder,femoral heads,and genitalia in order to reduce toxicity[79].With increasing use of implementation of intensitymodulated radiation therapy in the management of PSCC,it is prudent to reevaluate the efficacy of ILN EBRT.

4.2.3.Management of pN3 inguinal nodes with ENE or pelvic nodes with or without ENE

In patients with pN3 disease,adjuvant chemotherapy is commonly recommended as it has been demonstrated to improve OS after surgery.This is supported by a pooled retrospective analysis suggesting adjuvant chemotherapy may be superior for patients with pN3 following inguinopelvic lymph node dissection,though these patients were younger,had less aggressive histology and less bilateral inguinal disease [80].Other studies (all with less than 20 patients) have also suggested adjuvant chemotherapy can improve tumor control [81].More recently,neoadjuvant chemotherapy is being used in patients with positive PLNs,which is supported by data extrapolated from patients with unresectable,bulky,or fixed inguinal nodes.These data suggested about 50%response rates resulting in one-third of patients being alive at least 2 years after therapy [82,83].

Whether EBRT provides a benefit in this subset of patients is a topic of debate,as data are mixed and from heterogeneous small cohorts treated with various chemotherapy and radiation sequences.Tang et al.[84] described a multi-institutional cohort of 40 pN3 (pelvic node) patients treated with adjuvant pelvic radiation;and at a median follow-up of 9.3 months,they identified improved diseasespecific survival (14.4vs.8 months) and time to recurrence(7.7vs.5.3 months)with adjuvant pelvic radiation versus no radiation.A population-based analysis found that at a median follow-up of 25 months,concurrent chemoradiation(CRT)did not improve CSS in comparison to chemotherapy in all-comers,but was superior to chemotherapy alone in the pN3 subset(n=77)with a 2-year CSS of 51%versus 24%[84].The data by Johnstone et al.[85] included a pooled multiinstitutional cohort of 93 patients with pN3 disease and despite adjuvant EBRT (50 Gy in 25 fractions),81% of ENE sites had a recurrence in the treatment field.Interestingly,risk of recurrence was independent of ENE or whether adjuvant EBRT was administered,which may be related to an elevated baseline risk in this poor prognostic population.Yuan et al.[86] reported on 34 patients (88% received concurrent chemotherapy) treated with adjuvant radiation for pN2 and pN3 with a median dose of 50 Gy (range:42.5-64.8 Gy),which provided 60%locoregional control at a follow-up of 12 months.

Ager et al.[87] reported on 121 patients with ENE (74%inguinal and 25% pelvic) treated between 2002 and 2017 at two hospitals that underwent ILN dissection with or without dissection of PLN,followed by a complete course of adjuvant EBRT (41% received concurrent chemotherapy) and found a 5-year relapse free survival of 51%,CSS of 51%,and OS of 44%.The EBRT doses in this study varied from 45 Gy in 20 fractions or 50-60 Gy in 25-30 fractions;in-field recurrence was two-fold higher in patients receiving 50 Gy or less.Khurud et al.[88] recently reported a retrospective study of 128 men with pN3 (24% with pelvic nodes with 57% having ENE) treated with adjuvant chemotherapy(n=24;19%),radiation alone(n=16;12%)or multimodality therapy (48%) characterized by CRT(n=16;13%),sequential chemotherapy and radiation (n=31;24%),or chemotherapy and CRT(n=15;12%).Overall,about 50%of patients had a regional relapse,in which 19% recurred following RT (20% were in-field),though patients treated with intensified sequential chemotherapy and CRT adjuvant therapy had improved DFS.This study found chemotherapy and radiation have similar DFS and OS in only ILN positive patients,but sequential chemotherapy and CRT were superior in PLN+patients.

Choo et al.[89]evaluated 11 patients at Mayo Clinic who underwent inguinopelvic lymph node dissection (72% with pN3) and found a 2-year CSS of 55% with adjuvant CRT versus surveillance (28%);it should be noted the CRT group had a higher proportion of patients with pN3,greater than five lymph nodes,and ENE compared to the surveillance group.The EBRT target volumes in this study included the bilateral ILNs and PLNs with an average dose of 56 Gy in 28 fractions to involved regions and 45 Gy to uninvolved nodes,which resulted in 55% risk of locoregional relapse.Another case series reported by Jaipuria et al.[90] found that adjuvant EBRT in ILN+only patients provided better OS compared to chemotherapy,though in patients with PLN+disease,CRT provided no benefit over chemotherapy.

Last,a modern pooled study of 93 patients with pN3(ENE) in the ILNs demonstrated superior 3-year CSS(29%vs.16%) with adjuvant CRT versus adjuvant chemotherapy alone[91].Pond et al.[92]reported poor outcomes with CRT in locally-advanced PSCC (n=21) with a median OS of 10 months.Though the authors mention the median EBRT dose was 49 Gy,there is no separate description of the dose used in non-metastatic patients,which may be the reason why EBRT dose was associated with improved OS and progression-free survival for every 10 Gy increase [92].Overall,pN3 has variable outcomes with PLN positivity being associated with worse outcomes.Adjuvant CRT is expected to provide roughly 50%CSS at 2-5 years based on these data.

Overall,there is still uncertainty surrounding the effectiveness of adjuvant inguinal or pelvic EBRT in patients with node positive cancer due to the lack of randomized control trials.The majority of evidence is limited by small patient numbers,heterogenous treatment approaches as well as indications for treatment selection.Typically,radiotherapy should be avoided in patients that are cN0,as radiotherapy related complications outweigh the few benefits that patients may receive from treatment [55].Though prospective data have demonstrated that other anogenital squamous malignancies (e.g.,anus,cervical,and vulvar) have improved outcomes with CRT [30],the burden of supporting evidence in PSCC is scarce.The world eagerly awaits the results of the InPACT to resolve some of these questions,which also provide guidance on target delineation for radiation planning[11].In this regard,Fig.2 is an example of a patient treated with adjuvant CRT targeting the prepubic fat,bilateral ILN,and PLN basins.

5.Management of penile cancer metastases to the penis

Metastatic cancer to the penis is very rare with no consensus on the optimal treatment approach.The first case was described in the late 1800s by Eberth with about 500 cases described since then [93,94],with most being in the setting of metachronous spread [95].A review of the literature by Hizli and Berkmen [96] found the most common primary tumors metastasizing to the penis are the bladder (34.7%),prostate (29.8%),rectum-sigmoid colon(15.7%),and kidney(6.5%).Despite the infrequency,penile metastases should be addressed,even in the presence of multi-site metastases,as these patients may become symptomatic with swelling,ulceration,and severe pain.With advancements in imaging approaches [97],occult metastases may be identified without symptoms [98,99].

Malignant priapism,or painful induration and erection of the penis secondary to tumor invasion,may occur in 20%-40%of men,which requires palliative treatment[100].There are a handful of case series describing the efficacy of palliative radiotherapy for penile metastases with a recent review identifying 42 cases of malignant priapism originating from various primary origins;in this review,only 38%of cases were addressed with radiotherapy[100].A range of radiation doses have been described utilizing standard palliative approaches (e.g.,8 Gy in one fraction,20-30 Gy in 5-10 fractions) or more aggressive approaches up to 60 Gy in 30 fractions [100,101];notably,some patients achieved pain relief with lower doses,whereas other achieved minimal response with higher doses.Given the dearth of data to guide metastases to the penis,a multidisciplinary discussion should guide treatment recommendations with the overall goal of care directed at palliation to improve quality of life.

6.Radiation-related toxicities

Management of penile cancer with radiotherapy is associated with certain toxicities and potential risk for long-term complications.Complication risks differ whether the target is the intact penis or nodal basins and by the form and total dose of radiation utilized.The degree of skin toxicity may vary by intrinsic patient sensitivity,body habitus,dose per fraction,bolus administration,or use of chemotherapy.

Figure 2 Adjuvant EBRT to prepubic fat and bilateral ILNs and PLNs.Case of a 55-year-old male with hrHPV-pT3 N3 M0 poorly differentiated PSCC of the glans status post partial penectomy with mons panniculectomy requiring reconstruction with split thickness graft.Approximately 2 months later he underwent bilateral superficial and deep ILN dissection with pathology demonstrating negative margins at the primary site and 3/15 ILNs involved with malignancy with evidence of bilateral ENE.(A and B)Axial slices showing the prepubic space(green),bilateral ILNs (blue),and bilateral PLNs (pink) clinical target volumes;(C) Sagittal view demonstrating prepubic space and PLN coverage;(D) Coronal view showing prepubic space and ILN interface.Other organs at risk include bladder(yellow) and rectum (brown).The patient was treated with 52 Gy to the prepubic fat and bilateral PLNs and 62.4 Gy to the bilateral ILNs over 26 fractions with concurrent weekly cisplatin.EBRT,external beam radiotherapy;ILN,lymph node;PLN,pelvic lymph node;hrHPV,high-risk HPV;PSCC,penile squamous cell carcinoma;ENE,extranodal extension;R,rectum.

Acutely,EBRT delivered with conventional fractionation(e.g.,2 Gy per fraction) may result in mild penile edema,radiodermatitis,and moist desquamation.Most acute skin reactions were resolved in 2-4 weeks,but chronic skin changes such as telangiectasias,hyperpigmentation,and superficial scarring may present at later follow-up.Use of conventional fractionation may result in a skin necrosis risk of 1%-3%,whereas hypofractionated approaches can increase this risk to 8%-10% [34].Conservative measures to maintain skin barrier protection and maximize hygiene are necessary to minimize these toxicities.

The penis is susceptible to develop necrosis from brachytherapy with the risk varying based on LDR versus HDR approaches,depth of tumor invasion,and dose distribution required for target coverage.LDR experiences have reported necrosis risk at 0%-26% with HDR having a risk of 0%-8%.The acute moist desquamation may present 2-3 weeks after brachytherapy and can take upwards of 2-3 months to resolve.If necrosis develops,it usually occurs within the first 1-2 years [30].As stated previously,close attention to patient selection and volume-dose constraints provided by the ABS-GEC ESTRO guidelines[50]may reduce these risks compared to historical experiences.Following local tumor control,necrosis is the most common reason for loss of organ preservation,which is supported by the experience of Rozan et al.[37] where about 30% of men underwent penile amputation secondary to treatment related necrosis.Hyperbaric oxygen may be an effective treatment option for severe and refractory tissue necrosis[102].

A dreaded complication seen after radiation,either EBRT or brachytherapy,is meatal stenosis.Stenosis can cause major detriment to urinary and sexual quality of life.Similar to necrosis,the risk of stenosis can increase from 10%to 30%with the use of hypofractionated EBRT.Some LDR and HDR experiences have reported stenosis rates up to 45%and from 0%to 40%,respectively[10,34].This risk may vary based on interstitial versus surface mold approaches or proximity of needles to distal tip of glans [34].If stenosis develops acutely,it is usually treated with early iterative dilatation to minimize risk for chronic stricture formation.In one series,9% of patients required penectomy secondary to severe fibrosis,but this remains relatively uncommon[42].

With penile preservation,maintenance of sexual function is important for many men[103].A small study done by Delaunay et al.[104] found that approximately 60% of sexually active men maintained sexual activity after brachytherapy with 95% also maintaining erections.At a median follow-up of 5.9 years,Gambachidze et al.[105]reported 70% of men maintained sexual activity with little erectile dysfunction in a questionnaire study.Martz et al.[10] also reported no significant detriment in sexual function using the International Index of Erectile Dysfunction-5 score.Thus,there may be a high chance for maintenance of sexual function following definitive therapy to an intact penis.

Additionally,patients who have undergone total or partial penectomy resulting in perineal urethrostomy (PU)may require adjuvant radiation therapy for high-risk features.de Vries et al.[106] recently reported on a 20-year multi-institutional cohort of 299 patients undergoing PU and found a crude rate of 12% for developing stenosis,of which 74% required surgical revision within 1 year.Data on the use of radiation in the setting of a PU are limited.Within this same patient cohort,Johnstone [107] reported rates of PU stenosis in the subset that received adjuvant EBRT (n=37) were not significantly different compared to those not treated with EBRT (19%vs.11%);the adjuvant EBRT group had a lower frequency of surgical revision(5%vs.9%),which may be due to exclusion of the PU in the EBRT field unless positive surgical margins are appreciated.

The toxicity following AIRT or pelvic RT is not well defined.Modern series of ILN dissection suggested surgical complication risks (e.g.,wound infection,dehiscence,necrosis,and lymphedema)may range between 40% and 60%,but vary widely based on approach [55].In series that reported lymphedema rates,AIRT is associated with a risk between 22% and 45% [78,88-90,100,108].

The risk of secondary malignancy following radiation is also of concern,especially in younger men,but overall this risk remains extremely low.Ravi[109]described a cohort of five patients who were treated with EBRT(>50 Gy)for PSCC and later developed a secondary poorly-differentiated carcinoma at a mean of 13 years.Similarly,two cases have been described following interstitial brachytherapy after 15 years and a single case of angiosarcoma was reported at 18 years[110].Therefore,long-term surveillance in young men is warranted following radiotherapy to the penis.

7.Radiation in the era of molecular biology

Infection with high-risk HPV (hrHPV) has been associated with approximately 30%-50% of PSCC cases,but may vary depending on population studied and method of detection[111-113].Data regarding the prognostic impact of hrHPV infection are mixed.An earlier study by Bezerra et al.[114]examined 82 cases and detected hrHPV DNA in 31%of PSCC tumors,but after adjusting for clinicopathologic factors no difference in 10-year OS was noted based on hrHPV infection status.Similarly,in a study of grouped primary and metastatic PSCC patients (n=29),hrHPV infection status was also not prognostic of survival [115].In contrast,Lont et al.[116]described a series of 171 men(29%hrHPV+)and found differences in 5-year DFS favoring HPV positivity(92%vs.78%).In a separate and updated analysis within the overlapping Dutch cohort,hrHPV+remained associated with improved 5-year DFS(96%vs.82%)even after adjusting for other variables [117].Though there are contradictory findings across institutional cohorts,a recent systematic review and meta-analysis of 20 studies found both hrHPVand p16-positivity were associated with improved tumor control compared to HPV-or p16-negative patients [118].

There are little data on how HPV status influences responsiveness to EBRT in PSCC.This was first explored by Yuan et al.[119]in a study of 51 men(45%hrHPV+),which found that in men treated with adjuvant CRT (n=17),HPV+provided an absolute 45% improvement in 2-year locoregional control compared to HPV-men.Similarly,a multi-institutional study by Bandini et al.[120] found that peri-operative EBRT in 49 patients (82% adjuvant) resulted in improved median OS in the HPV+versus HPV-patients,which remained significant in propensity core matching up to 10 years of follow-up.Thus,it is possible that the molecular machinery of HPV+tumors is distinct from HPVtumors and that this may influence radiation sensitivity.A hypothesis-generating study using the genomic-adjusted radiation dose [121],which is derived from the radiosensitivity index,a 10-gene signature that estimates intrinsic radiation sensitivity [122],suggested 50% of PSCC patients treated with 50-54 Gy would achieve adequate locoregional control [86,123].These data suggested uniform radiation dosing has not yet been optimized based on underlying patient tumor biology.

HPV-driven PSCC tumors have distinct genomic profiles and mutational frequencies compared to their HPVcounterparts [124,125].A common finding in profiling HPVmediated tumors is the lack ofTP53mutations,which has been seen PSCC [120].The p53 biology is complex and context dependent,and thus p53 staining via immunohistochemistry may not fully recapitulate the complexity of p53-mediated radiation responses,which appear to be driven by dynamic signaling events in a tissue-dependent manner [126].Therefore,HPV status should be evaluated in future investigations describing the effects of RT or CRT in regard to PSCC response [127].Given the broad molecular orchestration guided by HPV genomes and p53,future studies are likely to identify novel biomarkers to help guide treatment decisions in this population.

8.Conclusion

Penile cancer is a rare disease with limited clinical trial data driving the majority of treatment decisions.As a result,the goal of management for the tumor should be to effectively treat the disease while balancing the importance of quality of life.Radiation therapy is underutilized and radiation oncologists should be proactive in educating surgical and dermatology colleagues of the utility of radiation as a functional penile-sparing modality.In specific instances,radiotherapy can be used in the adjuvant management of the primary and nodal sites post resection;however,there is lack of quality evidence demonstrating the effectiveness of radiotherapy in these cases.The data gathered from the InPACT will further help develop better management options for these patients.As the molecular revolution continues to advance,additional insights will be gained when comparing tumors by HPV infection status.At present,preliminary data suggest HPV+tumors may be more radiosensitive,but this requires further validation.

Author contributions

Study concept and design: Akshar Patel,Arash O.Naghavi,G.Daniel Grass.

Data acquisition:Akshar Patel,Arash O.Naghavi,G.Daniel Grass.

Data analysis: Akshar Patel,Arash O.Naghavi,G.Daniel Grass.

Drafting of manuscript: Akshar Patel,Arash O.Naghavi,Peter A.Johnstone,Philippe E.Spiess,G.Daniel Grass.

Critical revision of the manuscript: Peter A.Johnstone,Philippe E.Spiess,G.Daniel Grass.

Conflicts of interest

Philippe E.Spiess is the President of Global Society of Rare Genitourinary Tumors,the vice-chair NCCN bladder and penile cancer,and a member of ASCO/EAU penile cancer panel.Other authors declare no other conflict of interest.