This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2021 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada. Evaluation of the Guidelines for Penile Cancer Treatment: Overview and Assessment Abdulmajeed Aydh,1,2 Shahrokh F. Shariat,1,3,4,5,6,7,8,9 Reza Sari Motlagh,1 Ekaterina Laukhtina,1,9 Fahad Quhal,1,10 Keiichiro Mori,1,11 Hadi Mostafaei,1,12 Andrea Necchi,13 Benjamin Pradere1,14 1 Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 2 Department of Urology, King Faisal Medical City, Abha, Saudi Arabia 3 Department of Urology, Weill Cornell Medical College, New York, United States 4 Department of Urology, University of Texas Southwestern, Dallas, United States 5 Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic 6 European Association of Urology Research Foundation, Arnhem, Netherlands 7 Karl Landsteiner Institute, Vienna, Austria 8Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan 9 Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia 10 Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia 11 Department of Urology, Jikei University School of Medicine, Tokyo, Japan 12 Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 13 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 14 Department of Urology, University Hospital of Tours, Tours, France Abstract Introduction Medical organizations have provided evidence-based guidelines for penile cancer treatment. This current review aims to compare and appraise guidelines on penile cancer treatment to provide a useful summary for clinicians. Materials and Methods We searched in PubMed and Medline for guidelines published between January 1, 2010, and February 1, 2020. The search query terms were “penile cancer,” “penile tumor,” “guidelines,” and “penile malignancy.” In the final analysis, we include the most recent versions of relevant guidelines published in English. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument was used to appraise the quality of each guideline. Results In the final analysis, we included guidelines from the National Comprehensive Cancer Network (updated in 2020), The European Association of Urology (updated in 2018), and The European Society for Medical Oncology (published in 2013). The overall agreement among reviewers was excellent. The range of scores for each domain was as follows: scope and purpose (46% to 61%); stakeholder involvement (33% to 60%); rigor of development (34% to 69%); clarity and presentation (61% to 81%); applicability (33% to 59%) and editorial independence (52% to 78%). The European Association of Urology and National Comprehensive Cancer Network clinical practice guidelines received better scores according to the AGREE II evaluation. Conclusion Despite the effort made by the guidelines groups to make a practical guideline regarding penile cancer treatment, the actual available evidence is weak. However, we believe our recommendations offer clear guidance. Introduction Penile cancer is an aggressive disease that represents less than 1% of all malignancies in the United States and Europe[1,2]. Penile cancer is common in the elderly, with a peak incidence in the seventh decade of life[3]. The most com¬mon histological subtype for penile cancer is squamous cell carcinoma[4]. Given the complex nature of penile cancer, different therapeutic options are available. Furthermore, there is growing interest in molecularly targeted Key Words Competing Interests Article Information Guidelines, penile cancer, penile malignancy, penile tumor None declared. Received on December 22, 2020 Accepted on March 1, 2021 Soc Int Urol J.2021;2(3):171–186 DOI: https://doi:10.48083/TKFP8406 171SIUJ.ORG SIUJ • Volume 2, Number 3 • May 2021 REVIEW mailto:shahrokh.shariat%40meduniwien.ac.at?subject=SIUJ https://doi:10.48083/TKFP8406 http://www.siuj.org therapy, and tyrosine kinase inhibitors are showing promising results[5]. However, because of its rarity, most of the recommendations mainly rely on retrospective studies[6,7]. In the last decade, several scientific organizations have provided evidence-based guidelines to improve patients' selection of each treatment modality. The European Association of Urology (EAU) guidelines on Penile Cancer were first published in 2000 and were last updated in 2018. The National Comprehensive Cancer Network (NCCN) penile cancer guidelines were last updated in 2020, while the last European Society for Medical Oncology (ESMO) clinical practice guidelines was released in 2013. This study aims to conduct a review, comparison, and appraisal of the guidelines on the treatment of penile cancer to provide universal and practical guidance for physicians in their clinical decision-making. We aimed to provide authoritative guidance with clear recommendations from the best guidelines. Materials and Methods We searched PubMed and Medline for guidelines published between January 1, 2010, and February 1, 2020. The search terms were “penile cancer,” “penile tumor,” “guidelines,” and “penile malignancy.” Also, we searched through the websites of international urology and oncology societies for the most recent guidelines on penile cancer. In the final analysis, we included the most recent English version of each guideline. Non-English national guidelines were excluded. The Appraisal of Guidelines for Research and Evaluation Abbreviations AGREE II Appraisal of Guidelines for Research and Evaluation II NCCN National Comprehensive Cancer Network EAU European Association of Urology ESMO European Society for Medical Oncology EBRT external beam radiation therapy PLND pelvic lymph node dissection LOE level of evidence GOR grade of recommendation TABLE 1. Guidelines for the management penile cancer according to T stage Treatment EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE Tis Topical treatment with 5-fluorouracil (5-FU) or imiquimod 5-FU is an effective first-line treatment Strong recommendation Tis, Ta, and T1 penile cancer lesions may be amenable to conservative penile organ-sparing approaches, including topical therapy Considered appropriate 2A Penile-preserving techniques, including topical therapy (5% 5-fluorouracil and 5% imiquimod cream) C IV Laser ablation (Nd:YAG) or Carbon dioxide (CO2) laser is an effective treatment option Strong recommendation The use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes Considered appropriate 2B Laser therapy using CO2 or Nd: YAG laser C III Glans resurfacing Glans resurfacing, total or partial, can be a primary treatment for PeIN or a secondary Strong recommendation Glansectomy, removal of the glans penis, may be considered for patients with distal tumors Considered appropriate 2B Partial/total glans resurfacing C III Wide local excision with circumcision Glans resurfacing, total or partial, can be a primary treatment for PeIN or a secondary Penile tumors of the shaft may be treated with wide local excision, with or without circumcision Considered appropriate 2A Wide local excision and circumcision C IV Mohs surgery Historical technique Mohs surgery is an alternative to wide local excision in select cases 2B 172 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org II (AGREE II) instrument was used to appraise the quality of guidelines[8]. This instrument permits the evaluation of the scope and purpose of the guidelines, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. The overall assessment is the final mean of all domains, which gives an overview of each guideline score. The AGREE II recommends 2 or more appraisers. Therefore, each guideline was evaluated by 5 appraisers (BP, EL, FQ, HM, and KM) to enhance the authenticity of the assessment. The appraisal was performed after the completion of an online training module on AGREE II website[9]. The 5 reviewers were experienced in urologic oncology and were mentored by 2 oncologic urologists (SFS, BP) experienced in guidelines writing and grade of recommendation rating. Results Guidelines from 3 international organizations were included in the final analysis: the 2020 update of the NCCN guideline[10], the 2018 update of the EAU guidelines[11], and the 2013 update of the ESMO guidelines[12]. Level of evidence assessment and grading of recommendations Two guidelines (EAU and NCCN) provided a detailed and strict methodology for searching and acquisition of evidence from the literature. The ESMO guideline is an expert consensus statement so did not include a systematic literature search. All 3 guidelines (EAU, NCCN, and ESMO) provided a description of the systems used for grading the level of evidence. In the EAU guidelines, a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used[13,14]. For each recommendation within the guidelines, there was also an accompanying online strength rating form, which addresses several elements. The NCCN guidelines used the Categories of Evidence and Consensus to grade the recommendations; they also provide Categories of Preference to help users chose the optimal recommendation based on efficacy, safety, evidence, or affordability. The ESMO guidelines adapted the Infectious Diseases Society of America-United States Public Health Service Grading System[15]. continued on page 174 TABLE 1. Guidelines for the management penile cancer according to T stage Treatment EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE Tis Topical treatment with 5-fluorouracil (5-FU) or imiquimod 5-FU is an effective first-line treatment Strong recommendation Tis, Ta, and T1 penile cancer lesions may be amenable to conservative penile organ-sparing approaches, including topical therapy Considered appropriate 2A Penile-preserving techniques, including topical therapy (5% 5-fluorouracil and 5% imiquimod cream) C IV Laser ablation (Nd:YAG) or Carbon dioxide (CO2) laser is an effective treatment option Strong recommendation The use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes Considered appropriate 2B Laser therapy using CO2 or Nd: YAG laser C III Glans resurfacing Glans resurfacing, total or partial, can be a primary treatment for PeIN or a secondary Strong recommendation Glansectomy, removal of the glans penis, may be considered for patients with distal tumors Considered appropriate 2B Partial/total glans resurfacing C III Wide local excision with circumcision Glans resurfacing, total or partial, can be a primary treatment for PeIN or a secondary Penile tumors of the shaft may be treated with wide local excision, with or without circumcision Considered appropriate 2A Wide local excision and circumcision C IV Mohs surgery Historical technique Mohs surgery is an alternative to wide local excision in select cases 2B 173SIUJ.ORG SIUJ • Volume 2, Number 3 • May 2021 Evaluation of the Guidelines for Penile Cancer Treatment: Overview and Assessment http://siuj.org TABLE 1. Guidelines for the management penile cancer according to T stage, Cont'd Treatment EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE Ta, T1a (G1, G2) Wide local excision with circumcision Partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Penile tumors of the shaft may be treated with wide local excision, with or without circumcision Considered appropriate 2A Penile-preserving techniques, including wide local excision plus reconstructive surgery C III Glans resurfacing Partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Glansectomy may be considered for select patients with distal tumors Considered appropriate 2B Glansectomy with reconstruction Partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Glansectomy is not recommended unless required to ensure complete tumor eradication with negative margins Considered appropriate 2A Radiotherapy External beam radiotherapy or brachytherapy is radiotherapeutic options Strong recommendation 2B Consider <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy Considered appropriate 2B Radiotherapy delivered as EBRT or brachytherapy with interstitial implant C IV Laser ablation Small lesions can also be treated by laser therapy Strong recommendation The use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes Considered appropriate 2B Laser therapy C IV Partial penectomy Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A Mohs surgery Strong recommendation Mohs surgery is an alternative to wide local excision in select cases. Considered appropriate 2B STAGE T1B (G3) AND T2 Wide local excision plus reconstruction Local excision, partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Penile tumors of the shaft may be treated with wide local excision Considered appropriate 2A If tumor <50% of the glans and no invasion of the corpora cavernosa B III Glansectomy with circumcision and reconstruction Local excision, partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Glansectomy may be considered for select patients with distal tumors Considered appropriate 2A If tumor <50% of the glans and no invasion of the corpora cavernosa B III Radiotherapy External beam radiotherapy or brachytherapy is radiotherapeutic options Strong recommendation Consider <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy Considered appropriate 2B <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy III Total penectomy OR Partial Total glansectomy, with or without resurfacing of the corporeal heads, is recommended Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A Tumors with invasion into corpora cavernosa B III 174 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org TABLE 1. Guidelines for the management penile cancer according to T stage, Cont'd Treatment EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE Ta, T1a (G1, G2) Wide local excision with circumcision Partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Penile tumors of the shaft may be treated with wide local excision, with or without circumcision Considered appropriate 2A Penile-preserving techniques, including wide local excision plus reconstructive surgery C III Glans resurfacing Partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Glansectomy may be considered for select patients with distal tumors Considered appropriate 2B Glansectomy with reconstruction Partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Glansectomy is not recommended unless required to ensure complete tumor eradication with negative margins Considered appropriate 2A Radiotherapy External beam radiotherapy or brachytherapy is radiotherapeutic options Strong recommendation 2B Consider <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy Considered appropriate 2B Radiotherapy delivered as EBRT or brachytherapy with interstitial implant C IV Laser ablation Small lesions can also be treated by laser therapy Strong recommendation The use of therapeutic lasers to treat selected primary penile tumors has been reported with acceptable outcomes Considered appropriate 2B Laser therapy C IV Partial penectomy Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A Mohs surgery Strong recommendation Mohs surgery is an alternative to wide local excision in select cases. Considered appropriate 2B STAGE T1B (G3) AND T2 Wide local excision plus reconstruction Local excision, partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Penile tumors of the shaft may be treated with wide local excision Considered appropriate 2A If tumor <50% of the glans and no invasion of the corpora cavernosa B III Glansectomy with circumcision and reconstruction Local excision, partial glansectomy or total glansectomy with reconstruction are surgical options Strong recommendation Glansectomy may be considered for select patients with distal tumors Considered appropriate 2A If tumor <50% of the glans and no invasion of the corpora cavernosa B III Radiotherapy External beam radiotherapy or brachytherapy is radiotherapeutic options Strong recommendation Consider <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy Considered appropriate 2B <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy III Total penectomy OR Partial Total glansectomy, with or without resurfacing of the corporeal heads, is recommended Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A Tumors with invasion into corpora cavernosa B III continued on page 176 175SIUJ.ORG SIUJ • Volume 2, Number 3 • May 2021 Evaluation of the Guidelines for Penile Cancer Treatment: Overview and Assessment http://siuj.org TABLE 1. Guidelines for the management penile cancer according to T stage, Cont'd Treatment EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE T2 Total glansectomy Total glansectomy, with or without resurfacing of the corporeal heads, is recommended Strong recommendation 3 C III Radiotherapy Radiation therapy is an option Strong recommendation Consider <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy Considered appropriate 2B <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy D Total penectomy OR Partial Partial amputation should be considered in patients unfit for reconstructive surgery Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A Tumors with invasion into corpora cavernosa B III STAGE T3 Partial amputation with reconstruction or total penectomy Glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A T3-4 or N+: circumcision followed by EBRT with chemotherapy D Radiotherapy Radiation therapy is an option Strong recommendation EBRT with chemotherapy are treatment options Considered appropriate 3 STAGE T3 WITH INVASION OF THE URETHRA Partial penectomy or total penectomy Glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A T3-4 or N+: circumcision followed by EBRT with chemotherapy D Radiotherapy Radiation therapy is an option Strong recommendation EBRT with chemotherapy are treatment options Considered appropriate 2B STAGE T4 Partial penectomy or total penectomy Extensive partial amputation or total penectomy with perineal urethrostomy is the standard advisable treatment Weak recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A T3-4 or N+: circumcision followed by EBRT with chemotherapy D Radiotherapy Palliative radiotherapy is an option EBRT with chemotherapy are treatment options Considered appropriate 3 176 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org TABLE 1. Guidelines for the management penile cancer according to T stage, Cont'd Treatment EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE T2 Total glansectomy Total glansectomy, with or without resurfacing of the corporeal heads, is recommended Strong recommendation 3 C III Radiotherapy Radiation therapy is an option Strong recommendation Consider <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy Considered appropriate 2B <4 cm: Brachytherapy or EBRT >4 cm: EBRT with chemotherapy D Total penectomy OR Partial Partial amputation should be considered in patients unfit for reconstructive surgery Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A Tumors with invasion into corpora cavernosa B III STAGE T3 Partial amputation with reconstruction or total penectomy Glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A T3-4 or N+: circumcision followed by EBRT with chemotherapy D Radiotherapy Radiation therapy is an option Strong recommendation EBRT with chemotherapy are treatment options Considered appropriate 3 STAGE T3 WITH INVASION OF THE URETHRA Partial penectomy or total penectomy Glansectomy with distal corporectomy and reconstruction or partial amputation with reconstruction are standard Strong recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A T3-4 or N+: circumcision followed by EBRT with chemotherapy D Radiotherapy Radiation therapy is an option Strong recommendation EBRT with chemotherapy are treatment options Considered appropriate 2B STAGE T4 Partial penectomy or total penectomy Extensive partial amputation or total penectomy with perineal urethrostomy is the standard advisable treatment Weak recommendation Partial or total penectomy when invasion into the corpora cavernosum is necessary to achieve a negative margin Considered appropriate 2A T3-4 or N+: circumcision followed by EBRT with chemotherapy D Radiotherapy Palliative radiotherapy is an option EBRT with chemotherapy are treatment options Considered appropriate 3 177SIUJ.ORG SIUJ • Volume 2, Number 3 • May 2021 Evaluation of the Guidelines for Penile Cancer Treatment: Overview and Assessment http://siuj.org Treatment strategy according to stage Organ-sparing treatment in Tis, Ta, and T1a tumors All 3 guidelines (EAU, NCCN, and ESMO), advise organ-sparing approaches in patients diagnosed with Tis, Ta, and T1 penile cancer lesions. However, the EAU guidelines highlight the absence of randomized cont rol led t r ia ls or compa rat ive obser vat iona l studies for treatment options for localized penile cancer. Nevertheless, from a cosmetic and functional standpoint, balanced with the risk of recurrence and progression of these stages, penile preservation is considered superior to partial or total penectomy and should be performed for localized penile cancer (staged ≤ T1)[16]. Topical agents are the least invasive and easiest treatment options for superficial and localized lesions. TABLE 2. Author recommendations for penile cancer guidelines Topical Laser Surgery Radiotherapy Tis 5-fluorouracil (5FU) or imiquimod 5% for superficial lesions ± photo dynamic control Tis T2 glans Laser ablation with CO2 or Nd:YAG laser • Glans resurfacing (Removal of glans epithelium) for lesions confined to glans • Glansectomy (Leaving corpora intact compared to partial penectomy) • Circumcision for lesions confined to prepuce • Wide local excision + reconstruction ± skin grafting Ta, T1 & T2 confined to the glans X Ta T2 Radiotherapy by • External beam • (EBRT) or as • Brachytherapy T2 Corpora cavernosa (CC) X X • Partial penectomy + reconstruction T3 (Three) invasion of Urethra X X • Partial penectomy • Total penectomy with perineal urethrostomy T4 Adjacent structures X X • Neoadjuvant chemo + surgery in responders or Palliative EBRT Nodal metastases No palpable inguinal nodes Palpable (cN1/cN2) Fixed (cN3) Pelvic lymphadenopathy Tis, Ta G1, T1G1 > T1G2 Radical inguinal lymphadenectomy Neoadjuvant chemotherapy ± followed in responders by Radical inguinal lymphadenectomy Ipsilateral pelvic lymphadenectomy if (pN2) ≥ 2 inguinal nodes are involved on one side and if (pN3) Extracapsular nodal metastasis Surveillance Staging by Dynamic sentinel node biopsy Chemotherapy • Neoadj.: T4, fixed N3 • Adjuvant: pN2/pN3 Adjuvant chemo in pN2/pN3 patients after radical lymphadenectomy 3–4 cycles of TPF: paclitaxel, cisplatin, 5-fluorouracil (5FU) 178 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org Before their use, the EAU guidelines recommend performing a circumcision. The EAU and NCCN guidelines make clear that there is a requirement for long-term surveillance. Another option is laser therapy, which could be performed as day-case surgery. When laser therapy is performed, the EAU guidelines mandate a second biopsy before treatment is initiated. A partial or total glans resurfacing can be an alternative in the first- line treatment for penile intraepithelial lesions (PeIN) or could be proposed after topical or laser therapy failure. In the case of wide local excision, Mohs surgery can be proposed in selected cases according to the EAU and NCCN guidelines (Table 1). Summary of treatment recommendations: For patients w it h penile Tis or Ta, we recommend topical therapy[17,18] and excisional organ-sparing technique[19], a topical agent such as imiquimod (5%) or 5-fluorouracil (5FU) cream, circumcision and wide local excision, laser therapy, or complete glansectomy (Table 2). Invasive disease treatment confined to the glans T1/T2 For T1 and T2 tumors localized to the glans, the 3 guidelines proposed different strategies, including surgery with laser therapy, local excision, partial glansectomy, or total glansectomy, and radiotherapy or brachytherapy. For the treatment of invasive disease confined to the glans, the EAU and the ESMO guidelines agree on conservative approaches, such as wide local excision or glansectomy, while the NCCN guidelines recommended it only in T1 high grade (G3–4). For radiotherapy, the NCCN and the EAU guidelines recommended brachy t herapy or ex terna l bea m radiation therapy  (EBRT) for tumors less than 4 cm. A circumcision is mandated by the NCCN guidelines before radiot herapy (RT) to prevent radiation- related complications. For tumors larger than 4 cm, a multimodal treatment combining radiotherapy and chemotherapy is recommended (Table 1). Summary of treatment recommendations: Our recommendation for the treatment of invasive disease confined to the glans is a glansectomy with or without resurfacing with a partial thickness skin graft of the corporeal heads[20]. A partial amputation for patients who are not candidates for reconstructive surgery should be performed[21]. Radiotherapy may also be an option[22] (Table 2). Treatment of invasive disease T3/T4 For tumors with invasion of the corpora cavernosum, a partial or total penectomy is mandatory to achieve a total resection with negative margin according to the NCCN and the EAU guidelines. EBRT with concurrent chemotherapy is also an option in the NCCN guidelines, while it is the primar y treatment in the ESMO guidelines. The EAU guidelines consider radiation as a treatment option only for T3 and as a palliative treatment in T4 disease (Table 1). Summary of treatment recommendations: For the treatment of cT3, we recommend glansectomy with corporectomy and reconstruction or partial penectomy with reconstruction as a standard of care[23,24]. Total penectomy with perineal urethrostomy is considered in selected cases. For cT4 disease, the recommended treatment remains a total penectomy with perineal urethrostomy[24]. Neoadjuvant chemotherapy for the locally advanced disease should be systematically considered and proposed[25,26] (Table 2). Guidelines for treatment strategies for nodal metastases: cN0 The ESMO, NCCN, and EAU guidelines all recommend surveillance for Tis, Ta G1, and T1G1 stages. Invasive lymph node staging either by bilateral modified inguinal lymphadenectomy or by dynamic sentinel node biopsy is recommended for ≥ T1G2 (Table 3). There is currently no role for prophylactic radiation to the inguinal lymph nodes instead of lymph node dissection or biopsy[27]. Summary of treatment recommendations: There are considerable discussions among researchers in the management of cN0 disease. Nonetheless, we believe that it is justif ied to  recommend surveillance for Tis, Ta G1, and T1G1 if the patient is compliant[28]. In contrast, at least a dynamic sentinel node biopsy should be recommended to improve the outcome for ≥ T1G2 disease[29] (Table 2). Guidelines for treatment strategies for nodal metastases: cN1/cN2 A ll 3 guidelines recommend a radica l inguina l lymphadenectomy for clinically positive lymph nodes. The confirmation of clinically positive lymph nodes should be made by surgical resection and frozen section according to the EAU guidelines, while, according to the NCCN, the confirmation can be made by percutaneous biopsy, or by fine-needle aspiration (FNA) in the ESMO guidelines (Table 3). Summa r y of treatment recommendations: Radi cal inguinal lymphadenectomy seems to improve survival and should be recommended for every patient with cN1/N2[30] (Table 2). Guidelines for treatment strategies for nodal metastases: cN3 F o r f i x e d i n g u i n a l n o d a l m a s s o r p e l v i c lymphadenopathy (cN3), neoadjuvant chemotherapy 179SIUJ.ORG SIUJ • Volume 2, Number 3 • May 2021 Evaluation of the Guidelines for Penile Cancer Treatment: Overview and Assessment http://siuj.org continued on page 182 TABLE 3. Guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE CN0 Surveillance is only recommended in patients with pTis/pTa tumors Strong recommendation Most low-risk patients are followed with a surveillance as the probability of occult micro metastases in ILNs is low Considered appropriate 2A Low- risk (Tis, Ta, T1G1) and intermediate-risk (T1G2) are followed with surveillance B > T1G2: invasive lymph node staging is recommended by either bilateral modified inguinal lymphadenectomy or dynamic sentinel node biopsy Strong recommendation 2B For high-risk standard or modified ILND or DSNB is strongly recommended in high-risk Considered appropriate 2A DSNB is recommended in patients with non-palpable inguinal lymph nodes T1G2 or greater B STAGE CN1/CN2 A radical inguinal lymphadenectomy should be performed Strong recommendation 2B Percutaneous lymph node biopsy is considered standard Positive findings warrant an immediate ILND 2A Fine-needle aspiration (FNA) of the LN is standard for these patients (omitting the procedure for high-risk tumors to avoid delay of ILND) STAGE CN3 Multimodal treatment with neoadjuvant chemotherapy followed by radical lymphadenectomy in responders is recommended Weak recommendation Should receive neoadjuvant Chemotherapy followed by radical inguinal and PLND lymphadenectomy in responders Considered appropriate 2A Patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy C III Consider postoperative radiotherapy or chemoradiotherapy 2B Responders receive consolidation surgery (bilateral and deep ILND and ipsilateral PLND if possible) STAGE PELVIC LYMPH NOD Patients with 2 or more inguinal lymph node metastases on one side and/or extracapsular lymph node extension need to undergo ipsilateral pelvic lymphadenectomy Strong recommendation 2B PLND should be considered at the time or following ILND in patients with ≥ three positive inguinal nodes on the ipsilateral ILND site Considered appropriate 2A Patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy C III Bilateral PLND should be considered either at the time or following ILND in patients with ≥4 positive inguinal nodes Considered appropriate 2A Responders receive consolidation surgery (bilateral and deep ILND and ipsilateral PLND if possible) 180 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org followed by a radical lymphadenectomy is supported by both NCCN and EAU guidelines. The ESMO guidelines recommend a multimodal treatment including chemo- radiot herapy fol lowed by consolidation surger y (inguinal lymph node dissection [ILND] and ipsilateral pelvic lymph node dissection [PLND]). This treatment regimen is one of the options in the NCCN guidelines but is considered only as a palliative treatment in the EAU guidelines (Table 3). Summary of treatment recommendations: For cN3, we recommend a radical lymphadenectomy after neoadjuvant chemotherapy for every responder to improve disease-free survival[25] (Table 2). Enlarged pelvic lymph nodes For surgically resectable lesions, all 3 guidelines recommend neoadjuvant systemic chemotherapy, followed by unilateral/bilateral PLND in case of treatment response. The EAU guidelines recommend lymphadenectomy for ipsilateral PLND if 2 or more inguinal lymph nodes are affected on one side or if extracapsular nodal metastasis is reported, followed by adjuvant chemotherapy. For enlarged pelvic lymph nodes where surgery is not possible, the NCCN and the ESMO guidelines recommend chemo-radiotherapy (Table 3). Summary of treatment recommendations: PLND is recommended for patients with 2 or more inguinal lymph nodes affected on one side or if extra-nodal extension is found[31] (Table 2). Guidelines for chemotherapy Both the EAU and ESMO guidelines state that neoadjuvant chemotherapy followed by radical surgery is advisable in unresectable lymph node metastases. The NCCN g uidelines recommend neoadjuvant chemotherapy in patients with ≥ 4 cm inguinal lymph nodes (fixed or mobile). The EAU and ESMO guidelines recommend adjuvant chemotherapy after lymphadenectomy in patients with pN2/pN3 disease. In contrast, the NCCN guidelines recommended adjuvant chemotherapy only if it was not given preoperatively, and if the pathology shows high-risk features (Tables 3,4). Su m ma r y of t re at ment recom mend at ions: A neoadjuvant chemotherapy should be proposed systematically for patients with cN3 inguinal lymph nodes and discussed for all clinical lymph nodes ≥ 4cm. An adjuvant chemotherapy should be offered to patients with pN2/pN3 disease without previous systemic treatment. Three to 4 cycles of paclitaxel, cisplatin, 5-fluorouracil (5FU) are the recommended regimen[32–34] (Table 2). continued on page 182 TABLE 3. Guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE CN0 Surveillance is only recommended in patients with pTis/pTa tumors Strong recommendation Most low-risk patients are followed with a surveillance as the probability of occult micro metastases in ILNs is low Considered appropriate 2A Low- risk (Tis, Ta, T1G1) and intermediate-risk (T1G2) are followed with surveillance B > T1G2: invasive lymph node staging is recommended by either bilateral modified inguinal lymphadenectomy or dynamic sentinel node biopsy Strong recommendation 2B For high-risk standard or modified ILND or DSNB is strongly recommended in high-risk Considered appropriate 2A DSNB is recommended in patients with non-palpable inguinal lymph nodes T1G2 or greater B STAGE CN1/CN2 A radical inguinal lymphadenectomy should be performed Strong recommendation 2B Percutaneous lymph node biopsy is considered standard Positive findings warrant an immediate ILND 2A Fine-needle aspiration (FNA) of the LN is standard for these patients (omitting the procedure for high-risk tumors to avoid delay of ILND) STAGE CN3 Multimodal treatment with neoadjuvant chemotherapy followed by radical lymphadenectomy in responders is recommended Weak recommendation Should receive neoadjuvant Chemotherapy followed by radical inguinal and PLND lymphadenectomy in responders Considered appropriate 2A Patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy C III Consider postoperative radiotherapy or chemoradiotherapy 2B Responders receive consolidation surgery (bilateral and deep ILND and ipsilateral PLND if possible) STAGE PELVIC LYMPH NOD Patients with 2 or more inguinal lymph node metastases on one side and/or extracapsular lymph node extension need to undergo ipsilateral pelvic lymphadenectomy Strong recommendation 2B PLND should be considered at the time or following ILND in patients with ≥ three positive inguinal nodes on the ipsilateral ILND site Considered appropriate 2A Patients with fixed nodes should be considered for neoadjuvant chemoradiotherapy C III Bilateral PLND should be considered either at the time or following ILND in patients with ≥4 positive inguinal nodes Considered appropriate 2A Responders receive consolidation surgery (bilateral and deep ILND and ipsilateral PLND if possible) 181SIUJ.ORG SIUJ • Volume 2, Number 3 • May 2021 Evaluation of the Guidelines for Penile Cancer Treatment: Overview and Assessment http://siuj.org TABLE 3. Guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer, Cont'd EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE CHEMOTHERAPY Neoadjuvant chemotherapy using cisplatin- and the taxane- based triple combination should be used in patients with fixed, unresectable, nodal disease Strong recommendation 2A Neoadjuvant chemotherapy with TIP (paclitaxel, ifosfamide, and cisplatin) is preferred (prior to ILND) in patients with ≥4 cm inguinal lymphnodes (fixed or mobile) Considered appropriate 2A Neoadjuvant chemotherapy followed by radical surgery is advisable in unresectable or recurrent LN metastases C Strong recommendation 2B Adjuvant chemotherapy it is reasonable to give four courses of TIP in the adjuvant setting if it was not given preoperatively and the pathology shows high-risk features 2A Adjuvant chemotherapy is recommended in pN2-3 patients C STAGE RADIOTHERAPY Not recommended for nodal disease except as a palliative option Strong recommendation Adjuvant EBRT or chemoradiotherapy can also be considered for patients with high-risk features Considered appropriate 2B The role of adjuvant postoperative radiation is controversial TABLE 4. Guidelines of chemotherapy regimen for penile cancer EAU Guidelines NCCN Guidelines ESMO Guidelines Treatment Grade of recommendation Level of evidence Treatment Grade of recommendation Level of evidence Treatment Grade of recommendation Level of evidence NEOADJUVANT CHEMOTHERAPY (4 cycles) cisplatin- and taxane- based regimen Weak 2A (4 courses) TIP (paclitaxel, ifosfamide, and cisplatin) 2A Considered appropriate (4 courses) TIP (paclitaxel, ifosfamide, and cisplatin) C III ADJUVANT CHEMOTHERAPY (3 to 4 cycles) cisplatin, a taxane and 5-fluorouracil or ifosfamide Strong 2B (4 courses) Preferred regimen is TIP (paclitaxel, ifosfamide, and cisplatin) Other recommended regimen is 5- fluorouracil + cisplatin 2A Considered appropriate No clear recommendation 182 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org Guidelines for Adjuvant Radiotherapy NCCN guidelines indicate that adjuvant EBRT or chemo-radiotherapy can be considered for patients with high-risk features, but the EAU guidelines do not recommend it except for palliative treatment. According to the ESMO guidelines, the role of adjuvant radiotherapy in the management of penile cancer remains controversial (Tables 3,4). Summa r y of treatment recommendations: Adjuvant radiotherapy is recommended after PLND for patients with positive results in ILND[35,36]. Assessment of the quality of the guidelines with the AGREE II instrument The AGREE Instrument is a 23-item tool comprising 6 quality and 2 overall assessment domains. A unique dimension of guideline quality is captured in each domain. Table 3 shows the results of the guidelines appraisal by the 5 reviewers. For the Domain 1 scope and purpose, which is related to the specific health questions, the overall aim of the guideline, and the target population, EAU and NCCN both scored 61%, while ESMO scored only 46%. Concerning the stakeholder involvement focuses on the extent to which the guidelines were developed by the appropriate stakeholders, the lowest score was 33% for ESMO, while EAU and NCCN reached approximately the same score with 59% and 60%, respectively. Regarding rigor of development concerned with the approaches to formulate the recommendations and the process used to gather and make the evidence and to update them, the appraiser gave the best score to the EAU and NCCN guidelines with 69% and 61%, respectively; while the ESMO, with a score of 34% did not reach the expected standard. With respect to structure, language, format, and clarity of presentation, the NCCN had a score of 81%, followed by the EAU, with 77%, and the ESMO with 61%. Resource implications of applying the guideline, strategies to improve uptake, and applicability pertaining to the likely barriers to and facilitators of implementation were scored at 33%, 53%, and 59% for the ESMO, NCCN, and EAU guidelines, respectively. For editorial independence, which concerns there being no competing interests that might bias the formulation of recommendations, the scores were 78% for the EAU guidelines, 57% for the ESMO guidelines, and 52% for the NCCN guidelines. Overall assessment includes rating the recommendation of guidelines for practice use and the overall quality of the guidelines. The highest score was reached by the EAU guidelines with a total rate of 77%, and the lowest score by the ESMO guidelines with a rate of 40%, while the NCCN guidelines also reached a high rate with 73% (Table 5). TABLE 3. Guidelines for the management of nodal metastasis and adjuvant therapy for penile cancer, Cont'd EAU Guidelines NCCN Guidelines ESMO Guidelines Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence Recommendation Grade of recommendation Level of evidence STAGE CHEMOTHERAPY Neoadjuvant chemotherapy using cisplatin- and the taxane- based triple combination should be used in patients with fixed, unresectable, nodal disease Strong recommendation 2A Neoadjuvant chemotherapy with TIP (paclitaxel, ifosfamide, and cisplatin) is preferred (prior to ILND) in patients with ≥4 cm inguinal lymphnodes (fixed or mobile) Considered appropriate 2A Neoadjuvant chemotherapy followed by radical surgery is advisable in unresectable or recurrent LN metastases C Strong recommendation 2B Adjuvant chemotherapy it is reasonable to give four courses of TIP in the adjuvant setting if it was not given preoperatively and the pathology shows high-risk features 2A Adjuvant chemotherapy is recommended in pN2-3 patients C STAGE RADIOTHERAPY Not recommended for nodal disease except as a palliative option Strong recommendation Adjuvant EBRT or chemoradiotherapy can also be considered for patients with high-risk features Considered appropriate 2B The role of adjuvant postoperative radiation is controversial TABLE 4. Guidelines of chemotherapy regimen for penile cancer EAU Guidelines NCCN Guidelines ESMO Guidelines Treatment Grade of recommendation Level of evidence Treatment Grade of recommendation Level of evidence Treatment Grade of recommendation Level of evidence NEOADJUVANT CHEMOTHERAPY (4 cycles) cisplatin- and taxane- based regimen Weak 2A (4 courses) TIP (paclitaxel, ifosfamide, and cisplatin) 2A Considered appropriate (4 courses) TIP (paclitaxel, ifosfamide, and cisplatin) C III ADJUVANT CHEMOTHERAPY (3 to 4 cycles) cisplatin, a taxane and 5-fluorouracil or ifosfamide Strong 2B (4 courses) Preferred regimen is TIP (paclitaxel, ifosfamide, and cisplatin) Other recommended regimen is 5- fluorouracil + cisplatin 2A Considered appropriate No clear recommendation 183SIUJ.ORG SIUJ • Volume 2, Number 3 • May 2021 Evaluation of the Guidelines for Penile Cancer Treatment: Overview and Assessment http://siuj.org Discussion Clinical guidelines help physicians to choose the best treatment available for individual patients. Fewer guidelines are available in the case of rare diseases, and only 3 guidelines in English have been published on the management of penile cancer. The recommendations made in these guidelines are not always in agreement. Therefore, to help urologists in their decision-making process regarding therapy, we evaluated and compared the guidelines of the NCCN, EAU, and ESMO on the management of penile cancer. Using the AGREE II tool, we assessed the quality of the guidelines. We discuss the differences in terms of LOE and GOR that arise as a result of different methods of evaluation used. The EAU and NCCN guidelines incorporate more recent literature than the ESMO guidelines, which have not been updated for 7 years. The EAU guidelines use a modif ied Grading of Recommendations Assessment, Development, and Evaluation (GR ADE) methodolog y. For each recommendation within the guidelines, there is an accompanying online strength rating form that addresses several elements. The ESMO adapted the Infectious Diseases Society of America-United States Public Health Service Grading System. The level of evidence assessment and grading of recommendations in NCCN guidelines are based on randomized controlled trials, clinical trials, guidelines, systematic reviews, meta-analysis, and validation studies. Evaluation of LOE and GOR are more specified clearly in the NCCN guidelines than in the other 2 guidelines. Although these 3 guidelines developed in different ways, it is reassuring that they have considerable similarities, albeit some small but potentially significant differences between them. The evidence available is weak in penile cancer, and a consequence of the scarcity in evidence is that way, some recommendations are based on the panel’s review of the low-level evidence and expert opinion. One of the contentious points is the advantage of both neoadjuvant and adjuvant radiotherapy in the treatment of penile cancer patients with LN metastases. There is some evidence for adjuvant nodal radiotherapy in in vulvar carcinoma, which shares many characteristics with penile cancer[37,38]. However, high-quality evidence to suggest a clear benefit to radiotherapy in penile cancer is lacking[39,40]. In a retrospective study of 2458 patients in the SEER database (National Cancer Institute Surveillance, Epidemiology and End Results Program), no advantage was observed with the use of EBRT for penile cancer patients compared to surgery alone on cancer-specific survival[41]. A similar conclusion was reached by Franks et al., who reported poor long-term survival for patients treated with adjuvant radiotherapy[42]. These essential findings are consistent with those of other studies, which showed no patient benefit[43,44–48]. However, A series of recent studies have indicated that  adjuvant radiotherapy i mprove d su r v iv a l a nd de c re a s e d re c u r renc e rate[35,36,49]. TABLE 5. AGREE II evaluation of guidelines for the management of penile cancer Scope and purpose % Stakeholder involvement % Rigor of development % Clarity of presentation % Applicability % Editorial independence % Overall assessment % Final recommendations EAU GUIDELINES 61 59 69 77 59 78 77 Yes–3, Yes with modifications–2, No–0 NCCN GUIDELINES 61 60 61 81 53 52 73 Yes–3, Yes with modifications–2, No–0 ESMO GUIDELINES 46 33 34 61 33 57 40 Yes–0, Yes with modifications–2, No–3 184 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org Conclusion This is the first attempt to review and appraise guidelines for penile cancer management systematically. Although all guidelines strive to be evidence-based, some recommendations differ between the guidelines because the underlying evidence is poor. Also, these guidelines are produced in the United States and Europe, so that their applicability in other regions with a high incidence of penile cancer is uncertain. 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Long-term multicentre experience of adjuvant radiotherapy for pN3 squamous cell carcinoma of the penis. BJU Int.2020 Nov 29; Online ahead of print. doi: 10.1111/bju.15309. 186 SIUJ • Volume 2, Number 3 • May 2021 SIUJ.ORG REVIEW http://SIUJ.org