Penile Cancer: Clinical Guidelines

List of Abbreviations

IV – intravenous

Malignant neoplasm – malignant neoplasm

Penile cancer – penile cancer

WHO – World Health Organization

HPV – human papillomavirus

PLND – pelvic lymph node dissection

CT – computed tomography

Exercise therapy – therapeutic exercise

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

Ultrasound – ultrasound examination

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Second stage of rehabilitation – inpatient rehabilitation in medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual disease symptoms.

Duquen's operation – inguinofemoral lymph node dissection.

First stage of rehabilitation – rehabilitation during the period of specialized treatment for the primary disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the primary disease.

Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgical treatment/chemotherapy/radiation therapy).

Third stage of rehabilitation – rehabilitation during the early and late rehabilitation periods, and the period of residual effects of the disease in departments (offices) of rehabilitation, physiotherapy, therapeutic exercise, reflexology, manual therapy, psychotherapy, medical psychology, speech therapy (teacher-defectologist) offices providing medical care in outpatient settings, day hospitals, as well as by mobile teams at home (including in sanatorium-resort organizations).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Penile cancer (hereinafter referred to as PC) is an oncological disease associated with the development of a malignant neoplasm in the tissues of the penis.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Phimosis and chronic balanoposthitis contribute to the development of PC. An increased risk of PC has been proven in patients with psoriasis who received psoralen, phototherapy, and ultraviolet ray therapy, in smokers, as well as in men who had an early onset of sexual activity and multiple sexual partners. A correlation has been revealed between the risk of PC and human papillomavirus (HPV) types 16 and 18, which is detected in 50% of patients; in basaloid and verrucous variants of penile cancer, this figure reaches 22–66% [1, 2].

Diseases sporadically associated with PC include cutaneous horn, bowenoid papulosis of the penis, and obliterating balanoposthitis (lichen sclerosus). High-risk factors for squamous cell carcinoma of the penis (up to 30% of malignant transformations) are intraepithelial neoplasia (carcinoma in situ), giant Buschke–Löwenstein condyloma, erythroplasia of Queyrat, Bowen's disease, and Paget's disease [2].

1.3 Epidemiology of the Disease or Condition

PC is a rare oncological disease occurring with a frequency of 0.1–7.9 per 100,000 male population. In Europe, its incidence is 0.1–0.9 per 100,000, in the USA – 0.7–0.9 per 100,000; however, in some regions of Asia, Africa, and South America, this figure reaches 19 per 100,000. In these countries, PC accounts for 10–20% of all malignant tumors in men [1]. In Russia in 2017, the incidence rate was 0.67 per 100,000 [3].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems (hereinafter referred to as ICD-10), penile cancer is classified according to localization: for example, a malignant neoplasm of the foreskin of the penis will have code C60.0, and a malignant neoplasm of the body of the penis will have code C60.2.

Malignant neoplasm (hereinafter referred to as MN) of the penis (C60):

• C60.0 MN of the foreskin of the penis;

• C60.1 MN of the glans penis;

• C60.2 MN of the body of the penis;

• C60.8 MN of the penis overlapping other sites;

• C60.9 MN of the penis, unspecified.

1.5 Classification of the disease or condition

International Histological Classification of Tumors of the Penis (World Health Organization (WHO) Classification, 2016) [4]

More than 95% of malignant penile tumors are squamous cell carcinomas. Malignant melanomas and basal cell carcinomas are much less common. Mesenchymal tumors of the penis are extremely rare, accounting for barely 3% of cases (Kaposi sarcoma, angiosarcoma, epithelioid hemangioendothelioma). Cases of bladder, prostate, kidney, and rectal cancer metastasizing to the penis have been described.

The following types of penile squamous cell carcinoma are distinguished:

1. Non-HPV-associated squamous cell carcinoma:

– squamous cell carcinoma, usual type;

– pseudohyperplastic carcinoma;

– pseudoglandular carcinoma;

– verrucous carcinoma;

– papillary squamous cell carcinoma;

– adenosquamous carcinoma;

– sarcomatoid squamous cell carcinoma4

– mixed squamous cell carcinoma.

2. HPV-associated squamous cell carcinoma:

– basaloid squamous cell carcinoma;

– papillary-basaloid carcinoma;

– wart-like carcinoma;

– clear cell squamous cell carcinoma;

– lymphoepithelioma-like carcinoma.

There are 3 main growth patterns of penile cancer: superficial, nodular, and verrucous [5].

Staging

Penile tumor staging is performed in accordance with the 8th edition of the AJCC/UICC TNM classification (2017) [6] (Table 1).

Clinical TNM classification:

• cT – primary tumor;

• cTx – primary tumor cannot be assessed;

• cT0 – no evidence of primary tumor;

• cTis – carcinoma in situ;

• cTa – non-invasive verrucous (wart-like) carcinoma without destructive invasive growth;

• cT1 – tumor invades subepithelial connective tissue;

• cT1a – tumor invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (T1G1–2);

• cT1b – tumor invades subepithelial connective tissue, with lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3–4);

• cT2 – tumor invades corpus spongiosum with or without urethral invasion;

• cT3 – tumor invades corpus cavernosum with or without urethral invasion;

• cT4 – tumor invades other adjacent structures;

• cN – regional lymph nodes;

• cNx – regional lymph nodes cannot be assessed;

• cN0 – no palpable or visibly enlarged inguinal lymph nodes;

• cN1 – mobile palpable enlarged inguinal lymph node on one side;

• cN2 – mobile palpable multiple or bilateral inguinal lymph nodes;

• cN3 – fixed inguinal lymph node mass or pelvic lymph nodes enlarged unilaterally or bilaterally;

• cM – distant metastasis;

• cM0 – no distant metastasis;

• cM1 – distant metastasis present.

Pathomorphological TNM classification of penile cancer

Pathomorphological T categories correspond to clinical T categories. pN categories are based on biopsy or surgical removal of lymph nodes.

• pN – regional lymph nodes pNx – regional lymph nodes cannot be assessed;

• pN0 – no regional lymph node metastasis;

• pN1 – intranodal metastasis (without extracapsular extension) in 1 or 2 inguinal lymph nodes;

• pN2 – metastases in more than 2 inguinal lymph nodes on one side or bilateral inguinal lymph node involvement;

• pN3 – metastases in 1 or more pelvic lymph nodes, unilateral or bilateral inguinal lymph node metastases with extranodal tumor extension pM – distant metastasis;

• pM0 – no distant metastasis;

• pM1 – distant metastasis;

• G – histopathological grade;

• Gx – grade cannot be assessed;

• G1 – well-differentiated tumor;

• G2 – moderately differentiated tumor;

• G3 – poorly differentiated or undifferentiated tumor.

The grade is specified for usual squamous cell carcinoma. Specific types of carcinomas typically have a characteristic grade.

Table 1. Penile cancer staging according to T, N, M categories.

1.6 Clinical presentation of the disease or condition

In early stages, the disease is characterized by a small exophytic or flat lesion on the skin of the glans penis or prepuce, which gradually infiltrates the corpus spongiosum and/or corpora cavernosa. Infection of the disintegrating tumor often occurs, and urethral fistulae, perineal soft tissue phlegmon, and sepsis may develop. Bleeding from the primary tumor has been described. In the absence of treatment, autoamputation of the penis is possible.

Penile cancer is frequently accompanied by enlargement of the inguinal lymph nodes due to metastases or infectious lymphadenitis. Affected lymph nodes may coalesce into masses that invade the skin, forming external fistulae with purulent discharge. Impaired lymphatic drainage from the lower extremities can lead to edema.

The appearance of distant metastases causes symptoms corresponding to their localization.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

1. anamnestic data;

2. physical examination findings;

3. laboratory data;

4. instrumental examination data.

The clinical diagnosis is based on a combination of laboratory and instrumental test results:

1. physical examination (visual inspection and palpation) providing criteria that indicate a suspicious penile lesion;

2. pathological (morphological) examination report of the tumor tissue.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

• All patients with penile cancer are recommended to undergo a complete blood count to select additional diagnostic methods and determine the treatment strategy [1, 7].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• All patients with penile cancer are recommended to undergo a biochemical blood test (including determination of glucose, creatinine, urea, bilirubin, transaminases, alkaline phosphatase, and serum potassium levels) to select additional diagnostic methods and determine the treatment strategy [1, 7].

GOR CLOE 5Grade of Recommendation — C (Level of Evidence — 5)

• All patients with penile cancer are recommended to undergo a coagulogram, including the determination of prothrombin, prothrombin time, international normalized ratio (INR), activated partial thromboplastin time (aPTT), and fibrinogen, to select additional diagnostic methods and determine the treatment strategy [1, 7-10].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• All patients with penile cancer are recommended a urinalysis to select additional diagnostic methods and determine the treatment strategy [1, 7, 11, 153].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• All patients with penile cancer and clinical signs of infection of the primary tumor or regional metastases are recommended to undergo microbiological (culture) examination of the tumor discharge for aerobic and facultatively anaerobic opportunistic microorganisms in order to determine the treatment strategy for infectious complications and prevent sepsis [1, 7, 12, 13].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

2.4 Instrumental Diagnostics

Comment: MRI has low diagnostic efficacy in distinguishing cT1 and cT2 categories and has no advantages over visual inspection and palpation. The sensitivity and specificity of MRI in detecting the cT3 category reach 80% (95% CI: 70–87%) and 96% (95% CI: 85–99%), respectively. MRI with and without artificial erection showed similar accuracy in determining the cT category [89, 90].

Comment: according to a systematic literature review based on 12 studies including 479 patients with penile cancer, the sensitivity of [18F]FDG-PET/CT in detecting metastatic lymph nodes is 87%, specificity is 88%, and the pooled diagnostic odds ratio is 47 (95% CI 19–116). In meta-regression analysis, no variable was a source of study heterogeneity [87]. [18F]FDG-PET/CT does not detect penile cancer micrometastases [91].

2.5 Other Procedures

Comments: from 45% to 80% of penile cancer cases are associated with HPV, most commonly types 6, 16, and 18. Despite the fact that HPV is a risk factor for the development of this disease, a positive HPV status is associated with a favorable survival prognosis, which can be taken into account when forming treatment tactics [88].

Comments: morphological verification of the penile cancer diagnosis must be obtained prior to treatment initiation. To determine treatment tactics for both the primary tumor and regional metastases, it is necessary to determine the histological variant of the tumor, assess the T category, and grade of anaplasia (G). Morphological material for cytologic examination can be obtained by scraping or imprint smear, and for pathomorphological examination by open, core-needle, or aspiration biopsy. For small distal tumors (foreskin, glans penis), complete tumor excision is permissible for initial diagnosis verification. Examination of removed lymph nodes should include assessing the number of metastatically involved lymph nodes and determining the presence of extracapsular tumor extension [2, 18-20].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The prescription and use of medicinal products specified in the clinical guideline are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions described in the instructions, and dose adjustments may also be made taking into account the patient's condition.

3.1 Treatment of the primary tumor in patients with penile cancer

Due to the low incidence of penile cancer and the lack of randomized trials in this field, optimal management strategies for this category of patients have not been established. The universally accepted standard of care for the primary tumor in patients with penile cancer is penectomy. Given the high significance of the cosmetic and functional consequences of treating neoplasms in this location—including preserving appearance, the ability to urinate while standing, and maintaining sexual function—a number of alternative methods have been developed, including organ-sparing surgery, topical drug therapy, laser ablation, and radiotherapy aimed at preserving the penis.

3.1.1 Surgical treatment of the primary tumor in patients with penile cancer

The results of surgical treatment depend on the localization, size, T category, tumor anaplasia grade (G), and the scope of surgery. Organ-preserving treatment is associated with a higher rate of local recurrences (21.2%) compared to penectomy (0-10%), but allows for a better quality of life [22].

— in patients with Tis-T3 penile cancer, when technically feasible, organ-preserving surgeries are recommended, such as circumcision when the tumor is localized on the foreskin, microsurgical tumor removal with circumcision, wide local excision of the primary tumor with circumcision, glansiectomy with or without glans reconstruction, or partial penectomy [22, 23].

— in the absence of the possibility of organ-preserving surgical treatment, patients with T2-T3 tumors not extending to the crura are recommended to undergo penectomy [22, 23].

— for patients with category T3 tumors extending to the crura, penectomy is recommended [22-24].

— for patients with category T4 tumors extending to the tissues of the scrotum and/or spermatic cord, emasculation is recommended; if technically feasible, excision of the affected scrotal tissues with preservation of the testes is acceptable; the preserved testes are placed under the skin of the medial thighs [24].

— for patients with category T4 tumors whose extent precludes radical surgery, palliative debulking/sanitizing procedures are recommended prior to systemic and/or radiation therapy. The extent of the palliative sanitizing procedure is determined individually [24].

— for patients with category T4 tumors whose extent precludes radical surgery and who present with urethral fistulas, cystostomy is recommended prior to systemic and/or radiation therapy [25].

GGR BERL 3Grade of Recommendations – B (Evidence Level – 3).

3.1.2. Laser ablation of the primary tumor in patients with penile cancer

Cases of satisfactory long-term and functional outcomes of laser therapy in patients with Tis, T1a, and T1b penile cancer with G1-G2 anaplasia grades have been described. According to retrospective studies, the local recurrence rate after laser ablation is 18% with good cosmetic and functional outcomes [29, 30].

3.1.3 Local drug therapy for the primary tumor in patients with penile cancer

Topical medical therapy allows for a complete response in 23-70% of patients with penile cancer [31].

3.1.3 Radiotherapy for the primary tumor in patients with penile cancer

Radiotherapy provides long-term local control with penile preservation in 40% of cases in patients with T1–T2 penile cancer and in 38% of cases with T3–T4 categories. Late complications develop in 40% of treated patients [32, 33].

Circumcision is performed in all patients with penile cancer who are candidates for radiotherapy [32, 33].

Comment: no studies on the efficacy and safety of chemoradiotherapy in patients with penile cancer have been conducted. Some authors [35] indicate the possibility of adopting radiosensitizing chemotherapy regimens from treatment protocols for anal canal and vulvar cancer [28, 36-38, 85-86]:

#Cisplatin** 40 mg/m² IV weekly, 6 administrations in total (but not exceeding 70 mg per single administration) [28];

#Cisplatin** 60 mg/m² IV on days 1 and 29 + fluorouracil** 1000 mg/m²/day IV 24-hour infusion on days 1–4 and 29–32 [28];

#Mitomycin** 12 mg/m² IV on day 1 (but not exceeding 20 mg per single administration) + fluorouracil** 1000 mg/m²/day IV 24-hour infusion on days 1–4 and 29–32 [28];

#Capecitabine** 1650 mg/m²/day orally on radiotherapy days throughout the entire course of radiotherapy [28, 148, 149].

3.2. Treatment of patients with regional metastases of penile cancer

Penile cancer predominantly metastasizes via lymphogenous pathways. Inguinal lymph nodes are affected first, followed by pelvic lymph nodes. Bilateral lymph node involvement is characteristic, which is explained by the presence of lymphatic collaterals crossing at the root of the penis. Clinically, all patients with penile cancer are divided into those with palpable and non-palpable inguinal lymph nodes. There are no radiological criteria to differentiate between metastatic and unaffected lymph nodes in penile cancer. The only accurate method for assessing the N category is regional lymph node dissection, which is associated with a high rate of complications. Lymph node metastases dramatically worsen the prognosis, but early lymph node dissection improves survival in patients with penile cancer. A treatment algorithm for patients with regional metastases of penile cancer has been developed and is presented in Table 3 [39].

3.2.1 Treatment of patients with penile cancer and non-palpable inguinal lymph nodes

About 25% of patients with non-palpable inguinal lymph nodes have the pN+ category. Risk factors for micrometastases in clinically negative lymph nodes include pT>T1 category, anaplasia grade G>G1, and the presence of lymphovascular invasion. In the low-risk group (Ta, Tis, T1aG1), the probability of detecting metastases in non-palpable lymph nodes is 17%, in the intermediate-risk group (T1bG1-2) it is 29%, and in the high-risk group (T>T1 and/or G3-4) it is 47–73% [39, 40].

Comment: dynamic sentinel lymph node biopsy is performed by injecting ⁹⁹technetium nanocolloid [99mTc] (99mTc medronic acid, 99mTc sestamibi, 99mTc succimer, 99mTc phytate, 99mTc oxabifor) around the primary tumor 24 hours before surgery, followed by intraoperative detection, removal, and histological examination of the sentinel lymph node. A gamma probe allows identification of the sentinel lymph node in 97% of cases. The sensitivity of dynamic sentinel lymph node biopsy is 90–94%, and the false-negative rate reaches 12–15%. The diagnostic efficacy of dynamic sentinel lymph node biopsy depends on the operator's experience with this procedure. Optimal results are reported in clinical centers performing ≥20 procedures per year [41, 42].

In centers lacking the capability and experience to perform dynamic sentinel lymph node biopsy (<20 procedures per year) [40, 41], patients with penile cancer and non-palpable inguinal lymph nodes belonging to the low-risk group for inguinal lymph node metastasis (Ta, Tis, T1aG1) should undergo careful active surveillance [39].

Comment: this procedure is associated with a high complication rate (25–50%), including wound dehiscence, lymphedema, and wound suppuration [43, 44].

Comment: this intervention reduces the risk of surgical complications compared to standard ilioinguinal lymph node dissection, but is associated with a 15% risk of false-negative results [43, 44, 45].

3.2.2. Treatment of patients with penile cancer and palpable inguinal lymph nodes

3.2.2.1 Treatment of patients with penile cancer and palpable mobile inguinal lymph nodes <4 cm

Palpable inguinal lymph nodes are present in 58% (20–96%) of patients with penile cancer, while only 17–45% of them have regional metastases. In the remaining patients, lymph node enlargement is caused by lymphadenitis [41].

3.2.2.2 Treatment of patients with penile cancer and palpable mobile inguinal lymph nodes ≥4 cm

3.2.2.2. Treatment of patients with PSCC and palpable fixed inguinal lymph nodes of any size

3.2.3 Treatment of patients with PSCC and high risk of pelvic lymph node metastases, as well as enlarged pelvic lymph nodes

Pelvic lymph node metastases are detected only in patients with inguinal lymph node involvement. The risk of pelvic lymph node metastases is 23% with 2-3 inguinal metastases, and 56% with >3 inguinal metastases. Extranodal extension of metastases to inguinal lymph nodes increases the risk of pelvic metastases up to 30% [54, 55].

3.3 Chemotherapy in the treatment of patients with penile cancer

Due to the low incidence of PSCC in developed countries, large-scale studies on the medical treatment of PSCC have not been conducted. Small case series and individual clinical cases have demonstrated the efficacy of #cisplatin**-based polychemotherapy. The most studied regimen is TIP (#cisplatin**, #paclitaxel**, #ifosfamide** (see below)) [53]. A historical alternative to the TIP regimen is the PF combination (#cisplatin**, fluorouracil** (see below)), which has proven effective in a number of patients, although treatment-associated adverse events frequently necessitated dose reductions in published case series [56]. The use of regimens based on bleomycin** in patients with PSCC leads to a high rate of unacceptable toxicity [57].

The efficacy and safety of neoadjuvant chemotherapy in PSCC are poorly studied. However, in a phase II study, the objective response rate to neoadjuvant chemotherapy with the TIP regimen was 50%, with a long-term progression-free survival reaching 36.7% [53]. Cases of regression of both the primary tumor and regional metastases leading to an operable state after induction chemotherapy have been described [52].

Adjuvant chemotherapy for PSCC has not been studied. However, extrapolating scant data regarding the use of antineoplastic drugs in the neoadjuvant setting, it can be hypothesized that in patients with a high risk of progression who did not receive chemotherapy before surgery, adjuvant treatment may improve outcomes.

Some authors indicate the possibility of using radiosensitizers in patients with PSCC receiving external beam radiation therapy, using agents that have proven efficacy in squamous cell carcinoma of other localizations: #cisplatin** (as monotherapy or in combination with fluorouracil**), #mitomycin** (as monotherapy or in combination with fluorouracil**), as well as #capecitabine** (see below) [28, 35]. Optimal dosing regimens have not been established. The radiosensitization schedule is determined individually.

Second-line systemic therapy for PSCC is virtually unstudied. Isolated cases of achieving a response to #paclitaxel** monotherapy (see below) [58] and #cetuximab** (see below) have been described [59, 60].

• TIP (#paclitaxel** IV at 175 mg/m² on day 1, #ifosfamide** IV at 1200 mg/m2 on days 1, 2, and 3, #cisplatin** IV at 25 mg/m2 on days 1, 2, and 3), every 21 days. Perioperative chemotherapy includes 4 treatment cycles; standalone chemotherapy involves 4-6 treatment cycles [53, 61];

• PF (#cisplatin** IV at 70-80 mg/m2 on day 1, fluorouracil** IV at 800-1000 mg/m2 on days 2, 3, 4, 5) every 21 or 28 days. Perioperative chemotherapy includes 4 treatment cycles; standalone chemotherapy involves 4-6 treatment cycles [56].

• If there are contraindications to #cisplatin**, its replacement with #carboplatin** (intravenous drip, AUC 3-5, every 21 or 28 days) is permissible [62, 150].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

• #paclitaxel** monotherapy IV at 175 mg/m2 on day 1 every 21 days. The number of treatment cycles is determined individually [58];

• #cetuximab** monotherapy IV at 400 mg/m2 (subsequently 250 mg/m2) on day 1 every 7 days or IV at 400 mg/m2 (subsequently 500 mg/m2) on day 1 every 14 days. The number of treatment cycles is determined individually [28, 59, 60, 63, 152].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

3.4. Radiotherapy in the treatment of patients with penile cancer and regional lymph node metastases

Comment: Neoadjuvant radiation therapy in patients with penile cancer and regional lymph node metastases has not been studied. The results of studies on adjuvant irradiation are contradictory [64, 65].

Comment: no studies on the efficacy and safety of chemoradiotherapy in patients with penile cancer have been conducted. Some authors suggest adapting radiosensitizing chemotherapy regimens from treatment protocols for anal and vulvar cancer [28, 35-38, 85-86]:

#Cisplatin** 40 mg/m² IV weekly, 6 administrations in total (but no more than 70 mg per single dose) [28, 149];

#Cisplatin** 75 mg/m² IV on days 1 and 29 + fluorouracil** 1000 mg/m²/day IV 24-hour continuous infusion on days 1–4 and 29–32 [28, 151];

#Mitomycin** 10 mg/m² IV on days 1 and 29 (but no more than 20 mg per single dose) + fluorouracil** 1000 mg/m²/day IV 24-hour continuous infusion on days 1–4 and 29–32 [28, 149];

#Capecitabine** 1650 mg/m²/day orally on radiation therapy days throughout the entire course of radiation therapy [28, 85].

In individual cases, external beam radiation therapy targeting the region of regional metastasis up to a total cumulative dose (TCD) of 45–50.4 Gy, followed by irradiation of the surgical scar area or actually enlarged lymph nodes up to a TCD of 65–70 Gy, has been described [28, 66].

3.5. Pain management

The principles of analgesia and the optimal choice of pain management in patients with penile cancer suffering from chronic pain syndrome correspond to the pain management principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Medical Care".

3.6. Supportive therapy in patients with penile cancer

Comments. The principles of diagnosis, prophylaxis, and treatment of nausea and vomiting during antineoplastic drug therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vladimirova L. Yu. et al. Nausea and Vomiting [94].

https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting

Comments. The principles of diagnosis, prophylaxis, and treatment of bone complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Bagrova S. G. et al. Bone Pathology [96].

https://rosoncoweb.ru/standarts/?chapter=bone_pathology

Comments. The principles of diagnosis, prophylaxis, and treatment of venous thromboembolic complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Somonova O. V. et al. Thromboembolic Complications [100]. https://rosoncoweb.ru/standarts/?chapter=thromboembolism

Comments. A detailed algorithm for the diagnosis, prophylaxis, and treatment of febrile neutropenia and infectious complications, as well as principles of antibacterial therapy, are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sakaeva D. D. et al. Practical Guidelines for the Diagnosis and Treatment of Febrile Neutropenia [104].

https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia

Comments. The principles of diagnosis, prophylaxis, and treatment of hepatotoxicity are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Tkachenko P. E. et al. Hepatotoxicity [107].

https://rosoncoweb.ru/standarts/?chapter=hepatotoxicity

Comments. The principles of diagnosis, prophylaxis, and treatment of cardiovascular complications during antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vitsenya M. V. et al. Cardiovascular Toxicity [112]. https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity

Comments. The principles of diagnosis, prophylaxis, and treatment of skin complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Koroleva I. A. et al. Dermatological Reactions [114].

https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions

Comments. The principles of nutritional support are presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A. V. et al. Nutritional Support [117]. https://rosoncoweb.ru/standarts/?chapter=nutritional_support

Comments. A detailed algorithm for the diagnosis, prophylaxis, and treatment of nephrotoxicity is presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Gromova E. G. et al. Nephrotoxicity [121].

https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity

Comments. A detailed algorithm for the diagnosis, prophylaxis, and treatment of immune-mediated adverse events is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Protsenko S. A. et al. Immune-Mediated Adverse Events [126]. https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events

Comments. A detailed algorithm for the diagnosis, prophylaxis, and treatment of mucositis is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Semiglazova T. Yu. et al. Mucositis [129]. https://rosoncoweb.ru/standarts/?chapter=mucositis

Comments. The procedure and principles for the prevention and treatment of anemia correspond to the principles outlined in the clinical guidelines "Anemia in Malignant Neoplasms" (ID: CR624, approval year 2020, www.cr.rosminzdrav.ru) and in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Orlova R.V. et al. Anemia [132].

Comments. A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A.V. et al. Practical Guidelines for the Treatment of Anorexia-Cachexia Syndrome in Cancer Patients [134].

https://rosoncoweb.ru/standarts/?chapter=anorexia-cachexia

Comments. The choice of central access option is determined by the planned duration of the entire course of treatment, patient preferences, and anatomical features. For prolonged (over 3 months) courses of therapy, the most convenient option is the implantation of a subcutaneous venous port system. For shorter periods, a peripherally inserted central venous catheter can serve as an alternative. The principles of using central venous access are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Isyangulova A.Z. et al. Central Venous Access [136]. https://rosoncoweb.ru/standarts/?chapter=central_venous_access

Comments. Algorithms for vascular access selection, prevention, diagnosis, and treatment of extravasation are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Buydenok Yu.V. et al. Extravasation of Antineoplastic Drugs [138]. https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs

Comments. Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Kogoniya L.M. et al. Chronic Pain Syndrome [140]. https://rosoncoweb.ru/standarts/?chapter=chronic_pain_syndrome

Comments. Algorithms for the prevention, diagnosis, and treatment of infusion reactions are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Orlova R.V. et al. Infusion Reactions [142]. https://rosoncoweb.ru/standarts/?chapter=infusion_reactions

Comments. The principles of monitoring and management in cancer patients with chronic viral hepatitis are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Feoktistova P.S. et al. Chronic Viral Hepatitis [144]. https://rosoncoweb.ru/standarts/?chapter=chronic_viral_hepatitis

Comments. The principles of diagnosis, prevention, and treatment of neurological complications of antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Latipova D.Kh. et al. Neurological Complications [146].

https://rosoncoweb.ru/standarts/?chapter=neurological_complication

3.7 Medical Nutrition Therapy

To date, no reliable data have been obtained regarding the effect of dietary habits on the risk of developing penile cancer; therefore, any changes to the usual diet of patients are inappropriate unless dictated by the need to correct comorbid conditions or to stop or prevent complications of ongoing treatment (surgical, drug, or radiation).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, for most types of medical rehabilitation, there are no clinical studies involving patients with penile cancer. These recommendations are based on the fact that numerous studies, including meta-analyses and systematic reviews, have proven that various types of medical rehabilitation significantly accelerate functional recovery, shorten hospital stays after surgery, and reduce the incidence of complications and mortality in patients with other malignant neoplasms.

Rehabilitation should be carried out focusing on the general principles of rehabilitation for patients after surgical interventions and/or chemotherapy.

4.1. Pre-rehabilitation

Comments: Psychological support within the pre-rehabilitation plan improves mood and reduces levels of anxiety and depression. Patients who have undergone a course of psychological pre-rehabilitation adapt better to everyday life after surgical treatment.

4.2. Rehabilitation during surgical treatment

4.2.1. First stage of rehabilitation in surgical treatment

Comments. If indicated, it is necessary to combine positioning, exercise therapy, cryotherapy applied to the surgical area, medical massage, and electrotherapy for pain relief.

4.2.2. Second stage of rehabilitation

• weight control, prevention of obesity;

• prevention of erysipelas, skin care

GCP CLOE 5Level of Evidence – C (Grade of Recommendation – 5).

Comments: if lymphedema occurs, attention must be paid to the need for weight loss.

4.2.3. Third stage of rehabilitation

Comments: A combination of aerobic and strength training is recommended.

4.3. Rehabilitation During Chemotherapy

Comments: performing aerobic exercise during chemotherapy increases hemoglobin and erythrocyte levels and reduces the duration of leukopenia and thrombocytopenia [75].

Comments: the volume and intensity of exercise therapy during chemotherapy are selected individually based on the severity of fatigue (mild, moderate, severe), and exercise intensity is increased as the general condition improves.

5. Prevention and Dispensary Observation

Comments: the examination algorithm is determined by the attending physician depending on the clinical situation.

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical approbation, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", is organized and provided:

1. in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;

2. in accordance with the procedure for providing care in the profile "oncology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological care center or in a primary oncological office, primary oncological department, or outpatient department of an oncological dispensary.

When penile cancer is suspected or detected in a patient, general practitioners, district general practitioners, general family physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient oncological care center, a primary oncological office, or a primary oncological department of a medical organization to receive primary specialized health care.

Consultation at an outpatient oncological care center or at a primary oncological office or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or primary oncological department) shall organize the collection of biopsy (surgical) material, as well as organize other diagnostic studies necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to obtain biopsy (surgical) material or perform other diagnostic examinations in a medical organization that includes an outpatient oncological care center (primary oncological office, primary oncological department), the attending physician refers the patient to an oncological dispensary or a medical organization providing medical care to patients with malignant neoplasms of the penis.

The timeframe for performing pathomorphological examinations necessary for the histological verification of penile cancer must not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathomorphological bureau (department).

If penile cancer is suspected and/or detected in a patient during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine the management strategy and the need for additional specialized anti-tumor treatment methods.

An oncologist at the outpatient oncological care center (primary oncological office, primary oncological department) refers the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases for diagnosis clarification (if it is impossible for the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department to establish the diagnosis, including the extent of the oncological process and the stage of the disease) and for the provision of specialized, including high-tech, medical care.

The timeframe for initiating specialized, excluding high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to patients with oncological diseases must not exceed 14 calendar days from the date of histological verification of the malignant neoplasm or 14 calendar days from the date of establishing a preliminary diagnosis of the malignant neoplasm (in the absence of medical indications for pathomorphological examinations in an outpatient setting).

Specialized, including high-tech, medical care is provided by oncologists and radiotherapists in an oncological dispensary or in medical organizations providing medical care to patients with oncological diseases, which have a license, the necessary material and technical base, and certified specialists, in inpatient and day-patient settings, and includes the prevention, diagnosis, and treatment of oncological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with oncological diseases, the strategy for medical examination and treatment is determined by a concilium of oncologists and radiotherapists, involving other specialist physicians if necessary. The decision of the medical concilium is drawn up in the form of a protocol, signed by the participants of the medical concilium, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the profile of «oncology» are determined by a concilium of oncologists and radiation therapists, with the involvement of other medical specialists if necessary.

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1. presence of penile cancer complications requiring the provision of specialized medical care in an emergency and urgent form;

2. presence of complications from penile cancer treatment (surgical intervention, radiation therapy, drug therapy, etc.).

Indications for hospitalization in a medical organization in a planned form are:

1. the need to perform complex interventional diagnostic medical interventions requiring subsequent monitoring in an inpatient or day-inpatient setting;

2. the presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy—including contact, external beam, and other types of radiation therapy—drug therapy, etc.) requiring monitoring in an inpatient or day-inpatient setting.

Indications for discharging a patient from a medical organization are:

1. completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in a round-the-clock or day hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2. refusal by the patient or their legal representative of specialized (including high-tech) medical care in an inpatient or day-inpatient setting prescribed by the concilium of the cancer-care medical organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or inpatient medical interventions;

3. need to transfer the patient to another medical organization in the relevant medical specialty.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

Criteria for assessing the quality of medical care are given in Table 4.

7. Additional Information

The most significant prognostic factors for survival in penile cancer are the N category, the number and localization of affected lymph nodes, as well as tumor penetration of the lymph node capsule. Among patients with category N0, 5-year survival is 53–100 %, for N1–2 it is 27 %, and for N3 it is 0–38.4 %. The 5-year survival rate of patients with involvement of 1 lymph node is 50 %, and with 2 or more it is 7 %. In most cases, the tumor progresses slowly. The main causes of death are local complications of the tumor process (infection, bleeding) [21].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kaprin A.D., Academician of the Russian Academy of Sciences, D.Sc. in Medicine, Professor, Honored Physician of the Russian Federation, General Director of the National Medical Research Radiological Center, Head of the Department of Urology and Operative Nephrology with a Course in Oncourology at the Medical Institute of the Peoples' Friendship University of Russia.

2. Matveev V.B., Corresponding Member of the Russian Academy of Sciences, Professor, D.Sc. in Medicine, Deputy Director for Research and Innovation and Head of the Urological Department at the National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health, President of the Russian Society of Oncourologists.

3. Alekseev B.Ya., D.Sc. in Medicine, Professor, Deputy Director for Research at the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Volkova M.I., D.Sc. in Medicine, Associate Professor, Oncology Center No. 1 of the City Clinical Hospital named after S.S. Yudin, Professor at the Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

5. Pushkar D.Yu., Corresponding Member of the Russian Academy of Sciences, D.Sc. in Medicine, Professor, Head of the Department of Urology at the Russian University of Medicine of the Russian Ministry of Health (Moscow, Russia), Chief Urologist of the Russian Ministry of Health, Russian Society of Urology.

6. Govorov A.V., MD, PhD, Professor, Department of Urology, Russian University of Medicine, Russian Ministry of Health; Russian Society of Urology.

7. Kirichek A.A., Assistant, Department of Surgical Diseases with a Course in Oncology, F.P. Haass Moscow Medical and Social Institute; Oncologist, Moscow City Oncology Hospital No. 62 (Moscow, Russia), Russian Society of Urooncology.

8. Gorban N.A., PhD, Head of the Center for Pathomorphology and Molecular Genetic Diagnostics, Central Clinical Hospital with Policlinic of the Administration of the President of the Russian Federation, Russian Society of Oncopatologists.

9. Khalmurzaev O.A., PhD, Researcher, Urological Department, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health.

10. Kostin A.A., Deputy Director General for Science, National Medical Research Center for Radiology, Russian Ministry of Health.

11. Khmelevsky E.V., Head of the Radiotherapy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

12. Fedenko A.A., Head of the Department of Tumor Drug Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

13. Bolotina L.V. Head of the Chemotherapy Department, Department of Tumor Drug Therapy, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

14. Falaleeva N.A., Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

15. Filonenko E.V., Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

Supportive Care Section:

1. Bagrova Svetlana Gennadievna, PhD, Researcher, Chemotherapy Department No. 1, Department of Drug Therapy, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health

2. Buydenok Yury Vladimirovich, MD, PhD, Professor, Leading Researcher, Department of Interventional Radiology, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health

3. Vitsenya Marina Vyacheslavovna, PhD, Senior Researcher, Cardiologist, National Medical Research Center of Cardiology, Russian Ministry of Health

4. Vladimirova Lyubov Yuryevna, MD, PhD, Professor, Head of the Department of Antineoplastic Drug Therapy, National Medical Research Center of Oncology, Russian Ministry of Health

5. Gromova Elena Georgievna, MD, PhD, Anesthesiologist-Resuscitator, Department of Resuscitation and Intensive Care, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health

6. Isyangulova Alina Zulfatovna, PhD, Oncologist, Outpatient Department, Republican Clinical Oncology Dispensary named after Professor M.Z. Sigal of the Ministry of Health of the Republic of Tatarstan

7. Karaseva Vera Vitalievna, MD, PhD, Professor, Department of Oncology, Faculty of Advanced Medical Training, Pirogov Russian National Research Medical University, Russian Ministry of Health

8. Kogonia Lali Mikhailovna, MD, PhD, Professor, Department of Oncology, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky

9. Koroleva Irina Albertovna, MD, PhD, Professor, Department of Clinical Medicine of Postgraduate Education, Reaviz Medical University

10. Latipova Dilorom Khamidovna, PhD, Oncologist, Department of Antineoplastic Drug Therapy, Senior Researcher, Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health, Associate Professor, Department of Oncology, Saint Petersburg State Pediatric Medical University, Russian Ministry of Health

11. Orlova Rashida Vakhidovna, MD, PhD, Professor, Head of the Department of Oncology, Faculty of Medicine, Saint Petersburg State University, Chief Clinical Oncology Specialist, City Clinical Oncology Dispensary, Saint Petersburg

12. Protsenko Svetlana Anatolyevna, MD, PhD, Head of the Department of Chemotherapy and Innovative Technologies, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health

13. Sakaeva Dina Damirovna, MD, PhD, Professor, Deputy Chief Medical Officer for Oncology, Mother and Child Clinical Group

14. Semiglazova Tatyana Yuryevna, MD, PhD, Professor, Head of the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology, Russian Ministry of Health, Professor, Department, North-Western State Medical University named after I.I. Mechnikov, Russian Ministry of Health

15. Somonova Oksana Vasilievna, MD, PhD, Leading Researcher, Research Institute of Clinical Oncology, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health, Professor, Department of Clinical Biochemistry and Laboratory Diagnostics, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Russian Ministry of Health

16. Stenina Marina Borisovna, MD, PhD, Leading Researcher, Department of Clinical Pharmacology, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health

17. Sytov Alexander Viktorovich, PhD, Head of Department – Anesthesiologist-Resuscitator, Department of Resuscitation and Intensive Care, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health

18. Tkachenko Petr Evgenievich, PhD, General Practitioner, Gastroenterologist-Hepatologist, Department of Hepatology, Clinic of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology named after V.H. Vasilenko, I.M. Sechenov First Moscow State Medical University, Russian Ministry of Health

19. Tryakin Alexey Alexandrovich, MD, PhD, Deputy Director for Science, Head of Oncology Department of Drug Treatment Methods (Chemotherapy) No. 2, Research Institute of Clinical Oncology named after Acad. RAMS and RAS N.N. Trapeznikov, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health

20. Feoktistova Polina Sergeevna, PhD, Head of the Chemotherapy Department, Moscow City Clinical Research Center named after A.S. Loginov, Healthcare Department of Moscow

Healthcare Organization Section:

1. Nevolskikh A.A., MD, PhD, Deputy Director for Medical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

2. Ivanov S.A., Professor of the RAS, MD, PhD, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

3. Khaylova Zh.V., PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

4. Gevorkyan T.G., Deputy Director of the Research Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;

• urologists;

• radiologists;

• radiotherapists;

• surgeons;

• anesthesiologists-intensivists;

• general practitioners (internal medicine);

• general practitioners (family medicine);

• neurologists;

• medical geneticists;

• pathologists

Methods used for evidence collection/selection: search in electronic databases; analysis of current scientific developments on the problem of penile cancer in Russia and abroad; synthesis of practical experience of Russian and foreign specialists.

Table 1. Scale for assessing levels of evidence certainty for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence certainty for preventive, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing recommendation grades for preventive, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Appendix A3. Reference Materials

Current package inserts for medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.

Table 1. Algorithm for choosing the treatment method for the primary tumor in patients with penile cancer.

Table 2.

Algorithm for choosing treatment tactics for regional metastases in patients with penile cancer.

Table 3. Drug therapy regimens recommended for the treatment of penile cancer

Note. In regimens with pyrimidine analogues, fluorouracil** can be replaced by #capecitabine** 1650 mg/m2/day orally on radiation therapy days throughout the entire course of radiation therapy.

Appendix B. Physician Action Algorithms

Fig. 1. Flowchart for the management of a patient with verified penile cancer.

Appendix C. Patient Information

The patient is informed about the clinical presentation and methods of diagnosis/staging of penile cancer, and is introduced to various treatment methods and their potential outcomes/complications. The choice of treatment method should be made as a result of such a discussion after the patient has had the opportunity to ask all questions of interest.

It is necessary to encourage the patient not to be ashamed of the disease and to read popular science literature on penile cancer.

The patient should be informed about the nature of follow-up after penile cancer treatment and the importance of regular examinations.

Self-monitoring of the disease course by the patient is impossible; the frequency of doctor visits is determined individually in each specific case.

Recommendations for chemotherapy complications

In case of chemotherapy complications, it is necessary to contact an oncologist (chemotherapist).

1. If body temperature rises to 38 °C or higher:

• start taking antibiotics: as prescribed by the attending physician.

2. In case of stomatitis:

• diet with mechanical and thermal sparing of the mucosa;

• frequent mouth rinsing (every hour) – chamomile flowers, oak bark, sage leaves, lubricate the mouth with sea buckthorn fruit oil;

• treat the oral cavity as recommended by the attending physician.

3. In case of diarrhea:

• diet: exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meat, flour products, fermented milk products, and rice water are permitted. Drink plenty of fluids;

• take medications as prescribed by the attending physician.

4. In case of nausea:

• take medications as prescribed by the attending physician.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.