ILND Surgery Alone or after Chemotherapy with or without Radiation Therapy in Treating Patients with Advanced Penile Cancer

Inclusion Criteria

• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Male, aged 18 years or older
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Histologically-proven squamous cell carcinoma of the penis
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Stage: * Any T, N1 (i.e. a palpable mobile unilateral inguinal lymph node OR a single radiologically-abnormal inguinal lymph node with no evidence of extra-nodal extension), M0, or; * Any T, N2 (i.e. palpable mobile multiple or bilateral inguinal lymph nodes OR radiologically evident multiple or bilateral inguinal nodes with no evidence of extra-nodal extension), M0, or; * Any T, N3 (i.e. fixed inguinal nodal mass or any pelvic lymphadenopathy), M0
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Patients being considered for InPACT-neoadjuvant must have either: * Measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) criteria or; * A single, unilateral lymph node that does not meet RECIST criteria for measurable disease, but that is either palpable or radiologically abnormal, and with histological/cytological evidence of metastatic involvement; this applies only to low disease burden patients who would then be eligible for direct entry into arm A ** Patients with radiological evidence of macroscopic pelvic node involvement are eligible for randomization in InPACT-neoadjuvant but are not be eligible for entry into InPACT-pelvis
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Performance status Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Patient is fit to receive the randomization options for which he is being considered
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Hematology/biochemistry (as dictated by local hospital practice) should indicate fitness for randomization options and parameters should be in line with considerations specified in the summary of product characteristics; hematological parameters should not be supported by transfusion to enable entry into the trial; liver function and renal function tests must form part of the pre-treatment assessment for patients who may be randomized to receive paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy e.g. patients with impaired renal function may not be considered for arms B and C of InPACT-neoadjuvant but may be considered for arm A
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Nodal disease burden must be assessable, with all patients stratified into one of three categories (low / intermediate / high disease burden) in accordance with physical examination and Graafland radiological criteria
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Glomerular filtration rate (GFR) must be assessed for all patients; requirements for GFR vary with treatment eligibility: * GFR >= 50 mL/min: eligible for all treatment options * GFR 45–49 mL/min: eligible for surgery alone (arm A) and for synchronous chemoradiotherapy (arm C); not eligible for neoadjuvant TIP chemotherapy * GFR < 45 mL/min eligible for surgery alone (arm A) or radiotherapy (arm C with cisplatin omitted)
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Willing and able to comply with follow-up schedule
• INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Written informed consent
• INCLUSION CRITERIA FOR INPACT-PELVIS: Patient has met eligibility criteria for InPACT-neoadjuvant
• INCLUSION CRITERIA FOR INPACT-PELVIS: Patient has completed ILND within arms A, B or C of InPACT-neoadjuvant
• INCLUSION CRITERIA FOR INPACT-PELVIS: There must be no radiological evidence of residual inguinal disease on cross-sectional imaging performed after therapeutic inguinal lymph node dissection
• INCLUSION CRITERIA FOR INPACT-PELVIS: There must be no radiological evidence of pelvic lymphadenopathy on cross-sectional imaging performed after therapeutic inguinal lymph node dissection * Any patient who underwent synchronous ipsilateral pelvic lymph node dissection at the time of inguinal lymph node dissection is automatically ineligible for InPACT Pelvis
• INCLUSION CRITERIA FOR INPACT-PELVIS: Patient must be at high risk of relapse following ILND, risk of relapse being assigned on the basis of histological assessment of the ILND specimen; high-risk disease is defined as any patient where ILND reveals either: extranodal extension, bilateral nodal involvement, or 3 or more involved nodes; these patients should be considered at high risk of harbouring occult micrometastatic disease in the ipsilateral pelvic nodes
• INCLUSION CRITERIA FOR INPACT-PELVIS: Performance Status ECOG 0, 1 or 2
• INCLUSION CRITERIA FOR INPACT-PELVIS: Patient is fit to receive the randomization options for which he is being considered
• INCLUSION CRITERIA FOR INPACT-PELVIS: Hematology/biochemistry (as dictated by local hospital practice) should indicate fitness for randomization options and parameters should be in line with considerations specified in the summary of product characteristics; hematological parameters should not be supported by transfusion to enable entry into the trial
• INCLUSION CRITERIA FOR INPACT-PELVIS: Willing and able to comply with follow-up schedule
• INCLUSION CRITERIA FOR INPACT-PELVIS: Written informed consent
• INPACT-NEOADJUVANT ADDITIONAL ELIGIBILITY CRITERIA: Low disease burden * Patients with a single unilateral inguinal lymph node are classified as having a low disease burden and are not eligible for the randomized component of InPACT-neoadjuvant, i.e. are not eligible to receive neoadjuvant therapy within the trial
• INPACT-NEOADJUVANT ADDITIONAL ELIGIBILITY CRITERIA: Intermediate or high disease burden * Patients with intermediate or high disease burden, (high-risk disease on the radiological criteria of Graafland) are considered suitable to receive neoadjuvant therapy and, in the absence of any absolute contraindication to chemotherapy, are eligible for the randomized component of InPACT-neoadjuvant
• INPACT-PELVIS (RANDOMIZATION 2) ADDITIONAL ELIGIBILITY CRITERIA: High-risk disease is defined as any patient whose ILND reveals either extranodal extension, bilateral nodal involvement, or 3 or more involved nodes; these patients should be considered at high risk of harboring occult micrometastatic disease in the ipsilateral pelvic nodes; they are eligible for randomization 2 between prophylactic pelvic lymph node dissection (PLND) and surveillance

Exclusion Criteria

• Pure verrucous carcinoma of the penis
• Non-squamous malignancy of the penis
• Squamous carcinoma of the urethra
• Stage M1
• Previous chemotherapy or chemoradiotherapy outside of the InPACT trial
• Any absolute contraindication to chemotherapy if eligible for a chemotherapy/chemoradiotherapy randomization
• Concurrent malignancy (other than squamous cell carcinoma [SCC] or basal cell carcinoma of non-penile skin) that has required surgical or non-surgical treatment in the last 3 years
• Patients who are sexually active and unwilling to use effective contraception (if they are not already surgically sterile)
• Radiological evidence of macroscopic pelvic lymph node disease on post-ILND cross-sectional imaging (InPACT-pelvis only)
• Patients with regionally advanced (N1-3, M0) penile cancer with disease burden that is considered unresectable by the accredited InPACT surgeon utilizing standard inguinal, ilioinguinal lymphadenectomy resection and reconstructive techniques. For example, where procedures would require circumferential resection of the femoral or iliac vessels, or the requirement for hemipelvectomy * InPACT surgeon should consider reviewing the case with their National InPACT surgical lead where resectability is unclear