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

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

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

PRIMARY OBJECTIVES:
I. To determine if there is a role for neoadjuvant therapy and if so, whether chemotherapy or chemoradiotherapy produce superior outcomes (either for survival endpoints or for morbidity/quality of life endpoints).
II. To determine the additional survival benefit of prophylactic pelvic lymph node dissection (PLND) given after neoadjuvant chemoradiotherapy or with adjuvant chemoradiotherapy of the pelvic nodes over and above that of chemoradiotherapy alone in patients at high risk of recurrence following inguinal lymph node dissection (ILND).

SECONDARY OBJECTIVES:
I. To determine if neoadjuvant therapy prior to surgery (ILND) can reduce recurrence rates. (International Penile Advanced Cancer Trial [InPACT]-neoadjuvant)
II. To determine which is the more active of neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy. (InPACT-neoadjuvant)
III. To determine the operative/post-operative complication rate following neoadjuvant therapy of both types. (InPACT-neoadjuvant)
IV. To determine if neoadjuvant chemoradiotherapy is feasible in this setting. (InPACT-neoadjuvant)
V. To determine the rate of additional complications for the combination of PLND and chemoradiotherapy. (InPACT‐pelvis)

EXPLORATORY OBJECTIVES:
I. To determine the relationship between human papillomavirus (HPV) status and outcome for all groups studied.
II. To determine the impact on quality of life of the (sequential) treatments studied.

OUTLINE:

InPACT-NEOADJUVANT: Patients are randomized to 1 of 3 arms.

ARM A: Patients undergo standard of care ILND surgery.

ARM B: Patients receive paclitaxel intravenously (IV) over 3 hours on day 1, cisplatin IV over 2 hours on days 1-5 or 1-3, and ifosfamide IV over 1 hour on days 2-5 or 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Approximately 6-12 weeks after day 1 of the last cycle of neoadjuvant chemotherapy, patients undergo ILND surgery.

ARM C: Beginning 4 weeks after randomization, patients receive cisplatin IV and undergo intensity-modulated radiation therapy (IMRT) for 25 fractions over 5 weeks. Approximately 6 weeks after completion of neoadjuvant chemotherapy and IMRT, patients undergo ILND surgery.

InPACT-PELVIS: Patients with pathological high risk are randomized to 1 of 2 arms.

ARM P: Patients undergo PLND surgery. Beginning 8 weeks after PLND surgery, patients who have not received neoadjuvant chemotherapy and IMRT, receive cisplatin IV and undergo IMRT for 25 fractions over 5 weeks.

ARM Q: Patients undergo surveillance at fixed time-points according to local practice. Beginning 8 weeks after ILND surgery, patients who have not received neoadjuvant chemotherapy and IMRT, receive cisplatin IV and undergo IMRT for 25 fractions over 5 weeks.

Patients in all arms also undergo magnetic resonance imaging (MRI) and/or computed tomography (CT) throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.