Summary

This phase III trial studies how well inguinal lymph node dissection (ILND) surgery alone or after chemotherapy with or without intensity-modulated radiation therapy works in treating patients with penile cancer that has spread to other places in the body. Surgery is used to remove the lymph nodes and may be able to cure the cancer. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Intensity-modulated radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. It is not known whether having surgery after chemotherapy with or without radiation therapy is better than having surgery alone.

Objectives

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.

Eligibility

1. INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Male, aged 18 years or older
2. INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Histologically-proven squamous cell carcinoma of the penis
3. 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
4. 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
5. INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Performance status Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2
6. INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Patient is fit to receive the randomization options for which he is being considered
7. 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
8. 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
9. 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)
10. INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Willing and able to comply with follow-up schedule
11. INCLUSION CRITERIA FOR INPACT-NEOADJUVANT: Written informed consent
12. INCLUSION CRITERIA FOR INPACT-PELVIS: Patient has met eligibility criteria for InPACT-neoadjuvant
13. INCLUSION CRITERIA FOR INPACT-PELVIS: Patient has completed ILND within arms A, B or C of InPACT-neoadjuvant
14. 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
15. 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
16. 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
17. INCLUSION CRITERIA FOR INPACT-PELVIS: Performance Status ECOG 0, 1 or 2
18. INCLUSION CRITERIA FOR INPACT-PELVIS: Patient is fit to receive the randomization options for which he is being considered
19. 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
20. INCLUSION CRITERIA FOR INPACT-PELVIS: Willing and able to comply with follow-up schedule
21. INCLUSION CRITERIA FOR INPACT-PELVIS: Written informed consent
22. 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
23. 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
24. 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

Treatment Sites in Georgia