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

This phase III randomized 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.

Inclusion Criteria

• Histologically-proven squamous cell carcinoma of the penis
• 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
• Measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) criteria (InPACT-neoadjuvant only)
• Performance status Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2
• Patient is fit to receive the randomization options for which he is being considered
• 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
• Patients being considered for InPACT-neoadjuvant must fulfil additional eligibility criteria
• Patients being considered for InPACT-pelvis must fulfil additional eligibility criteria
• Willing and able to comply with follow-up schedule
• 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 randomised component of InPACT-neoadjuvant, i.e. are not eligible to receive neoadjuvant therapy within the trial
• 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 randomised component of InPACT-neoadjuvant
• InPACT-pelvis (randomisation 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 harbouring occult micrometastatic disease in the ipsilateral pelvic nodes. They are eligible for randomisation 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
• Patients with regionally advanced (N1-3, M0) penile cancer with disease burden that is considered unresectable by the credentialed InPACT surgeon utilising 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 resectablity is unclear

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.

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

Trial Phase Phase III

Trial Type Treatment

Lead Organization
ECOG-ACRIN Cancer Research Group

Principal Investigator
Curtis A. Pettaway

• Primary ID EA8134
• Secondary IDs NCI-2016-01502
• Clinicaltrials.gov ID NCT02305654