Introduction

Penile squamous cancer is rare in the United States, although more prevalent in other areas, particularly Africa, Asia and South America. Patients often present at a late stage, with clinical malignant adenopathy, initially to the groins, and then the pelvis. The rarity of this disease means that there is remarkably limited prospective evidence to guide treatment. Lymph node dissection can be both diagnostic and sometimes curative; however, surgery alone is often inadequate to effect a cure. Neoadjuvant chemotherapy, particularly the paclitaxel, ifosfamide and cisplatin (TIP) regimen, has been shown to have good efficacy in single-arm clinical trials for patients with bulky lymph node metastases.¹ Chemoradiation has become the care standard for initial management in patients with other forms of locally advanced squamous cell carcinoma, particularly head and neck, anal and vulvar cancers.^2–4 These data, in aggregate, form the basis for investigating different forms of presurgical therapy among patients with penile cancer and clinically or radiologically evident regional lymph node metastases.

Study Design

The aim of InPACT (NCT02305654) is to determine prospectively the potential benefits of chemotherapy or chemoradiation in addition to lymph node dissection in patients with clinical or radiological evidence of inguinal lymph node metastases. The study is sponsored by both the National Cancer Institute (with the Eastern Cooperative Oncology Group (ECOG-ACRIN) as lead) and Cancer Research UK (CRUK). Specifically, 2 important questions will be addressed in a 2-part study design: first, does neoadjuvant therapy of any kind improve outcomes (fig. 1, InPACT Neoadjuvant); second, in those patients who have undergone inguinal lymph node dissection and have adverse pathological features, does pelvic lymph node dissection plus chemoradiation improve survival compared to chemoradiation alone (InPACT Pelvis). The trial design consists of 2 sequential randomizations, termed InPACT neo-adjuvant and InPACT Pelvis. Patients are stratified by disease burden at registration, and this guides randomization. Notably, a patient who has a low disease burden (where preoperative therapy would be inappropriate) can still be enrolled in InPACT and go directly to surgery (Arm A). Such patients may still participate in the InPACT Pelvis component of the trial if they have adverse pathological features in the inguinal dissection specimen.

Figure 1. Trial schema for InPACT Neoadjuvant Study (A) and InPACT Pelvis Study (B).

The statistical design follows a Bayesian approach, which has been used successfully in other rare diseases, and which focuses on the probability of selecting the superior treatment regimen rather than formal hypothesis testing.^5,6

Clinical End Points

InPACT is designed to answer a number of important clinical questions using prospective data gathered from centers that have undergone a rigorous credentialing process. This will help to standardize all elements of the patient’s care including 1) pathology interpretation, 2) imaging and quality, 3) surgical (quality and extent), 4) systemic therapy and 5) radiation therapy. The data gathered from this trial may re-define the treatment paradigm of penile cancer, and at a minimum it will provide the best evidence to support treatment paradigms and lay a foundation for future trials.

The primary outcome of this trial (in all patients) is overall survival time, with secondary outcome measures in the overall study population including : 1) disease-specific survival time, 2) disease-free survival time, 3) treatment related toxicity, 4) the occurrence of surgical complications, 5) the feasibility of pathological nodal assessment after systemic chemotherapy, and 6) quality of life among participating centers. There are additional secondary outcome measures for the InPACT neoadjuvant treatment arm which include: 1) the rate of pathological complete remission, 2) surgical operability, and 3) the feasibility of on-schedule delivery of neoadjuvant therapy. Lastly, a secondary outcome measure for patients randomized to InPACT pelvis includes the occurrence of lower limb and scrotal edema given the delivery of both surgery and radiotherapy.

Entering Patients on Study

InPACT was conceived as an international prospective study to improve the management of patients with regional nodal metastases. Oversight committees in both the United Kingdom and in North America are responsible for credentialing sites and provide ongoing quality assurance of the treatment processes. Once a potentially eligible patient is identified for the study, trial study coordinators screen the subject for the following inclusion criteria including 1) age 18 years or older and 2) clinical staging of N1-N3 and M0. Prominent exclusion criteria are patients with distant metastases, with primary urethral cancer, with nonsquamous penile cancer and those with other concurrent malignancy.

The patient must have an ECOG performance status of 2 or less and must be fit for relevant randomization arms with suitable hematologic and serologic biochemical parameters. Other parameters to consider include suitable renal function as estimated by glomerular filtration rate (GFR) ≥50 ml/min (some discretion for GFR <50 ml/min is permitted and can affect treatment assignment for randomization). Palpable and measurable radiographic lymph node disease burden features stratify patients into one of 3 categories (low/intermediate/high): the disease burden category then affects how a patient would be registered and potentially randomized.⁷ Low burden patients are registered directly into Arm A (surgery alone) as noted above. Patients with a high disease burden (where surgery alone is unlikely to be curative) are randomized between Arms B and C (neoadjuvant therapy arms). If a patient has an intermediate burden of disease he could be randomized to Arm A, B or C.

Given trial complexity and rigor, the site study team will spend considerable time in the informed consent process to ensure that patients are aware and agreeable to study treatment, and followup procedures as a part of the informed consent process. Facilitation of the communication process with study sites is the role of the leadership team of the North American Surgical Oversite Committee (NASOC; see Appendix for contacts), which has instituted videoconferencing with all new study principal investigators and coordinators. The NASOC remains readily available to answer questions related to patient accrual, treatment or how to get new potential sites with an interest in InPACT up and running. The committee has also developed a new “quick reference” verification checklist that is available to study investigators and coordinators to ensure all study elements are completed (fig. 2).

Figure 2. InPACT Study verification checklist.

Figure 3. InPACT trial present vs targeted accruals with corresponding timelines.

InPACT Accrual Update

Based on the original statistical assumptions it was believed that about 400 patients with lymph node metastases could be accrued over a 5 year period. Planned recruitment centers would consist of supra-regional high volume centers in the United Kingdom with an anticipated 20 centers in the United States and Canada. It was anticipated that 200 of the total 400 patients would be accrued from the United States and Canada. It was estimated that if each site accrued 2 patients per year then at 5 years the accrual objective would be met with respect to the United States and Canada.

Unfortunately worldwide recruitment is lagging behind our initial projections. Once the study opened its first few sites in 2017, it was quickly realized that InPACT faced historic challenges related to 1) credentialing site participants including urologists, radiologists, radiation oncologist and pathologists, 2) getting sites IRB approved and open for accrual and, more recently, 3) COVID-19 and subsequent slowdowns in clinical research. The United Kingdom anticipated that European sites that had already expressed interest would be able to participate, but with the “Brexit” crisis all cooperative agreements were put on hold.

Despite the many challenges the trial has faced, 62 patients have been recruited to the trial worldwide with 6 centers open in the UK and 16 open in the U.S. and Canada (see table). The majority of patients (45, 72%) have been recruited in the U.S., where interest remains high. The table shows accrual sites and contacts in the U.S. and Canada. It is anticipated that at least 2 additional sites in the U.S. will open in 2021–2022. InPACT has also generated worldwide interest and the InPACT Trial Steering Committee has explored a number of opportunities to expand into South America (1 approved site), Mexico (1 approved site), Italy (1 site negotiating to open trial) and India (several sites negotiating to join the trial).

A decision was made in early 2021 to reduce the total study sample size to 200 patients. A Bayesian study design for 200 total patients accrued between the current date and 2024 (with an additional followup of 2 years) should provide sufficient endpoint data to meet the study objectives. Shown in figure 3 is the original projected accrual curve and the new projected accrual curve based upon 200 subjects. Given the projected accrual and sample size adjustments one can see from the new curve that accrual is more in line with the adjusted study target.

Summary

InPACT is a historic first in attempting to provide “level one” evidence for the management of surgically resectable inguinal/pelvic metastases in penile cancer utilizing multimodal treatment strategies. Investigators are committed to providing the highest quality data and patient care. Despite initial challenges, the InPACT leadership team remains cautiously optimistic that the study objectives will be achieved based upon the high interest levels among current partners and new international sites.