Investigators Strive to Refine Paradigm for Penile Cancer Treatment

Investigators are using a novel clinical trial design to test multiple treatment strategies in an effort to define the standard of care in squamous cell carcinoma of the penis, a disease that has been historically difficult to evaluate in prospective, randomized trials due to its rarity.^1,2

The phase 3 International Penile Advanced Cancer Trial (InPACT; NCT02305654), which is enrolling 400 patients with stage T, N1 to N3, M0 squamous cell carcinoma of the penis who have not received prior chemotherapy or chemoradiotherapy, will randomize patients twice to evaluate all combinations of therapy used to date.³

The standard modalities used to treat squamous cell carcinoma of the penis include surgery, chemotherapy, and radiotherapy (RT).⁴ Although surgery is rarely sufficient as a singular intervention for patients with inguinal node involvement, how to integrate and sequence chemotherapy and RT to maximize therapeutic benefit in this patient population remains unclear.¹

Squamous cell carcinoma of the penis is an aggressive cancer that represents 0.4% to 0.6% of all malignant neoplasms in the United States and Europe.² The 29% to 40% 5-year survival rate for patients with lymph node (LN)-positive disease and the limited amount of level 1 National Comprehensive Cancer Network (NCCN) evidence to guide treatment decisions translate to a need for clinical investigations that can expand the data available in this space to improve patient outcomes.^2,4

InPACT investigators aim to not only ascertain whether there is a signal for 1 or 2 optimal treatment sequences that lead to improved survival but also standardize them, to ensure that patients with squamous cell penile carcinoma are consistently offered the most effective interventions.

“There are very few men with this disease, and only about 1500 to 2000 men a year will be diagnosed with penile cancer in the United States, [complicating] accrual in clinical trials. For this reason, nobody knows what the correct treatment sequence is and how much is overtreatment and how much is undertreatment,” said Daniel M. Geynisman, MD, an assistant professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, and a member of the NCCN’s Testicular Cancer Panel.

“This is typically an underserved population, and the goal of this trial is to outline an evidence-based approach for men with lymph node–positive disease,” said Geynisman, who serves as principal investigator of the trial site at Fox Chase Cancer Center.

The primary end point of the InPACT study is overall survival. Secondary end points include disease-specific survival time, the number of patients with grade 3 or grade 4 toxicity, and disease-free survival, among other outcome measures (Figure).

Searching for the Optimal Sequence

Randomization 1: InPACT Neoadjuvant

InPACT’s Bayesian design allows for 2 sequential randomizations: InPACT Neoadjuvant and InPACT Pelvis. During the initial randomization period, patients will be randomized to 1 of 3 treatment arms as investigators assess whetherneoadjuvant therapy confers a benefit in this patient population. In arm A, patients will undergo standard surgery, inguinal lymph node dissection (ILND), to remove the lymph nodes near the groin where the cancer first presented. Patients in arm B will receive a maximum of 4 cycles of neoadjuvant paclitaxel, ifosfamide, and cisplatin, followed by ILND, and individuals in arm C will be treated with cisplatin and intensity-modulated x-ray therapy (IMRT) prior to ILND.³

The InPACT study’s evaluation of these therapeutic interventions is supported by existing evidence that suggests a benefit with multimodal treatment strategies, including perioperative RT, chemotherapy, and surgery. “The idea is to use systemic chemotherapy first, like we do in a lot of other high-risk cancers such as bladder cancer and breast cancer, to eliminate micrometastatic disease and then go on to surgery,” Geynisman said.

Whereas ILND and lymph node dissection (LND) are widely recognized as surgical interventions that improve survival outcomes for patients with LN-positive disease, retrospective and prospective data indicate that neoadjuvant cisplatin-based chemotherapy regimens may also confer a survival benefit.⁴

For example, results reported in 2010 from a phase 2 study (NCT00512096) of neoadjuvant paclitaxel, ifosfamide, and cisplatin and subsequent LND in 30 men with stage 3 or stage 4 squamous cell carcinoma showed that improved time to progression (P < .001) and overall survival (P = .001) were significantly associated with responses to perioperative chemotherapy. Half of the 30 patients who received chemotherapy had an objective response, and at the time of the last clinical assessment, 36.7% of the patients had not experienced disease recurrence.⁵

Administering chemotherapy in combination with IMRT may afford superior local disease control than neoadjuvant chemotherapy alone, “but it is not clear which approach is better, and for some men, both approaches may actually be overtreatment, which is why there is an arm that only involves inguinal lymph node dissection,” Geynisman said.

Results published in a 2018 study coauthored by Geynisman and Marc C. Smaldone, MD, MSHP, an associate professor in the Department of Surgical Oncology at Fox Chase Cancer Center, showed that only 66.8% of patients with LN-positive disease (750/1123) underwent LN dissection and many did not receive chemotherapy, despite both modalities’ potential to improve patient outcomes.4 In 2013, the NCCN recommended that all patients with LN-positive penile cancer undergo pelvic LND with or without RT and neoadjuvant chemotherapy.⁴

“This trial is so important because a large proportion of patients with penile cancer are not receiving guideline-recommended care,” said Smaldone. “InPACT will help establish appropriate guidelines and make sure that these patients receive the most up-to-date standard of care.”⁶

Randomization 2: InPACT Pelvis

Following stage 1 of the 2-part randomization plan, patients will be stratified based on their risk of recurrence. Only high-risk patients will be eligible for randomization in InPACT Pelvis.3 The objective of this second randomization stage is to determine whether prophylactic pelvic lymph node dissection (PLND) improves survival in patients at a high risk of recurrence following ILND, said Geynisman.

High-risk patients will be randomized to either prophylactic PLND (arm P), or no prophylactic PLND (arm Q). In arm P, patients who did not receive neoadjuvant chemotherapy in part 1 of randomization will be given adjuvant chemotherapy. Patients who received neoadjuvant chemotherapy will undergo prophylactic PLND. Patients randomized to arm Q will undergo surveillance. Individuals assigned to this arm who were not treated with neoadjuvant chemotherapy will be eligible for IMRT.³

Administering adjuvant chemotherapy to individuals who were not given neoadjuvant systemic therapy during the InPACT Neoadjuvant study will help answer the question of whether neoadjuvant chemotherapy is more advantageous than adjuvant chemotherapy.

At present, there is no conclusive evidence that favors one approach over the other.⁴

International Reach for a Rare Disease

Launched in collaboration with Cancer Research United Kingdom/Stand Up to Cancer and the United States National Cancer Institute, the InPACT study is currently enrolling across 17 sites in the United States and United Kingdom.^1,3

“This is a one-of-a-kind trial for this disease, and it is really the only trial trying to understand the best treatment for these patients in the world,” said Geynisman, who added that although the trial is actively accruing patients, enrollment is proceeding at a slow pace due to the rarity of squamous cell carcinoma of the penis.

“Usually trials for [uncommon] malignancies are open at large-volume sites, but that is not necessarily where the patients are, [so] it is important for care providers to know that this trial exists and to look for open sites in their area so that their patients can be referred to these places,” Geynisman concluded.

References

1. Canter DJ, Nicholson S, Watkin N, Hall E, Pettaway C. InPACT Executive Committee. The International Penile Advanced Cancer Trial (InPACT): rationale and current status. Eur Urol Focus. 2019;5(5):706-709. doi:10.1016/j.euf.2019.05.010

2. National Comprehensive Cancer Network Clinical Practice Guidelines In Oncology. Penile Cancer, version 1.2020. National Comprehensive Cancer Network. Published January 14, 2020. Accessed April 4, 2020. https://www.nccn.org/professionals/ physician_gls/pdf/penile.pdf

3. International Penile Advanced Cancer Trial (International Rare Cancers Initiative Study) (InPACT). ClinicalTrials.gov. Updated October 31, 2019. Accessed April 5, 2020. https://clinicaltrials. gov/ct2/show/NCT02305654

4. Joshi SS, Handorf E, Strauss D, et al. Treatment trends and outcomes for patients with lymph node-positive cancer of the penis. JAMA Oncol. 2018;4(5):643-649. doi:10.1001/jamaoncol.2017.5608

5. Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol. 2010;28(24):3851-3857. doi:10.1200/JCO.2010.29.5477

6. Geynisman D. Fox Chase offers InPACT trial for penile cancers. Fox Chase Cancer Center. Accessed May 5, 2020. https://www.foxchase.org/healthcare-professionals/physician-enewsletters/updates-urologic-oncology/Winter-2020/fox-chase-InPACT-Trial-Penile-Cancers