Penile Cancer Is Treatable, But the Armamentarium is Thin

Among men in the United States, incidence-based mortality (IBM) is growing for penile cancer even though incidence remained consistent from 2000 to 2018. Existing treatments are of limited efficacy, and there has been a lack research that might identify better options.

Penile squamous cell carcinoma (PSCC), the most common form of the disease, is a rare cancer in high-income countries, with prevalence of less than 1%. In contrast, the disease accounts for up to 10% of cancers in men in some African, Asian, and South American regions.1 The American Society of Clinical Oncology estimates that 2070 people will be diagnosed in the United States this year. In 2020, it was estimated that 36,068 worldwide were diagnosed with this disease.²

The disease can be fatal, but treatment is often successful—especially when diagnosed early. The 5-year overall survival (OS) rate in the United States for patients with this disease is 65%. For men with local disease, the 5-year OS rate is 80%, declining to 9% for those with distant metastases.²

However, the 5-year relative survival rate has declined slightly but steadily, dropping from 67.7% from 2000 to 2004 to 65.67% from 2010 to 2014.³ Philippe E. Spiess, MD, MS, an assistant chief of surgical services and senior member in the Department of Genitourinary Oncology at Moffitt Cancer Center, as well as a professor of oncology and urology in the Department of Urology at University of South Florida Morsani College of Medicine, said that medical science simply has not done enough for these patients.

“The simple reason I think we are seeing that, unfortunately, is that we have not developed, nor have we identified, very effective systemic therapies for patients with penile cancer. Oftentimes, we can cure early penile cancer, fortunately,” Spiess told OncLive^®. “However, when patients have advanced disease, I think we are still very challenged in identifying good chemotherapies or immunotherapies or combination treatments that are going to be very effective for patients.”

The current standard of systemic care is 4 courses of the TIP chemotherapy regimen, which is comprised of neoadjuvant paclitaxel at 175 mg/m² on day 1 plus 1200 mg/m² of ifosfamide and 25 mg/m² of cisplatin on days 1 and 3 for patients with N2 and N3 disease. In a landmark phase 2 study (NCT00512096) published in 2010, 23 of 30 men completed all 4 courses of therapy. The overall response rate in the 30 patients with this approach was 50% (95% CI, 31%-69%), which included 3 complete responses and 12 partial responses (PRs).⁴

More recently, investigators in China evaluated 19 men with advanced PSCC who received TIP treatment from June 2009 to June 2016. Five men previously underwent partial amputation of the penis. The remaining 14 patients had local carcinoma and fixed inguinal lymph node metastasis.⁵

Twelve patients achieved PRs and proceeded to surgery. Five patients underwent bilateral inguinal lymphadenectomy (ILND) and pelvic lymph node dissection (PLND), and 6 had partial amputation of the penis plus ILND and PLND. One patient had penectomy plus ILND and PLND.

“Early-stage penile cancer is curable with surgery alone,” Hao G. Nguyen, MD, PhD, the Richard and Leilani Grinold Endowed Professor in Urology and a professor in the department of urology at the University of California, San Francisco and chief urologic oncologist at the Zuckerberg San Francisco General Hospital and Trauma Center, told OncLive^®. “We have been relying on the same chemotherapy for the past decade or so. We have not made headway in terms of treating metastatic disease. [That is why] you see a static, or even a slight decline in, survival rate for penile cancer.”

He added that awareness of the disease is poor, and there is no established strategy for prevention or early detection. Furthermore, there is no biomarker or pathway to identify PSCC and although the disease is associated with human papillomavirus (HPV) infection in 50% of the cases, investigators do not know whether the HPV vaccine prevents penile cancer.

Depending on the size and extent of the lesion, partial or total penectomy is considered to be the standard oncologic treatment. However, amputation is disfiguring and has a significant negative effect on quality of life (QoL). European Association of Urology guidelines recommend penile-sparing surgery whenever possible, and there is some evidence to suggest that less invasive surgery is equally as effective.

In a systemic review of 88 studies involving 9578 men, European investigators found a cumulative mean 5-year recurrence-free rate of 82.0% with penile-sparing surgery vs 83.9% with amputation. Studies reporting poor recurrence-free rates involved patients who underwent penile-sparing surgery for advanced disease. In contrast, those reporting higher recurrence-free rates involved cohorts who received amputation for less advanced disease.⁶

No matter the method chosen, surgery has a negative impact on QoL. Additionally, patients reported more concerns about appearance and life interference due to disfigurement following amputative surgery. Investigators cautioned that the quality of evidence was poor but the findings support the use of penile-sparing surgery, if possible.

Gender and Sexuality Raise Unique Concerns

It has been documented that patients are very concerned about organ function posttreatment. Surgery “is usually associated with mutilation,” according to 1 report, and affects sexual and urinary functions and health-related QoL.

“Our goal is to have organ-sparing surgery without compromising an oncologic control in our surgery approach,” Nguyen explained. “I would say that depending on the location, if the lesion is at the tip of the gland, then most of the time, even in T2 disease, we should [be able to] spare a lot of the organ.”

Spiess said surgery has significant ramifications for cisgender, nonbinary, and transgender patients. Preserving sexual function is key for physical and emotional health.

“One thing with this type of cancer, which is underreported, is the implications it has on how patients identify themselves after they have had sometimes, unfortunately, fairly mutilating surgery of the penis and that area, and how it affects their sexual identity, and their relationships with their partners,” Spiess said. “What I do in my practice, and several centers have started to also do this, is [leverage] psychosocial counselors and essential educators to work with the patients. We screen them for depression, for suicidal ideation. [Traditionally,] that is something that has not been done very frequently. We need to be very aware [of this,] and support our patients [to help them to understand] how this is going to affect them. And this is going to be for many, many years to come.”

Spiess and Nguyen agreed that shame can prevent patients from seeking treatment. Findings from 1 small study conducted at Sweden’s Örebro University Hospital showed that 65% of patients delayed treatment for more than 6 months.⁷ Data show that a delay of just 3 months was associated with increased risks for adverse clinical characteristics, low penis-sparing rate, and poor sexual function restoration.⁸

Of the patients who delayed treatment, 23.2% stated that they were embarrassed to describe the problem to practitioners. Nearly 20% said they did not think their symptoms were serious.⁸

“To counter that, we have to build a way to screen for penile cancer into the healthcare system. We screen for prostate cancer; we screen for colorectal cancer,” Nguyen said. “Why not have every man get a penis exam on a yearly basis? Then, it takes away these feelings or emotions associated with the exam, and it is just makes everything more objective.”

References

1. Thomas A, Necchi A, Muneer A, et al. Penile cancer. Nat Rev Dis Primers. 2021;7(1):11. doi:10.1038/s41572-021-00246-5
2. Penile cancer: statistics. Cancer.net website. February 2022. Accessed June 27, 2022. https://bit.ly/3OslSRD
3. Deng X, Liu Y, Zhan X, et al. Trends in incidence, mortality, and survival of penile cancer in the United States: a population-based study. Front Oncol. Published online June 17, 2022. doi: 10.3389/fonc.2022.891623
4. 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
5. Xu J, Li G, Zhu SM, et al. Neoadjuvant docetaxel, cisplatin and ifosfamide (ITP) combination chemotherapy for treating penile squamous cell carcinoma patients with terminal lymph node metastasis. BMC Cancer. 2019;19(1):625. doi:10.1186/s12885-019-5847-2
6. Sakalis VI, Campi R, Barreto L, et al. What is the most effective management of the primary tumor in men with invasive penile cancer: a systematic review of the available treatment options and their outcomes. Eur Urol Open Sci. 2022;40:58-94. doi:10.1016/j.euros.2022.04.002
7. Skeppner E, Andersson SO, Johansson JE, et al. Initial symptoms and delay in patients with penile carcinoma. Scand J Urol Nephrol. 2012;46(5):319-325. doi:10.3109/00365599.2012.677473
8. Gao W, Song L-b, Yang J, et al. Risk factors and negative consequences of patient's delay for penile carcinoma. World J Surg Oncol. 2016;14:124. doi:10.1186/s12957-016-0863-z