Penile squamous cell carcinoma is a rare but serious form of cancer that requires careful, specialized treatment to preserve both health and quality of life. Understanding treatment options—from established surgical methods to new therapies being tested in clinical trials—can help patients and their families navigate this challenging diagnosis with greater confidence and hope.

How Treatment Helps Men with Penile Squamous Cell Carcinoma

When a man receives a diagnosis of penile squamous cell carcinoma, the main goal of treatment is to remove or destroy the cancer while preserving as much normal function and appearance of the penis as possible. The approach chosen depends on many factors, including how large the cancer is, where exactly it is located, whether it has spread to nearby lymph nodes or other parts of the body, and the patient’s overall health and personal wishes.^[1][13]

Treatment decisions are not made by one doctor alone. Instead, a team of specialists—including urologists, oncologists, pathologists, and radiation therapists—work together to create a personalized treatment plan. This team approach ensures that every aspect of the disease is considered and that the treatment chosen offers the best chance of controlling the cancer while minimizing side effects and preserving the patient’s quality of life.^[18]

Medical societies and expert groups have developed guidelines based on years of research and clinical experience. These guidelines help doctors recommend standard treatments that have been proven effective. At the same time, researchers continue to study new drugs and treatment methods in clinical trials, offering hope for even better outcomes in the future.^[6][13]

Early detection plays a critical role in successful treatment. When penile cancer is caught in its earliest stages—before it has grown deeply into tissues or spread to lymph nodes—treatment is often simpler, less invasive, and more likely to result in a cure. This is why men should never ignore unusual sores, lumps, or changes in the skin of the penis, and should seek medical attention promptly if anything seems wrong.^[1][2]

Standard Treatment Options for Penile Squamous Cell Carcinoma

Surgery: The Most Common Treatment

Surgery remains the primary and most effective treatment for most cases of penile squamous cell carcinoma. The type of surgery depends on how far the cancer has spread. For very early-stage cancers that only affect the surface layers of the skin, doctors may recommend a wide local excision, which means removing the cancer along with a small margin of healthy tissue around it. This approach aims to preserve as much of the penis as possible.^[7][11]

In some cases, especially when the cancer is confined to the foreskin, a simple circumcision (removal of the foreskin) may be sufficient. This is one of the least invasive surgical options and can be curative if the cancer has not spread beyond the foreskin.^[16][18]

For cancers that have grown deeper into the head (glans) of the penis, surgeons may perform a partial or total glansectomy, which means removing part or all of the glans. In some cases, the removed tissue can be replaced with a skin graft to help maintain appearance and function.^[18]

When the cancer is more advanced or has invaded deeper tissues, a partial penectomy (removal of part of the penis) may be necessary. Surgeons try to preserve as much length as possible while ensuring that all cancer cells are removed. In very advanced cases, a total penectomy (complete removal of the penis) may be the only option, though this is becoming less common as organ-preserving techniques improve.^[7][13]

Managing Lymph Nodes

One of the most important aspects of treating penile squamous cell carcinoma is managing the lymph nodes in the groin area. The cancer often spreads first to these nearby lymph nodes before reaching other parts of the body. The status of these lymph nodes is one of the strongest predictors of how well a patient will do long-term.^[13][15]

If enlarged lymph nodes are felt during physical examination, doctors will investigate whether they contain cancer cells. However, even when lymph nodes feel normal, there may still be microscopic cancer spread that cannot be detected by touch alone. For this reason, many patients undergo a procedure called dynamic sentinel node biopsy. This technique identifies and removes only the first few lymph nodes that drain from the tumor. If these nodes are free of cancer, the chance that other lymph nodes are affected is very low, and more extensive surgery may not be needed.^[13]

When lymph nodes do contain cancer, a more complete removal of lymph nodes, called lymphadenectomy, is usually recommended. This surgery helps prevent cancer from spreading further but can have side effects, including swelling of the legs (lymphedema) and delayed wound healing.^[15]

Topical Treatments for Early-Stage Disease

For very early cancers that have not grown beyond the top layers of skin—sometimes called penile intraepithelial neoplasia or carcinoma in situ—doctors may recommend non-surgical treatments. These include creams that contain chemotherapy drugs, such as 5-fluorouracil (5-FU), which kills cancer cells directly on the skin surface. Another cream, imiquimod, works by stimulating the body’s own immune system to attack cancer cells.^[7][16]

These creams are applied directly to the affected area for a period of weeks. They can cause redness, irritation, and peeling of the skin, but these side effects usually resolve after treatment ends. Topical treatments are most effective for small, superficial lesions and allow men to avoid surgery while still treating the cancer.^[17]

Laser Therapy and Cryotherapy

Laser therapy uses a focused beam of light to destroy cancer cells. It is particularly useful for small, early-stage cancers on the surface of the penis. The procedure can often be done on an outpatient basis and typically causes less scarring than traditional surgery.^[16][18]

Cryotherapy involves freezing the cancer cells with a special device. Like laser therapy, it is used for very early-stage cancers and can be an effective, less invasive option for carefully selected patients.^[16]

Radiation Therapy

Radiation therapy uses high-energy rays to kill cancer cells. It can be delivered from outside the body (external beam radiation) or from radioactive sources placed directly into or near the tumor (brachytherapy). Radiation is sometimes used as an alternative to surgery, particularly for men who want to avoid penile amputation or who have small, localized tumors.^[7][17]

One advantage of radiation therapy is that it may preserve sexual function better than some surgical options. However, radiation has its own risks. These can include pain, swelling, skin irritation, narrowing of the urethra (the tube through which urine passes), and, in some cases, damage to penile tissues that can lead to ulcers or necrosis (tissue death). Radiation also tends to be less effective if the tumor is infected or if it has grown deeply into surrounding structures.^[17]

Radiation therapy may also be used after surgery, particularly if the cancer has spread to lymph nodes or if there is a high risk of recurrence. In advanced cases where cure is not possible, radiation can help relieve symptoms such as pain or bleeding.^[18]

Chemotherapy for Advanced Disease

Chemotherapy involves using drugs that travel through the bloodstream to kill cancer cells throughout the body. It is most commonly used when penile squamous cell carcinoma has spread to lymph nodes or distant organs. Chemotherapy may be given before surgery (to shrink the tumor and make it easier to remove), after surgery (to kill any remaining cancer cells), or in combination with radiation therapy.^[15][17]

The most commonly used chemotherapy regimens for penile cancer include drugs containing cisplatin, often combined with other agents such as 5-fluorouracil or paclitaxel. While no single chemotherapy combination has been proven to be superior for all patients, cisplatin-based regimens are widely used because they have shown activity against this type of cancer.^[15]

Chemotherapy can cause side effects, including nausea, vomiting, fatigue, hair loss, and a weakened immune system that increases the risk of infections. Doctors work closely with patients to manage these side effects and adjust treatment as needed.^[11]

Mohs Micrographic Surgery

Mohs surgery is a specialized surgical technique in which the cancer is removed in very thin layers. After each layer is removed, it is immediately examined under a microscope to check for cancer cells. This process continues until no cancer cells remain. Mohs surgery allows surgeons to remove all of the cancer while sparing as much healthy tissue as possible, making it an attractive option for penile squamous cell carcinoma. This technique has been used successfully in select cases and offers excellent cancer control with maximal preservation of penile structure.^[1][7]

Innovative Treatments Being Tested in Clinical Trials

While standard treatments have proven effective for many men with penile squamous cell carcinoma, researchers around the world are working to develop new therapies that may offer better outcomes, fewer side effects, or more treatment options for patients whose cancers do not respond to standard approaches. These new treatments are tested through clinical trials—carefully designed research studies in which patients receive experimental therapies under close medical supervision.^[15]

Understanding Clinical Trial Phases

Clinical trials proceed through several phases. Phase I trials focus primarily on safety—determining what dose of a new drug can be given safely and identifying potential side effects. Phase II trials begin to assess whether the treatment is effective against the cancer and continue to monitor safety. Phase III trials compare the new treatment to the current standard treatment to see if it offers better results.^[15]

Targeted Therapies

One promising area of research involves targeted therapies—drugs that attack specific molecules or pathways that cancer cells need to grow and survive. Unlike traditional chemotherapy, which affects all rapidly dividing cells in the body, targeted therapies are designed to be more selective, potentially causing fewer side effects.

Researchers have found that some penile squamous cell carcinomas have abnormalities in certain growth factor receptors on the surface of cancer cells. One such receptor is the epidermal growth factor receptor (EGFR). Drugs that block EGFR are being studied to see if they can slow or stop the growth of penile cancer. Early studies have shown some promising results, though more research is needed to confirm their effectiveness.^[15]

Another target of interest is the network of blood vessels that tumors build to supply themselves with nutrients and oxygen—a process called angiogenesis. Drugs that block angiogenesis, called anti-angiogenic agents, are being tested in combination with chemotherapy to see if they can help control advanced penile cancer.^[15]

Immunotherapy

Immunotherapy is a type of treatment that helps the body’s own immune system recognize and attack cancer cells. This approach has revolutionized treatment for several other types of cancer, and researchers are now exploring whether it can help men with penile squamous cell carcinoma.

One form of immunotherapy involves drugs called checkpoint inhibitors. These drugs block proteins that prevent the immune system from attacking cancer cells. By removing this “brake” on the immune system, checkpoint inhibitors can allow immune cells to recognize and destroy cancer more effectively. Clinical trials are testing whether these drugs can benefit patients with advanced penile cancer, particularly those whose tumors are associated with human papillomavirus (HPV) infection.^[15]

Understanding Tumor Biology and Molecular Changes

As scientists learn more about the genetic and molecular changes that drive penile squamous cell carcinoma, they are discovering new potential targets for treatment. Some cancers are driven by mutations in genes that control cell growth, while others are influenced by viral infections, particularly HPV. Understanding these underlying mechanisms may lead to more personalized treatment approaches, where therapy is tailored to the specific characteristics of each patient’s tumor.^[9][15]

Research into the molecular basis of penile cancer is also helping to identify which patients are most likely to benefit from certain treatments. For example, tumors with specific genetic changes may be more sensitive to targeted therapies, while those with high levels of immune cell activity may respond better to immunotherapy.^[15]

Multimodality Approaches

Many clinical trials are testing combinations of different treatment types—for example, chemotherapy combined with radiation, or chemotherapy followed by surgery and then immunotherapy. These multimodality approaches aim to attack the cancer from multiple angles, increasing the chance of controlling or eliminating it. Studies have shown that for patients with advanced lymph node involvement, combining chemotherapy with surgery or radiation may improve outcomes compared to using any single treatment alone.^[15]

Where Clinical Trials Are Being Conducted

Clinical trials for penile squamous cell carcinoma are being conducted at specialized cancer centers around the world, including in the United States, Europe, and other regions. Because penile cancer is rare, many trials involve multiple institutions working together to enroll enough patients to generate meaningful results. Patients interested in participating in a clinical trial should discuss this option with their oncologist, who can help determine whether there are appropriate trials available and whether the patient meets the eligibility criteria.^[15]

Most common treatment methods

• Surgery
  • Wide local excision to remove the tumor along with a margin of healthy tissue
  • Circumcision for cancers confined to the foreskin
  • Partial or total glansectomy to remove part or all of the glans
  • Partial or total penectomy to remove part or all of the penis in more advanced cases
  • Mohs micrographic surgery to remove cancer layer by layer while sparing healthy tissue
  • Lymph node biopsy or lymphadenectomy to remove and examine lymph nodes in the groin
• Topical Therapy
  • 5-fluorouracil (5-FU) cream, a chemotherapy agent that kills cancer cells on the skin surface
  • Imiquimod cream, which stimulates the immune system to attack cancer cells
• Laser Therapy and Cryotherapy
  • Laser treatment uses focused light to destroy early-stage superficial cancers
  • Cryotherapy freezes cancer cells using a special device
• Radiation Therapy
  • External beam radiation delivers high-energy rays from outside the body
  • Brachytherapy places radioactive sources directly into or near the tumor
  • Used as primary treatment for organ preservation or after surgery to reduce recurrence risk
• Chemotherapy
  • Cisplatin-based regimens, often combined with 5-fluorouracil or paclitaxel
  • Used before surgery to shrink tumors, after surgery to kill remaining cancer cells, or for advanced disease
  • May be combined with radiation therapy (chemoradiotherapy)
• Immunotherapy (in clinical trials)
  • Checkpoint inhibitors that help the immune system recognize and attack cancer cells
  • Being tested in clinical trials for advanced penile cancer
• Targeted Therapy (in clinical trials)
  • Drugs targeting epidermal growth factor receptor (EGFR)
  • Anti-angiogenic agents that block tumor blood vessel formation
  • Being studied in combination with other treatments