Introduction
In the age group between 50 and 70 years, penile cancer is more prevalent, with a mean age of 67 years in some countries. The common penile malignancy is squamous cell carcinoma, which originates from the non-keratinized epithelium of the glans or the inner layer of the prepuce.1 The main types of HPV found in men with penile cancer are HPV 16, 18, 22, 31, 33, and 45. More than 20% of patients with penile cancer have been tested positive for HPV infection. Patients with HIV have an 8-fold increased risk. In uncircumcised men, Phimosis is the causation of penile cancer as smegma may be a precipitating factor. HIV and AIDS may be precipitating factors.2 The link between obesity BMI of >30 kg/m2. and penile cancer is well-known. 3.6 % of new cancers were attributed to high BMI. Caused by increased insulin and cortisol levels, with chronic inflammation. 3 One of the strong links of Squamous cell carcinoma of the penis {SCC} is chewing tobacco or smoking. A clear dose-relationship response for smoking and chewing was observed.4 PUVA poses an increased risk of squamous cell carcinoma on non-sun-exposed skin, few studies have examined its specific association with penile cancer. 5
Grading of Penile Cancer
Grade X Grade cannot be accessed.
Grade 1 Low-grade cancer.
Grade 2 Moderate to High grade cancer.
Grade 3 High-grade cancer with metastasis.
Table 1
Signs and symptoms of penile cancer.
Investigations
Medical history and physical exam: To evaluate symptomatology of Penile carcinoma.6
The membrane protein caveolin-1 (CAV1). CAV1 levels strongly increase in malignant epithelial cells, which was correlated with worse clinical outcomes.
The diagnosis of penile cancer is confirmed through biopsy.
Incisional and Excisional biopsy of Lesion: If the lesions are small such as nodule or lump done under local anesthesia.
Fine needle aspiration or CT guided needle biopsy: enlarged lymph node biopsy.
Chest X-ray: done to observe if cancer has spread to the lungs.
MRI helps in the detection and extent of inguinal and pelvic lymphadenopathy.7
Treatment of Penile carcinoma: Penile cancer is a highly curable disease when diagnosed on early-stage (0, I, and II stages), instead of advanced disease (III and IV stage) which remains hard to cure. Treatment of metastatic SCPC is associated with poor outcomes with a median OS of 6-12 months.
Early localized penile carcinoma has an excellent outcome with more than 70% long-term survival with local penile conservative approach using surgery or radiotherapy. About 30-40% of patients present with lymph node metastases in which long-term survival is just 20-30%.8
Stages of penile cancer and treatment
Table 2
Therapy of penile canceras per stage. 9
Topical treatment of non-invasive penile cancer
The two main topical treatments for non-invasive penile cancer are 5-fluorouracil (5-FU) and IQ {Imiquimod} 5 Fluoro Uracil exerts its chemotherapeutic effects through inhibition of the enzyme thymidylate synthetase. IQ is an immuno-modulating drug that acts on several levels of the adaptive immune system. It activates the cells of this aspect of the immune system through toll-like receptor 7 (TLR-7) causing secretion of cytokines such as interferon-alpha, interleukin 6 (IL-6) and tumour necrosis factor-alpha. The treatment is usually given 5 days a week for a period of 4 to 6 weeks. CIS penile cancer up to 57% of patients reported a complete response with a low number of adverse events. The common adverse effect is local skin irritation at the application site, headache, flu-like symptoms, and myalgia.10
In patients with metastatic disease, chemotherapy is undoubtedly the only possible effective treatment.
Adjuvant Chemotherapy
The adjuvant setting refers to chemotherapy after complete surgical treatment of the local disease and inguinal lymph node metastases.
This treatment is indicated after the removal of affected lymph nodes vincristine/bleomycin/ methotrexate combination treatment is usually administered.
Neoadjuvant chemotherapy
For patients with palpable lymph nodes and especially with large, immobile inguinal nodal metastases, recent studies have shown promising results for neoadjuvant chemotherapy. (vincristine/bleomycin/ methotrexate, Cisplatinum/bleomycin/methotrexate, cisplatinum/5-FU or cisplatinum/irinotecan) are used.
Advanced penile cancer holds a poor prognosis and must be approached via a multimodal treatment regimen that includes neoadjuvant chemotherapy followed by surgical resection.
Therapeutic and palliative chemotherapy in advanced metastatic penile cancer
The following chemotherapeutic regimens are employed:
Table 3
Chemotherapeutic regimens.
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Lines of Therapy in Penile Carcinoma based on various studies.11, 12, 13
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First Line Therapy |
Second Line Therapy |
Third Line Therapy |
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Cisplatin 75 mg/m2 (70-80) Day 1, 5 Fluorouracil 800-1000 mg/m2 for 4 days, Every 3-4 weeks
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5FU/Mitomycin |
Weekly Paclitaxel |
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Cisplatin or Carboplatin with capecitabine
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Carboplatin/Paclitaxel |
Immunotherapy |
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Vincristine + Methotrexate |
Sunitinib or Sorafenib |
Newer Investigational Drugs |
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Paclitaxel 175 mg/m2 on day 1 Ifosfamide 1,200 mg/m2 on days 1 to 3 , Cisplatin 25 mg/m2 on days 1 to 3
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Intraarterial cisplatin + Gemcitabine |
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Irinotecan (60 mg/m2) on days 1, 8 and 15 Cisplatin (80mg/m2)
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Cisplatin 8.5 mg m–2 Methotrexate 275 mg m–2 Mitomycin 1.2 mg m–2 Bleomycin 4 mg m–2. |
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Cetuximab + Cisplatin or Panitumumab (6 mg/kg, repeated every 2 weeks) (anti-EGFR monoclonal antibodies, with 50% of them showing a response to treatment, and a median PFS of ~ 3 months)
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Paclitaxel Epidermal growth factor receptor monoclonal antibody, nimotuzumab
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Anti-CTLA-4 agent Ipilimumab Anti-PD-1 agent nivolumab administered at standard doses was associated with a prominent response in a patient refractory to paclitaxel, Ifosfamide and cisplatin |
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Cemiplimab - (PD-1) inhibitor given intra-venously (3 mg/kg every 2 weeks) used for Cisplatin Resistant Metastatic Penile Cancer.
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Paclitaxel Epidermal growth factor receptor monoclonal antibody, nimotuzumab IgG1 antibodies bind to PD-L1 to inhibit PD-1.
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Intraarterial chemotherapy
The infused regimens are composed of methotrexate (110 mg m−2 per day), mitomycin C (4.5 mg m−2 per day), bleomycin (15 mg m−2 per day), cisplatin (35 mg m−2 per day), and 5-fluorouracil (1200 mg m−2 per day) These drugs were infused continuously by using the pump for 2 days in each course. The course was repeated at an interval of 4 weeks. This may be used as neoadjuvant therapy in most cases.14
Curative Radiotherapy
Represents an alternative to primary surgical resection for SCC, when surgery is not appropriate. RT may provide a palliative benefit after chemotherapy. High dose (60Gy) required, with significant adverse events. Palliative radiation remains the standard in unresectable inguinal lymph node metastases. Radiation treatment of the primary tumour is an alternative organ-preserving approach with good results in selected patients with T1-2 lesions < 4 cm in diameter. Radiotherapy results are best with penile brachytherapy with local control rates ranging from 70-90%. External beam radiotherapy and brachytherapy are associated with severe complications down the line, such as urethral stenosis, telangiectasia, fibrosis/atrophy, and penile necrosis. Local brachytherapy achieves lower local control rates compared to surgical treatment (70–90% versus 90–92% and 94–96% for glansectomy and glans resurfacing. 15, 16
Surgical manipulation
Radical surgery (partial or total penectomy with a negative surgical margin) remains the gold standard in managing invasive penile cancer.
Table 4
Surgical procedures
Psychological support
Depression and even suicidal thoughts are not uncommon in penile cancer sufferers, and this is an established field of study. Post-traumatic stress disorder (PTSD) could have important relevance. Sexual function was severely affected in patients treated with partial penectomy.17, 18
Conclusion
Penile carcinoma commonly occurs in the 6th or 7th decade of life, comes under the category of rare cancer but serious disease. The treatment of penile cancer is Stage-adapted treatment. Treatment Cycles generally last about 3 to 4 weeks. Some of the drugs used to treat penile cancer include: Cisplatin, Fluorouracil (5-FU). Paclitaxel Ifosfamide, Mitomycin C, Capecitabine. Often, 2 or more of these drugs are used together to treat penile cancer Prognosis is poor for patients with platinum refractory disease, with mOS of < 6 months.
Adjuvant radiation therapy must be considered for high-risk squamous cell carcinoma. The combination of cisplatin and 5-FU in neoadjuvant therapy improved the response rates up to 80% with 40% complete responses. PD-1 inhibition is now the standard of care for advanced squamous cell carcinoma. Platin-based chemotherapy or anti-EGFR can be prescribed in the second-line setting.
Surgery is the treatment of choice whenever the tumor is resectable. The glans penis is the most common site of penile cancer with 50% of newly diagnosed lesions isolated to the glans and 80% isolated to the glans and prepuce. Younger patients are often offered more penile-sparing approaches for primary tumors but more aggressive treatment such as lymphadenectomy for nodal disease. Glansectomy is indicated for larger or more advanced lesions. Side effects of surgery include erectile dysfunction, pain, discomfort, altered appearance, bleeding, trouble urinating, swelling, itching and lymphoedema. Quality of life post-surgery for penile cancer has shown that up to 40% of patients had a poor quality of life. In India 5 year survival rates were found to be 87% and 60% respectively in stage I and II respectively.