- Visibility 250 Views
- Downloads 26 Downloads
- Permissions
- DOI 10.18231/j.ijcaap.2022.025
-
CrossMark
Abstract
There is a relatively higher incidence of penile cancer in India 3.32 per 100 000 men, whereas Jewish men have the lowest incidence. The risk factors include phimosis, balanitis, and no circumcision. Human papillomavirus accounts for 40% of cases. Other factors include obesity, smoking, Psoralen UV- A therapy. Penile cancer is common above the age of 50 years. 95% of penile cancer is a squamous cell, carcinoma. Treatment of Penile carcinoma is stage wise, where surgery, partial or total penectomy, radiation therapy, or chemotherapy are a mainstay. Laser therapy is often used in the treatment of both CIS and low-grade/stage invasive disease. The neoadjuvant regimen often used is TIP, which consists of 4 cycles of paclitaxel, ifosfamide, and cisplatin. Nimotuzumab EGFR-antibody treatment as an alternative salvage treatment for advanced penile cancer. Immune Checkpoints blockades such as cabozantinib are evaluated in resistant diseases. Avelumab is currently tested in penile cancer patients in two ongoing trials.
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.
|
Growth or sore on the penis which does not heal within four weeks with bleeding or no bleeding. |
|
|
Foul-smelling discharge and rash on the penis. |
|
|
Thickening of the skin of the penis or Phimosis and change in the colour of the skin of the penis or foreskin. |
|
|
Penile ulceration, with fungating mass in severe cases. |
|
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
|
Stag es of Penile Cancer |
Clinical Picture |
Therapy |
|
Stage 0 |
Carcinoma in situ (CIS) and verrucous carcinoma |
Ca In situ: circumcision. local therapy (laser ablation, topical 5-FU or imiquimod, or cryotherapy) verrucous carcinoma - laser therapy, Mohs surgery, wide excision, or cryotherapy. |
|
Stage 1 |
Superficial layers are involved |
Glansectomy, or removal of part of the penis. Radiation therapy or laser ablation |
|
Stage 2 |
Deep into the tissues of the penis (such as the corpus spongiosum or cavernosum) – no lymphatic spread |
Partial or total penectomy |
|
Stage 3 |
Deep into the tissues of the penis (such as the corpus spongiosum or cavernosum) – lymphatic spread |
Chemotherapy (chemo) or chemo plus radiation |
|
Stage 4 |
The main tumor has grown into nearby tissues, like the prostate, bladder, scrotum |
Chemo plus radiation |
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:
|
Lines of Therapy in Penile Carcinoma based on various studies.[11], [12], [13]
|
||
|
First Line Therapy |
Second Line Therapy |
Third Line Therapy |
|
Cisplatin 75 mg/m2 (70-80) Day 1, 5 Fluorouracil 800-1000 mg/m2 for 4 days, Every 3-4 weeks
|
5FU/Mitomycin |
Weekly Paclitaxel |
|
Cisplatin or Carboplatin with capecitabine
|
Carboplatin/Paclitaxel |
Immunotherapy |
|
Vincristine + Methotrexate |
Sunitinib or Sorafenib |
Newer Investigational Drugs |
|
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
|
Intraarterial cisplatin + Gemcitabine |
|
|
Irinotecan (60 mg/m2) on days 1, 8 and 15 Cisplatin (80mg/m2)
|
||
|
Cisplatin 8.5 mg m–2 Methotrexate 275 mg m–2 Mitomycin 1.2 mg m–2 Bleomycin 4 mg m–2. |
||
|
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)
|
||
|
Paclitaxel Epidermal growth factor receptor monoclonal antibody, nimotuzumab
|
||
|
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 |
||
|
Cemiplimab - (PD-1) inhibitor given intra-venously (3 mg/kg every 2 weeks) used for Cisplatin Resistant Metastatic Penile Cancer.
|
||
|
Paclitaxel Epidermal growth factor receptor monoclonal antibody, nimotuzumab IgG1 antibodies bind to PD-L1 to inhibit PD-1.
|
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]
Mode of action of cetuximab and Panitumumab
Cetuximab and Panitumumab are two distinct monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR).
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.
|
1. |
Sentinel lymph node biopsy is the first node to receive the drainage directly from a tumor. Detection and pathological examination of the SLN is an important oncological procedure that minimizes morbidity related to extensive nodal dissection. |
|
2. |
Circumcision is generally recommended in men with CIS (carcinoma in situ). Circumcision is the surgical removal of the skin covering the tip of the penis. |
|
3. |
Mohs surgery, thin layers of cancer-containing skin are progressively removed and examined until only cancer-free tissue remains. Mohs surgery removes the smallest amount of healthy tissue, which minimizes scarring. |
|
4. |
Laser therapy has been used in the treatment of both CIS and low-grade/stage invasive disease. Its palliative surgery and is used for out patients. |
|
5. |
Glans resurfacing is a feasible organ‐preserving surgical option in correctly selected patients for both malignant and benign penile disease |
|
6. |
Total glansectomy: the excision of the glans penis from the corporal heads. Glansectomy with split-thickness skin graft reconstruction is a safe and effective treatment for men with localized penile cancer. |
|
7. |
Penectomy is an operation to remove all or part of a penis. Radical penectomy is indicated in most T3 and all T4 staged penile tumours. |
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.
Conflict of Interest
The authors declare no relevant conflicts of interest.
Source of Funding
None.
References
- Cardona C, García-Perdomo H. Incidence of penile cancer worldwide, : Systemic review and Meta analysis. Rev Panam Salud Publica. 2017;41. [Google Scholar] [Crossref]
- Kidd LC, Chaing S, Chipollini J, Giuliano AR, Spiess PE, Sharma P. Relationship between human papillomavirus and penile cancer-implications for prevention and treatment. Transl Androl Urol. 2017;6(5):791-802. [Google Scholar]
- Barnes K, Mcdowell B, Button A, Smith B, Lynch C, Gupta A. Obesity is associated with increased risk of invasive penile cancer. BMC Urol. 2016;16(1). [Google Scholar] [Crossref]
- Harish K, Ravi R. The role of tobacco in penile carcinoma. Br J Urol. 1995;75(3):375-7. [Google Scholar] [Crossref]
- Douglawi A, Masterson T. Updates on the epidemiology and risk factors for penile cancer. Transl Androl Urol. 2017;6(5):785-90. [Google Scholar]
- . NHS update on Penile cancer. . 2020. [Google Scholar]
- Akers C, Holden F. An overview of the diagnoses and treatments for penile cancer. Br J Nurs. 2020;29(9). [Google Scholar] [Crossref]
- AP, Noronha V, Joshi A, Tongaonkar H, Bakshi G, Prabhash K. Resistant metastatic penile carcinoma and response to biochemotherapy with paclitaxel and epidermal growth factor receptor monoclonal antibody, nimotuzumab. Indian J Med Paediatr Oncol. 2013;34(1):24-7. [Google Scholar] [Crossref]
- Poppel HV, Watkin N, Osanto S, Moonen L, Horwich A, Kataja V. Penile cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:vi115-24. [Google Scholar] [Crossref]
- AM, Brenton T, Wylie S, Corbishley C, Watkin N. Topical Therapy for non-invasive penile cancer (Tis)-updated results and toxicity. Transl Androl Urol. 2017;6(5):803-8. [Google Scholar] [Crossref]
- Hakenberg O, Protzel C. Chemotherapy in penile cancer. Ther Adv Urol. 2012;4(3):133-8. [Google Scholar] [Crossref]
- D’Aniello C, Cavaliere C, Facchini B, D’Errico D, Capasso M, Iovane G. Penile cancer: prognostic and predictive factors in clinical decision-making. Eur Rev Med Pharmacol Sci . 2020;24(23):12093-108. [Google Scholar]
- Cliff J, Britten A, Innes H, Mehmood Q, Birtle A, Elliott T. Retrospective Review of Chemotherapy Treatment for Locally Advanced and Metastatic Penile Cancer in the North West of England. Br J Med Med Res. 0191;6(2):149-57. [Google Scholar]
- Chiang P, Chen C, Shen Y. Intraarterial chemotherapy as the first-line therapy in penile cancer. Br J Cancer. 2009;111(6):1089-94. [Google Scholar] [Crossref]
- OH, Protzel C. Contemporary role of radiotherapy in the management of penile cancer. Transl Androl Urol. 2017;6(5):855-67. [Google Scholar] [Crossref]
- Hakenberg, O, Dräger D, Erbersdobler A, Naumann C, Jünemann K, Protzel C. The Diagnosis and Treatment of Penile Cancer. Dtsch Arztebl Int. 2018;115(39):646-52. [Google Scholar] [Crossref]
- Morelli G, Pagni C, Mariani G, Campo G, Menchini-Fabris R, Minervini R. A Minervini Glansectomy with split-thickness skin graft for the treatment of penile carcinoma. Int J Impotence Res. 2009;21(5):311-4. [Google Scholar] [Crossref]
- Hadway P, Sahdev V, Arya M, Muneer A. Recent developments and current management of penile cancer. Clin Pract. 2014;11(2):169-81. [Google Scholar] [Crossref]
- Abstract
- Introduction
- Grading of Penile Cancer
- Investigations
- Stages of penile cancer and treatment
- Topical treatment of non-invasive penile cancer
- Adjuvant Chemotherapy
- Neoadjuvant chemotherapy
- Therapeutic and palliative chemotherapy in advanced metastatic penile cancer
- Intraarterial chemotherapy
- Mode of action of cetuximab and Panitumumab
- Curative Radiotherapy
- Conclusion
- Conflict of Interest
- Source of Funding
- References