|Year : 2006 | Volume
| Issue : 4 | Page : 360-363
Penile carcinoma: The role of chemotherapy
Raju Titus Chacko
Department of Medical Oncology, Christian Medical College, Vellore, India
Raju Titus Chacko
Medical Oncology, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The role of cytotoxic chemotherapy in the management of carcinoma of the penis is not clearly defined. Patients may receive chemotherapy in the neoadjuvant setting to help optimize surgery, the adjuvant setting to improve outcomes with surgery and in the setting of advanced disease for palliation. Chemotherapy may also be combined with radiation to increase response rates and improve survival. We have briefly reviewed the possible roles of chemotherapy in the management of carcinoma of the penis and present a retrospective analysis of a cohort of patients who received chemotherapy at our centre for carcinoma of the penis.
Keywords: Cancer penis, chemotherapy
|How to cite this article:|
Chacko RT. Penile carcinoma: The role of chemotherapy. Indian J Urol 2006;22:360-3
Penile cancer, while relatively rare in the western world, is not uncommon in India and remains a disease with severe morbidity and mortality. The disease is observed with dramatically increased incidence in other parts of the world and in some countries constitutes 17-20% of all malignancies in males.
The risk of metastasis is related to the size, site and depth of involvement of the primary lesion. Metastasis occurs in a predictable pattern to inguinal lymph nodes followed by drainage into pelvic lymph nodes (and beyond). These deposits in the regional lymph nodes continue to enlarge if left untreated, causing skin necrosis, infections and erosion of the femoral vessels.
The histology, behavior and response to chemotherapy of penile carcinoma are similar to squamous cell carcinoma of the head and neck. Therefore, approaches that have proven to be successful in head and neck carcinoma have been applied to this disease.
There are many controversies regarding the management of penile cancer. There is general agreement that the treatment of the primary tumor needs to be more organ-preserving, in order to maintain sexual function and a better quality of life. The management of the lymph nodes however is still a much debated topic.
The low incidence of this disease in countries with good socioeconomic conditions and the absence of large or randomized trials leave standard practice largely undefined.
The current standard of treatment is surgical excision of all local disease including the lymph nodes. The role of chemotherapy has not been clearly defined, although it is practiced widely in the metastatic setting and less commonly in the neoadjuvant and adjuvant setting.
| Current status of chemotherapy|| |
Following definitive regional therapy with surgery alone, penile cancer often recurs regionally in patients who exhibit nodal metastases and poor prognostic features like: (i) more than two involved lymph nodes, (ii) bilateral involvement, (iii) evidence of extranodal extension and (iv) pelvic nodal metastases. In most cases, further therapy is often palliative in nature, as reported five-year survivals for patients with metastatic or regionally recurrent penile carcinoma range between 5 and 30%.,, It would be desirable in this setting, to have adjuvant therapeutic strategies. Adjuvant chemotherapy, given when the disease burden is minimal may improve outcomes especially in high-risk patients. The commonly used regimens are cisplatin and 5-Flurouracil or vincristine, methotrexate and bleomycin (VBM).
Several small series have shown improved survival in patients receiving chemotherapy following radical resection of lymph node metastases compared to historical patients treated with radical surgery alone.,, Pizzocaro et al have reported their experience with adjuvant VBM in the treatment of 25 patients with squamous carcinoma of the penis undergoing ilio-inguinal lymphadenectomy. Relapse occurred in only four patients (16%), with a five-year disease-free survival of 82%. Five-year disease-free survival in an earlier series of 31 similar patients treated with surgery alone was 37%. All relapses in the treated group occurred in patients with bilateral disease and no relapse occurred in any of the nine patients with only a single node involved.
Several combination chemotherapy protocols, which have shown effectiveness in treating squamous carcinoma of other sites-anus, esophagus, head and neck remain to be tested in carcinoma of the penis. Multi-institutional trials are required to enroll sufficient numbers of patients to provide meaningful data.
In patients exhibiting nodal and resectable soft tissue metastases, combination chemotherapy with surgical consolidation should be considered for patients with good performance status. Neoadjuvant chemotherapy (otherwise called induction chemotherapy or anterior chemotherapy) usually comprises three to six courses of methotrexate, bleomycin and cisplatin (MBP); vinblastine, bleomycin and methotrexate (VBM); or cisplatin with 5-fluorouracil. Partial responses have been seen in up to 64% of patients, but complete response rates have rarely surpassed 15% and have been short-lived.,,,, Aggressive multimodal approaches employing surgical consolidation and occasional radiation therapy to achieve disease-free status have been tried and in some cases have led to long-term survival.,,, Ideal candidates for surgical consolidation after chemotherapy include patients who demonstrate a partial response or greater and have no evidence of circumferential encasement of femoral or iliac arteries by the tumor.
Unfortunately, some patients may have disease progression while on chemotherapy and hence patients need close monitoring of the disease status and also may need emergent surgical intervention for palliation.
In Pizzocaro's series, of the 16 patients treated with neoadjuvant chemotherapy for fixed inguinal nodes, nine (56%) could be radically resected and five (31%) were probably cured. The authors observed that cisplatin plus 5-FU achieved the best results.
Similar results were seen in another cohort of 29 patients, who had a clinical response rate of 66%. Radical rescue surgery was performed in 38% of patients. Seventeen per cent were probably cured. Combining all the reported series an average response rate of 68.5%, radical surgery rate of 42.8% and survival rate of 23% can be achieved.
Delayed wound healing and or increased wound dehiscence rates may be increased following chemotherapy or radiation. This may particularly be true with regards to the groin. Most series have however not reported on this outcome.
The setting of primary chemotherapy would be ideal to test out new drugs and combinations. Further, tumor tissue would be easily accessible to evaluate molecular markers of response or chemo-sensitivity.
Combined modality strategies
The combination of chemotherapy and radiation has several theoretical advantages. These include the simultaneous treatment of local and distant sites of disease and the opportunity for synergy between these modalities. These benefits, however, must be balanced against the potential for enhanced toxicity to normal tissues which may result in skin breakdown, delayed wound healing or lymphedema. In other squamous cell carcinomas, especially locally advanced head and neck cancer, esophageal cancer and anal cancer concurrent chemo-radiation has led to improved outcomes. The cisplatin and infusional 5-fluorouracil regimen has been the most extensively studied and has formed the basis for many combined modality programs in these cancers.
Small studies in the 1980s and early1990s using bleomycin and radiation have shown durable responses up to 80% and survivals that are comparable with surgery. In addition there was the additional benefit of less mutilation and possible preservation of sexual function.
The morbidities reported in each of the combined modality series exceed that of radiotherapy given alone.,,
| Chemotherapy for advanced disease|| |
In patients with unresectable disease or metastases to bone, liver or lung, systemic chemotherapy is initially employed in patients with good performance status. Responses are often partial in nature and of short duration. Clearly, novel systemic strategies are needed. This challenging subset of patients with unrelenting carcinoma may require radiation or pharmacotherapy to optimize pain control and improve their overall quality of life.
Results in patients with widespread disease are usually modest, with a 32% (complete and partial) response rate and 12% treatment-related deaths. The response rate is similar irrespective of the regimen used although the toxicity may vary between regimens.,
Newer molecular targets and newer cytotoxic chemotherapy combinations show promising benefits in patients with squamous cell carcinoma in other parts of the body. These strategies should be explored in patients with carcinoma of the penis. For example, the epidermal growth factor receptor (EGFR) over-expression has been shown in patients with squamous cell carcinomas in the head and neck. The combination of EGFR antagonists and chemotherapy or radiotherapy has improved response rates and survivals in these tumors. The use of cetuximab, erlotinib or gefitinib has not yet been tested in squamous cell carcinomas of the penis. We need multi-institutional trials to test these multimodal approaches and novel chemotherapeutic agents and we need to assess how to best integrate multimodal therapies in patients with penile cancer.
| Materials and Methods|| |
The medical records of patients who received chemotherapy for squamous cell carcinoma of the penis from January 2001 to December 2004 in our centre were retrieved. Data related to the status of disease, previous treatments, chemotherapy given, response and toxicity due to chemotherapy and time to progression was collected, captured on a database and analyzed. Tumor response to chemotherapy was graded according to the common response criteria and toxicities were graded according to the common terminology criteria for adverse events (CTCAE Version 3).
| Results|| |
Twenty-seven patients with a diagnosis of squamous cell carcinoma of the penis were referred to the Medical oncology department for chemotherapy either because of metastatic disease (11 patients) or ilio-inguinal nodal involvement with associated extensive perinodal soft tissue infiltration (fixed nodes) (16 patients). Seven patients had extensive involvement of the skin over the nodes with fungation. Four of these patients had previously undergone ilio-inguinal block dissections and had local recurrence of tumor. The median age was 51 years (31-78 years). Patients were followed up till progression.
All patients had already undergone either a partial penectomy (14 patients) or a total penectomy prior to referral. Four patients had previously had bilateral inguinal block dissection and had local recurrence of tumor.
All patients received chemotherapy with cisplatin (70 mg/m 2, given on day 1, with the usual hydration and anti-emesis protocols) and continuous infusion 5-Flurouracil (800 mg/m 2 for 96 hours; days 1-4). A median of five cycles of chemotherapy was given. Patients were followed up till progression.
The response to chemotherapy is shown in [Table - 1]. The overall response rate (CR+PR) was 57% showing that squamous cell carcinoma of the penis was a moderately chemo-sensitive disease.
Eleven patients (41%) had Grade 3 or 4 toxicities while on treatment. Five patients had Grade 3 or 4 neutropenia. Two of these were complicated by febrile illnesses requiring hospital admission and antibiotics. Two patients had a drop in their glomerular filtration rate (GFR) Grade 2, probably related to cisplatin. Carboplatin was substituted for cisplatin in these cases. Two patients had Grade 3 chemotherapy-induced nausea and vomiting and required hospitalization for intravenous hydration and breakthrough anti-emetic medication.
Following chemotherapy 12 patients were determined to be operable. Four patients had bilateral lymph node dissections after chemotherapy. Eight patients had a unilateral inguinal lymph node dissection. Three of these were performed in the setting of metastatic disease as a palliative procedure. Four patients had a clinical complete response; in three of them lymph node dissections were unilateral and intended as a consolidation procedure. In two patients with bilateral groin disease the response to chemotherapy was complete on one side and dissection was only performed on the side with the partial response.
Variable degrees of necrosis were seen on the histology of the patients postchemotherapy. This was not quantified.
Five patients had problems with their surgical wounds. Two patients had wound infections and required antibiotics. Three patients needed prolonged dressing (more than four weeks). One of these had a discharging sinus for more than 12 weeks.
The median follow-up was seven months (range 2-43 months). The median time to progression was six months (range 2-43.). As of January 2006, six patients who had chemotherapy and surgery continued to be in complete remission beyond 24 months (and ongoing). Survival data was not available as patients who progressed were referred to their primary physicians for best supportive care and were lost to follow-up.
| Discussion|| |
We have described a cohort of patients treated with chemotherapy for advanced carcinoma of the penis. There was a 57% response to chemotherapy and this compares with the responses reported in the literature. This was achieved with acceptable toxicities that were manageable. The rescue surgery rate was 44%. The median progression-free survival was six months. Six of these patients (22%) have had disease-free survival of more than 24 months and are probably cured.
Variable degrees of necrosis were seen on the surgical pathology suggesting sensitivity of the tumor to the chemotherapy given. However, this was not graded or quantified and was not correlated with the clinical response or progression-free survival.
More than 40% of patients who had surgery had wound complications. This could be at least partly attributed to chemotherapy. The benefits of increased rescue surgery rate and progression-free survival however outweigh this risk.
We have seen a number of partial (and occasional complete) responses to chemotherapy and at times the chemotherapy has allowed a less aggressive resection. We have also seen patients in whom the nodal disease rapidly progressed on chemotherapy, resulting in necrotic ulcers and the need for a much more difficult and extensive palliative dissection. It would be idyllic if we were able to predict tumour response to chemotherapy. As newer and more effective forms of chemotherapy become available, we foresee a greater role, more often as initial treatment and with organ-sparing protocols for the primary tumor.
| Conclusions|| |
The role of chemotherapy has not been clearly defined in the context of squamous cell carcinomas of the penis. Complete surgical extirpation of tumor is currently the treatment of choice. However, a number of patients present at an advanced stage making surgery difficult. Chemotherapy is effective in producing tumor shrinkage in more than 50% of patients and may be useful to downsize the primary tumor and secondary nodes to enable less mutilating surgery and thus reduce morbidity.
Clearly randomized multicentric trials are needed to define its role. Future strategies should look at increasing the response rates and surgical rescue rates.
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[Table - 1]
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