Advanced Penile Cancer Research Articles

Lymph node metastases and prognosis in penile cancer

Lymph node status is a key prognostic factor in penile squamous cell carcinoma. Recently, growing evidence indicates a multimodality approach consisting of neoadjuvant chemotherapy followed by consolidation surgery improves the outcome of locally advanced penile cancer. Thus, accurate estimation of survival probability in node-positive penile cancer is critical for treatment decision making, counseling of patients and follow-up scheduling. This article reviewed evolving developments in assessing the risk for cancer progression based on lymph node related variables, such as the number of metastatic lymph nodes, bilateral lymph node metastases, the ratio of positive lymph nodes, extracapsular extension of metastatic lymph nodes, pelvic lymph node metastases, metastatic deposit in sentinel lymph nodes and N stage in TNM classification. Controversial issues surrounding the prognostic value of these nodal related predictors were also discussed.

Multimodality treatment of locally advanced penile cancer: A contemporary dosimetric comparison and case presentation.

346 Background: There is a paucity of data on the optimal therapy for locally advanced penile cancer (PC). However, advances in other HPV associated neoplasms utilizing combined modality therapy (CMT) have been encouraging. We describe the management of advanced PC with such an approach. Methods: The patient presented following partial penectomy and inguinal dissection with T2N3 disease and extra-capsular extension (ECE). In a multi-disciplinary setting, it was decided to treat him post-operatively with concurrent chemoradiation. CT data sets were used for dosimetric comparison of critical structures (small bowel, rectum, bladder, scrotum, testes, bone marrow, skin, bowel, and femoral heads) and plans were generated using conventional penile fields (3D), Intensity Modulated Radiation Therapy (IMRT), and Volumetric Modulated Arc Therapy (VMAT), minimizing dose to organs at risk while optimizing treatment dose. Results: The patient was treated with IMRT (45 Gy to penile stump, pelvic and inguinal nodes (INs) with a 9 Gy boost to left INs and 15 Gy boost to right INs, due to ECE) and weekly Cisplatin (20 mg/m2). IMRT gave similar coverage and avoidance of normal structures compared to VMAT but with lower mean scrotal dose ( IMRT 27.0 Gy , VMAT 29.9 Gy, 3D 45.6 Gy). There was no >grade II toxicities, with grade II scrotal edema and moist desquamation of bilateral inguinal folds, not requiring treatment breaks. Acute RT toxicities had near resolution at 1 month. The IMRT and VMAT plans vs. the 3D plan had lower mean doses to the normal structures. 3D planning had unacceptable max doses to femoral head (62 Gy) and scrotum (55 Gy). Small bowel, V15Gy ≤ 150 cc was achieved by all plans. Dose homogeneity was improved for IMRT/VMAT vs. 3D planning (max dose 119%). Conclusions: This is one of the first comparisons of contemporary radiation techniques in the multimodality setting of PC. We demonstrate that utilizing IMRT concurrently with Cisplatin is feasible and well tolerated suggesting it a reasonable strategy to obtain durable local control, without which the prognosis is uniformly dismal. Larger studies are warranted to explore this contemporary CMT approach to locally advanced PC.

Salvage treatment for metastatic penile cancer after first-line chemotherapy with paclitaxel, ifosfamide, and cisplatin: Analysis of response and survival outcomes.

340 Background: There are few effective salvage treatment options for men with advanced metastatic penile cancer. Patients who remain disease-free for 2 years after surgical removal of regional lymph node metastases are likely cured of the disease, but the survival is short for those who recur. Our objective was to estimate the efficacy of salvage treatments for metastatic penile cancer after neoadjuvant paclitaxel, ifosfamide, and cisplatin. Methods: Patients are from a 30-patient cohort who we saw between April 2000 and September 2008 presenting with stage TxN2-3M0 squamous cell carcinoma of the penis. All were treated with 1 to 4 courses of neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy prior to planned lymphadenectomy. For the patients who had progression or recurrence of disease, we retrospectively evaluated the salvage therapies given, response data, and survival times from the date of first progression. Results: Nineteen of the 30 patients (63.3%) had tumor progression and 17 received one or more salvage therapies. Median age at diagnosis was 57 years (range 24-72 years). The median survival from time of first progression was 5.8 months (range 3.7 to 30.9 months). Two of five patients (40%) who had received bleomycin, methotrexate, and cisplatin experienced an objective response (1 complete and 1 partial), and one (20%) developed pneumonitis. Two patients had received gemcitabine combinations without response. Two patients had received epidermal growth factor receptor-targeted therapy with gefitinib or cetuximab and cisplatin, both without response. Three patients had received chemo-radiotherapy, one with stable disease for 13.5 months and 2 with no apparent benefit. Five patients underwent salvage surgery, and they all progressed within 2 months with one case of fatal hemorrhage. Conclusions: Men with metastatic penile cancer that progresses through or recurs after front-line neoadjuvant chemotherapy have poor responses to the described salvage treatments, and median overall survival is less than 6 months. Emphasis should be placed on clinical trials for development of effective therapy in this setting.

Penile lymphoma presenting as an advanced penile cancer: report of a case

Penile lymphoma is a very rare neoplasm. We report the case of an 82-year-old man who presented with phimosis. The patient also complained of frequent and painful urination. Upon examination a painless penile ulcer and multiple inguinal lymph nodes were found. The shaft of the penis and the prostate were hard on palpation. Abdominal and transrectal ultrasound examination confirmed the involvement of the penis shaft and the prostate and also revealed involvement of the urinary bladder. Biopsy showed diffuse, large B-cell lymphoma. The patient was treated with systemic chemotherapy with full remission of the disease. We review the literature relevant to penile lymphoma and discuss this uncommon condition.

Penile cancer

This article reviews the epidemiology, diagnostic modalities and treatment of localized and advanced penile cancer, with special emphasis on most recent findings from the literature. Penile cancer is a rare disease and its treatment suffers from a paucity of evidence in the literature. Risk factors include phimosis with poor hygiene, human papilloma virus infections, chronic balanitis xerotica obliterans and smoking, among others. Surgical treatment for local disease remains the best option, but organ-preserving procedures provide good aesthetic and functional results with acceptable oncologic control. Regional disease, when present in the form of adenopathy, is best diagnosed with fine-needle aspiration, and treated with radical inguinal lymphadenectomy if resectable. Occult metastatic disease constitutes a challenge and is managed according to primary tumour risk factors. For nonresectable regional disease and metastases, neoadjuvant cisplatinum-based regimens are the best option, and provide a selection of patients who will be optimal candidates to consolidative surgical therapies. Penile cancer at its various stages constitutes a therapeutic challenge. Management should be increasingly confined to high volumes centres of excellence, allowing for clinical trials, which will hopefully provide a better understanding of the disease and the best treatment approach.

Urological cancer care pathways: development and use in the context of systematic reviews and clinical practice guidelines

BackgroundMaking healthcare treatment decisions is a complex process involving a broad stakeholder base including patients, their families, health professionals, clinical practice guideline developers and funders of healthcare.MethodsThis paper presents a review of a methodology for the development of urological cancer care pathways (UCAN care pathways), which reflects an appreciation of this broad stakeholder base. The methods section includes an overview of the steps in the development of the UCAN care pathways and engagement with clinical content experts and patient groups.ResultsThe development process is outlined, the uses of the urological cancer care pathways discussed and the implications for clinical practice highlighted. The full set of UCAN care pathways is published in this paper. These include care pathways on localised prostate cancer, locally advanced prostate cancer, metastatic prostate cancer, hormone-resistant prostate cancer, localised renal cell cancer, advanced renal cell cancer, testicular cancer, penile cancer, muscle invasive and metastatic bladder cancer and non-muscle invasive bladder cancer.ConclusionThe process provides a useful framework for improving urological cancer care through evidence synthesis, research prioritisation, stakeholder involvement and international collaboration. Although the focus of this work is urological cancers, the methodology can be applied to all aspects of urology and is transferable to other clinical specialties.

Approach to Treatment and its Outcome in Locally Advanced Penile Cancer

Introduction: Penile cancer is rare and one-third of patients present with locally advanced disease (T4 or nodal involvement) [1,2]. Despite treatment with a combination of penile and nodal surgery, radiotherapy and chemotherapy, outlook is poor (7–50% 5 year survival) with pelvic nodal involvement carrying a dismal prognosis (<5% 5 year survival) [2]. We describe our experience in the radiotherapy management of these patients, presenting over a 9 year period.

Identification of High Risk Pathological Node Positive Penile Carcinoma: Value of Preoperative Computerized Tomography Imaging

Patients with penile carcinoma, and 3 or more histopathologically proven unilateral metastatic inguinal nodes, and/or extranodal extension, and/or pelvic metastasis are considered a subgroup with prognostically unfavorable parameters for disease specific death and local recurrence after inguinal lymphadenectomy. We established radiographic criteria for the preoperative identification of such patients. Preoperative diagnostic computerized tomography studies of 30 patients with penile carcinoma with proven unilateral or bilateral lymph node metastasis were reviewed independently by 2 radiologists blinded for patient data. All computerized tomography images were analyzed per side (60). Several radiographic criteria were assessed for regional lymph nodes with short-axis diameter 8 mm or greater and/or central nodal necrosis. Sides were characterized as high risk if histopathology revealed 3 or more metastatic inguinal nodes and/or extranodal extension and/or pelvic nodal involvement. Histopathological nodal involvement was found in 38 sides (63%) including 22 sides (37%) defined as high risk. The presence of central nodal necrosis and/or irregular nodal border of the regional lymph nodes on the preoperative computerized tomography identified the high risk subgroup with a sensitivity of 95% (21 of 22) and a specificity of 82% (31 of 38). All 7 sides falsely designated as high risk harbored inguinal metastases but they were classified as low risk. The interobserver agreement of each radiographic parameter was almost perfect. The presence of central nodal necrosis and/or an irregular nodal border of the regional lymph nodes on preoperative computerized tomography images are accurate and reproducible criteria to identify high risk pathological node positive penile cancer. These criteria can be used for risk stratification and patient counseling.

Current and Future Strategies in the Diagnosis and Management of Penile Cancer

Penile cancer is an uncommon malignancy that has a devastating effect on the patient while also being challenging to diagnose and treat. By implementing preventive measures, we can decrease the incidence of this disease and improve the quality of life of our patients. Early detection plays an important role in disease control and proper diagnostic modalities must be used in order to accurately identify the cancer and its progression. Primary penile lesions should be initially approached when surgically feasible and clinically appropriate with penile preserving surgical techniques. Advances in inguinal lymph node detection and management, has improved the clinical outcome of penile cancer. Advanced penile cancer still portends a poor prognosis and should be approached via a multimodal treatment regimen. In this review, we address the importance of prevention, early detection, and the contemporary management of primary penile lesions, as well as the advances in inguinal lymph node disease detection and surgical treatment, for both localized and advanced disease.

Feasibility and Activity of Sorafenib and Sunitinib in Advanced Penile Cancer: A Preliminary Report

Introduction: We describe our experience with sorafenib and sunitinib in the treatment of chemotherapy-refractory advanced penile squamous cell carcinoma (SCC). Patients and Methods: Between May 2008 and June 2009, 6 advanced penile cancer patients were treated with sorafenib or sunitinib in our center. All of them had previously received at least two chemotherapy regimens. Tumor responses were evaluated by radiologic assessment and serum SCC antigen change. Immunohistochemical staining of CD34 and Ki-67 was performed in 3 paired tumor tissues before and after treatment. Results: In the 6 patients, 1 partial response and 4 stable diseases were observed. Three patients showed pain response and had an improvement in quality of life. After molecular-targeted therapies, reduction in microvessel density and Ki-67 labeling index was observed in paired specimens. Serum SCC antigen levels were decreased in 5 patients after 1 week of medication. The patient who achieved partial response had an SCC antigen reduction of nearly 95% after treatment with sunitinib. Serious adverse events were fatal infection and rupture of the femoral vessel, which were unlikely related to the medication. Conclusions: The feasibility and activity of sorafenib and sunitinib in our series suggest that this approach may be a promising alternative in chemotherapy-refractory advanced penile SCC.

Treatment of Visceral, Unresectable, or Bulky/Unresectable Regional Metastases of Penile Cancer

To review the treatment strategies among patients with Stage IV penile cancer to describe potentially curative or palliative therapy. The International Consultation on Urologic Disease for Penile Cancer subcommittee on the treatment of Stage IV penile cancer reviewed reports related to the topics of advanced penile cancer and metastatic penile cancer alone and combined with chemotherapy, radiotherapy, and inguinal lymphadenectomy. The reports were rated as to their level of evidence using the criteria of the Oxford Centre for evidence-based medicine. Treatment recommendations were made by consensus, with the appropriate grades determined from the level of evidence. The incidence of Stage IV disease using the current or modified TNM or Jackson descriptions was 0%-14%. Cisplatin-containing regimens were the most active, with patients exhibiting an average response and survival rate of 26% (range 15%-32%) and 5.5 months (range 4.7-7), respectively. Bleomycin-containing regimens were associated with significant pulmonary toxicity. The role of radiotherapy for advanced penile cancer has been largely palliative. Data have suggested that surgical consolidation among patients exhibiting an objective response to chemotherapy could be associated with durable survival. Treatment with a cisplatin-containing regimen in Stage IV penile cancer should be considered and might facilitate curative resection. The use of bleomycin was associated with a high level of toxicity and should be discouraged as first-line therapy. Surgical consolidation to achieve disease-free status or palliation should be considered in fit patients with an objective response to systemic chemotherapy. Palliative radiotherapy to inguinal or skeletal metastases might be of benefit.

A case of local advanced penile cancer treated with multimodality therapy

A 61-year-old man presented to our institution complaining of a putrescent left inguinal ulcerated tumor. Our diagnosis was penile cancer with bilateral inguinal lymph node metastasis and clinical staging T4N3M0. Here we report a case of local advanced penile cancer experimentally treated with a multimodal approach.

Activity and toxicity of paclitaxel in pretreated metastatic penile cancer patients

The objective of this study was to evaluate the use of paclitaxel in patients with advanced squamous cell penile cancer previously treated with neoadjuvant cisplatin-based chemotherapy. This was a single-arm, phase II, multicenter study. Patients were treated with 175 mg/m paclitaxel at a 3-week interval, until disease progression or irreversible toxicity. The primary end point was the objective response rate. Secondary end points were safety, progression-free survival, and overall survival. Twelve patients were enrolled. Partial responses were observed in 25% (3 of 12) of patients (95% confidence interval: 12-40%). Grade 3 neutropenia and oral mucositis were the most common side effects, each noted in three patients. Median progression-free survival was 4 months (range 2-6 months) and median overall survival was 6 months (range 3-10 months). Paclitaxel is well tolerated and associated with promising efficacy. Further trials, also in a neoadjuvant setting, are needed to corroborate our preliminary findings.

Multimodality therapy in penile cancer: when and which treatments?

Metastatic penile cancer typically comes to attention while the clinical extent of disease is limited to the inguinal or pelvic lymph nodes. Primary surgical management of lymph node metastases achieves tumor control and long-term survival for only a small percentage of these patients. To determine the optimal use of multimodality treatment in locally advanced penile cancer, we conducted a literature review. Relevant English-language literature was identified with the use of Medline; additional cited works not detected on the initial search were also reviewed. There is an emerging strategy of preoperative (neoadjuvant) combination chemotherapy to improve the progression-free survival of penile cancer patients with bulky regional lymph node metastases. Radiotherapy for inguinal metastases and postoperative (adjuvant) radiation for selected patients has also been effective in this setting. In patients with lymph node metastases, the benefit of ilioinguinal lymphadenectomy may be extended by the addition of neoadjuvant chemotherapy. Postoperative radiotherapy can be offered depending on the amount of residual disease after chemotherapy. Chemo-radiotherapy has been successful in squamous cell cancers from other sites (vulva and anal canal) and may be considered for unresectable penile cancer.

Taxanes in Combination with Cisplatin and Fluorouracil for Advanced Penile Cancer: Preliminary Results

BackgroundChemotherapy is emerging in the management of advanced penile cancer. ObjectiveTo evaluate the therapeutic activity of taxanes (T) in combination with cisplatin-fluorouracil (PF) for salvage of primarily unresectable or relapsed nodal metastases from squamous cell carcinoma (SCC) of the penis. Design, setting, and participantsSix consecutive patients were treated at Istituto Nazionale Tumori (INT), Milano, with neoadjuvant paclitaxel, cisplatin, and 5-fluorouracil (TPF) for unresectable (two cases) or recurrent nodal metastases (four cases) from SCC of the penis from 2004 to 2006. Informed consent was given by all patients. InterventionFour courses of neoadjuvant TPF were to be given before salvage surgery. MeasurementsPatients underwent computed tomography (CT) scans before starting chemotherapy, after two courses, and at the end of chemotherapy. Lymph node dissection was to be performed in responsive patients. Results and limitationsTwo patients received more than four courses: Both had pathologically documented complete remission, and they are alive and disease free >2 yr after chemotherapy. The other four patients received only two courses. The first patient had subjective intolerance to TPF: He underwent early postchemotherapy radical lymph node dissection, which documented >90% tumour necrosis: He is alive and disease free 46 mo after starting chemotherapy. Of the other three patients, one was not responsive, changed therapy, and died within 4 mo. The other two had a clinical complete remission after the first two courses. Both refused to complete chemotherapy, and they relapsed after 10 and 4 mo. Limitations are the small number of patients and protocol violation in three cases. ConclusionsTPF chemotherapy for unresectable or recurrent nodal metastases from SCC of the penis is promising, and the standard four courses of therapy are to be completed in responding patients. A larger series is necessary to confirm preliminary results.

A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992)

BackgroundThe aim of this study is to determine efficacy and feasibility of the combination regimen irinotecan and cisplatin in patients with cisplatin advanced penile cancer. Patients and methodsPatients with T3, T4, N1, N2, N3 or M1 cisplatin advanced penile cancer were treated with a combination of irinotecan (60 mg/m2) on days 1, 8 and 15 and cisplatin (80mg/m2) administered every 28 days. Patients were treated either in the neo-adjuvant setting for T3 or N1–N2 disease with a maximum of four cycles before surgery or up to eight cycles for T4 or N3 or M1 disease. The study was designed with the aim to exclude a response rate (complete response + partial response) <30% (α = 10%, power = 95%). ResultsTwenty-eight patients were included and evaluated for toxicity, and 26 eligible patients were evaluated for response. Toxicity was acceptable with three cases of grade 3 diarrhoea and two cases of grade 4 neutropenic fever. There were eight responses (two complete response and six partial response) (30.8%, 80% confidence interval 18.8% to 45.1%): three patients undergoing histological verification after chemotherapy had no evidence of malignancy. ConclusionThe study fails to demonstrate a response rate significantly >30%.The observation regarding M0 patients suggests to repeat this study in the neo-adjuvant setting.

Cisplatin and gemcitabine in the management of metastatic penile cancer

Penile cancer is rare and receives little public attention. There are few treatment options for advanced disease. The most active regimen to date is a combination of bleomycin, methotrexate, and cisplatin. However the treatment-related mortality is 11% and hence this combination has not been adapted as a standard of care. We report two cases of advanced penile cancer where a sustained palliative response was observed with combination chemotherapy using cisplatin and gemcitabine. Our experience demonstrates that this is a well tolerated regimen active in this setting.

Neoadjuvante und adjuvante Chemotherapie bei Patienten mit fortgeschrittenem Peniskarzinom

With an incidence of 0.1-0.9/100,000 men per year penile cancer is a rare cancer of the urogenital tract in Western Europe. At the time of initial diagnosis up to 45% of the patients already demonstrate metastatic disease and need some type of systemic treatment. It is the aim of this paper to review the current concepts of adjuvant and neoadjuvant chemotherapy for locally advanced penile cancer. A curative effect of combined surgical and cytotoxic management can only be achieved in patients with locoregional spread to the lymph nodes, but not with systemic spread. Although there are prospective randomized trials available indicating the optimal cytotoxic regime, cisplatin-based protocols or combination therapies with bleomycin, vincristine, and methotrexate appear to be the most effective options. Finally, there are no data available with regard to the effect of adjuvant chemotherapy on progression-free survival. In patients with locoregional bulky disease or with fixed inguinal lymph nodes, neoadjuvant chemotherapy will result in a partial response in 20-60% of patients and enables complete resection of the mass. For the future, the use of taxane-based chemotherapy as described for squamous cell cancer of other origin might improve outcome.

Neoadjuvant Chemotherapy Followed by Aggressive Surgical Consolidation for Metastatic Penile Squamous Cell Carcinoma

Combination chemotherapy for advanced penile cancer can produce partial response rates of up to 64%. Complete responses are rare, suggesting a need for adjunct therapies to facilitate cure. We evaluated patients with metastases who underwent surgical consolidation after responding to chemotherapy. We reviewed the records of 59 patients with advanced penile carcinoma treated from 1985 to 2000 and identified 10 treated with surgical consolidation after demonstrating a stable, partial or complete response to chemotherapy. Presenting tumor burden included pelvic and inguinal metastases. Surgical outcomes and survival were assessed. After chemotherapy 4 patients had a complete response, 1 had a partial response and 5 had stable disease. Three major perioperative complications, including postoperative bleeding, an episode of acute renal failure and deep venous thrombosis in 1 patient each, and 4 minor complications, including skin breakdowns in 3 and wound seroma in 1, occurred. Three cases were rendered pN0. All 3 patients received ifosfamide, paclitaxel and cisplatin chemotherapy. Seven patients had 3 or fewer metastatic lymph nodes following surgery, of whom 4 showed no disease and 3 died. All 3 patients with greater than 3 metastatic lymph nodes died. For all patients the 5-year actuarial survival rate was 40% with a median survival of 26 months. Patients with 3 or fewer and greater than 3 positive nodes had a median survival of 48 and 23 months, respectively (p = 0.116). Select patients with metastatic penile cancer that shows disease stabilization or a response to chemotherapy should be considered for surgical consolidation to extend survival.

Humoral Hypercalcemia of Penile Carcinoma

Hypercalcemia is a common life-threatening complication associated with several genitourinary malignancies. Parathyroid-related peptide has been shown to cause hypercalcemia in several solid tumors but rarely in penile cancer. We report a case of advanced penile cancer with hypercalcemia and associated dysphagia. Treatment is clinically challenging and should be definitive as soon as the patient has been stabilized. Serum calcium measurement can be used for monitoring the outcome and follow-up in such patients. Dysphagia is a rare but potential symptom of hypercalcemia, but additional studies are needed to prove this association.