An Update on Systemic Therapy for Penile Cancer

Irene Resch; Mohammad Abufaraj; Nicolai A. Hübner; Shahrokh F. Shariat

Disclosures

Curr Opin Urol. 2020;30(2):229-233. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: Whereas substantial advances have been made in systemic tumour therapy in the past decade, the prognosis of advanced squamous cell carcinoma (SCC) of the penis remains disproportionally poor. In this review, we aimed to present an update on systemic therapy of penile SCC highlighting the most recent data and future perspectives.

Recent findings: Lymph node metastases play a key role in treating and assessing the prognosis of patients with penile SCC. Data show longer overall survival with the use of adjuvant chemotherapy in patients with pelvic lymph node metastases and recent analyses lead to the development of a nomogramm predicting overall survival in connection with the use of perioperative chemotherapy. There are two pathways in the pathogenesis of penile cancer, including human papilloma virus related and unrelated, leading to many possible novel therapeutic targets. Other targeted therapies have been evaluated, which show promising results with the use of tyrosine kinase inhibitors.

Summary: Chemotherapy has shown moderate activity in advanced stages of the disease, however, the ideal timing of chemotherapy in patients with lymph node metastases is not entirely clear. Potential targets for future therapies exist, and are already being tested in other malignancies. Owing to the rarity of this condition, a robust evidence is lacking and it is of great importance to pursue further research to unveil several aspects of this disease, particularly in patients with recurrence, lymph node metastases or metastatic disease.

Introduction

Squamous cell carcinoma (SCC) of the penis is a rare tumour, with an incidence of 0.9–2.1 cases per 100 000 men per year in Europe.[1] It is accompanied by the fear of stigmatization, severe detriment in quality of life and, depending on the stage of the disease, high morbidity and mortality. Despite the advances in systemic tumour therapy in the past decade, the prognosis of advanced penile cancer remains disproportionally poor.[2] Owing to the rarity and limited data on penile SCC, which are often based on small retrospective studies, international collaborations are needed to design and undertake clinical trials with adequate power. In fact, international collaborations in penile cancer are rare, resulting in a paucity of trials.

Understanding tumour biology and its microenvironment is crucial to comprehend the mechanisms of tumour development, especially regarding the role of human papilloma virus stems.

In this review, we aimed to present an update on systemic therapy for penile cancer and highlight the most recent data and future perspective.

Chemotherapy

Lymph node metastases (LNM) play a key role in the management and prognosis of penile SCC.[3] Indeed, the extent of LNM is one of the major prognostic factors in patients with penile SCC. Patients with pN2 and pN3 stages have a 5-year cancer specific survival ranging from 17% to 60% and 0–17%, respectively.[4] Some patients with regional positive lymph nodes may benefit from a multimodal treatment strategy, depending on the extent of lymph node involvement. We know that in some cases surgery alone is neither sufficient, nor curative because of additional factors like extension of LNM, micrometastatic disease, adverse pathological features such as lymphovascular or perineural invasion as well as extra-nodal extension.[5]

The value of lymph node dissection (LND) has been firmly established in the literature. Patients with clinical suspicion of LNM that do not receive adequate LND have a dramatic detriment of their prognosis.[6]

The role of systemic chemotherapy in patients with lymph nodes positive penile SCC is controversially discussed, especially whether to give adjuvant or neo-adjuvant chemotherapy for clinically positive LNM. The effect of neoadjuvant chemotherapy is easier to put into clinical perspective, as response is measurable by imaging and disease, if surgery is carried out. The magnitude of response to neoadjuvant chemotherapy is a surrogate endpoint in early clinical trials. Adjuvant chemotherapy lacks a surrogate endpoint as of yet and relies solely on survival endpoints, requiring longer follow-up and more challenging clinical trial designs; but also prompting the acquisition of higher level evidence in the process.

The European association of urology guidelines recommend the administration of three or four cycles of cisplatin, taxane and 5 – fluouracil (TPF) or cisplatin, taxane and ifosfamid (TIP) in pN2 and pN3 tumours after radical lymphadenectomy and four cycles of a cisplatin and taxane-based regime in the neoadjuvant setting in case of unresectable or recurrent LNM.[3,7]

The currently available data is mainly based on retrospective studies which are limited by the small number of included patients. The recommendation for TIP is based on data from a phase II study by Pagliaro et al..[8] The authors found an objective response rate (ORR) of 50% in 30 patients with clinical N2–3 disease treated with three cycles of TIP in a neoadjuvant setting with overall survival (OS) of 17.1 months.[8] The establishment of the TPF regimen stems from retrospective analyses showing efficacy in penile SCC.[9] In a small, retrospective, analyses published by Necchi et al. patients receiving an adjuvant chemotherapy with TPF showed a better median OS than patients only receiving LND.[10] These data are better than those for TPF in the neoadjuvant setting. Yet a direct comparison is difficult as this data does not stem from a randomized trial and is based on a small sample size (n = 21).[10]

Data from a multi-institutional retrospective analysis showed a better survival in patients who received adjuvant chemotherapy after LND compared to patients who did not (21.7 months vs. 11.6 months).[11] Joshi et al. reported that patients with LNM receiving LND and systemic therapy had a statistically significant longer OS than patients who only received chemotherapy without LND (44.6 months versus 14.5 months).[12] They could not show a statistically significant association between administration of perioperative chemotherapy and OS.[12] Nicolai et al. evaluated the efficacy of TPF in the neoadjuvant and adjuvant setting for N2 and N3 patients.[13] The 2 years disease-free survival for patients receiving adjuvant therapy was 36.8%, compared to 7.1% for patients after neoadjuvant therapy. These data, whereas numerically in favour of adjuvant therapy was, again, not statistically significant, probably because of the small sample size (n = 47).[13] In patients with pelvic lymph node involvement, administration of adjuvant chemotherapy after LND was associated with improved OS, with a median overall survival of 21.7 months for patients receiving adjuvant chemotherapy versus 10.1 months for patients after surgery only.[11]

Based on recent data, rising mostly from retrospective analysis of small heterogeneous cohorts, a definitive answer concerning the best timepoint of systemic therapy in patients with LNM from penile SCC cannot be made. A central point, however, in all of the available data is the extent of lymph node involvement, as a prognostic factor.[12] The scarce data that is available show longer OS with the use of chemotherapy in lymph nodes positive patients that became statistically significant for the subgroup of patients with pelvic lymph nodes metastases and adjuvant therapy. Recent data from Necchi et al. support the idea that patients with limited extent of lymph nodes metastasis (N0-N2) have no, or less benefit from the use of systemic chemotherapy.[14] For these patients the potential benefit must be assessed cautiously, as side-effects of the combination-chemotherapy regimens can be substantial. Necchi et al. recommend the administration of a neoadjuvant chemotherapy in select cases with clinical N3 disease, using three cycles of a cisplatin-based combination therapy.[14] For patients with pathologic N3 disease after surgery, the authors consider the use of adjuvant chemotherapy; yet for clinical or pathologic stage N0–2 patients, currently there is no recommendation for the use of perioperative chemotherapy.[14]

The prognosis of patients with distant metastases is poor. Within the last three decades several trials have been conducted to evaluate the efficacy of various single and combination chemotherapies, with controversial results. In 1990, Gagliano et al.[15] investigated cisplatin as single agent with an 23% ORR. The results led to further examination of cisplatin-based combination therapies in several prospective trials. The combination chemotherapy PBM (cisplatin, methotrexat and bleomycin) evaluated by Haas et al. showed promising results.[16] Among 45 enrolled patients with metastatic penile SCC, five had complete and eight had partial responses. But because of severity of toxicity with five treatment related death, PBM is not recommended for standard use.[16] The EORTC single arm phase II trial evaluated the use of irinotecan and cisplatin with an ORR of 30%, not exceeding the results of prior studies.[17] On the basis of the prospective study by Pagliaro et al.[8] showing a 50% objective response rate for TIP (paclitaxel, ifosfamide and cisplatin) within the neoadjuvant setting, this combination chemotherapy is also implemented within the palliative setting. Apart from TIP, TPF (docetaxel, cisplatin and 5 FU) chemotherpy is a further option for first-line chemotherapy in metastatic penile SCC. The efficacy of TPF regimen was seen in a prospective single arm phase II trial by Zhang et al.[9,18] who could show an ORR of 38.5% and a median OS of 7 months, which is consistent with the results of previous trials in this setting.

Furthermore, recent data from the VinCap (Institute of Cancer Research, United Kingdom) trial showed promising results and a benefit for the use of Vinflunin in first-line setting, with an ORR of 27.3%, a clinical benefit rate of 45.5% and a median OS of 8.4 months (3.2–14.1).[19]

The prognosis of patients with recurrence after a chemotherapy or tumour progressing during a cisplatin-based chemotherapy is dismal, with an median OS of less than 6 months.[20] Currently there are no consistent guidelines for the second-line setting in metastatic penile SCC. A prospective trial by Challapalli et al.,[21] evaluating cabazitaxel was stopped after only 9 of the 17 planned patient were included, as none of them achieved clinical response to the therapy. Wang et al. evaluated the response to various agents in the second line setting in patients experiencing disease progression after chemotherapy.[20] Results show a median OS less than 6 months. Interestingly, five patients were included receiving PBM and two of them showed an objective response (one partial and one complete), but here again, with severe toxicity.[20]

Epidermal Growth Factor Receptor

Epidermal growth factor receptor (EGFR) overexpression is a common finding in penile SCC independent of human papilloma virus (HPV) status. In search of alternative treatment options, the human epidermal growth factors receptor (HER) family which consists of the EGFR (HER1), HER2, HER3 and HER4, has been of interest as a potential target for some time. In a retrospective study Chaux et al. assessed the EGFR expression of 112 penile SCC samples, rating them either as negative, low or high.[22] EGFR expression was negative in 13%, low in 44% and high in 44% of cases. There was no association with histologic subtypes, grade or HPV status.[22] These results are confirmed by a smaller retrospective analysis of 30 patients with early stage disease by Di Lorenzo et al.[23] They found all patients to be positive for EGFR by immunohistochemistry; however, 16 patients were also positive for cytosolic phosphorylated EGFR (p-EGFR), the activated form. The presence of cytosolic p-EGFR was the only factor that was independently associated with early disease recurrence and poor survival.[23] Although these studies are small, and do not allow for definitive conclusions, EGFR is consistently expressed, suggesting a possible role in tumour development of penile SCC. Earlier reports on antitumour activity of tyrosine kinase inhibitors (TKIs) targeting EGFR in penile SCC have been published. Carthon et al. reported their retrospective analysis of 24 patients with penile SCC treated with cetuximab, erlotinib or gefitinib in combination with chemotherapy, showing a median OS of 29.6 weeks, and only four partial responses.[24] However, these patients were very heterogeneous and in advanced stages of disease (T4 or N3 or M1).[24]

Now one of very few prospective trials in recent literature is a single arm Phase II trial by Necchi et al. assessing response to dacomitinib monotherapy in clinical N2–3 or M1 patients with penile SCC.[25] Dacomitinib is a modern, irreversible pan-HER TKI with an acceptable profile of side-effects, consistent with other EGFR TKIs.[25] In this trial, consisting of 28 patients, the authors showed an ORR of 32.1% including one complete response and eight partial responses. Although the ORR is lower than in other trials assessing neoadjuvant chemotherapy, it included also M1 patients. Chemotherapy for patients with M1 penile SCC have shown similar ORRs (Nicholson et al. 38.5% and Theodore et al. 30.8%).[9,17] OS was 13.7 months, yet when considering only the subgroup of locally advanced patients (e.g. lymph nodes involvement only, n = 20) OS increased to 20 months. This data allows some cautious enthusiasm as with similar ORR and OS the side-effects of dacomitinib are less severe than those of triple chemotherapy regimens, and might allow for a broader patient population to be eligible for systemic therapy.

Immunotherapy/Human Papilloma Virus

Immunotherapy has changed the landscape of oncology in the past years and has shown encouraging results in various malignancies. Currently the most commonly used immunotherapies are checkpoint inhibitors (CPI) targeting the CTLA-4 or the PD-1/PD-L1 pathway and both have shown activity in various cancers including SCC of the lung and head and neck.[26,27] Response to CPIs is often associated with a high tumour mutational burden (TMB), infiltration of immune cells and/or PD-L1 expression[28]

High TMB leads to many neoantigens, leading to better tumour recognition by the immune system, thus allowing a more potent response to CPI. In a retrospective comparison of 338 cutaneous SCC with 78 penile SCC patients, Jacob et al.[29] conducted that penile SCC is a unique version of SCC as its TMB was lower than within the ultraviolet light exposed counterparts. The TMB was comparable to cervical carcinoma and much lower than that of melanoma or bladder cancer.[30] However, tumour recognition by the immune system is also influenced by the expression of oncogenes that can be increased by the integration of viral DNA through infection with HPV. As up to 50% of penile SCC are considered HPV positive, this presents a potential biomarker in trial design for future CPI trials in penile SCC.

Immune cell infiltration plays also an important role in the response to CPI therapy. Tumours with lower TMB might still respond well to CPI if they have a high number of infiltrating lymphocytes within the tumour (e.g. renal cell carcinoma). This inflammatory tumour microenvironment (TME) can have a substantial impact on disease progression. Ottenhof et al. analysed 213 patients with available tissue toward infiltrating immune cells, HPV status and PD-L1 status.[31] They found a low number of infiltrating T-cells, a high number of infiltrating macrophages, HPV-negative status and PD-L1-positive status to be associated with lymph node-metastasis.[31] These results underline the complexity of the local TME as multiple potential biomarkers for the response to CPI lead to opposing clinical outcomes (i.e. high T-cell infiltration – better outcome/high PD-L1 expression – worse outcome). Although many immunotherapy trials are currently recruiting patients with penile SCC, a more in depth understanding of the TME is necessary to properly select patients that could benefit from CPI therapy.

Another factor for the TME is the pathway of carcinogenesis, which is distinctly different for HPV positive and negative tumours. Roughly 50% of penile SCC are HPV positive.[32] Similar to head and neck cancer (HNCC) that can be associated with HPV infection, HPV-positive penile SCC seems to have a better prognosis.[33,34] Currently this is a purely prognostic biomarker and has not led to targeted therapy strategy in penile SCC. However, through the pathway of HPV-positive carcinogenesis arise multiple potentially druggable targets and biomarkers, such as HPV oncogenes E6 and E7. This has been tried in HPV-dependant cervical cancer, using a therapeutic vaccine, Trimble et al.[35] could reach a 40% histopathologic regression. The use of patient-derived infiltrating lymphocytes specific for HPV E6/E7, that are harvested from tumour foci, cultivated, and then used to induce an antitumor immune response, has also been described by Stevanovic et al..[36] They achieved a 33% ORR (3/9 patients), including two lasting CRs.[36] Evaluating the relation between HPV status in penile cancer and response to chemotherapy, Yuan et al.[37] found a significant association between HPV positive tumours and response to chemoradiation (CRT) in patients with LNM, with a better LRC (locoregional rate), compared to HPV-negative patients. Furthermore, patients with positive HPV tumours often harbour a positive PD – L1 Status.[31] On the basis of these data, the role of the HPV status in the decision-making process regarding systemic therapies in penile carcinoma remains yet to be evaluated. The key role of all further trials will be to gather sufficient biomarker data, to create useful clinical decision tools for allocation of patients to different systemic therapies.

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