Is There a Benefit in Using Neoadjuvant Systemic Chemotherapy in Locally Advanced Penile Squamous Cell Carcinoma? – Beyond the Abstract

Penile cancer is a rare disease and it accounts for less than 1% of the malignancies in the United States.1 However, it remains quite a challenging malignancy to treat. Patients with disseminated inguinal and pelvic lymph node metastases have poor outcomes with 5-year survival reported of less than 15%.2 In the National Comprehensive Cancer Network© clinical practice guidelines, neoadjuvant systemic therapy is recommended for patients with fixed or bulky inguinal lymphadenopathy. However, to date, there are no prospective randomized controlled trials or meta-analyses evaluating the efficacy and safety of neoadjuvant regimens in this patient cohort.

We performed an electronic search in Embase® and MEDLINE® for studies reporting on patients who received preoperative neoadjuvant systemic chemotherapy for locally advanced penile cancer.3 After exclusion of case reports, systematic reviews, editorials and studies that evaluated immunotherapy or targeted therapy alone or in combination with neoadjuvant chemotherapy, 10 studies were included across the United States, Europe, and Asia. The number of included patients from each selected study ranged from six to 30 participants (median, 20 participants). Overall, the meta-analysis comprised 182 patients; 66 (36.3%) and 116 (63.7%) were treated with non-taxane-platinum (NTP) and TP taxane platinum (TP) regimens, respectively.

We then examined pooled results from 182 patients with an overall median follow-up of 31 months in this multi-institutional collaborative project. The pooled results demonstrated an objective response rate (ORR) of 53% (95% confidence interval [CI]: 42% to 64%), a pathological complete response (pCR) of 16%, grade ≥3 toxicity rate of 40% (95% CI: 19% to 64%), and overall mortality (OM) of 55% (95% CI: 40% to 70%) in patients treated with neoadjuvant chemotherapy. The 53% ORR and 16% pCR with neoadjuvant chemotherapy were consistent with the results of the only prospective (Phase II) trial that evaluated the merit of 4 cycles of TIP (paclitaxel, ifosfamide, and cisplatin).4  

Although the TIP regimen is the most accepted neoadjuvant chemotherapy regimen for penile cancer, any regimen proven effective against squamous cell carcinoma can be a potential therapeutic option for penile cancer in the absence of comparative studies of neoadjuvant chemotherapy. Thus, we have also conducted stratified sub-analyses to compare NTP to TP regimens. Our analysis revealed comparable ORR (55% vs 49%) and OM (54% vs 58%) between the regimens, with the exceptions of a pCR of 9% and 20% and a grade III toxicity rate of 26% and 49% for NTP vs. TP regimens, respectively.

Interestingly, although TP and NTP regimens yielded similar survival outcomes, pCR rates appeared different. This inconsistency might possibly be due to heterogeneity of treatment dose and the specific patient population included across studies rather than their actual therapeutic efficacy. Moreover, pCR to neoadjuvant chemotherapy might not necessarily reflect improved survival in advanced penile cancer. Another interesting finding was that NTP regimens appeared to be better tolerated than TP regimens based on the differences in frequency of grade ≥III adverse events. However, this should be interpreted in the context of the type of adverse event as the majority of the adverse events noted in TP regimens were hematologic rather than severe nephrotoxicity and cardiac toxicity.

Overall, our meta-analysis sets a benchmark for expected outcomes with the utilization of neoadjuvant systemic chemotherapy in men with locally advanced penile cancer. However, the inclusion of single-institutional and retrospective studies was a significant drawback of our study. The efficacy and toxicity profile of TP and NTP regimens should be properly assessed via multi-institutional randomized clinical trials. In this regard, we call for academic medical centers to support and participate in the ongoing InPACT study (International Penile Advanced Cancer Trial), which is the first prospective, randomized, Phase III trial for locally advanced penile cancer aiming to include 400 patients from the US, the UK, and Europe over a five-year period.

Written by: Ahmet Murat Aydin, MD, and Philippe E. Spiess, MD, MS, FRCS(C), FACS, Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

  1. Siegel, Rebecca L., Kimberly D. Miller, and Ahmedin Jemal. "Cancer statistics, 2016." CA: a cancer journal for clinicians 66, no. 1 (2016): 7-30.
  2. Graafland, Niels M., Hester H. van Boven, Erik van Werkhoven, Luc MF Moonen, and Simon Horenblas. "Prognostic significance of extranodal extension in patients with pathological node positive penile carcinoma." The Journal of urology 184, no. 4 (2010): 1347-1353.
  3. Azizi, Mounsif, Ahmet M. Aydin, Ali Hajiran, Andrew Lai, Ambuj Kumar, Charles C. Peyton, Suks Minhas et al. "Systematic Review and Meta-Analysis: Is There a Benefit in Using Neoadjuvant Systemic Chemotherapy in Locally Advanced Penile Squamous Cell Carcinoma?." The Journal of Urology (2020): 10-1097.
  4. Pagliaro, Lance C., Dallas L. Williams, Danai Daliani, Michael B. Williams, William Osai, Michael Kincaid, Sijin Wen, Peter F. Thall, and Curtis A. Pettaway. "Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study." Journal of Clinical Oncology 28, no. 24 (2010): 3851.
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