As published, in our center the response rates with neoadjuvant chemotherapy were fairly good, but the therapy was poorly tolerated and survival rates were disappointing.3 Therefore we decided in 2015 to move away from neoadjuvant chemotherapy and started a prospective chemoradiation therapy trial in penile cancer. We had been offering this treatment, based on our anal cancer chemoradiation protocol, for a couple of years in an institutional registration.
Due to the low incidence of penile cancer, especially in advanced stages, a two-arm design was not attainable. An optimistic hypothesis of 50% one-year progression free survival (PFS; versus 31% in the neoadjuvant chemotherapy trial) was adopted for sample size calculation. All patients with locally and/or regionally advanced and non-metastatic disease, either primary or recurrent, were offered trial participation. Locoregionally advanced penile cancer was defined by at least one of the following:
- A large or inoperable primary tumor (T3‐T4)
- Palpable nodes >3cm in diameter
- Fixed nodes or suspicion of extranodal extension (ENE) on imaging
- Pelvic nodal involvement.
Over the years, slowly but surely, patients were included. As expected, a heterogeneous group of patients was included and some minor deviations in the protocol occurred. All treatment decisions were discussed in our multidisciplinary tumor board. During follow-up, we noticed some patients fared really well, whereas in others curation seemed an unattainable goal. Preliminary results were presented at different (inter)national occasions, and final results are now published in the International Journal of Radiation Oncology, Biology, and Physics.
One-year PFS was 34% and two-year PFS 31%. Overall survival after one and two years was 73% and 46% respectively. Toxicity was acceptable with ≥1 grade 3 treatment-related adverse events in eleven patients (33%) and no grade 4 or 5 adverse events. All but one patient were able to complete the chemoradiation therapy. Although the primary endpoint of 50% PFS was not met, we conclude that CRT is a viable treatment option for locoregionally advanced penile carcinoma. With survival rates comparable to those of neoadjuvant chemotherapy and with less toxicity, we now offer chemoradiation as standard treatment for locoregionally advanced penile carcinoma in our center.
Unfortunately, we were not able to directly compare chemoradiation to other treatment strategies. Also, no quality of life measurements were taken. The role of surgery can be debated, as well as treatment of the other lymph node areas and the timing of response evaluation. Maybe radiation can be optimized with higher dosages similar to head and neck cancer (up to 70 Gy in 35 doses), or with genomic-adjusted radiation doses based on the radiosensitivity index.5,6
Unanswered questions will partially be answered in the prospective InPACT-trial, an international phase III trial in node-positive penile cancer that aims to determine the relative benefits of surgery, chemotherapy, and chemoradiotherapy.2 Furthermore, in the past years we conducted a non-randomized, phase II clinical trial to evaluate the efficacy of anti-PD-L1 immune therapy with or without radiotherapy for primary or recurring stage IV penile carcinoma reaching a 1-year PFS of 12.5% as presented at ASCO-GU 22.4 Hopefully, future studies will further improve our understanding and ability to cure advanced penile cancer.
Written by: Sarah Rosanne Ottenhof,1 Hielke Martijn de Vries,1 Barry Doodeman,2 Gerbert Lambertus Vrijenhoek,2 Vincent van der Noort,3 Maarten Lucas Donswijk,4 Jeantine Martina de Feijter,5 Eva Eline Schaake,2 Simon Horenblas,1 Oscar Roberto Brouwer,6 Michiel Simon van der Heijden,5 Floris Jop Pos2
- Departments of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Departments of Radiotherapy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Departments of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Departments of Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Departments of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Departments of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
References:
- Brouwer OR, Albersen M, Parnham A, et al. European Association of Urology-American Society of Clinical Oncology Collaborative Guideline on Penile Cancer: 2023 Update. Eur Urol. 2023 Mar 7:S0302-2838(23)02638-6.
- Canter DJ, Nicholson S, Watkin N, Hall E, Pettaway C. The International Penile Advanced Cancer Trial (InPACT): Rationale and Current Status. Eur Urol Focus. Published online June 2019.
- Djajadiningrat RS, Bergman AM, van Werkhoven E, Vegt E, Horenblas S. Neoadjuvant taxane-based combination chemotherapy in patients with advanced penile cancer. Clin Genitourin Cancer. 2015 Feb;13(1):44-9.
- Klaassen Z. ASCO GU 2022: Clinical Results of PERICLES: A Phase II Trial Investigating Atezolizumab +/- Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis. Urotoday.com. 2022 Feb. Weblink: ASCO GU 2022: Clinical Results of PERICLES: A Phase II Trial Investigating Atezolizumab +/- Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (UroToday.com)
- Lacas B, Carmel A, Landais C, et al; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiother Oncol. 2021 Mar;156:281-293.
- Yuan Z, Grass GD, Azizi M, et al. Intrinsic radiosensitivity, genomic-based radiation dose and patterns of failure of penile cancer in response to adjuvant radiation therapy. Reports Pract Oncol Radiother. 24(6):593-599.