Contouring guidelines, such as those provided by the InPACT trial (International Penile Advanced Cancer Trial)1 can be extremely useful. Still, the best approach for such a rare malignancy is centralization of care such as has been adopted in the United Kingdom for penile cancer.2 Centralization may not be popular with patients, and therefore support systems must be in place for travel and accommodation for both the patient and their essential family support. This approach allows experienced clinicians to manage the disease and facilitates development and accrual to clinical trials.
Guidelines have reflected the appalling lack of evidence for penile cancer management. Vulvar, anal and penile cancer are 3 very similar genital malignancies with largely squamous cell histology and similar nodal drainage pathways.3 For anal canal and vulvar cancer, the approach is organ-sparing concurrent chemotherapy and radiation. Dr Norm Nigro, a colorectal surgeon from Wayne State University lead the shift from abdominoperineal resection to anal-sparing chemoradiation, which is the recommended approach for all non-metastatic presentations of disease.4 For vulvar cancer, Dr Howard Homesley was the lead in the ground-breaking GOG 37 trial which compared pelvic lymph node dissection to pelvic and groin radiation for women following radical vulvectomy and bilateral inguinal lymph node dissection, showing improved cancer-specific (HR 0.39) and recurrence-free survival (HR 0.49) with mature follow-up for those receiving radiation.5 This led to the current National Comprehensive Cancer Network® (NCCN®) recommendation for a chemoradiation approach for all presentations of disease beyond T1. For penile cancer, the recommended approach for every stage and presentation has been surgical, with the addition of neoadjuvant chemotherapy for fixed or inoperable nodal disease.
However, the tide is finally beginning to turn. The 2023 ASCO-EAU Guideline Committee for Penile Cancer, led by Dr Oscar Brouwer, has endorsed a more balanced approach.6 Although the evidence remains weak at this time, a radiation-based approach is acknowledged as acceptable under certain circumstances and achieves a “2B” recommendation in the 2024 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).3 A recent publication by Ottenhof et al.7 adds considerably to the growing body of experience. Primary radiation was used for 33 men with locally advanced penile cancer. 88% had stage IV disease, either T4 with any N stage or any T stage with N3. The combination of capecitabine/mitomycin C with moderate dose radiation (49.5 Gy to the pelvis and 59.4 Gy/33/6.5 weeks to the primary and involved nodes) was completed in 32 of 33 men. The response rate was 73%, with 39% exhibiting a complete response as evaluated by post treatment PET/CT scan. 52% went on to subsequent surgery, either for residual or subsequent recurrence. With 41 months median follow up, the 1- and 2-year PFS was 34% and 31%, and overall survival was 73% and 46%
Furthermore, Level 1 evidence is on the way. The remarkable North American success of ECOG-ACRIN sponsored InPACT along with the UK partners, has brought us over halfway to the target accrual of 200 men with node positive penile cancer to elucidate the optimal sequencing of surgery, radiation, and chemotherapy. Amongst the endpoints, InPACT will be able to compare the efficacy and toxicity of neoadjuvant chemotherapy vs. neoadjuvant chemo-radiotherapy. This landmark multidisciplinary international collaboration is a model of how to investigate rare tumors.
Written by: Juanita Crook, MD, FRCPC, University of British Columbia, BCCancer, Kelowna, British Columbia, Canada
References:
- InPACT: International Penile Advanced Cancer Trial Physician and Research Staff Educational Material.
- Jakobsen JK, Pettaway CA, Ayres B. Centralization and Equitable Care in Rare Urogenital Malignancies: The Case for Penile Cancer. Eur Urol Focus. 2021;7(5):924-928.
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). © National Comprehensive Cancer Network, Inc. 2023.
- Nigro ND, Vaitkeviceus VK, Herskovic AM. Preservation of function in the treatment of cancer of the anus. Important Adv Oncol. 1989:161-177
- Kunos C, Simpkins F, Gibbons H, Tian C, Homesley H. Radiation therapy compared with pelvic node resection for node-positive vulvar cancer: a randomized controlled trial. Obstet Gynecol. 2009;114(3):537-546.
- 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. doi:10.1016/j.eururo.2023.02.027
- Ottenhof SR, de Vries HM, Doodeman B, et al. A Prospective Study of Chemoradiotherapy as Primary Treatment in Patients With Locoregionally Advanced Penile Carcinoma. Int J Radiat Oncol Biol Phys. 2023;117(1):139-147.