In Dr. Andrea Necchi’s study, there were 507 patients with penile squamous-cell carcinoma who received inguinal lymph node dissection that had suitable clinical information. Patients with HPV + penile squamous-cell carcinoma exhibited a lower clinical N-stage (p<0.001) and inguinal lymph node metastasis density (p<0.001). HPV+ patients had similar median overall survival (p=0.1) but longer restricted mean survival time than HPV- patients at different time-points. Furthermore, HPV+ patients treated with perioperative radiotherapy exhibited longer median overall survival (p=0.015) and longer restricted mean survival time compared to HPV- patients. Dr. Baciarello notes that the lack of prognostic ability of HPV status is different than the pooled analyses available from clinical trials, which showed a survival benefit for HPV positive patients (HR 0.61, 95% CI 0.38-0.98)1:
Dr. Baciarello notes that radiotherapy improved overall survival in HPV positive patients in Dr. Necchi’s study, but highlights that the sample size for these patients was very small (<50). Furthermore, there was a low incidence of MSI-high in these patients (0.7% for HPV negative patients). Whether immunotherapy is a reasonable treatment option for penile cancer remains to be determined, however, several small studies suggest that PD-L1 expression may be as high as 32%-64% for these tumors, suggesting a possible role for immunotherapy. Currently, there are at least 13 trials ongoing in this disease space, including men who progressed after cisplatin-based chemotherapy to receive avelumab (NCT03391479), pembrolizumab (NCT02837042), and nivolumab plus ipilimumab (NCT03333616). Additionally, the EudraCT trial is assessing the role of avelumab as maintenance therapy after cisplatin-based chemotherapy.
The next study discussed by Dr. Baciarello was the longitudinal cohort analysis of patients with metastatic penile cancer treated in a large quaternary academic center, presented by Dr. Liu. This study included 101 patients with metastatic penile cancer, of which 59% of patients received chemotherapy and 42% of patients that received best supportive care. For first-line systemic-therapy (n=59), there was a 45.8% clinical benefit rate with 8.5% complete responses, 15.3% partial responses, and 22.0% with stable disease. Patients receiving 2nd line subsequent therapy (n=17) had a 29.4% clinical benefit rate. Median progression-free survival for first- and second-line treatment was 3.2 (95% CI 2.1-5.2) and 2.2 (95% CI 0.9-4.3) months, respectively. The median overall survival for all patients was 6.2 months (95% CI 5.1-7.2). Median overall survival for first-line chemotherapy was 7.2 months (95% CI 5.9-8.5), for second-line chemotherapy was 4.5 months (95% CI 2.5-6.5), and for best supportive care patients was 2.0 months (95% CI 1.1-2.9). Dr. Baciarello notes that progressive disease represents more than half of these patients regardless of treatment line: 54.2% for first-line therapy, 70.6% for second-line therapy, and 66.7% for third-line therapy. Since metastatic disease has such a poor prognosis, she notes that it is important to refine treatments earlier in the disease process. The InPACT trial is an international penile advanced cancer trial that will evaluate the role of neoadjuvant chemotherapy/chemoradiotherapy for intermediate and high-risk patients, as well as the role of prophylactic pelvic lymph node dissection in patients with adverse pathologic features:
Dr. Baciarello concluded the penile cancer discussion noting that penile cancer is a very rare disease with a poor prognosis, and unlike other tumor types, patients die from lymph node disease rather than from visceral metastasis. Furthermore, because chemotherapy only has modest efficacy, we need more insights from biology and more prospective clinical trials.
Switching to testicular cancer, Dr. Baciarello highlighted that germ cell tumors account for ~1% of cancers worldwide, with a 10- and 20-year cumulative incidence of developing a metachronous contralateral cancer of 1.3% and 3.9%, respectively. The incidence of developing a second testicular cancer is higher for patients diagnosed before the age of 30, and men with seminoma have a higher risk of developing a second germ cell tumor. Furthermore, men with metastatic disease have a 50% lower risk of developing a contralateral testicular cancer than those with localized disease. The study presented by Hellesnes et al. showed that over a median follow-up of 16.3 years, there were 218 men diagnosed with a second testicular cancer after a median of 6.2 years (IQR 3.3-10.6) from the initial testicular cancer diagnosis. The median time to second testicular cancer was shorter after chemotherapy (5.5 years) than after surgery only (6.6 years). Overall, the 20-year crude cumulative incidence was 4.0% (95% CI 3.5-4.6), with lower incidence after chemotherapy (3.2 %, 95% CI 2.4-3.9) than after surgery only (5.4%, 95% CI 4.4-7.3). The second testicular cancer incidence was also lower for those ≥30 years (2.8%, 95% CI 2.2-3.4) at first testicular cancer diagnosis than those <30 years (6.0 %, 95% CI 4.9-7.1). Overall, the risk of second testicular cancer was 13-fold higher compared with the risk of developing testicular cancer in the general population (SIR 13.3, 95% CI 11.6-15.3). These results confirm what we already know, according to Dr. Baciarello, however, what is new is that for each cisplatin-based chemotherapy cycle administered, the risk for a second testicular cancer decreased monotonously, with significantly reduced risks after 3 (HR 0.53, 95% CI 0.29-0.97), 4 (HR 0.41, 95% CI 0.25-0.66) and >4 cycles (HR 0.21, 0.07-0.66). These results are taken into context with long-term follow-up of a clinical trial where patients with stage I seminoma had a contralateral cancer incidence rate reduced with carboplatin (2/573) compared to radiotherapy (15/904).2
Dr. Baciarello concluded the testicular cancer discussion, noting that men with a previous testicular cancer have an increased risk of developing a metachronous contralateral cancer, with the incidence higher among younger patients (age < 30 years). Chemotherapy appears to have a protective role, which is amplified with more cycles. A regular ultrasound examination of the remaining testis should be discussed in a follow-up, especially in younger men who did not receive chemotherapy.
Presented by: Giulia Baciarello, MD, Gustave Roussy, Universite Paris-Saclay, Villejuif, France
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020.
- Sand FL, Rasmussen CL, Frederiksen MH, et al. Prognostic significance of HPV and p16 status in Men Diagnosed with Penile Cancer: A Systematic Review and Meta-Analysis. Cancer Epidemiol Biomarkers Prev 2018 Oct;27(10):1123-1132.
- Oliver RT, Mead GM, Rustin GJS, et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: Mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol 2011 Mar 10;29(8):957-962.
706MO: Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma
707MO: Longitudinal Cohort Analysis of Patients with Metastatic Penile Cancer Treated in a Large Quaternary Academic Centre
708MO: Metachronous Contralateral Testicular Cancer in the Cisplatin Era: A Population-Based Cohort Study