In head and neck cancer, the presence of extranodal extension (ENE) in lymph nodes (LNs) has been shown prospectively to require adding chemotherapy to postoperative radiation therapy (RT). Limited data exist regarding ENE in LNs from primary penile cancer (PeCa).

To determine the association of RT and ENE in PeCa.

We retrospectively analyzed the outcomes of 93 patients with pT1-4 N3 M0 (American Joint Committee on Cancer 7th edition) squamous cell carcinoma of the penis across four international centers.

If the inguinal nodal specimen had ENE or two or more positive inguinal LNs, RT was delivered to an ipsilateral inguinal field. An ipsilateral pelvic field was added for positive pelvic LNs on dissection. The delivered dose was usually 50Gy in 25 daily fractions.

Clinical and demographic characteristics of relapse-free (RFS), disease-specific (DSS), and overall (OS) survival were compared by ENE status and receipt of adjuvant RT.

Seventy-two percent of patients had inguinal ENE, and 49% had pelvic ENE. On multivariable analysis (MVA) of ENE-negative patients, an OS benefit was noted with postoperative chemotherapy (p=0.038) and inguinopelvic RT (p=0.037). RFS suffered with worsening grade of the lesion (moderately: p=0.027; poorly: p=0.038), but was improved with groin (p=0.016) and inguinopelvic (p=0.006) RT. On MVA of patients with ENE, inguinopelvic RT was associated with better DSS (p=0.041). Grade impacted DSS (moderately: p=0.043; poorly: p=0.033), and poorly differentiated lesions impacted RFS (p=0.013).

Inguinopelvic RT may benefit regional control in PeCa patients with positive pelvic LNs, but this appears to be limited to those without ENE.

For patients with penile cancer and positive pelvic lymph nodes, postoperative radiation therapy was found to decrease the likelihood of disease recurrence in the groin or pelvis only if extranodal extension was absent.