Comparison Of The Clinical Behaviour Of N3 Hpv Related And Unrelated Head And Neck Cancer In The Imrt Era

N3 disease is accepted as having grave prognosis in all forms of head and neck cancer (HNC). We wished to compare clinical presentation, radiological nodal response, and neck outcome after definitive IMRT in N3 HPV-related (HPV+) vs -unrelated (HPV–) HNC. We retrospectively reviewed all N3 HNCs undergoing definitive IMRT ± chemotherapy from 2005-2015. HPV status was tested by p16 staining for all oropharyngeal cancers (OPC) and cancer of unknown primary (CUP). HPV untested laryngo-hypopharyngeal cancer (LHC) were considered HPV–. Clinical presentation, radiological complete response [CR, i.e. Lymph node (LN) ≤ 1.0 cm] at 8-12 weeks following IMRT, and oncologic outcomes were compared between HPV+ vs HPV– cohorts. Multivariable analyses (MVA) identified prognostic factors for regional failure (RF). Of 129 consecutive N3 HNC, HPV status was ascertained in 119 (92%) revealing 66 HPV+ (OPC/CUP: 65, LHC: 1) and 53 HPV– (OPC/CUP: 29, LHC: 24) cases. Compared to HPV–, HPV+ patients (pts) were younger (median 58 vs 62 years. p=0.006), had fewer smoking pack-years (median 14.5 vs 40 p<0.001), but similar proportions of T3-4 disease (47% vs 39%, p=0.48). HPV+ LNs were more often cystic (41% vs 23%, p=0.049), non-conglomerate (23% vs 8%, p=0.04), and had less skin invasion (30% vs 51% p=0.025) or carotid encasement (21% vs 42%, p=0.02). Rates of retropharyngeal LNs (38% vs 27%, p=0.11), bilateral LNs (45% vs 43%, p=0.85), necrotic LNs (85% vs 89%, p=0.60) and radiological extranodal extension (64% vs 64%, p>0.99) were similar. Concurrent systemic treatment was given in 83% HPV+ vs 57% HPV– (p=0.006). More HPV+ N3 achieved radiological CR (44% vs 25%, p=0.034). Post-IMRT neck dissection (PRND) was negative in all 3 CRs (HPV+ 2; HPV– 1) but positive in 5/19 (26%) HPV+ and 7/13 (58%) HPV– non-CRs (p=0.15). Median follow-up was 4.6 years. RF occurred in 36 (HPV+ 11, HPV– 25). No CR without PRND pts (HPV+: 27, HPV–: 12) had isolated RF. HPV+ pts had higher 3-year overall survival (67% vs 28%, p<0.001), local control (97% vs 85%, p=0.021), and regional control (RC) (85% vs 53%, p=0.021) but similar distant control (77% vs 60%, p=0.078). HPV– non-CR pts had lower 3-year RC vs CRs (43% vs 85%, p=0.01) and was marginally lower in HPV+ (76% vs 96%, p=0.05). No significant difference in 3-year RC was evident in CR pts by HPV status (96% vs 85%, p=0.44). Presence of post-IMRT necrotic LNs (HR 2.8, 95% CI 1.2-6.6, p=0.02) carried a higher RF risk in MVA. This study shows that HPV+ N3 HNC has unique clinical presentation (less dermal involvement and degree of carotid encasement) and outcomes, relative to HPV– HNC pts. CR is achievable in nearly half the HPV+ and a quarter of HPV- cases with IMRT. Although the sample size is small, pts with CR appear to have good RC in both cohorts. This suggests that careful surveillance is a reasonable option for those with CR. Presence of post-IMRT necrotic LN carries a higher RF risk.