Long-Term outcomes of induction chemotherapy-guided reduced-dose chemoradiotherapy in poor-risk HPV-Positive oropharyngeal Cancer: results from the sequential quarterback trials

IMPORTANCE: The rising incidence of HPV‐positive oropharynx cancer (HPV‐OPC) underscores the need for treatment strategies that maintain disease control while minimizing long‐term toxicity. This study reports the long‐term follow‐up of de‐escalation in poor prognosis HPV‐OPC, providing critical data for future studies. OBJECTIVE: To evaluate long‐term outcomes in patients with locally advanced HPV‐OPC treated with induction chemotherapy (IC) followed by reduced‐dose chemoradiation (rdCRT). We hypothesized that de‐escalated radiation therapy after IC would be non‐inferior to standard‐dose CRT (sdCRT). DESIGN: Two sequential clinical trials; Quarterback (QB) 1: phase III randomized control trial, QB 2: phase II non‐randomized trial; patient accrual conducted between December 2012 and February 2022; final data cutoff April 2025. Median follow‐up (IQR): 88.5 (64.6‐118.2) months. SETTING: Single‐institution academic center. PARTICIPANTS: 62 patients with HPV‐OPC were screened. 47 patients received rdCRT after IC and were included in the primary analysis. Key eligibility: smoking history ≤20 pack‐years, no active smoking, no distant metastases, molecularly confirmed HPV status. INTERVENTIONS: Three cycles of induction TPF (docetaxel, cisplatin, 5‐fluorouracil) followed by rdCRT (5600 cGy) with weekly carboplatin in clinical responders; non‐responders in both QB trials and responders in the control arm of QB1 received sdCRT (7000 cGy). MAIN OUTCOMES AND MEASURES: Primary endpoints: 3‐year locoregional relapse‐free survival (LRRFS) and 3‐year progression‐free survival (PFS). Secondary: overall survival (OS). Tertiary: disease‐specific survival. RESULTS: Among 47 patients treated with rdCRT after IC, the 3‐year and 5‐year LRRFS were 89.3% and 86.6%. PFS was 87.2% and 84.6% at 3 and 5 years. OS was 91.5% and 89.1% at 3 and 5 years. Six patients (13%) experienced locoregional failure, and two (4%) developed distant metastases. 7/8 treatment failures (87.5%) occurred in patients with extracapsular extension. CONCLUSIONS AND RELEVANCE: rdCRT following IC yields durable disease control in poor prognosis HPV‐OPC, with outcomes comparable to historical benchmarks. Extended follow‐up supports the safety and efficacy of this de‐escalation strategy, even in patients with aggressive disease characteristics, but also underscores the need for careful patient selection, particularly in those with extracapsular extension.