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

Abstract

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.