Human papillomavirus (HPV)‑associated oropharyngeal squamous cell carcinoma (OPSCC) has a distinct clinical course and generally more favourable prognosis than HPV‑negative disease. This multicentre Phase II study tested a de‑escalation approach in which upfront neoadjuvant chemotherapy with docetaxel, cisplatin and 5‑fluorouracil (NAC‑TPF) was delivered before surgery with the explicit goal of reducing or avoiding postoperative radiotherapy (PORT) or postoperative chemoradiotherapy (POCRT).
The rationale was to induce deep pathological and virological responses with systemic therapy so that surgical resection could be followed by observation rather than routine adjuvant radiation, potentially reducing late toxicity while maintaining oncological control.
Patients with resectable HPV‑associated OPSCC were enrolled. The protocol required that patients be candidates for upfront surgery with the usual option of PORT/POCRT if indicated after resection. All participants received three cycles of NAC‑TPF (docetaxel, cisplatin, 5‑fluorouracil) followed by transoral surgery.
The primary endpoint was central review of the pathological complete response (pCR) rate in the resected specimens after NAC‑TPF. Secondary assessments included measurement of tumour high‑risk HPV RNA in tissue, plasma circulating tumour HPV DNA (ctHPV DNA), and patient‑reported quality of life (QOL) using the EORTC core questionnaire.
Among 32 eligible patients, the trial reported a pathologically meaningful rate of complete responses after the neoadjuvant regimen. The centrally reviewed pCR at the primary site and lymph nodes was reported as 65.6%. A parallel virological complete response rate at both primary and nodal sites was 64.5%.
Although these rates demonstrate substantial treatment effect from NAC‑TPF, the investigators note that the predefined statistical primary endpoint for the trial was not met. The manuscript states that despite not meeting that formal endpoint, the magnitude of pCR was clinically relevant in the studied population.
Of the 32 eligible participants, 30 underwent transoral surgery following NAC‑TPF. Overall, R0 resection (microscopically margin‑negative) was confirmed in 31 patients.
Importantly for the de‑escalation objective, PORT or POCRT was avoided in the majority of patients: 91% of the cohort did not receive postoperative radiotherapy or chemoradiotherapy. This finding supports the feasibility of a strategy that uses systemic induction to reduce reliance on adjuvant radiation in selected patients with resectable HPV‑associated OPSCC.
The study measured plasma ctHPV DNA as a circulating biomarker of tumour burden and response. Twenty‑three patients showed undetectable ctHPV DNA levels after NAC‑TPF, consistent with the high rates of pathological and virological response observed in tissue.
The trial also assessed levels of high‑risk HPV RNA within tumour specimens, although detailed numeric correlations between tissue HPV RNA levels and outcomes beyond the reported virological complete response percentages are not provided in this summary.
Patient‑reported quality of life (QOL) was recorded using the 30‑item EORTC core instrument. The reported QOL trajectory showed recovery: all measured QOL scores either returned to baseline or improved within one year after treatment. This suggests that the combined approach of NAC‑TPF followed by transoral surgery—largely without adjuvant radiotherapy in this cohort—did not result in sustained deterioration in global QOL metrics within the first postoperative year.
In summary, NAC‑TPF produced a high rate of pCR (65.6%) and virological complete responses (64.5%) in resectable HPV‑associated OPSCC and permitted avoidance of PORT/POCRT in 91% of patients. Twenty‑three patients had undetectable ctHPV DNA after neoadjuvant therapy, and QOL recovered to baseline or improved within 12 months.
The authors emphasize that the primary statistical endpoint of the trial was not met, even though the observed pathological responses and the high rate of radiotherapy avoidance were described as clinically meaningful. The report does not include all detailed numeric data or long‑term oncological outcomes in this summary; those data are not publicly available but can be requested from the corresponding author.
The trial is registered (jRCT1041220029). The data generated in the study are not publicly available because of patient privacy and consent restrictions but are available on reasonable request from the corresponding author.
Overall, these Phase II results support the feasibility of an upfront NAC‑TPF de‑escalation strategy to reduce adjuvant radiotherapy in selected patients with HPV‑positive, resectable OPSCC, while acknowledging that the formal primary endpoint was not achieved and that further study is required to define long‑term benefit and safety.