Simple SummaryMost patients with HPV associated squamous cell carcinoma of the head and neck, treated with chemoradiotherapy, CRT, for cure, and who succumb to their disease, do so because of distant metastases. Even if a local recurrence as first site of treatment failure is rather low in this disease, characterised as being radiosensitive, such failures are still a problem. In this randomized phase II study we aimed to exploit whether induction chemotherapy IC, with two cycles of Taxotere, Cisplatin and 5-FU, TPF, could improve progression -free survival, PFS, by diminishing the rate of distant failures, administered before CRT. To reduce risk of toxicity from cumulated doses of cisplatin, concurrent chemotherapy during RT was given with cetuximab. To improve local control and mitigate the negative impact of a large tumor volume, an escalated RT dose was prescribed for patients with such tumors. PFS was found to be similar in the two study arms. However, even if not statistically significant, there were twice as many patients with distant relapses in the group of patients who had not IC. Overall survival was high and local recurrence as first site of failure was low, in 4.6% of patients and was similar for T1/T2 and locally bulky T3/T4 tumors. An escalated RT dose might have mitigated the negative impact of a large tumor volume but for some patients even this intensified treatment was insufficient. With respect to patients’ response to IC, 29% of the patients in this treatment arm could be identified to have no relapse whether locoregional or distant during the time of follow up. These data shed further light on the characteristics of this disease of importance for the planning of future studies. If induction chemotherapy with cisplatin could reliably help to select patients for de-escalated subsequent RT, cetuximab is considered a good candidate to be given concurrently with RT to diminish morbidity from cumulated doses of cisplatin. The role of escalated RT doses for selected patients with bulky T3 and T4 tumors, perhaps primarily for those who do not respond to IC should also be addressed in future studies.AbstractThe leading cause of death for patients with HPV associated squamous cell carcinoma of the head and neck (SCCHN) after treatment with chemoradiotherapy (CRT) nowadays is peripheral metastasis. This study investigated whether induction chemotherapy (IC) could improve progression free survival (PFS) and impact on relapse pattern after CRT. Methods: Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18–75 years, an ECOG performance status 0–1, and adequate organ functions. Results: From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4–92.8) in arm A and 78.4% (95% CI 69.5–88.3) in arm B (HR 1.39, 95% CI 0.69–2.79,p= 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. Conclusions: PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.