Clinical Investigation
The Phase 1/2 ACCEPT Trial: Concurrent Cetuximab and Intensity Modulated Radiation Therapy with Carbon Ion Boost for Adenoid Cystic Carcinoma of the Head and Neck

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Purpose

The adenoid cystic carcinoma (ACC), Erbitux, and Particle Therapy (ACCEPT) phase 1/2 trial (NCT01192087) evaluated a combined-modality approach (concurrent cetuximab and intensity modulated radiation therapy with carbon ion boost) for newly diagnosed nonmetastatic head and neck ACC.

Methods and Materials

Twenty-three patients with ACC were enrolled between June 2012 and June 2017 after initial diagnosis or postoperatively. All received a 400 mg/m2 cetuximab loading dose a week before radiation therapy, followed by weekly 250 mg/m2 doses starting on the first day of radiation therapy. The carbon ion radiation therapy boost was 24 Gy (relative biological effectiveness) in 8 daily fractions, followed by intensity modulated radiation therapy (54 Gy). The primary endpoint was safety and feasibility (defined based on Common Terminology Criteria for Adverse Events grade ≥3 events). Secondary endpoints included local and distant relapse, disease-free survival, and overall survival.

Results

Disease was most commonly in the paranasal sinuses (30%), palate (17%), and nasopharynx (17%). Nine (39%) patients underwent surgery (R1: 22%, R2: 78%). Median follow-up was 38.5 months. No patients experienced grade 4 to 5 events. Rates of grade 3 rash and radiation dermatitis were 17% and 22%, respectively. Grade 2 and 3 mucositis and dysgeusia occurred in 43% and 48% and in 9% and 0%, respectively. Grade 2 to 3 dysphagia and xerostomia were present in 43% and 4% and in 26% and 0%, respectively. At last follow-up, 5 (22%) patients experienced in-field relapse and 6 (26%) developed distant metastases. The 3-year disease-free survival was 67%, and median overall survival was 54 months.

Conclusions

Outcomes of this trial were satisfactory. Although the trial did not meet the predefined criteria of feasibility owing to the comparatively high rates of grade 3 dermatitis, numbers are comparable to existing data on cetuximab + radiation therapy.

Introduction

Adenoid cystic carcinomas (ACCs) account for a minority of head and neck neoplasms, and management is difficult for several reasons. First, few available randomized studies exist for these malignancies, on account of the relatively low incidence. Second, even though surgery is considered the mainstay of therapy, it is often incomplete or unmasks tumor-associated risk factors owing to the propensity for aggressive local spread and destruction. Third, delivery of postoperative radiation therapy (RT) for margin-positive or unresected cases also poses technical challenges. RT dose escalation for those clinical scenarios is associated with local/locoregional control benefits,1,2 but the ability to escalate with conventional photon RT is often limited by tolerance limits to surrounding organs at risk (OARs).

To this extent, safe dose escalation for these neoplasms (past the ∼60 Gy recommended dose1,2) can be better accomplished by particle therapy. Neutron RT has been studied for decades and affords high local control rates, but late toxicities remain a concern.3,4 Proton beam therapy (PBT) is a more widespread modality and allows for considerable dose escalation (eg, 76 Gy relative biological effectiveness [RBE] in the study by Pommier et al5). Carbon ion RT (CIRT) is a modality that is increasingly investigated for a variety of malignancies. The biophysical advantages comprise a higher RBE than photon RT or PBT while retaining the high physical conformity, a steeper dose gradient, and decreased lateral scattering as with PBT.6 These may translate to increased disease control by means of safer dose escalation (including higher biologically effective doses at discrete points of the beam path) while respecting normal tissue constraints. Several publications have highlighted the safety and efficacy of CIRT or photon/CIRT therapy for ACC, all of which illustrate improvements over historical photon-based data7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 in a variety of tumor localizations of the head and neck.

However, from the aforementioned studies, long-term durable local control remains a challenge even in the presence of dose escalation with heavy ion therapy, yielding 5-year local control rates of 60% to 70%.7,9 Although chemotherapy has been used as a radiosensitizer for head and neck squamous cell carcinomas, its efficacy in ACCs is markedly lower.18 Given that the vast majority of ACCs stain positive for the epidermal growth factor receptor,19 application of the anti–epidermal growth factor receptor antibody cetuximab may be useful. Additionally, although the primary aim of cetuximab is to improve local control by means of radiosensitization,20,21 it is possible that smaller effects on micrometastatic disease could also be exerted.22

To date, there have been no prospective trials evaluating CIRT and cetuximab for ACCs of the head and neck. The primary objective of the ACC, Erbitux, and Particle Therapy (ACCEPT) phase 1/2 trial was to evaluate the safety and feasibility (and, secondarily, outcomes) of a combined-modality approach (concurrent cetuximab and intensity modulated RT [IMRT] with CIRT boost) for newly diagnosed nonmetastatic ACC.

Section snippets

Study participants

This was an institutional review board–approved, single-center phase 1/2 trial of IMRT with boost CIRT and concurrent cetuximab (Clinicaltrials.gov number NCT01192087).23 Eligible patients were 18 to 70 years of age with newly diagnosed, pathologically confirmed, nonmetastatic ACC of the head and neck. Other inclusion criteria were T3 or T4 disease (by the American Joint Committee on Cancer 7th edition), microscopic or macroscopic perineural invasion, or partially or unresected disease.

Results

From June 2012 to June 2017, 23 consecutive patients were registered (no up-front dropouts or exclusions); recruitment was stopped accordingly after an interim analysis, and evaluation was performed on that population. Table 1 displays clinical characteristics of the study cohort. Disease was most commonly located in the paranasal sinuses (30%), palate (17%), and nasopharynx (17%). Ten (44%) cases had perineural invasion. Management details are outlined in Table 2. Nine (39%) patients underwent

Discussion

Head and neck ACC is a relatively uncommon neoplasm, for which durable long-term local control remains a concern; thus, prospectively studying novel treatment approaches is essential. This is the only known study of IMRT with a CIRT boost delivered with concurrent cetuximab.

This trial did not meet the predefined criteria of feasibility, largely owing to the relatively high rates of grade 3 dermatitis (22%) and mucositis (48%). Indeed, both of these parameters, as well as others (eg, dysgeusia

Conclusions

The Phase 1/2 ACCEPT Trial is a phase 1/2 study of concurrent cetuximab and IMRT with a CIRT boost for newly diagnosed nonmetastatic ACC. Outcomes were satisfactory, and although the trial did not meet the predefined endpoint of feasibility, the higher rates of grade 3 dermatitis and mucositis are comparable to established data on concurrent cetuximab and RT.

Acknowledgments

This work was supported by Heidelberg University. We thank our study coordinators, Dr Cornelia Jäkel and Dr Adriane Hommertgen, and the study nurses, Renate Haselmann, Karen Lossner, and Alexandros Gioules, for the support of this trial. We thank Dr Stefan Ibach and WiSP (Wissenschaftlicher Service GmbH, Langenfeld, Germany) for excellent monitoring and data management. We thank the Data Safety and Monitoring Board’s Prof. Dr Jürgen Krauss and Prof. Dr Robert Krempien for their excellent

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    This trial has received funding within a project grant from Merck KGaA, Darmstadt, Germany. The funding source does not play a role in study design, data collection, data analysis, data interpretation, or writing of the manuscript.

    Disclosures: S.A., D.B., S.R., and J.D. received grants from Accuray International Sàrl outside the submitted work. D.B. received grants from Novocure outside the submitted work. S.A. and J.D. received grants from Merck Serono GmbH outside the submitted work. J.D. received grants from CRI—The Clinical Research Institute GmbH, View Ray Inc, Accuray Incorporated, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Siemens Healthcare GmbH, Quintiles GmbH, Pharmaceutecal Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr Pychlau GmbH, and Nanobiotix A.A. outside the submitted work.

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