International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationThe 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
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
References (28)
- et al.
The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation
Int J Radiat Oncol Biol Phys
(1995) - et al.
Radiotherapy for advanced adenoid cystic carcinoma: Neutrons, photons or mixed beam?
Radiother Oncol
(2001) - et al.
Neutron versus photon irradiation for unresectable salivary gland tumors: Final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council
Int J Radiat Oncol Biol Phys
(1993) - et al.
COSMIC: A regimen of intensity modulated radiation therapy plus dose-escalated, raster-scanned carbon ion boost for malignant salivary gland tumors: Results of the prospective phase 2 trial
Int J Radiat Oncol Biol Phys
(2015) - et al.
High-LET radiotherapy for adenoid cystic carcinoma of the head and neck: 15 years' experience with raster-scanned carbon ion therapy
Radiother Oncol
(2016) - et al.
Multicenter study of carbon-ion radiation therapy for adenoid cystic carcinoma of the head and neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) study (1402 HN)
Int J Radiat Oncol Biol Phys
(2018) - et al.
Treatment outcomes of particle radiotherapy using protons or carbon ions as a single-modality therapy for adenoid cystic carcinoma of the head and neck
Radiother Oncol
(2014) - et al.
Results of a combination treatment with intensity modulated radiotherapy and active raster-scanning carbon ion boost for adenoid cystic carcinoma of the minor salivary glands of the nasopharynx
Oral Oncol
(2019) - et al.
Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival
Lancet Oncol
(2010) - et al.
Tolerance of normal tissue to therapeutic irradiation
Int J Radiat Oncol Biol Phys
(1991)
Incidence of skin toxicity in squamous cell carcinoma of the head and neck treated with radiotherapy and cetuximab: A systematic review
Crit Rev Oncol Hematol
Weekly cetuximab concurrent with IMRT aggravated radiation-induced oral mucositis in locally advanced nasopharyngeal carcinoma: Results of a randomized phase II study
Oral Oncol
Postoperative radiation therapy for major salivary gland malignancies
J Surg Oncol
Proton beam radiation therapy for skull base adenoid cystic carcinoma
Arch Otolaryngol Head Neck Surg
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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.