Between July 2010 and April 2011, twenty-nine patients were accrued to the COSMIC trial. No patient was excluded or had to discontinue therapy. All patients completed treatment as scheduled.
Thirteen patients with macroscopically complete resections (group R1) and 16 patients with either incomplete resection (7 pts) or inoperable tumors (9 pts) (group R2) were included. Median age was similar in both groups: 56 years (R2) and 55 years (R1). Most patients had adenoid cystic carcinoma (R2: 16/16 pts, R1: 8/13 pts) and only 5 patients in the R1-group had other histologies. The R2 group included a high number of MSGTs in the paranasal sinus, whereas there was a higher proportion of MSGTs of the large salivary glands in the R1-group. While many patients in the R2-group had very advanced disease (T4: 11 pts), tumor extent in the R1-group tended to be smaller (T4: 6 pts). For one patient in the R2-group a valid TNM staging for tumors of the external auditory canal does not exist, for two patients in the R1-group the pathological TNM stage is unknown. Three patients in the R2 group had known pulmonary metastases at presentation; none of the resected patients in R1 had distant metastases. Details of patients’ baseline characteristics can be found in Table .
Patient baseline characteristics
In all cases, treatment dose could be applied according to protocol (Table ) and dose prescription recommendations (<5% of CTV1 or 2 receiving less than 90% of the dose prescribed) were met in all patients. While CTV2 volumes are comparable in both groups, median CTV1 volume is much larger in the R2 group. The proportion of patients requiring more complex planning procedures such as intensity-modulated particle therapy (IMPT) remains essentially the same in both groups, while more patients in the R2 group underwent tomotherapy rather than step-and-shoot IMRT and more patients (R2: 6 pts; R1: 2 pts) underwent bilateral nodal irradiation in the R2 group (Table ).
Treatment tolerance and toxicity
Treatment was well tolerated although treatment including set-up, position verification, and irradiation for carbon ions takes between 30 and 45 min.
Treatment-related acute effects as assessed at completion of radiotherapy were generally mild with mucositis CTC °III occurring in 25% (R2) and 15.4% (R1). Despite comparatively extensive treatment fields, only mild xerostomia was observed; at completion of treatment, rates of xerostomia CTC°II were 15.4% in the R1 group and none in the R2 group. Almost all (100% in R2 and 84.6% in R1) reported severe to complete loss of taste by the end of treatment leading to weight loss in 81.3% (R2) and 69.2% (R1) of patients. There was no higher-grade dysphagia, only few patients (R1: 15.4%) reported dysphagia CTC°II. None of the patients required a feeding tube. However, due to dysgeusia and subsequent loss of appetite, we found a median weight loss of 5 kg (R2) and 5.5 kg (R1) in our patient cohort. Two patients in the R2 group and one patient in the R1 group showed reduced jaw opening prior to and at completion of therapy: one patient improved under therapy due to tumor regression. Roughly 37.5% of patients in R2 developed middle ear effusions during therapy and only 15.4% in R1.
Symptoms rapidly resolved after treatment, only one patient in the R2-group showed mucositis CTC°I at first follow-up (6–8 weeks post completion of treatment), otherwise there was no case of residual mucositis. Xerostomia was reported at an overall rate (CTC°I/II) in 75% (R2) and 84.6% (R1), only 12.5% of patients in the R2-group reported mild swallowing difficulties on their first follow-up appointment. All patients reported improvement of dysgeusia with dysgeusia slowly resolving with time and leading to further weight loss post completion of treatment in 18.8% (R2) and 30.8% (R1) (Table ). However, body weight had stabilized in all of these patients on their first follow-up.
Overall local response rate (complete and partial remissions) 6–8 weeks after completion of treatment in the R2 group is 68.8% (CR: 2/16 pts, PR: 9/16 pts, SD: 5/16 pts) according to RECIST. However, all of the patients showed signs of tumor response such as reduced contrast-enhancement on MRI, carbon ion dose distribution, initial and follow-up MRI scans of a patient with good PR is shown in Figures , , , . With our median follow up of 3 months [range 3–12 months], one of the partial remissions has already developed into a complete remission 6 months post treatment.
51 year old patient with adenoid cystic carcinoma extending from the right maxillary sinus into the right orbit and cavernous sinus, contrast-enhanced, T1-weighted MRI for treatment planning.
Axial carbon ion dose distribution (orbit/ cavernous sinus), 3-field IMPT, 100% corresponding to 24 GyE carbon ions.
Coronal carbon ion dose distribution, 3-field IMPT, 100% corresponding to 24 GyE carbon ions.
51 year old patient with adenoid cystic carcinoma, contrast-enhanced, T1-weighted MRI at first follow-up showing partial remission but highly reduced contrast-enhancement.
One patient with adenoid cystic carcinoma and pulmonary metastases in the R2-group unfortunately showed a very good locoregional PR but distant disease progression and is currently undergoing palliative chemotherapy. There was no other case of disease progression in either the R2 or the R1 group.