Rare entities in head-and-neck cancer: salvage re-irradiation with carbon ions

Patients were immobilized with a thermoplastic head–mask system. Contrast-enhanced computed tomography (CT) scans (3-mm slice thickness) were used for treatment planning, and contrast-enhanced T1-weighted magnetic resonance imaging (MRI) was used for image registration. Treatment planning was conducted using Syngo PT Planning version 13 (Siemens®, Erlangen, Germany). The clinical target volume (CTV) included the visible tumor on contrast-enhanced CT or MRI (gross tumor volume or GTV) with a margin of 2–5 mm for subclinical disease spread. The resection cavity was included in the CTV for patients with prior surgical resection. Depending on patient positioning and beam arrangement, an additional margin of 2–3 mm was added for the planning target volume (PTV).

Treatment was exclusively performed with carbon ions using the active raster-scanning method with daily image guidance by orthogonal X-rays. Imaging follow-up included a contrast-enhanced MRI or a CT scan of the head and neck 6–8 weeks after treatment completion and every 3 months within the first 2 years after CIR. Treatment-related toxicities were recorded with the same frequency during follow-up visits and examinations by a radiation oncologist at our institution. Furthermore, patients saw an ear, nose, and throat (ENT) specialist at each follow-up visit.

Statistical analysis was conducted using SPSS Statistics 25 (IBM®, New York, USA) and the software R version 3.4.3 (www.​r-project.​org). The median follow-up for overall survival (OS) was calculated using the inverse Kaplan-Meier method. Local control (LC) was evaluated from the time interval between the start of CIR to the first occurrence of local failure using the Response Evaluation Criteria in Solid Tumors (RECIST) [16]. Similarly, local and distant progression-free survival (L-PFS, D-PFS) were measured from the time of CIR start to the first occurrence of local or distant failure, respectively. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. OS was determined from the commencement of re-irradiation until death or last follow-up, whichever occurred first. Kaplan-Meier estimates for OS and PFS were tested for prognostic significance using the log-rank test and stepwise testing for significant cut-off values. The characteristics total dose of CIR (≥ 51 Gy (RBE) vs. < 51 Gy (RBE)), tumor histology (MEC vs. other), RT interval (≥ 2 years vs. < 2 years), distant metastatic spread (yes vs. no), and prior surgical resection (adjuvant vs. definitive CIR) were evaluated. Adverse events related to CIR were evaluated based on the patients’ medical records according to version 4.03 of the Common Terminology Criteria for Adverse Events (CTCAE).

Staging was conducted prior to CIR using the eighth edition of the Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) classification. The majority of recurrent tumors were of an advanced stage (T3/T4, n = 24, 88.9%). Only four patients (n = 4, 12.5%) had distant metastasis prior to CIR, most commonly in the lungs (n = 3, 75.0%). The majority of recurrent tumors were localized in the major salivary glands (n = 15, 46.9%), the nasopharynx (n = 7, 21.9%), and the paranasal sinuses (n = 6, 18.8%). The majority of tumors were classified prior to re-irradiation as MEC (n = 7, 21.9%), acinar cell carcinoma (n = 6, 18.8%), esthesioneuroblastoma (n = 5, 15.6%), and myoepithelial carcinoma (n = 3, 9.4%). One patient had small cell neuroendocrine carcinoma (Fig. 1). Seven patients (n = 7, 21.9%) underwent surgical resection prior to CIR. Recurrence was pathologically confirmed for the majority of patients (n = 18, 56.3%), but the recurrent tumor was inaccessible for biopsy in seven patients (n = 7, 21.9%) and was defined radiographically. Among those undergoing pathological confirmation, in four patients (n = 4, 12.5%) histology was different compared with that at primary diagnosis.

The median total dose of re-irradiation with carbon ions was 51 Gy (RBE) (range, 36–66 Gy (RBE)) with 3 Gy (RBE) per fraction in 5–6 fractions per week. None of the patients received simultaneous systemic therapies (e.g., chemotherapy) during CIR. On average, patients received four (range, 1–6) tumor-specific treatments (i.e., chemotherapy, surgery, or radiation treatment) before CIR. The median RT interval (i.e., time between initial RT and CIR) was 5.2 years (range, 0.6–46.5 years).

The initial RT was performed with 3D conformal RT in 12 patients (37.5%), intensity-modulated RT (IMRT) in 9 patients (28.1%), bimodal RT (IMRT and carbon ion boost) in 4 patients (12.5%), and other modalities (i.e., stereotactic body RT, cobalt therapy, or electron beam therapy) in 5 patients (15.6%) but was unknown in 2 patients (6.3%). Patients with bimodal RT received a median dose of 50 Gy (range, 50–54 Gy) with photon IMRT and a median dose of 24 Gy (RBE) (range, 18–24 Gy (RBE)) with carbon ions. The CTV and PTV of re-irradiation were 98.3 cubic cm (range, 13.3–550.6 cubic cm) and 137.1 cubic cm (range, 23.1–714.9 cubic cm), respectively. The median total tumor lifetime dose (equivalent in 2 Gy fractions, EQD2) after initial RT and CIR was 128.6 Gy (range, 105.8–146.5 Gy). An alpha-beta ratio of 10 Gy was used for all head and neck tumor entities, as previously reported [17]. Detailed patient and treatment characteristics are shown in Table 1.

The median follow-up interval after CIR was 18.1 months (range, 3.2–51.2 months). Almost all patients completed re-irradiation without interruption (n = 31, 96.9%). Treatment was cancelled for one patient due to newly diagnosed leptomeningeal spread. No severe acute (during the initial 90 days after CIR) or late treatment-related toxicities (≥ grade III) were observed after CIR. The most common low-grade acute toxicities included grade I and grade II (n = 12 and 1, 37.5 and 3.1%) radiation dermatitis and grade I and grade II oral mucositis (n = 4 and 4, 12.5 and 12.5%). Late treatment-related toxicities could be evaluated in 21 patients (n = 21, 65.6%) with available follow-up imaging and clinical data. Common low-grade late toxicities included grade I and grade II middle ear inflammation (n = 2 and 3, 9.5 and 14.3%), grade II dysgeusia (n = 3, 14.3%), and grade I and grade II (n = 2 and 3, 9.5 and 14.3%) hearing impairment. One patient developed a symptomatic blood–brain barrier disruption in the left temporal lobe 13.5 months after CIR that was treated with oral dexamethasone. Another patient with an MEC of the right cavernous sinus developed a brief generalized seizure, possibly related to CIR. Detailed information on acute and late treatment-related toxicities is shown in Table 2.

The median OS was 24.7 months (95% CI, 21.9–27.5 months). The median OS after CIR was 28.5 months for patients with an RT interval ≥ 2 years compared to 8.9 months for patients with an RT interval < 2 years (p = 0.001; Fig. 2). The 6-, 12- and 18-month OS after CIR was 87.1, 77.4, and 61.3%, respectively. In patients with metastatic disease prior to re-irradiation (n = 4, 12.5%) there was no significant difference regarding OS within the first 2 years after CIR (24.1 months vs. 24.7 months, p = 0.995). Patients with two prior irradiation treatments compared to one prior course of radiation therapy had a significantly worse OS (4.8 months vs. 25.6 months, p = 0.001). There was no difference in OS for patients who underwent definitive (n = 25, 78.1%) compared to adjuvant (n = 7, 21.9%) CIR (28.5 months vs. 24.1 months, p = 0.388). In addition, patients with MEC had a worse OS compared to other histologies but without statistical significance (18.1 months vs. 25.6 months, p = 0.225). A total of 14 patients (n = 14, 43.8%) survived at least 2 years after CIR.