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Particle therapy is a comparatively new radiotherapy treatment form allowing the application of extremely conformal treatment plans. In head and neck malignancies, especially in the paranasal sinus and anterior skull base, this technology is very valuable in order to maintain normal tissue tolerance of critical structures while still applying high doses to the tumour. The following paper will further explore the rationale of particle therapy and available clinical experience of the most commonly treated malignancies arising in these anatomical sites. The potential of particle therapy for re-irradiation in tumours of the paranasal sinus and anterior skull base will also be summarised., (© 2020 S. Karger AG, Basel.)

Background: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques., Methods: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method., Results: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC., Conclusions: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated., (© 2015 American Cancer Society.)

Cytotoxic ribonucleases such as the leopard frog derivative Ranpirnase (Onconase(®)) have emerged as a valuable new class of cancer therapeutics. Clinical trials employing single agent Ranpirnase in cancer patients have demonstrated significant clinical activity and surprisingly low immunogenicity. However, dose-limiting toxicity due to unspecific uptake of the RNase into non-cancerous cells is reached at relatively low concentrations of > 1 mg/m(2). We have in the present study generated a dimeric anti-EGFR Ranpirnase-diabody fusion protein capable to deliver two Ranpirnase moieties per molecule to EGFR-positive tumour cells. We show that this compound mediated far superior efficacy for killing EGFR-positive tumour cells than a monomeric counterpart. Most importantly, cell killing was restricted to EGFR-positive target cells and no dose-limiting toxicity of Ranpirnase-diabody was observed in mice. These data indicate that by targeted delivery of Ranpirnase non-selective toxicity can be abolished and suggests Ranpirnase-diabody as a promising new drug for therapeutic interventions in EGFR-positive cancers., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Treatment of local relapse in adenoid cystic carcinoma (ACC) following prior radiation remains a challenge: without the possibility of surgical salvage patients face the choice between palliative chemotherapy and re-irradiation. Chemotherapy yields response rates around 30% and application of tumouricidal doses is difficult due to proximity of critical structures. Carbon ion therapy (C12) is a promising method to minimize side-effects and maximize re-treatment dose in this indication. We describe our initial results for re-irradiation in heavily pre-treated ACC patients., Methods: Patients treated with carbon ion therapy between 04/2010 and 05/2013 (N=52pts, median age: 54 a) were retrospectively evaluated regarding toxicity (NCI CTC v.4), tumour response (RECIST) and control rates. 48pts (92.3%) received carbon ions only, 4pts received IMRT plus C12., Results: 4pts were treated following R1-resection, 43pts for inoperable local relapse. Most common tumour sites were paranasal sinus (36.5%), parotid (19.2%), and base of skull (17.3%). Pts received a median dose of 51GyE C12/63Gy BED and cumulative dose of 128Gy BED [67-182Gy] after a median RT-interval of 61months. Median target volume was 93ml [9-618ml]. No higher-grade (>°II) acute reactions were observed, 7pts showed blood-brain-barrier changes (°I/II: 8pts; °III: 2pts), 1 pt corneal ulceration, xerophthalmia 7pts, °IV bleeding 1 pt, tissue necrosis 2pts, otherwise no significant late reactions. Objective response rate (CR/PR) was 56.6%. With a median follow-up of 14months [1-39months] local control and distant control at 1a are 70.3% and 72.6% respectively. Of the 18pts with local relapse, 13pts have recurred in-field, 1 pt at the field edge, 3pts out of field, and one in the dose gradient., Conclusion: Despite high applied doses, C12 re-irradiation shows moderate side-effects, response rates even in these heavily pre-treated patients are encouraging and present a good alternative to palliative chemotherapy. Though most local recurrences occur within the high-dose area, further dose escalation should be viewed with caution., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Purpose: To evaluate efficacy and toxicity clinical in the intensified treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) with the combination of chemotherapy, the EGFR antibody cetuximab, and intensity-modulated radiation therapy (IMRT) in a concomitant boost concept., Methods: REACH is a prospective, bi-centric phase II trial of carboplatin/5-FU and cetuximab weekly combined with IMRT. Primary endpoint is locoregional control, secondary endpoints include acute radiation effects and adverse events. Evaluation of disease response is carried out according to the Response Evaluation Criteria in Solid Tumors (RECIST); toxicity is assessed using NCI CTC v 3.0., Results: Treatment was tolerated moderately well, acneiforme erythema occurred in 74.1% (grade II/III), mucositis grade III in 28.6%, and radiation dermatitis grade III in 14.3%. Higher-grade side-effects resolved quickly until the first follow-up post treatment. Objective response rates were promising with 28.6% CR at first follow-up and 92.9% thereafter., Conclusion: The combination of standard carboplatin/5-FU and cetuximab is feasible and results in promising objective response rates. The use of an IMRT concomitant boost is practicable in a routine clinical setting resulting in only moderate overall toxicity of the regimen., Trial Registration Number: ISRCTN87356938.

Purpose: To present an approach to fast, interfractional adaptive RT in intensity-modulated radiation therapy (IMRT) of head and neck tumors in clinical routine. Ensuring adequate patient position throughout treatment proves challenging in high-precision RT despite elaborate immobilization. Because of weight loss, treatment plans must be adapted to account for requiring supportive therapy incl. feeding tube or parenteral nutrition without treatment breaks., Methods and Materials: In-room CT position checks are used to create adapted IMRT treatment plans by stereotactic correlation to the initial setup, and volumes are adapted to the new geometry. New IMRT treatment plans are prospectively created on the basis of position control scans using the initial optimization parameters in KonRad without requiring complete reoptimization and thus facilitating quick replanning in daily routine. Patients treated for squamous cell head and neck cancer (SCCHN) in 2006-2007 were evaluated as to necessity/number of replannings, weight loss, dose, and plan parameters., Results: Seventy-two patients with SCCHN received IMRT to the primary site and lymph nodes (median dose 70.4 Gy). All patients received concomitant chemotherapy requiring supportive therapy by feeding tube or parenteral nutrition. Median weight loss was 7.8 kg, median volume loss was approximately 7%. Fifteen of 72 patients required adaptation of their treatment plans at least once. Target coverage was improved by up to 10.7% (median dose). The increase of dose to spared parotid without replanning was 11.7%. Replanning including outlining and optimization was feasible within 2 hours for each patient, and treatment could be continued without any interruptions., Conclusion: To preserve high-quality dose application, treatment plans must be adapted to anatomical changes. Replanning based on position control scans therefore presents a practical approach in clinical routine. In the absence of clinically usable online correction methods, this approach allows significant improvement of target volume coverage and continuous parotid sparing without treatment delays., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Treatment of surgically unresectable recurrence in the head and neck region remains a therapeutic problem with the only curative option being a second course of radiation with a tumouricidal dose. We report initial toxicity and efficacy of charged particle therapy in this situation., Methods: Treatment-related side-effects of patients treated with charged particle beams for recurrent tumours of the head and neck were prospectively collected and patient data was retrospectively analysed with regard to toxicity and efficacy of the treatment according to CTCAE v. 4.03 and RECIST., Results: Treatment was tolerated well without any severe acute toxicity. In non-chordoma/chondrosarcoma patients, overall response rate was 53.3% at 8 weeks post RT. 4/5 chordoma/chondrosarcoma patients showed no signs of further tumour progression., Conclusion: Initial experience of re-irradiation with scanned particle beams in recurrent tumours of the head and neck seems feasible and encouraging. Further follow-up is needed to investigate potential late effects., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: To investigate toxicity and efficacy in high-risk malignant salivary gland tumors (MSGT) of the head and neck. Local control in R2-resected adenoid cystic carcinoma was already improved with a combination of IMRT and carbon ion boost at only mild side-effects, hence this treatment was also offered to patients with MSGT and microscopic residual disease (R1) or perineural spread (Pn+)., Methods: From November 2009, all patients with MSGT treated with carbon ion therapy were evaluated. Acute side effects were scored according to CTCAE v.4.03. Tumor response was assessed according to RECIST where applicable., Results: 103 patients were treated from 11/2009 to 03/2011, median follow-up is 6 months. 60 pts received treatment following R2 resections or as definitive radiation, 43 patients received adjuvant radiation for R1 and/or Pn+. 16 patients received carbon ion treatment for re-irradiation. Median total dose was 73.2 GyE (23.9 GyE carbon ions + 49,9 Gy IMRT) for primary treatment and 44.9 GyE carbon ions for re-irradiation. All treatments were completed as planned and generally well tolerated with no > CTC°III toxicity. Rates of CTC°III toxicity (mucositis and dysphagia) were 8.7% with side-effects almost completely resolved at first follow-up.47 patients showed good treatment responses (CR/PR) according to RECIST., Conclusion: Acute toxicity remains low in IMRT with carbon ion boost also in R1-resected patients and patients undergoing re-irradiation. R2-resected patients showed high rates of treatment response, though follow-up is too short to assess long-term disease control.

Purpose: To report our experience on disease control and functional outcome using three modern combined-modality approaches for definitive radiochemotherapy of locally advanced SCCHN with modern radiotherapy techniques: radiochemotherapy (RChT), radioimmunotherapy (RIT) with cetuximab, or induction chemotherapy with docetaxel, cisplatin, and 5-FU (TPF) combined with either RChT or RIT., Methods: Toxicity and outcome was retrospectively analysed in patients receiving definitive RChT, RIT, or induction chemotherapy followed by RChT or RIT between 2006 and 2009. Outcome was estimated using Kaplan-Meier analyses, toxicity was analysed according to CTCAE v 3.0., Results: Thirty-eight patients were treated with RChT, 38 patients with RIT, 16 patients received TPF followed by either RChT or RIT. Radiotherapy was mostly applied as IMRT (68%). Long-term toxicity was low, only one case of grad III dysphagia requiring oesophageal dilatation, no case of either xerostomia ≥ grade II or cervical plexopathy were observed. Median overall survival (OS) was 25.7 months (RChT) and 27.7 months (RIT), median locoregional progression-free survival (PFS) was not reached yet. Subgroup analysis showed no significant differences between TPF, RChT, and RIT despite higher age and co-morbidities in the RIT group. Results suggested improved OS, distant and overall PFS for the TPF regimen., Conclusion: Late radiation effects in our cohort are rare. No significant differences in outcome between RChT and RIT were observed. Adding TPF suggests improved progression-free and overall survival, impact of TPF on locoregional PFS was marginal, therefore radiotherapeutic options for intensification of local treatment should be explored.

Purpose: To investigate in a simulation study whether using a variable relative biological effectiveness (RBE) in calculation and optimization of intensity-modulated proton therapy (IMPT) instead of using an RBE of 1.1 would result in significant changes in the RBE-weighted dose (RWD) distributions., Methods and Materials: For 4 patients with head-and-neck tumors, three IMPT plans were prepared respectively. The first plan was physically optimized (IMPT-PO plan), and the RWD was calculated with a constant RBE of 1.1. Then the plan's RWD was recalculated (IMPT-R plan) using a variable RBE model taking into account the linear energy transfer (LET) and tissue-specific radiobiological parameters. The third IMPT plan was optimized using a biological optimization routine (IMPT-BO plan)., Results: Comparing the IMPT-PO and IMPT-R plans, we observed that the RWD in radioresistant tissues was more sensitive to the LET than in radiosensitive tissues. The IMPT-R plans were in general more inhomogeneous than the IMPT-PO plans. The differences of RWD distributions for all volumes between IMPT-PO and IMPT-BO plans complied with predefined dose-volume constraints. The average LET was significantly lower in IMPT-BO plans than in IMPT-R plans., Conclusion: In radioresistant normal tissues caution has to be used regarding the LET distribution because these are most sensitive to changes in the LET. Biological optimization of IMPT plans based on the organ-specific biological parameters and LET distributions is feasible., (Copyright © 2011 Elsevier Inc. All rights reserved.)