Abstract
Treatment of localized cancer with protons therapy (PT) seems an appealing alternative to photons. PT has been available for decades and has unique dose distribution properties with the so-called Bragg-peak enabling protons to stop after their maximum depth is reached within millimeters. PT allows sparing of normal tissues and organs to a much greater extent than photons, even when modern photon techniques like intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) are involved. Whereas IMRT and VMAT techniques have demonstrated their superiority to older 3D-conformal irradiation techniques, there is still a large gap between the theoretical advantages of PT due to its superior dose distribution and high-level clinical evidence, particularly in head and neck cancer (HNC). So far, mostly non-randomized clinical studies exist with clinical results in oropharyngeal, nasopharyngeal, sinonasal, periorbital, and salivary gland cancer. The limited broad availability of this treatment method and its unknown cost-effectiveness need to be evaluated. In this chapter, we discuss the currently available evidence of PT for HNCs and viable options to generate further evidence like the model-based approach.
You have full access to this open access chapter, Download conference paper PDF
Similar content being viewed by others
Keywords
- Proton Therapy
- Intensity modulated proton therapy
- Multifield optimization
- Comperative planning
- Dosimetric benefits
- Model-based approach
- NTCP
- Normal tissue sparing
- Patient selection
- Robust treatment planning
Introduction
Radiation therapy (RT) is a mainstay of treatment for patients with head and neck cancer (HNC). At present, the most common form of RT is external beam photon therapy. The development of intensity-modulated radiotherapy (IMRT) and more recently advanced forms of IMRT such as volumetric modulated arc therapy (VMAT) allowed improvements in dose conformality in target volumes and reduction of high doses in nearby healthy tissues and organs at risk (OARs). This resulted in a drastic reduction of the most common forms of RT-associated toxicity in HNCs such as xerostomia [1,2,3,4], and dysphagia [5]. However, technological advances in photon therapy to further optimize the dose distribution are reaching the limits imposed by the physics of photon radiation. In consequence, IMRT’s usage of multi-angled radiation fields has led to a redistribution of the integral dose causing alternative toxicities such as fatigue by the low dose bath of the posterior cranial fossa [6]. Therefore, alternative methods of radiation delivery with distinct physical properties are required to further refine the therapeutic index of RT.
For decades, proton therapy (PT) offers attractive options for technological advances in RT, potentially leading to a reduction in treatment-related toxicities or an isotoxic dose escalation through dosimetric advantages over photon therapy. PT is the standard of care for skull-base tumours which are characterized by a challenging tumour location and proximity to critical structures. In recent years, the use of PT has expanded to numerous other head and neck disease sites such as nasopharynx, oropharynx, nasal cavity and paranasal sinus, periorbital, and salivary glands including reirradiation.
Physical Properties of Proton Therapy
Dosimetric Benefits of Proton Therapy
Photon and proton beams are different forms of ionizing radiation causing DNA damage in cancer cells. Both are elementary particles with different physical properties and energy deposition profiles in tissue favouring protons for treatment in cancer patients (Fig. 8.1). Photons are electromagnetic packets of energy, which are massless and have an infinite range in patient tissue. In contrast, protons have a physical mass and the range of a proton in patient tissue is a function of its initial energy. A monoenergetic proton beam releases most of the energy in the distal part of its path in a characteristic peak, the so-called Bragg Peak. By using a range of energies a spread out Bragg Peak (SOBP) can be created that allows highly conformal treatment of tumour target volumes. The absence of an exit dose beyond the target volume allows for precise sparing of adjacent OARs. Additionally, the entry portion of the proton beam receives less integral dose compared with a photon beam. In summary, proton beams offer several advantages over photon beams in cancer treatment, including the ability to more precisely spare surrounding healthy tissues and the potential to deliver lower integral doses to the patient.
PT uses passive scattering or active scanning techniques. The passive scattering beam technique was introduced first, using scattering devices to broaden the proton beam and a range-modulation device to create the SOBP. This technique requires patient individualized scattering devices, which are expensive to create and limit the ability of this technique for adaptive planning in case of excessive weight loss of the patient or changes of the anatomy. A more recent form of PT is the active scanning technique which uses magnets to deflect the proton beam. Using this technique, the radiation dose is delivered to the target volume layer by layer with protons of different energies. Inverse planning methods are used to deliver highly conformal doses to the target volume with either single field optimization (SFO) or multifield optimization (MFO) with MFO being generally more conformal than SFO. Intensity-modulated proton therapy (IMPT) takes advantage of MFO with each individual radiation field delivering an inhomogeneous dose to the target volume to minimize radiation exposure of OARs. Comparative HNC treatment plans with IMRT show dosimetric advantages of IMPT (Fig. 8.2). Several recent studies have confirmed the dosimetric advantages of IMPT for unilateral HNCs [8], oropharyngeal carcinoma (OPC) [9], adjuvant RT of OPC [10], and in cases of HNC re-irradiation [11].
Dosimetric Uncertainties of Proton Therapy for Head and Neck Patients
While the sharp dose fall-off beyond the Bragg Peak is considered to be a primary beneficial property of PT for OAR sparing, it is also the source of significant uncertainties in dose delivery and a possible cause of underdosage in the tumour volume. For instance, proton beams passing the nasal cavity or paranasal sinuses should be avoided due to variable fillings of these structures which can lead to significant distortions of the proton irradiation fields. A general approach for a robust PT treatment plan is the usage of MFO and careful selection of beam angles avoiding heterogeneous tissues. The dose distribution of PT is sensitive to the correct conversion of computed tomography (CT) Hounsfield units to proton stopping power [13, 14], image artifacts and interfraction, and interfield motion [15]. Uncertainties arise at multiple steps of the typical radiation oncology workflow and countermeasures exist (Fig. 18.3). Robust treatment plans that are clinically acceptable can be created when the aforementioned uncertainties are taken into account as part of multi-criteria optimization simulating these uncertainties or combinations thereof [16, 17]. Robust IMPT planning is based on the clinical target volume (CTV) without using margins for a planning target volume (PTV) [18] (Fig. 18.4). Instead of relying on precise proton ranges, robust optimization often relies on the sharp lateral penumbra of proton beams.
A further source of uncertainty is the relative biological effectiveness (RBE) of protons which is a factor multiplied by the proton dose to calculate the biological equivalent photon dose. Currently, a homogeneous value of 1.1 for the proton RBE is used in clinical practice, but there have been studies that suggest a variability of RBE with higher values close to the Bragg Peak [19]. While the clinical relevance of a variable RBE is unclear especially in regards to normal tissue toxicity, some treatment planning systems allow for biological uncertainties optimization by locating higher RBE values inside the target volume while avoiding OARs.
Take Home Message for Physical Properties of Proton Therapy
-
Protons have a different energy deposition profile than photons suitable for cancer treatment.
-
Protons have several physical properties that are beneficial for normal tissue sparring: (1) release of most of the energy in the Bragg Peak, (2) steep dose fall-off beyond the Bragg Peak, (3) lower integral dose in the entry path, and (4) a sharp lateral penumbra.
-
By using a range of energies a spread out Bragg Peak can be created which is highly conformal to the target volume.
-
Proton therapy is subject to range uncertainties which can be successfully mitigated with robust optimization of the treatment plan.
Patient Selection for Proton Therapy
While protons, from a physical point of view, have more favourable properties for RT than photons, there is a lack of evidence from randomized controlled trials (RCTs) comparing IMRT vs IMPT and investigating differences in toxicity profiles. The “ALARA” principle states that ionizing radiation should be applied to humans “as low as reasonably possible” motivating the fast introduction of modern photon radiation techniques like IMRT and VMAT into clinical practice, because they allowed for better dose conformity to the target volume and sparing of OARs. Due to the significantly higher costs of PT, the question arises to what extent PT translates into a clinically relevant reduction of toxicities [21].
Alternative evidence-based approaches to RCTs rely on predicting RT related toxicities via Normal Tissue Complication Probability (NTCP) models, to identify patients who benefit most from PT (model-based selection) and to continuously validate this patient selection process (model-based validation).
Normal Tissue Complication Probability Models for Head and Neck Cancer
RT to the head and neck has various potentially severe acute and late side effects. The relationship between the dose distribution in OARs and the probability to develop RT-related side effects are described by NTCP models. In general, the probability of a side effect will increase with higher doses and larger volumes in the OAR to receive certain doses [22]. Side effects are assessed by medical healthcare professionals (investigator-reported outcomes) preferably in combination with direct reports of the patients (patient-reported outcomes (PROs)). Sophisticated grading scales have been developed for both investigator-reported outcomes such as the Common Terminology Criteria for Adverse Events (CTCAE) [23] and PROs such as the European Organisation for Research and Treatment of Cancer Quality of Life Head and Neck Module (EORTC QLQ-HN43) [24]. Most relevant dose-volume parameters vary from the observed side effect and OARs, e.g. the mean dose to the parotid glands for xerostomia [25], and in some cases may even depend on multiple dose-volumen parameters, e.g. the mean dose to the superior pharyngeal constrictor muscle and the mean dose to the supraglottic area for swallowing dysfunction [26]. The most reliable NTCP models are obtained from prospective clinical trials which are validated in an independent external cohort. Some models improve their predictive performance by considering patient factors (e.g. age) and treatment related factors (e.g. concomitant chemotherapy) which are then called multivariable NTCP models. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) was an effort to accumulate the evidence for dose–response models and dose-volume constraints which was published in 2010 [27]. Since then more NTCP models have been developed which incorporate PROs and/or evaluated modern RT techniques for xerostomia [25, 28,29,30] (Fig. 8.5), dysphagia and feeding tube dependency [26, 31,32,33], hypothyroidism [34], laryngeal edema [35], emetogenesis [36] and acute mucositis [33].
Model-Based Approach
The general idea behind the model-based approach is patient selection for either IMPT or IMRT based on an expected reduction of RT-associated toxicities as predicted by NTCP models. A major challenge with this approach is that many NTCP models are based on patient cohorts which received photon therapy with outdated techniques and that their validity for IMPT have not been demonstrated. To this end, existing NTCP models have been verified with external validation cohorts receiving PT. While a drop in the performance of the NTCP models could be noticed, the models demonstrated robustness and generally remained to be valid [37].
The model-based approach works with the following steps (Fig. 8.6):
-
(1)
For every patient in silico planning comparative (ISPC) studies are created and the best photon (VMAT) and proton (IMPT) treatment plans are compared.
-
(2)
NTCP models are used to predict the probability of the most relevant acute and late RT induced side effects for both treatment plans.
-
(3)
It is determined to which extent the difference in dose (Δdose) translates into a large difference in complication probability (ΔNTCP) of acute and late side effects. This step is crucial since not all Δdose translate into ΔNTCP which can be the case in two situations: the VMAT treatment plan is already sufficiently optimized and has a low probability of complication which cannot be significantly improved with IMPT, or 2) both the IMPT and VMAT treatment plans are located at the upper end of the NTCP curve and the Δdose is too small to result into a lower complication probability.
-
(4)
If a predefined threshold for ΔNTCP is reached, e.g. the probability of severe complication is 5% lower with IMPT than with VMAT, the patient is selected for treatment with IMPT (model-based selection).
-
(5)
After treatment, actual complications in patients are observed and NTCP models are validated (model-based validation).
The model-based approach has been approved and accepted by the Dutch Health care institute for selection of patients for PT. In the National Indication Protocol Proton therapy (NIPP) the following ΔNTCP thresholds and CTCAE grades are used for patient selection: no ΔNTCP threshold for grade 1 side effects, ΔNTCP ≥ 10% for grade 2 or ΔNTCP ≥ 5% for grade 3 or higher. A further criterion for PT selection is the sum of ΔNTCPs of all grade 2 or higher side effects exceeding the threshold of 15%.
In a first evaluation of the model-based approach by Tambas et al. [39] 35% of patients (n = 221) with HNCs in distinct anatomical loci (oropharynx, larynx, nasopharynx, hypopharynx, oral cavity) and mostly higher stage (stage III/IV 83%) qualified for PT according to the NIPP thresholds. In the sub-group of patients with OPCs the PT qualification rate was with 65% even higher.
Randomized Controlled Trials for Proton Therapy
A RCT is the most scientifically reliable method of hypothesis testing and is considered the gold standard for evaluation of the efficacy of an intervention. There might be situations where a RCT should be preferred over the model-based approach: concerns regarding a decreased tumour control probability; concerns regarding increased side effects, e.g. due to range uncertainties or an unknown RBE; in healthcare systems that require a RCT for reimbursement.
As pointed out by Widder et al. [40], including patients in a RCT who are unlikely to experience lower toxicity from PT due to a low Δdose and/or ΔNTCP, will only increase the noise and decrease the power of the study. For a particularly costly intervention like PT, even a positive RCT with an unselected patient cohort will provoke questions about patients who benefit most from PT in order to reduce costs in the health care system. In consequence, even in a setting of RCT, patient enrichment by the model-based selection is preferable to generate further evidence of the benefits of PT.
Take Home Message for Patient Selection for Proton Therapy
-
Normal Tissue Complication Probability (NTCP) models can be used to estimate the probability of acute and late toxicities associated with photon and proton radiotherapy.
-
The model-based approach assumes a clear dose-dependence for RT-related toxicities best described by the NTCP-models, which serve as a selection tool for comparative photon and proton treatment plans.
-
The Netherlands consensus for model-based selection implies a reduction of ≥10% and ≥5% for a grade 2 or 3 side effects, respectively, which would qualify the patient for proton treatment.
-
With the model-based approach, patient cohorts of randomized controlled trials can be enriched with patients who are likely to profit from proton therapy.
Outcomes After Proton Therapy of Head and Neck Cancers
Skull-Base Chordomas and Chondrosarcomas
Skull-base chordomas and chondrosarcomas are locally aggressive malignancies that belong to the group of sarcomas and are characterized by a close proximity to critical structures. Chordomas are rare malignancies with an incidence <0.1 per 100,000 [41]. Skull-base chordomas mostly arise from the clivus and often become clinically apparent with cranial nerve deficits, sensorimotor deficits, pituitary dysfunction, or hydrocephalus. Without treatment the average overall survival (OS) is short (6–24 months) [42]. Chondrosarcomas comprise a heterogeneous group of slow-growing sarcomas originating from cartilage-producing cells in areas of enchondral ossification and have an incidence of 0.2 per 100,000 [43]. Surgery is the primary treatment, however due to the location a gross total resection often cannot be achieved. In chordomas, surgery alone results in a high local recurrence rate of 58% [44]. Adjuvant RT is of crucial importance to reach acceptable rates of local control (LC). Since the main site of recurrence is local and the chances of salvage surgery are remote, LC is directly associated with OS. A clear dose–response relationship with LC could be observed. Median PTV doses of <60 Gy, 60 Gy and 66.6 Gy resulted in a 5-year LC of 28% [45], 39% [46] and 50% [47]. Chordomas and chondrosarcomas have a relatively high radioresistance and RT should aim for target volume doses above 70 Gy for best responses. This is especially challenging at the skull-base since the optimal doses exceed the tolerance of proximal neural structures such as the brainstem, spinal cord, and optic nerves and chiasm.
Multiple studies have reported outcomes of PT and skull-base chordomas [48,49,50,51,52,53,54,55,56] and chondrosarcomas [51, 52, 55, 56]. Munzenrider et al. have published so far results for the largest patient cohort (n = 519) who received 66–83 Gy (RBE) as a combination of photon and proton RT. The median follow-up was 41 months. The 5-year LC and OS was 73 and 80% for chordomas and 98 and 91% for chondrosarcomas. Male chordomas patients had a significantly higher 5-years LC than females (81 vs. 65%, p = 0.035). The following significant toxicities were reported: three (0.8%) patients died from brain stem injury, 8 (2.2%) experienced temporal lobe injury (Fig. 8.7), hearing loss, cranial neuropathy, or endocrinopathy. More recent studies could confirm similar rates for LC [48, 50, 57] and higher grade toxicities [54, 58, 59]. In summary, PT has allowed for dose intensification that resulted in improved clinical outcomes and tolerable toxicity profiles.
Sinonasal Cancers
Sinonasal cancers (SC) are a heterogeneous group and comprise of malignancies from the nasal cavity and paranasal sinuses including the maxillary, ethmoid, frontal, and sphenoid sinuses and the middle ear. SCs are very rare with an incidence of 8.7 per 1.000.000 [61]. The histology is mostly squamous cell carcinomas (SCCs) followed by adenocarcinomas [62]. Risk factors for SCs are occupational exposures, e.g. wood dust, leather dust, formaldehyde, nickel and chromium compounds [63]. After mesothelioma, sinonasal cancers are the second most common malignancies in number of cases associated with occupational exposure [64]. Surgery is the preferred primary treatment of SCs and small tumours with complete gross tumour resection have an excellent prognosis. However, many SCs are detected at a later stage which makes complete resection difficult.
In a meta-analysis by Patel et al. [65] a subgroup analysis comprising 16 trials and 539 patients specifically compared PT with IMRT and found a significantly higher disease-free survival (DFS) at 5 years (hazard ratio (HR) = 1.44, 95% confidence interval (CI) = [1.01–2.05], p = 0.045) and locoregional control (LRC) at longest follow-up (HR = 1.26, 95%CI = [1.05–1.51], p = 0.011) in favour of PT.
A large study by Resto et al. [66] comprised 102 patients who received a combination of adjuvant photon RT and PT. The median total dose was 71.6 Gy (range 55.4–79.4 Gy) with a median of 57.1% delivered via protons (range 22.9%–84.8%). The study had a median follow-up of 5.1 years. The 5-year LC of patients with complete resection, partial resection and biopsy were 95%, 82% and 87%. The extent of surgical resection was associated with improved OS (p = 0.02), DFS (p = 0.009) and distant relapse (p = 0.03).
In a comparative study by Lewis et al. [67] VMAT and IMPT treatment plans for patients (n = 10) with SCs were created and dosimetric parameters compared (Fig. 8.8). IMPT was superior for dosimetric parameters of the brain (mean, V10, V30), brainstem (max dose/D0.01), ipsilateral cochlea (V30), contralateral cochlea (mean), contralateral lacrimal gland (mean), contralateral parotid (mean), spinal cord (max dose/D0.01) and inferior for the ipsilateral eye (mean) and ipsilateral lens (mean). The secondary malignancy risk with VMAT was 3.35 times higher (95%CI = [1.92,5.89]) than with IMPT. The authors conclude that IMPT better spared OARs not immediately adjacent to the target volume and reduced the risk of secondary malignancies.
In a study by Pasalic et al. [68], patients (n = 64) with SCs of mostly advanced stage (T4 disease 46%) and mostly olfactory neuroblastoma as histology (28%) received PT and were evaluated for toxicities by physician-assessed toxicities (PATs) and PROs. The 3-year LC, DFS and OS were 88%, 76%, and 82%. PATs were assessed with CTCAE and PROs with the Xerostomia-Related Quality-of-Life Scale (XeQoLS), MD Anderson Dysphagia Inventory (MDADI), and Functional Assessment of Cancer Therapy (FACT) scales. No late grade 3 or higher PATs were observed. Significant changes in PROs from baseline were observed in the acute and sub-acute phase, but no chronic sequelae.
Periorbital Tumours
Periorbital tumours refer to malignancies in proximity to optic structures, including the nasopharynx, the nasal cavity and paranasal sinuses, and the dura of different histologies. Surgery and adjuvant RT are often indicated in the presence of high risk features like positive resection margins, bone invasion, high-grade disease, positive lymph nodes and/or perineural invasion. Historically, periorbital tumours were treated with orbit exenteration in order to ensure a margin-negative resection. Orbit-sparing RT treatments are an alternative to orbital exenteration which aim to preserve visual function and maintain high rates of LC. The complex anatomy of this region and the proximity to critical structures such as the globe, cornea, lacrimal gland and duct system, tumours of the periorbital locations are particularly difficult to treat with RT.
In a study by Holliday et al. [69], patients (n = 20) with periorbital tumours were treated with global-sparing surgery and PT. The median radiation dose was 60 Gy (RBE) (range: 50–70 Gy) and 11 patients received concomitant chemotherapy. After a median follow-up of 27 months, LC was 100% (1 regional and 1 distant relapse). Toxicities were graded by CTCAE. There were 3 (15%) occurrences for grade 3 epiphora and 3 (15%) for grade 3 exposure keratopathy (damage to the cornea caused by prolonged exposure to air and instability of the tear film due to incomplete eye lid closure). Patients experiencing these toxicities had a higher maximum dose to the ipsilateral cornea (median 46.3 Gy (RBE) vs. 37.4 Gy (RBE), p = 0.017). Visual acuity decreased in 4 patients (20%).
In the study by El-Sawy et al. [70], patients (n = 14) received treatment for periorbital tumours (lacrimal sac or nasolacrimal duct carcinoma). Globe-sparing treatment was conducted in 10 patients and 4 patients received orbit exenteration. 13 patients received postoperative RT as IMRT (n = 5) or PT (n = 7) (median dose 60 Gy). Globe sparing was successful in all 10 patients after a median follow-up of 27 months. 9 patients (90%) maintained or improved their baseline visual acuity.
Damico et al. (2021) [71] evaluated 17 patients with tumours in paranasal sinuses, nasal cavity, or nasopharynx within 2 cm of the eye and optic apparatus that were treated with passive scatter PT and had comparative VMAT plans available. Median follow-up was 19.7 months. 14 patients received globe-sparing surgery and post operative RT, 3 received definitive RT. PT significantly reduced mean doses to the optic nerves and chiasm, pituitary gland, lacrimal glands and cochlea. Only 1 patient experienced grade 3 late toxicity (hearing impairment). The 18-month cumulative incidence of local failure was 19.1% and 1-year OS was 80.9%.
Additional studies are warranted for this entity to evaluate optimal patient setup, IMPT planning specifications, and dose tolerance limits of OARs.
Salivary Gland Cancer
Malignancies of the salivary glands are rare with incidences varying between 0.05 and 2 per 100.000 [72]. Tumours are mostly adenocarcinomas of the parotid which is the largest salivary gland. The etiology of salivary gland cancer is largely unknown. The primary treatment is surgery followed by postoperative RT for adverse features. Unilateral RT benefits from IMPT versus IMRT due to the absence of the exit dose (Fig. 8.9).
Bhattasali et al. [73] reported on nine patients with unresectable node-negative head and neck adenoid cystic carcinoma (ACC) who received definitive IMPT and concurrent cisplatin. The prescription dose was 70 Gy (RBE) in 33 fractions. Median follow-up was 27 months (range 9.2–48.3 months). 4 patients had complete response (CR), 4 patients partial response (PR) and 1 patient showed progression. 5 patients experienced grade 3 toxicities and one patient grade 4 optic nerve disorder.
In a study by Romesser et al. [74], 41 patients with either major salivary gland cancer or cutaneous SCC were either treated with IMRT (n = 18, 43.9%) or passively scattered PT (n = 23, 56.1%). Gross disease was treated with normofractionated 70 Gy (RBE), close or microscopically positive margin with 66 Gy (RBE), high-risk volumes such as the tumour bed with 60 Gy (RBE). A reduction of grade 2 or greater acute dysgeusia (5.6 vs. 65.2%, p < 0.001), mucositis (16.7 vs. 52.2%, p = 0.019), and nausea (11.1 vs. 56.5%, p = 0.003) in favour of PT was observed.
Zakeri et al. [75] treated 68 patients with major salivary gland tumours with IMPT. Patients with positive margins received 66 to 70 Gy (RBE) and close margins/clear margins with 60 to 66 Gy (RBE) to the postoperative bed. Oncological outcomes were excellent with 3-year rates of LC, progression-free survival (PFS), and OS of 95.1% (95%CI = [89.9%,100.0%]), 80.7% (95%CI = [70.2%,92.7%]), and 96.1% (95%CI = [90.9%,100.0%]). Acute grade 3 dermatitis was observed in 9 (13.2%) patients. One patient developed late grade 3 osteoradionecrosis of the mandible.
Oropharyngeal Cancers
In the study by Tambas et al. [39], evaluating the model-based approach, 65% of OPC patients were predicted to benefit from IMPT. OPC with association of human papillomavirus (HPV) have a rapid increase in incidence. Since this patient cohort has a particularly good prognosis, improvements of late toxicities is one of the most important considerations. Current RCTs use de-escalation protocols for total radiation doses, target volumes, and combinations with systemic treatments to reduce morbidities with the aim to not sacrify oncologic outcomes. PT can provide other measures for a substantial reduction of radiation injury. There is a growing body of studies demonstrating that PT offer unique chances for dose reductions in virtually all organs (Fig. 8.10) and tissues at risk, thereby decreasing acute toxicity and long-term morbidity without compromising the radiation dose to target volumes and oncologic outcome (Table 8.1).
A case-matched analysis by Blanchard et al. [77] evaluated patients with IMPT (n = 50) and IMRT (n = 1000). 20% of patients received unilateral irradiation. It could be demonstrated that IMPT significantly decreased the necessity for feeding tube placement during treatment (odds ratio (OR) = 0.53; p = 0.011) and resulted in a significant reduction of the composite endpoint of grade 3 weight loss or feeding tube placement at 3 months (OR = 0.44) and 1 year (OR = 0.23; p < 0.05). There was no difference in OS or PFS between the study arms.
Several studies have evaluated PROs and could demonstrate the benefits of PT, including significant reductions in mucositis, xerostomia, dysgeusia, nutrition, dental problems, fatigue, and physical function [78,79,80,81].
The largest PROs study to date is a comparative analysis by Manzar et al. [78] reporting PATs and PROs of patients receiving IMPT (n = 46) or VMAT (n = 259) with either 70 Gy (RBE) definitively or 60–66 Gy (RBE) postoperatively. In the cohort receiving unilateral RT (n = 44), significant improvements for IMPT could be identified in PROs including dry mouth, sticky saliva, and taste (p < 0.05). Improvements in PATs could be observed for IMPT in regards to mucositis, pain, weight loss, and fatigue, while VMAT induced less mucosal infection and dermatitis. IMPT was associated with a relative risk reduction of 22.3% for narcotic use at the end of treatment. Feeding tube dependency within 30 days of RT was significantly lower among patients treated with IMPT (19.6% versus 46.3%, OR = 0.27, 95%CI = [0.12,0.59], p = 0.001). Additionally, a significantly lower rate of acute hospitalization was observed in the IMPT-arm (OR = 0.21, 95%CI = [0.07,0.6], p = 0.009). No difference in the 1-year OS could be detected between the study-arms (VMAT 91.3% vs IMPT 92.6%, p = 0.98).
A study by Bagley et al. (2020) [79] evaluated patients (n = 69) treated for OPC with IMPT in regards to PROs for xerostomia using the Xerostomia-Related QoL Scale (XeQoLS). Greatest xerostomia-related impairment was recorded at 6 weeks on treatment, followed by a 49% improvement 10 weeks after RT. PROs improved subsequently but remained above baselines after 2 years. Late xerostomia PRO scores were correlated with the mean oral cavity dose (p = 0.038), baseline score (p = 0.001), stage (p = 0.008) and N status (p = 0.006).
The current evidence in support of PT, particularly the benefits as assessed by PROs, warrants further investigation via RCTs: The “Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck” (NCT01893307) is a non-inferiority phase II/III RCT comparing IMPT with IMRT for OPC [82]. The primary endpoint is PFS at 3 years, with secondary endpoints of PATs and PROs. The “TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)” trial is a multicenter, phase III RCT of IMRT versus IMPT for OPC [83]. The primary endpoints are PROs as physical toxicity composite score, and feeding tube dependency or severe weight loss at 12 months after treatment.
Nasopharyngeal Cancers
Nasopharyngeal cancers (NPC) are chemoradiosensitive, and, therefore, RT plays a crucial role in both the definitive and adjuvant settings. This particular region includes critical neurological structures that can be affected by the high doses of RT which can result in hearing impairment, optic neuropathy, or temporal lobe necrosis [88]. Several studies demonstrated improved target volume coverage and reduced dose to OARs with IMPT vs IMRT and helical tomotherapy [89, 90]. Studies with clinical evidence on oncological outcomes and toxicities after PT are summarized in Table 8.2.
A phase II study by Chan et al. [91] evaluated patients (n = 23) with stage III-IVB NPCs treated with PT. Prescribed dose was 70 Gy (RBE) in 35 fractions. The chemotherapy regimen consisted of 3 cycles of concurrent cisplatin (100 mg/m2) on days 1, 22, and 43 followed by adjuvant cisplatin (80 mg/m2) on day 1 and fluorouracil (1,000 mg/m2/d) on days 1 through 4 every 4 weeks for 3 cycles. Toxicity was graded with CTCAE. At a median follow-up of 28 months, none of the patients had local or regional relapse. 2-year DFS and OS were 90% and 100%. Grade 3 hearing impairment was present in 29% and weight loss in 38% of patients. 48% of patients required feeding tube placement during treatment.
Lewis et al. [92] published a study for a cohort of 10 NPC patients treated with platinum-based concurrent chemoradiation using IMPT (prescribed dose of 70 Gy (RBE) in 33 fractions) and treatment plan comparison with IMRT. Median follow-up of this study was 24.5 months (range, 19–32 months). 2-year LRC and OS were excellent with 100% and 88.9%. Acute grade 3 toxicity dermatitis (n = 4) and acute grade 3 mucositis (n = 1) were reported. No patient experienced late grade 3 or higher toxicities. The dosimetric comparisons revealed significant differences in OAR mean doses in favour for IMPT in 13 out of 29 evaluated OARs.
A 2:1 case-matched analysis with patients (n = 20) receiving IMRT for NPC found a significantly lower rate of feeding tube placement with IMPT (20% vs. 65%; p = 0.02) [93].
Beddok et al. [94] analyzed patients (n = 17) with stages III–IVa NPC, who received a definitive treatment with a combined photon and proton-boost therapy and concurrent chemotherapy. Patients with stage III and IVa were 12% and 88%. The prescribed doses were 70–78 Gy (RBE). Median follow-up was 98 months. After 2-,5- and 10-years LRC was 94%, 86% and 86% and OS 88%, 74%, and 66%. Three patients (17.6%) developed distant metastasis. Late grade 3 toxicities were observed in regards to hearing loss (n = 4, 23.5%) and osteroradionecrosis (n = 1, 5.9%). One patient died from necrosis-induced nasopharynx bleeding.
Take Home Message for Outcomes after Proton Therapy of Head and Neck Cancers
-
Skull base tumours: Proton therapy is the standard of care and allowed for dose intensification resulting in improved clinical outcomes and tolerable toxicity profiles.
-
Periorbital tumours: Proton therapy is part of orbit-sparing multidisciplinary concepts, and further studies are warranted to find optimal parameters and dose constraints for IMPT.
-
Salivaryry gland cancer: Proton therapy delivers excellent oncological outcomes and favourable toxicity profiles for unilateral radiation.
-
Oropharyngeal cancers: Competitive dose planning studies showed protons offering unique chances for dose reductions in virtually all organs-at-risk with the possibility of toxicity reduction without dose de-escalation in the target volumes. Toxicity reduction is of particular importance in HPV-positive patients with a good prognosis. Randomized phase III trials comparing IMPT with IMRT are underway.
-
Nasopharyngeal cancers: Proton therapy offered dosimetric advantages at critical neurological structures and excellent oncological outcomes.
References
Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011;12(2):127–36.
Ghosh–Laskar S, Yathiraj PH, Dutta D, Rangarajan V, Purandare N, Gupta T, et al. Prospective randomized controlled trial to compare 3‐dimensional conformal radiotherapy to intensity‐modulated radiotherapy in head and neck squamous cell carcinoma: long‐term results. Head & Neck. 2016;38(S1).
Marta GN, Silva V, de Andrade CH, de Arruda FF, Hanna SA, Gadia R, et al. Intensity-modulated radiation therapy for head and neck cancer: systematic review and meta-analysis. Radiother Oncol. 2014;110(1):9–15.
Gupta T, Agarwal J, Jain S, Phurailatpam R, Kannan S, Ghosh-Laskar S, et al. Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol. 2012;104(3):343–8.
Nutting C, Rooney K, Foran B, Pettit L, Beasley M, Finneran L, et al. Results of a randomized phase III study of dysphagia-optimized intensity modulated radiotherapy (Do-IMRT) versus standard IMRT (S-IMRT) in head and neck cancer. JCO. 2020;38(15_suppl):6508.
Gulliford SL, Miah AB, Brennan S, McQuaid D, Clark CH, Partridge M, et al. Dosimetric explanations of fatigue in head and neck radiotherapy: an analysis from the PARSPORT Phase III trial. Radiother Oncol. 2012;104(2):205–12.
Moreno AC, Frank SJ, Garden AS, Rosenthal DI, Fuller CD, Gunn GB, et al. Intensity modulated proton therapy (IMPT)—The future of IMRT for head and neck cancer. Oral Oncol. 2019;1(88):66–74.
Kandula S, Zhu X, Garden AS, Gillin M, Rosenthal DI, Ang KK, et al. Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. Med Dosim. 2013;38(4):390–4.
Holliday EB, Kocak-Uzel E, Feng L, Thaker NG, Blanchard P, Rosenthal DI, et al. Dosimetric advantages of intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: a case-matched control analysis. Med Dosim. 2016;41(3):189–94.
Apinorasethkul O, Kirk M, Teo K, Swisher-McClure S, Lukens JN, Lin A. Pencil beam scanning proton therapy vs rotational arc radiation therapy: a treatment planning comparison for postoperative oropharyngeal cancer. Med Dosim. 2017 Spring;42(1):7–11.
Eekers DBP, Roelofs E, Jelen U, Kirk M, Granzier M, Ammazzalorso F, et al. Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial. Radiother Oncol. 2016;121(3):387–94.
Blanchard P, Gunn GB, Lin A, Foote RL, Lee NY, Frank SJ. Proton therapy for head and neck cancers. Semin Radiat Oncol. 2018;28(1):53–63.
Schneider U, Pedroni E, Lomax A. The calibration of CT hounsfield units for radiotherapy treatment planning. Phys Med Biol. 1996;41(1):111–24.
Schaffner B, Pedroni E. The precision of proton range calculations in proton radiotherapy treatment planning: experimental verification of the relation between CT-HU and proton stopping power. Phys Med Biol. 1998;43(6):1579–92.
Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 2: the potential effects of inter-fraction and inter-field motions. Phys Med Biol. 2008;53(4):1043–56.
Chen W, Unkelbach J, Trofimov A, Madden T, Kooy H, Bortfeld T, et al. Including robustness in multi-criteria optimization for intensity-modulated proton therapy. Phys Med Biol. 2012;57(3):591–608.
Liu W, Zhang X, Li Y, Mohan R. Robust optimization of intensity modulated proton therapy. Med Phys. 2012;39(2):1079–91.
Unkelbach J, Paganetti H. Robust proton treatment planning: physical and biological optimization. Semin Radiat Oncol. 2018;28(2):88–96.
Peeler CR, Mirkovic D, Titt U, Blanchard P, Gunther JR, Mahajan A, et al. Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma. Radiother Oncol. 2016;121(3):395–401.
Beddok A, Vela A, Calugaru V, Tessonnier T, Kubes J, Dutheil P, et al. Proton therapy for head and neck squamous cell carcinomas: a review of the physical and clinical challenges. Radiother Oncol. 2020;1(147):30–9.
Lievens Y, Pijls-Johannesma M. Health economic controversy and cost-effectiveness of proton therapy. Semin Radiat Oncol. 2013;23(2):134–41.
Trott KR, Doerr W, Facoetti A, Hopewell J, Langendijk J, van Luijk P, et al. Biological mechanisms of normal tissue damage: Importance for the design of NTCP models. Radiother Oncol. 2012;105(1):79–85.
Common Terminology Criteria for Adverse Events (CTCAE)|Protocol Development | CTEP [Internet]. [cited 2022 May 14]. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.
Singer S, Amdal CD, Hammerlid E, Tomaszewska IM, Castro Silva J, Mehanna H, et al. International validation of the revised European Organisation for Research and Treatment of Cancer Head and Neck Cancer Module, the EORTC QLQ-HN43: Phase IV. Head Neck. 2019;41(6):1725–37.
Dijkema T, Raaijmakers CPJ, Ten Haken RK, Roesink JM, Braam PM, Houweling AC, et al. Parotid gland function after radiotherapy: the combined michigan and utrecht experience. Int J Radiat Oncol *Biology*Phys. 2010;78(2):449–53.
Christianen MEMC, Schilstra C, Beetz I, Muijs CT, Chouvalova O, Burlage FR, et al. Predictive modelling for swallowing dysfunction after primary (chemo)radiation: results of a prospective observational study. Radiother Oncol. 2012;105(1):107–14.
Bentzen SM, Constine LS, Deasy JO, Eisbruch A, Jackson A, Marks LB, et al. Quantitative analyses of normal tissue effects in the clinic (QUANTEC): an introduction to the scientific issues. Int J Radiat Oncol *Biology*Phys. 2010;76(3, Supplement):S3–9.
Houweling AC, Philippens MEP, Dijkema T, Roesink JM, Terhaard CHJ, Schilstra C, et al. A comparison of dose–response models for the parotid gland in a large group of head-and-neck cancer patients. Int J Radiat Oncol *Biology*Phys. 2010;76(4):1259–65.
Beetz I, Schilstra C, van der Schaaf A, van den Heuvel ER, Doornaert P, van Luijk P, et al. NTCP models for patient-rated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: the role of dosimetric and clinical factors. Radiother Oncol. 2012;105(1):101–6.
Deasy JO, Moiseenko V, Marks L, Chao KSC, Nam J, Eisbruch A. Radiotherapy dose–volume effects on salivary gland function. Int J Radiat Oncol *Biology*Phys. 2010;76(3, Supplement):S58–63.
Dale T, Hutcheson K, Mohamed AS, Lewin JS, Gunn GB, Rao AU, et al. Beyond mean pharyngeal constrictor dose for beam path toxicity in non-target swallowing muscles: dose–volume correlates of chronic radiation-associated dysphagia (RAD) after oropharyngeal intensity modulated radiotherapy. Radiother Oncol. 2016;118(2):304–14.
Wopken K, Bijl HP, van der Schaaf A, van der Laan HP, Chouvalova O, Steenbakkers RJHM, et al. Development of a multivariable normal tissue complication probability (NTCP) model for tube feeding dependence after curative radiotherapy/chemo-radiotherapy in head and neck cancer. Radiother Oncol. 2014;113(1):95–101.
Bhide SA, Gulliford S, Schick U, Miah A, Zaidi S, Newbold K, et al. Dose–response analysis of acute oral mucositis and pharyngeal dysphagia in patients receiving induction chemotherapy followed by concomitant chemo-IMRT for head and neck cancer. Radiother Oncol. 2012;103(1):88–91.
Boomsma MJ, Bijl HP, Christianen MEMC, Beetz I, Chouvalova O, Steenbakkers RJHM, et al. A prospective cohort study on radiation-induced hypothyroidism: development of an NTCP model. Int J Radiat Oncol *Biology*Phys. 2012;84(3):e351–6.
Rancati T, Fiorino C, Sanguineti G. NTCP modeling of subacute/late laryngeal edema scored by fiberoptic examination. Int J Radiat Oncol *Biology*Phys. 2009;75(3):915–23.
Kocak-Uzel E, Gunn GB, Colen RR, Kantor ME, Mohamed ASR, Schoultz-Henley S, et al. Beam path toxicity in candidate organs-at-risk: assessment of radiation emetogenesis for patients receiving head and neck intensity modulated radiotherapy. Radiother Oncol. 2014;111(2):281–8.
Blanchard P, Wong AJ, Gunn GB, Garden AS, Mohamed ASR, Rosenthal DI, et al. Toward a model-based patient selection strategy for proton therapy: external validation of photon-derived normal tissue complication probability models in a head and neck proton therapy cohort. Radiother Oncol. 2016;121(3):381–6.
Langendijk JA, Boersma LJ, Rasch CRN, van Vulpen M, Reitsma JB, van der Schaaf A, et al. Clinical trial strategies to compare protons with photons. Semin Radiat Oncol. 2018;28(2):79–87.
Tambas M, Steenbakkers RJHM, van der Laan HP, Wolters AM, Kierkels RGJ, Scandurra D, et al. First experience with model-based selection of head and neck cancer patients for proton therapy. Radiother Oncol. 2020;1(151):206–13.
Widder J, van der Schaaf A, Lambin P, Marijnen CAM, Pignol JP, Rasch CR, et al. The quest for evidence for proton therapy: model-based approach and precision medicine. Int J Radiat Oncol *Biology*Phys. 2016;95(1):30–6.
Stiller CA, Trama A, Serraino D, Rossi S, Navarro C, Chirlaque MD, et al. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project. Eur J Cancer. 2013;49(3):684–95.
Kamrin RP, Potanos TLJN, Pool JL. An evaluation of the diagnosis and treatment of chordoma. J Neurol Neurosurg Psychiatry. 1964;27(2):157–65.
Volpe NJ, Liebsch NJ, Munzenrider JE, Lesseil S. Neuro-ophthalmologic findings in chordoma and chondrosarcoma of the skull base. Am J Ophthalmol. 1993;115(1):97–104.
Pamir MN, Kiliç T, Türe U, Ozek MM. Multimodality management of 26 skull-base chordomas with 4-year mean follow-up: experience at a single institution. Acta Neurochir (Wien). 2004;146(4):343–54; discusion 354.
Rich TA, Schiller A, Suit HD, Mankin HJ. Clinical and pathologic review of 48 cases of chordoma. Cancer. 1985;56(1):182–7.
Forsyth PA, Cascino TL, Shaw EG, Scheithauer BW, O’Fallon JR, Dozier JC, et al. Intracranial chordomas: a clinicopathological and prognostic study of 51 cases. J Neurosurg. 1993;78(5):741–7.
Debus J, Schulz-Ertner D, Schad L, Essig M, Rhein B, Thillmann CO, et al. Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol *Biology*Phys. 2000;47(3):591–6.
Noël G, Feuvret L, Dhermain F, Mammar H, Haie-Méder C, Ponvert D, et al. [Chordomas of the base of the skull and upper cervical spine. 100 patients irradiated by a 3D conformal technique combining photon and proton beams]. Cancer Radiother. 2005;9(3):161–74.
Igaki H, Tokuuye K, Okumura T, Sugahara S, Kagei K, Hata M, et al. Clinical results of proton beam therapy for skull base chordoma. Int J Radiat Oncol *Biology*Phys. 2004;60(4):1120–6.
Ares C, Hug EB, Lomax AJ, Bolsi A, Timmermann B, Rutz HP, et al. Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol *Biology*Phys. 2009;75(4):1111–8.
Weber DC, Malyapa R, Albertini F, Bolsi A, Kliebsch U, Walser M, et al. Long term outcomes of patients with skull-base low-grade chondrosarcoma and chordoma patients treated with pencil beam scanning proton therapy. Radiother Oncol. 2016;120(1):169–74.
Demizu Y, Mizumoto M, Onoe T, Nakamura N, Kikuchi Y, Shibata T, et al. Proton beam therapy for bone sarcomas of the skull base and spine: a retrospective nationwide multicenter study in Japan. Cancer Sci. 2017;108(5):972–7.
Hug EB, Loredo LN, Slater JD, Devries A, Grove RI, Schaefer RA, et al. Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg. 1999;91(3):432–9.
Deraniyagala RL, Yeung D, Mendenhall WM, Li Z, Morris CG, Mendenhall NP, et al. Proton therapy for skull base chordomas: an outcome study from the university of Florida proton therapy institute. J Neurol Surg B Skull Base. 2014;75(1):53–7.
Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull base. Strahlenther Onkol. 1999;175(2):57–63.
Grosshans DR, Zhu XR, Melancon A, Allen PK, Poenisch F, Palmer M, et al. Spot scanning proton therapy for malignancies of the base of skull: treatment planning, acute toxicities, and preliminary clinical outcomes. Int J Radiat Oncol *Biology*Phys. 2014;90(3):540–6.
Feuvret L, Bracci S, Calugaru V, Bolle S, Mammar H, De Marzi L, et al. Efficacy and safety of adjuvant proton therapy combined with surgery for chondrosarcoma of the skull base: a retrospective, population-based study. Int J Radiat Oncol *Biology*Phys. 2016;95(1):312–21.
McDonald MW, Linton OR, Moore MG, Ting JY, Cohen-Gadol AA, Shah MV. Influence of residual tumor volume and radiation dose coverage in outcomes for clival chordoma. Int J Radiat Oncol *Biology*Phys. 2016;95(1):304–11.
Morimoto K, Demizu Y, Hashimoto N, Mima M, Terashima K, Fujii O, et al. Particle radiotherapy using protons or carbon ions for unresectable locally advanced head and neck cancers with skull base invasion. Jpn J Clin Oncol. 2014;44(5):428–34.
Miyawaki D, Murakami M, Demizu Y, Sasaki R, Niwa Y, Terashima K, et al. Brain injury after proton therapy or carbon ion therapy for head-and-neck cancer and skull base tumors. Int J Radiat Oncol Biol Phys. 2009;75(2):378–84.
Youlden DR, Cramb SM, Peters S, Porceddu SV, Møller H, Fritschi L, et al. International comparisons of the incidence and mortality of sinonasal cancer. Cancer Epidemiol. 2013;37(6):770–9.
Franchi A, Miligi L, Palomba A, Giovannetti L, Santucci M. Sinonasal carcinomas: recent advances in molecular and phenotypic characterization and their clinical implications. Crit Rev Oncol Hematol. 2011;79(3):265–77.
Binazzi A, Ferrante P, Marinaccio A. Occupational exposure and sinonasal cancer: a systematic review and meta-analysis. BMC Cancer. 2015;15(1):49.
Rushton L, Hutchings SJ, Fortunato L, Young C, Evans GS, Brown T, et al. Occupational cancer burden in Great Britain. Br J Cancer. 2012;107(Suppl 1):S3–7.
Patel SH, Wang Z, Wong WW, Murad MH, Buckey CR, Mohammed K, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 2014;15(9):1027–38.
Resto VA, Chan AW, Deschler DG, Lin DT. Extent of surgery in the management of locally advanced sinonasal malignancies. Head Neck. 2008;30(2):222–9.
Lewis L, Kreinbrink P, Richardson M, Westerfield M, Doberstein M, Zhang Y, et al. Intensity modulated proton therapy better spares non-adjacent organs and reduces the risk of secondary malignant neoplasms in the treatment of sinonasal cancers. Med Dosim. 2022;47(2):117–22.
Pasalic D, Ludmir EB, Allen PK, Thaker NG, Chapman BV, Hanna EY, et al. Patient-reported outcomes, physician-reported toxicities, and treatment outcomes in a modern cohort of patients with sinonasal cancer treated using proton beam therapy. Radiother Oncol. 2020;1(148):258–66.
Holliday EB, Esmaeli B, Pinckard J, Garden AS, Rosenthal DI, Morrison WH, et al. A Multidisciplinary orbit-sparing treatment approach that includes proton therapy for epithelial tumors of the orbit and ocular adnexa. Int J Radiat Oncol *Biology*Phys. 2016;95(1):344–52.
El-Sawy T, Frank SJ, Hanna E, Sniegowski M, Lai SY, Nasser QJ, et al. Multidisciplinary management of lacrimal sac/nasolacrimal duct carcinomas. Ophthal Plast Reconstr Surg. 2013;29(6): https://doi.org/10.1097/IOP.0b013e31829f3a73.
Damico NJ, Wu AK, Kharouta MZ, Eitan T, Pidikiti R, Jesseph FB, et al. Proton beam therapy in the treatment of periorbital malignancies. Int J Particle Ther. 2021;7(4):42–51.
Assessment UENC for E. Cancer incidence in five continents: Volume VIII [Internet]. 2009 [cited 2022 May 16]. Available from: https://hero.epa.gov/hero/index.cfm/reference/details/reference_id/729990.
Bhattasali O, Holliday E, Kies MS, Hanna EY, Garden AS, Rosenthal DI, et al. Definitive proton radiation therapy and concurrent cisplatin for unresectable head and neck adenoid cystic carcinoma: a series of 9 cases and a critical review of the literature. Head Neck. 2016;38(S1):E1472–80.
Romesser PB, Cahlon O, Scher E, Zhou Y, Berry SL, Rybkin A, et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiother Oncol. 2016;118(2):286–92.
Zakeri K, Wang H, Kang JJ, Lee A, Romesser P, Mohamed N, et al. Outcomes and prognostic factors of major salivary gland tumors treated with proton beam radiation therapy. Head Neck. 2021;43(4):1056–62.
Leeman JE, Romesser PB, Zhou Y, McBride S, Riaz N, Sherman E, et al. Proton therapy for head and neck cancer: expanding the therapeutic window. Lancet Oncol. 2017;18(5):e254–65.
Blanchard P, Garden AS, Gunn GB, Rosenthal DI, Morrison WH, Hernandez M, et al. Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer—a case matched analysis. Radiother Oncol. 2016;120(1):48–55.
Manzar GS, Lester SC, Routman DM, Harmsen WS, Petersen MM, Sloan JA, et al. Comparative analysis of acute toxicities and patient reported outcomes between intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) for the treatment of oropharyngeal cancer. Radiother Oncol. 2020;1(147):64–74.
Bagley AF, Ye R, Garden AS, Gunn GB, Rosenthal DI, Fuller CD, et al. Xerostomia-related quality of life for patients with oropharyngeal carcinoma treated with proton therapy. Radiother Oncol. 2020;1(142):133–9.
Sharma S, Zhou O, Thompson R, Gabriel P, Chalian A, Rassekh C, et al. Quality of life of postoperative photon versus proton radiation therapy for oropharynx cancer. Int J Particle Ther. 2018;5(2):11–7.
Sio TT, Lin HK, Shi Q, Gunn GB, Cleeland CS, Lee JJ, et al. Intensity modulated proton therapy versus intensity modulated photon radiation therapy for oropharyngeal cancer: first comparative results of patient-reported outcomes. Int J Radiat Oncol *Biology*Phys. 2016;95(4):1107–14.
Frank SJ, Blanchard P, Lee JJ, Sturgis EM, Kies MS, Machtay M, et al. Comparing intensity-modulated proton therapy with intensity-modulated photon therapy for oropharyngeal cancer: the journey from clinical trial concept to activation. Semin Radiat Oncol. 2018;28(2):108–13.
Price J, Hall E, West C, Thomson D. TORPEdO—a phase III Trial of Intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer. Clin Oncol. 2020;32(2):84–8.
Slater JD, Yonemoto LT, Mantik DW, Bush DA, Preston W, Grove RI, et al. Proton radiation for treatment of cancer of the oropharynx: Early experience at Loma Linda University Medical Center using a concomitant boost technique. Int J Radiat Oncol *Biology*Phys. 2005;62(2):494–500.
Gunn GB, Blanchard P, Garden AS, Zhu XR, Fuller CD, Mohamed AS, et al. Clinical outcomes and patterns of disease recurrence after intensity modulated proton therapy for oropharyngeal squamous carcinoma. Int J Radiat Oncol *Biology*Phys. 2016;95(1):360–7.
Takayama K, Nakamura T, Takada A, Makita C, Suzuki M, Azami Y, et al. Treatment results of alternating chemoradiotherapy followed by proton beam therapy boost combined with intra-arterial infusion chemotherapy for stage III–IVB tongue cancer. J Cancer Res Clin Oncol. 2016;142(3):659–67.
Meijer TWH, Scandurra D, Langendijk JA. Reduced radiation-induced toxicity by using proton therapy for the treatment of oropharyngeal cancer. BJR. 2020;93(1107):20190955.
Holliday EB, Frank SJ. Proton therapy for nasopharyngeal carcinoma. Chin Clin Oncol. 2016;5(2):25.
Taheri-Kadkhoda Z, Björk-Eriksson T, Nill S, Wilkens JJ, Oelfke U, Johansson KA, et al. Intensity-modulated radiotherapy of nasopharyngeal carcinoma: a comparative treatment planning study of photons and protons. Radiat Oncol. 2008;3(1):4.
Widesott L, Pierelli A, Fiorino C, Dell’Oca I, Broggi S, Cattaneo GM, et al. Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation. Int J Radiat Oncol *Biology*Phys. 2008;72(2):589–96.
Chan A, Adams JA, Weyman E, Parambi R, Goldsmith T, Holman A, et al. A phase II trial of proton radiation therapy with chemotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2012;84(3):S151–2.
Lewis GD, Holliday EB, Kocak-Uzel E, Hernandez M, Garden AS, Rosenthal DI, et al. Intensity-modulated proton therapy for nasopharyngeal carcinoma: decreased radiation dose to normal structures and encouraging clinical outcomes. Head Neck. 2016;38(S1):E1886–95.
Holliday EB, Garden AS, Rosenthal DI, Fuller CD, Morrison WH, Gunn GB, et al. Proton therapy reduces treatment-related toxicities for patients with nasopharyngeal cancer: a case-match control study of intensity-modulated proton therapy and intensity-modulated photon therapy. Int J Particle Ther. 2015;2(1):19–28.
Beddok A, Feuvret L, Noel G, Bolle S, Deberne M, Mammar H, et al. Efficacy and toxicity of proton with photon radiation for locally advanced nasopharyngeal carcinoma. Acta Oncol. 2019;58(4):472–4.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Copyright information
© 2023 The Author(s)
About this paper
Cite this paper
Budach, V., Thieme, A. (2023). Proton Therapy for Head and Neck Cancer. In: Vermorken, J.B., Budach, V., Leemans, C.R., Machiels, JP., Nicolai, P., O'Sullivan, B. (eds) Critical Issues in Head and Neck Oncology. Springer, Cham. https://doi.org/10.1007/978-3-031-23175-9_8
Download citation
DOI: https://doi.org/10.1007/978-3-031-23175-9_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-23174-2
Online ISBN: 978-3-031-23175-9
eBook Packages: MedicineMedicine (R0)