Photon vs. proton radiation therapy in head and neck cancer: a review of dosimetric advantages and patient quality of life
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Abstract
Radiotherapy (RT) is a cornerstone in the management of head and neck cancer (HNC), with the choice of RT type profoundly affecting patient outcomes, symptom severity, and quality of life (QoL). This review examines photon and proton RT types for HNC, focusing on dosimetric advantages, efficacy, and side effect profiles. Understanding these factors is crucial to minimizing adverse effects, enhancing QoL for patients, and effectively improving oncology’s clinical praxis. While photon-based therapies, such as intensity-modulated radiation therapy and volumetric modulated arc therapy, are widely used and effective, proton therapy, including intensity-modulated proton therapy (IMPT) and pencil beam scanning (PBS), offers distinct physical advantages. Photon therapies allow for precise dose distribution but often result in higher integral doses to surrounding healthy tissues. In contrast, protons enable highly conformal dose distributions with minimal exit dose beyond the target, a property that significantly reduces radiation exposure to organs at risk. Background research and comparative analysis demonstrate that proton therapy techniques, particularly IMPT and PBS, outperform photon-based methods in sparing critical structures and thus reducing acute and late treatment-related morbidities, such as xerostomia and dysphagia. As a consequence, patient-reported outcome measures and the overall QoL results suggest that proton therapies lead to better treatment results with fewer severe side effects and improved symptom management. In conclusion, proton therapy, particularly IMPT, shows promise as a treatment of choice for HNC, minimizing toxicities and enhancing QoL. However, continued research and evidence-based approaches are still essential to properly validate and refine proton therapy applications in HNC treatment paradigms and also effectively translate them into future clinical practice.
Keywords
INTRODUCTION
Epidemiology and significance of HNC
Head and neck cancer (HNC) represents a critical and growing challenge in global oncology. With over 600,000 new cases diagnosed annually and more than 300,000 deaths, HNC stands as the seventh most common cancer worldwide[1-3]. This alarming prevalence is driven by an aging population and the persistent adoption of high-risk behaviors particularly in developing regions[2,3]. As a result, the burden of HNC is expected to rise substantially in the coming decades. Characterized by malignancies arising from squamous cells in the mucosal linings of the head and neck, HNC encompasses cancers of the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity, and salivary glands. Laryngeal cancer remains the most frequently diagnosed among these[4]. The etiological landscape of HNC is dominated by prolonged tobacco use, alcohol abuse, and high-risk human papillomavirus infections[5-7].
Current treatment landscape and challenges
To address the growing burden of the disease and its associated challenges, significant advances in treatment approaches have contributed to a decline in cancer-related mortality, leading to an increasing population of HNC survivors[8]. This decline is largely attributed to the advancements in various treatment modalities, including surgery, chemotherapy, and particularly, radiotherapy[5].
Radiotherapy (RT) has been a cornerstone in the treatment of HNC, evolving significantly over the years to improve precision and minimize adverse effects. Traditional photon therapy, which has long been a standard approach, has seen significant advancements with the development of more sophisticated techniques such as intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). More recently, proton therapy has emerged as a promising alternative, offering potential benefits in reducing the collateral damage to surrounding healthy tissues[9].
The treatment of HNC is inherently complex, often necessitating a multidisciplinary approach tailored to the specific characteristics of the tumor. Radiotherapy, whether through photons or protons, plays a pivotal role in this regimen. Both types of RT aim to maximize tumor control while sparing healthy tissues as much as possible. However, this goal is particularly challenging in the head and neck region due to the concentration of critical structures - such as the salivary glands, oral mucosa, pharyngeal muscles, larynx, spinal cord, and optic pathways - that are highly sensitive to radiation[9]. Even low doses to these organs can result in debilitating side effects, including xerostomia, dysphagia, and oral mucositis, which profoundly affect speech, swallowing, and overall quality of life (QoL)[10]. After all, the acute and long-term side effects associated with RT can profoundly affect patients’ daily lives[3,11,12]. Additionally, excessive radiation exposure to adjacent healthy tissues may increase the risk of long-term complications such as fibrosis, vascular damage, or secondary malignancies, emphasizing the importance of minimizing dose spillover[13]. Precision in radiation delivery is crucial not only for protecting these sensitive structures but also for achieving an optimal therapeutic ratio, where the dose to the tumor is maximized without exceeding the tolerance of normal tissues. As advances in radiotherapy continue, there is a growing focus on the clinical benefits and dosimetric precision provided by both proton and photon radiation therapy.
Clinical benefits and dosimetric precision of proton vs. photon radiation therapy
Proton therapy, with its unique ability to deliver targeted doses through the Bragg peak phenomenon, enhances the therapeutic ratio by reducing collateral dose to healthy tissues, thereby lowering the probability of both acute and chronic toxicities[14]. Furthermore, precise dosimetry is essential for overcoming challenges such as tumor hypoxia and anatomical changes during treatment, which can affect the tumor's response to radiation[15]. By reducing the dose to organs at risk (OARs), proton therapy also mitigates the risk of radiosensitization, where sublethal damage to healthy tissues increases their vulnerability to subsequent radiation exposure or other therapies[16].
Photon-based therapies, despite their efficacy, often involve a higher volume of healthy tissue being exposed to low-dose radiation, which can lead to increased acute radiation responses. These include mucositis, radioepidermitis, lymphocytopenia, and other side effects that impair patients’ well-being and recovery[3,11]. This exposure is particularly challenging as it can inhibit lymphocyte proliferation and function, leading to a spectrum of toxicities that affect patients' overall health and quality of life during and after treatment[3,11]. Speech, swallowing, and breathing capabilities are commonly harmed in HNC patients undergoing radical treatments[9]. Among these, oral mucositis is a painful disorder characterized by ulcers in the mouth, arising from the rapidly dividing cells in the oral cavity, which are especially vulnerable to irradiation damage[17]. Additionally, radiation-induced mucositis is a significant source of pain and consequently reduces QoL[9]. Another debilitating side effect commonly experienced by HNC patients is radiation-induced xerostomia, or dry mouth, which also severely impacts their quality of life[18].
Proton therapy, in contrast, offers a distinct dosimetric advantage due to its physical properties, particularly the Bragg peak phenomenon, which refers to the sharp increase in energy deposition by protons at a specific depth in tissue, allowing for highly localized dose delivery with minimal exit dose beyond the target. This property reduces radiation exposure to surrounding healthy tissues and minimizes side effects[9,19]. Despite its theoretical superiority, the relative biological effectiveness (RBE) - a measure of the biological damage caused by a given type of radiation - of protons compared to photons is an area of active research. While the RBE for protons is typically considered to be 1.1, indicating that protons are slightly more effective than photons in causing biological damage, this value can vary near the Bragg peak, complicating exact dosimetric comparisons[6,7]. To better understand how these dosimetric advantages influence treatment strategies, it is essential to consider their direct implications on treatment decisions and outcomes.
Implications for treatment decisions in HNC
The selection of the appropriate RT type is a critical decision in the treatment of HNC due to its profound impact on patient outcomes, including the severity of symptoms, the correlation of symptoms with dosimetric values, and related toxicity and overall QoL[20]. While proton therapy has shown promise in reducing severe radiation-induced complications and potentially lowering rehabilitation costs, photon-based therapies remain widely used and effective. This review aims to conduct an extensive examination of the various RT types available for HNC, with a particular focus on comparing their dosimetric advantages, efficacy, and side effect profiles. Understanding these factors seems crucial, as the ultimate goal of any therapy is not only to treat cancer but also to minimize adverse effects and enhance the QoL for patients. By evaluating the correlation between different RT types and their impact on patient symptoms and QoL, we seek to address a fundamental question in oncology: how can we optimize treatment to ensure that the benefits of cancer control are not overshadowed by the burden of treatment-related side effects? This inquiry is vital in advancing patient-centered care and guiding future therapeutic choices in the management of HNC.
ASSESSING PATIENTS QUALITY OF LIFE
Investigating patients' subjective experiences and symptoms in prospective clinical comparative effectiveness research (CER) for process interventions or oncology treatments is crucial for guiding decision-making procedures[21]. Background research regarding the assessment of QoL in HNC patients indicates that the use of EORTC QLQ-C30 and QLQ-HN35 questionnaires constitutes the gold standard for that assessment. These standardized tools facilitate comprehensive evaluations at various treatment time points, capturing both global QoL (via QLQ-C30) and specific treatment-related side effects such as local pain, xerostomia, swallowing difficulties, sticky saliva, and weight loss (via QLQ-HN35). The majority of studies employ these tools pre-treatment, post-treatment, and in extended follow-up periods, offering a longitudinal perspective on patients' well-being throughout their cancer journey[22-24]. A number of published researches, apart from the QLQ-C30 and QLQ-HN35, provided insights into patient-reported outcomes, and augmented their assessments with additional tools in order to capture further aspects of patient experiences. These supplementary methods included resilience scales, symptom inventories, and functional impairment indices, enhancing the multidimensional understanding of how HNC and its treatments impact patients’ QoL[25,26]. However, due to the diversity of assessment tools, variability in data presentation across the studies hinders direct quantitative comparisons, emphasizing the need for standardized reporting practices in future research endeavors to enable more precise comparisons across studies.
According to literature, researchers evaluating radiation therapy for head and neck cancers have also utilized additional methods to assess patient’s QoL. These include the MD Anderson symptom inventory for head and neck cancer (MDASI-HN), which evaluates symptom severity such as pain, fatigue, and emotional distress[27-29]. For specifically evaluating swallowing-related QoL, the MD Anderson Dysphagia Inventory (MDADI) assesses functional and emotional aspects associated with dysphagia. This method includes items focused on swallowing difficulty, eating duration, fear of choking, and the broader impact of swallowing issues on daily activities. On the other hand, patient-reported outcome measures have also been used to capture self-reported data on health status, symptoms, and overall well-being[30]. Many studies have used visual analog scales alongside other questionnaires that enable patients to rate specific aspects of their health or symptoms on a continuous scale[31,32]. Additionally, Performance Status Scales like the Karnofsky Performance Status Scale and ECOG Performance Status gauge functional abilities and their influence on QoL[33,34].
Participant demographics varied widely across studies, with sample sizes ranging from 30 to 1,083 individuals. The predominant inclusion of smaller cohorts (21 out of 24 studies with fewer than 200 participants) underscores the logistical challenges in conducting large-scale QoL studies in this patient population. Nevertheless, studies by Liao et al., Van den Bosch et al., and van der Laan et al. represented significant outliers with larger participant cohorts, offering valuable insights into QoL variations across diverse patient demographics and treatment modalities[23,24,35].
The findings underscore consistent trends in QoL trajectories: initial decline during the active treatment phase followed by gradual improvement post-treatment[20]. This pattern was evident across various treatment techniques, including radiotherapy (IMRT, VMAT), surgical interventions, and combinations thereof. Notably, studies by Cengiz et al. and Lu et al. highlighted sustained or improved QoL outcomes even in long-term follow-ups up to 24 years, indicating resilience and adaptation among certain patient groups[36,37].
It is important to mention that throughout background research, the challenges associated with data uniformity and statistical comparability remain the critical existing limitations. Standardizing data collection methodologies and implementing new assessment tools could mitigate these challenges, ultimately fostering a more nuanced understanding of treatment impacts on QoL in HNC patients. Moving forward, efforts to enhance methodological rigor and broaden the scope of QoL assessment tools will be crucial in refining patient-centered care strategies and improving outcomes in this vulnerable population.
THE IMPORTANCE OF RADIATION THERAPY TYPE SELECTION
HNC includes a range of diverse diseases that arise from the mucosal surfaces of the oral cavity, pharynx, and larynx. Recent advances in both molecular and clinical research highlight the variability observed across different subsites within the head and neck region[38]. The high heterogeneity and molecular complexity underscore the need for targeted therapies that offer precise dose distribution and sparing of surrounding healthy tissues, such as the parotid glands, the oral cavity, and the pharyngeal constrictors, which are highly radiosensitive. The type of irradiation, whether photon or proton therapy, significantly influences dose distribution, making the selection of appropriate radiation treatment type crucial[39]. Thus, a comprehensive analysis of the dosimetric profiles of each RT type is essential. Furthermore, in the case of HNC RT, it is important to acknowledge that significant changes in patient anatomy, such as weight loss and tumor shrinkage, can alter the depth of the target and the position of OARs, thus impacting the accuracy of dose distribution. This constitutes another important factor in the adequate selection of treatment. However, the effectiveness of this analysis should focus not only on the radiobiological cancer destruction and patient’s treatment but also on the therapeutic effects, including symptoms, dosimetric toxicities to OARs, and eventual impacts on patients’ QoL, as previously stated.
In terms of RT, IMRT and VMAT are advanced photon-based radiation techniques widely used in the treatment of HNC. These methods enable the delivery of precise radiation doses with steep dose gradients, significantly enhancing the sparing of surrounding healthy tissues compared to traditional 3D conformal radiotherapy[40,41]. This precision significantly reduces treatment-related toxicity and potentially improves patients’ QoL. More precisely, IMRT utilizes multiple static beams with varying intensities, while VMAT delivers radiation through continuous arcs, adjusting the dose rate and gantry speed dynamically. Both techniques allow for more tailored dose distributions, effectively targeting tumors while minimizing exposure to critical structures such as the salivary glands, spinal cord, and brainstem[42]. On the other hand, Proton radiation therapy offers distinct physical advantages over photon therapy due to the Bragg peak phenomenon, which allows protons to deposit their maximum energy directly within the tumor with minimal exit dose, further enhancing the protection of adjacent normal tissues[43]. In HNC, this precise dose distribution is particularly beneficial, potentially reducing long-term side effects and improving functional outcomes for patients[44]. For a more comprehensive understanding of the effects of these advanced techniques on dose distribution, QoL, and symptom severity, a detailed comparison between IMRT, VMAT, and proton therapy would be beneficial. This analysis will illuminate the distinct advantages and potential drawbacks of each treatment approach, especially regarding their influence on patient outcomes.
Comparing intensity-modulated photon radiotherapy and intensity-modulated proton therapy
Both techniques represent two sophisticated approaches that achieve maximizing tumor control while minimizing exposure to surrounding healthy tissues. The primary advantage of IMRT is its ability to deliver high radiation doses to complex tumor geometries while sparing adjacent normal tissues. However, photons, due to their physical properties, deposit energy along their entire path in the biological matter, leading to a higher integral dose to non-target healthy tissues. Contrary to that, IMPT uses protons, which have distinct physical advantages. Protons possess a finite range in tissue, culminating in the Bragg peak - a sharp increase in dose deposition just before they stop. This enables highly conformal dose distributions with simultaneous minimal exit dose, reducing radiation exposure to the surrounding healthy tissues. Therefore, this superior dose distribution of IMPT holds a potential role in reducing treatment-related dosimetric toxicities and, therefore, improving patient outcomes and QoL.
Dosimetric characteristics
Dosimetric studies have highlighted the benefits of IMPT in sparing normal tissues[45]. Research indicates that IMPT can significantly reduce doses to critical structures of normal tissue such as the parotid glands, the contralateral submandibular, the spinal cord, the oral cavity, and the brainstem[46]. Grant et al. and
Figure 1. (A) Axial and (B) sagittal images of the dosimetric distribution in IMPT and IMRT, for a patient with oropharyngeal cancer (OPC) after radiation therapy treatment planning. No copyright This work has been identified as being free of known restrictions under copyright law, including all related and neighboring rights. Copyright 2016, Reproduced from Ref.[50].
A comparative dosimetric analysis for OPC patients treated with IMPT showed substantial reductions in mean doses to the hard palate, the mandible, the anterior and posterior oral cavity, the larynx, and the esophagus[49]. Furthermore, the same study proved that lower doses in central nervous system structures led to a decrease in symptoms such as vomiting and nausea[49]. These findings underscored the dosimetric superiority of IMPT over IMRT in sparing healthy tissue from extra radiation exposure[46]. Moreover, recent advancements have underscored the critical role of IMPT in re-irradiation for HNC patients, a group often facing complex cumulative dose challenges. Studies indicate that IMPT’s precision can mitigate risks associated with overlapping radiation fields, particularly in OARs[51]. This capability is essential in reducing complications such as carotid blowout syndrome and osteoradionecrosis, which are directly linked to excessive cumulative doses to the carotid arteries and bone structures, respectively, as Embring et al. observed[51]. For instance, cumulative dose constraints for carotid arteries have been established at approximately 120 Gy to prevent catastrophic vascular events, emphasizing the importance of sparing strategies achievable with proton therapy[52]. Moreover, IMPT demonstrates enhanced control in composite dose-volume histograms, allowing tailored re-irradiation plans that prioritize tumor control while minimizing severe late toxicities[53]. However, it is important to mention that despite the hopeful dosimetric analysis of IMPT, the efficacy and safety of the method in the clinical context are critical and need to be further studied and analyzed.
Patient symptoms and quality of life
While dosimetric advantages of IMPT are evident in literature, the translation of these benefits into improved clinical outcomes and patients’ QoL remains crucial. Radiotherapy-induced symptom burden is a significant concern, especially in HNC, where patients experience multiple local and systemic inflammatory responses. Studies using validated PRO tools, such as the MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN), have attempted to quantitatively document these effects during the first
Other studies corroborate these observations. For example, the study of Hutcheson et al. indicated that 20% of patients receiving IMPT required a feeding tube compared to 48% of those receiving IMRT, indicating a potential clinical benefit of IMPT in reducing treatment-related morbidity[54]. However, the discrepancy between physician-reported outcomes and patient-reported outcomes also highlights the need for prospective clinical trials to clarify the findings and validate the clinical significance of IMPT's dosimetric advantages.
Cao et al. investigated the prevalence of xerostomia symptoms in OPC patients treated with either IMRT or IMPT, focusing on identifying dosimetric factors associated with the risk of xerostomia[55]. Their findings indicated that the incidence of moderate-severe xerostomia was comparable between the IMPT and the IMRT groups up to 18 months post-treatment. However, IMPT showed significantly lower rates of moderate-severe xerostomia at 18-24 month and 24-36 month periods (6% vs. 20%; P = 0.01). During the late xerostomia period (24-36 months), high dose/volume exposures (V25-V70) in the oral cavity were correlated with increased rates of moderate-severe xerostomia (P < 0.05), whereas salivary gland dosimetric variables did not. Thus, IMPT was associated with reduced late xerostomia in OPC patients, with oral cavity dosimetric parameters being the key predictors[55].
On the other hand, a recent analysis by Grant et al. evaluating longitudinal swallowing outcomes in a cohort of OPC patients revealed similar trends in swallowing function between treatments with IMRT and IMPT. The study utilized the MD Anderson Dysphagia Inventory (MDADI) at baseline, 6, 12, and 24 months post-treatment. Specifically, MDADI scores for IMRT were 88.3 at baseline, 73.8 at 6 months, 78.6 at 12 months, and 83.3 at 24 months, compared to 88.2, 77.0, 80.5, and 80.1 for IMPT, respectively. While direct comparisons are still limited due to differences in patient populations and potential confounding factors, the trajectory of swallowing function appears comparable between IMRT and IMPT in this specific research[56].
As previously mentioned, IMRT and IMPT represent advanced radiotherapy techniques with distinct physical properties and dosimetric profiles. However, translating dosimetric advantages into tangible clinical benefits and improved QoL remains an ongoing challenge. Further prospective randomized clinical trials are essential to fully elucidate the potential of IMPT in the management of OPC and to refine radiotherapy strategies for optimal patient care. Currently, there is no prospective Level I evidence for Proton Beam Therapy (PBT) in most adult cancers, including oropharyngeal squamous cell carcinoma (OPSCC). However, TORPEdO, the first UK clinical trial for PBT, shows promise in improving treatment-related toxicities and health-related QoL for patients. This Phase III multicenter, open-label, randomized controlled trial compares IMPT with IMRT to reduce treatment-related toxicities in patients with advanced OPSCC[57]. The trial includes extensive training to minimize variations in radiotherapy planning and a strong translational research component by collecting imaging data, physics data, blood, and tissue samples to refine patient selection for IMPT. TORPEdO enrolled its first patient on February 25, 2020, paused recruitment due to COVID-19, and later resumed activities in 16 centers, aiming to complete recruitment by October 2023[57].
Thus, it is safe to say that overall, both IMRT and IMPT represent advanced radiotherapy modalities designed to optimize tumor control while minimizing damage to healthy tissues. IMRT excels in delivering high doses to tumors with complex geometries and has established efficacy and accessibility, though it often results in higher integral doses to non-target tissues. IMPT, on the other hand, employs the Bragg peak phenomenon to achieve superior dose precision, reducing exit doses and sparing critical structures more effectively. These characteristics make IMPT particularly advantageous for reducing toxicities and improving outcomes in select patient populations.
Comparing volumetric modulated arc therapy and intensity-modulated proton therapy
Volumetric modulated arc therapy (VMAT) represents a significant advancement in radiation oncology, offering enhanced precision and efficiency in delivering therapeutic doses to malignant tumors while sparing surrounding healthy tissues. VMAT achieves this by enabling dynamic modulation of the radiation beam's intensity and shape during continuous arc rotation of the linear accelerator around the patient. This approach differs from the IMRT technique, which administers radiation from multiple static angles. Collectively, VMAT, IMRT, and IMPT illustrate a technological continuum aimed at optimizing the therapeutic ratio in RT.
The study of Manzar et al. aimed to determine if the dosimetric advantages of IMPT over VMAT in treating OPC can be translated into clinical benefits[58]. A total of 46 IMPT and 259 VMAT patients were treated with a median follow-up of 12 months for IMPT and 30 months for VMAT. Their results indicated that IMPT was associated with significantly lower rates of PEG-tube placement as well as with reduced hospitalization within 60 days post-therapy. The benefits of IMPT were even more pronounced in the patient groups treated with concomitant chemoradiotherapy (CRT). Furthermore, IMPT demonstrated a 22.3% relative risk reduction in end-of-treatment narcotic use, with patients also reporting fewer instances of cough and dysgeusia. Additionally, those treated with CRT reported a reduced sense of illness after treatment, decreased reliance on feeding tubes, and improved swallowing function. Provider-assessed toxicities indicated that IMPT resulted in less pain and mucositis, although there was a higher incidence of mucosal infection[58].
Chou et al. conducted a comparative study on the outcomes of patients with nasopharyngeal carcinoma who were treated with IMPT and VMAT[59]. The analysis was performed retrospectively using propensity score matching. Survival outcomes were assessed through the Kaplan-Meier method, and the multivariate Cox proportional hazards regression analysis was employed to identify independent survival predictors. Binary toxicity endpoints were analyzed using both the Cox model and logistic regression. A total of
In cases where significant anatomical changes occur in patients undergoing HNC RT, Góra et al. highlighted that adaptive radiotherapy (ART) can potentially address the issue by implementing regular replanning during treatment to adjust doses and improve precision[60]. Dosimetric evaluation of recalculated plans using CT1 and CT2 showed increasing doses to OARs for both VMAT and IMPT[60]. According to their results, for VMAT, the target coverage remained acceptable in three cases, whereas it decreased for all IMPT plans. Adaptation of treatment reduced the D2% for the brainstem by 6.7 Gy for VMAT and by 8 Gy for IMPT in specific patients. The D2% reductions for the spinal cord were even more significant, reaching 9 and 14 Gy, respectively. Thus, ART improved target dose homogeneity, particularly for IMPT, with D2% reductions up to 8 Gy, while D98% increased by 1.2 Gy, enhancing overall dose distribution. Due to the fact that IMPT is more conformal, dosimetric changes were more pronounced compared to VMAT.
To summarize, VMAT and IMPT both aim to optimize radiation delivery while minimizing harm to surrounding healthy tissues. VMAT's efficiency stems from its dynamic arc-based radiation delivery, whereas IMPT demonstrates precision in sparing critical structures. Comparative studies show IMPT's clinical benefits, including reduced rates of feeding tube dependency and body weight loss during treatment. However, VMAT remains effective and widely accessible, offering excellent therapeutic outcomes in many cases. These findings suggest that treatment modalities should be selected based on patient-specific needs and clinical scenarios.
Comparing volumetric modulated arc therapy and intensity-modulated photon therapy with pencil beam scanning proton therapy
Pencil beam scanning (PBS) proton therapy represents a cutting-edge modality in radiation oncology, characterized by its ability to deliver highly conformal proton doses to neoplastic tissues while minimizing radiation exposure to adjacent normal structures[61]. This technique employs a finely collimated proton beam that systematically “paints” the target volume in a raster-like fashion, enabling superior dose distribution and sparing of healthy tissues. In contrast, IMRT and VMAT utilize photon beams and achieve dose modulation through multiple fixed or rotational beam angles, respectively. While IMRT and VMAT have significantly advanced the precision and efficiency of photon-based therapies, PBS proton therapy leverages the distinct dosimetric advantages of protons, such as the Bragg peak, to achieve exceptional tissue sparing and potentially improved clinical outcomes.
In the study by Sharma et al., patient-reported outcomes were collected from individuals treated with either PBS or IMRT/VMAT[62]. QoL was assessed using validated questionnaires administered before RT, and at 3, 6, and 12 months post-RT. The study included 64 patients, with 31 (48%) receiving PBS and 33 (52%) IMRT/VMAT. The results showed that patients treated with PBS experienced significantly lower radiation doses to several normal structures compared to those treated with IMRT/VMAT. These dosimetric advantages of PBS were also reflected in higher scores on both head and neck-specific and general QoL tools. Notably, patients in the PBS group reported significantly less xerostomia at multiple time points, specifically at 6 and 12 months post-treatment. Representative radiation plans demonstrated significant sparing of the anterior oral cavity with PBS compared to IMRT and VMAT [Figure 2]. Generally, the mean radiation dose was considerably lower for PBS patients across most salivary structures, except for the submandibular glands and ipsilateral parotid. Furthermore, structures such as the contralateral buccal mucosa, contralateral parotid and submandibular glands, oral tongue, and upper and lower lips received one-third to ten-fold lower mean doses with PBS[62].
Figure 2. VMAT (A) vs. PBS treatment planning comparison (B) for the axial (left) and sagittal (right) planes of patient with tongue carcinoma. Both plans received 60 Gy in 30 fractions while the PBS plan illustarets lower doses to the structures of the oral cavity. Distributed under Creative Commons CC-BY. Copyright 2018, Reproduced from Ref.[62].
The study by Swisher-McClure et al. attempted to evaluate the dosimetric advantages of PBS proton therapy vs. IMRT in the treatment of parotid gland cancers[63]. Specifically, the researchers retrospectively analyzed data from eight patients who had received external beam radiation therapy, generating separate IMRT and PBS treatment plans for each patient. Both plans prescribed a dose of 60 Gy for IMRT and 60 Gy (RBE) for PBS. Dose-volume relationships for target volumes and organs at risk were assessed for each treatment technique using the Wilcoxon signed-rank test. Their results indicated that PBS significantly reduced the mean dose to several structures compared to IMRT. These structures included the following: oral cavity (0.58 vs. 13.48 Gy, P = 0.01), contralateral parotid gland (0.003 vs. 4.64 Gy, P = 0.01), ipsilateral submandibular gland (16.59 vs. 38.94 Gy, P = 0.03), the ipsilateral temporal lobe (2.86 vs. 9.59 Gy, P = 0.01), the mandible (V50: 7.4% vs. 12.8%, P = 0.01,) and contralateral submandibular gland
Figure 3. Comparison of dose distribution and dose-volume histograms between IMRT and PBS treatment plans. Copyright 2016, Reproduced from Ref.[63].
Another study investigated the optimal treatment planning for non-squamous cell carcinoma of the head and neck by comparing the dose distributions of various plans, including PBS with or without a patient-specific aperture system (PSAS), passive-scattering proton therapy (PSPT), and IMRT. Additionally, the study evaluated the clinical results and toxicities of PBS with PSAS, including the changes in QoL of patients. 30 patients were treated using PBS with PSAS. For 20 randomly selected patients, dose distributions of PBS with or without PSAS, PSPT, and IMRT plans were compared [Figure 4]. Additionally, all patients completed EORTC quality of life survey forms (QLQ-C30 and QLQ-HN35) before initiating therapy and 12 months after proton therapy. The results indicated that a 95% conformity number of the PBS with PSAS plan was the optimum, while significant differences were detected among the four plans
Figure 4. Dosimetric treatment planning comparison for each irradiation method. Copyright 2019, Reproduced from Ref.[64].
Eventually, PBS proton therapy offers unparalleled precision in sparing healthy tissues compared to photon-based modalities such as IMRT and VMAT. Studies have demonstrated PBS's superiority in reducing radiation doses to critical structures like salivary glands, the oral cavity, and the brainstem, while maintaining excellent target coverage. Additionally, PBS shows promise in improving patient-reported outcomes, particularly in QoL metrics such as reduced xerostomia and lower toxicities. Despite these advantages, further prospective studies are essential to fully understand PBS’s clinical efficacy and long-term benefits in head and neck cancers.
CONCLUSION
In this comprehensive review of radiotherapy types for head and neck cancer (HNC), we focus on the comparison between photon-based therapies, including IMRT and VMAT, vs. proton therapy, including IMPT and PBS. This review extends beyond a typical dosimetric analysis, such as dose distribution and protection of OARs, to relevant radiation-induced toxicities and especially patient-oriented QoL. While photon-based therapies such as IMRT and VMAT offer advantages by precisely targeting tumors and sparing healthy tissues, concerns remain regarding their integral dose deposition profiles and potential toxicity risks to surrounding normal tissues. In contrast, proton therapy, particularly IMPT and PBS, leverages the unique physical properties of protons to achieve highly conformal dose distributions with minimal exit dose beyond the target area. This ability not only enhances the protection of OARs but also leads to lower rates of acute and late treatment-related morbidity such as xerostomia, dysphagia, and mucositis. Studies utilizing patient-reported outcome measures consistently indicate improved QoL outcomes among patients treated with proton therapy compared to those treated with photon-based techniques.
In conclusion, this review underscores the pivotal role of proton therapy, particularly IMPT, as a promising treatment option for HNC, offering substantial benefits in minimizing treatment-related toxicities and improving QoL outcomes compared to traditional photon therapies. However, to further solidify its clinical integration, continued research is essential. Specifically, there is a pressing need for long-term longitudinal studies on patient-reported outcomes to assess sustained QoL improvements, particularly with respect to late toxicities such as xerostomia and dysphagia. Additionally, cost-benefit analyses that evaluate the long-term economic impact of proton therapy, considering both direct treatment costs and the potential savings from reduced side effects and rehabilitation, are critical for validating its widespread adoption. Furthermore, comparative toxicity profiles should be addressed through well-designed randomized clinical trials to correlate dosimetric advantages with actual clinical outcomes, particularly focusing on hospitalization rates and functional recovery. Lastly, emerging technologies and hybrid treatment models integrating proton therapy with other modalities, such as immunotherapy or hybrid photon-proton approaches, warrant further exploration to enhance both clinical efficacy and cost-effectiveness. These specific research areas will be crucial in refining proton therapy's application and guiding future clinical practice in HNC treatment.
DECLARATIONS
Acknowledgments
English editing has been performed using Chat GPT Version 3.5 (OpenAI, San Francisco, CA, USA).
Authors’ contributions
Conceptualization, investigation, writing - original draft preparation: Kiafi P, Kouri MA
Methodology: Kouri MA, Kiafi P, Patatoukas G, Kouloulias V, Platoni K, Chalkia M, Kollaros N, Perisanidis C, Kougioumtzopoulou A, Nikolatou-Galitis O
formal analysis: Kiafi P, Kouri MA, Patatoukas G, Chalkia M
writing - review and editing: Kiafi P, Kouri MA, Patatoukas G, Kouloulias V, Platoni K, Kougioumtzopoulou A, Perisanidis C, Chalkia M, Nikolatou-Galitis O
supervision: Kouloulias V, Platoni K, Nikolatou-Galitis O
Supervision, writing - review and editing: Kyrodimos E
All authors have read and agreed to the published version of the manuscript.
Availability of data and materials
Not applicable.
Financial support and sponsorship
None.
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
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Kiafi, P.; Chalkia, M.; Kouri, M. A.; Patatoukas, G.; Kollaros, N.; Kougioumtzopoulou, A.; Nikolatou-Galitis, O.; Kyrodimos, E.; Perisanidis, C.; Kouloulias, V.; Platoni, K. Photon vs. proton radiation therapy in head and neck cancer: a review of dosimetric advantages and patient quality of life. J. Cancer. Metastasis. Treat. 2024, 10, 31. http://dx.doi.org/10.20517/2394-4722.2024.79
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