Proton Therapy for Head and Neck Cancers

doi:10.1016/j.semradonc.2017.08.004

Seminars in Radiation Oncology

Volume 28, Issue 1, January 2018, Pages 53-63

https://doi.org/10.1016/j.semradonc.2017.08.004 Get rights and content

Because of its sharp lateral penumbra and steep distal fall-off, proton therapy offers dosimetric advantages over photon therapy. In head and neck cancer, proton therapy has been used for decades in the treatment of skull-base tumors. In recent years the use of proton therapy has been extended to numerous other disease sites, including nasopharynx, oropharynx, nasal cavity and paranasal sinuses, periorbital tumors, skin, and salivary gland, or to reirradiation. The aim of this review is to present the physical properties and dosimetric benefit of proton therapy over advanced photon therapy; to summarize the clinical benefit described for each disease site; and to discuss issues of patient selection and cost-effectiveness.

Introduction

Radiotherapy for head and neck cancer can be delivered as a definitive treatment or as an adjuvant treatment after surgery.¹ The vast majority of treatments are currently given as external beam photon therapy. Over the past 20 years, the use of intensity-modulated photon therapy (IMRT), and more recently volumetric modulated arc therapy, has allowed considerable improvement in treatment conformality and reduction of high doses to neighboring critical structures. Consequently, this has drastically reduced the incidence of major forms of toxicity, most notably xerostomia2, 3; however, the improvements in physical delivery of photon therapy have reached a plateau and come at the cost of alternative toxic effects such as fatigue, nausea, hair loss, and oral mucositis,2, 4 and further improvements in the therapeutic ratio require alternative methods of radiation delivery.

In this context, proton therapy has emerged as a novel means to reduce toxicity and potentially further improve tumor control. The unique physical properties of charged particles allow a steep dose gradient with a reduced integral dose delivered to the patient in a proportion that can meaningfully reduce dose-related toxicity. The aims of this review are to present the current evidence on the use of proton therapy for the treatment of head and neck cancers. After discussing the physical properties of protons and the dosimetric advantages of proton therapy over IMRT, we will review the potential clinical implications of this dosimetric benefit, the clinical experience to date in adult patients, and the best way to further collect evidence while selecting patients for the most appropriate form of radiation therapy.

Section snippets

References Search

Although this report is not a formal systematic review in that it does not rely on multiple databases and a broad search strategy, we conducted a Pubmed search in the process of writing this review by using the following search equation: ((“proton therapy” OR “protontherapy” OR “proton beam therapy” OR “particle therapy” OR “hadrontherapy” OR “hadron therapy” OR “proton radiation” OR “proton beam radiation”) AND (head and neck cancer)). The final search was performed on March 22, 2017 by 1

Physical Properties and Dosimetric Results

A focused beam of protons is accelerated by a particle accelerator that can be used for therapeutic purposes. The main characteristics of protons that explain their dosimetric superiority over photons are (1) the absence of exit dose beyond the target and (2) the sharper lateral dose distribution secondary to protons' heavier mass relative to photons. The Bragg peak phenomenon is the sharp increase in dose deposited at the end of the particle range, and results from the charged nature of

Clinical Implications of Dosimetric Advantage—Patient Selection for Proton Therapy

Radiation therapy to the head and neck has several potentially serious acute and late adverse effects. In the acute phase, patients can experience severe mucositis, pain, fatigue, thickened secretions, altered taste, dehydration, weight loss, nausea, vomiting, or dermatitis. Numerous acute and late toxic effects have been shown to be dose and volume related, with the probability and severity of toxicity or dysfunction directly correlated with higher doses and larger volumes. These findings have

Skull-Base Chordomas and Chondrosarcomas

These tumors were historically the first ones to be treated with proton therapy, owing to their proximity to the brainstem and optic tract and the need for high radiation doses that cannot be delivered safely with photon therapy, for which 5-year survival rates were historically about 25%.40, 41 Although gross total resection is a major prognostic factor in chordomas and chondrosarcomas, it is often not achieved because of the location and extent of the tumor. The largest series of patients

Demonstrating the Value of Proton Therapy—Gathering Prospective Comparative Evidence

The value of a treatment is defined as the outcomes obtained divided by the cost, measured over the entire cycle of care.⁶⁷ The cost of particle therapy has been evaluated in several studies37, 68, 69, 70, 71, 72, 73 and was recently summarized in a systematic review.⁷⁴ Most of these studies currently convey that the cost of delivering proton therapy is approximately 2-3 times higher than for delivering IMRT. However, the cost difference is reduced when costs are considered over the entire

Conclusion—Technical Evolution—Cooperation

Proton therapy represents the latest technical improvement of radiation therapy, and has demonstrated clinical efficacy and the potential for toxicity reduction compared with photon therapy. Per National Comprehensive Cancer Network guidelines, proton therapy is a standard of care for base of skull tumors and is an option for periorbital tumors. The use of proton therapy is expanding for other head and neck tumor sites as well. Novel forms of proton therapy such as IMPT, and technical

References (86)

C.M. Nutting 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)
G. Peng et al.
A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma
Radiother Oncol
(2012)
D.I. Rosenthal et al.
Beam path toxicities to non-target structures during intensity-modulated radiation therapy for head and neck cancer
Int J Radiat Oncol Biol Phys
(2008)
S.J. Frank et al.
Multifield optimization intensity modulated proton therapy for head and neck tumors: a translation to practice
Int J Radiat Oncol Biol Phys
(2014)
N. Fukumitsu et al.
Dose distribution resulting from changes in aeration of nasal cavity or paranasal sinus cancer in the proton therapy
Radiother Oncol
(2014)
M. Palmer et al.
The optimal timing for off-line adaptive planning for bilateral head-and-neck IMPT is week 4
Int J Radiat Oncol Biol Phys
(2012)
G.B. Gunn et al.
Clinical outcomes and patterns of disease recurrence after intensity modulated proton therapy for oropharyngeal squamous carcinoma
Int J Radiat Oncol Biol Phys
(2016)
A.P. Brown et al.
Proton therapy for carcinoma of the nasopharynx: a study in comparative treatment planning
Int J Radiat Oncol Biol Phys
(1989)
J.M. Slater et al.
Carcinoma of the tonsillar region: Potential for use of proton beam therapy
Int J Radiat Oncol Biol Phys
(1992)
R. Miralbell et al.
Potential improvement of three dimension treatment planning and proton therapy in the outcome of maxillary sinus cancer
Int J Radiat Oncol Biol Phys
(1992)

S. Kandula 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)

E.B. Holliday 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)

O. Apinorasethkul et al.

Pencil beam scanning proton therapy vs rotational arc radiation therapy: A treatment planning comparison for postoperative oropharyngeal cancer

Med Dosim

(2017)

D.B.P. Eekers 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)

A. Eisbruch et al.

Chemo-IMRT of oropharyngeal cancer aiming to reduce dysphagia: Swallowing organs late complication probabilities and dosimetric correlates

Int J Radiat Oncol Biol Phys

(2011)

A.C. Houweling 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 Biol Phys

(2010)

I. Beetz 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)

J.O. Deasy et al.

Radiotherapy dose-volume effects on salivary gland function

Int J Radiat Oncol Biol Phys

(2010)

M.E.M.C. Christianen et al.

Predictive modelling for swallowing dysfunction after primary (chemo)radiation: Results of a prospective observational study

Radiother Oncol

(2012)

K. Wopken 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)

M.J. Boomsma et al.

A prospective cohort study on radiation-induced hypothyroidism: development of an NTCP model

Int J Radiat Oncol Biol Phys

(2012)

T. Rancati et al.

NTCP modeling of subacute/late laryngeal edema scored by fiberoptic examination

Int J Radiat Oncol Biol Phys

(2009)

E. Kocak-Uzel 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)

S.A. Bhide 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)

E. Sapir et al.

Predictors of dysgeusia in patients with oropharyngeal cancer treated with chemotherapy and intensity modulated radiation therapy

Int J Radiat Oncol

(2016)

A. Jakobi et al.

Identification of patient benefit from proton therapy for advanced head and neck cancer patients based on individual and subgroup normal tissue complication probability analysis

Int J Radiat Oncol Biol Phys

(2015)

J.A. Langendijk et al.

Selection of patients for radiotherapy with protons aiming at reduction of side effects: The model-based approach

Radiother Oncol

(2013)

J. Widder et al.

The quest for evidence for proton therapy: Model-based approach and precision medicine

Int J Radiat Oncol

(2016)

Q. Cheng et al.

Development and evaluation of an online three-level proton vs photon decision support prototype for head and neck cancer—Comparison of dose, toxicity and cost-effectiveness

Radiother Oncol

(2016)

B.L.T. Ramaekers et al.

Protons in head-and-neck cancer: Bridging the gap of evidence

Int J Radiat Oncol Biol Phys

(2013)

P. Blanchard 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)

C. Catton et al.

Chordoma: Long-term follow-up after radical photon irradiation

Radiother Oncol

(1996)

L. Feuvret 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

(2016)

C. Ares 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 Biol Phys

(2009)

M.W. McDonald et al.

Influence of residual tumor volume and radiation dose coverage in outcomes for clival chordoma

Int J Radiat Oncol Biol Phys

(2016)

S.H. Patel 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)

S. Zenda et al.

Phase II study of proton beam therapy as a nonsurgical approach for mucosal melanoma of the nasal cavity or para-nasal sinuses

Radiother Oncol

(2016)

J.D. Slater 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 Biol Phys

(2005)

P. Blanchard 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)

T.T. Sio 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 Biol Phys

(2016)

P.B. Romesser et al.

Proton beam reirradiation for recurrent head and neck cancer: Multi-institutional Report on feasibility and early outcomes

Int J Radiat Oncol Biol Phys

(2016)

J. Phan et al.

Reirradiation of Head and Neck Cancers With Proton Therapy: Outcomes and Analyses

Int J Radiat Oncol Biol Phys

(2016)

E.B. Holliday 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 Biol Phys

(2016)

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Neurological complications of modern radiotherapy for head and neck cancer
2024, Radiotherapy and Oncology
Radiotherapy is one of the mainstay treatment modalities for the management of non-metastatic head and neck cancer (HNC). Notable improvements in treatment outcomes have been observed in the recent decades. Modern radiotherapy techniques, such as intensity-modulated radiotherapy and charged particle therapy, have significantly improved tumor target conformity and enabled better preservation of normal structures. However, because of the intricate anatomy of the head and neck region, multiple critical neurological structures such as the brain, brainstem, spinal cord, cranial nerves, nerve plexuses, autonomic pathways, brain vasculature, and neurosensory organs, are variably irradiated during treatment, particularly when tumor targets are in close proximity. Consequently, a diverse spectrum of late neurological sequelae may manifest in HNC survivors. These neurological complications commonly result in irreversible symptoms, impair patients’ quality of life, and contribute to a substantial proportion of non-cancer deaths. Although the relationship between radiation dose and toxicity has not been fully elucidated for all complications, appropriate application of dosimetric constraints during radiotherapy planning may reduce their incidence. Vigilant surveillance during the course of survivorship also enables early detection and intervention. This article endeavors to provide a comprehensive review of the various neurological complications of modern radiotherapy for HNC, summarize the current incidence data, discuss methods to minimize their risks during radiotherapy planning, and highlight potential strategies for managing these debilitating toxicities.
Using the gamma-index analysis for inter-fractional comparison of in-beam PET images for head-and-neck treatment monitoring in proton therapy: A Monte Carlo simulation study
2024, Physica Medica
In-beam Positron Emission Tomography (PET) is a technique for in-vivo non-invasive treatment monitoring for proton therapy. To detect anatomical changes in patients with PET, various analysis methods exist, but their clinical interpretation is problematic. The goal of this work is to investigate whether the gamma-index analysis, widely used for dose comparisons, is an appropriate tool for comparing in-beam PET distributions. Focusing on a head-and-neck patient, we investigate whether the gamma-index map and the passing rate are sensitive to progressive anatomical changes.
We simulated a treatment course of a proton therapy patient using FLUKA Monte Carlo simulations. Gradual emptying of the sinonasal cavity was modeled through a series of artificially modified CT scans. The in-beam PET activity distributions from three fields were evaluated, simulating a planar dual head geometry. We applied the 3D-gamma evaluation method to compare the PET images with a reference image without changes. Various tolerance criteria and parameters were tested, and results were compared to the CT-scans.
Based on 210 MC simulations we identified appropriate parameters for the gamma-index analysis. Tolerance values of 3 mm/3% and 2 mm/2% were suited for comparison of simulated in-beam PET distributions. The gamma passing rate decreased with increasing volume change for all fields.
The gamma-index analysis was found to be a useful tool for comparing simulated in-beam PET images, sensitive to sinonasal cavity emptying. Monitoring the gamma passing rate behavior over the treatment course is useful to detect anatomical changes occurring during the treatment course.
Validation of Fully Automated Robust Multicriterial Treatment Planning for Head and Neck Cancer IMPT
2024, International Journal of Radiation Oncology Biology Physics
Our purpose was to compare robust intensity modulated proton therapy (IMPT) plans, automatically generated with wish-list–based multicriterial optimization as implemented in Erasmus-iCycle, with manually created robust clinical IMPT plans for patients with head and neck cancer.
Thirty-three patients with head and neck cancer were retrospectively included. All patients were previously treated with a manually created IMPT plan with 7000 cGy dose prescription to the primary tumor (clinical target volume [CTV]7000) and 5425 cGy dose prescription to the bilateral elective volumes (CTV5425). Plans had a 4-beam field configuration and were generated with scenario-based robust optimization (21 scenarios, 3-mm setup error, and ±3% density uncertainty for the CTVs). Three clinical plans were used to configure the Erasmus-iCycle wish-list for automated generation of robust IMPT plans for the other 30 included patients, in line with clinical planning requirements. Automatically and manually generated IMPT plans were compared for (robust) target coverage, organ-at-risk (OAR) doses, and normal tissue complication probabilities (NTCP). No manual fine-tuning of automatically generated plans was performed.
For all automatically generated plans, voxel-wise minimum D_98% values for the CTVs were within clinical constraints and similar to manual plans. All investigated OAR parameters were favorable in the automatically generated plans (all P < .001). Median reductions in mean dose to OARs went up to 667 cGy for the inferior pharyngeal constrictor muscle, and median reductions in D_0.03cm³ in serial OARs ranged up to 1795 cGy for the spinal cord surface. The observed lower mean dose in parallel OARs resulted in statistically significant lower NTCP for xerostomia (grade ≥2: 34.4% vs 38.0%; grade ≥3: 9.0% vs 10.2%) and dysphagia (grade ≥2: 11.8% vs 15.0%; grade ≥3: 1.8% vs 2.8%).
Erasmus-iCycle was able to produce IMPT dose distributions fully automatically with similar (robust) target coverage and improved OAR doses and NTCPs compared with clinical manual planning, with negligible hands-on planning workload.
Treatment planning comparison for head and neck cancer between photon, proton, and combined proton–photon therapy – From a fixed beam line to an arc
2024, Radiotherapy and Oncology
This study investigates whether combined proton–photon therapy (CPPT) improves treatment plan quality compared to single-modality intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) for head and neck cancer (HNC) patients. Different proton beam arrangements for CPPT and IMPT are compared, which could be of specific interest concerning potential future upright-positioned treatments. Furthermore, it is evaluated if CPPT benefits remain under inter-fractional anatomical changes for HNC treatments.
Five HNC patients with a planning CT and multiple (4–7) repeated CTs were studied. CPPT with simultaneously optimized photon and proton fluence, single-modality IMPT, and IMRT treatment plans were optimized on the planning CT and then recalculated and reoptimized on each repeated CT. For CPPT and IMPT, plans with different degrees of freedom for the proton beams were optimized. Fixed horizontal proton beam line (FHB), gantry-like, and arc-like plans were compared.
The target coverage for CPPT without adaptation is insufficient (average V95%=88.4 %), while adapted plans can recover the initial treatment plan quality for target (average V95%=95.5 %) and organs-at-risk. CPPT with increased proton beam flexibility increases plan quality and reduces normal tissue complication probability of Xerostomia and Dysphagia. On average, Xerostomia NTCP reductions compared to IMRT are −2.7 %/-3.4 %/-5.0 % for CPPT FHB/CPPT Gantry/CPPT Arc. The differences for IMPT FHB/IMPT Gantry/IMPT Arc are + 0.8 %/-0.9 %/-4.3 %.
CPPT for HNC needs adaptive treatments. Increasing proton beam flexibility in CPPT, either by using a gantry or an upright-positioned patient, improves treatment plan quality. However, the photon component is substantially reduced, therefore, the balance between improved plan quality and costs must be further determined.
Evaluation of decentralised model-based selection of head and neck cancer patients for a proton treatment study. DAHANCA 35
2024, Radiotherapy and Oncology
Proton treatment can potentially spare patients with H&N cancer for substantial treatment-related toxicities. The current study investigated the reproducibility of a decentralised model-based selection of patients for a proton treatment study when the selection plans were compared to the clinical treatment plans performed at the proton centre.
Sixty-three patients were selected for proton treatment in the six Danish Head and Neck Cancer (DAHANCA) centres. The patients were selected based on normal tissue complication probability (NTCP) estimated from local photon and proton treatment plans, which showed a ΔNTCP greater than 5%-point for either grade 2 + dysphagia or grade 2 + xerostomia at six months. The selection plans were compared to the clinical treatment plans performed at the proton centre.
Of the 63 patients, 49 and 25 were selected based on an estimated benefit in risk of dysphagia and xerostomia, respectively. Eleven patients had a potential gain in both toxicities. The mean ΔNTCP changed from the local selection plan comparison to the clinical comparison from 6.9 to 5.3 %-points (p = 0.01) and 7.3 to 4.9 %-points (p = 0.03) for dysphagia and xerostomia, respectively. Volume differences in both CTV and OAR could add to the loss in ΔNTCP. 61 of the 63 clinical plans had a positive ΔNTCP, and 38 had a ΔNTCP of 5%-points for at least one of the two endpoints.
A local treatment plan comparison can be used to select candidates for proton treatment. The local comparative proton plan overestimates the potential benefit of the clinical proton plan. Continuous quality assurance of the delineation procedures and planning is crucial in the subsequent randomised clinical trial setting.
Identification of Induced Radionuclides Produced from Dental Metals in Proton Beam Therapy for Head and Neck Cancer
2023, Advances in Radiation Oncology
To identify the induced radionuclides produced from dental metals in proton beam therapy and investigate the accuracy of the Monte Carlo (MC) simulation by comparing the measured radioactivity.
Two dental metals of pure titanium and gold-silver-palladium alloy, commonly used in Japan, were used in this study. The dental metal placed at the center of Spread-out Bragg Peak was irradiated by 150-MeV passive scattering proton beam. The gamma rays emitted from the activated dental metals were measured using a high purity germanium (HPGe) detector. The induced radionuclides were identified from the measured gamma-ray energies. Furthermore, the Particle and Heavy Ion Transport code System v.3.24 and DCHAIN were used for the MC simulation. The measured radionuclides and their radioactivity were compared with the simulation results.
In the MC simulation for the activated titanium, vanadium-47, with a half-life of 32.6 minutes had the strongest radioactivity among the induced radionuclides. The energy peaks of gamma rays emitted from titanium-51, scandium-43, scandium-44, and annihilation gamma rays were observed for the activated titanium in the HPGe detector. In the MC simulation for the activated gold-silver-palladium alloy, silver-108, with a half-life of 2.4 minutes had the strongest radioactivity. The energy peaks of gamma rays emitted from silver-104, silver-104 m, silver-108, and annihilation gamma rays were observed for the activated gold-silver-palladium alloy in the HPGe detector. Furthermore, the induced radionuclides and their radioactivity in the MC simulation were consistent with the measurement results for both dental metals, except for a few radionuclides.
We identify the induced radionuclides produced from 2 dental metals and compared their radioactivity between the measurements and the MC simulation. Although the identification of the induced radionuclides using the MC simulation remains uncertain, the MC simulation can be clinically effective for pre-estimating the induced radionuclides in proton beam therapy.

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^☆: Grant or financial support: Supported in part by the National Institutes of Health (NIH), United States, by Cancer Center Support (Core) Grant CA016672 and U19 CA021239 to The University of Texas MD Anderson Cancer Center.

^☆☆: Conflict of interest: none.

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Proton Therapy for Head and Neck Cancers☆,☆☆

Introduction

Section snippets

References Search

Physical Properties and Dosimetric Results

Clinical Implications of Dosimetric Advantage—Patient Selection for Proton Therapy

Skull-Base Chordomas and Chondrosarcomas

Demonstrating the Value of Proton Therapy—Gathering Prospective Comparative Evidence

Conclusion—Technical Evolution—Cooperation

Lancet Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Med Dosim

Med Dosim

Med Dosim

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

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Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

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Int J Radiat Oncol Biol Phys

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Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

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Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys