Clinical publication highlights

Clinical publication highlights

IBA - Clinical publication highlights

On this page, you find a comprehensive summary of the key outcome papers published on proton therapy.

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We hope you enjoy reading the abstracts, as well as the full text articles. 

Key papers October – December 2020


Outcomes following limited-volume proton therapy for multifocal spinal myxopapillary ependymoma

A study by the Jacksonville group reported the disease control and toxicity in 12 pediatric patients with multifocal spinal Spinal myxopapillary ependymoma (MPE) treated with limited-volume proton therapy. Median age was 13.5 years. Proton radiotherapy was given as adjuvant therapy after primary surgery in five patients (42%) and for recurrence in seven (58%). No patient received prior radiation. Eleven patients (92%) had evidence of gross disease at radiotherapy. Eleven patients received 54 GyRBE; one received 50.4 GyRBE. With the median follow-up of 3.6 years, the five-year actuarial rates of local control, progression-free survival, and overall survival were 100%, 92%, and 100%, respectively. One patient experienced an out-of-field recurrence in the spine superior to the irradiated region. No patients developed in-field recurrences. Following surgery and irradiation, one patient developed grade three spinal kyphosis and one patient developed grade 2 unilateral L5 neuropathy. This study concluded that 54 GyRBE to a limited volume appears effective for disseminated spinal MPE in both the primary and salvage settings, sparing children the toxicity of full craniospinal irradiation. Compared with historical reports, this approach using proton therapy improves the therapeutic ratio, resulting in minimal side effects and high rates of disease control. (Publication via )



Image-Guided Hypofractionated Proton Therapy in Early-Stage Non-Small Cell Lung Cancer: A Phase 2 Study

A study by the Jacksonville group that investigated treatment outcomes and toxicities when delivering hypofractionated PT. 22 patients with T1 to T2 N0M0 NSCLC (45% T1, 55% T2) received image-guided hypofractionated PT. Patients underwent 4DCT simulation following fiducial marker placement, and daily image guidance was performed. Nine patients (41%) were treated with 48 GyRBE in 4 fractions for peripheral lesions, and 13 patients (59%) were treated with 60 GyRBE in 10 fractions for central lesions. The median follow-up for all patients was 3.5 years (range, 0.2-8.8 years). The overall survival rates at 3 and 5 years were 81% and 49%, respectively. Cause-specific survival rates at 3 and 5 years were 100% and 75%, respectively. The 3-year local, regional, and distant control rates were 86%, 85%, and 95%, respectively. Four patients experienced in-field recurrences between 18 and 45 months after treatment. One patient (5%) developed a late grade 3 bronchial stricture requiring hospitalization and stent. The study concluded that the image-guided hypofractionated PT for early-stage NSCLC provides promising local control and long-term survival with a low likelihood of toxicity. Regional nodal and distant relapses remain a problem. (Publication via S )

Proton therapy for thoracic malignancies: a review of oncologic outcomes

This review examined PBT physical properties, treatment techniques including the recent advances in planning and delivery, and clinical outcomes for each of the major thoracic malignancies, including lung cancer, esophageal cancer, mesothelioma, thymic cancer, and primary mediastinal lymphoma. The review pointed out that despite clear dosimetric benefit with PBT in thoracic radiotherapy, the improvement in clinical outcomes remains to be seen. Nevertheless, with the incorporation of newer techniques, PBT remains a promising modality and ongoing randomized studies will clarify its role to determine which patients with thoracic malignancies receive the most benefit. Re-irradiation, advanced disease requiring high cardio-pulmonary irradiation volume and younger patients will likely derive maximum benefit with modern PBT. (Publication via



Efficacy and feasibility of proton beam radiotherapy using the simultaneous integrated boost technique for locally advanced pancreatic cancer

A study by the NCC, Korea group analyzed 81 patients with locally advanced pancreatic cancer (LAPC), treated with PBT simultaneous integrated boost (SIB) technique. The prescribed doses to planning target volume (PTV)1 and PTV2 were 45 or 50 GyE and 30 GyE in 10 fractions, respectively. With the median follow-up time 19.6 months, the study reported that the median overall survival (OS) times of all patients and of those in groups I (no chemotherapy), II (with maintenance chemotherapy), and III (upfront and maintenance chemotherapy) were 19.3 months, 15.3 months, 18.3 months, and 26.1 months, respectively (p = 0.043). Acute and late grade ≥ 3 toxicities related to PBT were not observed. PBT with the SIB technique showed promising OS for LAPC patients with a safe toxicity profile, and intensive combinations of PBT and chemotherapy could improve OS in these patients. (publication via )



The Potential Role of Intensity-Modulated Proton Therapy in Hepatic Carcinoma in Mitigating the Risk of Dose De-Escalation

A cohort of 30 patients was retrospectively selected as "at-risk" of dose de-escalation due to the proximity of the target volumes to dose-limiting healthy structures. IMPT plans were compared to volumetric modulated arc therapy (VMAT) RapidArc (RA) plans. The maximum dose prescription foreseen was 75 Gy in 3 fractions. This plan comparison study found that IMPT and VMAT plans resulted in equivalent target dose for CTV and PTV, however significant improvements were observed with IMPT for all organs at risk such as the ribs, chest wall, heart, duodenum, stomach and bowel bag. Twenty patients violated one or more binding constraints with RA, while only 2 with IMPT. Some dose de-intensification would have been required to respect the constraints. IMPT might result in advantages compared to photon-based VMAT for HCC patients to be treated with ablative SBRT in mitigating the risk of dose de-escalation. (publication via L )

Hypofractionated proton beam radiotherapy in patients with unresectable liver tumors: multi-institutional prospective results from the Proton Collaborative Group

This study analyzed the data of 63 patients with liver tumors received definitive PBT treatment from the registry of the Proton Collaborative Group. Thirty (48%) had hepatocellular carcinoma (HCC) and 25 (40%) had intrahepatic cholangiocarcinoma (ICC). The median dose and biological equivalent dose (BED) delivered was 58.05 GyE (range 32.5-75) and 80.5 GyE (range 53.6-100), respectively. Thirteen patients (21%) were treated with 5-fraction regimens, 46 (73%) were treated with 15-fraction regimens, and 4 (6%) were treated with 25-fraction regimens. Fifty-one (81%) of patients experienced at least one radiation-induced toxicity. Three patients (4.8%) experienced at least one grade ≥ 3 toxicity. One HCC patient experienced grade 4 hyperbilirubinemia and grade 3 back pain. One ICC patient experienced grade 3 sinus bradycardia and another ICC patient experienced grade 3 abdominal pain. There were no grade 5 toxicities. With median follow-up of 5.1 months, the local control (LC) rate at 1 year was 91.2% for HCC and 90.9% for ICC. The 1-year LC was significantly higher (95.7%) for patients receiving BED greater than 75.2 GyE than for patients receiving BED of 75.2 GyE or lower (84.6%, p = 0.029). The overall survival rate at 1 year was 65.6% for HCC and 81.8% for ICC. The study concluded that hypofractionated PBT resulted in excellent LC, sparing of the uninvolved liver, and low toxicity, even in the setting of dose-escalation. Higher dose correlated with improved LC, highlighting the importance of PBT especially in patients with recurrent or bulky disease. (publication via J )



Proton beam radiotherapy for esophagus cancer: state of the art

The majority of esophageal cancer patients are diagnosed with locoregionally confined disease, which is often amenable to curative intent therapy. Chemoradiotherapy (CRT) improves overall survival (OS) in stage II and III esophagus cancer in the neoadjuvant and definitive settings. Due to the close proximity of organs at risk (OARs), including lungs, heart, stomach, bowel, kidneys, and spinal cord, esophageal CRT can result in profound acute and late toxicities. Photon-based radiotherapy exposes OARs to significant doses of radiation, whereas proton beam therapy (PBT) delivers a more conformal dose to the target and minimize the volume of OARs exposed to radiation. This review discussed the evolution of photon and proton-based radiotherapy techniques, rationale, dosimetric and clinical studies comparing outcomes of photon- and proton-based techniques, ongoing prospective trials, and future directions of PBT as a means of reducing toxicity and improving oncologic outcomes for patients with esophagus cancer. (Publication via K )



Comparative Analysis of 5-Year Clinical Outcomes and Patterns of Failure of Proton Beam Therapy (PBT) versus Intensity-Modulated Radiotherapy (IMRT) for Prostate Cancer in the Postoperative Setting

This case-matched study analyzed 260 prostate cancer patients including 65 treated with PBT and 195 IMRT. At a median follow-up of 59 months, biochemical failure (BF), local failure (LF), regional failure (RF), distant failure (DF), and mortality rates were 45% (n=29), 2% (n=1), 9% (n=6), 9% (n=6), and 2% (n=1) for PBT, and 41% (n=80), 3% (n=5), 7% (n=13), 9% (n=18), and 5% (n=9) for IMRT (all p>0.05). RT modality was not significantly associated with BF (all p>0.05), nor with LF (p=0.82), RF (p=0.11), DF (p=0.36), or all-cause mortality (p=0.69). Patterns of failure were qualitatively similar between cohorts (DF: bone, retroperitoneal nodes, lung). This study concluded that PBT yielded similar long-term disease-related outcomes and patterns of failure to IMRT in the post-prostatectomy setting. (Publication via

Multivariate normal tissue complication probability models for rectal and bladder morbidity in prostate cancer patients treated with proton therapy

The study included rectum and bladder DVHs, 2D rectal dose maps and relevant patient/treatment characteristics from 1151 prostate cancer cases treated with PT. Prospectively scored Grade 2 late rectal bleeding (n = 156 (15%)) and Grade 3+ GU morbidity (n = 51 (4%)) were entered into a multivariate logistic regression analysis. This study found that Anticoagulant use and age were the most prominent predictors in the NTCP models. V75Gy of the rectal wall and the bladder was a predictor in the DVH-based models of the rectum and bladder respectively. (Publication via


Secondary cancer risk

Comparing second cancer risk for multiple radiotherapy modalities in survivors of Hodgkin lymphoma

Using Excess Absolute Risk (EAR) models, this study compared the risk of secondary cancer for Hodgkin lymphoma survivors after either IMRT or PBT radiation treatment. Organ-specific parameters were generated to model their uncertainties which the total EAR were around 13%, decreasing to around 2-5% for relative EAR comparisons. This study found that IMPT decreased the average risk by 40% compared to the IMRT plan, 28% compared to the Volumetric Modulated Arc Therapy plan whereas the 3D Conformal Radiation Therapy plan is equivalent within the uncertainty. (Publication via



Roadmap: proton therapy physics and biology

This review presented the roadmap for proton therapy development, which included further research in the advanced dose shaping capabilities of proton therapy cause susceptibility to uncertainties; the high degrees of freedom in dose delivery offer room for further improvements; the limited experience and understanding of optimizing pencil beam scanning; and the biological effects differ from photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because proton therapy treatments are, on average, still more expensive compared to conventional photon-based treatment options. This roadmap highlights the current state and future direction in proton therapy categorized into four different themes, "improving efficiency", "improving planning and delivery", "improving imaging", and "improving patient selection".

Key papers May-September 2020


Proton Therapy Reduces the Likelihood of High-Grade Radiation-Induced Lymphopenia in Glioblastoma Patients: Phase II Randomized Study of Protons vs. Photons. This is a randomized phase II trial compared the radiation-induced grade 3+ lymphopenia (G3+L), which was defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, for patients of glioblastoma received PT (n=28) or XRT (n=56), concomitantly with temozolomide. This study found rates of G3+L were lower in PT vs. XRT (P=0.024)). Sex, baseline ALC, and whole brain V20 were the strongest predictors of G3+L. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.(publication via

Head and Neck

Past, present and future of proton therapy for head and neck cancer. The latest review article on PT for head and neck cancer. Head and neck cancer patients are living longer due to epidemiological shifts and advances in treatment options. Long-term toxicity from radiation treatment has become a major concern that may be better mitigated by proton therapy. This review examined the evidence of proton therapy in major subsites within the head and neck to facilitate a greater understanding of the full risks and benefits of proton therapy for head and neck cancer. (publication via


Clinical results of active scanning proton therapy for primary liver tumors. This study reported clinical outcomes of 18 patients including 14 patients with hepatocellular carcinoma (HCC) and 3 patients with intrahepatic cholangiocarcinoma (ICC), treated with active scanning PT. One-year overall survival (OS) was 63%. A significant correlation between worse OS and patient performance status, vascular invasion, and tumor stage was recorded. One-year local control was 90%. Toxicity was low, with a decrease in Child-Pugh score ⩾2 points detected in one patient. No cases of classic radiation-induced liver disease occurred. (publication via

Phase II Study of Hypofractionated Proton Beam Therapy for Hepatocellular Carcinoma. Published by the NCC group in Korea, this study reported outcomes of 45 patients including 37 had recurrent and/or residual disease treated with PBT to a total dose of 70 Gy equivalent in 10 fractions. No grade ≥3 acute toxicity occurred. The median follow-up duration was 35.1 months, local progression occurred in two patients (8.7%). The 3-year rates of LPFS and overall survival (OS) were 95.2% and 86.4%. The study concluded that hypofractionated PBT showed promising LPFS and OS. (publication via


Incidence and Onset of Severe Cardiac Events After Radiotherapy for Esophageal Cancer. The relatively higher cardiac dose exposure for esophageal cancer (EC) may result in the earlier onset of cardiac diseases. This MD Anderson study analyzed 479 patients treated with either IMRT or PBT either preoperatively or definitively. This study found that G3+ cardiac events occurred in 18% of patients at a median of 7 months with a median follow-up time of 76 months. Preexisting cardiac disease (p = 0.001) and radiation modality (IMRT vs PBT) (p = 0.027) were significantly associated with G3+ cardiac events. The mean heart dose, particularly of less than 15 Gy, was associated with reduced G3+ events. Furthermore, G3+ cardiac events were associated with worse overall survival (p = 0.041). This study suggested that optimal treatment approaches should be taken to reduce cumulative doses to the heart, especially for patients with preexisting cardiac disease. (publication via

Proton Beam Therapy Is a Safe and Effective Treatment in Elderly Patients With Esophageal Squamous Cell Carcinoma (ESCC). This study from Japan reported results of 54 esophageal cancer patients who are over 75 years old treated with PBT. 38 inoperable patients (70.4%) and 16 operable patients (29.6%). The five-year overall and cancer-specific survival rates were 56.2% and 71.7%, respectively. The five-year local control rate was 61.8%, and local recurrence occurred within 13 months in 82.4% of patients. There was no grade 3 or higher toxicity, excluding three patients with grade 3 esophageal ulcers. The authors concluded that PBT may become an alternative treatment with lower toxicity in elderly patients with ESCC, compared to surgery or conventional X-ray radiotherapy. (publication via


Scanning Beam Proton Therapy (SPT) Versus Photon IMRT for Stage III Lung Cancer: Comparison of Dosimetry, Toxicity, and Outcomes. This study reviewed dosimetric data and clinical outcomes of 64 stage III lung cancer patients treated with SPT (34) + IMRT (30). Mean dose to lung, heart, and esophagus was lower in the SPT group, with most benefit in the low-dose region (lungs, 9.7 Gy vs 15.7 Gy for SPT vs IMRT, respectively [P = .004]; heart, 7 Gy vs 14 Gy [P = .001]; esophagus, 28.2 Gy vs 30.9 Gy [P = .023]). Esophagitis and dermatitis grades were not different between the 2 groups. Grade 2+ pneumonitis was 21% in the SPT group and 40% in the IMRT group (P = .107). Overall survival and progression-free survival were not different between SPT and IMRT. The study concluded that there was no statistically significant difference in toxicity rates or survival, although there may have been a trend toward lower rates of pneumonitis. (publication via


Proton Reirradiation: Expert Recommendations for Reducing Toxicities and Offering New Chances of Cure in Patients With Challenging Recurrence Malignancies. Published in Seminar Radiation Oncology, this review article evaluated clinical data up-to-date on proton reirradiation for local and regional recurrence. As photon reirradiation can be associated with considerable risks of high grade acute and late toxicities, protons offer significant advantages for reirradiation. The renowned experts in the fields of lung cancer, head and neck malignancies, and pelvic malignancies provided assessment on proton reirradiation. In conclusion, this review article pointed out that in select patients, PT is often the best modality for delivering reirradiation. IMPT offers increased dose conformality and even further advantages over photon therapy in the setting of reirradiation. IMPT and volumetric image-guidance with proton therapy makes reirradiation dose escalation more feasible. (publication via

Model-based approach

First experience with model-based selection of head and neck cancer patients for proton therapy. Published by the Groningen group in the Green Journal, this study reported the first experience in model-based selection (MBS) of HNC patients in the Netherlands. 227 patients were included in this study where 141 (62%) qualified for plan comparison when exceeded any ΔNTCP-thresholds defined in Dutch National Indication Protocol.  80 (35%) patients were eventually selected for proton therapy. Most patients were selected based on the ΔNTCP for dysphagia-related toxicities. The study concluded that model-based selection of patients with HNC for proton therapy is clinically feasible. Approximately one third of HNC patients qualify for protons. (publication via

Key papers March - April 2020


Combining Immunotherapy with Radiation Therapy in Non-Small Cell Lung Cancer. As immunotherapy, especially the immune checkpoint inhibitors have recently been demonstrated to improve survival in metastatic and locally advanced non-small cell lung cancer (NSCLC), this review article looked into the current roles of radiation therapy as immunostimulatory with the potential to enhance the efficacy of immunotherapy. This review detailed the intersection of radiotherapy and immunotherapy, their potential to have combined synergistic responses, and highlighted existing preclinical and clinical data and ongoing clinical trials of combined immunotherapy and radiotherapy across all NSCLC stages. (publication via )

NTCP Models for Severe Radiation Induced Dermatitis After IMRT or Proton Therapy for Thoracic Cancer Patients. In order to analyze the incidence of acute radiation induced dermatitis (RD) and develop normal tissue complication probability (NTCP) models for severe RD in thoracic cancer patients treated with Intensity-Modulated RT (IMRT) or Passive Scattering Proton Therapy (PSPT), this study analyzed 166 NSCLC patients prospectively treated at a single institution with IMRT (103 patients) or PSPT (63 patients). All patients were treated to a prescribed dose of 60 to 74 Gy in conventional daily fractionation with concurrent chemotherapy. The Lyman-Kutcher-Burman (LKB) NTCP model recast for absolute dose-surface histogram (DSH) and the multivariable logistic model were adopted. This study reported that 15 of 166 (9%) patients developed severe dermatitis (grade 3). RT technique did not impact RD incidence. The total gross tumor volume (GTV) size was the only non dosimetric variable significantly correlated with severe RD (p = 0.027). The NTCP models showed comparably high prediction and calibration performances. (publication via )

Lyman-Kutcher-Burman normal tissue complication probability modeling for radiation-induced esophagitis in non-small cell lung cancer patients receiving proton radiotherapy. Published in the Green Journal, this MD Anderson study developed and tested a Lyman-Kutcher-Burman (LKB) NTCP to predict radiation-induced esophagitis (RE) in NSCLC patients receiving passive-scattering proton therapy (PSPT). For the 328 NSCLC patients treated with PSPT, grade 2-3 RE was observed in 136 (41.5%) patients, and no grade 4-5 RE was reported. The optimism-corrected AUC was 0.783 and the test showed significant agreement between predicted and observed morbidity. The authors concluded that their NTCP model showed good predictive performance, however external validation of the model is warranted. (publication via )

Hypofractionated Proton Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase I Trial From the University of Florida and Proton Collaborative Group. Published in the Red Journal, this study reported the safety data from the first multicenter phase I trial investigating the use of hypofractionated proton therapy with concurrent chemotherapy for patients with stage II or III NSCLC. This study followed a stepwise 5+2 dose-intensification protocol with the following dose arms: (1) 2.5 GyRBE/fraction to 60 GyRBE; (2) 3.0 GyRBE/fraction to 60 GyRBE; (3) 3.53 GyRBE/fraction to 60.01 GyRBE; and (4) 4.0 GyRBE/fraction to 60 GyRBE. Eighteen patients were treated, including 5 patients on arms 1 and 2, 7 patients on arm 3, and 1 patient on arm 4. Two SAEs occurred among 7 patients treated at 3.53 GyRBE/fraction; however, per outside expert review, both were attributed to chemotherapy and unrelated to radiotherapy. Although this study closed early due to slow accrual and competing enrollment in NRG 1308 before accrual was met, the authors concluded that hypofractionated proton therapy delivered at 2.5-3.53 GyRBE/fraction to a dose of 60 GyRBE with concurrent chemotherapy has an acceptable toxicity profile. (publication via

Perspectives on the model-based approach to proton therapy trials: A retrospective study of a lung cancer randomized trial. Published in the Green Journal, this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. Three widely used NTCP models for radiation pneumonitis (RP), applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected ΔNTCP value was above a threshold of 5%. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. The authors concluded that the uncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint. (publication via


Acute Toxicities After Proton Beam Therapy Following Breast-Conserving Surgery for Breast Cancer: Multi-institutional Prospective PCG Registry Analysis. This is the report of the prospective multi-institutional Proton Collaborative Group registry study. 82 patients received PBT and their adverse events (AEs) were recorded prospectively at each institution. Median follow-up was 8.1 months. Median dose was 50.4 Gy in 28 fractions. 90% patients received a lumpectomy bed boost and 83% patients received regional nodal irradiation. Six patients (7.3%) experienced grade 3 AEs (5 with dermatitis, 5 with breast pain). Body mass index (BMI) was associated with grade 3 dermatitis (P = .015). Fifty-eight patients (70.7%) experienced grade ≥2 dermatitis. The authors concluded that PBT including RNI after BCS is well-tolerated. Elevated BMI is associated with grade 3 dermatitis. (publication via )

End-of-Range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer. Published in the Red Journal, this MGH study looked into the possible causes to the high rate of rib fracture that reported in the recent MGH prospective trial (NCT01340495) which revealed improved dosimetry, favorable disease control, and minimal toxicity, but an increased rib fracture rate of around 7%, as compared to about 1.3% for patients with breast cancer after contemporary external beam radiation therapy. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). 13 of 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased, suggesting possible end-of-range radiobiological effects with increased RBE. The authors concluded that the increased rib fracture rate is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy. (publication via )


Patient Reported Outcomes Following Proton Pencil Beam Scanning vs. Passive Scatter/Uniform Scanning for Localized Prostate Cancer: Secondary Analysis of PCG 001-09. This study evaluated PROs with the Expanded Prostate Cancer Index Composite (EPIC) instrument for men with localized PC enrolled in PCG 001-09 (NCT01255748) that were treated with proton PBS or PS/US. Three-hundred-and-four men completed EPIC at baseline (72 received PBS and 232 received PS/US). This study compared mean changes in EPIC scores, as well as the proportions of men experiencing a one- and two-fold minimally important difference (MID) in domain scores. The proportion of men reporting a 1-MID decline at 12 months for PBS and PS/US was 34.3% and 27.4% for urinary QOL (P = 0.27); 40. 1% and 40.9% for bowel QOL (P = 0.36); and 30. 1% and 36.6% for sexual QOL (P = 0.94). Corresponding 2-MID declines for PBS and PS/US were observed in 26.9% and 13.2% of men for urinary QOL (P = 0.01), 35.3% and 29.1% for bowel QOL (P = 0.33); and 16.4% and 18.1% for sexual QOL (P = 0.76). The results of this analysis show differences between PBS and PS/US with regards to two-fold MID changes in urinary function at 12 months, but no differences for average score declines over time. (publication via )

Head and Neck

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. This study compared 46 IMPT and 259 VMAT patients acute toxicities and reported that IMPT was associated with lower PEG-tube placement (p = 0.001) and less hospitalization ≤60 days post-RT (p < 0.001), with subgroup analysis revealing strongest benefits in patients treated definitively or with concomitant chemoradiotherapy (CRT). IMPT was associated with a relative risk reduction of 22.3% for end-of-treatment narcotic use. Patients reported reduced cough and dysgeusia with IMPT (p < 0.05); patients treated definitively or with CRT also reported feeling less ill, reduced feeding tube use, and better swallow. IMPT is associated with improved patient reported outcomes. Mucositis, dysphagia, and pain were decreased with IMPT. (publication via )


Late contrast enhancing brain lesions in proton treated low-grade glioma patients: clinical evidence for increased periventricular sensitivity and variable RBE. Late radiation-induced contrast enhancing brain lesions (CEBL) on MR images after proton therapy of brain tumors have been observed to occur frequently in regions of high linear energy transfer (LET) and in proximity to the ventricular system. Published in the Red Journal, the Heidelberg study analyzed 110 low-grade glioma patients treated with proton therapy to determine if the risk for CEBLs is increased in proximity to the ventricular system and if there is a relationship between relative biological effectiveness (RBE) and LET. Out of 110 patients, 23 exhibited one or several CEBLs on follow-up MR images. This study also presented a voxel-level model that predicts the localization of late MRI contrast change and extrapolate a patient-level model that allows treatment-plan based risk prediction. The findings of this study present clinical evidence for an increased risk in ventricular proximity and for a proton RBE that increases significantly with increasing LET. (publication via )

Proton beam therapy utilization in adults with primary brain tumors in the United States. Based on the National Cancer Database, a total of 1,296 patients received PBT from 2004 and 2015 for treatment of their primary brain tumor. High-grade glioma, medulloblastoma, ependymoma, other glioma, other malignant, and other benign intracranial histologies made up 39%, 20%, 13%, 12%, 13%, and 2% of the cohort, respectively. The number of patients treated per year increased from 34 to 300 in years 2004 to 2015. The majority of the patient population was 18-29 years of age (59%), Caucasian race (73%), had median reported income of over $63,000 (46%), were privately insured (68%), and were treated at an academic institution (70%). (publication via )


Comparison of clinical outcomes between passive scattering versus pencil-beam scanning proton beam therapy for hepatocellular carcinoma. A study by the Samsung group from Korea published in the Green Journal. A total of 103 patients treated with proton therapy including 70 in the PS group and 33 in the PBS group were analyzed. This study found no significant differences in the rates of overall survival (OS), in-field local control (IFLC), out-field intrahepatic control (OFIHC), extrahepatic progression-free survival (EHPFS), and complete response (CR) between the matched groups. There is no significant difference in the toxicity profiles between PS and PBS PBT for primary HCC. (publication via )

Proton beam re-irradiation for gastrointestinal malignancies: a systematic review. A systematic review assessing for reports of proton-beam reirradiation for recurrent or second primary GI cancers. 7 included studies reported on proton-beam re-irradiation for the following disease sites: esophageal (n=2), pancreas (n=1), liver (n=2), rectal (n=1), and anal (n=1). Study sizes varied from as few as 1 to as many as 83 patients. Local control rates, with variable follow-up, ranged from 36-100%. All median overall survival values, when reported, were greater than 1 year. Across all studies, there were 2 acute (esophagopleural fistula in esophageal cancer, small bowel perforation in pancreatic cancer) and 1 late (esophageal ulcer in esophageal cancer) grade 5 toxicities, all favored to be due to progressive disease, rather than proton-beam re-irradiation. (publication via )

Proton beam radiotherapy for anal and rectal cancers. A review article looked at the current status of PBT for anal and rectal cancers. PBT offers appealing potential to reduce toxicity, increase patient compliance, minimize treatment breaks, and enable dose escalation or hypofractionation, however, data on the benefit of PBT for rectal and anal cancer is derived primarily from preclinical planning studies for neoadjuvant treatment, therefore unclear whether statistically significant differences in dose distributions translate to meaningful differences in acute and late toxicity. In cases where prognosis is favorable, PBT may mitigate long-term morbidity such as secondary malignancies, femoral fractures, and small bowel obstruction. (publication via )

Proton beam radiotherapy for pancreas cancer. A review article examined up to date data of PBT for pancreatic cancer. For both resectable and unresectable pancreatic cancer, the clinical outcome data is limited but very encouraging and supports the need for additional trials to fully explore the benefits of PBT. Existing data indicate that PBT combined with chemotherapy in the preoperative, adjuvant, and definitive settings is extremely well-tolerated and allows for the possibility of dose intensification. Several ongoing trials are investigating hypofractionated dose-escalated proton radiotherapy in combination with chemotherapy for unresectable/marginally resectable disease. (publication via )

Proton beam therapy for liver cancers. A review article examined the latest utilization of PBT for hepatocellular carcinoma and cholangiocarcinoma, as well as liver metastasis. The dosimetric advantage of PBT over XRT in sparing uninvolved liver from low and moderate doses clearly translates into clinically meaningful benefit for some patients with liver cancer. PBT for HCC has been evaluated over several decades with low rates of toxicity and excellent long-term LC even in patients with large tumors. Based on these outcomes, PBT receives the highest level of support (Group 1 recommendation) in the 2017 ASTRO Proton Beam Therapy Model Policy. For patients with intrahepatic cholangiocarcinoma and liver metastases, favorable tumor control, survival, and toxicity outcomes have been demonstrated after ablative PBT; however, additional research is needed to better understand the role of such therapy in the context of other liver-directed therapies. While the potential benefit from PBT for liver cancers, especially HCC, is largely undisputed, there is a lack of guidance about optimal patient selection for PBT. As such, identifying patient subgroups that are most appropriate for PBT should be a priority in future research. (publication via )

The emerging role of proton therapy for esophagus cancer. This review article discussed the emerging role of PBT for esophageal cancer, including rationale, treatment planning, early dosimetric and clinical comparisons of PBT with photon-based techniques, ongoing prospective trials, and potential areas of opportunity for the incorporation of PBT with the goal of improving outcomes for patients with esophageal cancer. Clinical data support the feasibility, efficacy, and favorable AE profile for curative intent proton-based CRT for esophageal cancer, in addition, suggesting PBT may be associated with improved survival potentially attributable to toxicity reduction, including cardiopulmonary sparing or through a reduction in severe treatment-related lymphopenia which has been associated with disease recurrence and OS. (Publication via )

Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer. Published in JCO (Journal of Clinical Oncology), this randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between PBT and IMRT for locally advanced esophageal cancer. 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. This study reported the mean TTB was 2.3 times higher for IMRT (39.9) than PBT (17.4); the mean postoperative complications score was 7.6 times higher for IMRT (19.1) versus PBT (2.5); the 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. This study concluded that for locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS. (publication via )


The role of proton therapy in pediatric malignancies: Recent advances and future directions. This systematic review provides latest outcomes data after proton therapy across the common pediatric disease sites. It discusses the main attempts to assess comparative efficacy between proton and photon radiotherapy concerning toxicity, and recent efforts of multi-institutional registries aimed at accelerating research to better define the optimal treatment paradigm for children requiring radiotherapy for cure. (Publication via )


Three-Year Results of a Prospective Statewide Insurance Coverage Pilot for Proton Therapy: Stakeholder Collaboration Improves Patient Access to Care. Prior authorization remains a barrier to proton therapy access and is associated with frequent denials and treatment delays. This insurance coverage study is conducted with a statewide self-funded employer (n = 186,000 enrollees), incorporating a value-based analysis and ensuring preauthorization for appropriate indications. Coverage was ensured for prospective trials and five evidence-supported anatomic sites. This study found that appropriate access to proton therapy does not necessitate overuse or significantly increase comprehensive medical costs. Objective evidence-based coverage polices ensure appropriate patient selection. Stakeholder collaboration can streamline patient access while reducing administrative burden. (publication via )

The European Organisation for Research and Treatment of Cancer, State of Science in Radiation Oncology and Priorities for Clinical Trials Meeting Report. This meeting identified five themes i.e. radiobiology-based biomarkers, new technologies - particularly proton beam therapy, combination systemic and radiation therapy, management of oligometastatic disease and AI opportunities as the potential advances and research priorities in the field of radiation oncology. Detailed recommendations for research focus have been made. (Publication via )

Particle therapy in Europe. A review article looked at the status of clinical utilization of particle therapy such as protons or heavier ions in Europe. From the aspects of clinical experience and current indications, randomized clinical trials and new evidence-based methodologies to the prospective clinical databases and collaborative networks, the authors suggested that particle therapy holds great promise to improve the therapeutic outcome of cancer patients treated with this modality, however, there is an urgency to produce high quality clinical evidence. The collaboration across institutions and countries is needed to secure evidence-based implementation of particle therapy. (publication via )

Key papers January - February 2020


Long-term Health Related Quality of Life in Pediatric Brain Tumor Survivors Treated with Proton Radiotherapy at <4 Years of Age. Fifty-nine brain tumor children < 4 years old received PRT were followed for the median 9.1 years (5.5-18 years). The report of long-term health related quality of life (HRQoL) was assessed by child self report and parent proxy report, with which the result was presented by total core (78.4 and 72.9); physical (82.9 and 75.2), psychosocial (76.0 and 71.6) emotional (74.4 and 70.7), social (81.2 and 75.1), school (72.4 and 69.9). Parent-reported HRQoL fell within a previously defined range for healthy children in 37.5% of patients, and for children with severe health conditions in 45% of patients. This study concluded that long-term HRQoL among brain tumor survivors treated with proton therapy at a very young age is variable with over a third achieving HRQoL levels commensurate with healthy children. (publication via


Neurocognitive function and quality of life after proton beam therapy for brain tumour patients. published in the Green Journal, this multicenter study reported 62 brain tumor adult patients neurocognitive function after PBT. For two years of followup time, this study reported that self-reported and objectively measured neurocognition and most other QoL domains remained largely stable. Slight deterioration was associated with tumors located in the left hemisphere and with an increase in relative volume of the anterior cerebellum that received doses of 30-40 Gy(RBE). (publication via

Head and Neck

Reduced radiation-induced toxicity by using proton therapy for the treatment of oropharyngeal cancer. Published in the British Journal of Radiology by the Groningen group, this review paper examined the outcome reports of oropharyngeal cancer patients treated PBT patients. Oropharyngeal cancer has better survival than patients with squamous cell carcinoma of other head and neck subsites, especially when related to human papillomavirus. The prevention of radiation-induced xerostomia and dysphagia and subsequent improvement of health-related quality of life can be obtained by applying proton therapy. Proton therapy results in lower dose levels in multiple organs at risk, which translates into reduced acute toxicity. The model-based approach for selecting patients for proton therapy in the Netherlands was discussed in this review. (publication via

Minimal acute toxicity from proton beam therapy for major salivary gland cancer. This multicenter study reported acute toxicity outcomes of patients with major salivary gland cancers registered on the Proton Collaborative Group REG001-09 trial (NCT01255748). 105 patients including parotid (N = 90) and submandibular gland (N = 15) tumors, were treated with PBT to the median dose of 66.5 GyE in 33 fractions across seven institutions. The result shown that with the median follow-up 14.3 months, acute grade 2 or higher toxicity included nausea (1.5%), dysgeusia (4.8%), xerostomia (7.6%), mucositis (10.5%) and dysphagia (10.5%). The study concluded that PBT should be strongly considered when ipsilateral radiation therapy is indicated for major salivary gland cancer based on a considerably lower incidence of acute grade 2 or higher toxicity in this analysis compared to historical IMRT outcomes. (publication via


Therapeutic results of proton beam therapy with concurrent chemotherapy for cT1 esophageal cancer and salvage endoscopic therapy for local recurrence. This study from Japan reported the efficacy of 44 clinical T1 esophageal cancer patients treated with concurrent chemo-proton therapy (CCPT). 43 patients (98%) achieved primary complete response. Among the 44 patients, the 3-year overall survival rate was 95.2%. Five patients (11%) developed local recurrence. The study concluded that CCPT is an effective treatment for cT1 ESCC and careful endoscopic follow-up allows preferable local control with salvage endoscopic treatment. (publication via


Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators. With Medline database, the study found that limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet. (publication via 


ACR-ASTRO Practice Parameter for the Performance of Proton Beam Radiation Therapy. Published in the American Journal of Clinical Oncology, The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for proton beam radiation therapy. This practice parameter is developed to serve as a tool in the appropriate application of this evolving technology in the care of cancer patients or other patients with conditions where radiation therapy is indicated. It addresses clinical implementation of proton radiation therapy, including personnel qualifications, quality assurance standards, indications, and suggested documentation. It is to guide technical use of proton therapy to focus on the best practices required to deliver proton therapy safely and effectively. (publication via 

A population-based assessment of proton beam therapy utilization in California. Based on data from California Cancer Registry, this study reported that of the 2,499,510 people with a cancer diagnosis during the study period, 578,632 (23%) received some type of RT, and of these, 8609 received PBT (1.5%). PBT was most often used to treat cancers of the prostate (41.3%), breast (14.0%), eye (11.7%), lung (6.1%), and brain (6.0%). PBT use was highest in 2003-2004 and then declined over time. PBT use was significantly associated with being white or male, younger age, higher socioeconomic status, Medicare or dual Medicare-Medicaid insurance, uninsured/self-pay status, and proximity to treatment. (publication via

Insurance Coverage for Adjuvant Proton Therapy in the Definitive Treatment of Breast Cancer. Published by the Jacksonville group, this study set to determine factors that influence insurance approval for breast cancer patients for whom adjuvant proton therapy (PT) is recommended. Among 131 insured patients, 96 patients (73%) had policies that "covered" PT, it was found that insurance "coverage" for PT was not associated with final approval nor was lack of "coverage" associated with denial. Insurance approval was obtained for 93/96 patients (97%) with insurance that covered PT versus 23/35 patients (66%) whose insurance did not cover PT. This study found that the only parameter that significantly influenced approval for treatment with PT was insurance type combined with potential coverage with ultimate approval rates ranging from 54% to 100%. (publication via )

Trends, Quality, and Readability of Online Health Resources on Proton Radiotherapy. Published in the Red Journal, this study examined the quality and readability of the Internet for online health resources (OHR) about proton radiotherapy (PRT). This study found that the volume of search on "proton therapy" increased by an average of 2.0% each year for the last 15 years, however PRT websites require reading levels much higher than currently recommended, making PRT OHR less accessible to the average patient. High quality online resources at the appropriate reading level may increase comprehension of PRT and improve patient autonomy and informed decision among radiation oncology patients. (publication via

Design, Implementation, and in Vivo Validation of a Novel Proton FLASH Radiation Therapy System. Published in the Red Journal by the UPenn group, this paper reported the effect of FLASH proton versus standard dose rate PRT on tumors and normal tissues in mice. Dose rates of 78 ± 9 Gy per second and 0.9 ± 0.08 Gy per second for the FLASH and standard PRT were delivered. Whole abdominal FLASH PRT at 15 Gy significantly reduced the loss of proliferating cells in intestinal crypts compared with standard PRT. Studies with local intestinal irradiation at 18 Gy revealed a reduction to near baseline levels of intestinal fibrosis for FLASH-PRT compared with standard PRT. Despite this difference, FLASH-PRT did not demonstrate tumor radioprotection after 12 or 18 Gy irradiation. The study concluded that FLASH-PRT decreases acute cell loss and late fibrosis after whole-abdomen and focal intestinal RT, whereas tumor growth inhibition is preserved between the 2 modalities. (publication via 

Hadrontherapy for cancer. An overview of HTA reports and ongoing studies Hadron therapy often refers to proton therapy (PBT) and carbon ion therapy (CIRT) are not new technologies, but have been subject to assessment by several Health Technology Assessment (HTA) agencies over the past years. This review paper summarized the evidence findings from most recent HTA reports and provided a description of currently ongoing clinical studies. The main claimed benefit of PBT and CIRT is a reduction in toxicity compared to conventional radiation therapy, resulting in fewer harms and a lower risk of induced secondary malignancies. The overview of available evidence for PBT is drawn from five HTA reports on a total of 16 oncology indications, including 295 primary studies of any study design. All included HTA reports concluded that the quality of research is low and that there is insufficient evidence to support the claimed benefits of PBT. This review also pointed out that there is a lack of agreement on the appropriate study design and lack of coordination between centers in the production of joint research protocols to generate the necessary evidence. This has led to the production of numerous small, poorly designed and reported studies. (publication via  

Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer. Published in JAMA, the paper by the UPenn group accessed PBT side effects in the concurrent chemoradiotherapy for locally advanced cancer setting. 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent were matched with 391 PBT and 1092 photon-based therapy. The result shown that proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least grade 3 (0.31; 95% CI, 0.15-0.66, P = .002), 90-day adverse events of at least grade 2 (0.78; 95% CI, 0.65-0.93, P = .006), and decline in performance status during treatment (0.51; 95% CI, 0.37-0.71; P < .001). There was no difference in disease-free or overall survival. (Publication via )

Key papers November - December 2019


Hypofractionated Radiation Therapy for Unresectable/Locally Recurrent Intrahepatic Cholangiocarcinoma. This study by MGH retrospectively analyzed 66 patients with unresectable intrahepatic cholangiocarcinoma (ICC) who were treated with hypofractionated proton (32 patients) or photon (34 patients) radiation therapy (HF-RT). Median RT dose was 58.05 Gy, all delivered in 15 daily fractions. The 2-year outcomes were 84% local control (LC) and 58% OS. On multivariate analysis for OS, compared with photon RT, there was a trend towards improved survival with proton RT (HR 0.50; p = 0.05). This study concluded that HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent ICC. (publication accessible via )

Clinical Outcomes of Patients With Unresectable Cholangiocarcinoma Treated With Proton Beam Therapy. This study from Taiwan retrospectively examined 30 patients with unresectable CC who were treated with PBT to a total dose of 72.6 GyRBE. The 1-year local control, regional control, and distant metastases-free rates were 88%, 86%, and 68%, respectively. The median overall survival and progression-free survival were 19.3 and 10.4 months. The most common acute toxicity was acute skin reactions which were rarely severe (grade III: 7% of patients). Three and 2 patients had grade III-IV toxicities and radiation-induced liver disease. There were no deaths caused by PBT or concurrent chemotherapy. The authors concluded that PBT is clinically useful in patients with unresectable CC. (publication accessible via )

Proton beam therapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus. Hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT) is rare and regarded as an advanced disease stage with poor prognosis. This study from Japan reported outcomes of 21 HCC patients with IVCTT treated with proton therapy. For acute toxicities, dermatitis of grade 1-2 was observed in all patients, but no grade 3 or higher late toxicity events were encountered. The overall survival (OS) rates for all patients were 62%, 33%, and 19% at 1, 2, and 3 years, respectively. No local recurrences for the treated lesions, including IVCTT, were observed. The authors concluded that PBT is safe and effetive and is an important treatment option for HCC patients with IVCTT. (publication accessible via )

Head and Neck

Proton radiotherapy and treatment delay in head and neck squamous cell carcinoma. Based on the national cancer database, there were total of 175,088 patients with HNSCC receiving either photon or proton RT. This analysis pointed out that patients receiving proton RT were more likely to be white, reside in higher income areas, and have private insurance. Proton RT was associated with delayed RT initiation compared to photon RT (median 59 days vs. 45, P < 0.001). Receipt of proton therapy was independently associated with RT initiation beyond 6 weeks after diagnosis or surgery. In the context of adjuvant proton RT, increases in treatment delay were associated with worse overall survival. This study concluded that use of proton therapy is associated with delayed RT in both the definitive and adjuvant settings for patients with HNSCC and could be associated with poorer outcomes. (publication accessible via )

High-dose conformal proton therapy for clinical perineural invasion in cutaneous head and neck cancer. Perineural invasion (PNI) is an uncommon (<5%) which refers to tumor cell invasion extensive enough to cause clinically detectable deficits of the involved nerve. It is a high-risk feature observed with non-melanomatous skin cancer (NMSC) more commonly seen in those with squamous cell carcinoma. The primary management options including radiotherapy with or without surgery, with local control rates exceeding 50%. Given the overwhelming influence of local control on disease control and survival, dose escalation and complication mitigation through hyperfractionated and high-dose conformal skull-base proton therapy are strategies to improving the therapeutic window in patients with cutaneous head and neck cancer with clinical PNI. (publication accessible via

Minimal acute toxicity from proton beam therapy for major salivary gland cancer. This is a multi-institutional study enrolled on the Proton Collaborative Group REG001-09 trial (NCT01255748).  This study evaluated treatment parameters and acute toxicity outcomes of patients with major salivary gland cancers. 105 patients including parotid (N = 90) and submandibular gland (N = 15) were treated to the median PBT dose of 66.5 GyE in 33 fractions. This study reported acute grade 2 or higher toxicity included nausea (1.5%), dysgeusia (4.8%), xerostomia (7.6%), mucositis (10.5%) and dysphagia (10.5%). The authors concluded that PBT should be strongly considered when ipsilateral radiation therapy is indicated for major salivary gland cancer based on a considerably lower incidence of acute grade 2 or higher toxicity in this analysis compared to historical IMRT outcomes. (publication accessible via )

Trends and Disparities of Proton Therapy Use among Patients with Head and Neck Cancer: Analysis from the National Cancer Database (2005-14). This is a study by the Memorial Sloan Kettering based on the national cancer database. This analysis found that among the 220,491 patients who received any radiation therapy as part of their initial treatment course, only 417 (0.2%) of whom received proton therapy. The use of protons had a small increase from 0.13% in 2005-06 to 0.41% by 2013-14 (P < .001). The most common primary sites treated with proton therapy were the nasal cavity/nasopharynx and the oral cavity. Most patients had T4 disease. This study concluded that proton use has undergone an incremental increase in the United States but remains an uncommon modality for the treatment of primary head and neck cancer. (publication accessible via 

Proton Beam Therapy for Locally Recurrent Parotid Gland Cancer. This study from Japan evaluated outcomes of PBT for locally recurrent parotid gland cancer. Ten patients were treated to 70.2 Gy equivalents in 32 fractions. With the median follow-up of 24 months, the study reported that the 1-year overall survival and local control rates were 80 %, and the 3-year overall survival and local control rates were 60 %, and no patient experienced grade 3-5 toxicities. This study concluded that PBT could be applied effectively and safely for patients with locally recurrent parotid gland cancer. (publication accessible via )

A Multi-Institutional Experience of Proton Beam Therapy for Sinonasal Tumors. Sixty-nine patients with sinonasal tumors underwent curative intent PBT including 42 patients received de novo irradiation and 27 received reirradiation. With the median follow-up for surviving patients of 26.4 months, this study reported the 3-year overall survival (OS), freedom from distant metastasis, freedom from disease progression, and freedom from locoregional recurrence for de novo irradiation were 100%, 84.0%, 77.3%, and 92.9%, and 76.2%, 47.4%, 32.1%, and 33.8%, respectively for re-RT patients. There were 11 patients with acute grade 3 toxicities. Late toxicities occurred in 15% of patients, with no grade ≥3 toxicities. No patients developed vision loss or symptomatic brain necrosis. This study concluded that PBT may be a safe and efficacious treatment option for patients with sinonasal tumors. (publication accessible via 


Clinical outcomes and toxicity of proton beam radiation therapy for re-irradiation of locally recurrent breast cancer. This retrospective study analyzing 16 patients with locally recurrent breast cancer who underwent re-irradiation to the chest wall with PBT to the median dose of 50.4 CGyE in 28 fractions. With the median follow-up time was 18.7 months, this study reported no local failures observed after re-irradiation. Grade 3-4 acute skin toxicity was observed in 5 (31.2%) patients. Four (25%) patients developed chest wall infections during or shortly (2 weeks) after re-irradiation. Late grade 3-4 fibrosis was observed in only 3 (18.8%) patients. Grade 5 toxicities were not observed. Pneumonitis, telangiectasia, rib fracture, and lymphedema occurred in 2 (12.5%), 4 (25%), 1 (6.3%), and 1 (6.3%) patients, respectively. This study concludes that re-irradiation with PBT for recurrent breast cancer has acceptable toxicities. (publication accessible via


Proton therapy for non-small cell lung cancer: the road ahead. This latest review article examined the up-to-date clinical data of PBT for both early stage and locally advanced stage NSCLC. In particular, this review analyzed the reasons for the negative results of the only randomized phase II trial for a benefit of protons over photons in advanced NSCLC. This review points out that the greater experience in proton planning and delivery could lead to better outcomes, and such experience is a requisite to achieving desired results. The overall lesson learned from utilizing the suboptimal design and execution of the phase II study will be hard-felt throughout the coming years. This only RCT result exacerbates the conundrum faced by those attempting to test proton therapy in NSCLC mainly due to insurance companies wanting data before they authorize a modality (protons). This review again stated that we must have more randomized results in order to understand whether proton therapy does provide a benefit in the advanced NSCLC setting. In addition, this review confirms that promises of protons in terms of reducing toxicity and suggests ways of advancing protons for NSCLC to the next level. (publication accessible via )


Hypofractionated Proton Therapy in Early Prostate Cancer: Results of a Phase I/II Trial at Loma Linda University. A cohort of 146 patients with low-risk prostate cancer were treated to 60 Gy (cobalt Gy equivalent) of proton therapy (20 fractions of 3.0 Gy per fraction) in 4 weeks. With the median followup of 42 months, this study reported that acute grade 2 urinary toxicity occurred in 16% of the patients; acute grade 2 or higher gastrointestinal toxicity was seen in 1.7%. At 9 months, 1 patient had late grade 3 urinary toxicity, which resolved by 12 months; no grade 3 gastrointestinal toxicities occurred. The 3-year biochemical survival rate was 99.3% (144/145). This study made a conclusion that hypofractionated proton therapy of 60 Gy in 20 fractions was safe and effective for patients with low-risk prostate cancer. (publication accessible via

MRI-based IMPT planning for prostate cancer. Published in the Green Journal, this study led by MGH aimed to quantify the clinical applicability of converted MR images as a substitute of CT for IMPT treatment of the prostate. Using MRCAT (Magnetic Resonance for Calculating ATtenuation), a Philips-developed technology which produces a synthetic CT image consisting of five HU from a specific set of MRI acquisitions, IMPT plans were generated on the MRCAT for each of ten patient.  The plans were then recomputed onto the nominal planning CT for each patient with robustness analyses performed. This study found that MRCAT plans and their recomputated CT plans showed excellent agreement, with dose perturbations due to setup shifts and range uncertainties well within clinical acceptance. This study concludes the clinical acceptability of substituting MR converted the relative proton stopping power ratio (RSP) images instead of CT for IMPT planning of prostate cancer. This further translates into higher contouring accuracy along with lesser imaging dose. (publication accessible via

Proton beam therapy delivered using pencil beam scanning vs. passive scattering/uniform scanning for localized prostate cancer: Comparative toxicity analysis of PCG 001-09. This study compared PBS toxicity rates with those of passive scattering/uniform scanning (PS/US) in a prospective multicenter registry. For low-to-intermediate risk patients treated with PS/US (n = 1105) or PBS (n = 238), this study found that acute grade ≥2 GI toxicity in PBS did not significantly differ from that with PS/US (2.9% and 2.1%, respectively; P = 0.47), but acute grade ≥2 GU toxicity was significantly higher with PBS (21.9% and 15.1%; P < 0.01). Late grade ≥2 GI and GU toxicities did not differ significantly between groups. This is the first multi-institutional comparative effectiveness evaluation of PBT techniques in prostate cancer, and the authors concluded that differences in acute GU toxicity warrant further evaluation with prospective data. (publication accessible via


Clinical Outcomes of Recurrent Intracranial Meningiomas Treated with Proton Beam Reirradiation. This is a retrospective analysis of 16 patients who received PBRT reRT for recurrent meningiomas. The median PBRT dose was 60 Gy(RBE) and the median follow-up was 18.8 months. At last follow-up, 7 intracranial recurrences (44%) and 3 disease-related deaths (19%) were found. Median cohort PFS was 22.6 months, with 1- and 2-year PFS of 80% and 43%, respectively. Median OS was not achieved, with 1- and 2-year OS of 94% and 73%; all deaths were felt to be related to meningioma. Overall late grade 3+ toxicity rate was 31%. The authors concluded that PBRT reRT achieved fair intracranial control with low rates of radionecrosis at 1 year after reRT. However, strategies to achieve durable outcomes are needed, particularly for high-grade tumors. (publication accessible via 


Superior Intellectual Outcomes After Proton Radiotherapy Compared With Photon Radiotherapy for Pediatric Medulloblastoma. Published in the Journal of Clinical Oncology, this multi-center study compared the intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT. This study examined intelligence data from 79 patients (37 PRT, 42 XRT) and reported that the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The authors concluded that PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, and this study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma. (publication accessible via )

Outcomes following proton therapy for Ewing sarcoma of the cranium and skull base. This study by the University of Florida, Jacksonville, reviewed 25 patients (≤21 years old) with nonmetastatic Ewing sarcoma of the cranium and skull base treated with PBT. This study reported that with the median follow-up of 3.7 years, the 4-year local control, disease-free survival, and overall survival rates were 96%, 86%, and 92%, respectively, with no patient lost. Two patients experienced in-field recurrences. One patient experienced bilateral conductive hearing loss requiring aids, two patients developed intracranial vasculopathy, and 6 patients required hormone replacement therapy for neuroendocrine deficits. None developed a secondary malignancy. This study concludes that PBT is associated with a favorable therapeutic ratio in children with large Ewing tumors of the cranium and skull base with excellent local control and no marginal recurrences, however treatment dosimetry predicts limited long-term neurocognitive and neuroendocrine side effects. (publication accessible via

Health economics

A systematic review of health economic evaluations of proton beam therapy for adult cancer: Appraising methodology and quality. This review appraised the cost-utility analyses (CUAs) in terms of the methodology and quality for proton therapy. Having identified seven PBT CUA studies in adult disease, the review pointed out that health economic evaluations of PBT were based on the single arm studies or dose-response models derived from radiobiological and epidemiological studies. These CUAs were lack of transparency (clarity in the description and assumptions of the model and identification of model inputs) and validity (how well the model reflects reality) which the external validation of the model outputs was absent. The review concluded that the transparency and external validation were key areas for improvement in future CUAs for PBT. (publication accessible via


Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer. Published in JAMA Oncology, this study was set to assess whether PRT in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy. Based on the database of a large academic health system, this retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent. This study reported that inn propensity score weighted-analyses, proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least grade 3 (P = .002), 90-day adverse events of at least grade 2 (P = .006), and decline in performance status during treatment (P < .001). There was no difference in disease-free or overall survival. The conclusion of this study is that proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival. Prospective trials are warranted to validate these results. (publication accessible via )

Proton beam therapy - perspectives on the National Health Service England clinical service and research programme. A review on proton therapy situation in the UK. Since the first proton therapy center opening in Manchester in 2018, by September 2019, 108 patients had started treatment, 60 pediatric, 19 teenagers and young adults, and 29 adults. The review highlighted the vision of building a research capability including translational pre-clinical biological and physical studies such as exploring differences of DNA damage between proton irradiation and X-rays; cellular processes of DNA damage response; the effects on tumor and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents and the ultra-high dose rate FLASH irradiation. (publication accessible via )

Incorporating NTCP into Randomized Trials of Proton Versus Photon Therapy. This study proposed and simulated a model-based methodology to incorporate heterogeneous treatment benefit of proton therapy versus photon therapy into randomized trial designs, using radiation-induced pneumonitis (RP) as an exemple. ΔNTCP data from in silico treatment plans for photon therapy and proton therapy for patients with locally advanced lung cancer as well as randomly sampled clinical risk factors were included in simulations of trial outcomes. By converting trial results into probability distributions, this study demonstrated large heterogeneity in predicted benefit, and provided a randomized measure of the precision of individual benefit estimates. The authors suggested quantifying the benefit of proton therapy referral, based on the combination of NTCP models, clinical risk factors, and traditional randomization. (publication accessible via 

Dose distribution of intensity-modulated proton therapy with and without a multi-leaf collimator for the treatment of maxillary sinus cancer: a comparative effectiveness study. Using collimation can sharpen the penumbra towards surrounding normal tissue in the low energy region of the proton beam, this study from Japan thus examined how much the dose to the normal tissue was reduced when IMPT with PBS was performed using a multi-leaf collimator (MLC) for patients with maxillary sinus cancer. 26 patients' plans were compared based on D2% and the mean dose to the posterior retina, lacrimal gland, eyeball, and parotid gland were compared between with MLC and without MLC. With MLC, this study found that D2% for the ipsilateral optic nerve was significantly reduced by 0.48 Gy, and the mean dose for the ipsilateral optic nerve was significantly reduced by 1.04 Gy, and the mean dose to the optic chiasm was significantly reduced by 0.70 Gy. The dose to most OARs and the planning at risk volumes were also reduced. This study concluded that the use of an MLC during IMPT for maxillary sinus cancer may be useful for preserving vision and preventing complications. (publication accessible via  )

Retrospective analysis of reduced energy switching and room switching times on throughput efficiency of a multi-room proton therapy center. A 4-room center treating ~90 patients/day, treating for ~7 years underwent a software upgrade which reduced room and energy switching times from ~30 to~20 sec and ~4 sec to ~0.5 sec respectively, this study by ProCure NJ and MSKCC compared patient volumes in two 4 month periods before and after the software change. This study found that for bilateral head and neck and prostate patients, the beam waiting time was reduced by nearly a factor of 3 and the beam delivery times were reduced by nearly a factor of 2.5, and the gantry capacity has increased from approximately 30 patients to 40-45 patients in a 16 h daily operation. (publication accessible via )

Key papers July - October 2019


Clinical Results of Proton Beam Therapy for Esophageal Cancer: Multicenter Retrospective Study in Japan. A large retrospective study of 202 patients (90 inoperable patients and 100 patients (49.5%) had stage III/IV cancer) who were treated with PBT in Japan. This study reported that the 3-year and 5-year overall survival rate was 66.7% and 56.3%. The five-year local control rate was 64.4%. There were two patients with grade three pericardial effusion (1%) and a patient with grade three pneumonia (0.5%). No grade 4 or higher cardiopulmonary toxicities were observed. The authors concluded that PBT for esophageal cancer was not inferior in efficacy and had lower rates of toxicities in comparison to photon radiotherapy. (publication accessible via

A Comparison of Patient-Reported Health-Related Quality of Life During Proton Versus Photon Chemoradiotherapy for Esophageal Cancer. This study by Mayo Clinic aimed to compare Functional Assessment of Cancer Therapy - Esophagus (FACT-E) questionnaire changes during proton (PRT) or photon (XRT) chemoradiotherapy (CRT) for esophageal cancer (EC). 125 patients completed a baseline and post-treatment FACT-E; 63 received XRT and 62 received PRT. This study found that less mean decline in FACT-E score was observed for PRT vs XRT (-12.7 vs -20.6, p=0.026). The authors concluded that for patients receiving CRT for EC, PRT was associated with less decline in FACT-E scores compared to XRT. (publication accessible via


Proton Therapy For Lymphomas: Current State Of The Art. A review of latest development on lymphomas management with proton therapy, including details of proton physic properties, delivery techniques of passive scattering and pencil beam scanning and clinical outcomes. The review evaluated the promising clinical outcomes of PT for Hodgkin lymphoma and Non-Hodgkin lymphoma, even more promising in the setting of relapsed/refractory disease, despite that the reports were often small number of patients by single institute. The review also discussed the uncertainties of PT including RBE and variation caused by tissue density and target motion. Finally the review looked into comparison between proton and photon-based techniques for lymphoma patients, and concluded that a careful selection of patients who may benefit from PT, after a proper plan comparison with modern photon therapy might be a significant step towards.  (publication accessible via ) 

Prostate cancer

Particle therapy for prostate cancer: The past, present and future. A review article by the Japanese researchers about the particle radiotherapy in comparison to photon-based radiation for prostate cancer. Due to a lack of direct evidence, the superiority of particle beam RT over photon beam RT for prostate cancer has not been confirmed in terms of the rates of overall survival or bRFS as end-points. The available data reviewed showed that treatment outcomes with particle beam RT, and the adverse events induced by particle beam RT have consistently been acceptable. Although long-term observation in a large-scale randomized study is necessary for the most accurate evaluation of the efficacy of particle beam RT for prostate cancer, but particle beam RT seems a reasonable RT method delivering a high RT dose safely. The Japanese radiation oncology society is carrying out a multi-institutional prospective study of IMRT, PBT and CIRT, and registration of all studies will be completed by April 2020. (publication accessible via

Cross-modality applicability of rectal normal tissue complication probability models from photon- to proton-based radiotherapy. This study aimed to assess the applicability of photon-based NTCP models to rectum morbidity outcomes following PT for prostate cancer patients. The data of gastrointestinal morbidities (grade >=2) reported by 1151 prostate cancer patients treated with passive scattering PT and 159 patients treated with conventional 3DCRT were analyzed. This study found that photon-based rectal NTCP models either over- or underestimated the clinically observed gastrointestinal morbidity when used on the proton cohort, but four of the six photon-based NTCP models showed a good fit to the photon outcome data. This study concluded that large differences in morbidity predictions between cohorts and modalities, therefore NTCP models should be carefully investigated prior to clinical application. (publication accessible via )

Comparative toxicity outcomes of proton-beam therapy versus intensity-modulated radiotherapy for prostate cancer in the postoperative setting. A case-matched cohort analysis study compared acute and late genitourinary (GU) and gastrointestinal (GI) toxicity outcomes in patients with prostate cancer (PC) who received treatment with postprostatectomy IMRT versus PBT. Three hundred seven men (IMRT, n = 237; PBT, n = 70) were identified, generating 70 matched pairs. The study found that although PBT was superior at reducing low-range (volumes receiving 10% to 40% of the dose, respectively) bladder and rectal doses (all P ≤ .01), treatment modality was not associated with differences in clinician-reported acute or late GU/GI toxicities (all P ≥ .05). Five-year grade ≥2 GU toxicity free survival was 61.1% for IMRT and 70.7% for PBT; and 5-year grade ≥3 GU and GI toxicity free survival was >95% for both groups (all P ≥ .05). (publication accessible via

Extreme hypofractionated proton radiotherapy for prostate cancer using pencil beam scanning: Dosimetry, acute toxicity and preliminary results. A study by the research group in Prague. Two hundred patients with early-stage prostate cancer were treated with IMPT on extreme hypofractionated schedule (36.25 GyE in five fractions), including 93 patients (46.5%) of low-risk, 107 patients (53.5%) intermediate-risk and 29 patients (14.5%) who had neoadjuvant hormonal therapy. With the median follow-up time of 36 months, this study reported acute toxicity was GI (grade) G1-17%, G2-3.5%; GU G1-40%, G2-19%; and no G3 toxicity was observed; late toxicity was GI G1-19%, G2-5.5%; GU G1-17%, G2-4%; and no G3 toxicity was observed. PSA relapse was observed in one patient (1.08%) in the low-risk group and in seven patients (6.5%) in the intermediate-risk group. This study concluded that extreme hypofractionated PBT for prostate cancer is feasible with a low rate of acute toxicity and promising late toxicity and effectivity. (publication accessible via


Protons versus Photons for Unresectable Hepatocellular Carcinoma: Liver Decompensation and Overall Survival. Published in the Red Journal, this single-institution retrospective study compared clinical outcomes of proton versus photon ablative radiation therapy in patients with unresectable HCC. 49 patients were treated with protons and  84 patients with photons to a total dose of 45 Gy in 15 fractions or 30 Gy in 5 to 6 fractions. Patients treated with protons had higher incidence of underlying cirrhosis, while those treated with photons had worse baseline Child-Pugh score and worse baseline ALBI score. With the median follow-up of 14 months, this study reported that proton therapy improved OS (P = .008). The median OS for proton- and photon-treated patients was 31 and 14 months, and the 2-yar OS for proton- and photon-treated patients was 59.1% and 28.6%. There was no difference in local control at 2 years of 93% and 90% for protons and photons. 21 patients developed nonclassic RILD, including 4 proton-treated and 17 photon treated patients which proton therapy was associated with decreased risk of nonclassic RILD (P= .03). This study concluded that proton radiation therapy was associated with improved survival, which may be driven by decreased incidence of posttreatment liver decompensation. (publication accessible via

A comparison of the outcomes between surgical resection and proton beam therapy for single primary hepatocellular carcinoma. There were 314 and 31 patients with single primary nodular HCC ≤ 100 mm without vessel invasion who underwent surgical resection (SR) and PBT were analyzed. The study reported that the median survival time in the SR group was significantly better than in the PBT group (104.1 vs. 64.6 months, p = 0.008) with no difference on the relapse-free survival (RFS) between the two groups. The study concluded that SR may therefore be favorable as an initial treatment for HCC compared to PBT. (publication accessible via )

Proton beam therapy versus stereotactic body radiotherapy for hepatocellular carcinoma: practice patterns, outcomes, and the effect of biologically effective dose escalation. With the National Cancer Database for T1-2N0 HCC patients receiving PBT or SBRT, a total of 71 patients received PBT and 918 patients received SBRT were analyzed. The study reported that PBT was associated with longer survival than SBRT, despite being delivered to HCC patients with multiple poor prognostic factors. PBT may also allow for safer BED escalation, which also independently associated with outcomes. (publication accessible via


Optimizing neoadjuvant radiotherapy for resectable and borderline resectable pancreatic cancer using protons. Approximately 25% of patients diagnosed with pancreatic cancer present with non-metastatic resectable or borderline resectable disease. Preoperative radiotherapy would improve local-regional control, and when preoperative radiotherapy delivered with protons, significant bowel and gastric tissue-sparing is achieved and clinical outcomes indicate that proton therapy does not increase the risk of operative complications nor extend the length of the procedure. Providing the outcomes of a series of 5 patients who received high-dose proton radiotherapy as definitive treatment for unresectable disease who were ultimately able to undergo pancreatectomy, the authors argued that preoperative radiotherapy directed to gross disease and regional lymphatic beds at high risk of harboring microscopic disease appears to be an oncologically rational intervention to reduce this risk, and that proton-based preoperative radiotherapy should be considered for patients with resectable and borderline resectable disease. (publication accessible via 


Proton beam therapy reirradiation for breast cancer: Multi-institutional prospective PCG registry analysis. This study analyzed 50 patients received PBT reRT for breast cancer in the prospective Proton Collaborative Group (PCG) registry. Median reRT dose was 55.1 Gy and median cumulative dose was 110.6 Gy (70.6-156.8). ReRT included regional nodes in 84% (66% internal mammary node [IMN]). Grade 3 AEs were experienced by 16% of patients (10% acute, 8% late). All grade 3 AEs occurred in patients receiving IMN reRT (P = 0.08). At 1 year, LRFS was 93%, and OS was 97%. This study concluded that PBT reRT is well tolerated with favorable local control. Toxicity was acceptable despite median cumulative dose > 110 Gy (publication accessible via

Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol. This is the trial protocol of RadComp. This multi-center trial sets the objective to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer, hypothesizing that the 10-year estimate major cardiovascular events (MCE) rate of 3.5% for the proton arm as compared to that of 6.3% of the photon arm. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. Recruitment began in February 2016 and will continue through the end of 2021.  (publication accessible via ) 

Phase II Study of Proton Beam Radiation Therapy for Patients With Breast Cancer Requiring Regional Nodal Irradiation. This study evaluated 70 patients among who 63 patients (91%) had left-sided breast cancer, two had bilateral breast cancer, and five had right-sided breast cancer; 65 (94%) had stage II to III breast cancer; 68 (99%) received systemic chemotherapy; 50 (72%) underwent immediate reconstruction.  With the median follow-up of 55 months, the study reported that among 62 surviving patients, the 5-year rates for locoregional failure and overall survival were 1.5% and 91%. One patient developed grade 2 RP, and none developed grade 3 RP. No grade 4 toxicities occurred. The authors concluded that PBT for breast cancer has low toxicity rates and similar rates of disease control compared with historical data of conventional RT. (publication accessible via 

Head and Neck

Early clinical outcomes of helical tomotherapy/intensity-modulated proton therapy combination in nasopharynx cancer. A study from Korea evaluated the feasibility of combining helical Tomotherapy (HT) and intensity-modulated proton therapy (IMPT) in treating patients with nasopharynx cancer (NPC). 98 patients received definitive RT with concurrent chemotherapy (CCRT) received the initial 18 fractions delivered by HT, and, after rival plan evaluation on the adaptive re-plan, the later 12 fractions were delivered either by HT in 63 patients (64.3%, HT only) or IMPT in 35 patients (35.7%, HT/IMPT combination). This study reported that in all patients, grade ≥ 2 mucositis (69.8% vs 45.7%, P = .019) and grade ≥ 2 analgesic usage (54% vs 37.1%, P = .110) were found to be less frequent in HT/IMPT group. In matched patients, grade ≥ 2 mucositis were still less frequent numerically in HT/IMPT group (62.9% vs 45.7%, P = .150). The author concluded that more favorable acute toxicity profiles were achievable by HT/IMPT combination in treating NPC patients. (publication accessible via )

TORPEdO - A Phase III Trial of Intensity-modulated Proton Beam Therapy Versus Intensity-modulated Radiotherapy for Multi-toxicity Reduction in Oropharyngeal Cancer. This is the UK's first proton clinical trial. Published in the Clinical Oncology, this editorial provided the rational and the plan of the trial. It is a multicenter phase III trial of IMPT versus IMRT for oropharyngeal squamous cell carcinoma (OPSCC), with the primary objective to assess whether IMPT compared with IMRT reduces late treatment-related toxicities in patients with locally advanced OPSCC who require treatment with concurrent chemotherapy and bilateral neck radiotherapy. Secondary objectives include validation of a biomarker (NTCP model) as a predictor of benefit from IMPT versus IMRT and an assessment of cost-effectiveness. TORPEdO is a flagship study and will position the UK's two NHS proton facilities as international centers for IMPT clinical research to inform evidence-based clinical practice and improve treatment outcomes for patients. (publication accessible via 


Proton therapy for locally advanced non-small cell lung cancer. A review article by MD Anderson group. Using particle-beam therapy rather than photons offers the potential for further advantages because of the unique depth-dose characteristics of the particles, which can be exploited to allow still higher dose escalation to tumors with greater sparing of normal tissues, with the ultimate goal of improving local tumor control and survival while preserving quality of life by reducing treatment-related toxicity. However, current clinical evidence is available from preclinical studies, from retrospective, single-institution clinical series, from analyses of national databases, and from single-arm prospective studies in addition to several ongoing randomized comparative trials. (publication accessible via )

Proton Beam Therapy for Histologically or Clinically Diagnosed Stage I Non-small Cell Lung Cancer (NSCLC): The First Nationwide Retrospective Study in Japan. Six hundred sixty-nine patients with 682 tumors with histologically or clinically diagnosed Stage I NSCLC who received passive-scattering PBT in Japan were retrospectively reviewed to analyze survivals, local control, and toxicities. This study found that the 3-year overall survival (OS) and progression-free survival (PFS) rates for all patients were 79.5% and 64.1%. The incidence of Grade 2, 3, 4, and 5 pneumonitis was 9.8%, 1.0%, 0%, and 0.7%, respectively. The incidence of Grade ≥3 dermatitis was 0.4%. No Grade 4 or severe adverse events, other than pneumonitis, were observed. This study concluded that PBT appears to yield acceptable survival rates, with a low rate of toxicities. (publication accessible via ) 


Practice patterns among radiation oncologists treating pediatric patients with proton craniospinal irradiation. This survey study aimed to assess current practice patterns regarding the vertebral bodies (VB) coverage for pediatric patients undergoing CSIWith the 28 responses, 23 physicians sometimes treat the entire VB and five physicians report always treating the entire VB. Most common responses regarding anterior CTV expansion for uncertainty were no expansion (n=9) and 3-4 mm (n=8). Most physicians modify the anterior CTV margin to protect normal structures, most commonly esophagus (n=15), thyroid (n=6), heart (n=5), bowel (n=4), and pharynx (n=2). The practice varies amongst radiation oncologists in respect to target delineation, CTV expansions and modifications for organs at risk. These data suggest the radiation oncology community may benefit from a standardized approach to pediatric proton based CSI. (publication accessible via

Outcome and patterns of relapse in childhood parameningeal rhabdomyosarcoma treated with proton beam therapy. Published in the Red Journal, the study by WPE reported outcomes of PBT for 46 pediatric patients with parameningeal rhabdomyosarcoma (pRMS). Wit a median follow-up time of 2.9 years, the estimated 2-year local control (LC), metastasis-free survival (MFS), event-free survival (EFS), and overall survival (OS) were 83.8%, 87.8%, 76.9% and 88.9%. No acute or late local toxicity exceeding grade 3 was observed. The authors concluded that PBT was effective and well feasible even in a critical cohort. Still, local relapse within the target volume of the RT remains an important issue in pRMS and new treatment strategies are needed. (publication accessible via )

Patterns of failure and toxicity profile following proton beam therapy for pediatric bladder and prostate rhabdomyosarcoma (B/P-RMS). This study reported outcomes of 19 patients of B/P-RMS treated with PBT. With a median follow-up of 66.2 months, 5-year overall survival (OS) and progression-free survival (PFS) were 76%. Four patients (21%) experienced disease relapse, all presenting with local failure. The 5-year local control (LC) rate was 76%. Acute grade 2 toxicity was observed in two patients (11%, transient proctitis). Late grade 2+ toxicity was observed in three patients (16%; n = 1 grade 2 skeletal deformity; n = 3 transient grade 2 urinary incontinence; one patient experienced both). This study concluded that PBT for B/P-RMS offers promising disease-related outcomes with an acceptable toxicity profile. (publication accessible via )

Normal tissue complication probability models in plan evaluation of children with brain tumors referred to proton therapy. 40 patients treated with PBT were selected for VMAT re-plan. The VMAT and delivered PT plans were compared by dose/volume metrics and NTCP models related to growth hormone deficiency, auditory toxicity, visual impairment, xerostomia, neurocognitive outcome and secondary brain and parotid gland cancers. The results showed that reductions in population median NTCP were significant for auditory toxicity (VMAT: 3.8%; PT: 0.3%), neurocognitive outcome (VMAT: 3.0 IQ points decline at 5 years post RT; PT: 2.5 IQ points), xerostomia (VMAT: 2.0%; PT: 0.6%), excess absolute risk of secondary cancer of the brain (VMAT: 9.2%; PT: 6.7%) and salivary glands (VMAT: 2.8%; PT:0.5%). PT reduced the volumes of normal tissues exposed to radiation, particularly low-to-intermediate dose levels, and this was reflected in lower NTCP. (publication accessible via )

Paediatric proton therapy. A review article that emphasizes proton beam therapy is an important therapeutic component in multidisciplinary management in pediatric oncology because of reduction of radiation-related long-term side-effects and secondary malignancy. This review evaluates current data from clinical and dosimetric studies on the treatment of tumors of the central nervous system, soft tissue and bone sarcomas of the head and neck region, paraspinal or pelvic region, and retinoblastoma. (publication accessible via

Proton therapy following induction chemotherapy for pediatric and adolescent nasopharyngeal carcinoma. A study by the Jacksonville group. Seventeen patients with nonmetastatic nasopharyngeal carcinoma underwent double-scattered proton therapy. With the median follow-up of 3.0 years, the study reported the overall survival, progression-free survival, and local control rates were 100%. Serious late side effects included cataract (n = 1), esophageal stenosis requiring dilation (n = 1), sensorineural hearing loss requiring aids (n = 1), and hormone deficiency (n = 5, including three with isolated hypothyroidism). This study concluded that following induction chemotherapy, moderate-dose proton therapy can potentially reduce toxicity in the brain and skull base region without compromising disease control. (publication accessible via )


Lower doses to hippocampi and other brain structures for skull-base meningiomas with intensity modulated proton therapy compared to photon therapy. This study systematically compared intensity modulated proton therapy (IMPT), non-coplanar volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) for skull base meningiomas. For twenty patients, target diameter >3 cm,  IMPT plans significantly improved dose conformity to the target volume as compared to plans of VMAT and IMRT. And IMPT allows for a considerable dose reduction in the hippocampi, normal brain and other OARs compared to both non-coplanar VMAT and IMRT, which may lead to a clinically relevant reduction of late neurocognitive side effects. (publication accessible via )


Non-homologous end joining is more important than proton linear energy transfer in dictating cell death. Published in the Red Journal, this study tried to identify biological factors that may yield a therapeutic advantage of proton therapy versus photon therapy. Specifically, the role of non-homologous end-joining (NHEJ) and homologous recombination (HR) in the survival of cells in response to clinical photon and proton beams. With the tested cell lines, the results indicate that NHEJ deficiency is more important in dictating cell survival than proton LET. Cells with disrupted HR through BRCA1 mutation showed increased radiosensitivity only for high-LET protons. This study highlights the importance of tumor biology in dictating treatment modality, as well as suggesting BRCA1 as a potential biomarker for proton therapy response.  (publication accessible via )

Systematic review of methodology used in clinical studies evaluating the benefits of proton beam therapy. The dosimetric advantages of PBT over photon radiotherapy may be clear but the translation of this benefit into clinically meaningful reductions in toxicities and improved quality-of-life (QoL) needs to be determined. This systematic review examined the methodology used in clinical trials that reported PBT benefits. Out of the 219 studies included, prospective studies comprised 89/219 (41%), and of these, the number of randomised phase II and III trials were 5/89 (6%) and 3/89 (3%) respectively. Of all the phase II and III trials, 18/24 (75%) were conducted at a single PBT centre. Over one-third of authors recommended an increase in length of follow up. Research design and/or findings were poorly reported in 74/89 (83%) of prospective studies. Patient reported outcomes were assessed in only 19/89 (21%) of prospective studies. (publication accessible via )

Abscopal Effect Following Proton Beam Radiotherapy in a Patient With Inoperable Metastatic Retroperitoneal Sarcoma. The first case report of an abscopal effect in a patient of retroperitoneal sarcomas (RPS) treated with proton therapy. A 67 year-old female with inoperable metastatic unclassified round cell RPS was treated with palliative proton radiotherapy only to the primary tumor. Following completion of radiotherapy, the patient demonstrated complete regression of all un-irradiated metastases, and near complete response of the primary lesion without additional therapy. Abscopal effects are rare and incompletely understood, involving a balance of radiation's immunogenic and immunosuppressive effects. (publication accessible via ) 

Active-Scanned Protons and Carbon Ions in Cancer Treatment of Patients With Cardiac Implantable Electronic Devices: Experience of a Single Institution. A study by Heidelberg group looked into if ionizing radiation influenced the function of cardiac implantable electronic devices (CIED's) leading to malfunctions with potentially severe consequences. 31 patients (22 received treatment with carbon ion and 10 with proton) were analyzed, among whom 3 patients had an implantable cardioverter-defibrillator (ICD) and 28 patients had a pacemaker at the time of treatment. The cumulative number of fractions was 582 and the cumulative number of documented controls after RT was 504. This analysis reported that treatment of CIED-patients with protons and carbon ions was safe without any incidents. (publication accessible via )

Key papers March - June 2019


Consensus Report From the Miami Liver Proton Therapy Conference.  This paper is based on the Liver Focus Group supported by IBA. An International group of 22 liver cancer experts from 18 institutions were brought together in Miami, Florida to discuss the optimal utilization of PBT for primary and metastatic liver cancer. A primary rationale for PBT is sparing uninvolved liver and PBT should be considered if mean liver dose (MLD) and low dose liver constraints cannot be achieved with XRT. A consensus is reached among the experts that PBT should be more strongly considered for HCC patients with the following: • At least CP-B cirrhosis • High tumor-to-liver ratio • Larger tumor size • Smaller uninvolved liver volume • Higher number of tumors • Prior RT to the liver. Future studies should focus on identifying which patient subgroups achieve the greatest clinical advantage from PBT to guide treatment decision making. (publication accessible via

Proton beam therapy outcomes for localized unresectable hepatocellular carcinoma. A MD Anderson study published in the Green Journal reported outcomes of forty-six patients with HCC, Child-Pugh class of A or B, no prior radiotherapy treated with PBT to a total dose of 97.7 GyE (range, 33.6-144 GyE) administered in 15 fractions. Actuarial 2-year LC and OS rates were 81% and 62% respectively; median OS was 30.7 months. Patients receiving BED ≥90 GyE had a significantly better OS than those receiving BED <90 GyE .The most common toxicities were grade 1 fatigue (33%), skin erythema (24%), nausea (22%), anorexia (11%) and vomiting (13%). Acute grade 3 toxicities were recorded in 6 (13%) patients. No grade 3 or greater CTCAE hepatic toxicity or classical RILD was recorded. This study concluded that high-dose PBT is associated with high rates of LC and OS for unresectable HCC. Dose escalation may further improve outcomes. (publication accessible via )


Clinical outcomes after intensity-modulated proton therapy with concurrent chemotherapy for inoperable non-small cell lung cancer. Published in the Green Journal, this study by MD Anderson reported disease control, survival, and toxicity in patients with advanced inoperable non-small cell lung cancer (NSCLC) receiving concurrent chemotherapy and intensity-modulated proton therapy (IMPT). Fifty-one patients were enrolled with a median follow-up time of 23.0 months. Median OS and DFS (disease free survival) times were 33.9 months and 12.6 months. The 3-year local control rate was 78.3%. Grade 3 toxicity rate of 18% (9 events: 4 esophagitis, 3 dermatitis, 1 esophageal stricture, and 1 fatigue) and no grade 4 or 5 toxicity. The most common grade 2 toxic effects were esophagitis (22 [43%]), dermatitis (16 [31%]), pain (15 [29%]), and fatigue (14 [27%]). The authors concluded that treatment of inoperable NSCLC with IMPT and concurrent chemotherapy achievesd excellent disease control with tolerable toxicity. (publication accessible via )

Hypofractionated proton beam therapy for centrally located lung cancer. This study from Japan reported outcomes of 39 patients who received hypofractionated PBT for centrally located cT1-2N0M0. Twenty-four patients (62%) were treated with 80 Gy (RBE) in 20 fractions, whereas eight (21%) were treated with 66 Gy (RBE) in 10 fractions. The 2-year progression-free survival (PFS) and overall survival (OS) rates were 86 and 100% for T1 disease and 56 and 94% for T2 disease. Dyspnoea of grade 3 was noted in one patient (3%), and pneumonitis of grade 2 was noted in four patients (10%). The authors concluded that hypofractionated PBT may be a very safe and effective treatment option for centrally located early lung cancer. (publication accessible via )

Quantification of global lung inflammation using volumetric 18F-FDG PET/CT parameters in locally advanced non-small-cell lung cancer patients treated with concurrent chemoradiotherapy: a comparison of photon and proton radiation therapy. This study evaluated pre-treatment and post-treatment F-FDG PET/CT of 18 locally advanced NSCLC patients treated with definitive photon or proton RT. In nine patients treated with photon RT, significant increases in bilateral lung inflammation, but no significant change in lung inflammation was noted in the nine patients treated with proton therapy. Future larger studies are needed to determine whether this difference correlates with lower risks of radiation pneumonitis in NSCLC patients treated with proton therapy. (publication accessible via )


Post-mastectomy intensity modulated proton therapy after immediate breast reconstruction: Initial report of reconstruction outcomes and predictors of complications. Published in the Green Journal, the Mayo Clinic group reported outcomes of 51 women among who 42 had bilateral reconstruction treated with unilateral IMPT. Conventional fractionation (median 50 Gy/25 fractions) was administered in 37 (73%) and hypofractionation (median 40.5 Gy/15 fractions) in 14 (27%) patients. Median mean heart, ipsilateral lung V20Gy, and CTV-IMN V95% were 0.6 Gy, 13.9%, and 97.4%. Maximal acute dermatitis grade was 1 in 32 (63%), 2 in 17 (33%), and 3 in 2 (4%) patients. Among irradiated breasts, hypofractionation was significantly associated with reconstruction failure. This study concluded that IMPT following immediate breast reconstruction spared underlying organs and had low rates of acute toxicity. Reconstruction complications are more common in irradiated breasts, and reconstructive outcomes appear comparable with photon literature. (publication accessible via

Quantification of Acute Skin Toxicities in Patients with Breast Cancer Undergoing Adjuvant Proton versus Photon Radiation Therapy: A Single Institutional Experience. Published in the Red Journal, the study by University of Maryland examined the acute skin toxicity in the form of radiation dermatitis (RD) or skin hyperpigmentation (SH) after proton or photon radiotherapy. The highest recorded grades of acute RD and SH were analyzed in 86 patients undergoing adjuvant radiation therapy to the breast with or without regional lymph nodes after lumpectomy (breast-conserving surgery) or mastectomy with either proton pencil-beam scanning (n = 39) or photon (n = 47). This study reported that the highest reported grade of RD was significantly higher in women undergoing proton radiation compared with photon radiation. Grade ≥2 RD was present in 69.2% versus 29.8% of patients receiving proton and photon therapy (P = .002). Rates of grade 3 RD were 5.1% versus 4.3% for proton versus photon radiation (P = .848). Overall, there were no significant differences in rates of SH between modalities. There were no grade 4 to 5 toxicities in either cohort. (Publication accessible via )

Comparison of supine or prone crawl photon or proton breast and regional lymph node radiation therapy including the internal mammary chain. A planning study conducted by a group of collective researchers in Europe. For six left sided breast cancer patients, treatment plans were made using non-coplanar volumetric modulated arc photon therapy (VMAT) or pencil beam scanning intensity modulated proton therapy (IMPT) to compare supine (S) and prone-crawl (P) position for irradiaiton to whole breast (WB) and loco-regional lymph node regions, including the internal mammary chain (LN_IM). This study reported that the average mean heart doses for S or P VMAT were 5.6 or 4.3 Gy, and 1.02 or 1.08 GyRBE for IMPT (p < 0.001 for IMPT versus VMAT). The average mean lung doses for S or P VMAT were 5.91 or 2.90 Gy and 1.56 or 1.09 GyRBE for IMPT. In high-risk patients, average (range) thirty-year mortality rates from radiotherapy-related cardiac injury and lung cancer were estimated at 6.8% or 3.8% for S or P VMAT, and 1.6% or 1.2% for S or P IMPT, respectively. This study indicated that radiation-related mortality risk could outweigh the ~8% disease-specific survival benefit of WB + LN_IM radiotherapy for S VMAT but not P VMAT. IMPT carries the lowest radiation-related mortality risks. (publication accessible via


Four-year outcomes from a prospective phase II clinical trial of moderately hypofractionated proton therapy for localized prostate cancer. Published in the Red Journal, the researchers of Upenn and Groningen reported the clinical and patient-reported outcomes for patients with prostate cancer treated with hypofractionated proton therapy (HFPT). 184 men with low to intermediate-risk prostate cancer were enrolled on this trial of 70Gy in 28 fractions of HFPT. Median follow-up was 49.2 months. Four-year rates of biochemical failure free survival were 93.5%.  The incidence of acute grade 2 or higher gastrointestinal and urologic toxicities were 3.8% and 12.5%. The 4-year incidence of late grade 2 or higher urologic and gastrointestinal toxicity was 7.6% and 13.6%, respectively. One late grade 3 GI toxicity was reported. All late toxicities were transient. Patient reported IPSS (International Prostate Symptom Score), IIEF (International Index of Erectile Function), and EPIC (Expanded Prostate Cancer Index Composite) scores had no significant long term changes following completion of HFPT. (publication accessible via )

Patient-Reported Sexual Survivorship Following High-Dose Image-Guided Proton Therapy for Prostate Cancer. A study by the Jacksonville group published in the Green Journal aimed to identify baseline predictive factors that impact long-term erectile function. 676 potent men at base line with localized prostate cancer treated with HD-IGRT (high dose image-guided) protons alone, to a median dose of 78 Gy(RBE) (range, 72–82 Gy[RBE]) in 36 to 39 fractions. The potency rates at 6 months, 2 years, and 5 years were 81%, 68%, and 61%. This study found that baseline response to EPIC Q57 (ability to have an erection) and pre-existing heart disease are two factors enabling prediction of sexual function. At 5 years, the most favorable group reported "very good" on Q57 had an 80% potency rate; the intermediate group reported "good" on Q57 had no baseline cardiac disease with a 62% potency rate; and the remaining poor risk group had a 37% potency rate. (publication accessible via

Early and late side effects, dosimetric parameters and quality of life after proton beam therapy and IMRT for prostate cancer: a matched-pair analysis. A study by the researchers of Dresden and Heidelberg. Eighty-eight patients with localized prostate cancer treated with PBT (31) or IMRT (57) were matched using propensity score. This study reported no significant differences in GI and GU toxicities between both treatment groups except for late urinary urgency, which was significantly lower after PBT (IMRT: 25.0%, PBT: 0%, p = .047). The change of constipation was significantly better at 3 months after PBT compared to IMRT (p = .034). This study concluded that overall QoL and the risks of early and late GU and GI toxicities were similar for conventionally fractionated IMRT and PBT. (publication accessible via )


Proton Radiotherapy for Isolated Local Recurrence of Primary Resected Pancreatic Ductal Adenocarcinoma. This study by the Hyogo group in Japan analyzed 30 patients who had initially undergone surgery but isolated local recurrence occurred. PBT was administered with dose of 67.5 (GyE) in 19 to 25 fractions. Four patients (13.3%) experienced acute grade ≥ 3 gastrointestinal toxicities. After a median follow-up period of 17.6 months, this study reported the median overall, progression-free, and local progression-free survival rates were 26.1, 12.3, and 41.2 months. This study concluded that PBT after surgery was well tolerated and produced good locoregional control and should be considered for eligible patients. (publication accessible via )

Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer. A study by the Tsukuba group in Japan repored outcomes of 42 unresectable locally advanced pancreatic cancer patients treated with PBT and concurrent chemotherapy. This study reported the 1-year/2-year OS rates from the start of CCRT were 77.8/50.8% with median survival time of 25.6 months. The 1-year/2-year LC rate from CCRT start was 83.3/78.9% with a median time to local recurrence of more than 36 months. Late adverse events of grades 1 and 2 were found in 3 and 2 patients. No late adverse effects of grade 3 or higher were observed. The authors concluded that proton beam concurrent chemoradiation lengthened survival periods compared to previous photon concurrent chemoradiation data and higher dose irradiation prolonged LC and OS for unresectable locally advanced pancreatic cancer patients. (publication accessible via )

Chordoma and Chondrosarcoma

A prospective clinical trial of proton therapy for chordoma and chondrosarcoma: Feasibility assessment. This study evaluated outcome of PBT for chordomas and chondrosarcomas. 20 adult patients with nonmetastatic chordomas of the skull base (n = 10), sacrum (n = 5), and cervical spine (n = 3), and skull base chondrosarcomas (n = 2) were treated with median dose of 73.8 Gy(RBE) using PRT-only (n = 6) or combination PRT/IMRT (n = 14). The 3-year local control and progression-free survival was 86% and 81%. There were no deaths. Two patients had acute grade 3 toxicity (both fatigue). One had late grade 3 toxicity (epistaxis and osteoradionecrosis). The authors concluded that the reported local control, survival, and toxicity were favorable following PRT. (publication accessible via )


Efficacy of proton therapy in children with high-risk and locally recurrent neuroblastoma. Eighteen patients with high-risk (n = 16) and locally recurrent neuroblastoma (n = 2) were treated with proton therapy. With a median follow-up of 60.2 months, this study reported the five-year progression-free survival (PFS) was 64%, and the five-year overall survival (OS) was 94%. No radiation-related nephropathy or hepatopathy was reported. The authors concluded that proton therapy provided high rates of local control with acceptable toxicity for neuroblastoma, further advances in systemic therapy are needed for the improved control of systemic disease. (publication accessible via )

Increased distance from a treating proton center is associated with diminished ability to follow patients enrolled on a multicenter radiation oncology registry. A paper by MGH published in the Green Journal evaluated the factors that affect maximum follow-up time among MGH Pediatric Proton Consortium Registry (PPCR) participants. Among the 333 PPCR patients, the median follow-up was 2.4 years and median distance away from the proton center was 256.4 km. Loss in average follow up was 0.53 years for patients living outside >121 km from the proton center compared to those living within 121 km. Loss in average follow-up was also associated with Medicaid insurance. The authors concluded that increased distance from treating centers may adversely affect clinical outcomes research. Sharing of medical information among care providers and improved collection methods are needed to effectively evaluate the benefits of proton therapy.  (publication accessible via )

Patterns of failure following proton beam therapy for head and neck rhabdomyosarcoma (RMS). A MD Anderson study published in the Green Journal reported on the patterns of failure following proton beam therapy (PBT) for pediatric H&N RMS. 46 patients were analyzed. With median follow-up of 3.9 years, five-year overall survival was 76%, and five-year progression-free survival was 57%. Seventeen patients (37%) experienced relapse, including 7 with local failure (LF). Five-year local control (LC) was 84%. Tumor size greater than 5 cm predicted increased risk of LF, intracranial extension (ICE) and delayed RT delivery after week 4 of chemotherapy predicted increased risk of relapse. This study concluded that PBT confers excellent LC, and a favorable late toxicity profile as compared with prior photon RT data. This study also raised concerns regarding excess failures among patients with ICE. (publication accessible via )

Improved neuropsychological outcomes following proton therapy relative to x-ray therapy for pediatric brain tumor patients. This study analyzed 125 children who received radiation (XRT or PRT) and had post-treatment neuropsychological evaluation including intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning. This study compared XRT cohort and PRT cohort and found that PRT was associated with higher full-scale IQ (p=0.048) and processing speed (p=0.007) relative to XRT, with trend toward higher verbal IQ (p=0.06) and general adaptive functioning (p=0.07). The authors concluded that PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment. (publication accessible via )

Prospective, Longitudinal Comparison of Neurocognitive Change in Pediatric Brain Tumor Patients Treated with Proton Radiotherapy versus Surgery Only. 93 patients (22 proton CSI, 31 proton focal, and 40 surgery only) received annual neurocognitive evaluations for up to 6 years, including Full Scale IQ (FSIQ), Verbal Comprehension (VCI), Perceptual Reasoning (PRI), Working Memory (WMI), and Processing Speed Index (PSI) scores. This study found that the proton focal and surgery only groups exhibited stable neurocognitive scores over time across all indexes (all p>0.05). In the proton CSI group, WMI, PSI, and FSIQ scores declined significantly (p=0.036, 0.004, and 0.017, respectively), while VCI and PRI scores were stable (all p>0.05). This study concluded that outcomes were similar whether patients received focal PRT or no radiotherapy, but proton CSI emerged as a neurocognitive risk factor, consistent with photon outcomes research. (publication accessible via )

Are further studies needed to justify the use of proton therapy for paediatric cancers of the central nervous system? A review article published in the Green Journal. Having analyzed the available data of PBT for paediatric cancers of the central nervous system (CNS), this study found that PBT provided survival and tumour control outcomes comparable, and frequently superior, to photon therapy. The use of protons was shown to decrease the incidence of severe acute and late toxicities, including reduced severity of endocrine, neurological, IQ and QoL deficits. This review makes concludsion that current evidence supports PBT effectiveness and potential benefits in reducing the incidence of late-onset toxicities and second malignancies. For stronger evidence, it is highly desired for future studies to improve current reporting by (1) highlighting the paediatric patient cohort's outcome (in mixed patient groups), (2) reporting the follow-up time, (3) clearly indicating the toxicity criteria used in their evaluation, and (4) identifying the risk group. (publication accessible via )


Comparison between patient-reported outcomes after enucleation and proton beam radiotherapy for uveal melanomas: a 2-year cohort study. This study compared differential effects of enucleation and PBR on 115 uveal melanoma patients based on the patient-reported outcomes. This study found that PBR patients reported greater impairments of central and peripheral vision (P = 0.009) and reading difficulties (P = 0.002) over 24 months. Patients treated by enucleation experienced greater functional problems at 6 months, which abated at 12 and 24 months. This study pointed out that it is important that patients and clinicians consider long-standing difficulties of visual impairment associated with PBR and temporary 6-month difficulties in activities related to depth perception associated with enucleation. (publication accessible via )


The first prototype of spot-scanning proton arc treatment delivery. Published in the Green Journal, the Beaumont group reported the first prototype of spot-scanning arc treatment (SPArc) delivery on IBA Proteus®One. The brain SPArc plan with similar or superior plan quality was delivered in 4 mins compared to total 11 mins for the clinical treatment of the three-field IMPT plan. The measurements and simulations demonstrated the feasibility of SPArc treatment within the clinical requirements. (publication accessible via )

Key papers January - February 2019


Increased Risk of Pseudoprogression among Pediatric Low-Grade Glioma Patients Treated with Proton versus Photon Radiotherapy.

Pseudoprogression (PsP) is a recognized phenomenon after radiotherapy (RT) for glioma. This study evaluated 83 pediatric low-grade glioma (LGG) patients treated with IMRT (39%) and PBT (61%), and found that 37% patients scored PsP including IMRT patients (25%) and PBT patients (45%). Local progression occurred in 10 patients: 7 IMRT patients (22%) and 3 PBT patients (6%), with a trend toward improved local control for PBT patients. This study concluded that there was substantial rates of PsP among pediatric LGG patients, particularly those treated with PBT. PsP should be considered when assessing response to RT in LGG patients within the first year after RT. (publication accessible via )

Head and neck

A Model-Based Approach to Predict Short-Term Toxicity Benefits With Proton Therapy for Oropharyngeal Cancer.

A study by UPenn and Groningen. For patients with advanced-stage oropharynx cancer treated with curative intent (PBT, n = 30; IMRT, n = 175), NTCP models were developed. The models were then applied to the PBT-treated patients to compare predicted and observed clinical outcomes. Five binary endpoints were analyzed at 6 months after treatment: dysphagia ≥ grade 2, dysphagia ≥ grade 3, xerostomia ≥ grade 2, salivary duct inflammation ≥ grade 2, and feeding tube dependence. This study found that PBT was associated with statistically significant reductions in the mean NTCP values for each endpoint at 6 months after treatment, with the largest absolute differences in rates of ≥grade 2 dysphagia and ≥grade 2 xerostomia. This study demonstrates an NTCP model-based approach to compare predicted patient outcomes when randomized data are not available. (publication accessible via )

Intensity modulated proton therapy (IMPT) - The future of IMRT for head and neck cancer

A review article looked at the development of RT advances. There is a growing awareness of the potential clinical benefits of proton therapy over IMRT in the definitive, postoperative and reirradiation settings given the unique physical properties of protons. Evidence of the clinical translation of dosimetric advantages of IMPT over IMRT has been demonstrated with documented toxicity reductions. Ongoing investigations in image-guidance techniques and robust optimization methods are promising to address particle range uncertainties and high sensitivity to anatomical changes. (publication accessible via )


Clinical intensity-modulated proton therapy for Hodgkin lymphoma: which patients benefit the most?

21 HL patients treated with deep inspiration breath-hold pencil-beam scanning (PBS) PT. Normal tissue radiation doses were calculated and compared to doses from 3D-conformal and partial-arc volumetric modulated (PartArc) photon RT. This study reported that treatment with PBS was well tolerated and provided with good local control. PBS significantly reduced the mean dose to the heart, breast, lungs, spinal cord and esophagus, but some high dose measures and hot spots were increased with PBS compared to PartArc. PBS provided dosimetric advantages for patients whose clinical treatment volume extended below the 7th thoracic level and for female patients with axillary disease. (publication accessible via )


Is Proton Therapy a "Pro" for Breast Cancer? A Comparison of Proton vs. Non-proton Radiotherapy Using the National Cancer Database.

With the national cancer database, a total of 724,492 patients were identified: 871 received PRT and 723,621 received non-PRT. The factors found to be significant for receipt of PRT (all p < 0.05) include academic facility, South and West location, left-sided, ER-positive and mastectomy. This study reported that PRT was not associated with OS for all patients. PRT remained not significant after stratifying for subsets likely associated with higher heart radiation doses, including: left-sided, inner-quadrant, mastectomy, node positivity, N2-N3 disease, and lymph node irradiation (LNI). This study concluded that further studies are required to determine non-OS benefits of PRT. In the interim, given the high cost of protons, only well-selected patients should receive PRT unless enrolled on a clinical trial. (publication accessible via

Chordoma and Chondrosarcoma

The role of dose escalation and proton therapy in perioperative or definitive treatment of chondrosarcoma and chordoma: An analysis of the National Cancer Data Base.

This study analyzed a total of 863 patients with chondrosarcoma and 715 patients with chordoma treated with proton or conventional radiation therapy.  This study found that for chondrosarcoma, a high dose and proton therapy were associated with improved OS at 5 years. For chordoma, proton therapy was associated with improved OS at 5 years and a high dose for chordoma was significant for improved OS. The authors concluded that in the largest retrospective series to date, dose escalation and proton radiotherapy were associated with improved OS in patients with chondrosarcoma and chordoma (publication accessible via )


Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X-ray and proton therapy.

Idiopathic pulmonary fibrosis (IPF) is associated with fatal complications after radiotherapy (RT) for lung cancer patients. This study evaluated 264 patients with stage I-II non-small cell lung cancer (NSCLC) treated with definitive RT alone, and analyzed 30 patients (11.4%) who had underlying IPF. Among these, X-ray and proton RT were delivered to 22 and 8 patients. All living patients were followed-up at least 9 months. Treatment-related death occurred in four patients (18.2%) treated with X-ray but none with proton therapy. The 1-year overall survival (OS) rate in patients treated with X-ray and proton was 46.4 and 66.7%, respectively, and patients treated with proton therapy showed a tendency of better survival compared to X-ray (p = 0.081). This study concluded that RT is associated with serious treatment-related complications in patients with IPF. Proton therapy may be helpful to reduce these acute and fatal complications.  (publication accessible via )

Impact of unfavorable factors on outcomes among inoperable stage II-IV Non-small cell lung cancer patients treated with proton therapy

A study by the Jacksonville group. 90 consecutive patients with unresectable stage II-IV (oligometastatic) NSCLC were treated with PT. Unfavorable factors including age ≥80 years, stage IV, weight loss >10% in 3 months, performance status (PS) ≥2, FEV1 < 1.0 or O2 dependency, prior lung cancer, prior lung surgery, prior 2nd cancer in the past 3 years, and prior chest irradiation were evaluated. The study reported the 2-year OS was 52% and 45% (p = .8522), and 2-year PFS was 21% and 44% (p = .0207), for favorable and unfavorable risk patients, and concluded that most patients treated with PT for LA-NSCLC have unfavorable risk factors, but these patients had similar outcomes to favorable-risk patients. Enrollment in future clinical trials may improve if eligibility is less restrictive. (publication accessible via )

Proton beam therapy is a safe and feasible treatment for patients with second primary lung cancer after lung resection

A study from Japan reported 19 patients who were diagnosed with second primary lung cancer after lung resection, underwent PBT. This study reported the three-year overall survival rate was 63.2% and the three-year local control rate was 84.2%. No grade 4 or 5 toxicities were observed after PBT. The authors concluded that PBT is a safe and feasible treatment for second primary lung cancer compared to surgery or X-ray radiotherapy. PBT may become a treatment choice for patients with second primary lung cancer after lung resection. (publication accessible via )


A Comparison of Grade 4 Lymphopenia With Proton Versus Photon Radiation Therapy for Esophageal Cancer. Grade 4 lymphopenia (G4L) during radiation therapy (RT) is associated with higher rates of distant metastasis and decreased overall survival. 79 patients received XRT (27% 3-dimensional chemo-RT and 73% intensity modulated RT) and 65 received PRT (100% pencil-beam scanning) were evaluated. The study reported that G4L was significantly higher in patients who received XRT versus those who received PRT (56% vs 22%; P < .01). (publication accessible via


Analysis of Gastrointestinal Toxicity in Patients Receiving Proton Beam Therapy for Prostate Cancer: A Single-Institution Experience.

A study by the Seattle group. 192 prostate cancer patients were treated with PBT. With the median follow-up of 1.7 years, most of the observed GI toxicity (>90%) was in the form of rectal bleeding (RB). GR2+ GI toxicity and RB actuarial rates specifically at 2 years were 21.3% and 20.4%, respectively. GR3 toxicity was rare, with only 1 observed RB event. No GR4/5 toxicity was seen. High EPIC bowel domain quality of life was maintained in the 2 years after treatment.  (publication accessible via

Long-term results of a phase II study of hypofractionated proton therapy for prostate cancer: moderate versus extreme hypofractionation

A study by the Korean group of National Cancer Center. Eighty-two patients with T1-3bN0M0 prostate cancer were randomized to one of five arms: Arm 1, 60 cobalt gray equivalent (CGE)/20 fractions/5 weeks; Arm 2, 54 CGE/15 fractions/5 weeks; Arm 3, 47 CGE/10 fractions/5 weeks; Arm 4, 35 CGE/5 fractions/2.5 weeks; and Arm 5, 35 CGE/5 fractions/4 weeks. In the current exploratory analysis, these ardms were categorized into the moderate hypofractionated (MHF) group (52 patients in Arms 1-3) and the extreme hypofractionated (EHF) group (30 patients in Arms 4-5). At a median follow-up of 7.5 years, this study reported the 7-year biochemical failure-free survival (BCFFS) of 76.2% for the MHF group and 46.2% for the EHF group (p = 0.005). Acute GU toxicities were more common in the MHF than the EHF group (85 vs. 57%, p = 0.009), but late GI and GU toxicities did not differ between groups. The authors concluded that the efficacy of EHF is potentially inferior to that of MHF and that further studies are warranted, therefore, to confirm these findings. (publication accessible via )

A Literature Review of Proton Beam Therapy for Prostate Cancer in Japan

A literature review on published works related to proton beam therapy for prostate cancer in Japan. 23 articles were analyzed including fourteen observational studies, most of which focused on the adverse effects, seven articles interventional studies related on treatment planning, equipment parts, as well as target positioning and two secondary data analysis. This review concluded that PBT can be a suitable treatment option for localized prostate cancer, and despite the favorable results of proton beam therapy, future research should include more patients and longer follow-up schedules to clarify the definitive role of PBT. (publication accessible via )


What Conditions Make Proton Beam Therapy Financially Viable in Western Canada?

This is a business case and concluded the potential for a financially viable PBT facility in Western Canada. A single-vault, compact PBT unit operating 10 hours/day could treat 250 patients annually. A 100 Albertans, with accepted indications, such as the curative-intent treatment of chordomas, ocular melanomas, and selected pediatric cancers, would likely benefit annually from PBT's improved conformality and/or reduced integral dose compared to RT. The estimated capital cost was $40 million for a single beamline built within an ongoing capital project. Operating costs were $4.8 million/year at capacity. With 50% capacity reserved for non-Albertans at a cost recovery of $45,000/patient, a Western Canadian PBT facility would achieve net positive cash flow by year eight of clinical operations, assuming Alberta-to-USA referrals reach 21 patients/year by 2024 and increase at 3%/year thereafter.  (publication accessible via )

Key papers November - December 2018


Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy. Published in the Green Journal, this study by Memorial Sloan Kettering Cancer reported early outcomes of postmastectomy proton radiation including clinical efficacy and toxicities. 42 patients who received mastectomy were treated with adjuvant chest wall and regional nodal proton therapy. With median followup of 35 months, there was one local failure, which occurred on the chest wall within the radiation field, approximately 2.5 years after the completion of radiation; zero regional nodal failure; and six distant failures. The 3-year rate of locoregional disease-free survival was 96.3%, metastasis-free survival was 84.1%, and overall survival was 97.2%. All patients developed grade 1 or 2 acute skin toxicity and there was no grade 3 or 4 acute skin toxicity. Proton radiation is able to achieve excellent target coverage with median PTV V95 over 95% and heart sparing with median mean heart dose less than 1 Gy (RBE). The authors concluded that post-mastectomy proton radiation has shown excellent locoregional control rates and favorable toxicity profile. Long-term adverse effect of heart-sparing radiation will require longer follow-up time and randomized clinical trials. (publication accessible via )

Improved long-term patient-reported health and well-being outcomes of early-stage breast cancer treated with partial breast proton therapy. This cross sectional survey study by Loma Linda University compared patient-reported QoL outcomes among women with stage 0-2 disease treated with lumpectomy followed by whole breast irradiation (WBI, 50 Gy x-ray delivered to the entire breast, followed by a 10-Gy boost to the tumor bed, delivered five days per week for approximately six weeks), or partial breast proton irradiation (PBPT, 40 CGE in 10 daily fractions). This study concluded that QoL in PBPT‐treated women is, at 5‐10 years post‐treatment, significantly better than those treated with WBI for all domains analyzed. PBPT patients reported less pain, less fatigue, fewer restrictions in daily activities, and better cosmetic results over several corroborating domains. Results confirm that PBPT is not only an effective BCT treatment option for early‐stage disease, but that it also presents significantly improved overall outcomes many years out from treatment, across many domains. (publication accessible via )

Head and neck

Radiation-Related Alterations of Taste Function in Patients With Head and Neck Cancer: a Systematic Review. A review by MD Anderson group on patients' taste sensation after radiotherapy. This review pointed out that developing standardized tools for assessment of taste function and conducting prospective studies in larger population of HNC is the need of the hour, because reliable and validated study tools for assessing radiotherapy-induced taste alterations is lacking, even though majority of HNC patients undergoing radiotherapy suffer from altered taste function and often complain of inability to taste their food, reduced food intake, and weakness. By using Intensity-Modulated Proton Therapy in HNC patients, the authors anticipate preserving the taste sensation by reducing the dose of radiation to the taste buds. (publication accessible via )

A Quantitative Clinical Decision-support Strategy Identifying Which Oropharyngeal Head and Neck Cancer Patients may Benefit the Most from Proton Radiation Therapy. Published in the Red Journal, this study detailed the model base approach for identifying patients for proton treatment. NTCP models for dysphagia, esophagitis, hypothyroidism, xerostomia and oral mucositis were used to estimate NTCP for 33 oropharyngeal HNC patients previously treated with photon IMRT, then comparative proton therapy plans were generated. This study found that based on the institutional delivered photon IMRT doses, and the achievable proton therapy doses, the average QALY reduction from all HNC RT complications for photon and proton therapy was 1.52 QALYs vs. 1.15 QALYs, with proton therapy sparing 0.37 QALYs on average. The QALYs spared with proton RT varied considerably between patients, from 0.06 to 0.84 QALYs. Younger patients with p16-positive tumors who smoked ≤10 pack-years may benefit most from proton therapy. (publication accessible via )


Adopting Advanced Radiotherapy Techniques in the Treatment of Paediatric Extracranial Malignancies: Challenges and Future Directions. A review article examined reports on pediatric organ motion, in anticipation of the increasing application of advanced radiotherapy techniques in pediatric radiotherapy. Misappropriation of target margins could result in disease recurrence from geometric miss or unnecessary irradiation of normal tissue, organ motion and deformation increase the complexity of defining safety margins. In particular, the optimal margin to account for internal organ motion in children remains largely undefined. Continuing efforts to characterize motion in children and young people is necessary to optimally define safety margins and to realize the full potential of intensity-modulated radiotherapy, magnetic resonance-guided radiotherapy and intensity-modulated proton beam therapy. (publication accessible via )

Radiation for ETMR: Literature review and case series of patients treated with proton therapy. Embryonal tumors with multilayered rosettes (ETMRs) are aggressive tumors that typically occur in young children. This study reported the outcomes of seven patients treated with proton therapy. Their median age at diagnosis was 33 months (range 10-57 months) and their median overall survival (OS) was 16 months (range 8-64 months), with three patients surviving 36 months or longer. This study also included a literature review that of identified 204 cases of ETMR, the median OS of 10 months (range 0.03-161 months), and the median OS of 18 long-term survivors (≥36 months) in the literature was 77 months (range 37-184 months). The study concluded that the outcomes of patients with ETMR treated with proton therapy are encouraging compared to historical results. (publication accessible via )

Hypothyroidism after craniospinal irradiation with proton or photon therapy in patients with medulloblastoma. This study reviewed ninety-five patients (54 XRT and 41 PRT) treated with craniospinal irradiation (CSI) who had baseline and yearly follow-up for thyroid studies. With a median time post radiation of 3.8 years in PRT and 9.6 years in XRT, 33/95 (34.7%) patients developed hypothyroidism. Hypothyroidism developed in 25/54 (46.3%) who received XRT vs. 8/41 (19%) in the PRT group (HR =1.85, p = .14). The study concluded that the use of PRT in patients with medulloblastoma was associated with numerically lower but not significantly lower risk of hypothyroidism. Further studies including larger numbers and longer follow up must be performed to assess whether lower radiation doses achieved with PRT show statistically significant differences. (publication accessible via )

Patterns of proton therapy use in pediatric cancer management in 2016: An international survey. Published in the Green Journal, this survey study presented the data from 40 participating centers (participation rate: 74%), a total of 1,860 patients treated in 2016 (North America: 1205, Europe: 432, Asia: 223). More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents. The authors concluded that the low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients. (publication accessible via )


Intensity-modulated proton therapy decreases dose to organs at risk in low-grade glioma patients: results of a multicentric in silico ROCOCO trial. Patients with low-grade glioma (LGG) have a prolonged survival expectancy, therefore long-term side effects caused by radiotherapy is a concern. This multicenter planning study compared treatment plans using intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), tomotherapy (TOMO) and intensity-modulated proton therapy (IMPT) for 25 LGG patients having undergone postoperative radiotherapy. This study reported that the low dose volume to the majority of OARs was significantly reduced when using IMPT compared to VMAT. Whether this will lead to a significant reduction in neurocognitive decline and improved quality of life is to be determined in carefully designed future clinical trials. (publication accessible via )

Proton vs. Photon Radiation Therapy for Primary Gliomas: An Analysis of the National Cancer Data Base. This is the first study that compares the outcomes of patients treated with photon based radiotherapy vs. proton based radiotherapy for patients with gliomas. Based on the National Cancer Data Base (NCDB), patients with a diagnosis of World Health Organization (WHO) Grade I-IV glioma between the years of 2004-13 included 49,405 patients treated with XRT and 170 patients treated with PBT were compared on the overall survival rate. With multivariable analysis and propensity score, all patients treated with PBT were found to have superior median and 5 year survival than patients treated with XRT: 45.9 vs. 29.7 months (p = 0.009) and 46.1 vs. 35.5% (p = 0.0160). This study concluded that PBT is associated with improved OS compared to XRT for patients with gliomas. This finding warrants verification in the randomized trial setting in order to account for potential patient imbalances not adequately captured by the NCDB, such as tumor molecular characteristics and patient performance status. (publication accessible via )


Management of invasive squamous cell carcinomas of the conjunctiva Treatment of invasive conjunctival carcinoma. This retrospective analysis reviewed the outcomes and management of conjunctival carcinomas defined as ≤0.2mm invasion of the chorion (miSCC) or over (SCC). Of 39 SCC and 15 miSCC patients, mitomycin was administered in 93.3% and 20.5% of miSCC and SCC, respectively (p<0.001). Proton therapy was used in 0% and 92.0% of miSCC and SCC respectively (p<0.001). The 24-month incidence of local relapse was 14.8% including 20% and 12% for miSCC and SCC, respectively (p=0.079). Irradiation was the only prognostic factor associated with a lower risk for local relapse. This study concluded that miSCC had slightly worse relapse rates compared with SCC. Post-operative proton therapy used in SCC only, was associated with a lower risk for relapse.  (publication accessible via )

Skull base

Treatment outcomes of proton or carbon ion therapy for skull base chordoma: a retrospective study. An outcome report by the Hyogo Ion Beam Medical Center in Japan. Twenty-four patients including eleven (46%) received PT and 13 (54%) received CIT reported the five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT. The study concluded that both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable. (publication accessible via


Proton beam therapy for gastrointestinal cancers: past, present, and future. A review on recent data that PBT for upper GI cancers may decrease acute toxicity and late complications and improve treatment compliance. The authors examined proton therapy dosimetric benefits, published clinical data and ongoing clinical trials about esophageal cancer, gastric cancer, liver cancer and pancreatic cancer, and concluded that given the accruing data showing a strong relationship between clinical outcomes and low dose received by organs at risk, there is a strong rationale to consider PBT, while not all patients likely benefit from PBT, mounting retrospective data indicate that ongoing and future  clinical trials may demonstrate that PBT provides clinically meaningful benefit for a subset of patients with GI cancers. (publication accessible via )

Effectiveness of Particle Radiotherapy in Various Stages of Hepatocellular Carcinoma: A Pilot Study. A retrospective report from Japan. Eighty-three patients with HCC underwent particle therapy including proton beam radiation in 58 patients and carbon ion radiation in 25 patients were analyzed.  Patients were categorized into early-stage HCC (single HCC measuring ≤3 cm, Barcelona Clinic Liver Cancer [BCLC] stage 0 or A) (group A, n = 30), those with intermediate-stage HCC (HCCs measuring ≥3 cm but inoperable or multinodular and transcatheter arterial embolization [TACE]-refractory, BCLC stage B) (group B, n = 31), and those with advanced-stage HCC (HCC with portal invasion or extrahepatic metastasis) (group C, n = 22). This study reported that the rates of local control of the target tumor at 1 year and 2 years were 86.3 and 84.8%. The overall survival rates at 1, 2, and 3 years were 83.0, 65.6, and 55.1%, respectively. Patients in group A showed the best survival rates (100.0% at 1 year and 85.9% at 2 years). The 1-year survival rate was poor in group C (63.6%) despite a good local tumor control rate of 74.7%. The overall survival rates were significantly better in groups A and B than in group C. This study concluded that the local control rates after PRT were sufficiently high compared to TACE or sorafenib. Thus, PRT should be adopted for patients with difficult-to-treat HCC in the early and intermediate stages. (publication accessible via )


Proton Therapy in Non-small Cell Lung Cancer. A review on PBT for NSCLC. The review pointed out that despite early results suggesting improvements or at least comparable outcomes, the most recent randomized comparisons have failed to show significant differences in toxicity and local control between photon and proton therapy. As newer PBT techniques (e.g., intensity-modulated proton therapy) are increasingly utilized, more dramatic improvements in tumor control and toxicity may be demonstrated. There may be certain subpopulations in which the benefits of proton therapy are greater, such as central early-stage tumors, previously irradiated tumors, and locally advanced tumors, while others may best be treated with traditional photon techniques. As immunotherapy becomes more prevalent in the treatment of NSCLC, improving local control and limiting the toxicity contributed by radiation will be increasingly important. (publication accessible via )


Proton therapy for prostate cancer: A review of the rationale, evidence, and current state.  A review examined the dosimetric rationale and theoretical benefit of proton radiation for prostate cancer and the current state of the clinical evidence for efficacy and toxicity, derived from both large claim-based datasets and prospective patient-reported data. This review pointed out that the published data are mixed, and clinical equipoise persists, for that only the results of a large prospective randomized clinical trial currently accruing and also a large prospective pragmatic comparative study, will provide more rigorous evidence regarding the clinical and comparative effectiveness of proton therapy for prostate cancer. (publication accessible via )


The Insurance Approval Process for Proton Radiation Therapy: A Significant Barrier to Patient Care. Published in the Red Journal, this study analyzed 1753 patients with thoracic or head and neck (HN) cancer considered for proton therapy including 903 (553 thoracic, 350 HN) entered the insurance process, rates of and times to approval and successful appeal after initial denial were calculated. Approval rates by Medicare (n=538) and private insurance (n=365) were 91% and 30% on initial request. Of the 306 patients initially denied coverage, 276 appealed the decision, and denial was overturned for 189 patients (68%; median time 21 days from initial inquiry). This study concluded that despite an 87% ultimate approval rate for proton therapy, the insurance process is a resource-intensive barrier to patient access associated with significant time delays to cancer treatment. (publication accessible via )

Proton beam therapy for cancer in the era of precision medicine. A general review on PBT inlcuding dosimetric advantage, clinical data on PBT for ocular tumor, skull base, paraspinal tumors (chondrosarcoma and chordoma), and unresectable sarcomas, reirradiation and pediatrics, as well as the expanded applications as treatment for malignancies of head and neck, lung, liver, breast and prostate. This review also discussed the considerable challenges in PBT application touching upon technology development, dealing with anatomical changes and biological effectiveness. (publication accessible via )

Key papers August - October 2018


Pediatric Localized Intracranial Ependymomas: A Multicenter Analysis of the Société Française de lutte contre les Cancers de l'Enfant (SFCE) from 2000 to 2013. This study was to analyze survival and prognostic factors for intracranial ependymoma treated with postoperative radiation therapy in the 13 main French pediatric RT reference centers. Of the 202 patients analyzed, 62% received conformal RT verses 29% for intensity modulated RT and 8% for proton beam therap. The study confirmed that tumor grade was the only prognostic factor for local relapse and disease free survival (DFS). Tumor grade, age, and extent of resection were independent prognostic factors for overall survival. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival. (publication accessible via )

Radiation Induced Cerebral Microbleeds in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy. A retrospective study was performed on 100 pediatric patients with primary brain tumors treated with PBT. Cerebral microbleeds (CMBs) were diagnosed by examining serial MRIs. The study found that the percentage of patients with CMBs was 43%, 66%, 80%, 81%, 83%, and 81% at 1-year, 2-years, 3-years, 4-year, 5-years, and greater than 5 years from completion of proton radiotherapy. The majority (87%) of CMBs were found in areas of brain exposed to ≥ 30 Gy. The study concluded that CMBs develop in a high percentage of pediatric patients with brain tumors treated with proton radiotherapy within the first few years following treatment. These findings demonstrate similarities with CMBs that develop in pediatric brain tumor patients treated with photon radiotherapy.   (publication accessible via )

Current status of proton therapy outcome for paediatric cancers of the central nervous system - Analysis of the published literature. In childhood cancer survivors, over 60% report one or more radiation-related late toxicities while half of these adverse events are graded as life-threatening or severe. Owing to the unique nature of dose delivery with proton therapy a reduction of low doses to normal tissues is achievable, and is believed to allow for a decrease in long-term treatment-related side effects. This review analyzed 74 papers published from year 2000 onwards, and found that proton therapy provides survival and tumour control outcomes comparable to photon therapy. Reduced incidence of severe acute and late toxicities was also reported including reduced severity of endocrine, neurological, IQ and QoL deficits. This review concluded that current evidence surrounding proton therapy use in paediatric patients supports its effectiveness and potential benefits in reducing the incidence of severe toxicities in later life. (publication accessible via )

Current status of proton therapy outcome for paediatric cancers of the central nervous system - Analysis of the published literature. In childhood cancer survivors, over 60% report one or more radiation-related late toxicities while half of these adverse events are graded as life-threatening or severe. Owing to the unique nature of dose delivery with proton therapy a reduction of low doses to normal tissues is achievable, and is believed to allow for a decrease in long-term treatment-related side effects. This review analyzed 74 papers published from year 2000 onwards, and found that proton therapy provides survival and tumour control outcomes comparable to photon therapy. Reduced incidence of severe acute and late toxicities was also reported including reduced severity of endocrine, neurological, IQ and QoL deficits. This review concluded that current evidence surrounding proton therapy use in paediatric patients supports its effectiveness and potential benefits in reducing the incidence of severe toxicities in later life. (publication accessible via )


PROTON THERAPY FOR ADULTS WITH MEDIASTINAL LYMPHOMAS: THE INTERNATIONAL LYMPHOMA RADIATION ONCOLOGY GROUP (ILROG) GUIDELINES. Radiation treatment techniques that increase the excess radiation dose to organs at risk (OARs) puts patients at risk of increased side effects, especially late toxicities, among adult lymphoma survivors. Minimizing radiation to OARs in adults patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the deciding factor for the choice of treatment modality. Proton therapy may help reduce the radiation dose to the OARs and reduce toxicities, especially the risks of cardiac morbidity and second cancers. This modern guideline aims to identify the adult lymphoma patients who may derive the greatest benefit from proton, along with an analysis of the advantages and disadvantages of the proton treatment (publication accessible via )


Development and validation of NTCP models for acute side-effects resulting from proton beam therapy of brain tumours. The German researchers from Dresden, Essen and Heidelberg together developed a NTCP model for acute side-effects including alopecia, scalp erythema, headache, fatigue and nausea, after proton therapy. The study reported that V35Gy (absolute volume receiving 35 Gy) for erythema grade ≥1, D2% (dose to 2% of the volume) for alopecia grade ≥1 and D5% for alopecia grade ≥2. The study concluded that the NTCP model was developed and successfully validated for scalp erythema and alopecia in primary brain tumour patients treated with PBT. (publication accessible via )


Lymphocyte-Sparing Effect of Proton Therapy in Patients with Esophageal Cancer Treated with Definitive Chemoradiation. This MD Anderson study compared IMRT and PBT chemoradiation for esophageal cancer. Patients who had IMRT and PBT matched by propensity score (n = 220) were not different with respect to age, sex, stage, performance status, tumor location, histology, tumor target volume, or induction chemotherapy. This study found that IMRT, compared to PBT, was associated with increased risk of grade 4 lymphopenia in patients with greater target volume, and PBT reduces the risk of severe, treatment-related lymphopenia, particularly in tumors of the lower esophagus.  (publication accessible via  )


Proton Therapy for Primary Breast Cancer. A review by Hug EB on PT for breast cancer. The author stated that in a small but significant percentage of patients requiring adjuvant radiotherapy for left-sided breast cancer, photon-based RT can lead to cardiac complications during long-term follow-up. Dosimetric comparison has identified advantages of proton therapy in accomplishing sparing of the heart with increasing target complexity while permitting uncompromised target coverage of the chest wall ± breast plus draining lymphatics. Early clinical data indicate good clinical tolerance to proton therapy without unexpected complications. Several clinical trials are presently ongoing to prospectively confirm a clinical benefit and to identify the subgroup of patients benefitting most from proton therapy for breast cancer. (publication accessible via )


Proton therapy for hepatocellular carcinoma (HCC): Current knowledges and future perspectives. A review by the Samsung Medical Center, Korea on radiotherapy for HCC, discussed the physical properties, current clinical data, technical issues, and future perspectives on PBT for the treatment of HCC. This review confirmed dosimetric advantages of PT, and presented literature that reported the favorable clinical outcomes and improved safety of PBT for HCC patients compared with X-ray therapy. However, there are some technical issues regarding the use of PBT in HCC, including uncertainty of organ motion and inaccuracy during calculation of tissue density and beam range, all of which may reduce the robustness of a PBT treatment plan. (publication accessible via )


Cost effectiveness of prostate cancer radiotherapy. This review article by Konski A, examined the data of cost-effectiveness analyses of various radiotherapy modalities including 3DCRT, IMRT, hypofractionated RT, SBRT and PBT, as well as external beam RT verse other treatments such as watchful waiting, radical prostatectomy, cryotherapy and brachytherapy. The author concluded that these analyses were a proxy to show value as the overall cost of medical care has risen.  Cost effectiveness analyses of newer therapies, however, may need to morph into value evaluations as healthcare systems evaluate adopting value based payment models that use disease specific reimbursement.   (publication accessible via )

Initial report of the genitourinary and gastrointestinal toxicity of post-prostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy. A retrospective analysis on 100 patients' acute and late genitourinary (GU) and gastrointestinal (GI) toxicities associated with post-prostatectomy proton therapy. Acute and late maximum toxicities, respectively were: GU grade 0 (14%; 18%), 1 (71%; 62%), 2 (15%; 20%), ≥3 (0), and GI: grade 0 (66%; 73%), 1 (34%; 27%), ≥2 (0). This study concluded that post-prostatectomy PT for prostate cancer is feasible with a favorable GU and GI toxicity profile acutely and through early follow up. (publication accessible via )

Early toxicity and patient reported quality-of-life in patients receiving proton therapy for localized prostate cancer: a single institutional review of prospectively recorded outcomes. A study by the Seattle group analyzed 231 patients of localized prostate cancer treated with protons. Median follow-up was 1.7 years. Grade 3 toxicity was seen in 5/192 patients. No grade 4 or 5 toxicity was seen. Patient reported quality-of-life showed no change in urinary function post-radiation by IPSS scores. Only younger age was associated with decreased sexual toxicity. EPIC bowel domain scores declined from 96 at baseline (median) by an average of 5.4 points at 1-year post-treatment, with no further decrease over time. (publication accessible via )

Initial toxicity, quality-of-life outcomes, and dosimetric impact in a randomized phase 3 trial of hypofractionated versus standard fractionated proton therapy for low-risk prostate cancer. A multi-center prospective phase 3 randomized trial aimed to identify differences in toxicity and quality-of-life outcomes between standard fractionation and extreme hypofractionated radiation. This report analyzed the results of the first 75 patients, comparing 38 Gy relative biologic effectiveness (RBE) in 5 fractions (n = 46) versus 79.2 Gy RBE in 44 fractions (n = 29). With the median follow-up was 36 months, the study reported low AE rates in both study arms, and early temporary differences in genitourinary scores disappeared over time. The study also found no differences in the EPIC domains of bowel symptoms, sexual symptoms, or bowel ≥G2 toxicities. (publication accessible via )

Head and Neck

Proton Radiotherapy for Recurrent or Metastatic Head and Neck Cancers with Palliative Quad Shot. A retrospective study by MSKCC etc multi-centers. 26 patients with recurrent or metastatic cancers were treated with palliative proton RT to the head and neck with quad shot (3.7 Gy twice daily for 2 days). Seventeen (65%) patients received ≥ 3 quad-shot cycles and 23 (88%) had prior head and neck RT. Overall palliative response was 73% (n = 19). The most common presenting symptom was pain (50%; n = 13), which improved in 85% (n = 22) of all patients. The overall grade-1 acute-toxicity rate was 58% (n = 15), and no acute grade 3 to 5 toxicities were observed. The authors concluded that proton quad-shot regimen demonstrates favorable palliative response and toxicity profile. (publication accessible via )

Proton Beam Therapy in Combination with Intra-Arterial Infusion Chemotherapy for T4 Squamous Cell Carcinoma of the Maxillary Gingiva. A retrospective study by Southern Tohoku Proton Therapy Center, Japan, analyzed 30 patients with T4 squamous cell carcinoma of the maxillary gingiva treated with radiation and intra-arterial infusion chemotherapy. Radiotherapy was using boost proton beam therapy for primary tumor and neck lymph node tumors, following 36-40 Gy photon radiation therapy delivered to the prophylactic area, to a total dose of 70.4-74.8 Gy. The 3-year local control and overall survival rates were 69% and 59%, respectively. Major grade 3 or higher acute toxicities included mucositis, neutropenia, and dermatitis in 12 (40%), 5 (17%), and 3 (10%) patients, respectively. No grade 3 or higher late toxicities were observed. The authors suggested that PBT in combination with intra-arterial infusion chemotherapy was not inferior to other treatment protocols and should be considered as a safe and effective option. (publication accessible via )

Endoscopic Resection Followed by Proton Therapy With Pencil Beam Scanning for Skull Base Tumors. A study by MSKCC compared PBS and IMRT radiation plans in the preoperative and postoperative settings for two patients with advanced skull base tumors following endoscopic resection. The benefits of PBS over IMRT appear greater in the postoperative setting following endoscopic resection with improved sparing of critical organs at risk. The conclusion by the authors is that the multidisciplinary approach of endoscopic resection followed by PBS represents a treatment paradigm with potential for improvements in toxicity reduction. (publication accessible via )


Reirradiation for locoregionally recurrent non-small cell lung cancer. In the context of definitive retreatment, increasing reRT dose can potentially improve OS and offer a chance of cure, particularly in patients with limited loco-regionally recurrent disease. However, retreatment can be challenging for fear of excessive toxicities and the inability to safely deliver definitive (≥60 Gy) doses. This review article examined the advanced radiation techniques including IMRT, SBRT and proton approach in reRT setting. The review concluded that patient selection is critical in order to maximize the benefits of reRT. Prospective clinical studies are needed to optimize patient selection and to facilitate the integration of these different radiation modalities into the management of locally recurrent lung cancer. (publication accessible via )

Advanced radiation techniques for locally advanced non-small cell lung cancer: intensity-modulated radiation therapy and proton therapy. This review article examined clinical outcomes data of IMRT and PBT for locally advanced NSCLC. This review pointed out that PBT is not considered the standard of care for locally advanced NSCLC, likely because of the limited comparative data to IMRT, increased cost, and added technical considerations. However, dosimetric data suggests both PS-PT and IMPT can better spare certain OARs than IMRT, with IMPT providing the greatest  dosimetric benefit but potentially requiring additional adjustments for uncertainties associated with beam range and organ motion. Given the increasing recognition of the importance of heart dose for NSCLC, proton therapy may provide a benefit over IMRT for certain anatomically challenging tumors on a case-by-case basis. Proton therapy may help achieve safer dose escalation, and re-irradiation with proton therapy appears feasible for carefully selected patients. (publication accessible via )

Patterns of Local-Regional Failure after Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy with Concurrent Chemotherapy for Non-Small Cell Lung Cancer. Published in the Red Journal, this retrospective analysis by MD Anderson group reviewed 212 patients treated with IMRT and PT, most (152 [72%]) had no failure; of the 60 patients with failure, 27 (45%) had Local Failure (within the ITV); 23 (38%) had Marginal Failure (between the ITV and PTV+10mm); and 10 (17%) had Regional Failure (>10 mm outside the PTV). MF rates were no different for IMRT or PSPT patients. The study concluded that no differences in LF, MF, or RF patterns were found for IMRT vs. PSPT. Proton therapy more often required adaptive planning, and the techniques used for adaptive planning did not compromise tumor control. (publication accessible via )

Clinical outcomes of image-guided proton therapy for histologically confirmed stage I non-small cell lung cancer (NSCLC). The interim results of two trials by the researchers in Nagoya, Japan, which aims to assess the efficacy and safety of image-guided proton therapy (IGPT) for either medically inoperable or operable stage I NSCLC. Fifty-five patients (IA in 33 patients and IB in 22 patients; inoperable in 21 patients and operable in 34 patients) were treated with proton for peripherally located tumors 66 Gy (RBE)) in 10 fractions (n = 49) and centrally located tumors 72.6 Gy(RBE) in 22 fractions (n = 6). The study reported the 3-year overall survival, progression-free survival, and local control rates of 87%, 74%, and 96%. Grade 2 toxicities observed were radiation pneumonitis in 5 patients (9%), rib fracture in 2 (4%), and chest wall pain in 5 (9%). There were no grade 3 or higher acute or late toxicities. The conclusion is that IGPT appears to be effective and well tolerated for all patients with stage I NSCLC. (publication accessible via )

Validation of Effective Dose as a Better Predictor of Radiation Pneumonitis (RP) Risk than Mean Lung Dose (MLD): Secondary Analysis of a Randomized Trial. Published in the Red Journal, this retrospective analysis by MD Anderson group reviewed 203 patients treated with protons or IMRT to 66-74 Gy(RBE) in 33-37 fractions with concurrent carboplatin/paclitaxel. By analyzing the 46 experienced grade ≥2 radiation pneumonitis at a median 3.7 months, this study found that  the effective dose (Deff) with n=0.5 (corresponding to root mean squared dose) is a better predictor of RP than MLD. Differences between Deff and MLD indicate that delivering higher doses to smaller lung volumes (vs. lower doses to larger volumes) increases RP risk. (publication accessible via )

Clinical outcomes of image-guided proton therapy for histologically confirmed stage I non-small cell lung cancer (NSCLC). The interim results of two trials by the researchers in Nagoya, Japan, which aims to assess the efficacy and safety of image-guided proton therapy (IGPT) for either medically inoperable or operable stage I NSCLC. Fifty-five patients (IA in 33 patients and IB in 22 patients; inoperable in 21 patients and operable in 34 patients) were treated with proton for peripherally located tumors 66 Gy (RBE)) in 10 fractions (n = 49) and centrally located tumors 72.6 Gy(RBE) in 22 fractions (n = 6). The study reported the 3-year overall survival, progression-free survival, and local control rates of 87%, 74%, and 96%. Grade 2 toxicities observed were radiation pneumonitis in 5 patients (9%), rib fracture in 2 (4%), and chest wall pain in 5 (9%). There were no grade 3 or higher acute or late toxicities. The conclusion is that IGPT appears to be effective and well tolerated for all patients with stage I NSCLC. (publication accessible via )

Validation of Effective Dose as a Better Predictor of Radiation Pneumonitis (RP) Risk than Mean Lung Dose (MLD): Secondary Analysis of a Randomized Trial. Published in the Red Journal, this retrospective analysis by MD Anderson group reviewed 203 patients treated with protons or IMRT to 66-74 Gy(RBE) in 33-37 fractions with concurrent carboplatin/paclitaxel. By analyzing the 46 experienced grade ≥2 radiation pneumonitis at a median 3.7 months, this study found that  the effective dose (Deff) with n=0.5 (corresponding to root mean squared dose) is a better predictor of RP than MLD. Differences between Deff and MLD indicate that delivering higher doses to smaller lung volumes (vs. lower doses to larger volumes) increases RP risk. (publication accessible via )


Initial experience with intensity modulated proton therapy for intact, clinically localized pancreas cancer: Clinical implementation, dosimetric analysis, acute treatment-related adverse events, and patient-reported outcomes. A Mayo Clinic study reported outcomes of IMPT for intact and clinically localized pancreatic cancer. 13 patients with localized pancreatic cancer underwent concurrent chemoradiation therapy utilizing IMPT to a dose of 50 Gy.  All patients completed treatment without radiation therapy breaks. The median weight loss during treatment was 1.6 kg (range, 0.1-5.7 kg). No patients experienced grade ≥3 treatment-related AEs. The study concluded that pencil-beam scanning IMPT was feasible and offered significant reductions in radiation exposure to multiple gastrointestinal organs at risk. (publication accessible via )

Current and emerging radiotherapy strategies for pancreatic adenocarcinoma: stereotactic, intensity modulated and particle radiotherapy. A review article by MD Anderson examined the available outcome data of IMRT, SBRT and proton and carbon ion therapy for locally advanced pancreatic cancer, and pointed out that retrospective evidence suggests prolonged survival for patients who receive biological equivalent doses above 70 Gy (as compared to conventional 50 Gy in 25–28 fractions). The advancements in treatment techniques and imaging modalities have enabled the effective and safe delivery of higher doses of radiation, and there is evidence that these higher doses may translate to better outcomes. (publication accessible via )


Proton therapy for low-grade gliomas in adults: A systematic review. A review by University of Gothenburg, Sweden. After screening 601 publications, nine articles were deemed eligible for in-depth analysis. This review found that proton treatment plans compared favorably to photon-plans regarding dose to uninvolved neural tissue. Fatigue (27-100%), alopecia (37-85%), local erythema (78-85%) and headache (27-75%) were among the most common acute toxicities after proton therapy. One study reported no significant long-term cognitive impairments. Limited data was available on long-term survival. One study reported a 5-year overall survival of 84% and 5-year progression-free survival of 40%. This review concluded that published data from clinical studies using proton therapy for adults with LGG are scarce, and controlled clinical studies are urgently warranted to determine if the potential benefits based on comparative treatment planning translate into clinical benefits. (publication accessible via

National practice patterns of proton versus photon therapy in the treatment of adult patients with primary brain tumors in the United States. With National Cancer Database, 73,073 adult patients with primary brain tumors treated with radiation were analyzed (n = 72,635 [99.4%] photon therapy, n = 438 [0.6%] proton therapy). Several factors predicted for receipt of proton therapy, including younger age (p = .041), highest income quartile (p = .007), treatment at academic institutions (p < .001), in regional facilities outside the Midwest/South (p < .001), diagnosis in more recent years (p = .003), fewer comorbidities (p < .001) and non-glioblastoma histology (p < .001). (publication accessible via )

Proton therapy for low-grade gliomas in adults: A systematic review. A review by University of Gothenburg, Sweden. After screening 601 publications, nine articles were deemed eligible for in-depth analysis. This review found that proton treatment plans compared favorably to photon-plans regarding dose to uninvolved neural tissue. Fatigue (27-100%), alopecia (37-85%), local erythema (78-85%) and headache (27-75%) were among the most common acute toxicities after proton therapy. One study reported no significant long-term cognitive impairments. Limited data was available on long-term survival. One study reported a 5-year overall survival of 84% and 5-year progression-free survival of 40%. This review concluded that published data from clinical studies using proton therapy for adults with LGG are scarce, and controlled clinical studies are urgently warranted to determine if the potential benefits based on comparative treatment planning translate into clinical benefits. (publication accessible via

National practice patterns of proton versus photon therapy in the treatment of adult patients with primary brain tumors in the United States. With National Cancer Database, 73,073 adult patients with primary brain tumors treated with radiation were analyzed (n = 72,635 [99.4%] photon therapy, n = 438 [0.6%] proton therapy). Several factors predicted for receipt of proton therapy, including younger age (p = .041), highest income quartile (p = .007), treatment at academic institutions (p < .001), in regional facilities outside the Midwest/South (p < .001), diagnosis in more recent years (p = .003), fewer comorbidities (p < .001) and non-glioblastoma histology (p < .001). (publication accessible via )

Registry and clinical trial

Prospective data registration and clinical trials for particle therapy in Europe. By Langendijk et al, this article presents the 'work package 1' of the European Proton Therapy Network (EPTN WP1). In order to establish a firm basis for evidence-based particle therapy at the European level, this work package will set up a worldwide prospective data registration programme for nine different tumour sites. This programme aims to provide more insights into the current practice and results across all European particle therapy centres with regard to radiation-induced toxicity and. The prospective data registration provides major opportunities to continuously improve the quality of particle therapy, to synchronize selection criteria and to create more homogeneous patient cohorts to evaluate results. In addition, this proagramme will define the requirements for high quality clinical trials in order to enhance high quality clinical trial proposals and determine alternative methods for RCT, such as the model-based approach. (publication accessible via )

Key papers April - June 2018


Risk of Radiation Vasculopathy and Stroke in Pediatric Patients Treated With Proton Therapy for Brain and Skull Base Tumors. To examine the rate of and identify risk factors for vasculopathy after proton therapy in pediatric patients with central nervous system and skull base tumors, the Jacksonville group analyzed 644 pediatric patients with central nervous system and skull base tumors were treated with proton therapy in their center. (publication accessible via )

Meta-analysis of the incidence and patterns of second neoplasms (SNs) after photon craniospinal irradiation (CSI) in children with medulloblastoma (MB). This meta-analysis reported that the 10-year cumulative incidence was 6.1% for all SNs, including 3.1% for SBNs (benign) and 3.7% for SMNs (malignant), with a majority in areas of exit RT dose. Studies are needed to determine whether the use of proton therapy, which has no exit RT dose, is associated with a lower incidence of SNs. (publication accessible via )

Proton therapy for central nervous system tumors in children. A systematic review conducted by John Hopkin and MGH.  It highlighted the capability of protons to decrease radiation exposure for children is regarded as an important advance in pediatric cancer care, particularly for central nervous system (CNS) tumors. Favorable clinical outcomes have been reported and justify the increased cost and burden of this therapy. (publication accessible via )

National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury. Reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. A workshop was organized including twenty-seven physicians, physicists, and researchers from 17 institutions with expertise to discuss this issue. And the report of this workshop is published in the Red Journal. (publication accessible via )



Protons vs Photons for Brain and Skull Base Tumors. A systematic review summarizes the literature regarding the role of proton therapy compared to photon therapy in the treatment of adult brain and skull base tumors, including chordoma/chondrosarcoma, glioma, meningioma, pituitary tumor, acoustic neuroma, and craniopharyngioma.  (publication accessible via


Head and Neck

Proton Therapy for Head and Neck Cancer. A systematic review by MSKCC summarized the published clinical research, and the authors believe that widespread adoption of proton therapy will elucidate the true value of proton beam therapy and give a greater understanding of the full risks and benefits of proton therapy in head and neck cancer. (publication accessible via )



Does Proton Therapy Offer Demonstrable Clinical Advantages for Treating Thoracic Tumors? A review by the MD Anderson group examined the available data with regard to proton therapy for thoracic malignancies, and presented the unique challenges in translating the dosimetric advantages of proton therapy to clinical benefit for patients with thoracic tumors. Extensive improvements are needed in all aspects of the treatment process, from simulation, planning algorithms, and volumetric image guidance through to real-time tracking and treatment adaptation. (publication accessible via )



Potential Morbidity Reduction with Proton Radiation Therapy for Breast Cancer. A systematic review by MSKCC about the increasing emphasis on the mitigation of iatrogenic morbidity, with particular attention to heart and lung exposure in those receiving adjuvant chemoradiation. The paper summarized the dosimetric evidence and early clinical evidence that supports the efficacy and feasibility of proton radiation in breast cancer. (publication accessible via )



Finding Value for Protons: The Case of Prostate Cancer? A review by UPenn examined the dosimetric data and clinical outcome reports. Clinical studies largely suggest no difference in urinary side effects or erectile dysfunction. Regarding rectal toxicity, some studies found PBT was worse, others suggested PBT was better, and still others concluded there was no meaningful difference at all. A comparative trial has commenced the Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL) trial. (publication accessible via )


Clinical trial

Clinical Trial Strategies to Compare Protons with Photons. Langendijk et al. the Groningen group on clinical trial strategies to compare protons and photons. The authors suggested that for the clinical validation of the added value of protons to improve local control, randomized controlled trials are required. However, for the added value of protons to prevent side effects, both model-based validation and randomized controlled trials can be used. (Publication accessible via )

Key papers January - March 2018


Proton Beam Therapy for Iris Melanomas in 107 Patients. A study reported outcomes of 107 iris melanoma patients treated with protons. Proton therapy showed efficacy and limited morbidity in iris melanomas. (publication accessible via )


Proton therapy for pediatric head and neck malignancies
. A study conducted by the UPenn group reported acute toxicities and early outcomes following PBT for pediatric head and neck malignancies. The study demonstrated low rates of acute toxicity and local control rates similar to historical reports. (publication accessible via )

Esophageal cancer

Clinical outcomes of intensity modulated proton therapy and concurrent chemotherapy in esophageal carcinoma (EC). 19 patients with EC treated with IMPT concurrently with chemotherapy. Clinical complete response was achieved in 84%. The most common grade 3 acute toxicities were esophagitis and fatigue. IMPT is an effective treatment for EC, with high tumor response, good local control, and acceptable acute toxicity.  (publication accessible via )

Key papers November - December 2017


Proton Beam Therapy for Iris Melanomas in 107 Patients. A study reported outcomes of 107 iris melanoma patients treated with protons. Proton therapy showed efficacy and limited morbidity in iris melanomas. (publication accessible via )


Proton therapy for pediatric head and neck malignancies. A study conducted by the UPenn group reported acute toxicities and early outcomes following PBT for pediatric head and neck malignancies. The study demonstrated low rates of acute toxicity and local control rates similar to historical reports. (publication accessible via )

Esophageal cancer

Clinical outcomes of intensity modulated proton therapy and concurrent chemotherapy in esophageal carcinoma (EC). 19 patients with EC treated with IMPT concurrently with chemotherapy. Clinical complete response was achieved in 84%. The most common grade 3 acute toxicities were esophagitis and fatigue. IMPT is an effective treatment for EC, with high tumor response, good local control, and acceptable acute toxicity.  (publication accessible via )

Severe lymphopenia during neoadjuvant chemoradiation for esophageal cancer: A propensity matched analysis of the relative risk of proton versus photon-based radiation therapy.Compared the relative risk of radiation-induced lymphopenia between IMRT and PBT in esophageal cancer (EC) patients undergoing neoadjuvant chemoradiation therapy (nCRT), PBT was significantly associated with a reduction in grade 4 lymphopenia risk. (publication accessible via )


Acute toxicity of image-guided hypofractionated proton therapy for localized prostate cancer. A study reported toxicity of 526 localized prostate cancer patients treated with proton therapy and demonstrated the safety of HFPT for localized PCa patients in terms of acute toxicity.  (publication accessible via )

Minimal toxicity after proton beam therapy for prostate and pelvic nodal irradiationresults from the proton collaborative group REG001-09 trial. This PCG study evaluated toxicity outcomes for non-metastatic prostate cancer patients who received pelvic radiation therapy. The study demonstrated PBT significantly less acute GI toxicity than is expected using IMXT which may be related to small bowel sparing from PBT. (publication accessible via )


Proton therapy for locally advanced breast cancer: A systematic review of the literature.This systematic review reported that protons offered a better target coverage than photons, even compared with intensity modulation radiation therapy (including static or rotational IMRT or tomotherapy). Protons decreased mean heart dose by a factor of 2 or 3, i.e. 1 Gy with proton therapy versus 3 Gy with conventional 3D, and 6 Gy for IMRT. (publication accessible via )


Key papers May - October 2017

Head and Neck

Proton therapy for head and neck cancer: expanding the therapeutic window. Published in the Lancet Oncology, this review article summarized the recent published outcomes of proton therapy head and neck cancer. In reviewing PT for different subsites including unilateral irradiation, oropharyngeal carcinoma, nasopharyngeal carcinoma, sinonasal cancer, tumors of the skull base and reirradiation, the authors pointed out that the clinical benefits of PT in terms of toxicity sparing are becoming increasingly apparent ranging from incremental to substantial in the selected patient groups. (Publication accessible via )


Consensus Guidelines for Implementing Pencil-Beam Scanning Proton Therapy for Thoracic Malignancies on Behalf of the PTCOG Thoracic and Lymphoma Subcommittee. This consensus provides guidance for implementing PBS for thoracic treatments. IMPT represents the latest advanced PT technology, however motion uncertainty, tissue density heterogeneity of chest organs can have a significant impact on dose distribution. This consensus guidelines list strategies and steps for PBS IMPT. (Publication accessible via )

Proton Beam Radiotherapy and Concurrent Chemotherapy for Unresectable Stage III Non-Small-Cell Lung Cancer: Final Results of a Phase 2 Study. Published in JAMA Oncology, this MD Anderson study reported the final (5-year) results of a prospective study of 64 patients unresectable stage III NSCLC treated with concurrent chemotherapy and passively scattered PBT (74-Gy relative biological effectiveness). The authors concluded that concurrent chemotherapy and PBT to treat unresectable NSCLC afford promising clinical outcomes and rates of toxic effects compared with historical photon therapy data. (Publication accessible via )


Evidence-based Review on the Use of Proton Therapy in Lymphoma from the Particle Therapy Cooperative Group (PTCOG) Lymphoma Subcommittee. In an effort to draw attention to the use of proton therapy in lymphoma, and as a resource for future consideration of proton therapy coverage for lymphoma by other expert panels and insurance agencies, the PTCOG lymphoma subcommittee has developed an evidence-based review on the use of proton therapy in lymphoma. The committee recommended that proton therapy should be reasonably considered in appropriately selected lymphoma patients when it can significantly decrease the dose to critical structures. (publication accessible via )


Systematic assessment of clinical outcomes and toxicities of proton radiotherapy for reirradiation. This review assessed clinical outcomes and toxicity profiles by evaluating available evidence regarding PBT reRT. The authors posit that PBT may be the safest option to reirradiate patients with locoregional recurrences, and thus PBT may be the best approach for offering select patients a new chance of cure. (publication accessible via )


Quality of Life and Patient-Reported Outcomes Following Proton Radiation Therapy: A Systematic Review. Evaluating quality of life (QOL) and patient-reported outcomes (PROs) is essential to establishing PBT's "value" in oncologic therapy. This systematic review reported that PBT provides favorable QOL/PRO profiles for select brain, head/neck, lung, and pediatric cancers; measures for prostate and breast cancers were more modest. These results have implications for cost-effective cancer care and prudently designed QOL evaluation in ongoing trials. (publication accessible via )


Key papers March - April 2017

Liver cancer

Analysis of repeated proton beam therapy for patients with hepatocellular carcinoma.  Published in the Green Journal, the researchers in Japan reported outcomes of 83 patients treated with definitive repeated PBT. Patients received a median doses for the 1st, 2nd, 3rd and 4th treatments were 71.0, 70.0, 70.0, and 69.3 GyE, and there was no severe acute toxicity, and no radiation-induced liver dysfunction (RILD) was observed. The 2- and 5-year OS rates were 87.5% and 49.4%. (Publication accessible via )

Breast cancer

Joint Estimation of Cardiac Toxicity and Recurrence Risks after Comprehensive Nodal Photon versus Proton Therapy for Breast Cancer. Published in the Red Journal, this study generated proton plans for 41 left-side breast cancer patients who underwent postlumpectomy comprehensive nodal photon irradiation, then evaluated the risks of cardiotoxicity and breast cancer recurrence. It is reported that proton therapy can reduce the predicted risk of cardiac toxicity by up to 2.9% and risk of recurrence of breast cancer by 0.9%, compared to modern photon techniques. (Publication accessible via )

Pediatric cancer

Supine craniospinal irradiation in pediatric patients by proton pencil beam scanning. Published in the Green Journal by the Trento group in Italy, this paper reported methods and techniques for performing PBS CSI effectively. Special methods included 1) supine patient position 2) field-junctions via the ancillary-beam technique 3) lens-sparing by three beam whole brain irradiation 4) applied a movable snout and beam splitting technique to reduce the lateral penumbra for dose reduction to kidney. (Publication accessible via )

Patient selection

Using a knowledge-based planning solution to select patients for proton therapy. Published in the Green Journal, a knowledge-based-planning solution developed by the Dutch group for proton therapy patient selection is reported to provide efficient, patient-specific selection for protons by using plan-libraries to model and predict organ-at-risk (OAR) dose-volume-histograms (DVH). (Publication accessible via )

Key papers October 2016 - March 2017


Patterns of care in proton therapy for children. Published in the Red Journal, this paper examined patterns of treatments received for pediatric patients with primary CNS malignancies. The authors pointed out that as we continue to demonstrate the potential benefits of PBT in children, efforts are needed to expand the accessibility of PBT for children of all socioeconomic background and regions of the country. (Publication accessible

Lifetime attributable risk of radiation-induced secondary cancer. A group of Japanese researchers compared the lifetime attributable risk of secondary cancer (LAR) induced by proton therapy and IMRT in pediatric patients. The paper reported that for categories of brain, head and neck, thoracic, abdominal and whole craniospinal irradiation, the LAR of PBT was significantly lower than IMRT. (Publication accessible )


PRONTOX – a randomized control trial. Although radiochemotherapy with photons is the standard treatment for now for locally advanced NSCLC, but acute radiation-induced toxicity such as esophagitis and pneumonitis can be potentially life-threatening. The Dresden group has commenced this randomized control trial that aims to show a decrease of 39% to 12% of early and intermediate radiation-induced toxicity using proton therapy. (Publication accessible )

Long-term outcome of a prospective study of dose-escalated proton therapy for early-stage non-small cell lung cancer. This MD Anderson study published in the Green Journal reported proton therapy for early stage NSCLC patients who were not suitable for SBRT due to lesion size and location. The study reported encouraging 5-year overall survival rate and recurrence-free rate. The authors concluded that this long-term follow-up data demonstrated proton therapy with ablative doses is well tolerated and effective in medically inoperable early-stage NSCLC. (Publication accessible )


Long-term outcomes of proton therapy for previously untreated hepatocellular carcinoma (HCC). The Japanese group in University of Tsukuba conducted this retrospective study of 129 patients with stage 0 to C disease (BCLC) treated with proton therapy. The study reported favourable long-term efficacies with mild adverse effect in BCLC stage 0 to C patients. (Publication accessible )


Evidence-based medicine

Establishing evidence-based indications for proton therapy. An overview of current clinical trials of proton therapy published in the Red Journal. A total 122 ongoing trials with target enrolment of over 42,000 patients. The most common PBT clinical trials are about gastrointestinal tract tumors, tumors of the central nervous system and prostate cancer. There are 5 randomized studies between proton and photon are on lung, esophagus, head and neck, prostate and breast. The paper demonstrated that PBT clinical trials are rapidly expanding. (Publication accessible )

Patient estimates for proton therapy

Published in the Green Journal, this ESTRO-HERO (Health Economics in Radiation Oncology) analysis reported about 4 million new cancer patients are predicted in 2025 in Europe, a 15.9% increase compared to the number of 2012, and about 2 million cancer patients would have an indication for radiotherapy in 2025, a 16.1% increase from year 2012. New radiotherapy techniques enable delivery precision and less toxic effects combined with new chemotherapy could also influence the number of candidates for radiotherapy treatments. This paper is to raise awareness for resource planning and placing investments to adequately manage demands of cancer patients. (Publication accessible:

Key papers January - October 2016

Head and neck cancer

A retrospective study reported that proton therapy significantly reduced toxicity compared with IMRT for head and neck tumors. The toxicity outcome confirm the dosimetry advantages of proton which resulted in significantly lower rates of grade 2 or above acute dysgeusia, mucositis and nausea. (Publication accessible via )

A matched analysis compared PBRT and IMRT for nasopharynx and paranasal sinus cancers with concurrent chemotherapy, reported that PBRT was associated with a lower opioid pain requirement and a lower rate of gastrostomy tube dependence. (Publication accessible via )

Proton therapy can be a safe and effective curative reirradiation strategy for head and neck cancer, with acceptable rates of toxicity and durable disease control. A study reported encouraging 2-year rates of local regional control, overall survival and late toxicity. (Publication accessible via )

Hodgkin lymphoma

A registry study of collective proton centres reported a 2-year relapse-free survival of 85% with no grade 3 toxicity occurred. Hodgkin lymphoma young survivors are at great risk of developing chronic morbidities and secondary cancer, these patients may derive considerable benefit with proton therapy. (Article accessible via )

Gastrointestinal malignancy

A randomized trial comparing proton therapy with transarterial chemoembolization (TACE) for hepatocellular carcinoma, reported a trend toward improved local tumour control, progression-free survival, and significantly fewer hospitalization days after proton treatment. (Publication accessible via )


A systematic review examined clinical outcomes and toxicities of proton therapy for gastrointestinal neoplasms. The findings include that proton therapy was associated with reduced toxicity for esophageal cancer and pancreatic cancer while achieving similar disease control and survival compared to photon techniques. For hepatocellular carcinoma, proton therapy demonstrated a trend towards improved local control and progression-free survival. (Publication accessible via )


A systematic review reported findings on clinical outcomes and toxicity of proton therapy for breast cancer. Toxicity was comparable or improved to published photon data. Proton offers excellent potential to minimize the risk of cardiac events, keeping the mean heart dose at ≤1Gy. (Publication accessible via )



A large series of 1327 localized prostate cancer patients reported 5-year biochemical control rate, toxicity and patient-reported quality of life after proton therapy. The study concluded that image guided proton therapy provided excellent biochemical control rates and the actuarial rates of high-grade toxicity were low.  Publication accessible via )

Cost effectiveness

A systematic review of the cost-effectiveness of proton therapy found that proton therapy was a cost-effective option for several pediatric brain tumors, selected left-sided breast cancer, selected head and neck cancer and locoregionally advanced non-small cell lung cancer. (Publication accessible via )

Clinical Decision

A clinical decision support system (PRODECIS) for choosing proton or photon modality for head and neck patients. Based on evaluation and comparison of dosimetry, toxicity, and cost-effectiveness, the system successfully quantified patients for proton or photon treatment choice. Publication accessible via )



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