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 January - February 2019

Pediatric

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 https://www.ncbi.nlm.nih.gov/pubmed/30753704 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30625409 )


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 https://www.ncbi.nlm.nih.gov/pubmed/30616799 )

Lymphoma

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 https://www.ncbi.nlm.nih.gov/pubmed/30708133 )

Breast

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 https://www.ncbi.nlm.nih.gov/pubmed/30693271)

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 https://www.ncbi.nlm.nih.gov/pubmed/30644538 )

Lung

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 https://www.ncbi.nlm.nih.gov/pubmed/30691496 )


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 https://www.ncbi.nlm.nih.gov/pubmed/30656994 )


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 https://www.ncbi.nlm.nih.gov/pubmed/30585704 )

Esophagus

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 https://www.ncbi.nlm.nih.gov/pubmed/30706012)

Prostate

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 https://www.ncbi.nlm.nih.gov/pubmed/30706013)


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 https://www.ncbi.nlm.nih.gov/pubmed/30630500 )


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 https://www.ncbi.nlm.nih.gov/pubmed/30621278 )

Others

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 https://www.ncbi.nlm.nih.gov/pubmed/30723643 )

Key papers November - December 2018

Breast

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 https://www.ncbi.nlm.nih.gov/pubmed/30414757 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30453388 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30411162 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30496877 )

Pediatric  

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 https://www.ncbi.nlm.nih.gov/pubmed/30361128 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30582019 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30537887 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30414759 )

CNS

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 https://www.ncbi.nlm.nih.gov/pubmed/30474448 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30547008 )

Ocular  

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 https://www.ncbi.nlm.nih.gov/pubmed/30552889 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30477528

GI

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 https://www.ncbi.nlm.nih.gov/pubmed/30505599 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30488022 )

Lung

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 https://www.ncbi.nlm.nih.gov/pubmed/30483900 )

Prostate

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 https://www.ncbi.nlm.nih.gov/pubmed/30527342 )

Others

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 https://www.ncbi.nlm.nih.gov/pubmed/30557675 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30541578 )

Key papers August - October 2018

Pediatric

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 https://www.ncbi.nlm.nih.gov/pubmed/30102193 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30092336 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30326423 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30326423 )

Lymphoma

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 https://www.ncbi.nlm.nih.gov/pubmed/30108066 )

Brain

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 https://www.ncbi.nlm.nih.gov/pubmed/30033385 )

Esophagus

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 https://www.ncbi.nlm.nih.gov/pubmed/30079369  )

Breast

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 https://www.ncbi.nlm.nih.gov/pubmed/30069176 )

Liver

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 https://www.ncbi.nlm.nih.gov/pubmed/30065555 )

Prostate

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 https://www.ncbi.nlm.nih.gov/pubmed/30050797 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30028227 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30223877 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30202801 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30246055 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30223580 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30208224 )

Lung

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 https://www.ncbi.nlm.nih.gov/pubmed/30206496 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30206493 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30165127 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30305125 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30165127 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30305125 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30165127 )

Pancreas  

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 https://www.ncbi.nlm.nih.gov/pubmed/30202800 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30198024 )

CNS

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 https://www.ncbi.nlm.nih.gov/pubmed/30292166)

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 https://www.ncbi.nlm.nih.gov/pubmed/30280620 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30292166)

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 https://www.ncbi.nlm.nih.gov/pubmed/30280620 )

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 https://www.ncbi.nlm.nih.gov/pubmed/30056852 )

Key papers April - June 2018

Pediatric

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 https://www.ncbi.nlm.nih.gov/pubmed/29730064 )

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 https://www.ncbi.nlm.nih.gov/pubmed/29683953 )

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 https://www.ncbi.nlm.nih.gov/pubmed/29630784 )

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 https://www.ncbi.nlm.nih.gov/pubmed/29619963 )

 

CNS

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 https://www.ncbi.nlm.nih.gov/pubmed/29735196)

 

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 https://www.ncbi.nlm.nih.gov/pubmed/29744681 )

 

Lung

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 https://www.ncbi.nlm.nih.gov/pubmed/29735187 )

 

Breast

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 https://www.ncbi.nlm.nih.gov/pubmed/29735190 )

 

Prostate

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 https://www.ncbi.nlm.nih.gov/pubmed/29735189 )

 

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 https://www.ncbi.nlm.nih.gov/pubmed/29735194 )

Key papers January - March 2018

Eye

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 https://www.ncbi.nlm.nih.gov/pubmed/29128229 )

Pediatric

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 https://www.ncbi.nlm.nih.gov/pubmed/29058370 )

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 https://www.ncbi.nlm.nih.gov/pubmed/29114596 )

Key papers November - December 2017

Eye

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 https://www.ncbi.nlm.nih.gov/pubmed/29128229 )

Pediatric

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 https://www.ncbi.nlm.nih.gov/pubmed/29058370 )

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 https://www.ncbi.nlm.nih.gov/pubmed/29114596 )

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 https://www.ncbi.nlm.nih.gov/pubmed/29248170 )

Prostate

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 https://www.ncbi.nlm.nih.gov/pubmed/29098520 )

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 https://www.ncbi.nlm.nih.gov/pubmed/29034790 )

Breast

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 https://www.ncbi.nlm.nih.gov/pubmed/29197746 )

 

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 https://www.ncbi.nlm.nih.gov/pubmed/28456587 )

Lung

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 https://www.ncbi.nlm.nih.gov/pubmed/28816159 )

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 https://www.ncbi.nlm.nih.gov/pubmed/28727865 )

Lymphoma

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 https://www.ncbi.nlm.nih.gov/pubmed/28943076 )

Reirradiation

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 https://www.ncbi.nlm.nih.gov/pubmed/28941560 )

QoL

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 https://www.ncbi.nlm.nih.gov/pubmed/29028221 )

 

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 https://www.ncbi.nlm.nih.gov/pubmed/28366501 )


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 https://www.ncbi.nlm.nih.gov/pubmed/28244411 )


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 https://www.ncbi.nlm.nih.gov/pubmed/28283192 )

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 https://www.ncbi.nlm.nih.gov/pubmed/28411963 )

Key papers October 2016 - March 2017

Pediatric

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 https://www.ncbi.nlm.nih.gov/pubmed/27816365

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 https://www.ncbi.nlm.nih.gov/pubmed/27789564 )


Lung

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 https://www.ncbi.nlm.nih.gov/pubmed/27846903 )

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 https://www.ncbi.nlm.nih.gov/pubmed/28139305 )


Liver

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 https://www.ncbi.nlm.nih.gov/pubmed/28012214 )

 

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 https://www.ncbi.nlm.nih.gov/pubmed/28068231 )

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: http://www.thegreenjournal.com/article/S0167-8140(16)00074-8/fulltext)

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 http://www.ncbi.nlm.nih.gov/pubmed/26867969 )

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 http://www.ncbi.nlm.nih.gov/pubmed/26922239 )

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 https://www.ncbi.nlm.nih.gov/pubmed/27325480 )


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 https://www.ncbi.nlm.nih.gov/pubmed/27579554 )

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 https://www.ncbi.nlm.nih.gov/pubmed/27084661 )

 

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 http://www.ncbi.nlm.nih.gov/pubmed/27563457 )

Breast

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 https://www.ncbi.nlm.nih.gov/pubmed/26995159 )

 

Prostate

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 http://www.ncbi.nlm.nih.gov/pubmed/27084658 )

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 http://www.ncbi.nlm.nih.gov/pubmed/26828647 )

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 http://www.ncbi.nlm.nih.gov/pubmed/26924342 )

 

 

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