Combined, yet separate: cocktails of carriers (not drugs) for actinium-225 α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers.

Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid tumors even when they moderately express the targeted markers. At this limit of lower tumor-absorbed doses, to maintain efficacy, the few(er) intratumorally delivered alpha-particles need to traverse/hit as many different cancer cells as possible. We complement antibody-radioconjugate therapies with a separate nanocarrier delivering a fraction of the same total injected radioactivity to tumor regions geographically different than those affected by targeting antibodies; these carrier-cocktails collectively distribute the alpha-particle emitters better. METHODS: The efficacy of actinium-225 delivered by our carrier-cocktails was assessed in vitro and on mice with orthotopic MDA-MB-436 and/or MDA-MB-231 triple-negative breast cancers and/or an ectopic BxPC3 pancreatic cancer. Cells/tumors were chosen to express low-to-moderate levels of HER1, as model antibody-targeted marker. RESULTS: Independent of cell line, antibody-radioconjugates were most lethal on cell monolayers. On spheroids, with radii greater than alpha-particles' range, carrier-cocktails improved killing efficacy (p < 0.0500). Treatment with carrier-cocktails decreased the MDA-MB-436 and MDA-MB-231 orthotopic tumor volumes by 73.7% and 72.1%, respectively, relative to treatment with antibody-radioconjugates alone, at same total injected radioactivity; these carrier-cocktails completely eliminated formation of spontaneous metastases vs. 50% and 25% elimination in mice treated with antibody-radioconjugates alone. In BxPC3 tumor-bearing mice, carrier-cocktails increased the median survival to 25-26 days (in male-female animals) vs. 20-21 days of mice treated with antibody-radioconjugates alone (vs. 17 days for non-treated animals). Survival with carrier-cocktail radiotherapy was further prolonged by pre-injecting low-dose, standard-of-care, gemcitabine (p = 0.0390). CONCLUSION: Tumor-agnostic carrier-cocktails significantly enhance the therapeutic efficacy of existing alpha-particle radionuclide-antibody treatments.

Novel concept of "sequential particle radiotherapy" with atezolizumab plus bevacizumab for hepatocellular carcinoma with portal vein tumor thrombus.

Owing to the high objective response rate of atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC), the concept of sequential conversion to local treatment has recently become mainstream. The conversion concept is mainly applied to Barcelona Clinic for Liver Cancer (BCLC) stage B cases, and radiotherapy is rarely considered as a conversion local treatment. We herein report three patients who were treated with the novel concept of "sequential particle radiotherapy," consisting of Atez/Bev therapy followed by particle radiotherapy (PRT) for HCC with advanced portal vein tumor thrombus (Vp3/4 PVTT). All patients achieved partial response radiologically and were switched to PRT. All patients were recurrence free at 1 year after the introduction of Atez/Bev therapy without any additional treatment. This upcoming combination strategy includes the advocacy of sequential concepts for BCLC stage C cases and the introduction of PRT as a local treatment after Atez/Bev.

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks.

Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.

Focused Ion Microbeam Irradiation Induces Clustering of DNA Double-Strand Breaks in Heterochromatin Visualized by Nanoscale-Resolution Electron Microscopy.

BACKGROUND: Charged-particle radiotherapy is an emerging treatment modality for radioresistant tumors. The enhanced effectiveness of high-energy particles (such as heavy ions) has been related to the spatial clustering of DNA lesions due to highly localized energy deposition. Here, DNA damage patterns induced by single and multiple carbon ions were analyzed in the nuclear chromatin environment by different high-resolution microscopy approaches. MATERIAL AND METHODS: Using the heavy-ion microbeam SNAKE, fibroblast monolayers were irradiated with defined numbers of carbon ions (1/10/100 ions per pulse, ipp) focused to micrometer-sized stripes or spots. Radiation-induced lesions were visualized as DNA damage foci (γH2AX, 53BP1) by conventional fluorescence and stimulated emission depletion (STED) microscopy. At micro- and nanoscale level, DNA double-strand breaks (DSBs) were visualized within their chromatin context by labeling the Ku heterodimer. Single and clustered pKu70-labeled DSBs were quantified in euchromatic and heterochromatic regions at 0.1 h, 5 h and 24 h post-IR by transmission electron microscopy (TEM). RESULTS: Increasing numbers of carbon ions per beam spot enhanced spatial clustering of DNA lesions and increased damage complexity with two or more DSBs in close proximity. This effect was detectable in euchromatin, but was much more pronounced in heterochromatin. Analyzing the dynamics of damage processing, our findings indicate that euchromatic DSBs were processed efficiently and repaired in a timely manner. In heterochromatin, by contrast, the number of clustered DSBs continuously increased further over the first hours following IR exposure, indicating the challenging task for the cell to process highly clustered DSBs appropriately. CONCLUSION: Increasing numbers of carbon ions applied to sub-nuclear chromatin regions enhanced the spatial clustering of DSBs and increased damage complexity, this being more pronounced in heterochromatic regions. Inefficient processing of clustered DSBs may explain the enhanced therapeutic efficacy of particle-based radiotherapy in cancer treatment.

Particle radiation therapy in the management of malignant glioma: Early experience at the Shanghai Proton and Heavy Ion Center.

BACKGROUND: The objective of this study was to evaluate the outcomes of patients with high-grade glioma who received treatment with particle radiotherapy. METHODS: Between June 2015 and October 2018, 50 consecutive and nonselected patients with glioblastoma multiforme (n = 34) or anaplastic glioma (n = 16) were treated at the Shanghai Proton and Heavy Ion Center. Twenty-four patients received proton radiotherapy (at a dose of 60 gray-equivalents in 30 daily fractions), and 26 patients received proton radiotherapy plus a carbon-ion radiotherapy (CIRT) boost in various dose-escalating schemes. All patients received temozolomide because of their age or their O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Progression-free survival (PFS) and overall survival (OS) rates, as well as treatment-induced toxicities, were analyzed. RESULTS: At a median follow-up of 14.3 months (range, 4.8-39.6 months), the 12-month and 18-month OS rates were 87.8% (95% CI, 77.6%-98.0%) and 72.8% (95% CI, 56.7%-88.9%), respectively, and the 12-month and 18-month PFS rates were 74.2% (95% CI, 60.9%-87.5%) and 59.8% (95% CI, 43.1%-76.5%), respectively. Univariate analyses revealed that age (>50 vs ≤50 years), World Health Organization grade (3 vs 4), and Karnofsky performance status (>80 vs ≤80) were significant prognosticators for OS, and IDH mutation and World Health Organization grade were significant for predicting PFS. Furthermore, MGMT promoter methylation, performance status, and age showed a trend toward predicting PFS. No significant predictive factors for PFS or OS were identified in multivariate analyses. Twenty-nine patients experienced grade 1 treatment-related acute adverse effects, and 11 developed grade 1 (n = 6) or grade 2 (n = 5) late adverse effect of radiation-induced brain necrosis. No grade 3, 4, or 5 toxicities were observed. CONCLUSIONS: Particle radiotherapy produced 18-month OS and PFS rates of 72.8% and 59.8%, respectively, with acceptable adverse effects in patients with high-grade glioma. Particle radiotherapy at a dose ≥60 gray-equivalents appears to be safe and potentially effective.

Outcomes of orbital malignancies treated with eye-sparing surgery and adjuvant particle radiotherapy: a retrospective study.

BACKGROUND: To report the clinical experience of eye sparing surgery (ESS) and adjuvant carbon-ion or proton radiotherapy (CIRT or PRT) for orbital malignancies. METHODS: An analysis of the retrospective data registry from the Shanghai Proton and Heavy Ion Center for patients with orbital tumors was conducted. The 2-year local progression-free, regional recurrence-free, distant metastasis-free, progression-free, and overall survival (LPFS, RRFS, DMFS, PFS, OS) rates as well as associated prognostic indicators were analyzed. Radiotherapy-induced acute and late toxicities were summarized. RESULTS: Between 7/2014 to 5/2018, 22 patients with orbital malignancies of various pathologies received ESS followed by CIRT (18), PRT (1), or PRT + CIRT boost (3). With a median follow-up of 20.25 (range 3.8-38.8) months, the 2-year OS, PFS, LPFS, RRFS, and DMFS rates were 100, 57.9, 92.9, 93.3, and 72.8%, respectively. No acute severe (i.e., ≥grade 3) toxicity was observed. Two patients experienced severe visual impairment as late toxicities. CONCLUSION: With few observed acute and late toxicities, particle radiotherapy following ESS provided effective local control with infrequent severe toxicities for patients with orbital malignancies.

111In- and 225Ac-Labeled Cixutumumab for Imaging and α-Particle Radiotherapy of IGF-1R Positive Triple-Negative Breast Cancer.

Insulin growth factor receptor (IGF-1R) is overexpressed in many cancers of epithelial origin, where it confers enhanced proliferation and resistance to therapies targeted at other receptors. Anti-IGF-1R monoclonal antibodies have not demonstrated significant improvements in patient outcomes in clinical trials. Humanized monoclonal antibody cixutumumab (IMC-A12) binds to IGF-1R with low nM affinity. In this study, cixutumumab was conjugated with p-SCN-Bn-DOTA and radiolabeled with 111In or 225Ac for imaging or radiotherapy using a triple-negative breast cancer (TNBC) model SUM149PT. The antibody conjugate showed low nM affinity to IGF-1R, which was not affected by conjugation and radiolabeling procedures. Cixutumumab immunoconjugates were effectively internalized in SUM149PT and were cytotoxic to the cells with an EC50 of 225Ac-cixutumumab (0.02 nM) that was almost 5000-fold less than that of unlabeled cixutumumab (95.2 nM). MicroSPECT imaging of the SUM149PT xenograft showed the highest tumor uptake occurred at 48 h post injection and was 9.9 ± 0.5% injected activity per gram (%IA/cc). In radiotherapy studies, we evaluated the effect of the specific activity of 225Ac-cixutumumab on efficacy following a tail vein injection of two doses (days 0 and 10) of the investigation agent or controls. Cixutumumab (2.5 mg/kg) prolonged the survival of the SUM149PT tumor-bearing mice with a median survival of 87 days compared to the PBS control group (median survival of 62 days). Median survival of high specific activity 225Ac-cixutumumab (8 kBq/µg, 225 nCi, 0.05 mg/kg) was 103.5 days compared to 122 days for low specific activity 225Ac-cixutumumab (0.15 kBq/µg, 225 nCi, 2.5 mg/kg). Additionally, low specific activity radioimmunoconjugate led to complete tumor remission in 2/6 mice. The data suggest that the efficacy of cixutumumab can be enhanced by radiolabeling with 225Ac at a low specific activity.

Efficacy and toxicity of particle radiotherapy in WHO grade II and grade III meningiomas: a systematic review.

OBJECTIVEAdjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma.METHODSA literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies.RESULTSEleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases.CONCLUSIONSDespite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed.

Reirradiation for recurrent head and neck cancers using charged particle or photon radiotherapy.

OBJECTIVE: To examine the outcomes of reirradiation for recurrent head and neck cancers using different modalities. METHODS: This retrospective study included 26 patients who received charged particle radiotherapy (CP) and 150 who received photon radiotherapy (117 CyberKnife radiotherapy [CK] and 36 intensity-modulated radiotherapy [IMRT]). Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. RESULTS: Higher prescribed doses were used in CP than photon radiotherapy. The 1­year overall survival (OS) rates were 67.9% for CP and 54.1% for photon radiotherapy (p = 0.15; 55% for CK and 51% for IMRT). In multivariate Cox regression, the significant prognostic factors for better survival were nasopharyngeal cancer, higher prescribed dose, and lower tumor volume. IPTW showed a statistically significant difference between CP and photon radiotherapy (p = 0.04). The local control rates for patients treated with CP and photon radiotherapy at 1 year were 66.9% (range 46.3-87.5%) and 67.1% (range 58.3-75.9%), respectively. A total of 48 patients (27%) experienced toxicity grade ≥3 (24% in the photon radiotherapy group and 46% in the CP group), including 17 patients with grade 5 toxicity. Multivariate analysis revealed that younger age and a larger planning target volume (PTV) were significant risk factors for grade 3 or worse toxicity. CONCLUSION: CP provided superior survival outcome compared to photon radiotherapy. Tumor volume, primary site (nasopharyngeal), and prescribed dose were identified as survival factors. Younger patients with a larger PTV experienced toxicity grade ≥3.

Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute.

BACKGROUND: Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS. PROCEDURES: Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2-16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3-23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE). RESULTS: With a mean follow-up of 41 months (range, 9-106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67-94%) and the 5-year overall survival was 73% (95% CI, 69-96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94-96%). CONCLUSIONS: Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton-photon and photons series; observed toxicity was acceptable.

Particle Radiation Therapy for Gastrointestinal Cancers.

Particle irradiation of cancerous disease has gained great traction in recent years. The ability for particle therapy centers to deliver radiation with a highly conformal dose distribution while maintaining minimal exit or excess dose delivered to normal tissue, coupled with various biological advantages particularly found with heavy-ion beams, enables treatment of diseases inapproachable with conventional radiotherapy. Here, we present a review of the current status of particle therapy with regard to cancers of the gastrointestinal tract, including esophagus, liver, pancreas, and recurrent rectal cancer.

Particle radiotherapy using protons or carbon ions for unresectable locally advanced head and neck cancers with skull base invasion.

OBJECTIVE: To study the oncological outcome of the patients with unresectable locally advanced primary head and neck cancers invading the skull base, treated with particle radiotherapy. METHODS: Fifty-seven patients with unresectable primary head and neck cancers invading the skull base received proton or carbon ion radiotherapy as definitive treatment at Hyogo Ion Beam Medical Center between 2003 and 2009. Forty-seven patients were treated with proton radiotherapy and 10 patients were treated with carbon ion radiotherapy. A retrospective review was performed with clinical charts and recorded imagings. RESULTS: With a median follow-up of 32 months, the 3-year actual survival and local progression-free rates of all the patients were 61 and 56%, respectively. The 3-year actual survival rates of adenoid cystic carcinoma, squamous cell carcinoma, olfactory neuroblastoma, adenocarcinoma and malignant melanoma were 83, 44, 75, 0 and 38%, respectively. The 3-year actual local control rates of adenoid cystic carcinoma, squamous cell carcinoma, olfactory neuroblastoma, adenocarcinoma and malignant melanoma were 63, 31, 83, 50 and 0%, respectively. Distant metastasis was observed in 13 of 25 patients in adenoid cystic carcinoma, two of 14 patients in squamous cell carcinoma, one of six patients with olfactory neuroblastoma, two of four patients with adenocarcinoma, three of four patients with malignant melanoma and two of three patients with undifferentiated carcinoma. Mucositis and dermatitis were seen as acute toxicities. The most common late toxicity was visual disorder. Grades 2, 3 and 4 visual disorders were observed in seven, five and two patients, respectively. CONCLUSIONS: Proton and carbon ion radiotherapy resulted in satisfactory local control in patients with locally advanced unresectable primary head and neck cancers invading the skull base.

Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: Prospective phase 2 MARCIE trial.

BACKGROUND: Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). METHODS: A total of 33 patients were enrolled from July 2012 until July 2020. The study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was the 3-year progression-free survival (PFS), and the secondary endpoints included overall survival, safety and treatment toxicities. RESULTS: With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7%, and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in 1 patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. CONCLUSIONS: Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve a superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.

Robot-assisted system for non-invasive wide-range flexible eye positioning and tracking in particle radiotherapy.

Particle (proton, carbon ion, or others) radiotherapy for ocular tumors is highly dependent on precise dose distribution, and any misalignment can result in severe complications. The proposed eye positioning and tracking system (EPTS) was designed to non-invasively position eyeballs and is reproducible enough to ensure accurate dose distribution by guiding gaze direction and tracking eye motion. Eye positioning was performed by guiding the gaze direction with separately controlled light sources. Eye tracking was performed by a robotic arm with cameras and a mirror. The cameras attached to its end received images through mirror reflection. To maintain a light weight, certain materials, such as carbon fiber, were utilized where possible. The robotic arm was controlled by a robot operating system. The robotic arm, turntables, and light source were actively and remotely controlled in real time. The videos captured by the cameras could be annotated, saved, and loaded into software. The available range of gaze guidance is 360° (azimuth). Weighing a total of 18.55 kg, the EPTS could be installed or uninstalled in 10 s. The structure, motion, and electromagnetic compatibility were verified via experiments. The EPTS shows some potential due to its non-invasive wide-range flexible eye positioning and tracking, light weight, non-collision with other equipment, and compatibility with CT imaging and dose delivery. The EPTS can also be remotely controlled in real time and offers sufficient reproducibility. This system is expected to have a positive impact on ocular particle radiotherapy.

Evaluation of proton and carbon ion beam models in TReatment Planning for Particles 4D (TRiP4D) referring to a commercial treatment planning system.

PURPOSE: To investigate the accuracy of the treatment planning system (TPS) TRiP4D in reproducing doses computed by the clinically used TPS SyngoRT. METHODS: Proton and carbon ion beam models in TRiP4D were converted from SyngoRT. Cubic plans with different depths in a water-tank phantom (WP) and previously treated and experimentally verified patient plans from SyngoRT were recalculated in TRiP4D. The target mean dose deviation (ΔDmean,T) and global gamma index (2%-2 mm for the absorbed dose and 3%-3mm for the RBE-weighted dose with 10% threshold) were evaluated. RESULTS: The carbon and proton absorbed dose gamma passing rates (γ-PRs) were ≥99.93% and ΔDmean,T smaller than -0.22%. On average, the RBE-weighted dose Dmean,T was -1.26% lower for TRiP4D than SyngoRT for cubic plans. In TRiP4D, the faster analytical 'low dose approximation' (Krämer, 2006) was used, while SyngoRT used a stochastic implementation (Krämer, 2000). The average ΔDmean, T could be reduced to -0.59% when applying the same biological effect calculation algorithm. However, the dose recalculation time increased by a factor of 79-477. ΔDmean,T variation up to -2.27% and -2.79% was observed for carbon absorbed and RBE-weighted doses in patient plans. The γ-PRs were ≥93.92% and ≥91.83% for patient plans, except for one proton beam with a range shifter (γ-PR of 64.19%). CONCLUSION: The absorbed dose between TRiP4D and SyngoRT were identical for both proton and carbon ion plans in the WP. Compared to SyngoRT, TRiP4D underestimated the target RBE-weighted dose; however more efficient in RBE-weighted dose calculation. Large variation for proton beam with range shifter was observed. TRiP4D will be used to evaluate doses delivered to moving targets. Uncertainties inherent to the 4D-dose reconstruction calculation are expected to be significantly larger than the dose errors reported here. For this reason, the residual differences between TRiP4D and SyngoRT observed in this study are considered acceptable. The study was approved by the Institutional Research Board of Shanghai Proton and Heavy Ion Center (approval number SPHIC-MP-2020-04, RS).

An international approach to estimating the indications and number of eligible patients for carbon ion radiation therapy (CIRT) in Australia.

BACKGROUND AND PURPOSE: To establish the treatment indications and potential patient numbers for carbon ion radiation therapy (CIRT) at the proposed national carbon ion (and proton) therapy facility in the Westmead precinct, New South Wales (NSW), Australia. METHODS: An expert panel was convened, including representatives of four operational and two proposed international carbon ion facilities, as well as NSW-based CIRT stakeholders. They met virtually to consider CIRT available evidence and experience. Information regarding Japanese CIRT was provided pre- and post- the virtual meeting. Published information for South Korea was included in discussions. RESULTS: There was jurisdictional variation in the tumours treated by CIRT due to differing incidences of some tumours, referral patterns, differences in decisions regarding which tumours to prioritise, CIRT resources available and funding arrangements. The greatest level of consensus was reached that CIRT in Australia can be justified currently for patients with adenoid cystic carcinomas and mucosal melanomas of the head and neck, hepatocellular cancer and liver metastases, base of skull meningiomas, chordomas and chondrosarcomas. Almost 1400 Australian patients annually meet the consensus-derived indications now. CONCLUSION: A conservative estimate is that 1% of cancer patients in Australia (or 2% of patients recommended for radiation therapy) may preferentially benefit from CIRT for initial therapy of radiation resistant tumours, or to boost persistently active disease after other therapies, or for re-irradiation of recurrent disease. On this basis, one national carbon ion facility with up to four treatment rooms is justified for Australian patients.

Radiation induced lymphopenia - a possible critical factor in current oncological treatment.

BACKGROUND: The effect of ionizing radiation on the immune system during the treatment of malignant tumors has long remained a point of great interest. This issue is currently gaining importance, especially in connection with the advancing development and availability of immunotherapeutic treatment. During cancer treatment, radiotherapy has the ability to influence the immunogenicity of the tumor by increasing the expression of certain tumor-specific antigens. These antigens can be processed by the immune system, stimulating the transformation of naïve lymphocytes into tumor-specific lymphocytes. However, at the same time, the lymphocyte population is extremely sensitive to even low doses of ionizing radiation, and radiotherapy often induces severe lymphopenia. Severe lymphopenia is a negative prognostic factor for numerous cancer dia-gnoses and negatively impacts the effectiveness of immunotherapeutic treatment. AIM: In this article, we summarize the possible influence of radiotherapy on the immune system, with a particular emphasis on the impact of radiation on circulating immune cells and the subsequent consequences of this influence on the development of cancer. CONCLUSION: Lymphopenia is an important factor influencing the results of oncological treatment, with a com-mon occurrence during radiotherapy. Strategies to reduce the risk of lymphopenia consist of accelerating treatment regimens, reducing target volumes, shortening the beam-on time of irradiators, optimizing radiotherapy for new critical organs, using particle radiotherapy, and other procedures that reduce the integral dose of radiation.

Daily Head and Neck Treatment Assessment for Optimal Proton Therapy Planning Robustness.

Robust optimization in proton therapy ensures adequate target coverage; however, validation of fractional plan quality and setup uncertainty in patients has not been performed. We aimed to assess plan robustness on delivered head and neck proton plans classified into two categories: (1) primary only (PO) and (2) primary and neck nodal (PNN) coverage. Registration at the machine was utilized for daily CBCT to generate a synthetic CT. The dose for the clinical target volume (CTV) and organs at risk (OAR) was compared to the expected robustness bands using 3.5% range uncertainty and 3 mm vs. 5 mm setup uncertainty. The fractional deviation was defined as D95% and V100% outside of uncertainty constraints. About 203 daily fractions from 6 patients were included for analysis. The percentage of fractions that exceeded robustness calculations was greater in 3 mm as compared to 5 mm setup uncertainty for both CTV and OAR volumes. PO plans had clinically insignificant average fractional deviation, less than 1%, in delivered D95% and V100%. In comparison, PNN plans had up to 2.2% average fractional deviation in delivered V100% using 3 mm robustness. Given the need to balance dose accuracy with OAR sparing, we recommend the utilization of 3 mm setup uncertainty as an acceptable simulation of the dose delivered.

The role of particle radiotherapy in the treatment of skull base tumors.

The skull base is an anatomically and functionally critical area surrounded by vital structures such as the brainstem, the spinal cord, blood vessels, and cranial nerves. Due to this complexity, management of skull base tumors requires a multidisciplinary approach involving a team of specialists such as neurosurgeons, otorhinolaryngologists, radiation oncologists, endocrinologists, and medical oncologists. In the case of pediatric patients, cancer management should be performed by a team of pediatric-trained specialists. Radiation therapy may be used alone or in combination with surgery to treat skull base tumors. There are two main types of radiation therapy: photon therapy and particle therapy. Particle radiotherapy uses charged particles (protons or carbon ions) that, due to their peculiar physical properties, permit precise targeting of the tumor with minimal healthy tissue exposure. These characteristics allow for minimizing the potential long-term effects of radiation exposure in terms of neurocognitive impairments, preserving quality of life, and reducing the risk of radio-induced cancer. For these reasons, in children, adolescents, and young adults, proton therapy should be an elective option when available. In radioresistant tumors such as chordomas and sarcomas and previously irradiated recurrent tumors, particle therapy permits the delivery of high biologically effective doses with low, or however acceptable, toxicity. Carbon ion therapy has peculiar and favorable radiobiological characteristics to overcome radioresistance features. In low-grade tumors, proton therapy should be considered in challenging cases due to tumor volume and involvement of critical neural structures. However, particle radiotherapy is still relatively new, and more research is needed to fully understand its effects. Additionally, the availability of particle therapy is limited as it requires specialized equipment and expertise. The purpose of this manuscript is to review the available literature regarding the role of particle radiotherapy in the treatment of skull base tumors.