The sensitivity of radiobiological models in carbon ion radiotherapy (CIRT) and its consequences on the clinical treatment plan: Differences between LEM and MKM models.

PURPOSE: Carbon ion radiotherapy (CIRT) relies on relative biological effectiveness (RBE)-weighted dose calculations. Japanese clinics predominantly use the microdosimetric kinetic model (MKM), while European centers utilize the local effect model (LEM). Despite both models estimating RBE-distributions in tissue, their physical and mathematical assumptions differ, leading to significant disparities in RBE-weighted doses. Several European clinics adopted Japanese treatment schedules, necessitating adjustments in dose prescriptions and organ at risk (OAR) constraints. In the context of these two clinically used standards for RBE-weighted dose estimation, the objective of this study was to highlight specific scenarios for which the translations between models diverge, as shortcomings between them can influence clinical decisions. METHODS: Our aim was to discuss planning strategies minimizing those discrepancies, ultimately striving for more accurate and robust treatments. Evaluations were conducted in a virtual water phantom and patient CT-geometry, optimizing LEM RBE-weighted dose first and recomputing MKM thereafter. Dose-averaged linear energy transfer (LETd) distributions were also assessed. RESULTS: Results demonstrate how various parameters influence LEM/MKM translation. Similar LEM-dose distributions lead to markedly different MKM-dose distributions and variations in LETd. Generally, a homogeneous LEM RBE-weighted dose aligns with lower MKM values in most of the target volume. Nevertheless, paradoxical MKM hotspots may emerge (at the end of the range), potentially influencing clinical outcomes. Therefore, translation between models requires great caution. CONCLUSIONS: Understanding the relationship between these two clinical standards enables combining European and Japanese based experiences. The implementation of optimal planning strategies ensures the safety and acceptability of the clinical plan for both models and therefore enhances plan robustness from the RBE-weighted dose and LETd distribution point of view. This study emphasizes the importance of optimal planning strategies and the need for comprehensive CIRT plan quality assessment tools. In situations where simultaneous LEM and MKM computation capabilities are lacking, it can provide guidance in plan design, ultimately contributing to enhanced CIRT outcomes.

Meningioma WHO I with involvement of the optical structures-does proton therapy lead to changes in quality of life with regard to subjective visual performance?

BACKGROUND: In addition to local tumor control, the aim of any curative radio-oncological treatment is to maintain quality of life. In the treatment of patients with meningioma with a close relationship to optical structures, the preservation of visual performance is a particular challenge. Use of proton therapy can reduce the dose burden to organs at risk immediately adjacent to the tumor. The aim of this study was to score the subjective assessment of visual performance in patients with meningioma involving the optical structures before and after proton therapy. METHODS: All proton-treated patients with meningioma WHO I whose planning target volumes (PTV) included parts of the optic nerve and/or chiasm were included in this study. Subjective assessment of visual performance was evaluated using the Visual Disorder Scale (VDS) of the EORTC QLQ-BN20 questionnaire. This scale includes values from 0 to 100, whereby high values reflect a high degree of subjective symptom burden and thus subjective visual impairment. The visual acuity in externally performed eye tests at baseline and follow-ups (FU) was also evaluated. The timepoints for testing were before the start of radiotherapy, at the end of treatment, and 3, 6, 12, and 24 months in FU (times t1-t6). All patients with at least the first annual postradiation FU at the time of the evaluation were included. The correlation between VDS changes and potential influencing factors such as previous therapies, dosimetric data, initial tumor volume, and tumor shrinkage 1 year after treatment was assessed. RESULTS: A total of 56 patients (45 female/11 male) aged 24-82 years (mean ± SD = 53.9 ± 13.3) treated between March 2017 and September 2019 were included in the analysis. The prescription dose was 54.0 Gy (RBE) with active scanned proton therapy. The mean/D2% dose ± SD for the optic chiasm and ipsilateral optic nerve was 43.4 ± 8.9 Gy (RBE)/49.9 ± 7.1 Gy (RBE) and 35.6 ± 11.7 Gy (RBE)/51.7 ± 4.8 Gy (RBE); the mean/D2% dose ± SD of the contralateral optic nerve was 18.8 ± 12.1 Gy (RBE)/42.4 ± 14.6 Gy (RBE), respectively. A total of 302 data collections were available (t1/t2/t3/t4/t5/t6: n = 56/56/48/56/52/34). Median observation time was 23.6 months. Mean symptom burden decreased over time (mean VDS: t1 29.8 ± 27.9; t2 25.0 ± 27.9; t3 21.8 ± 26.0; t4 22.2 ± 26.0; t5 21.4 ± 26.2; t6 17.3 ± 23.6) with statistically significant improvement at 3­ and 6­month FU as well as 1 year after proton therapy (p = 0.0205; p = 0.0187; p = 0.0054). Objective eye tests available in 41/52 patients confirm the trend towards improved visual acuity (97.5% stable/improved until 24-month FU). However, no potential predictor for VDS changes was revealed. CONCLUSION: Proton treatment of patients with meningioma WHO I with involvement of optical structures does not impair subjective visual performance. After treatment, there is a significant improvement in perceived visual performance.

The trends and significance of SSTR PET/CT added to MRI in follow-up imaging of low-grade meningioma treated with fractionated proton therapy.

PURPOSE: Overexpression of the somatostatin receptor (SSTR) has led to adoption of SSTR PET/CT for diagnosis and radiotherapy planning in meningioma, but data on SSTR expression during follow-up remain scarce. We investigated PET/CT quantifiers of SSTR tracers in WHO grade I meningioma following fractionated proton beam therapy (PBT) compared to standard response assessment with MRI. METHODS: Twenty-two patients diagnosed with low-grade meningioma treated by PBT were included. Follow-up included clinical visits, MRI, and [68Ga]Ga-DOTATOC PET/CT scans. Radiologic tumor response, MRI and PET volume (VMRI and VPET), maximum and mean standardied uptake value (SUVmax/SUVmean), total lesion activity (TLA), and heterogeneity index (HI) were evaluated. RESULTS: Median follow-up was 35.3 months (range: 6.4-47.9). Nineteen patients (86.4%, p = 0.0009) showed a decrease of SUVmax between baseline and first follow-up PET/CT (median: -24%, range: -53% to +89%) and in 81.8% of all cases, the SUVmax, SUVmean, and TLA at last follow-up were eventually lower than at baseline (p = 0.0043). Ambiguous trends without significance between the timepoints analyzed were observed for VPET. HI increased between baseline and last follow-up in 75% of cases (p = 0.024). All patients remained radiologically and clinically stable. Median VMRI decreased by -9.3% (range 0-32.5%, p < 0.0001) between baseline and last follow-up. CONCLUSION: PET/CT in follow-up of irradiated meningioma showed an early trend towards decreased binding of SSTR-specific tracers following radiation and MRI demonstrated consistently stable or decreasing tumor volume. Translational research is needed to clarify the underlying biology of the subsequent increase in SSTR PET quantifiers.

Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy.

Objective: To compare radiation-induced toxicity and dosimetry parameters in patients with locally advanced nasopharyngeal cancer (LANPC) treated with a mixed-beam (MB) approach (IMRT followed by proton therapy boost) with an historic cohort of patients treated with a full course of IMRT-only.Material and methods: Twenty-seven patients with LANPC treated with the MB approach were compared to a similar cohort of 17 patients treated with IMRT-only. The MB approach consisted in a first phase of IMRT up to 54-60 Gy followed by a second phase delivered with a proton therapy boost up to 70-74 Gy (RBE). The total dose for patients treated with IMRT-only was 69.96 Gy. Induction chemotherapy was administrated to 59 and 88% and concurrent chemoradiotherapy to 88 and 100% of the MB and IMRT-only patients, respectively. The worst toxicity occurring during the entire course of treatment (acute toxicity) and early-late toxicity were registered according to the Common Terminology Criteria Adverse Events V4.03.Results: The two cohorts were comparable. Patients treated with MB received a significantly higher median total dose to target volumes (p = .02). Acute grade 3 mucositis was found in 11 and 76% (p = .0002) of patients treated with MB and IMRT-only approach, respectively, while grade 2 xerostomia was found in 7 and 35% (p = .02) of patients treated with MB and IMRT-only, respectively. There was no statistical difference in late toxicity. Local progression-free survival (PFS) and progression-free survival curves were similar between the two cohorts of patients (p = .17 and p = .40, respectively). Local control rate was 96% and 81% for patients treated with MB approach and IMRT-only, respectively.Conclusions: Sequential MB approach for LANPC patients provides a significantly lower acute toxicity profile compared to full course of IMRT. There were no differences in early-late morbidities and disease-related outcomes (censored at two-years) but a longer follow-up is required to achieve conclusive results.

The future of radiation-induced abscopal response: beyond conventional radiotherapy approaches.

Advances in the immunological pharmaceuticals, such as checkpoint inhibitors and agonists, have positive implications for the future of the radiotherapy abscopal response. A once rare phenomenon, whereby distant nonirradiated tumor sites regressed after radiotherapy alone, may become more common when combined with the immune modulating agents. Radiotherapy can increase neoantigen expression, increased tumor PD-L1 expression, increase MHC class I expression, reverse exhausted CD8 T cells and increase tumor-infiltrating tumors within the tumor microenvironment. These changes in the tumor and the tumor microenvironment after radiotherapy could potentiate responses to anti-CTL-4, anti-PD-L1/PD-1 and other immunotherapy agents. Thus, advances in checkpoint inhibitors have increased interest in re-evaluation of the role of conventional radiotherapy approaches on the immune system. We reviewed newer nonconventional approaches such as SBRT-PATHY, GRID, FLASH, carbon ion and proton therapy and their role in eliciting immune responses. We believe that combining these novel radiation methods may enhance the outcome with the newly US FDA approved immune modulating agents.

Preoperative chemotherapy and carbon ions therapy for treatment of resectable and borderline resectable pancreatic adenocarcinoma: a prospective, phase II, multicentre, single-arm study.

BACKGROUND: Pancreatic adenocarcinoma is a high-mortality neoplasm with a documented 5-years-overall survival around 5%. In the last decades, a real breakthrough in the treatment of the disease has not been achieved. Here we propose a prospective, phase II, multicentre, single-arm study aiming to assess the efficacy and the feasibility of a therapeutic protocol combining chemotherapy, carbon ion therapy and surgery for resectable and borderline resectable pancreatic adenocarcinoma. METHOD: The purpose of this trial (PIOPPO Protocol) is to assess the efficacy and the feasibility of 3 cycles of FOLFIRINOX neoadjuvant chemotherapy followed by a short-course of carbon ion radiotherapy (CIRT) for resectable or borderline resectable pancreatic adenocarcinoma patients. Primary outcome of this study is the assessment of local progression free survival (L-PFS). The calculation of sample size is based on the analysis of the primary endpoint "progression free survival" according to Fleming's Procedure. DISCUSSION: Very preliminary results provide initial evidence of the feasibility of the combined chemotherapy and CIRT in the neoadjuvant setting for resectable or borderline resectable pancreatic cancer. Completion of the accrual and long term results are awaited to see if this combination of treatment is advisable and will provide the expected benefits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03822936 registered on January 2019.

Stereotactic body radiation therapy for mediastinal lymph node metastases: how do we fly in a 'no-fly zone'?

PURPOSE: To evaluate the treatment-induced toxicity (as primary endpoint) and the efficacy (as secondary endpoint) of stereotactic body radiation therapy (SBRT) in the treatment of mediastinal lymph nodes (LNs) in the so-called no-fly zone (NFZ) in cancers with various histology. MATERIAL AND METHODS: Forty-two patients were retrospectively analyzed. Institutional dose/volume constraints for organs at risk (OARs) derived by published data were strictly respected. The correlation between treatment-related variables and toxicity was investigated by logistic regression, Chi-squared test or Fisher's exact test. Overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS) and local control (LC) were collected from the follow-up reports. The impact of potential predictive factors on LC, PFS and OS were estimated by Cox proportional-hazard regression. RESULTS: Median follow-up time was 16 months (range 1-41). Four patients had esophageal G1 toxicity. Ten and six patients had G1 and G2 pulmonary toxicity, respectively. Treatment site and irradiation technique were significantly correlated with G ≥ 2 and G ≥ 1 toxicity, respectively. OS probability at 19 months was 88.3% and corresponded to CSS. LC probability at 16 months was 66.3% (median LC duration: 22 months, range 1-41). Fifteen patients (35.7%) were disease-free at 25 months (median time, range 1-41). The biologically effective dose (BED) and the target dose coverage indexes were significantly correlated with LC. CONCLUSIONS: SBRT can be considered as a safe treatment option for selected patients with oligo-metastases/recurrences in the NFZ, if strict dose/volume constraints are applied.

Carbon-fiber-reinforced PEEK fixation system in the treatment of spine tumors: a preliminary report.

BACKGROUND: Protocols including combination of surgery and radiotherapy are more and more frequent in the treatment of bone tumors of the spine. In metastatic disease, combination of surgery and radiotherapy is since long time accepted, as based on clinical evidence. In primary tumors, combination of surgery and radiotherapy can be considered in all the cases in which a satisfactory oncological margin cannot be achieved: high-grade malignancies, recurrent tumors, huge tumors expanding in an extracompartimental area, and when tumor-free margin requires unacceptable functional sacrifices. However, metal implants are an obstacle in the collaboration between surgeons and radiation oncologists. Carbon-fiber-reinforced polyethil-ether-ether-ketone (CFR-PEEK) composite implants could make easier and more effective the treatment as radiolucent and not interfering with ionizing radiation and accelerated particles. The purpose of this article is to report the preliminary results from a cohort of patients treated with CFR-PEEK and to evaluate the safety and the non-inferiority of the device respect the commonly used titanium implants. MATERIALS AND METHODS: This study concerns an ambispective cohort series of 34 tumor patients (14 metastases and 20 primaries, most of them recurrent) submitted to thoracic and lumbar spine fixation with a CFR-PEEK composite implants. Oncologic surgery was palliative decompression and fixation in 9 cases, tumor excision in 21, and enbloc resection in 4. Data collected for this preliminary report were all intraoperative remarks, incidence of complications, changes in neurological status, local control, and survival. All the cases were followed 6-36 months (mean 13 months). RESULTS: Only one intraoperative screw breakage occurred out of 232 implanted screws. Pain control and neurological improvement were the early clinical results. Two sacral screws loosening were found at 9 and 12 months in multilevel constructs performed on multirecurrent tumors. Six local recurrences were early found thanks to the implant radiolucency. Radiation oncologists' opinion was favourable as concerning better treatment planning on CT and lacking of scattering effect during the treatment. CONCLUSIONS: No artifacts on imaging studies mean early local recurrence detection. For radiation oncologists, no artifacts on imaging studies mean easier planning and no scattering effect means more effective and safe radiotherapy, particularly when particles are used. Moreover, it seems that the clinical use of CFR-PEEK composite implants may be safe and at least comparable with the commonly used titanium implants in terms of intraoperative complications, stability at weight bearing and at functional recovery. Larger patient series and longer follow-up are required to confirm these data.

Hadrontherapy from the Italian Radiation Oncologist point of view: face the reality. The Italian Society of Oncological Radiotherapy (AIRO) survey.

Hadrontherapy has been in constant progress in the past decades. Due to the increasing interest in this field and the spreading of the technique in Italy and worldwide, the Italian Society of Radiation Oncology surveyed (by an online survey) its members regarding their perception of hadrontherapy. The survey outline addressed different items all related to hadrontherapy, such as: demographics (3 items), personal knowledge (5 items), actual use in clinical practice (5 items), and future perspectives and development (5 items). The survey was filled in by 224 radiation oncologists (RO). Among them, 74.6 % were RO with more than 5 years of clinical practice, and only 10.4 % RO in training. Median age was 46 years (range 27-77). 32.24 % admitted average knowledge about heavy particles radiobiology rationale and 32.42 % about the ongoing particle therapy clinical trials. Radioresistant tumors are perceived as-principal indications for carbon ions in 39.3 % of responders, and pediatric malignancies for protons in 37 %. Re-irradiation is highly recommended for 52.2 %. Strikingly, 38.8 % of participating ROs reported that, in the daily clinical practice, approximately less than 1 out of 10 patients asks to be referred for hadrontherapy. On the other side, 35.7 % claimed need for at least 3 up to 5 particle therapy centers in Italy. Overall, the results of the present survey highlight the interest of the Italian RO community for particle therapy among the other radiotherapy technique. Analysis of our results might picture the clinical attitude of the RO community towards hadrontherapy in Italy, and help in promoting targeted initiatives to spread clinical results and knowledge about technical innovations in this field.

MRI quantification of pancreas motion as a function of patient setup for particle therapy -a preliminary study.

Particle therapy (PT) has shown positive therapeutic results in local control of locally advanced pancreatic lesions. PT effectiveness is highly influenced by target localization accuracy both in space, since the pancreas is located in proximity to radiosensitive vital organs, and in time as it is subject to substantial breathing-related motion. The purpose of this preliminary study was to quantify pancreas range of motion under typical PT treatment conditions. Three common immobilization devices (vacuum cushion, thermoplastic mask, and compressor belt) were evaluated on five male patients in prone and supine positions. Retrospective four-dimensional magnetic resonance imaging data were reconstructed for each condition and the pancreas was manually segmented on each of six breathing phases. A k-means algorithm was then applied on the manually segmented map in order to obtain clusters representative of the three pancreas segments: head, body, and tail. Centers of mass (COM) for the pancreas and its segments were computed, as well as their displacements with respect to a reference breathing phase (beginning exhalation). The median three-dimensional COM displacements were in the range of 3 mm. Latero-lateral and superior-inferior directions had a higher range of motion than the anterior-posterior direction. Motion analysis of the pancreas segments showed slightly lower COM displacements for the head cluster compared to the tail cluster, especially in prone position. Statistically significant differences were found within patients among the investigated setups. Hence a patient-specific approach, rather than a general strategy, is suggested to define the optimal treatment setup in the frame of a millimeter positioning accuracy.

Tumour seeding in the surgical pathway after resection of skull base chordoma.

AIM: The aim of this study is to review the clinical series in which tumour seeding was reported after skull base surgery for chordomas. BACKGROUND: The occurrence of implantation of cancer cells during surgical procedures for the removal of chordoma is a rare event described by a number of authors in a few patient series and case reports. MATERIALS AND METHODS: Literature search was performed by PubMed and Scopus by using the words "surgical tumour seeding, tumour implantation, surgical pathway recurrence, skull base chordoma, and clivus chordoma". RESULTS: Six retrospective series and 7 case reports were included in the analysis. In total, 34 patients are described with pathway recurrence, 30 at a single site and 4 at multiple sites. In the 5 largest chordoma series, the rate of occurrence of surgical seeding ranged from 1.3% to 7.3% (3.9%). In the 34 patients diagnosed with tumour seeding, the most frequent surgical approach was trans-nasal/trans-sphenoidal, that was used in 12 cases. The median time from primary treatment to surgical pathway tumour seeding ranged from 7 to 78 months. Data of the treatment of seeding are available in 26/34 patients. All of them underwent a new surgery, 6 received additional external beam radiotherapy, and 2 intraoperative radiotherapy. CONCLUSIONS: The risk of surgical seeding should be taken into consideration when deciding on the surgical approach and the planning treatment volume for postoperative radiation therapy. The surgical pathway should be included in follow-up studies to diagnose this peculiar type of treatment failure possibly at an early phase.

Review of photon and proton radiotherapy for skull base tumours.

An extremely large variety of benign and malignant tumours occur at skull base; these tumour lesions are in the proximity to structures deputed to relevant physiologic functions, limiting extensive surgical approaches to this body district. Most recent progresses of surgery and radiotherapy have allowed to improve local control with acceptable rates of side effects. Various photon radiotherapy techniques are employed, including 3-dimensional conformal radiotherapy, intensity modulated radiotherapy (IMRT), stereotactic radiotherapy (SRT) and brachytherapy that is manly limited to the treatment of primary or recurrent nasopharyngeal carcinoma. Proton beam radiotherapy is also extensively used thanks to its physical characteristics. Our review, focusing in particular on meningioma, chordoma, and chondrosarcoma, suggests that proton therapy plays a major role in the treatment of malignant tumours whereas photon therapy still plays a relevant role in the treatment of benign tumour lesions.

MR Imaging for Selection of Patients for Partial Breast Irradiation: A Systematic Review and Meta-Analysis.

PURPOSE: To systematically review articles that estimated the ineligibility for partial breast irradiation (PBI) after magnetic resonance (MR) imaging. MATERIALS AND METHODS: No ethics committee approval was needed. A systematic search was performed by using MEDLINE and EMBASE. The rate of patients eligible at standard assessment (ie, clinical examination, mammography, and/or ultrasonography) but ineligible after MR imaging was a study outcome. Odds ratios (ORs) were calculated to identify predictors. Quality was appraised by using the Strengthening Reporting of Observational Studies in Epidemiology checklist. RESULTS: Of 93 retrieved articles, six were included (total, 3136 patients). For PBI eligibility, all studies applied National Surgical Adjuvant Breast and Bowel Project B-39 criteria. Ineligibility at standard assessment varied from 21% to 80%; MR imaging prompted ineligibility for PBI in 6%-25% of patients who were initially deemed eligible or in 2%-20% if calculated on the overall number of patients initially screened. Meta-regression showed a negative correlation between ineligibility at standard assessment and ineligibility after MR imaging (P < .001). The pooled percentage of patients eligible at standard assessment but ineligible after MR imaging was 11% (95% confidence interval [CI]: 6%, 19%). Predictors for ineligibility after MR imaging were cancers stage pT2 or greater versus less than stage pT2 (OR, 8.8 [95% CI: 4.7, 16.7]; P < .001), invasive lobular histopathologic results versus invasive ductal pathologic results (OR, 3.0 [95% CI: 1.6, 6.6]; P = .007), pre- versus postmenopausal status (OR, 1.9 [95% CI: 1.3, 2.6]; P < .001), invasive cancer versus ductal carcinoma in situ (OR, 1.6 [95% CI: 1.0, 2.4]; P = .031). Study quality ranged from 17 to 20 (maximum quality, 22). The risk of publication bias was moderate. CONCLUSION: One of nine women (11%), who on the sole basis of standard assessment were candidates to undergo PBI, was found to be ineligible after undergoing MR imaging. Breast MR imaging should be used to select patients for PBI.

New frontiers in proton therapy: applications in breast cancer.

PURPOSE OF REVIEW: The aim of this article is to review published data on proton therapy in the multimodality treatment of breast cancer so as to provide an overview of the advantages and critical issues relating to this irradiation modality. RECENT FINDINGS: In-silico studies show a clear advantage in terms of dose homogeneity to the target and dose reduction to the non-target structures including heart, lungs, and healthy breast tissues. Clinical studies have shown the feasibility of proton therapy in breast cancer and allowed optimizing the technique by using multiple beams and intensity modulation. SUMMARY: Proton therapy is able to optimize the dose to the target and to reduce the irradiation of the healthy tissues. Clinical studies are expected to show a decreased risk of late side effects with potential improvement of the quality of life of breast cancer patients.

Position statement on ethics, equipoise and research on charged particle radiation therapy.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

Radiation therapy for retroperitoneal sarcoma.

PURPOSE: Retroperitoneal sarcomas (RPS) are rare tumours with an annual reported incidence of 2.7 per million persons. In spite of improvements in both diagnostic imaging and therapeutic strategies, patients afflicted by RPS still have poor prognoses. There are currently many different therapeutic strategies for these rare tumours and combining several different multi-modality strategies have not proved to have superior long-term clinical results. This review analyses the available published data and discusses multi-modality management of this rare entity. In particular, the role of radiation therapy, treatment-related side effects and the use of modern radiation treatment techniques will be discussed. MATERIALS AND METHODS: A comprehensive literature search was conducted using PubMed in January 2011. Relevant international articles published from January 1980 to January 2011 were assessed. The keywords for search purposes were: retroperitoneum, sarcoma, radiotherapy, and radiation therapy. The search was limited to articles published in English. All articles were read in full by the authors and selected for inclusion based on relevance to this article. CONCLUSIONS: The addition of radiation therapy (RT) to wide surgical excision for RPS has improved local control rates when compared with surgery alone. Preoperative RT is preferred over postoperative RT. New types and delivery techniques in radiation therapy could further improve patient outcomes. Emerging therapies that employ charged particles (such as protons and carbon ions) are expected to be superior in sparing of normal tissues and efficacy over conventional photon therapy radiation, due to their physical and radiobiological properties.

Proton beam radiotherapy: report of the first ten patients treated at the "Centro Nazionale di Adroterapia Oncologica (CNAO)" for skull base and spine tumours.

PURPOSE: The Italian National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO), equipped with a proton and ion synchrotron, started clinical activity in September 2011. The clinical and technical characteristics of the first ten proton beam radiotherapy treatments are reported. MATERIALS AND METHODS: Ten patients, six males and four females (age range 27-73 years, median 55.5), were treated with proton beam radiotherapy. After one to two surgical procedures, seven patients received a histological diagnosis of chordoma (of the skull base in three cases, the cervical spine in one case and the sacrum in three cases) and three of low-grade chondrosarcoma (skull base). Prescribed doses were 74 GyE for chordoma and 70 GyE for chondrosarcoma at 2 GyE/fraction delivered 5 days per week. RESULTS: Treatment was well tolerated without toxicity-related interruptions. The maximal acute toxicity was grade 2, with oropharyngeal mucositis, nausea and vomiting for the skull base tumours, and grade 2 dermatitis for the sacral tumours. After 6-12 months of follow-up, no patient developed tumour progression. CONCLUSIONS: The analysis of the first ten patients treated with proton therapy at CNAO showed that this treatment was feasible and safe. Currently, patient accrual into these as well as other approved protocols is continuing, and a longer follow-up period is needed to assess tumour control and late toxicity.

Sacral-Nerve-Sparing Planning Strategy in Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy.

To minimize radiation-induced lumbosacral neuropathy (RILSN), we employed sacral-nerve-sparing optimized carbon-ion therapy strategy (SNSo-CIRT) in treating 35 patients with pelvic sarcomas/chordomas. Plans were optimized using Local Effect Model-I (LEM-I), prescribed DRBE|LEM-I|D50% (median dose to HD-PTV) = 73.6 (70.4-76.8) Gy (RBE)/16 fractions. Sacral nerves were contoured between L5-S3 levels. DRBE|LEM-I to 5% of sacral nerves-to-spare (outside HD-CTV) (DRBE|LEM-I|D5%) were restricted to <69 Gy (RBE). The median follow-up was 25 months (range of 2-53). Three patients (9%) developed late RILSN (≥G3) after an average period of 8 months post-CIRT. The RILSN-free survival at 2 years was 91% (CI, 81-100). With SNSo-CIRT, DRBE|LEM-I|D5% for sacral nerves-to-spare = 66.9 ± 1.9 Gy (RBE), maintaining DRBE|LEM-I to 98% of HD-CTV (DRBE|LEM-I|D98%) = 70 ± 3.6 Gy (RBE). Two-year OS and LC were 100% and 93% (CI, 84-100), respectively. LETd and DRBE with modified-microdosimetric kinetic model (mMKM) were recomputed retrospectively. DRBE|LEM-I and DRBE|mMKM were similar, but DRBE-filtered-LETd was higher in sacral nerves-to-spare in patients with RILSN than those without. At DRBE|LEM-I cutoff = 64 Gy (RBE), 2-year RILSN-free survival was 100% in patients with <12% of sacral nerves-to-spare voxels receiving LETd > 55 keV/µm than 75% (CI, 54-100) in those with ≥12% of voxels (p < 0.05). DRBE-filtered-LETd holds promise for the SNSo-CIRT strategy but requires longer follow-up for validation.

Investigation on the physical dose filtered by linear energy transfer for treatment plan evaluation in carbon ion therapy.

BACKGROUND: Large tumor size has been reported as a predicting factor for inferior clinical outcome in carbon ion radiotherapy (CIRT). Besides the clinical factors accompanied with such tumors, larger tumors receive typically more low linear energy transfer (LET) contributions than small ones which may be the underlying physical cause. Although dose averaged LET is often used as a single parameter descriptor to quantify the beam quality, there is no evidence that this parameter is the optimal clinical predictor for the complex mixed radiation fields in CIRT. PURPOSE: Purpose of this study was to investigate on a novel dosimetric quantity, namely high-LET-dose ( D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ , the physical dose filtered based on an LET threshold) as a single parameter estimator to differentiate between carbon ion treatment plans (cTP) with a small and large tumor volume. METHODS: Ten cTPs with a planning target volume, PTV ≥ 500 cm 3 $\mathrm{PTV}\ge {500}\,{{\rm cm}^{3}}$ (large) and nine with a PTV < 500 cm 3 $\mathrm{PTV}<{500}\,{{\rm cm}^{3}}$ (small) were selected for this study. To find a reasonable LET threshold ( L thr $\textrm {L}_{\textrm {thr}}$ ) that results in a significant difference in terms of D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ , the voxel based normalized high-LET-dose ( D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) distribution in the clinical target volume (CTV) was studied on a subset (12 out of 19 cTPs) for 18 LET thresholds, using standard distribution descriptors (mean, variance and skewness). The classical dose volume histogram concept was used to evaluate the D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ distributions within the target of all 19 cTPs at the before determined L thr $\textrm {L}_{\textrm {thr}}$ . Statistical significance of the difference between the two groups in terms of mean D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ volume histogram parameters was evaluated by means of (two-sided) t-test or Mann-Whitney-U-test. In addition, the minimum target coverage at the above determined L thr $\textrm {L}_{\textrm {thr}}$ was compared and validated against three other thresholds to verify its potential in differentiation between small and large volume tumors. RESULTS: An L thr $\textrm {L}_{\textrm {thr}}$ of approximately 30 keV / µ m ${30}\,{\rm keV/}\umu {\rm m}$ was found to be a reasonable threshold to classify the two groups. At this threshold, the D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ were significantly larger ( p < 0.05 $p<0.05$ ) in small CTVs. For the small tumor group, the near-minimum and median D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ (and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) in the CTV were in average 9.3 ± 1.5 Gy $9.3\pm {1.5}\,{\rm Gy}$ (0.31 ± 0.08) and 13.6 ± 1.6 Gy $13.6\pm {1.6}\,{\rm Gy}$ (0.46 ± 0.06), respectively. For the large tumors, these parameters were 6.6 ± 0.2 Gy $6.6\pm {0.2}\,{\rm Gy}$ (0.20 ± 0.01) and 8.6 ± 0.4 Gy $8.6\pm {0.4}\,{\rm Gy}$ (0.28 ± 0.02). The difference between the two groups in terms of mean near-minimum and median D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ ( D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) was 2.7 Gy (11%) and 5.0 Gy (18%), respectively. CONCLUSIONS: The feasibility of high-LET-dose based evaluation was shown in this study where a lower D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ was found in cTPs with a large tumor size. Further investigation is needed to draw clinical conclusions. The proposed methodology in this work can be utilized for future high-LET-dose based studies.

Dose averaged linear energy transfer optimization for large sacral chordomas in carbon ion therapy.

BACKGROUND: Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose-averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. PURPOSE: The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)-weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). METHODS: Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV-HD) larger than 250 cm 3 $250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE-weighted median dose prescription with the local effect model (LEM) was D RBE , 50 % = 73.6 Gy $\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ , L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and L min = 100 keV / µ m $\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$ . To compare the LETd optimized against reference plans, LETd and RBE-weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios ( ± 3.5 % $\pm 3.5\%$ range uncertainty and ± 3 mm $\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). RESULTS: The optimization method with L min = 60 keV / µ m $\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) in the CTV-HD by 8.9 ± 1.5 keV / µ m $8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ ( 27 % $27\%$ ) (and 6.9 ± 1.3 keV / µ m $6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ ( 17 % $17\%$ )), without significant difference in the RBE-weighted dose. By allowing ± 5 % $\pm 5\%$ over- and under-dosage in the target, the LET d , 98 % ${\rm {LET}}_{{\rm {d,}}98\%}$ (and LET d , 50 % ${\rm {LET}}_{{\rm {d,}}50\%}$ ) can be increased by 11.3 ± 1.2 keV / µ m $11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ ( 34 % $34\%$ ) (and 11.7 ± 3.4 keV / µ m $11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ ( 29 % $29\%$ )), using the optimization parameters L min = 80 keV / µ m $\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ . The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. CONCLUSIONS: Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE-weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE-weighted dose robustness and acquiring more in-room images remain crucial and inevitable aspects during treatment.