The Role of Carbon Ion Therapy in the Changing Oncology Landscape-A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy.

BACKGROUND: Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research. METHODS: To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO's clinical activity over the last 10 years of CIRT. RESULTS: The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types. CONCLUSIONS: After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access.

Proton Therapy, Magnetic Nanoparticles and Hyperthermia as Combined Treatment for Pancreatic BxPC3 Tumor Cells.

We present an investigation of the effects on BxPC3 pancreatic cancer cells of proton therapy combined with hyperthermia, assisted by magnetic fluid hyperthermia performed with the use of magnetic nanoparticles. The cells' response to the combined treatment has been evaluated by means of the clonogenic survival assay and the estimation of DNA Double Strand Breaks (DSBs). The Reactive Oxygen Species (ROS) production, the tumor cell invasion and the cell cycle variations have also been studied. The experimental results have shown that the combination of proton therapy, MNPs administration and hyperthermia gives a clonogenic survival that is much smaller than the single irradiation treatment at all doses, thus suggesting a new effective combined therapy for the pancreatic tumor. Importantly, the effect of the therapies used here is synergistic. Moreover, after proton irradiation, the hyperthermia treatment was able to increase the number of DSBs, even though just at 6 h after the treatment. Noticeably, the magnetic nanoparticles' presence induces radiosensitization effects, and hyperthermia increases the production of ROS, which contributes to cytotoxic cellular effects and to a wide variety of lesions including DNA damage. The present study indicates a new way for clinical translation of combined therapies, also in the vision of an increasing number of hospitals that will use the proton therapy technique in the near future for different kinds of radio-resistant cancers.

In Vitro Effects of Photon Beam and Carbon Ion Radiotherapy on the Perineural Invasion of Two Cell Lines of Neurotropic Tumours.

Primary mucosal melanoma (PMM) and pancreatic ductal adenocarcinoma (PDAC) are two aggressive malignancies, characterized by intrinsic radio-chemoresistance and neurotropism, a histological feature resulting in frequent perineural invasion (PNI), supported by neurotrophic factors secreted in the tumour microenvironment (TME), such as neurotrophin-3 (NT-3). Carbon-ion radiotherapy (CIRT) could represent an effective option in unresectable PMM and PDAC. Only a few data about the effects of CIRT on PNI in relation to NT-3 are available in the literature, despite the numerous pieces of evidence revealing the peculiar effects of this type of radiation on tumour cell migration. This in vitro study investigated for the first time the response of PMM and PDAC cells to NT-3 and evaluated the effects of conventional photon beam radiotherapy (XRT) and CIRT on cell viability, proliferation, and migration. Our results demonstrated the greater capacity of C-ions to generally decrease cell viability, proliferation, and migration, while the addition of NT-3 after both types of irradiation determined an increase in these features, maintaining a dose-dependent trend and acting more effectively as a chemoattractant than inductor in the case of migration.

Immune checkpoint inhibitors and Carbon iON radiotherapy In solid Cancers with stable disease (ICONIC).

ICONIC is a multicenter, open-label, nonrandomized phase II clinical trial aiming to assess the feasibility and clinical activity of the addition of carbon ion radiotherapy to immune checkpoint inhibitors in cancer patients who have obtained disease stability with pembrolizumab administered as per standard-of-care. The primary end point is objective response rate, and the secondary end points are safety, survival and disease control rate. Translational research is an exploratory aim. The planned sample size is 27 patients. The study combination will be considered worth investigating if at least four objective responses are observed. If the null hypothesis is rejected, ICONIC will be the first proof of concept of the feasibility and clinical activity of the addition of carbon ion radiotherapy to immune checkpoint inhibitors in oncology.

ICONIC is a multicenter, open-label, nonrandomized, phase II clinical trial aiming to evaluate the feasibility and clinical activity of the addition of carbon ion radiotherapy to immune checkpoint inhibitors in cancer patients who have obtained disease stability with pembrolizumab administered as per standard-of-care. Considering that no clinical trials have been conducted thus far to assess the safety of the association between immune checkpoint inhibitors and carbon ion radiotherapy, the current clinical study will provide controlled data about the safety of this unprecedented therapeutic combination. Clinical Trial Registration: NCT05229614 (ClinicalTrials.gov).

Factors released by low and high-LET irradiated fibroblasts modulate migration and invasiveness of pancreatic cancer cells.

Introduction: Radiotherapy represents a major treatment option for patients with pancreatic cancer, however, its benefits remain limited also due to the ability of cancer cells to migrate to the surrounding tissues. Low-LET ionizing radiation is well known to promote tumor cell migration and invasion, nevertheless, little data provided by studies using high-LET radiation has led to ambiguous findings. What is hypothesized to be fundamental in the modulation of migration of tumor cells exposed to ionizing radiation is the influence of the microenvironment. Therefore, the properties of cells that populate the tumor stroma cannot be ignored when studying the influence of radiation on the migratory and invasive capacity of cancer cells. This is especially important in the case of pancreatic malignancies that are characterized by an abundance of stromal cells, including cancer-associated fibroblasts, which are known to orchestrate the cross-talk with tumor cells. Aim: The current study aims to investigate whether the presence of factors released by irradiated fibroblasts affects the migratory and invasive capacity of pancreatic cancer cells exposed to different doses of photons or C-ions. Materials and methods: AsPC-1 and AG01522 cells were irradiated with the same dose of photons or C-ions at room temperature. Through Boyden chamber assay, we tested whether factors secreted by irradiated fibroblasts may influence tumor cell migration, while the invasiveness of AsPC-1 cells was assessed using matrigel precoated inserts in which medium collected from non-irradiated (0 Gy), photon and C-ion irradiated fibroblasts, was added. Data were analyzed by Student t-test using GraphPad software. The mean ± s.d. was determined with a significance level of p<0.05. Results: In the presence of conditioned medium collected from 1 Gy and 2 Gy photon irradiated fibroblasts, the number of migrated tumor cells increased (P<0.0360, P<0.0001) but decreased at 4 Gy dose (P<0.002). There was a trend of reduction in migration (P<0.0460, P<0.038, P<0.0024, P<0.0002), as well as a decrease in invasiveness (P<0.0525, P<0.0035, P<0.0868, P<0.0310) after exposure to 0.5 Gy, 1 Gy, 2 Gy and 4 Gy of C-ions. Conclusions: The presence of irradiated fibroblasts affected the invasiveness capability of pancreatic cancer cells, probably by the reciprocal release of soluble factors whose production is differently modulated after high or low-LET radiation. Understanding the effects of irradiation on the metastatic potential of pancreatic cancer cells is of utmost importance for improving the outcome and tailoring the therapeutic approach. This challenging scenario requires a continuous and multidisciplinary approach that involves clinicians together with researcher experts in oncological and radiation treatment. In the last years, including preclinical experiences in a multidisciplinary approach has proved to be a winning strategy in clinical oncological research.

Ultrasound-assisted carbon ion dosimetry and range measurement using injectable polymer-shelled phase-change nanodroplets: in vitro study.

Methods allowing for in situ dosimetry and range verification are essential in radiotherapy to reduce the safety margins required to account for uncertainties introduced in the entire treatment workflow. This study suggests a non-invasive dosimetry concept for carbon ion radiotherapy based on phase-change ultrasound contrast agents. Injectable nanodroplets made of a metastable perfluorobutane (PFB) liquid core, stabilized with a crosslinked poly(vinylalcohol) shell, are vaporized at physiological temperature when exposed to carbon ion radiation (C-ions), converting them into echogenic microbubbles. Nanodroplets, embedded in tissue-mimicking phantoms, are exposed at 37 °C to a 312 MeV/u clinical C-ions beam at different doses between 0.1 and 4 Gy. The evaluation of the contrast enhancement from ultrasound imaging of the phantoms, pre- and post-irradiation, reveals a significant radiation-triggered nanodroplets vaporization occurring at the C-ions Bragg peak with sub-millimeter shift reproducibility and dose dependency. The specific response of the nanodroplets to C-ions is further confirmed by varying the phantom position, the beam range, and by performing spread-out Bragg peak irradiation. The nanodroplets' response to C-ions is influenced by their concentration and is dose rate independent. These early findings show the ground-breaking potential of polymer-shelled PFB nanodroplets to enable in vivo carbon ion dosimetry and range verification.

Evaluation of the Response of HNSCC Cell Lines to γ-Rays and 12C Ions: Can Radioresistant Tumors Be Identified and Selected for 12C Ion Radiotherapy?

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Thirty percent of patients will experience locoregional recurrence for which median survival is less than 1 year. Factors contributing to treatment failure include inherent resistance to X-rays and chemotherapy, hypoxia, epithelial to mesenchymal transition, and immune suppression. The unique properties of 12C radiotherapy including enhanced cell killing, a decreased oxygen enhancement ratio, generation of complex DNA damage, and the potential to overcome immune suppression make its application well suited to the treatment of HNSCC. We examined the 12C radioresponse of five HNSCC cell lines, whose surviving fraction at 3.5 Gy ranged from average to resistant when compared with a larger panel of 38 cell lines to determine if 12C irradiation can overcome X-ray radioresistance and to identify biomarkers predictive of 12C radioresponse. Cells were irradiated with 12C using a SOBP with an average LET of 80 keV/µm (CNAO: Pavia, Italy). RBE values varied depending upon endpoint used. A 37 gene signature was able to place cells in their respective radiosensitivity cohort with an accuracy of 86%. Radioresistant cells were characterized by an enrichment of genes associated with radioresistance and survival mechanisms including but not limited to G2/M Checkpoint MTORC1, HIF1α, and PI3K/AKT/MTOR signaling. These data were used in conjunction with an in silico-based modeling approach to evaluate tumor control probability after 12C irradiation that compared clinically used treatment schedules with fixed RBE values vs. the RBEs determined for each cell line. Based on the above analysis, we present the framework of a strategy to utilize biological markers to predict which HNSCC patients would benefit the most from 12C radiotherapy.

Multimodal evaluation of 19F-BPA internalization in pancreatic cancer cells for boron capture and proton therapy potential applications.

PURPOSE: One of the obstacles to the application of Boron Neutron Capture Therapy (BNCT) and Proton Boron Fusion Therapy (PBFT) concerns the measurement of borated carriers' biodistribution. The objective of the present study was to evaluate the in vitro internalization of the 19F-labelled p-boronophenylalanine (19F-BPA) in the human cancer pancreatic cell line (PANC-1) for the potential application of BNCT and PBFT in pancreatic cancer. The 19F-BPA carrier has the advantage that its bio-distribution may be monitored in vivo using 19F-Nuclear Magnetic Resonance (19F NMR). MATERIALS AND METHODS: The 19F-BPA internalization in PANC-1 cells was evaluated using three independent techniques on cellular samples left in contact with growing medium enriched with 13.6 mM 19F-BPA corresponding to a 11B concentration of 120 ppm: neutron autoradiography, which quantifies boron; liquid chromatography hyphenated to tandem mass spectrometry and UV-Diode Array Detection (UV-DAD), which quantifies 19F-BPA molecule; and 19F NMR spectroscopy, which detects fluorine nuclei. RESULTS: Our studies suggested that 19F-BPA is internalized by PANC-1 cells. The three methods provided consistent results of about 50% internalization fraction at 120 ppm of 11B. Small variations (less than 15%) in internalization fraction are mainly dependent on the proliferation state of the cells. CONCLUSIONS: The ability of 19F NMR spectroscopy to study 19F-BPA internalization was validated by well-established independent techniques. The multimodal approach we used suggests 19F-BPA as a promising BNCT/PBFT carrier for the treatment of pancreatic cancer. Since the quantification is performed at doses useful for BNCT/PBFT, 19F NMR can be envisaged to monitor 19F-BPA bio-distribution during the therapy.

Ovarian Cancer Radiosensitivity: What Have We Understood So Far?

Radiotherapy has been increasingly considered as an active treatment to combine with other approaches (i.e., surgery, chemotherapy, and novel target-based drugs) in ovarian cancers to palliate symptoms and/or to prolong chemotherapy-free intervals. This narrative review aimed to summarize the current knowledge of the radiosensitivity/radioresistance of ovarian cancer which remains the most lethal gynecological cancer worldwide. Indeed, considering the high rate of recurrence in and out of the radiotherapy fields, in the era of patient-tailored oncology, elucidating the mechanisms of radiosensitivity and identifying potential radioresistance biomarkers could be crucial in guiding clinical decision-making.

In Vivo Evaluation of Multifunctional Gold Nanorods for Boron Neutron Capture and Photothermal Therapies.

The incidence and mortality of cancer demand more innovative approaches and combination therapies to increase treatment efficacy and decrease off-target side effects. We describe a boron-rich nanoparticle composite with potential applications in both boron neutron capture therapy (BNCT) and photothermal therapy (PTT). Our strategy is based on gold nanorods (AuNRs) stabilized with polyethylene glycol and functionalized with the water-soluble complex cobalt bis(dicarbollide) ([3,3'-Co(1,2-C2B9H11)2]-), commonly known as COSAN. Radiolabeling with the positron emitter copper-64 (64Cu) enabled in vivo tracking using positron emission tomography imaging. 64Cu-labeled multifunctionalized AuNRs proved to be radiochemically stable and capable of being accumulated in the tumor after intravenous administration in a mouse xenograft model of gastrointestinal cancer. The resulting multifunctional AuNRs showed high biocompatibility and the capacity to induce local heating under external stimulation and trigger cell death in heterogeneous cancer spheroids as well as the capacity to decrease cell viability under neutron irradiation in cancer cells. These results position our nanoconjugates as suitable candidates for combined BNCT/PTT therapies.

The Proton-Boron Reaction Increases the Radiobiological Effectiveness of Clinical Low- and High-Energy Proton Beams: Novel Experimental Evidence and Perspectives.

Protontherapy is a rapidly expanding radiotherapy modality where accelerated proton beams are used to precisely deliver the dose to the tumor target but is generally considered ineffective against radioresistant tumors. Proton-Boron Capture Therapy (PBCT) is a novel approach aimed at enhancing proton biological effectiveness. PBCT exploits a nuclear fusion reaction between low-energy protons and 11B atoms, i.e. p+11B→ 3α (p-B), which is supposed to produce highly-DNA damaging α-particles exclusively across the tumor-conformed Spread-Out Bragg Peak (SOBP), without harming healthy tissues in the beam entrance channel. To confirm previous work on PBCT, here we report new in-vitro data obtained at the 62-MeV ocular melanoma-dedicated proton beamline of the INFN-Laboratori Nazionali del Sud (LNS), Catania, Italy. For the first time, we also tested PBCT at the 250-MeV proton beamline used for deep-seated cancers at the Centro Nazionale di Adroterapia Oncologica (CNAO), Pavia, Italy. We used Sodium Mercaptododecaborate (BSH) as 11B carrier, DU145 prostate cancer cells to assess cell killing and non-cancer epithelial breast MCF-10A cells for quantifying chromosome aberrations (CAs) by FISH painting and DNA repair pathway protein expression by western blotting. Cells were exposed at various depths along the two clinical SOBPs. Compared to exposure in the absence of boron, proton irradiation in the presence of BSH significantly reduced DU145 clonogenic survival and increased both frequency and complexity of CAs in MCF-10A cells at the mid- and distal SOBP positions, but not at the beam entrance. BSH-mediated enhancement of DNA damage response was also found at mid-SOBP. These results corroborate PBCT as a strategy to render protontherapy amenable towards radiotherapy-resilient tumor. If coupled with emerging proton FLASH radiotherapy modalities, PBCT could thus widen the protontherapy therapeutic index.

A New Platinum-Based Prodrug Candidate for Chemotherapy and Its Synergistic Effect With Hadrontherapy: Novel Strategy to Treat Glioblastoma.

Glioblastoma (GBM) is the most common tumor of the central nervous system. Current therapies, often associated with severe side effects, are inefficacious to contrast the GBM relapsing forms. In trying to overcome these drawbacks, (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(IV), also called Pt(IV)Ac-POA, has been recently synthesized. This new prodrug bearing as axial ligand (2-propynyl)octanoic acid (POA), a histone deacetylase inhibitor, has a higher activity due to (i) its high cellular accumulation by virtue of its high lipophilicity and (ii) the inhibition of histone deacetylase, which leads to the increased exposure of nuclear DNA, permitting higher platination and promoting cancer cell death. In the present study, we investigated the effects induced by Pt(IV)Ac-POA and its potential antitumor activity in human U251 glioblastoma cell line using a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, TEM, and Western blotting analyses. In addition, the synergistic effect of Pt(IV)Ac-POA associated with the innovative oncological hadrontherapy with carbon ions was investigated, with the aim to identify the most efficient anticancer treatment combination. Our in vitro data demonstrated that Pt(IV)Ac-POA is able to induce cell death, through different pathways, at concentrations lower than those tested for other platinum analogs. In particular, an enduring Pt(IV)Ac-POA antitumor effect, persisting in long-term treatment, was demonstrated. Interestingly, this effect was further amplified by the combined exposure to carbon ion radiation. In conclusion, Pt(IV)Ac-POA represents a promising prodrug to be incorporated into the treatment regimen for GBM. Moreover, the synergistic efficacy of the combined protocol using chemotherapeutic Pt(IV)Ac-POA followed by carbon ion radiation may represent a promising approach, which may overcome some typical limitations of conventional therapeutic protocols for GBM treatment.

Effects of Photons Irradiation on 18F-FET and 18F-DOPA Uptake by T98G Glioblastoma Cells.

The differential diagnosis between brain tumors recurrence and early neuroinflammation or late radionecrosis is still an unsolved problem. The new emerging magnetic resonance imaging, computed tomography, and positron emission tomography diagnostic modalities still lack sufficient accuracy. In the last years, a great effort has been made to develop radiotracers able to detect specific altered metabolic pathways or tumor receptor markers. Our research project aims to evaluate irradiation effects on radiopharmaceutical uptake and compare the kinetic of the fluorinate tracers. T98G glioblastoma cells were irradiated at doses of 2, 10, and 20 Gy with photons, and 18F-DOPA and 18F-FET tracer uptake was evaluated. Activity and cell viability at different incubation times were measured. 18F-FET and 18F-DOPA are accumulated via the LAT-1 transporter, but 18F-DOPA is further incorporated, whereas 18F-FET is not metabolized. Therefore, time-activity curves (TACs) tend to plateau with 18F-DOPA and to a rapid washout with 18F-FET. After irradiation, 18F-DOPA TAC resembles the 18F-FET pattern. 18F-DOPA activity peak we observed at 20 min might be fictitious, because earlier time points have not been evaluated, and a higher activity peak before 20 min cannot be excluded. In addition, the activity retained in the irradiated cells remains higher in comparison to the sham ones at all time points investigated. This aspect is similar in the 18F-FET TAC but less evident. Therefore, we can hypothesize the presence of a second intracellular compartment in addition to the amino acidic pool one governed by LAT-1, which could explain the progressive accumulation of 18F-DOPA in unirradiated cells.

Hadron Therapy, Magnetic Nanoparticles and Hyperthermia: A Promising Combined Tool for Pancreatic Cancer Treatment.

A combination of carbon ions/photons irradiation and hyperthermia as a novel therapeutic approach for the in-vitro treatment of pancreatic cancer BxPC3 cells is presented. The radiation doses used are 0-2 Gy for carbon ions and 0-7 Gy for 6 MV photons. Hyperthermia is realized via a standard heating bath, assisted by magnetic fluid hyperthermia (MFH) that utilizes magnetic nanoparticles (MNPs) exposed to an alternating magnetic field of amplitude 19.5 mTesla and frequency 109.8 kHz. Starting from 37 °C, the temperature is gradually increased and the sample is kept at 42 °C for 30 min. For MFH, MNPs with a mean diameter of 19 nm and specific absorption rate of 110 ± 30 W/gFe3o4 coated with a biocompatible ligand to ensure stability in physiological media are used. Irradiation diminishes the clonogenic survival at an extent that depends on the radiation type, and its decrease is amplified both by the MNPs cellular uptake and the hyperthermia protocol. Significant increases in DNA double-strand breaks at 6 h are observed in samples exposed to MNP uptake, treated with 0.75 Gy carbon-ion irradiation and hyperthermia. The proposed experimental protocol, based on the combination of hadron irradiation and hyperthermia, represents a first step towards an innovative clinical option for pancreatic cancer.

Re-irradiation With Carbon Ion Radiotherapy for Pelvic Rectal Cancer Recurrences in Patients Previously Irradiated to the Pelvis.

BACKGROUND/AIM: Re-irradiation of locally recurrent rectal cancer poses challenges due to the proximity of critical organs, such as the bowel. This study aimed at evaluating the safety and efficacy of re-irradiation with Carbon Ion Radiotherapy (CIRT) in rectal cancer patients with local recurrence. PATIENTS AND METHODS: Between 2014 and 2018, 14 patients were treated at the National Center of Oncological Hadrontherapy (CNAO Foundation) with CIRT for locally recurrent rectal cancer. RESULTS: All patients concluded the treatment. No G≥3 acute/late reaction nor pelvic infections were observed. The 1-year and 2-year local control rates were, 78% and 52%, respectively, and relapse occurred close to the bowel in 6 patients. The 1-year and 2-year overall survival rates were 100% and 76.2% each; while the 1-year and 2-year metastasis free survival rates were 64.3% and 43%. CONCLUSION: CIRT as re-irradiation for locally recurrent rectal cancer emerges as a safe and valid treatment with an acceptable rate of morbidity of surrounding healthy tissue.

Outcome and Toxicity of Carbon Ion Radiotherapy for Axial Bone and Soft Tissue Sarcomas.

BACKGROUND/AIM: Definitive radiotherapy for bone and soft tissues sarcomas benefits patients deemed unfit for surgery; poor outcomes have been reported with conventional photons, while interesting preliminary results have been described with particle in single-Institution experiences. The aim of the study was to retrospectively evaluate preliminary results of carbon ion radiotherapy (CIRT) in patients with axial bone and soft tissue sarcomas (BSTS) treated with curative intent at the National Center for Oncological Hadrontherapy (CNAO). PATIENTS AND METHODS: From January 2013 to September 2018, 54 patients with axial BSTS were treated with CIRT at CNAO. Their median age was 50 years (range=19-79 years), males/females=1.4:1. Tumor site was the pelvis in 50% of cases (n=27), thoracic region in 24% (n=13), cervical spine in 15% (n=8) and lumbar in 11% (n=6). A total of 76% (n=41) of patients had primary disease, while 24% (n=13) had recurrent disease. Before CIRT, surgery was performed in 47% of cases, including positive margins (R1) in 8 patients, and macroscopic residual disease (R2) in 17. Histological subtypes were mainly represented by chondrosarcomas in 39% (n=21) of patients and osteosarcomas in 24% (n=13). Pre-treatment chemotherapy was administered in 40% of cases (n=22); no patient received previous radiotherapy. All treatments were performed with active scanning CIRT for a median total dose of 73.6 Gy (range=70.4-76.8 Gy), in 16 fractions (4 fractions per week). RESULTS: Median follow-up was 24 months (range=4-61 months). Four patients were lost to follow-up. Acute toxicities were mild, no >G2 event was reported and no treatment interruption was required. For late toxicity, only G3 neuropathy was detected in 4% of cases (n=2). With a median time to local progression of 13 months (3-35), 15 local failures were observed, resulting in 2- and 3-year local control rates of 67.4% for both. Distant progression occurred in 12 patients, with 1-year progression-free survival (PFS) rate of 97.5%; 2- and 3-year rates were 92.2%. Fifteen patients died resulting in 1- 2- and 3-years overall survival (OS) rates of 87.1%, 75.4% and 64%, respectively. At log-rank test, gross total volume (GTV) >1,000 ml was found to be predictive of local failure (p=0.04), pre-treatment chemotherapy was found to be significantly related to PFS and OS (p=0.02 and p=0.016); also, recurrent disease and distant progression were significantly related to OS (p=0.019 and p=0.0013). Cox proportional-hazards model confirmed that GTV >1,000 ml was related to worse local control (p=0.0010). CONCLUSION: CIRT for axial BSTS resulted in mild toxicity, showing promising results in terms of clinical outcomes. A longer follow-up is warranted.

Is Proton Beam Radiotherapy Worthwhile in the Management of Angiosarcoma of the Scalp?

In inoperable patients, the management of angiosarcoma of the scalp is challenging. Due to intrinsic, dosimetric and radiobiological properties, proton beam radiotherapy may be an effective and safe option to offer to these difficult-to-cure patients. Here, we report a case of angiosarcoma of the scalp treated successfully with proton beam radiotherapy. Angiosarcoma is a rare malignancy concerning around 2% of soft-tissue sarcomas and 5% of cutaneous soft-tissue sarcomas. Cutaneous angiosarcomas can occur in any part of the body, but the head and neck region is a common primary site and the scalp is a frequent site in elderly patients.

[The risk of second radiation-induced cancer from hadrontherapy compared to traditional radiotherapy]. / Il rischio di secondo tumore radioindotto da adroterapia rispetto alla radioterapia tradizionale.

SUMMARY: Radiation therapy increasingly plays a fundamental role in the treatment of cancer. Since the survival of cancer patients is continuously improving, the late effects of treatments, including those related to radiation treatment, can affect the quality of life and health and of the patients themselves to a greater extent. Especially in the last 20 years, with the implementation of new techniques/forms of radiation therapy, the risk of developing radiation-induced tumors following radiation therapy has become a hotly debated topic. Malignant tumors induced by radiation therapy represent a particularly important problem for pediatric patients, who are intrinsically more sensitive to carcinogens than adults and have a longer life expectancy. To date, there is only one study in the literature, from 2019, which analyzes the risk of secondary tumors after carbon ion radiation compared to surgery or photon treatment and refers to patients treated for prostate cancer. Despite the high degree of uncertainty, the data acquired so far suggest that particle radiation therapy, especially with protons delivered with active scanning, carries a lower risk of radiation-induced tumors than conventional photon therapies. This is largely due to the lower doses to which healthy tissues are exposed and the low relative risk associated with exposure to neutrons throughout the body, especially when active scanning beams are used.

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.

The Role of Particle Therapy in the Risk of Radio-induced Second Tumors: A Review of the Literature.

One of the most important late side-effects of radiation therapy is the development of radiation-induced secondary malignancies. In the last years, this topic has significantly influenced treatment decision-making as the number of long-term cancer survivors has significantly increased with advances in treatment modalities. All efforts are being made to prevent the incidence of tumors induced by radiation. In this review article we summarize the current knowledge about treatment-related secondary cancers with a particular attention to hadrontherapy.