Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) is activated by DNA single-strand breaks (SSB) or at stalled replication forks to facilitate DNA repair. Inhibitors of PARP efficiently kill breast, ...ovarian, or prostate tumors in patients carrying hereditary mutations in the homologous recombination (HR) genes BRCA1 or BRCA2 through synthetic lethality. Here, we surprisingly show that PARP1 is hyperactivated in replicating BRCA2-defective cells. PARP1 hyperactivation is explained by the defect in HR as shRNA depletion of RAD54, RAD52, BLM, WRN, and XRCC3 proteins, which we here show are all essential for efficient HR and also caused PARP hyperactivation and correlated with an increased sensitivity to PARP inhibitors. BRCA2-defective cells were not found to have increased levels of SSBs, and PAR polymers formed in HR-defective cells do not colocalize to replication protein A or gammaH2AX, excluding the possibility that PARP hyperactivity is due to increased SSB repair or PARP induced at damaged replication forks. Resistance to PARP inhibitors can occur through genetic reversion in the BRCA2 gene. Here, we report that PARP inhibitor-resistant BRCA2-mutant cells revert back to normal levels of PARP activity. We speculate that the reason for the sensitivity of HR-defective cells to PARP inhibitors is related to the hyperactivated PARP1 in these cells. Furthermore, the presence of PAR polymers can be used to identify HR-defective cells that are sensitive to PARP inhibitors, which may be potential biomarkers.
Abstract
Background
The aim of this study is to evaluate results in terms of local control (LC), overall survival (OS), and toxicity profile and to better identify factors influencing clinical ...outcome of skull base chordoma treated with proton therapy (PT) and carbon ion radiotherapy (CIRT).
Methods
We prospectively collected and analyzed data of 135 patients treated between November 2011 and December 2018. Total prescription dose in the PT group (70 patients) and CIRT group (65 patients) was 74 Gy relative biological effectiveness (RBE) delivered in 37 fractions and 70.4 Gy(RBE) delivered in 16 fractions, respectively (CIRT in unfavorable patients). LC and OS were evaluated using the Kaplan–Meier method. Univariate and multivariate analyses were performed, to identify prognostic factors on clinical outcomes.
Results
After a median follow-up of 49 (range, 6–87) months, 14 (21%) and 8 (11%) local failures were observed in CIRT and PT group, respectively. Five-year LC rate was 71% in CIRT cohort and 84% in PT cohort. The estimated 5-year OS rate in the CIRT and PT group was 82% and 83%, respectively. On multivariate analysis, gross tumor volume (GTV), optic pathways, and/or brainstem compression and dose coverage are independent prognostic factors of local failure risk. High rate toxicity grade ≥3 was reported in 11% of patients.
Conclusions
Particle radiotherapy is an effective treatment for skull base chordoma with acceptable late toxicity. GTV, optic pathways, and/or brainstem compression and target coverage were independent prognostic factors for LC.
Key Points
• Proton and carbon ion therapy are effective and safe in skull base chordoma.
• Prognostic factors are GTV, organs at risk compression, and dose coverage.
• Dual particle therapy and customized strategy was adopted.
Abstract Background and purpose In carbon ion radiotherapy (CIRT), the use of different relative biological effectiveness (RBE) models in the RBE-weighted dose (DRBE ) calculation can lead to ...deviations in the physical dose (Dphy ) delivered to the patient. Our aim is to reduce target Dphy deviations by converting prescription dose values. Material and methods Planning data of patients treated at the National Institute of Radiological Sciences (NIRS) were collected, with prescribed doses per fraction ranging from 3.6 Gy (RBE) to 4.6 Gy (RBE), according to the Japanese semi-empirical model. The Dphy was Monte Carlo (MC) re-calculated simulating the NIRS beamline. The local effect model (LEM)_I was then applied to estimate DRBE . Target median DRBE ratios between MC + LEM_I and NIRS plans determined correction factors for the conversion of prescription doses. Plans were re-optimized in a LEM_I-based commercial system, prescribing the NIRS uncorrected and corrected DRBE. Results The MC + LEM_I target median DRBE was respectively 15% and 5% higher than the NIRS reference, for the lowest and highest dose levels. Uncorrected DRBE prescription resulted in significantly lower target Dphy in re-optimized plans, with respect to NIRS plans. Conclusions Prescription dose conversion factors could minimize target physical dose variations due to the use of different radiobiological models in the calculation of CIRT RBE-weighted dose.
Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron ...irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours.
Highlights•mMKM to LEM conversion of dose prescription/constraints affects treatment outcomes. •LEM-68.8 Gy(RBE) correctly reproduces mMKM-64 Gy(RBE) for ACC patients. •ACC relapses were mainly ...related to CTV under-dosage due to OARs sparing. •mMKM OARs constraints require correction when applied to LEM plans.
The growing interest in proton therapy (PT) in recent decades is justified by the evidence that protons dose distribution allows maximal dose release at the tumor depth followed by sharp distal dose ...fall-off. But, in the holistic management of head and neck cancer (HNC), limiting the potential of PT to a mere dosimetric advantage appears reductive. Indeed, the precise targeting of PT may help evaluate the effectiveness of de-escalation strategies, especially for patients with human papillomavirus associated-oropharyngeal cancer (OPC) and nasopharyngeal cancer (NPC). Furthermore, PT could have potentially greater immunogenic effects than conventional photon therapy, possibly enhancing both the radiotherapy (RT) capability to activate anti-tumor immune response and the effectiveness of immunotherapy drugs. Based on these premises, the aim of the present paper is to conduct a narrative review reporting the safety and efficacy of PT compared to photon RT focusing on NPC and OPC. We also provide a snapshot of ongoing clinical trials comparing PT with photon RT for these two clinical scenarios. Finally, we discuss new insights that may further develop clinical research on PT for HNC.
Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) ...and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy.
The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study.
So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors.
ClinicalTrials.gov identifier: NCT02838602 . Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.
Salivary gland cancers (SGCs) are rare, accounting for less than 5% of all malignancies of the head and neck region, and are morphologically heterogeneous. The diagnosis is mainly based on histology, ...with the complementary aid of molecular profiling, which is helpful in recognizing some poorly differentiated, borderline, or atypical lesions. Instrumental imaging defines the diagnosis, representing a remarkable tool in the treatment plan. Ultrasound and magnetic resonance are the most common procedures used to describe the primary tumour. The treatment of SGCs is multimodal and consists of surgery, radiotherapy, and systemic therapy; each treatment plan is, however, featured on the patient and disease’s characteristics. On 24 June 2022, in the meeting “Current management and future challenges in salivary gland cancers” many experts in this field discussed the state of the art of SGCs research, the future challenges and developments. After the meeting, the same pool of experts maintained close contact to keep these data further updated in the conference proceedings presented here. This review collects the insights and suggestions that emerged from the discussion during and after the meeting per se.
(1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy ...(IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔD
≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (-12.5%), brain necrosis (-2.3%), mucositis (-3.2%), tinnitus (-8.6%), hypothyroidism (-9.3%), and trismus (-5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3-T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain.
To estimate the impact of dose calculation approaches adopted in different treatment planning systems (TPSs) on proton therapy dose delivered with pencil beam scanning (PBS). Treatment plans for six ...regular volumes in water and 15 clinical cases were optimized with Syngo-VC13 and exported for forward recalculation with Raystation-V7.0 pencil beam (RS-PBA) and Monte Carlo (RS-MC) algorithms and with the independent Fluka-MC engine. To verify clinical consistency between the two TPS dosimetric outcomes, the average percentage variations of clinical target volume (CTV) D
, D
and D
, adopted for plan prescription and evaluation, were considered. Ionization chamber measurements served as a further reference for comparison in homogeneous conditions. CTV dose volume histogram (DVH) analysis and gamma evaluation with 3 mm-3% agreement criteria quantified the dose deviation of TPS calculation algorithms, in heterogeneous conditions, against the Fluka-MC code. CTV D
, representing the plan dose prescription goal, was higher on average over H&N cases of (3.9 ± 0.9)% and (2.3 ± 0.6)% as calculated with RS-PBA and RS-MC, respectively, compared to Syngo. For tumors located in the pelvis district, average D
variations of (1.6 ± 0.7)% and (1.2 ± 0.7)% were found. Syngo underestimated target near maximum doses with respect to all computation systems. Calculation accuracy in heterogeneous conditions of RS-PBA H&N plans resulted poor when a range shifter was required. Target DVH and γ-analysis showed excellent agreement between RS-MC and Fluka-MC, with γ-pass rates >98% for all patient groups. Different TPS dose calculation approaches mainly affected dose delivered in H&N proton treatments, while minor deviations were found for pelvic tumors. RS-MC proved to be the most accurate TPS dose calculation algorithm when compared to an independent MC simulation code.
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