Our goal is to develop countermeasures for pulmonary injury following unpredictable events such as radiological terrorism or nuclear accidents. We have previously demonstrated that captopril, an angiotensin converting enzyme (ACE) inhibitor, is more effective than losartan, an angiotensin type-1 receptor blocker, in mitigating radiation-pneumopathy in a relevant rodent model. In the current study we determined the dose modifying factors (DMFs) of captopril for mitigation of parameters of radiation pneumonitis. We used a whole animal model, irradiating 9–10-week-old female rats derived from a Wistar strain (WAG/RijCmcr) with a single dose of irradiation to the thorax of 11, 12, 13, 14 or 15 Gy. Our study develops methodology to measure DMFs for morbidity (survival) as well as physiological endpoints such as lung function, taking into account attrition due to lethal radiation-induced pneumonitis. Captopril delivered in drinking water (140–180 mg/m2/day, comparable with that given clinically) and started one week after irradiation has a DMF of 1.07–1.17 for morbidity up to 80 days (survival) and 1.21–1.35 for tachypnea at 42 days (at the peak of pneumonitis) after a single dose of ionizing radiation (X-rays). These encouraging results advance our goals, since DMF measurements are essential for drug labeling and comparison with other mitigators.
radiation-pneumopathy; DMF; DRF; ACE inhibitors; breathing rate
The aim of the present study was to assess recovery from hematopoietic and gastrointestinal damage by Ex-RAD®, also known as ON01210.Na (4-carboxystyryl-4-chlorobenzylsulfone, sodium salt), after total body radiation. In our previous study, we reported that Ex-RAD, a small-molecule radioprotectant, enhances survival of mice exposed to gamma radiation, and prevents radiation-induced apoptosis as measured by the inhibition of radiation-induced protein 53 (p53) expression in cultured cells. We have expanded this study to determine best effective dose, dose-reduction factor (DRF), hematological and gastrointestinal protection, and in vivo inhibition of p53 signaling. A total of 500 mg/kg of Ex-RAD administered at 24 h and 15 min before radiation resulted in a DRF of 1.16. Ex-RAD ameliorated radiation-induced hematopoietic damage as monitored by the accelerated recovery of peripheral blood cells, and protection of granulocyte macrophage colony-forming units (GM-CFU) in bone marrow. Western blot analysis on spleen indicated that Ex-RAD treatment inhibited p53 phosphorylation. Ex-RAD treatment reduces terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay (TUNEL)-positive cells in jejunum compared with vehicle-treated mice after radiation injury. Finally, Ex-RAD preserved intestinal crypt cells compared with the vehicle control at 13 and 14 Gy. The results demonstrated that Ex-RAD ameliorates radiation-induced peripheral blood cell depletion, promotes bone marrow recovery, reduces p53 signaling in spleen and protects intestine from radiation injury.
Ex-RAD; GM-CFU; gastrointestinal; radioprotection
The purpose of this study is to develop a procedure for eradicative brachytherapy that can deliver a curative boost dose to bulky (>4 cm) vaginal stump recurrence of uterine cancer without risk of damaging surrounding organs. We separated risk organs (the rectum and sigmoid) from the target during brachytherapy, with a hyaluronate gel injection into the pararectal space via the percutaneous paraperineal approach under local anesthesia. The rectum anchored to the sacrum by native ligament was expected to shift posteriorly. We encountered a patient with bulky stump recurrence of uterine cancer, approximately 8 cm in maximum diameter. She was complaining of abdominal pain and constipation due to bowel encasement. Following 50 Gy of external beam radiotherapy, we applied a single fraction of brachytherapy under gel separation and delivered 14.5 Gy (50.8 GyE: equivalent dose in 2-Gy fraction calculated with linear quadratic model at α/β = 3) to the target. The gel injection procedure was completed in 30 min without complications. A total irradiation dose of 100.8 GyE was delivered to the target and the cumulative minimum dose to the most irradiated rectosigmoidal volume of 2 cc (cumulative D2cc) was calculated as 58.5 GyE with gel injection, and was estimated to be 96 GyE without. Over three years, the local stump tumor has completely disappeared, with no complications. Brachytherapy with a pararectal gel injection can be a safe and effective eradicative option for bulky vaginal stump recurrence.
high dose rate brachytherapy; recurrence; vaginal stump; uterine cancer; hyaluronate
Growing evidence has demonstrated that microRNAs (miRNAs) play an important role in regulating cellular radiosensitivity. This study aimed to explore the role of miRNAs in non-Hodgkin's lymphoma (NHL) radiosensitivity. Microarray was employed to compare the miRNA expression profiles in B cell lymphoma cell line Raji before and after a 2-Gy dose of radiation. A total of 20 differentially expressed miRNAs were identified including 10 up-regulated and 10 down-regulated (defined as P < 0.05). Among the differentially expressed miRNAs, miR-148b was up-regulated 1.53-fold in response to radiation treatment. A quantitative real-time polymerase chain reaction (PCR) assay confirmed the up-regulation of miR-148b after radiation. Transient transfection experiments showed that miR-148b was up-regulated by miR-148b mimic and down-regulated by miR-148b inhibitor in the Raji cells. A proliferation assay showed that miR-148b could inhibit the proliferation of Raji cells before and after radiation. A clonogenic assay demonstrated that miR-148b sensitized Raji cells to radiotherapy. MiR-148b did not affect the cell cycle profile of post-radiation Raji cells compared with controls. An apoptosis assay showed that miR-148b enhanced apoptosis of Raji cells after irradiation. Taken together, these results demonstrate that miR-148b increased the radiosensitivity of NHL cells probably by promoting radiation-induced apoptosis, which suggests that miR-148b plays an important role in the response of NHL to ionizing radiation.
miR-148b; ionizing radiation; non-Hodgkin's lymphoma; Raji cell; apoptosis
Radiotherapy alone has several limitations for treating lung cancer. Inhalation, a non-invasive approach for direct delivery of therapeutic agents to the lung, may help to enhance the therapeutic efficacy of radiation. Up-regulating beclin1, known as a tumor suppressor gene that plays a major role in autophagy, may sensitize tumors and lead to tumor regression in lungs of K-rasLA1 lung cancer model mice. To minimize the side-effects of radiotherapy, fractionated exposures (five times, 24-h interval) with low dose (2 Gy) of radiation to the restricted area (thorax, 2 cm) were conducted. After sensitizing the lungs with radiation, beclin1, complexed with a nano-sized biodegradable poly(ester amine), was prepared and delivered into the murine lung via aerosol three times/week for four weeks. In a histopathological analysis, animals treated with beclin1 and radiation showed highly significant tumor regression and low progression to adenocarcinoma. An increase in the number of autophagic vacuoles and secondary lysosomes was detected. Dissociation of beclin1-bcl2 stimulated autophagy activation and showed a synergistic anti-tumor effect by inhibiting the Akt-mTOR pathway, cell proliferation and angiogenesis. The combination of radiation with non-invasive aerosol delivery of beclin1 may provide a prospect for developing novel therapy regimens applicable in clinics.
Radiation; Beclin1; aerosol delivery; lung cancer
We measured the physical and radiobiological characteristics of 1 GeV protons for possible applications in stereotactic radiosurgery (image-guided plateau-proton radiosurgery). A proton beam was accelerated at 1 GeV at the Brookhaven National Laboratory (Upton, NY) and a target in polymethyl methacrylate (PMMA) was used. Clonogenic survival was measured after exposures to 1–10 Gy in three mammalian cell lines. Measurements and simulations demonstrate that the lateral scattering of the beam is very small. The lateral dose profile was measured with or without the 20-cm plastic target, showing no significant differences up to 2 cm from the axis A large number of secondary swift protons are produced in the target and this leads to an increase of approximately 40% in the measured dose on the beam axis at 20 cm depth. The relative biological effectiveness at 10% survival level ranged between 1.0 and 1.2 on the beam axis, and was slightly higher off-axis. The very low lateral scattering of relativistic protons and the possibility of using online proton radiography during the treatment make them attractive for image-guided plateau (non-Bragg peak) stereotactic radiosurgery.
proton therapy; radiosurgery; image-guided radiotherapy; proton radiography; RBE
The stimulation effect that some beneficial agronomic qualities have exhibited in present-generation plants have also been observed due to ion implantation on plants. However, there is relatively little knowledge regarding the molecular mechanism of the stimulation effects of ion-beam implantation. In order to extend our current knowledge about the functional genes related to this stimulation effect, we have reported a comprehensive microarray analysis of the transcriptome features of the promoted-growth rice seedlings germinating from seeds implanted by a low-energy N+ beam. The results showed that 351 up-regulated transcripts and 470 down-regulated transcripts, including signaling proteins, kinases, plant hormones, transposable elements, transcription factors, non-coding protein RNA (including miRNA), secondary metabolites, resistance proteins, peroxidase and chromatin modification, are all involved in the stimulating effects of ion-beam implantation. The divergences of the functional catalog between the vacuum and ion implantation suggest that ion implantation is the principle cause of the ion-beam implantation biological effects, and revealed the complex molecular networks required to adapt to ion-beam implantation stress in plants, including enhanced transposition of transposable elements, promoted ABA biosynthesis and changes in chromatin modification. Our data will extend the current understanding of the molecular mechanisms and gene regulation of stimulation effects. Further research on the candidates reported in this study should provide new insights into the molecular mechanisms of biological effects induced by ion-beam implantation.
implantation with low-energy ion beam; stimulation effect; analysis of microarray
The purpose of this retrospective study is to investigate the impact of concurrent chemotherapy on definitive radiotherapy for the International Federation of Gynecology and Obstetrics (FIGO) IIIb cervical cancer. Between 2000 and 2009, 131 women with FIGO IIIb cervical cancer were treated by definitive radiotherapy (i.e. whole pelvic external beam radiotherapy for 40–60 Gy in 20–30 fractions with or without center shielding and concomitant high-dose rate intracavitary brachytherapy with 192-iridium remote after loading system for 6 Gy to point A of the Manchester method). The concurrent chemotherapy regimen was cisplatin (40 mg/m2/week). After a median follow-up period of 44.0 months (range 4.2–114.9 months) and 62.1 months for live patients, the five-year overall survival (OS), loco-regional control (LRC) and distant metastasis-free survival (DMFS) rates were 52.4, 80.1 and 59.9%, respectively. Univariate and multivariate analyses revealed that lack of concurrent chemotherapy was the most significant factor leading to poor prognosis for OS (HR = 2.53; 95% CI 1.44–4.47; P = 0.001) and DMFS (HR = 2.53; 95% CI 1.39–4.61; P = 0.002), but not for LRC (HR = 1.57; 95% CI 0.64–3.88; P = 0.322). The cumulative incidence rates of late rectal complications after definitive radiotherapy were not significantly different with or without concurrent chemotherapy (any grade at five years 23.9 vs 21.7%; P = 0.669). In conclusion, concurrent chemotherapy is valuable in definitive radiotherapy for Japanese women with FIGO IIIb cervical cancer.
cervical cancer; IIIb; chemotherapy; radiotherapy; HDR
We have proposed four dimensional (4D) digitally reconstructed radiography (DRR) for verifying a lung tumor position during volumetric modulated arc therapy (VMAT). An internal target volume (ITV) was defined based on two clinical target volumes (CTVs) delineated on maximum exhalation and maximum inhalation images acquired by 4D planning computed tomography (CT). A planning target volume (PTV) was defined by adding a margin of 5 mm to the ITV on the maximum exhalation 3D CT images. A single-arc VMAT plan was created on the same CT data using Pinnacle SmartArc with a maximum multi-leaf collimator leaf speed of 1 mm/degree, thereby resulting in quasi-conformal field shapes while optimizing each beam intensity for each gantry angle. During VMAT delivery, cone-beam CT (CBCT) projection data were acquired by an on-board kilovoltage X-ray unit and a flat panel 2D detector. Four CBCT image sets with different respiratory phases were reconstructed using in-house software, where respiratory phases were extracted from the projection data. Subsequently a CTV was delineated on each of the 4D CBCT images by an oncologist. Using the resulting 4D CBCT data including the CTV contours, 4D DRRs during the VMAT delivery were calculated as a function of gantry angle. It was confirmed that the contoured CTV was within the radiation field during the four-fraction lung VMAT delivery. The proposed 4D DRR may facilitate the verification of the position of a respiratory moving lung tumor during VMAT delivery on each treatment day.
DRR; VMAT; 4D; in-treatment
We investigated the uncertainty in patient set-up margin analysis with a small dataset consisting of a limited number of clinical cases over a short time period, and propose a method for determining the optimum set-up margin. Patient set-up errors from 555 registration images of 15 patients with prostate cancer were tested for normality using a quantile-quantile (Q-Q) plot and a Kolmogorov–Smirnov test with the hypothesis that the data were not normally distributed. The ranges of set-up errors include the set-up errors within the 95% interval of the entire patient data histogram, and their equivalent normal distributions were compared. The patient set-up error was not normally distributed. When the patient set-up error distribution was assumed to have a normal distribution, an underestimate of the actual set-up error occurred in some patients but an overestimate occurred in others. When using a limited dataset for patient set-up errors, which consists of only a small number of the cases over a short period of time in a clinical practice, the 2.5% and 97.5% intervals of the actual patient data histogram from the percentile method should be used for estimating the set-up margin. Since set-up error data is usually not normally distributed, these intervals should provide a more accurate estimate of set-up margin. In this way, the uncertainty in patient set-up margin analysis in radiation therapy can be reduced.
Prostate; set-up error; SM; PTV
Ionizing radiation induces biological effects not only in irradiated cells but also in non-irradiated cells, which is called the bystander effect. Recently, in vivo and in vitro experiments have suggested that both gap junction hemichannel connexin43 (Cx43) and extracellular adenosine triphosphate (ATP) released from cells play a role in the bystander effect. We have reported that γ-irradiation induces ATP release from B16 melanoma cells, which is dependent on the P2X7 receptor. However, the mechanism of ATP release caused by irradiation remains unclear. We here show the involvement of Cx43 in P2X7 receptor-dependent ATP release after 0.5 Gy γ-irradiation. Inhibitors of gap junction hemichannels and an inhibitory peptide for Cx43 (gap26), but not an inhibitory peptide for pannexin1 (Panx1), significantly blocked γ-irradiation-induced ATP release from B16 melanoma cells. We confirmed high expression of Cx43 mRNA in B16 melanoma cells. These results suggest involvement of Cx43 in radiation-induced ATP release. We found that after 0.5 Gy γ-irradiation tyrosine phosphorylation was significantly blocked by P2X7 receptor antagonist, but not gap26, suggesting that tyrosine phosphorylation is a downstream event from the P2X7 receptor. Since tyrosine kinase inhibitor significantly suppressed radiation-induced ATP release, tyrosine phosphorylation appears to play an important role in the Cx43-mediated ATP release downstream of the P2X7 receptor. In conclusion, the Cx43 hemichannel, which lies downstream of the P2X7 receptor, is involved in ATP release in response to radiation. Our results suggest a novel mechanism for radiation-induced biological effects mediated by both ATP and Cx43.
γ-ray; ATP release; P2X7 receptor; connexin43; tyrosine kinase
Intensity-modulated radiation therapy (IMRT) has recently become popular in Japan. Prostate cancer is indisputably one of the main targets of IMRT. However, the current status and interfacility differences in dose-prescription policies for prostate IMRT are unknown. Therefore, a nationwide survey of 43 institutions that had implemented prostate IMRT was conducted by sending a questionnaire regarding the above-mentioned issues. Thirty-three institutions (77%) had responded to the questionnaire by the end of October 2010. A total of 5245 patients with localized prostate cancer had been treated with IMRT by the end of 2009. Regular multileaf collimator-based techniques were the most common beam delivery method. Dose-prescription policies were divided into four major categories: isocenter-based (@isocenter), dose delivered to 95% of the planning target volume (PTV) (D95)-based (D95@PTV), mean dose to the PTV-based (Mean@PTV), and mean dose to the clinical target volume (CTV)-based (@CTV). The mean doses of the CTV and PTV, and the volume of the PTV receiving 95% of the dose (V95) were significantly higher with the D95@PTV policy than with the other prescription policies. Low-dose areas and hot spots were observed within the PTV in plans with @isocenter and @CTV policies. In conclusion, there are currently considerable differences among institutions in Japan regarding target doses for prostate IMRT. The D95@PTV prescription policy resulted in significant dose escalation compared with the other policies. These differences should be taken into consideration when interpreting treatment outcomes and creating multi-institutional protocols in the future.
intensity-modulated radiation therapy; prostate cancer; target dose prescription
This study was undertaken to assess the diagnostic value of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography with computed tomography ([18F]-FDG-PET/CT) in the detection of radiation toxicity in normal bone marrow using Tibet minipigs as a model. Eighteen Tibet minipigs were caged in aseptic rooms and randomly divided into six groups. Five groups (n = 3/group) were irradiated with single doses of 2, 5, 8, 11 and 14 Gy of total body irradiation (TBI) using an 8-MV X-ray linear accelerator. These pigs were evaluated with [18F]-FDG-PET/CT, and their marrow nucleated cells were counted. The data were initially collected at 6, 24 and 72 h after treatment and were then collected on Days 5–60 post-TBI at 5-day intervals. At 24 and 72 h post-TBI, marrow standardized uptake value (SUV) data showed a dose-dependent decrease in the radiation dose range from 2–8 Gy. Upon long-term observation, SUV and marrow nucleated cell number in the 11-Gy and 14-Gy groups showed a continuous and marked reduction throughout the entire time course, while Kaplan–Meier curves of survival showed low survival. In contrast, the SUVs in the 2-, 5- and 8-Gy groups showed early transient increases followed by a decline from approximately 72 h through Days 5–15 and then normalized or maintained low levels through the endpoint; marrow nucleated cell number and survival curves showed approximately the same trend and higher survival, respectively. Our findings suggest that [18F]-FDG-PET/CT may be helpful in quickly assessing the absorbed doses and predicting the prognosis in patients.
[18F]-FDG-PET/CT; total body irradiation; bone marrow; Tibet minipigs
The purpose of this study is to clarify the effect of a heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), in combination with X-rays or carbon-ion beams on cell killing in human oral squamous cell carcinoma LMF4 cells. Cell survival was measured by colony formation assay. Cell-cycle distribution was analyzed by flow cytometry. Expression of DNA repair-related proteins was investigated by western blotting. The results showed 17-AAG to have synergistic effects on cell lethality with X-rays, but not with carbon-ion beams. The 17-AAG decreased G2/M arrest induced by X-rays, but not by carbon-ion beams. Both X-ray and carbon-ion irradiation up-regulated expression of non-homologous end-joining-associated proteins, Ku70 and Ku80, but 17-AAG inhibited only X-ray-induced up-regulation of these proteins. These results show that 17-AAG with X-rays releases G2/M phase arrest; cells carrying misrepaired DNA damage then move on to the G1 phase. We demonstrate, for the first time, that the radiosensitization effect of 17-AAG is not seen with carbon-ion beams because 17-AAG does not affect these changes.
heat shock protein 90; 17-allylamino-17-demethoxygeldanamycin (17-AAG); carbon-ion beam irradiation; radiosensitization
The purpose of the present investigation was to study the effects of ionizing radiation on endothelial cells derived from diverse normal tissues. We first compared the effects of radiation on clonogenic survival and tube formation of endothelial cells, and then investigated the molecular signaling pathways involved in endothelial cell survival and angiogenesis. Among the different endothelial cells studied, human hepatic sinusoidal endothelial cells (HHSECs) were the most radio-resistant and human dermal microvascular endothelial cells were the most radio-sensitive. The radio-resistance of HHSECs was related to adenosine monophosphate-activated protein kinase and p38 mitogen-activated protein kinase-mediated expression of MMP-2 and VEGFR-2, whereas the increased radio-sensitivity of HDMECs was related to extracellular signal-regulated kinase-mediated generation of angiostatin. These observations demonstrate that there are distinct differences in the radiation responses of normal endothelial cells obtained from diverse organs, which may provide important clues for protection of normal tissue from radiation exposure.
ionizing radiation; normal endothelial cells; angiogenesis
It is unclear how to effectively mitigate against irradiation injury. In this study, we studied the capacity of recombinant human insulin-like growth factor-I (rhIGF-I) on hematologic recovery in irradiated BALB/c mice and its possible mechanism. BALB/c mice were injected with rhIGF-I subcutaneously at a dose of 100 μg/kg twice daily for 7 days after total body irradiation. Compared with a saline control group, treatment with rhIGF-I significantly improved the survival of mice after lethal irradiation (7.5 Gy). It was found that treatment with rhIGF-I not only could increase the frequency of Sca-1+ cells in bone marrow harvested at Day 14 after irradiation, but also it could decrease the apoptosis of mononuclear cells induced by irradiation as measured by flow cytometry, suggesting that rhIGF-I may mediate its effects primarily through promoting hematopoietic stem cell/progenitor survival and protecting mononuclear cells from apoptosis after irradiation exposure. Moreover, we have found that rhIGF-I might facilitate thrombopoiesis in an indirect way. Our data demonstrated that rhIGF-I could promote overall hematopoietic recovery after ionizing radiation and reduce the mortality when administered immediately post lethal irradiation exposure.
insulin-like growth factor-I; irradiation injury; hematopoietic recovery; apoptosis
A combination of four-dimensional computed tomography with 18F-fluorodeoxyglucose positron emission tomography (4D CT-FDG PET) was used to delineate gross tumor volume (GTV) in esophageal cancer (EC). Eighteen patients with EC were prospectively enrolled. Using 4D images taken during the respiratory cycle, the average CT image phase was fused with the average FDG PET phase in order to analyze the optimal standardized uptake values (SUV) or threshold. PET-based GTV (GTVPET) was determined with eight different threshold methods using the auto-contouring function on the PET workstation. The difference in volume ratio (VR) and conformality index (CI) between GTVPET and CT-based GTV (GTVCT) was investigated. The image sets via automatic co-registrations of 4D CT-FDG PET were available for 12 patients with 13 GTVCT values. The decision coefficient (R2) of tumor length difference at the threshold levels of SUV 2.5, SUV 20% and SUV 25% were 0.79, 0.65 and 0.54, respectively. The mean volume of GTVCT was 29.41 ± 19.14 ml. The mean VR ranged from 0.30 to 1.48. The optimal VR of 0.98, close to 1, was at SUV 20% or SUV 2.5. The mean CI ranged from 0.28 to 0.58. The best CI was at SUV 20% (0.58) or SUV 2.5 (0.57). The auto-contouring function of the SUV threshold has the potential to assist in contouring the GTV. The SUV threshold setting of SUV 20% or SUV 2.5 achieves the optimal correlation of tumor length, VR, and CI using 4D-PET/CT images.
FDG PET/CT; gross tumor volume; radiotherapy; esophageal cancer
To investigate the influence of chronic hypoxia and anoxia on cell survival after low- and high-LET radiation, CHO-K1 cells were kept for 24 h under chronic hypoxia (94.5% N2; 5% CO2; 0.5% O2) or chronic anoxia (95% N2; 5% CO2). Irradiation was performed using 250 kVp X-rays or carbon ions with a dose average LET of 100 keV/μm either directly under the chronic oxygenation states, or at different time points after reoxygenation. Moreover, the cell cycle distribution for cells irradiated under different chronic oxic states was measured over 24 h during reoxygenation. The measurements showed a fairly uniform cell cycle distribution under chronic hypoxia, similar to normoxic conditions. Chronic anoxia induced a block in G1 and a strong reduction of S-phase cells. A distribution similar to normoxic conditions was reached after 12 h of reoxygenation. CHO cells had a similar survival under both acute and chronic hypoxia. In contrast, survival after irradiation under chronic anoxia was slightly reduced compared to that under acute anoxia. We conclude that, in hamster cells, chronic anoxia is less effective than acute anoxia in inducing radioresistance for both X-rays and carbon ions, whereas in hypoxia, acute and chronic exposures have a similar impact on cell killing.
radiosensitivity; hypoxia; anoxia; carbon ions; cell cycle distribution
PARTNER (Particle Training Network for European Radiotherapy) is a project funded by the European Commission's Marie Curie-ITN funding scheme through the ENLIGHT Platform for 5.6 million Euro. PARTNER has brought together academic institutes, research centres and leading European companies, focusing in particular on a specialized radiotherapy (RT) called hadron therapy (HT), interchangeably referred to as particle therapy (PT). The ultimate goal of HT is to deliver more effective treatment to cancer patients leading to major improvement in the health of citizens. In Europe, several hundred million Euro have been invested, since the beginning of this century, in PT. In this decade, the use of HT is rapidly growing across Europe, and there is an urgent need for qualified researchers from a range of disciplines to work on its translational research. In response to this need, the European community of HT, and in particular 10 leading academic institutes, research centres, companies and small and medium-sized enterprises, joined together to form the PARTNER consortium. All partners have international reputations in the diverse but complementary fields associated with PT: clinical, radiobiological and technological. Thus the network incorporates a unique set of competencies, expertise, infrastructures and training possibilities. This paper describes the status and needs of PT research in Europe, the importance of and challenges associated with the creation of a training network, the objectives, the initial results, and the expected long-term benefits of the PARTNER initiative.
radiation therapy; hadron therapy; cancer; imaging; training
We report the initial toxicity data with scanned proton beams at the Italian National Center for Hadrontherapy (CNAO). In September 2011, CNAO commenced patient treatment with scanned proton beams within two prospective Phase II protocols approved by the Italian Health Ministry. Patients with chondrosarcoma or chordoma of the skull base or spine were eligible. By October 2012, 21 patients had completed treatment. Immobilization was performed using rigid non-perforated thermoplastic-masks and customized headrests or body-pillows as indicated. Non-contrast CT scans with immobilization devices in place and MRI scans in supine position were performed for treatment-planning. For chordoma, the prescribed doses were 74 cobalt grey equivalent (CGE) and 54 CGE to planning target volume 1 (PTV1) and PTV2, respectively. For chondrosarcoma, the prescribed doses were 70 CGE and 54 CGE to PTV1 and PTV2, respectively. Treatment was delivered five days a week in 35–37 fractions. Prior to treatment, the patients' positions were verified using an optical tracking system and orthogonal X-ray images. Proton beams were delivered using fixed-horizontal portals on a robotic couch. Weekly MRI incorporating diffusion-weighted-imaging was performed during the course of proton therapy. Patients were reviewed once weekly and acute toxicities were graded with the Common Terminology Criteria for Adverse Events (CTCAE). Median age of patients = 50 years (range, 21–74). All 21 patients completed the proton therapy without major toxicities and without treatment interruption. Median dose delivered was 74 CGE (range, 70–74). The maximum toxicity recorded was CTCAE Grade 2 in four patients. Our preliminary data demonstrates the clinical feasibility of scanned proton beams in Italy.
The European PARTNER project developed a prototypical system for sharing hadron therapy data. This system allows doctors and patients to record and report treatment-related events during and after hadron therapy. It presents doctors and statisticians with an integrated view of adverse events across institutions, using open-source components for data federation, semantics, and analysis. There is a particular emphasis upon semantic consistency, achieved through intelligent, annotated form designs. The system as presented is ready for use in a clinical setting, and amenable to further customization. The essential contribution of the work reported here lies in the novel data integration and reporting methods, as well as the approach to software sustainability achieved through the use of community-supported open-source components.
hadron therapy; proton therapy; data federation; web portal; eHealth; cancer informatics
The present paper reports and discusses the results concerning both the inter- and intrafraction accuracy achievable combining the immobilization system employed in patients with head-and-neck, brain and skull base tumors with image guidance at our particle therapy center. Moreover, we investigated the influence of intrafraction time on positioning displacements. A total of 41 patients treated between January and July 2011 represented the study population. All the patients were immobilized with a tailored commercial thermoplastic head mask with standard head-neck rest (HeadSTEP®, IT-V). Patient treatment position was verified by two orthogonal kilovoltage images acquired through a ceiling imaging robot (Siemens, Erlangen, Germany). The analysis of the applied daily corrections during the first treatment week before and after treatment delivery allowed the evaluation of the interfraction and intrafraction reproducibility of the thermoplastic mask, respectively. Concerning interfraction reproducibility, translational and rotational systematic errors (Σs) were ≤2.2 mm and 0.9º, respectively; translational and rotational random errors (σs) were ≤1.6 mm and 0.6º, respectively. Regarding the intrafraction accuracy translational and rotational Σs were ≤0.4 mm and 0.4º, respectively; translational and rotational σs were ≤ 0.5 mm and 0.3º, respectively. Concerning the time-intrafraction displacements correlation Pearson coefficient was 0.5 for treatment fractions with time between position checks less than or equal to median value, and 0.2 for those with time between position controls longer than the median figure. These results suggest that intrafractional patient motion is smaller than interfractional patient motion. Moreover, we can state that application of different imaging verification protocols translate into a relevant difference of accuracy for the same immobilization device. The magnitude of intrafraction displacements correlates with the time for short treatment sessions or during the early phase of long treatment delivery.
accuracy; immobilization systems; image-guided radiation therapy; particle therapy