Gold microspheres: a selective technique for producing biologically effective dose enhancement

PURPOSE: To investigate dose enhancement and radiosensitization associated with electrons produced and scattered from gold particles suspended in cells in vitro and with tumour cells growing in vivo irradiated with low-energy photons. MATERIALS AND METHODS: CHO-K1, EMT-6 and DU-145 cells were irradiated with kilovoltage X-ray and Cs-137 beams in slowly stirred suspensions in the presence of various concentrations of gold particles ( 1.5-3.0 microm); cell survival was measured by clonogenic assay. Gold particles were injected directly into EMT-6 tumours growing in scid mice prior to their irradiation. Tumour cell killing was assayed by an in vivo-in vitro technique. RESULTS: Dose enhancement was confirmed by both Fricke dosimetry and cell killing for 100, 140, 200 and 240 kVp X-rays, but not for Cs-137 gamma-rays. For the chemical dosimeter, a dose enhancement (DMF) of 1.42 was measured for 1% gold particle solutions irradiated with 200 kVp X-rays. When rodent and human cells were irradiated in the presence of 1% gold particles, DMF values at the 10% survival level ranged from 1.36 to 1.54, with an overall average value of 1.43. Preliminary attempts to deliver these gold particles to tumour cells in vivo by intra-tumour injection resulted in modest radiosensitization but extremely heterogeneous distribution. CONCLUSIONS: An increased biologically effective dose can be produced by gold microspheres suspended in cell culture or distributed in tumour tissue exposed to kilovoltage photon beams. With the increasing use of interstitial brachytherapy with isotopes that produce low-energy photons, high-Z particles might find a role for significantly improving the therapeutic ratio.     

Integrating external beam and prostate seed implant dosimetry for intermediate and high-risk prostate cancer using biologically effective dose: Impact of image registration technique

PURPOSECombining external beam radiation therapy (EBRT) and prostate seed implant (PSI) is efficacious in treating intermediate- and high-risk prostate cancer at the cost of increased genitourinary toxicity. Accurate combined dosimetry remains elusive due to lack of registration between treatment plans and different biological effect. The current work proposes a method to convert physical dose to biological effective dose (BED) and spatially register the dose distributions for more accurate combined dosimetry.METHODS AND MATERIALSA PSI phantom was CT scanned with and without seeds under rigid and deformed transformations. The resulting CTs were registered using image-based rigid registration (RI), fiducial-based rigid registration (RF), or b-spline deformable image registration (DIR) to determine which was most accurate. Physical EBRT and PSI dose distributions from a sample of 91 previously-treated combined-modality prostate cancer patients were converted to BED and registered using RI, RF, and DIR. Forty-eight (48) previously-treated patients whose PSI occurred before EBRT were included as a “control” group due to inherent registration. Dose-volume histogram (DVH) parameters were compared for RI, RF, DIR, DICOM, and scalar addition of DVH parameters using ANOVA or independent Student's t tests (α = 0.05).RESULTSIn the phantom study, DIR was the most accurate registration algorithm, especially in the case of deformation. In the patient study, dosimetry from RI was significantly different than the other registration algorithms, including the control group. Dosimetry from RF and DIR were not significantly different from the control group or each other.CONCLUSIONSCombined dosimetry with BED and image registration is feasible. Future work will utilize this method to correlate dosimetry with clinical outcomes.     

Validation of a commercial software dose calculation for Y-90 microspheres

PURPOSESeveral new commercial software packages have become available that can calculate the tumor and normal tissue dose distributions from post-treatment PET-CT scans for Y-90 microsphere treatments of liver lesions. This work seeks to validate the MIM SurePlan Liver Y90 software by comparing its results to a previously developed Monte Carlo derived voxel dose kernel calculation method.METHODSWe analyzed 10 patients who had treatments for metastatic liver cancer and created contours on post Y-90 treatment PET-CT images. We then performed dose calculations using three methods and compared the results. The first two methods calculated the dose using MIM SurePlan Liver Y90’s LDM (Local Deposition Method) and the VSV (Voxel S Value) algorithms. The third method calculated the dose using a publicly available Fluka Monte Carlo-derived dose kernel (MCK) calculation (used as ground truth). We investigated 3D Gamma passing rates and several dosimetric parameters.RESULTSA total of 3%/3 mm 3D gamma passing rates averaged 99.3% for the VSV and 78.9% for LDM. Compared to the MCK distribution, the differences for combined target GTV V_70Gy and normal liver and/or lobe mean doses were small. Larger differences were seen in GTV mean doses and D₉₅, likely due to large dose gradients in the treated regions combined with differences in dose kernel, dose grid and finite volume effects.CONCLUSIONSThe MIM SurePlan Liver Y90 VSV algorithm agreed well with the MCK calculation for patients treated with Y-90 microspheres based on the gamma analysis and several dosimetric parameters. Larger dosimetric differences in lesion mean doses and D₉₅ suggests that these metrics are less robust to changes in calculation grid location and finite volume effects for small lesions.     

Roentgen ray dose for effective aluminum filtering

The aluminium equivalent of the effective prefiltration of an X-ray tube assembly varies significantly with the tube voltage. Neglecting this fact has up to now led to considerable differences in stated dose values. Corrected values for the whole appropriate range of tube voltages and Al filtrations are indicated.     

Biphasic and monophasic repair: comparative implications for biologically equivalent dose calculations in pulsed dose rate brachytherapy of cervical carcinoma

Objective:

To consider the implications of the use of biphasic rather than monophasic repair in calculations of biologically-equivalent doses for pulsed-dose-rate brachytherapy of cervix carcinoma.

Methods:

Calculations are presented of pulsed-dose-rate (PDR) doses equivalent to former low-dose-rate (LDR) doses, using biphasic vs monophasic repair kinetics, both for cervical carcinoma and for the organ at risk (OAR), namely the rectum. The linear-quadratic modelling calculations included effects due to varying the dose per PDR cycle, the dose reduction factor for the OAR compared with Point A, the repair kinetics and the source strength.

Results:

When using the recommended 1 Gy per hourly PDR cycle, different LDR-equivalent PDR rectal doses were calculated depending on the choice of monophasic or biphasic repair kinetics pertaining to the rodent central nervous and skin systems. These differences virtually disappeared when the dose per hourly cycle was increased to 1.7 Gy. This made the LDR-equivalent PDR doses more robust and independent of the choice of repair kinetics and α/β ratios as a consequence of the described concept of extended equivalence.

Conclusion:

The use of biphasic and monophasic repair kinetics for optimised modelling of the effects on the OAR in PDR brachytherapy suggests that an optimised PDR protocol with the dose per hourly cycle nearest to 1.7 Gy could be used. Hence, the durations of the new PDR treatments would be similar to those of the former LDR treatments and not longer as currently prescribed.

Advances in knowledge:

Modelling calculations indicate that equivalent PDR protocols can be developed which are less dependent on the different α/β ratios and monophasic/biphasic kinetics usually attributed to normal and tumour tissues for treatment of cervical carcinoma.The use of low-dose-rate (LDR) brachytherapy (BT) for cervical cancer is being phased out and replaced by either high-dose-rate (HDR) or pulsed-dose-rate (PDR) BT [1–4]. At the Christie Hospital in Manchester, UK, PDR has been implemented in place of LDR for the BT component of a combined external beam (EB) and BT treatment of cervical carcinoma [4]. The Groupe Europeen de Curietherapie–European Society for Radiotherapy & Oncology (GEC-ESTRO) recommendations [5] were used to calculate the equivalent prescribed doses of PDR BT compared with those of the formerly used LDR-BT protocol [6]. Those guidelines use generic values of linear-quadratic parameters and monophasic repair kinetics. For the organs at risk (OARs), biphasic repair has become a more accurate characterisation of the repair kinetics. This is based on clinical evidence of a slow repair component for skin telangiectasia [7], oral mucosa [8] and subcutaneous fibrosis [9]. There is also more detailed knowledge of the two fast and slow components for clonogenic cells in mouse kidney [10], rat spinal cord paralysis [11], mouse pneumonitis [12,13] and pig skin early reactions [14].PDR BT uses cycles (or pulses) of 0.5–1.0 Gy given usually at 1–1.5-h intervals, and dose distributions using PDR or LDR can be made virtually identical [15]. It was shown that 1 Gy cycles at intervals of 1–3 h (varied among animal studies) resulted in similar biological effects from the same total doses delivered continuously at 0.50–0.75 Gy per hour. Higher doses per cycle and different cycle intervals resulted in deviations from equivalence because of biphasic repair, in particular for late-reacting tissues [16,17]. The therapeutic ratio of PDR vs LDR depends on cycle dose size and interval and tissue repair characteristics [α/β ratios and repair half-times (T_1/2)]. In normal tissues with a T_1/2<0.5-h component, PDR may be more damaging than LDR [18], but the effect should be reduced if the dose per cycle is <1 Gy [16,19].The present study reports calculations of LDR-equivalent PDR doses using biphasic vs monophasic repair kinetics for both the tumour and for the OAR, and the consequent implications.     

Entrance dose measurement: a simple and reliable technique.

Verification of tumor dose for patients undergoing external beam radiotherapy is an important part of quality assurance programs in radiation oncology. Among the various methods available, entrance dose in vivo is one reliable method used to verify the tumor dose delivered to a patient. In this work, entrance dose measurements using LiF:Mg;Ti and LiF:Mg;Cu;P thermoluminescent dosimeters (TLDs) without buildup cap was carried out. The TLDs were calibrated at the surface of a water equivalent phantom against the maximum dose, using 6- and 10-MV photon and 9-MeV electron beams. The calibration geometry was such that the TLDs were placed on the surface of the "solid-water" phantom and a calibrated ionization chamber was positioned inside the phantom at calibration depth. The calibrated TLDs were then utilized to measure the entrance dose during the treatment of actual patients. Measurements were also carried out in the same phantom simultaneously to check the stability of the system. The dose measured in the phantom using the TLDs calibrated for entrance dose to 6-and 10-MV photon beams was found to be close to the dose determined by the treatment planning system (TPS) with discrepancies of not more than 4.1% (mean 1.3%). Consequently, the measured entrance dose during dose delivery to the actual patients with a prescribed geometry was found to be compatible with a maximum discrepancy of 5.7% (mean 2.2%) when comparison was made with the dose determined by the TPS. Likewise, the measured entrance dose for electron beams in the phantom and in actual patients using the calibrated TLDs were also found to be close, with maximum discrepancies of 3.2% (mean 2.0%) and 4.8% (mean 2.3%), respectively. Careful implementation of this technique provides vital information with an ability to confidently accept treatment algorithms derived by the TPS or to re-evaluate the parameters when necessary.     

90Y树脂微球选择性内放射治疗放射防护检测与剂量评估

目的对90Y树脂微球选择性内放射治疗过程进行放射防护检测和剂量评估,为放射防护工作提供参考。方法对90Y树脂微球介入手术治疗各操作环节和患者体表的外照射水平进行检测,估算相关人员的受照剂量水平。结果90Y树脂微球分装及转运过程的剂量率水平为1.12~454μSv/h,手术操作过程为2.06~58.2μSv/h;3名患者术后0.5 h,体表5 cm和1 m处的剂量率分别为22.7~64.1和0.82~2.55μSv/h。按照每年200例患者的工作量,90Y树脂微球药物操作对工作人员年个人有效剂量贡献为0.12~1.03 mSv/年,术后患者对公众、家属及陪护志愿者的个人有效剂量贡献为0.02~0.24 mSv/年。结论在患者治疗、护理和出院过程中,工作人员、陪护志愿者和公众的照射剂量均低于(GB 18871-2002«电离辐射防护与辐射源安全基本标准»)中的剂量限值和医疗机构设定的管理目标值。     

The midline dose distribution for a three-field radiotherapy technique.

At the University of Florida, head and neck cancer often is irradiated using parallel opposed lateral fields (with inferior borders slanted superiorly) and an anterior low neck field. A common criticism is that overlap may occur at the match-line junction of the three fields, resulting in an increased risk of radiation myelitis. One setup for treatment of the oropharynx and two for the larynx were irradiated in an anthropomorphic head and neck phantom made of tissue-equivalent polyacrylamide gel with a two-dimensional thermoluminescent dosimeter array in its sagittal midplane. The results showed that no excess radiation dose was measured at the junction of the three fields. The "spinal cord dose," as percentage of dose to the central axis of the primary field, was as follows: oropharynx setup, 15% to 100%; larynx setup with midline tracheal block, 10% to 90%; larynx setup without tracheal block, 10% to 90%. In conclusion, the University of Florida three-field technique for head and neck cancer produces no measured increase in dose at field junctions.     

Challenges for managing the cumulative effective dose for patients

Notwithstanding that 100 mSv is not a threshold for radiation effects, cumulative effective dose (CED) for patients of ≥100 mSv derived from recurrent imaging procedures with ionising radiation has been recently the topic of several publications. The International Commission on Radiological Protection has alerted on the problems to use effective dose for risk estimation in individual patients but has accepted to use this quantity for comparison the relative radiation risks between different imaging modalities. A new International Commission on Radiological Protection document on the use of effective dose (including medicine), is in preparation. Recently published data on the number of patients with CED ≥100 mSv ranged from 0.6 to 3.4% in CT and around 4% in interventional radiology. The challenges to manage the existing situation are summarised. The main aspects identified are: 1) New technology with dose reduction techniques. 2) Refinements in the application of the justification and optimisation for these groups of patients. 3) Patient dose management systems with alerts on the cumulative high doses. 4) Education on the proper use of cumulative effective dose for referrers and practitioners including information for patients. 5) Future research programmes in radiation biology and epidemiology may profit the patient dose data from the groups with high cumulative dose values.

Cumulative effective doses for patients derived from recurrent imaging procedures with ionising radiation has been a topic of interest in the scientific literature since many years. However, its attention has been heightened in the last year with numerous publications, stating that at 100 mSv of effective dose, many organs may receive doses of 100 mGy or more.It was in 2009 when on one hand, IAEA announced its smart card project to track radiation exposure history of patients and on other hand a paper by Sodickson et al provided data on patients who underwent recurrent diagnostic CT examinations over the prior 22 years.^1,2 The approach was well received by the professional community³ but with the fear of its misuse.^4,5 In 2012, Durand et al⁴ considered it “dangerous” to use this approach for cancer risk estimations. Sometimes, it may cause patients or poorly informed physicians “to irrationally decide against medically indicated CT scans.” The authors remind the International Commission on Radiological Protection (ICRP) advice on this issue: “The use of effective dose is not appropriate for estimating the risk to an individual patient resulting from a diagnostic X-ray exam.”In 2014, Whalsh et al revisited the topic in a Commentary in the British Journal of Radiology focussing on the justification.⁶ One of the main aspects was if the radiation risks from previous examinations should affect the future procedures. The authors indicate that allowing cumulative dose estimates to influence whether a patient should get a scan would be equivalent to introducing dose limits for patients and, rather than improving patient safety, would unnecessarily restrict access to radiation-based diagnostic examinations.In the first ever multinational survey among referring physicians from 28 countries, the support for a system that provides radiation exposure history of the patient was demonstrated.⁷ A study from Finland covering 33 institutions in the Helsinki-Uusimaa Hospital District indicated that patient-specific justification and optimisation becomes possible using the tracking of radiologic procedures and radiation dose of individual patients.⁸Some recent papers have collected data to estimate number of patients with cumulative effective doses (CED) ≥100 mSv derived from recurrent CT examinations alone.^3,9,10 The papers estimated that around 0.9 million patients with CED ≥100 mSv are likely occurring every year globally.^3,9 The dose management systems used in some of the hospitals involved in these studies were able to calculate organ and effective doses allowing the analysis of the cumulative doses in the patients. In one of the papers,⁹ data were collected from 324 hospitals involving a total of 488 CT scanners in USA and 1 country in Central Europe (2.5 million patients with 4.8 million CT exams). The patients with CED ≥100 mSv vary from 0.64% to 3.4% in the different hospitals or institutions included in the study. Another paper contains the data of about 70,000 patients from 20 countries: 18 of them in Europe, 1 in Africa, and 1 in Asia with an average of 0.65% of 702,205 patients undergoing CT scans with CED ≥100 mSv.³The IAEA convened a meeting in 2019 with participants from 26 countries, representatives of various organisations, and experts in radiology, medical physics, radiation biology, and epidemiology.³ The meeting led to a Call for Action stating the need for urgent actions by all stakeholders to address the issue of high cumulative radiation doses to patients. The actions include development of appropriateness criteria/referral guidelines by professional societies for patients who require recurrent imaging studies, development of CT machines with lower radiation dose than today by manufacturers, and development of policies by risk management organisations to enhance patient radiation safety. Alert values for cumulative radiation exposures of patients should be set up and introduced in dose monitoring systems.³In another recent study with interventional radiology practices, Xinhua et al studied 25,253 patients who underwent 46,491 fluoroscopy-guided procedures (from January 2010 to January 2019). It was concluded that in 4% of them, the CED was ≥100 mSv and median age of the first procedures was 60 years. Around 80% patients underwent all of their procedures within 365 days.¹¹The automatic patient dose registries are able to set alarms informing clinicians in special situations. The referral criteria for patients with several (or many) previous imaging procedures involving moderated or high doses may be revisited¹⁰ and specific optimisation strategies could be considered in some cases. The European Working Group on “Dose Management” launched by the Eurosafe Imaging from the European Society of Radiology recommended setting alert trigger levels, to be able to send these alerts to professionals and to store and display cumulative patient dose values.¹²In a very recent paper Kachelrieß and Rehani identified several technology-related factors of the CT systems that can be used by manufacturers of CT equipment to achieve substantial reduction in radiation dose to the patients while maintaining or improving the image quality¹³ in line with need identified in recent papers.^3,9,10 The advances in the new systems used for interventional procedures may also allow remarkable decreases in patient doses.According to the ICRP recommendations, we should not use the radiation protection quantity “effective dose” to estimate radiation risks for individual patients.¹⁴ A new ICRP document on the use of effective dose (including medicine) is in preparation. Nevertheless, effective dose is useful to compare the doses and relative risks of different imaging modalities (e.g. CT, fluoroscopy-guided interventional procedures and nuclear medicine). This comparison is also useful for referrers when they balance the benefits and risks of the different examinations before suggesting one imaging modality.⁷ The quantity effective dose may also be useful to inform patients when they ask on the meaning of the different radiation units that may be included in the clinical reports: “mGy.cm” for CT, or Gy.cm² for interventional procedures, or MBq of a certain radiopharmaceutical in nuclear medicine procedures.The use of effective dose may have important limitations as the uncertainty in the calculation, the different implications on the patient risk depending on the age and gender, the radiation dose for the different organs and tissues may be distinct despite having the same value for effective dose. In many cases, effective doses can be estimated from a single conversion factor multiplying the practical radiation unit offered by the X-ray system or the activity of the radiopharmaceutical, and with this approach, the uncertainty may be much higher than using Monte Carlo calculations.The five main aspects to consider in the management of the cumulative effective doses could be summarised as follow:

1. Impact of technology: New technology with dose reduction techniques, especially for the high dose imaging modalities (CT, Interventional and PET-CT)^15,16 should be developed and promoted. Moreover, when available in health centres, they must be used for the high dose procedures. COCIR, the European Trade Association representing the medical imaging, radiotherapy, health ICT and electromedical industries, is doing an important effort to reduce the age of the imaging equipment in Europe to allow introducing the low dose techniques.¹⁷
2. Justification and optimisation: Professional societies could develop appropriateness criteria for patients who need series of imaging studies using ionising radiation. This group of patients may require some re-evaluation of the justification criteria, and improvements in the optimisation strategies for future procedures.
3. Patient dose management systems: Some alerts based on the cumulative dose should be included in the dose management systems. If effective doses are not available, other dosimetric quantities available from the X-ray systems may be used. However, these alerts should not be used to discourage any procedure if it is medically indicated. The clinical decision support systems may incorporate these alerts. The European Directive 2013/59/Euratom requires estimation of population doses from medical exposures and these data are required for the UNSCEAR surveys.
4. Proper use of cumulative dose: Education on the proper use of cumulative effective dose should be included in the training programmes for referrers and practitioners including the proper information for patients. In some cases, patients may accept a small additional radiation risk for a fast diagnosis or a second opinion, and this may be ethically acceptable as part of the autonomy and rights of the patient.¹⁸
5. Data for research: The future research programmes in radiation biology and epidemiology could use the data from the groups of patients with high dose values collected by the dose management systems allowing to estimate organ and effective doses.

     

How to estimate effective dose for CT patients

• Rehani et al provide important insight into the status quo of CT dose and call an urgent attention to the high-dose group receiving over 100 mSv. • It is crucial to clearly understand the calculation algorithm of effective dose behind the CT dose reporting systems and potential uncertainties.     

Linear quadratic model and biologically equivalent dose for single fraction treatments.

The linear quadratic model has been used to calculate the biologically equivalent dose for single fraction treatments. Our calculations suggest that for late reacting tissue, such as the brain, a single fraction of 1440 cGy is equivalent to a conventional treatment of 5000 cGy in 25 fractions.