Daily online adaptive magnetic resonance image (MRI) guided stereotactic body radiation therapy for primary renal cell cancer

Stereotactic body radiotherapy (SBRT) has demonstrated promising outcomes for patients with early-stage, medically inoperable, primary renal cell carcinoma (RCC) in large multi-institutional studies and prospective clinical trials. The traditional approach used in these studies consisted of a CT-based planning approach for target and organ-at-risk (OAR) volume delineation, treatment planning, and daily treatment delivery. Alternatively, MRI-based approaches using daily online adaptive radiotherapy have multiple advantages to improve treatment outcomes: (1) more accurate delineation of the target volume and OAR volumes with improved soft tissue visualization; (2) gated beam delivery with biofeedback from the patient; and (3) potential for daily plan adaptation due to changes in anatomy to improve target coverage, reduce dose to OARs, or both. The workflow, treatment planning principles, and aspects of treatment delivery specific to this technology are outlined using a case example of a patient with an early-stage RCC of the right kidney treated with MRI-guided SBRT using daily adaptive treatment to a dose of 42 Gy in 3 fractions.     

Interobserver variability in target volume delineation for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer

Objectives:Quantify target volume delineation uncertainty for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer. Define optimal imaging sequences for target delineation.Methods:Six experienced radiation oncologists delineated clinical target volumes (CTVs) on CT and 2D and 3D-MRI in three patients with rectal cancer, using consensus contouring guidelines. Tumour GTV (GTVp) was also contoured on MRI acquired week 0 and 3 of radiotherapy. A STAPLE contour was created and volume and interobserver variability metrics were analysed.Results:There were statistically significant differences in volume between observers for CT and 2D-MRI-defined CTVs (p < 0.05). There was no significant difference between observers on 3D-MRI. Significant differences in volume were seen between observers for both 2D and 3D-MRI-defined GTVp at weeks 0 and 3 (p < 0.05). Good interobserver agreement (IOA) was seen for CTVs delineated on all imaging modalities with best IOA on 3D-MRI; median Conformity index (CI) 0.74 for CT, 0.75 for 2D-MRI and 0.77 for 3D-MRI. IOA of MRI-defined GTVp week 0 was better compared to CT; CI 0.58 for CT, 0.62 for 2D-MRI and 0.7 for 3D-MRI. MRI-defined GTVp IOA week three was worse compared to week 0.Conclusion:Delineation on MRI results in smaller volumes and better IOA week 0 compared to CT. 3D-MRI provides the best IOA in CTV and GTVp. MRI-defined GTVp on images acquired week 3 showed worse IOA compared to week 0. This highlights the need for consensus guidelines in GTVp delineation on MRI during treatment course in the context of dose escalation MRI-guided rectal boost studies.Advances in knowledge:Optimal MRI sequences for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer have been defined.     

Random variation in rectal position during radiotherapy for prostate cancer is two to three times greater than that predicted from prostate motion

Objective:

Radiotherapy for prostate cancer does not explicitly take into account daily variation in the position of the rectum. It is important to accurately assess accumulated dose (D_A) to the rectum in order to understand the relationship between dose and toxicity. The primary objective of this work was to quantify systematic (Σ) and random (σ) variation in the position of the rectum during a course of prostate radiotherapy.

Methods:

The rectum was manually outlined on the kilo-voltage planning scan and 37 daily mega-voltage image guidance scans for 10 participants recruited to the VoxTox study. The femoral heads were used to produce a fixed point to which all rectal contours were referenced.

Results:

Σ [standard deviation (SD) of means] between planning and treatment was 4.2 mm in the anteroposterior (AP) direction and 1.3 mm left–right (LR). σ (root mean square of SDs) was 5.2 mm AP and 2.7 mm LR. Superior–inferior variation was less than one slice above and below the planning position.

Conclusion:

Our results for Σ are in line with published data for prostate motion. σ, however, was approximately twice as great as that seen for prostate motion. This suggests that D_A may differ from planned dose in some patients treated with radiotherapy for prostate cancer.

Advances in knowledge:

This work is the first to use daily imaging to quantify Σ and σ of the rectum in prostate cancer. σ was found to be greater than published data, providing strong rationale for further investigation of individual D_A.Radiotherapy is a clinically effective and cost effective curative treatment for prostate cancer. The major dose-limiting organ at risk is the rectum, located posterior to the prostate. In our centre, inverse-planned intensity-modulated radiotherapy (IMRT) has been delivered to the prostate since 2007.¹ We use the TomoTherapy® Hi-Art® System (TomoTherapy Inc., Madison, WI), along with other machines. This system delivers image-guided IMRT (IG-IMRT).For standard treatment, a kilo-voltage (kV) CT scan is acquired for radiotherapy planning. When the patient comes for treatment each day (usually 20–37 treatments), a lower-resolution longitudinally shorter mega-voltage (MV) CT scan is acquired. The patient is then moved, so that the position of the prostate on the MV scan matches its position on the kV scan, and the treatment is delivered.¹ At present, no allowance is made for the position of the rectum on the MV CT scan. If this were to be different at the time of treatment compared with the time of planning, then the dose delivered to the organ that day (“delivered dose”) might differ from the planned dose.A variety of studies have demonstrated rectal motion in patients treated with radiotherapy for prostate cancer.^2–9 These studies have been small and have tended to rely on a limited number of images acquired during treatment. Several studies have confirmed differences between planned and delivered doses to the rectum.^2,6,7,10,11 These early data support the hypothesis that accumulated dose (D_A) to the rectum over the course of treatment differs from the planned dose in some patients. Development of methods to accurately estimate D_A is critical for a better understanding of the relationship between dose and effect. This would allow us to advance radiotherapy for the individual patient and is an important radiotherapy research priority.^12–14A major impediment to progress is the need for an automated system to track the material elements of the rectum from day to day, both in order to calculate delivered dose in a timely fashion and to do so for a significant number of patients. We carried out the present study in order to understand the location of rectal voxels during a course of prostate radiotherapy, by parameterizing this organ. We tracked the position of the rectum from day to day over the course of treatment and compared the position each day with that at the time of planning. It was important to describe the daily position and to quantify differences within and between patients.     

The use of molecular imaging combined with genomic techniques to understand the heterogeneity in cancer metastasis

Tumour heterogeneity has, in recent times, come to play a vital role in how we understand and treat cancers; however, the clinical translation of this has lagged behind advances in research. Although significant advancements in oncological management have been made, personalized care remains an elusive goal. Inter- and intratumour heterogeneity, particularly in the clinical setting, has been difficult to quantify and therefore to treat. The histological quantification of heterogeneity of tumours can be a logistical and clinical challenge. The ability to examine not just the whole tumour but also all the molecular variations of metastatic disease in a patient is obviously difficult with current histological techniques. Advances in imaging techniques and novel applications, alongside our understanding of tumour heterogeneity, have opened up a plethora of non-invasive biomarker potential to examine tumours, their heterogeneity and the clinical translation. This review will focus on how various imaging methods that allow for quantification of metastatic tumour heterogeneity, along with the potential of developing imaging, integrated with other in vitro diagnostic approaches such as genomics and exosome analyses, have the potential role as a non-invasive biomarker for guiding the treatment algorithm.Although continual improvements in diagnosis, surgical techniques and radiation oncology have together provided improved survival for many forms of human cancers, a majority of deaths from cancer are caused by the development and continuous growth of metastases that are resistant to conventional therapies. Similarly, although the use of systemic non-targeted and targeted adjuvant therapies has helped to prevent the spread of tumour cells from the primary site and is now a standard practice for many tumour types, the emergence of resistant disease continues to be a significant cause of patient mortality. These features provide an insight into the dynamic nature of the signalling network within the tumour cells,¹ and human cancers are now being increasingly recognized as heterogeneous, characterized by distinct pathological, genomic, clinical and therapeutic features.Nearly 150 years after the original theory of tumours originating from immature cells by Virchow,² innovative technological approaches unequivocally demonstrate the cellular heterogeneity of tumours, composed of distinct subpopulations of cancer cells within (“intra”) and between (“inter”) tumours of individual patients. These subpopulations are characterized by specific genetic and morphological profiles, representing the clonal selection and evolution of that tumour.^3,4 This heterogeneity provides a powerful internal mechanism through which tumour cells can ultimately escape environmental stresses, including oncological therapies, posing a considerable challenge for translational researchers.There is considerable evidence that the tumour microenvironment actively contributes to tumour heterogeneity.⁵ Arguably the best example of this is the “pre-metastatic niche”, defined as the creation of an ideal thriving environment for the primary tumour to “seed” to. Through the secretion of cytokines, chemokines and growth factors, the primary tumour “primes” a distal site to become an ideal niche/target organ, favourable for future metastatic colonization.⁶ Although in some cases the target organ is already primed for metastatic spread and many organs may have “seeding” of cells, only a few will take “root”.⁷ Increasing understanding of tumour heterogeneity demands an effort from researchers to establish and understand pre-metastatic changes within distant organs and their major drivers.This new paradigm of cancer heterogeneity has yet to be fully assimilated into everyday patient management. It has been well documented with certain cancers that imaging signals can show phenotypic tumour heterogeneity and have clinical implications; for example, in radio-iodine imaging of metastatic thyroid cancer, some metastatic lesions may not take up radio-iodine and therefore will be unaffected by radio-iodine therapy. However, for the majority of tumours, biopsies remain the standard of care for assessing tumour biology but cannot be expected to represent the entirety of a tumour in this tumour heterogenic era.⁴ Many physicians advocate the re-biopsy of metastatic disease at re-presentation for histological analysis and comparison with the primary, in an attempt to improve the choice of therapy upon relapse, having taken into account, for instance, intertumoral heterogeneity between the primary and metastatic disease.⁸ Repeated biopsy of tumour tissue is invasive, may be practically difficult, has resource implications and is clearly confounded by intratumoral heterogeneity. These shortcomings give huge potential to the recent advances in molecular imaging, which have the ability to visualize and quantify heterogeneity of tumour receptor expression, metabolism, apoptosis, blood flow or structure, non-invasively over time, i.e. at baseline and to assess response to treatment.Owing to space constraints, we can only select a subset of imaging techniques for illustration purposes; a more comprehensive précis of the different image modalities has been reviewed elsewhere.⁸     

Does a too risk-averse approach to the implementation of new radiotherapy technologies delay their clinical use?

Radiotherapy is a generally safe treatment modality in practice; nevertheless, recent well-reported accidents also confirm its potential risks. However, this may obstruct or delay the introduction of new technologies and treatment strategies/techniques into clinical practice. Risks must be addressed and judged in a realistic context: risks must be assessed realistically. Introducing new technology may introduce new possibilities of errors. However, delaying the introduction of such new technology therefore means that patients are denied the potentially better treatment opportunities. Despite the difficulty in quantitatively assessing the risks on both sides of the possible choice of actions, including the “lost opportunity”, the best estimates should be included in the overall risk–benefit and cost–benefit analysis. Radiotherapy requires a sufficiently high level of support for the safety, precision and accuracy required: radiotherapy development and implementation is exciting. However, it has been anxious with a constant awareness of the consequences of mistakes or misunderstandings. Recent history can be used to show that for introduction of advanced radiotherapy, the risk-averse medical physicist can act as an electrical fuse in a complex circuit. The lack of sufficient medical physics resource or expertise can short out this fuse and leave systems unsafe. Future technological developments will continue to present further safety and risk challenges. The important evolution of radiotherapy brings different management opinions and strategies. Advanced radiotherapy technologies can and should be safely implemented in as timely a manner as possible for the patient groups where clinical benefit is indicated.Whilst the statistics confirm that radiotherapy is a generally safe treatment modality in practice,¹ recent well-reported accidents and incidents also confirm its potential risks.² These necessitate careful approaches to testing, implementation, commissioning and quality assurance (QA) throughout, building in safety and radiation protection at every level. This needs appropriate time and resource. However, there is an argument that too strong a focus on these issues can potentially overestimate the risks and lead to a too risk-averse approach of overtesting and/or lack of confidence. This, in turn, may obstruct or delay the introduction of new technologies and treatment strategies/techniques into clinical practice. Considering the significant improvements in possible treatment methods and the potential for improved patient outcomes, there is a present feeling among some professionals that such delays mean that patients are denied timely access to these better care possibilities. This may vary with national health system situations or local circumstances in a particular centre.After the last few decades of very rapid evolution in radiotherapy technology and techniques, we may have reached a critical situation that divides professional opinion. Wide and rapid availability of advanced techniques to the relevant patient groups is required, to support maximum benefit. However, this must be provided within an optimized and appropriate safety and radiation protection testing framework, which is sufficiently, but not overly, risk-averse. The occurrence of accidents, resulting in injury or death of one or more patients, continues to challenge professionals to find the correct balance. These issues were aired in a recent debate at the ESTRO meeting in Vienna (April 2014), summarized here.     

21 years of Biologically Effective Dose

In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for “biologically equivalent dose”, from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be “triangulated” to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion “How Fractionation Really Works”. BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation.In 1989 the British Journal of Radiology (BJR) published an article [1] that introduced the term BED, biologically effective dose, as a linear quadratic (LQ)-based formula with an overall time factor included, to replace Dr Frank Ellis''s (1969) nominal standard dose (NSD) and the Orton and Ellis (1973) time–dose factor (TDF) tables.(1)Where n fractions of d Gy are given in an overall time of T days and tumour repopulation doesn''t start until day Tk (using k for kick-off, or onset, of the delayed repopulation during fractionated irradiation).Dr Ellis had designed NSD as a much-needed concept, distinct from physical dose, because dose alone obviously fails to represent the effect on biological tissues if it is delivered in one instead of 30 daily fractions, or at a different dose rate or radiation quality. NSD was for normal tissues only; repopulation had been discovered in tumours in rats and mice but was thought not to occur in human tumours during continued “daily” irradiation, until nearly a decade later (“Labelling indices go to zero...” Tubiana, oral comment in a conference in Rome, 1969). The main contribution of BED was just to add a simple overall time factor on to the equally simple LQ equation, log cell kill = αd+ βd², which had been in regular, but not universal, use in radiotherapy since before 1980. Somehow, BED stuck and continues to be useful. Does it need modifying yet? Its record, of mainly avoiding accidental overdoses for late complications, has remained intact for nearly 30 years because those effects of late complications didn''t depend on overall time, but only on dose-per-fraction if intervals between fractions were more than 6 h.     

Locally advanced cervical cancer in renal transplant patients: A dilemma between control and toxicity

PurposeTreatment of locally advanced cervical cancer in patients with a renal graft requires precautions. The graft is usually in a pelvic position, close to the clinical target volume (CTV). Preserving the graft while ensuring local control is a challenge we have faced in two occasions. We report our experience.Methods and MaterialsWe report the cases of 2 patients treated at our institution with a modified workup and therapeutic approach compared with our standard approach. The clinical and technical aspects of both treatments were systematically reviewed and contrasted with reports previously cited in the literature.ResultsThe first patient received external beam conformal radiotherapy (total dose: 30 Gy in the pelvis) followed by two sessions of MRI-guided brachytherapy (2 × 15 Gy to 90% of the intermediate risk CTV). The second one received pelvic intensity-modulated radiation therapy (total dose: 45 Gy) followed by MRI-guided brachytherapy delivering 15 Gy to 90% of the intermediate risk CTV. Both patients had a complete response and were still in remission more than 2 years after treatment while retaining their graft. No severe late toxicity was reported.ConclusionsExternal beam radiotherapy followed by brachytherapy is feasible in locally advanced cervical cancer, despite the presence of a kidney graft near the targets. Image-guided adaptive brachytherapy allowed an accurate evaluation of the dose distribution, reaching the recommended treatment thresholds with optimal protection of the graft.     

Intensity modulated proton therapy

Intensity modulated proton therapy (IMPT) implies the electromagnetic spatial control of well-circumscribed “pencil beams” of protons of variable energy and intensity. Proton pencil beams take advantage of the charged-particle Bragg peak—the characteristic peak of dose at the end of range—combined with the modulation of pencil beam variables to create target-local modulations in dose that achieves the dose objectives. IMPT improves on X-ray intensity modulated beams (intensity modulated radiotherapy or volumetric modulated arc therapy) with dose modulation along the beam axis as well as lateral, in-field, dose modulation. The clinical practice of IMPT further improves the healthy tissue vs target dose differential in comparison with X-rays and thus allows increased target dose with dose reduction elsewhere. In addition, heavy-charged-particle beams allow for the modulation of biological effects, which is of active interest in combination with dose “painting” within a target. The clinical utilization of IMPT is actively pursued but technical, physical and clinical questions remain. Technical questions pertain to control processes for manipulating pencil beams from the creation of the proton beam to delivery within the patient within the accuracy requirement. Physical questions pertain to the interplay between the proton penetration and variations between planned and actual patient anatomical representation and the intrinsic uncertainty in tissue stopping powers (the measure of energy loss per unit distance). Clinical questions remain concerning the impact and management of the technical and physical questions within the context of the daily treatment delivery, the clinical benefit of IMPT and the biological response differential compared with X-rays against which clinical benefit will be judged. It is expected that IMPT will replace other modes of proton field delivery. Proton radiotherapy, since its first practice 50 years ago, always required the highest level of accuracy and pioneered volumetric treatment planning and imaging at a level of quality now standard in X-ray therapy. IMPT requires not only the highest precision tools but also the highest level of system integration of the services required to deliver high-precision radiotherapy.The practice of proton radiotherapy covers 50 years since the first proton patient at the Berkeley Lawrence Livermore Laboratory (Berkeley, CA). In that period, a few post-research proton accelerators have been transformed into semi-clinical facilities and commenced treatments. One such facility at the Harvard Cyclotron Laboratory (Cambridge, MA) had a 160 MeV accelerator well suited for the treatment of cranial neoplasms¹ in parallel with similar practice in Sweden,² eyes³ and large field treatments.⁴ These sites were managed in three semi-independent clinical programmes that persist today at the F H Burr Proton Therapy Center at the Massachusetts General Hospital in Boston.The large field programme required the development of proton field scattering and energy modulation techniques to achieve uniform fields and spread-out Bragg peak modulated (SOBP) fields of constant penetration range and modulation. The large field programme was only possible after the introduction of CT to model these fields, with apertures and range compensators to control the lateral extent and penetration around the three dimensional (3D) target volume extent as identified on CT.^5,6 The fields were created by mechanical means, which allowed their early clinical use in the absence of electronic controls.The practice of SOBP proton radiotherapy required all the quality management features of modern radiotherapy: volumetric treatment planning, accurate immobilization and verification and on-treatment imaging. The practice of SOBP proton radiotherapy established the axiom of radiotherapy: accuracy improves healthy tissue dose avoidance and target coverage and higher target dose achieves cure. The promise and realization of cure was demonstrated in patients with otherwise incurable chordoma.^7,8 The practice of SOBP proton radiotherapy persists today, and most patients are still treated with SOBP fields.The primary proton beam out of an accelerator is, in the absence of scattering materials, a collimated well-circumscribed “pencil” beam and easily manipulated by electromagnetic means. The proton pencil beam allows dose modulation in the patient with four degrees of freedom: number of protons (NP) to control the local dose deposition, energy to control the local penetration and magnetic deflection to control the off-axis position. The size of the pencil beam is a fifth degree of freedom although not readily available. Spot size control would positively impact delivery efficiency, as “larger” spots can deliver more protons in vivo given safety constraints (see section on back-of-the-envelope calculations), albeit possibly with an increase of integral dose. The spot size is typically characterized by the gaussian width σ of the pencil beam lateral intensity distribution and quantified in air at the isocentre.Proton pencil beams thus have one (or two) more degrees of freedom, penetration dose modulation, compared with intensity modulated radiotherapy [IMRT or volumetric arc therapy (VMAT)] fields. Proton fields (at dose equilibrium) exhibit the charged-particle Bragg peak depth dose characterized by a sharp dose increase, the “spot” at the energy characteristic penetration range and absence of dose beyond this distal range. The full electromagnetic control of the heavy-charged-particle pencil beam combined with the Bragg peak and absence of distal dose makes pencil beam scanning (PBS) an easier and more powerful delivery system for modulated therapy compared with the mechanical multileaf collimators (MLCs) required in X-ray IMRT (or VMATs), as well as the creation of SOBP fields.We use the label “pencil beam (spot) scanning” (where “spot” refers to the location of the Bragg peak in the patient) for the technical mode of delivery and the label “intensity modulated proton therapy (IMPT)” for the clinical mode of PBS where each individual field is allowed to assume an arbitrary dose distribution, and only the full set of fields in the treatment fraction, as in IMRT, assumes the desired dose fraction distribution. Other clinical modes exist, but IMPT is simply the desired, although presumably the most challenging, goal of PBS and our focus here.Clinical PBS was systematically developed and applied at the Paul Scherrer Institute in Villigen Switzerland.^9,10 Their original clinical system consisted of a very compact isocentric gantry combined with a couch and a scanning system that scanned a single line of pencil beams (i.e. irradiating planes in the patient) and thus required patient movement to accommodate multiple planes. The gantry transported protons at a fixed set of constant energies, whose energy at the patient was modulated by a set of mechanical degraders. The system implemented full modulation of all pencil beam parameters, albeit by considerable mechanical means. This unique design demonstrates, amongst other things, the possible variability of delivery systems, although all modern systems employ near-complete electromagnetic modes to implement scanning. Nevertheless, modern system designs and choice of components will influence the technical and clinical quality of scanning.As stated, technical, physical and clinical challenges remain for the effective clinical deployment of IMPT. A pre-IMPT point–counterpoint argued that while IMPT may in-silico outperform IMRT, its expense and complexity exceeds that of IMRT and that of SOBP treatments.¹¹ A rebuttal¹² argued that IMPT will become generally available and its use necessary to fully exploit the dosimetric advantages of proton radiotherapy. Indeed, IMPT (or more precisely PBS) delivery technology is now standard and is, in fact, more cost-effective and simpler in terms of commissioning¹³ and operation compared with other delivery modes of proton radiotherapy. Overall costs, depending on accounting, are generally assumed to be twice that of IMRT and remain an issue.The sections below elaborate on these individual issues. We argue that clinical IMPT requires a system approach whereby the current (i.e. in X-ray radiotherapy) individuality of treatment management components must be integrated to achieve optimal performance. Optimal performance combined with exploitation of dosimetric advantages, in turn, can lead to an improved cost profile. The hypothesis is if IMRT is cost-effective in some end point (see, for example, Kohler et al¹⁴), then IMPT can exceed this cost-effectiveness criterion through additional dose advantages or through increased performance such as may be achieved through hypofractionation.     

MRI-based pre-planning in patients with cervical cancer treated with three-dimensional brachytherapy

Objective

The aim of this study was to analyse the feasibility and determine the benefits of MRI-based pre-planning with CT/MRI data fusion in patients with cervical cancer treated with radical radiotherapy.

Methods

Patients underwent MRI examination prior to external beam radiotherapy and prior to the first and fourth fraction of brachytherapy with applicators in place. Insertion of applicators at the radiology department was performed under paracervical anaesthesia. The benefit of MRI pre-planning was determined by comparing conventional treatment planning with dose specification to “point A” and dose specification to 90% of the high-risk clinical target volume (HR-CTV D90). Tolerance of MRI evaluation with applicators, coverage of HR-CTV and dose–volume parameters for organs at risk (OAR) has been assessed in 42 brachytherapy procedures.

Results

Insertion of applicators at the radiology department was successful in all patients and there were no complications. The target dose was higher for MRI planning than for conventional planning (5.3 Gy vs 4.5 Gy). Maximum doses in the bladder and rectum were significantly lower (p<0.05) for MRI planning than for the conventional approach (6.49 Gy vs 7.45 Gy for bladder; 4.57 Gy vs 5.06 Gy for rectum). We found no correlation between the International Commission on Radiation Units (ICRU) point dose for OAR and the maximum dose in OAR. Nevertheless, a strong correlation between the maximum dose in OAR and the minimal dose in a volume of 2 cm³ has been observed.

Conclusion

MRI-based pre-planning with consecutive CT/MRI data fusion is feasible and safe, with the advantage of increasing the dose to the tumour and decreasing the dose to the organs at risk.Brachytherapy plays a major role in the therapeutic management of patients with cervical cancer [1-4]. Classical brachytherapy techniques used ²²⁶Ra introduced with an applicator. The Stockholm and Paris methods for intracavitary radiation were described as early as 1914 and 1919. Modern techniques are based on afterloading devices (¹³⁷Cs, ¹⁹²Ir) where application and irradiation are separated from each other. During the last three decades, the development of remote afterloading machines has enabled complete radiation protection. High dose rate (HDR) brachytherapy using remote afterloading systems has been widely accepted, particularly for the treatment of gynaecological tumours.Clinical approaches in brachytherapy are based on treatment principles established more than half a century ago. In patients with cervical cancer, treated with intracavitary brachytherapy, the dose is prescribed at a selected reference “point A”. This point is defined as a spot 2 cm lateral to the cervical canal and 2 cm superior to the ovoids. The dose for OAR is reported using individual points for the bladder and rectum. In clinical practice, dose calculations are often made from radiographs. In the late 1990s, MRI-guided adaptive brachytherapy was first introduced into treatment planning for brachytherapy. MRI allows tailoring of dose distribution according to the tumour topography while sparing critical adjacent organs [5-10]. Target volume definitions for MRI and recommendations for concepts in treatment planning have been published by the Gynaecological GEC-ESTRO Working Group [11-14]. The clinical impact of MRI usage in brachytherapy of cervical cancer was confirmed by Pötter et al [15] in 2007. Image-guided adaptive radiotherapy based on MRI has shown outstanding improvements in outcome: more than 90% local control and less than 5% major morbidity for locally advanced disease. Recently, Dimopoulos et al [16] showed an improvement in local control with image-guided brachytherapy and increasing dose in patients with cervical cancer.However, MRI is not routinely available in radiotherapy departments, and transport of patients from MRI units to radiotherapy departments is associated with a high risk of bleeding, perforation and significant changes in the position of applicators. As there was no MRI scanner available in our department, MRI evaluation with applicators in situ was incorporated into clinical practice by using MRI-based pre-planning with consecutive CT/MRI data fusion. This study aimed to evaluate the feasibility of applicator insertion under paracervical anaesthesia directly within the radiology department and to determine the benefit of CT and MRI data fusion for MRI-based treatment planning in comparison with the conventional planning approach.     

Endovascular treatment of aortoiliac aneurysms: From intentional occlusion of the internal iliac artery to branch iliac stent graft

Approximately 20%-40% of patients with abdominal aortic aneurysms can have unilateral or bilateral iliac artery aneurysms and/or ectasia. This influences and compromises the distal sealing zone during endovascular aneurysm repair. There are a few endovascular techniques that are used to treat these types of aneurysms, including intentional occlusion/over-stenting of the internal iliac artery on one or both sides, the “bell-bottom” technique, and the more recent method of using an iliac branch stent graft. In some cases, other options include the “snorkel and sandwich” technique and hybrid interventions. Pelvic ischemia, represented as buttock claudication, has been reported in 16%-55% of cases; this is followed by impotence, which has been described in 10%-17% of cases following internal iliac artery occlusion. The bell-bottom technique can be used for a common iliac artery up to 24 mm in diameter given that the largest diameter of the stent graft is 28 mm. There is a paucity of data and evidence regarding the “snorkel and sandwich” technique, which can be used in a few clinical scenarios. The hybrid intervention is comprised of a surgical operation, and is not purely endovascular. The newest branch stent graft technology enables preservation of the anterograde flow of important side branches. Technical success with the newest technique ranges from 85%-96.3%, and in some small series, technical success is 100%. Buttock claudication was reported in up to 4% of patients treated with a branch stent graft at 5-year follow-up. Mid- and short-term follow-up results showed branch patency of up to 88% during the 5-6-year period. Furthermore, branch graft occlusion is a potential complication, and it has been described to occur in 1.2%-11% of cases. Iliac branch stent graft placement represents a further development in endovascular medicine, and it has a high technical success rate without serious complications.     

Joint STFC Futures/BIR workshop “Cancer care: new detector and sensor technologies and their potential impact”, Harwell Oxford, 5–6 October 2011

The workshop “Cancer care: new detector and sensor technologies and their potential impact”, organised jointly by the Science and Technology Facilities Council (STFC) and the British Institute of Radiology, brought together representatives from the cancer community (clinicians, medical physicists, National Health Service representatives and general practitioners with an interest in cancer) and STFC-supported scientists involved in basic research in physics and technology. The workshop aimed to raise awareness of the cancer challenge, share knowledge and identify novel solutions in the area of detectors and sensors to addressing the cancer challenge. A further aim of this workshop was to commence discussion on the formation of new multidisciplinary community networks. The workshop identified the synergies between the two communities and the potential for developing new collaborative ideas and projects.     

What we know and what we don't know about cancer risks associated with radiation doses from radiological imaging

Quantifying radiation-induced cancer risks associated with radiological examinations is not easy, which has resulted in much controversy. We can clarify the situation by distinguishing between higher dose examinations, such as CT, positron emission tomography–CT or fluoroscopically guided interventions, and lower dose “conventional” X-ray examinations. For higher dose examinations, the epidemiological data, from atomic bomb survivors exposed to low doses and from direct epidemiological studies of paediatric CT, are reasonably consistent, suggesting that we do have a reasonable quantitative understanding of the individual risks: in summary, very small but unlikely to be zero. For lower dose examinations, we have very little data, and the situation is much less certain, however, the collective dose from these lower dose examinations is comparatively unimportant from a public health perspective.The debates about the cancer risks associated with very low-dose radiation exposures will surely not end soon. Even if we really could quantitate the risks (or lack of risks) associated with some very low radiation doses, we would immediately start to wonder about the risks associated with further lower doses. We will focus here on what we know (and what we do not know) about the cancer risks associated with doses from radiological imaging.Almost all radiological doses are “small”, in the context of, for example, radiotherapeutic doses; however, one can clearly distinguish between low radiological doses associated with many conventional examinations such as dental or chest examinations (organ doses typically <0.5 mGy) and higher radiological doses associated with CT, positron emission tomography (PET)-CT or fluoroscopically guided complex interventions (organ doses for a single examination or series of examinations typically between 5 and 100 mGy). As we shall discuss, this divide in dose ranges corresponds quite well to the dose range where we do know a good deal about radiation risks (5–100 mGy) and the dose range (<1 mGy) where we know far less.We shall discuss briefly what we know and do not know in both these radiation dose ranges, but it is important to view these considerations in the context of the potential benefits associated with the corresponding imaging procedure.¹ When a radiological examination of any sort is clinically justified, its benefits will almost always far outweigh any radiation risks. That being said, we still need to optimize radiological examinations (use the lowest dose consistent with obtaining the required information) and to justify radiological examinations (minimize clinically unnecessary procedures); however, the significance of such optimization and justification depends entirely on the magnitude (if any) of the associated radiation risks.^1–3     

Surface dose and build-up region measurements with wedge filters for 6 and 18 MV photon beams

Purpose  

High-energy photons are most commonly used in radiotherapy to treat cancer. Wedge filters are required to obtain homogeneous dose distribution in the patient. Different wedge filter types create different surface doses. In this study, the effect of the virtual and physical wedge filters on the surface and build-up region doses was examined for 6- and 18-MV high-energy photon beams.     

Deoxyribonucleic acid damage-associated biomarkers of ionising radiation: current status and future relevance for radiology and radiotherapy

Diagnostic and therapeutic radiation technology has developed dramatically in recent years, and its use has increased significantly, bringing clinical benefit. The use of diagnostic radiology has become widespread in modern society, particularly in paediatrics where the clinical benefit needs to be balanced with the risk of leukaemia and brain cancer increasing after exposure to low doses of radiation. With improving long-term survival rates of radiotherapy patients and the ever-increasing use of diagnostic and interventional radiology procedures, concern has risen over the long-term risks and side effects from such treatments. Biomarker development in radiology and radiotherapy has progressed significantly in recent years to investigate the effects of such use and optimise treatment. Recent biomarker development has focused on improving the limitations of established techniques by the use of automation, increasing sensitivity and developing novel biomarkers capable of quicker results. The effect of low-dose exposure (0–100 mGy) used in radiology, which is increasingly linked to cancer incidences, is being investigated, as some recent research challenges the linear-no-threshold model. Radiotherapy biomarkers are focused on identifying radiosensitive patients, determining the treatment-associated risk and allowing for a tailored and more successful treatment of cancer patients. For biomarkers in any of these areas to be successfully developed, stringent criteria must be applied in techniques and analysis of data to reduce variation among reports and allow data sets to be accurately compared. Newly developed biomarkers can then be used in combination with the established techniques to better understand and quantify the individual biological response to exposures associated with radiology tests and to personalise treatment plans for patients.Research into the identification of biomarkers of radiation exposure is an emerging and developing area with multiple possible benefits for patients, doctors and the general public. A radiation biomarker is a biological entity that changes after exposure to radiation, allowing exposed individuals to be identified and, with some biomarkers, a dose to be estimated. There are different types of biomarkers, including chromosome aberrations, protein expression or gene expression. Some can measure accurately the dose received, while others can only indicate if a dose was received. Biomarkers can help clinicians manage treatment for a patient exposed accidentally to the wrong radiation dose or on purpose through radiotherapy. They may be able to predict the treatment response of a tumour and estimate the risk of acute or late effects in normal tissues. Biomarkers can also identify the dose received by the patient in a full or partial body exposure. Such information can help inform the necessary medical treatment plan for the patient, and it may also identify patients with a high likelihood of developing cancer in the future so that regular monitoring can be set up.     

基于磁共振加速器系统头颈部肿瘤自适应放射治疗的剂量学评估

目的 探讨头颈部肿瘤患者基于磁共振加速器系统开展自适应放射治疗的可行性。方法 回顾性分析2019年在中山大学肿瘤防治中心采用磁共振加速器上开展自适应放射治疗的6例头颈部肿瘤患者,共计128个治疗分次的在线自适应治疗计划。评估分次间靶区处方剂量覆盖和危及器官最大剂量或平均剂量的变化情况。然后将每个治疗分次计划剂量叠加后,比较靶区处方剂量覆盖和各危及器官剂量与参考计划的差异。结果 分次间靶区和危及器官剂量评估结果显示,靶区处方剂量覆盖变化<1%,均满足临床要求。脑干、视交叉、视神经、眼球分次间最大剂量和平均剂量变化较小,但眼晶状体剂量变化最大可达98%。累积剂量评估结果显示,靶区处方剂量覆盖和参考计划无明显差别（<1%）,脑干、视交叉、视神经、眼球的剂量低于参考计划。眼晶状体剂量变化明显,其剂量高于参考计划最大为31.7%。结论 靶区与危及器官的累积受照剂量和分次间剂量均满足临床要求,磁共振加速器系统开展头颈部肿瘤自适应放射治疗方案是可行的。眼晶状体实际受照剂量与参考计划差异较大,应在临床中予以考虑。     

On bolus for megavoltage photon and electron radiation therapy

Frequently, in radiation therapy one must treat superficial lesions on cancer patients; these are at or adjacent to the skin. Megavoltage photon radiotherapy penetrates through the skin to irradiate deep-seated tumors, with skin-sparing property. Hence, to treat superficial lesions, one must use a layer of scattering material to feign as the skin surface. Although megavoltage electron beams are used for superficial treatments, one occasionally needs to enhance the dose near the surface. Such is the function of a “bolus,” a natural or synthetically developed material that acts as a layer of tissue to provide a more effective treatment to the superficial lesions. Other uses of boluses are to correct for varying surface contours and to add scattering material around the patient's surface. Materials used as bolus vary from simple water to metal and include various mixtures and compounds. Even with the modernization of the technology for external-beam therapy and the emergence of various commercial boluses, the preparation and utilization of a bolus in clinical radiotherapy remains an art. Considering the varying experiences and practices, this paper briefly summarizes available boluses that have been proposed and are employed in clinical radiotherapy. Although this review is not exhaustive, it provides some initial guidance and answers questions that may arise in clinical practice.     

Molecular biology: the key to personalised treatment in radiation oncology?

We know considerably more about what makes cells and tissues resistant or sensitive to radiation than we did 20 years ago. Novel techniques in molecular biology have made a major contribution to our understanding at the level of signalling pathways. Before the “New Biology” era, radioresponsiveness was defined in terms of physiological parameters designated as the five Rs. These are: repair, repopulation, reassortment, reoxygenation and radiosensitivity. Of these, only the role of hypoxia proved to be a robust predictive and prognostic marker, but radiotherapy regimens were nonetheless modified in terms of dose per fraction, fraction size and overall time, in ways that persist in clinical practice today. The first molecular techniques were applied to radiobiology about two decades ago and soon revealed the existence of genes/proteins that respond to and influence the cellular outcome of irradiation. The subsequent development of screening techniques using microarray technology has since revealed that a very large number of genes fall into this category. We can now obtain an adequately robust molecular signature, predicting for a radioresponsive phenotype using gene expression and proteomic approaches. In parallel with these developments, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) can now detect specific biological molecules such as haemoglobin and glucose, so revealing a 3D map of tumour blood flow and metabolism. The key to personalised radiotherapy will be to extend this capability to the proteins of the molecular signature that determine radiosensitivity.Molecular biology developments have, over the past 20 years, provided us with a remarkable array of techniques, enhancing our understanding of how tumour and normal tissues respond to radiation damage. As these techniques grow increasingly sophisticated, their application should, in theory, present opportunities to improve the effectiveness of radiotherapy.However, as we look at how radiotherapy is performed today we see a discipline founded on 100 years of practice-based, empirical development, recently enhanced by impressive advances in dose delivery and image-guided procedures. These developments have brought us to a point where dose deposition is already highly tailored, to a tolerance of ∼2% for most tissues of the body, which is much more accurate than any pharmaceutical agent. Yet, are we really delivering dose where it needs to go for maximal therapeutic gain?     

Biology-guided radiotherapy: redefining the role of radiotherapy in metastatic cancer

The emerging biological understanding of metastatic cancer and proof-of-concept clinical trials suggest that debulking all gross disease holds great promise for improving patient outcomes. However, ablation of multiple targets with conventional external beam radiotherapy systems is burdensome, which limits investigation and utilization of complete metastatic ablation in the majority of patients with advanced disease. To overcome this logistical hurdle, technical innovation is necessary. Biology-guided radiotherapy (BgRT) is a new external beam radiotherapy delivery modality combining positron emission tomography-computed tomography (PET-CT) with a 6 MV linear accelerator. The key innovation is continuous response of the linear accelerator to outgoing tumor PET emissions with beamlets of radiotherapy at subsecond latency. This allows the deposited dose to track tumors in real time. Multiple new hardware and algorithmic advances further facilitate this low-latency feedback process. By transforming tumors into their own fiducials after intravenous injection of a radiotracer, BgRT has the potential to enable complete metastatic ablation in a manner efficient for a single patient and scalable to entire populations with metastatic disease. Future trends may further enhance the utility of BgRT in the clinic as this technology dovetails with other innovations in radiotherapy, including novel dose painting and fractionation schemes, radiomics, and new radiotracers.