D.J. Noble

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity

There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.

Exploiting biological and physical determinants of radiotherapy toxicity to individualize treatment

The recent advances in radiation delivery can improve tumour control probability (TCP) and reduce treatment-related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally, IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day to day. Daily image guidance scans can be used to identify the position of normal tissue structures and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues that limits radiotherapy (RT) dose and therefore tumour control. However, the dose–response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of RT. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be owing to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In patients with prostate cancer receiving curative RT, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses was −2.7u2009Gy (5%), and a dose reduction was seen in 7 of the 10 cases. If dose escalation was performed to take rectal dose back to the planned level, this should increase the mean TCP (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical RT who might benefit from either dose escalation, suggesting improved tumour cure or reduced toxicity or both.

Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy

Background and purpose For the first time, delivered dose to the rectum has been calculated and accumulated throughout the course of prostate radiotherapy using megavoltage computed tomography (MVCT) image guidance scans. Dosimetric parameters were linked with toxicity to test the hypothesis that delivered dose is a stronger predictor of toxicity than planned dose. Material and methods Dose–surface maps (DSMs) of the rectal wall were automatically generated from daily MVCT scans for 109 patients within the VoxTox research programme. Accumulated-DSMs, representing total delivered dose, and planned-DSMs, from planning CT data, were parametrised using Equivalent Uniform Dose (EUD) and ‘DSM dose-width’, the lateral dimension of an ellipse fitted to a discrete isodose cluster. Associations with 6 toxicity endpoints were assessed using receiver operator characteristic curve analysis. Results For rectal bleeding, the area under the curve (AUC) was greater for accumulated dose than planned dose for DSM dose-widths up to 70 Gy. Accumulated 65 Gy DSM dose-width produced the strongest spatial correlation (AUC 0.664), while accumulated EUD generated the largest AUC overall (0.682). For proctitis, accumulated EUD was the only reportable predictor (AUC 0.673). Accumulated EUD was systematically lower than planned EUD. Conclusions Dosimetric parameters extracted from accumulated DSMs have demonstrated stronger correlations with rectal bleeding and proctitis, than planned DSMs.

Highly Conformal Craniospinal Radiotherapy Techniques Can Underdose the Cranial Clinical Target Volume if Leptomeningeal Extension through Skull Base Exit Foramina is not Contoured

Aims Craniospinal irradiation (CSI) remains a crucial treatment for patients with medulloblastoma. There is uncertainty about how to manage meningeal surfaces and cerebrospinal fluid (CSF) that follows cranial nerves exiting skull base foramina. The purpose of this study was to assess plan quality and dose coverage of posterior cranial fossa foramina with both photon and proton therapy. Materials and methods We analysed the radiotherapy plans of seven patients treated with CSI for medulloblastoma and primitive neuro-ectodermal tumours and three with ependymoma (total n = 10). Four had been treated with a field-based technique and six with TomoTherapy™. The internal acoustic meatus (IAM), jugular foramen (JF) and hypoglossal canal (HC) were contoured and added to the original treatment clinical target volume (Plan_CTV) to create a Test_CTV. This was grown to a test planning target volume (Test_PTV) for comparison with a Plan_PTV. Using Plan_CTV and Plan_PTV, proton plans were generated for all 10 cases. The following dosimetry data were recorded: conformity (dice similarity coefficient) and homogeneity index (D2 − D98/D50) as well as median and maximum dose (D2%) to Plan_PTV, V95% and minimum dose (D99.9%) to Plan_CTV and Test_CTV and Plan_PTV and Test_PTV, V95% and minimum dose (D98%) to foramina PTVs. Results Proton and TomoTherapy™ plans were more conformal (0.87, 0.86) and homogeneous (0.07, 0.04) than field-photon plans (0.79, 0.17). However, field-photon plans covered the IAM, JF and HC PTVs better than proton plans (P = 0.002, 0.004, 0.003, respectively). TomoTherapy™ plans covered the IAM and JF better than proton plans (P = 0.000, 0.002, respectively) but the result for the HC was not significant. Adding foramen CTVs/PTVs made no difference for field plans. The mean Dmin dropped 3.4% from Plan_PTV to Test_PTV for TomoTherapy™ (not significant) and 14.8% for protons (P = 0.001). Conclusions Highly conformal CSI techniques may underdose meninges and CSF in the dural reflections of posterior fossa cranial nerves unless these structures are specifically included in the CTV.

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary ‘VoxTox’ research programme

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.

The future of image-guided radiotherapy—is image everything?

MR-based image-guided (IG) radiotherapy via all-in-one MR treatment units (MR-linacs) is one of the hottest topics in contemporary radiotherapy research. From ingenious engineering solutions to complex physical problems, researchers have developed machines with the promise of superior image quality, and all the advantages this may confer. Benefits include better tumour visualisation, online adaptation and the potential for image biomarker-based personalised RT. However, it is important to remember that the technical challenges are real. In many instances, they are skillfully managed rather than abolished, a point illustrated by the wide variety of MR-linac designs. The proposed benefits also deserve careful inspection. Better visibility of the primary tumour on an IG scan cannot be bad, but does not automatically equate to better IG, which often depends on a more generalised match to daily anatomy. MR-linac will undoubtedly be a rich milieu to search for IMBs, but these will need to be carefully validated, and similar work with CT-based biomarkers using existing, cheaper, and more widely available hardware is currently ongoing. Online adaptation is an attractive concept, but practicalities are complex, and more work is required to understand which patients will benefit from plan adaptation, and when. Finally, the issue of cost cannot be overlooked, nor can the research community’s responsibilities to global healthcare inequalities. MR-linac is an exciting and ingenious technology, which merits both investment and research. It may not, however, have the future to itself.

Anatomical change during radiotherapy for head and neck cancer, and its effect on delivered dose to the spinal cord

Highlights • A cohort of 133 head & neck cancer patients treated with TomoTherapy was examined.• Differences between planned and delivered maximum spinal cord dose were small.• Substantial weight loss and anatomical change during treatment was observed.• No link between weight loss or anatomical change, and dose differences was seen.

Zielvolumenkonzepte in der Strahlentherapie und ihre Bedeutung für die Bildgebung

ZusammenfassungKlinisches ProblemEine erfolgreiche strahlentherapeutische Behandlung erfordert eine präzise Lokalisierung des Tumors, v.u202fa. basierend auf der Bildgebung.Herkömmliche VerfahrenBestrahlung der Tumorregion einschließlich eines Sicherheitssaums ohne Protokoll.Moderne TherapieverfahrenDas Zielvolumen besteht aus dem GTV mit dem sichtbaren Tumoranteil, dem CTV mit den mikroskopischen Tumorausläufern sowie dem PTV mit einem zusätzlichen Sicherheitssaum, der eine korrekte Dosisabdeckung des GTV und CTV gewährleistet. Der Saum des CTV basiert auf historischen Patientendaten. Der PTV-Saum basiert auf einer Abschätzung von Ungenauigkeiten bei der Planung und Durchführung der Behandlung. Normalgewebe müssen die gleiche Sorgfalt und Konsistenz bei der Konturierung erfahren, da ihre Gewebstoleranz die Dosis im Tumor limitieren kann. Eine effektive Behandlungsplanung setzt auch eine Konturierung der Risikoorgane voraus. Seriell angelegte Risikoorgane profitieren von einem zusätzlichen Volumen („planning organ at risk volume“, PRV), um deren Dosis besser begrenzen zu können.DiagnostikJe besser die Bildgebung ist, umso verlässlicher wird die Definition des GTV, und umso erfolgreicher verläuft die Therapie. Der Einsatz unterschiedlicher Bildgebungssequenzen und Untersuchungsmodalitäten ist oft hilfreich. Es ist möglich, dass es unterschiedliche CTV gibt, die, abhängig von der Tumorlast, unterschiedliche Dosen erfordern.LeistungsfähigkeitDie Definition standardisierter Zielvolumina nach den ICRU-Reportsxa050, 62 und 83 ist die Basis für eine individualisierte Bestrahlungsplanung nach einheitlichen Kriterien und auf hohem qualitativem Niveau.BewertungDie Strahlentherapie ist ein interdisziplinäres Fach, welches auf die Radiodiagnostik als Teampartner nicht verzichten kann. Der regelmäßige Dialog zwischen Radioonkologen und Radiodiagnostikern ist für die Zielvolumendefinition und damit auch für den Patienten ganz entscheidend.Empfehlung für die PraxisBildgebung zur Bestrahlungsplanung erfordert höchste Qualität und den Einsatz funktioneller Bildgebung sowie eine enge Kooperation mit einem einschlägig erfahrenen diagnostischen Radiologen.AbstractClinical issueSuccessful radiotherapy requires precise localization of the tumor and requires high-quality imaging for developing a treatment plan.Standard treatmentIrradiation of the tumor region, including axa0safety margin.Treatment innovationsThe target volume consists of the gross tumor volume (GTV) containing visible parts of the tumor, the clinical target volume (CTV) covering the GTV plus invisible tumor extensions, and the planning target volume (PTV) to account for uncertainties. The non-GTV parts of the CTV are based on historical patient data. The PTV margins are based on axa0calculation of possible uncertainties during planning, setup, or treatment. Normal tissue deserves the identical care in contouring, since its tolerance may limit the tumor dose, taking into account the contours of organs at risk. Serial risk organs benefit from defining axa0planning organ of risk volume (PRV) to better limit the dose delivered to them.Diagnostic work-upThe better the imaging, the more reliable the definition of the GTV and treatment success will be. Multiple imaging sequences are desirable to support the delineation of the tumor. They may result in different CTVs that, depending on their tumor burden, may require different doses.PerformanceThe definition of standardized target volumes according to the ICRU reportsxa050, 62, and 83 forms the basis for an individualized radiation treatment planning according to unified criteria on axa0high-quality level.AchievementsRadio-oncology is by nature interdisciplinary, the diagnostic radiologist being an indispensable team partner. Axa0regular dialogue between the disciplines is pivotal for target volume definition and treatment success.Practical recommendationsImaging for target volume definition requires highest quality imaging, the use of functional imaging methods and close cooperation with axa0diagnostic radiologist experienced in this field.CLINICAL ISSUEnSuccessful radiotherapy requires precise localization of the tumor and requires high-quality imaging for developing a treatment plan.nnnSTANDARD TREATMENTnIrradiation of the tumor region, including axa0safety margin.nnnTREATMENT INNOVATIONSnThe target volume consists of the gross tumor volume (GTV) containing visible parts of the tumor, the clinical target volume (CTV) covering the GTV plus invisible tumor extensions, and the planning target volume (PTV) to account for uncertainties. The non-GTV parts of the CTV are based on historical patient data. The PTV margins are based on axa0calculation of possible uncertainties during planning, setup, or treatment. Normal tissue deserves the identical care in contouring, since its tolerance may limit the tumor dose, taking into account the contours of organs at risk. Serial risk organs benefit from defining axa0planning organ of risk volume (PRV) to better limit the dose delivered to them.nnnDIAGNOSTIC WORK-UPnThe better the imaging, the more reliable the definition of the GTV and treatment success will be. Multiple imaging sequences are desirable to support the delineation of the tumor. They may result in different CTVs that, depending on their tumor burden, may require different doses.nnnPERFORMANCEnThe definition of standardized target volumes according to the ICRU reportsxa050, 62, and 83 forms the basis for an individualized radiation treatment planning according to unified criteria on axa0high-quality level.nnnACHIEVEMENTSnRadio-oncology is by nature interdisciplinary, the diagnostic radiologist being an indispensable team partner. Axa0regular dialogue between the disciplines is pivotal for target volume definition and treatment success.nnnPRACTICAL RECOMMENDATIONSnImaging for target volume definition requires highest quality imaging, the use of functional imaging methods and close cooperation with axa0diagnostic radiologist experienced in this field.

Tumour Volume and Dose Influence Outcome after Surgery and High-dose Photon Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine

AIMSnTo evaluate the long-term outcomes of patients with chordoma and low-grade chondrosarcoma after surgery and high-dose radiotherapy.nnnMATERIALS AND METHODSnHigh-dose photon radiotherapy was delivered to 28 patients at the Neuro-oncology Unit at Addenbrookes Hospital (Cambridge, UK) between 1996 and 2016. Twenty-four patients were treated with curative intent, 17 with chordoma, seven with low-grade chondrosarcoma, with a median dose of 65xa0Gy (range 65-70xa0Gy). Local control and survival rates were calculated using the Kaplan-Meier method.nnnRESULTSnThe median follow-up was 83 months (range 7-205 months). The 5 year disease-specific survival for chordoma patients treated with radical intent was 85%; the local control rate was 74%. The 5 year disease-specific survival for chondrosarcoma patients treated with radical intent was 100%; the local control rate was 83%. The mean planning target volume (PTV) was 274.6xa0ml (median 124.7xa0ml). A PTV of 110xa0ml or less was a good predictor of local control, with 100% sensitivity and 63% specificity. For patients treated with radical intent, this threshold of 110xa0ml or less for the PTV revealed a statistically significant difference when comparing local control with disease recurrence (Pxa0=xa00.019, Fishers exact test). Our data also suggest that the probability of disease control may be partly related to both target volume and radiotherapy dose.nnnCONCLUSIONnOur results show that refined high-dose photon radiotherapy, following tumour resection by a specialist surgical team, is effective in the long-term control of chordoma and low-grade chondrosarcoma, even in the presence of metal reconstruction. The results presented here will provide a useful source for comparison between high-dose photon therapy and proton beam therapy in a UK setting, in order to establish best practice for the management of chordoma and low-grade chondrosarcoma.

Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy

Abstract To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is documentclass[12pt]{minimal} usepackage{amsmath} usepackage{wasysym} usepackage{amsfonts} usepackage{amssymb} usepackage{amsbsy} usepackage{upgreek} usepackage{mathrsfs} setlength{oddsidemargin}{-69pt} begin{document} }{}