Radiation therapy is afflicted by a multitude of geometric uncertainties, which must be compensated to ensure treatment success. Such mitigation is currently achieved by enlarging the apparent target volume by various safety margins. This thesis investigated uncertainty sources relating to target position and extent in oesophageal carcinoma, both static and dynamic, and evaluated their impact in a combined model. The first were errors inherent to delineation of the gross tumour volume (GTV), where computed tomography (CT) imaging, the overall modality of choice for target volume delineation (TVD), has a tendency to overestimate target extent. Two rival modalities, [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and endoscopic ultrasound (EUS), are generally expected to yield more accurate assessments. EUS has previously suffered from a difficulty in transferring its findings to the spatial domain in which TVD is undertaken. This limitation was overcome here through the use of endoscopically implanted fiducial markers visible on the planning CT. This has enabled their inclusion in TVD and allowed a direct comparison of FDG-PET and EUS based target extents, which were found to agree quite well on average, but showed occasional discrepancies on the order of a few cm. Recently published reports on inter-observer variability (IOV) in TVD of oesophageal carcinoma were summarised with a particular focus on its reduction afforded by the use of fiducial markers. The influence of IOV was investigated more widely in other tumour entities, where it was shown to increase during the course of treatment, mostly due to differing adaptation practices.
Microscopic disease extension (MDE), undetectable prior to treatment with current imaging techniques, constituted the second uncertainty source. Reports on histopathological measurements of MDE incidence and its distance from the main tumour were reviewed and spatial measurements extracted to derive a combined estimate of the distribution of extension distances. The overall incidence was estimated as 14.6%, with individual studies reporting widely differing values. Conventional margin widths to compensate for MDE were extracted from the pooled distribution and found to largely agree with the common clinical choice of 3–5 cm, but associated with broad confidence intervals. The addition of such margins to the GTV defines the clinical target volume (CTV). Most studies acknowledged tissue deformations as a major problem, but not all implemented means to prevent or correct it. Preliminary measurements on oesophageal resection specimens were presented, wherein fiducial markers were used to measure tissue deformations, and might ultimately be used to correct spatial measurements of MDE. Fiducial markers also facilitated the study of inter-fractional target mobility in a cohort (n=23) receiving daily orthogonal X-ray imaging for target positioning verification. Markers were found capable of detecting target misalignments, which were a common occurrence with 54% and 15% of analysed markers and treatment fractions showing displacements from their planned position in excess of 5 and 10mm, respectively. Mobility amplitudes were highest in the longitudinal direction and a dependence on tumour location was hinted at, with motion more restricted for proximally located lesions. Measures of systematic and random mobility components were extracted to derive safety margins, which are added to the CTV to form the planning target volume (PTV). A radiobiological model of tumour control probability (TCP) was then evaluated under different uncertainty scenarios. It simplified the tumour system to its longitudinal dimension, which is most affected by the aforementioned phenomena, and simulated positional uncertainties, as well as MDE. The differential impact of systematic and random mobility components on TCP was demonstrated and margin widths sufficient to limit TCP reduction to 1% could best be described by a quadratic combination of their magnitudes. This composition was still applicable when MDE was introduced and mitigated by a conventional margin, but the relative impact of both components shifted. The addition of a PTV margin to the CTV afforded the MDE-positive subpopulation similar protection against positional uncertainties as the same margin achieved without consideration of MDE. The MDE-negative subpopulation attained a much improved tolerance to positional uncertainties through the CTV margin, which also propagated to the overall population. An alternative mitigation of MDE was attempted by optimising the applied dose distribution to an assumed tumour cell density distribution motivated by the literature, which decreases towards the target edge. The optimisation maximised TCP while preserving the integral dose delivered with a conventional margin, under the assumption that this translates into a similar likelihood of normal tissue toxicity. Reduced doses could be delivered to lower cell density regions without sacrificing overall TCP, but this reduction was modest despite vastly diminished cell densities. When this spared dose was redistributed so as to enlarge the treated area, negligible TCP change was observed, but redistribution to the central target did result in appreciably improved TCP in both subpopulations. These effects persisted when positional uncertainties were added and when MDE incidence was increased to the most extreme value reported in the literature.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:74547 |
| Date | 23 April 2021 |
| Creators | Apolle, Rudi |
| Contributors | Troost, Esther G. C., Thorwarth, Daniela, Technische Universität Dresden |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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