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Advancing magnetic resonance imaging (MRI) guided adaptive radiotherapy techniques for prostate cancer
No full textAdvances in radiotherapy technology have increased precision of treatment delivery, improved cure rates and decreased side effects. The advent of MR-Linacs, which are hybrids of an MRI scanner and linear accelerator, holds potential to further transform the management of cancers. MRI-guided adaptive radiotherapy (MRIgART) facilitates superior soft tissue definition within the pelvis and enables daily adaptive replanning allowing for possibilities such as dose escalation, tumour tracking and further sparing of normal tissue. Building upon previous research, this thesis delves into multiple aspects of this innovative treatment in the non-metastatic prostate cancer setting.
This thesis begins with an exploration of aspects of the MR-Linac workflow. I investigate the hypothesis that high levels of inter- and intraobserver variability exists in prostate delineation during online treatment and compare this to ‘normal’ variability which is evaluated in an offline setting on MR-Linac acquired MR images. The factors that might contribute to inter- and intraobserver variability are also investigated. Further work concentrates on whether autocontours, propagated by rigid and deformable image registration, using the Monaco treatment planning system can be utilised, instead of clinician-drawn contours, for daily treatment on the Elekta MR-Linac.
I then examine clinical outcomes of MRIgART for localised prostate cancer with moderately hypofractionated radiotherapy. I report toxicity, early biochemical response and patient-reported outcomes from the MOMENTUM study, a multicentre international registry study for patients who received treatment on the Unity MR-Linac.
With moderately hypofractionated radiotherapy established as the standard of care, the prostate cancer community has turned its focus towards ultrahypofractionated radiotherapy. The potential benefits of the MR-Linac can be harnessed to deliver this. I explore whether intrafractional changes in anatomy contribute to significant variations in dose delivered to organ-at-risk structures during 5-fraction radiotherapy.
Finally, I turn my attention to the postoperative setting. Significant variability exists amongst the multiple guidelines currently in use for delineating the prostate bed using CT-guided radiotherapy. I assess baseline interobserver variability in prostate bed contouring on MRI images obtained from the MR-Linac and using this data, create consensus guidelines for contouring the prostate bed clinical target volume (CTV) for MRIgART. Lastly, I investigate the impact of these guidelines on interobserver variability. Using these guidelines, further research looking at the benefits of MRIgART in the postoperative setting may be carried out.
The findings presented in this thesis lay the groundwork for realising the full potential of MRIgART for treating prostate cancer
CRISPR-Cas9 Screening Identifies KRAS-Induced COX2 as a Driver of Immunotherapy Resistance in Lung Cancer.
No full textOncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells. Oncogenic KRAS potently induced COX2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX2/PGE2 remodeled the tumor microenvironment by inducing proinflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer. Significance: COX2 signaling via prostaglandin E2 is a major mediator of immune evasion driven by oncogenic KRAS that promotes immunotherapy and KRAS-targeted therapy resistance, suggesting effective combination treatments for KRAS-mutant lung cancer
Inter- and Intra-Patient Repeatability of Radiomic Features from Multiparametric Whole-Body MRI in Patients with Metastatic Prostate Cancer.
Get PDF(1) Background: We assessed the test-re-test repeatability of radiomics in metastatic castration-resistant prostate cancer (mCPRC) bone disease on whole-body diffusion-weighted (DWI) and T1-weighted Dixon MRI. (2) Methods: In 10 mCRPC patients, 1.5 T MRI, including DWI and T1-weighted gradient-echo Dixon sequences, was performed twice on the same day. Apparent diffusion coefficient (ADC) and relative fat-fraction-percentage (rFF%) maps were calculated. Per study, up to 10 target bone metastases were manually delineated on DWI and Dixon images. All 106 radiomic features included in the Pyradiomics toolbox were derived for each target volume from the ADC and rFF% maps. To account for inter- and intra-patient measurement repeatability, the log-transformed individual target measurements were fitted to a hierarchical model, represented as a Bayesian network. Repeatability measurements, including the intraclass correlation coefficient (ICC), were derived. Feature ICCs were compared with mean ADC and rFF ICCs. (3) Results: A total of 65 DWI and 47 rFF% targets were analysed. There was no significant bias for any features. Pairwise correlation revealed fifteen ADC and fourteen rFF% feature sub-groups, without specific patterns between feature classes. The median intra-patient ICC was generally higher than the inter-patient ICC. Features that describe extremes in voxel values (minimum, maximum, range, skewness, and kurtosis) showed generally lower ICCs. Several mostly shape-based texture features were identified, which showed high inter- and intra-patient ICCs when compared with the mean ADC or mean rFF%, respectively. (4) Conclusions: Pyradiomics texture features of mCRPC bone metastases varied greatly in inter- and intra-patient repeatability. Several features demonstrated good repeatability, allowing for further exploration as diagnostic parameters in mCRPC bone disease
Exploring the barriers to, and importance of, participant diversity in early-phase clinical trials: an interview-based qualitative study of professionals and patient and public representatives.
Get PDFOBJECTIVES: To explore the importance of, and barriers to achieving, diversity in early-phase clinical trials. DESIGN: Qualitative interviews analysed using thematic analysis. SETTING AND PARTICIPANTS: Five professionals (clinical researchers and methodologists) and three patient and public representatives (those with experience of early-phase clinical trials and/or those from ethnic minority backgrounds) were interviewed between June and August 2022. Participants were identified via their institutional web page, existing contacts or social media (eg, X, formerly known as Twitter). RESULTS: Professionals viewed that diversity is not currently considered in all early-phase clinical trials but felt that it should always be taken into account. Such trials are primarily undertaken at a small number of centres, thus limiting the populations they can access. Referrals from clinicians based in the community may increase diversity; however, those referred are often not from underserved groups. Referrals may be hindered by the extra resources required to approach and recruit underserved groups and participants often having to undertake 'self-driven' referrals. Patient and public representatives stated that diversity is important in research staff and that potential participants should be informed of the need for diversity. Those from underserved groups may require clarification regarding the potential harms of a treatment, even if these are unknown. Education may improve awareness and perception of early-phase clinical trials. We provide 14 recommendations to improve diversity in early-phase clinical trials. CONCLUSIONS: Diversity should be considered in all early-phase trials. Consideration is required regarding the extent of diversity and how it is addressed. The increased resources needed to recruit those from underserved groups may warrant funders to increase the funds to support the recruitment of such participants. The potential harms and societal benefits of the research should be presented to potential participants in a balanced but accurate way to increase transparency
International Survey on Frailty Assessment in Patients with Cancer.
Get PDFBACKGROUND: Frailty negatively affects the outcomes of patients with cancer, and its assessment might vary widely in the real world. The objective of this study was to explore awareness and use of frailty screening tools among the ONCOassist healthcare professionals (HCPs) users. MATERIALS AND METHODS: We sent 2 emails with a cross-sectional 15-item survey in a 3-week interval between April and May 2021. Differences in the awareness and use of tools according to respondents' continents, country income, and job types were investigated. RESULTS: Seven hundred thirty-seven HCPs from 91 countries (81% physicians, 13% nurses, and 5% other HCPs) completed the survey. Three hundred and eighty-five (52%) reported assessing all or the majority of their patients; 518 (70%) at baseline and before starting a new treatment. Three hundred and four (43%) HCPs were aware of performance status (PS) scores only, 309 (42%) age/frailty/comorbidity (AFC) screening, and 102 (14%) chemotoxicity predictive tools. Five hundred and thirty-seven (73%) reported using tools; 423 (57%) just PS, 237 (32%) AFC, and 60 (8%) chemotoxicity ones. Reasons for tools non-use (485 responders) were awareness (70%), time constraints (28%), and uselessness (2%). There were significant differences in awareness and use of screening tools among different continents, country income, job types, and medical specialties (P < .001 for all comparisons). CONCLUSION: Among selected oncology HCPs, there is still a worldwide lack of knowledge and usage of frailty screening tools, which may differ according to their geography, country income, and education. Targeted initiatives to raise awareness and education are needed to implement frailty assessment in managing patients with cancer
A step and shoot intensity modulated technique for total body irradiation.
No full textINTRODUCTION: Total body irradiation (TBI) is a part of the conditioning regimen for bone marrow transplant.At the Royal Marsden (Sutton, UK) and Rigshospitalet (Copenhagen, Denmark), we introduced a step and shoot IMRT (SS IMRT) technique for TBI. This technique requires no equipment other than that used to deliver other external beam radiation. In this paper, we describe this technique and report on data from the two clinics. MATERIALS AND METHODS: The patients were positioned supine, supported by vacuum bag(s). The entire body of the patients were CT scanned with 5 mm slices. Multiple multi-leaf collimator (MLC) defined fields were used.In-vivo dosimetry was performed at the Royal Marsden for 113 patients.Calculated doses for 18 adult and 4 paediatric patients from Rigshospitalet were extracted. RESULTS: The in-vivo data from the Royal Marsden showed that the mean TLD measured dose difference was -1.9% with a standard deviation of 4.5%.SS IMRT plans for 22 patients from Rigshospitalet resulted in mean doses to the brain, lungs and kidneys all within the range of 11.1-11.8 Gy, while the V(12 Gy) was below 5% for the brain, 2% for the lungs and 0% for the kidneys. DISCUSSION: SS IMRT is feasible for TBI and can deliver targeted doses to the organs at risk
Handling Incomplete or Late-Onset Toxicities in Early-Phase Dose-Finding Clinical Trials: Current Practice and Future Prospects.
No full textPURPOSE: The way late-onset toxicities are managed can affect trial outcomes and participant safety. Specifically, participants often might not have completed their entire follow-up period to observe any toxicities before new participants would be recruited. We conducted a methodological review of published early-phase dose-finding clinical trials that used designs accounting for partial and complete toxicity information, aiming to understand (1) how such designs were implemented and reported and (2) if sufficient information was provided to enable the replicability of trial results. METHODS: Until March 26, 2023, we identified 141 trials using the rolling 6 design, the time-to-event continuous reassessment method (TITE-CRM), the TITE-CRM with cycle information, the TITE Bayesian optimal interval design, the TITE cumulative cohort design, and the rapid enrollment design. Clinical settings, design parameters, practical considerations, and dose-limiting toxicity (DLT) information were extracted from these published trials. RESULTS: The TITE-CRM (61, 43.3%) and the rolling 6 design (76, 53.9%) were most frequently implemented in practice. Trials using the TITE-CRM had longer DLT assessment windows beyond the first cycle compared with the rolling 6 design (52.5% v 6.6%). Most trials implementing the TITE-CRM (91.8%, 56 of 61) failed to describe essential parameters in the protocols or the study result papers. Only five TITE-CRM trials (8.2%, 5 of 61) reported sufficient information to enable replication of the final analysis. CONCLUSION: When compared with trials using the rolling 6 design, those implementing the TITE-CRM design exhibited notable deficiencies in reporting essential details necessary for reproducibility. Inadequate reporting quality of advanced model-based trial designs hinders their credibility. We provide recommendations that can improve transparency, reproducibility, and accurate interpretation of the results for such designs
First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors.
No full textPURPOSE: Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of tuvusertib monotherapy. PATIENTS AND METHODS: Ascending tuvusertib doses were evaluated in 55 patients with metastatic or locally advanced unresectable solid tumors. A safety monitoring committee determined dose escalation based on PK, PD, and safety data guided by a Bayesian 2-parameter logistic regression model. Molecular responses (MR) were assessed in circulating tumor DNA samples. RESULTS: Most common grade ≥3 treatment-emergent adverse events were anemia (36%), neutropenia, and lymphopenia (both 7%). Eleven patients experienced dose-limiting toxicities, most commonly grade 2 (n = 2) or 3 (n = 8) anemia. No persistent effects on blood immune cell populations were observed. The RDE was 180 mg tuvusertib QD (once daily), 2 weeks on/1 week off treatment, which was better tolerated than the MTD (180 mg QD continuously). Tuvusertib median time to peak plasma concentration ranged from 0.5 to 3.5 hours and mean elimination half-life from 1.2 to 5.6 hours. Exposure-related PD analysis suggested maximum target engagement at ≥130 mg tuvusertib QD. Tuvusertib induced frequent MRs in the predicted efficacious dose range; MRs were enriched in patients with radiological disease stabilization, and complete MRs were detected for mutations in ARID1A, ATRX, and DAXX. One patient with platinum- and PARP inhibitor-resistant BRCA wild-type ovarian cancer achieved an unconfirmed RECIST v1.1 partial response. CONCLUSIONS: Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing
Is There a Special Role for Ovarian Hormones in the Pathogenesis of Lobular Carcinoma?
No full textLobular carcinoma represent the most common special histological subtype of breast cancer, with the majority classed as hormone receptor positive. Rates of invasive lobular carcinoma in postmenopausal women have been seen to increase globally, while other hormone receptor-positive breast cancers proportionally have not followed the same trend. This has been linked to exposure to exogenous ovarian hormones such as hormone replacement therapy. Reproductive factors resulting in increased lifetime exposure to endogenous ovarian hormones have also been linked to an increased risk of lobular breast cancer, and taken together, these data make a case for the role of ovarian hormones in the genesis and progression of the disease. In this review, we summarize current understanding of the epidemiological associations between ovarian hormones and lobular breast cancer and highlight mechanistic links that may underpin the etiology and biology
An alternative NURF complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions.
No full textEfficient treatment of acute myeloid leukemia (AML) patients remains a challenge despite recent therapeutic advances. Here, using a CRISPRi screen targeting chromatin factors, we identified the nucleosome-remodeling factor (NURF) subunit BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well-studied PHD2-BROMO chromatin reader domains of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML