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Exploring the role of stereotactic body radiotherapy to sites of oligoprogression to improve outcomes
No full textmproved treatments for metastatic non-small cell lung cancer (NSCLC) and prostate cancer has unearthed a clinical state called oligoprogressive disease (OPD). OPD is poorly defined, broadly speaking it features progression in only a few sites of disease, on a background of other metastatic lesions remaining responsive to the current line of systemic treatment. Some patients are treated with stereotactic body radiotherapy (SBRT) to these resistant clones, to exploit the ongoing effects from systemic treatment to the responding lesions, although there is limited prospective evidence supporting this. SBRT is a well tolerated treatment in oligometastatic disease (OMD) but there are limited data on the efficacy of treating bone metastases with SBRT, and the toxicity associated with treating an older, frailer population with a higher burden of metastatic disease such as with OPD. Little is known about the prevalence of OPD in prostate cancer or in NSCLC during immunotherapy treatment which is now widely used.
Methods
Preliminary research into OPD in prostate and NSCLC are presented, including early toxcity results from the TRAP trial and the impact of a novel, trial specific virtual multi-disciplinary team meeting (vMDT) on eligibility and recruitment within the HALT trial. Both are prospective phase II trials assessing the outcomes of patients treated with SBRT for OPD in prostate and NSCLC.
Retrospective electronic records at a single centre were interrogated to explore the patterns of progression amongst patients treated with abiraterone or enzalutamide for castration resistant prostate cancer (CRPC) and immunotherapy for NSCLC. Outcomes of patients treated for bone OMD with SBRT were evaluated.
Results:
The prevalence of OPD was between 21-35%, with a trend towards better progression free survival with the use of SBRT. SBRT to bone OMD achieved low rates of local failure (5.9%). Review of early toxcity data for the first 41 patients recruited to the TRAP trial found only one patient (2.4%) experienced grade 3+ toxicity possibly associated with SBRT. A central vMDT for eligible patients on recruitment of patients to the HALT trial deemed 27% of patients registered as not eligible for the trial.
There is a need for further clarification of the definition of OPD to provide clarity of which patients would be eligible for SBRT. The results of this thesis support the need for randomised phase III trials
Intrinsic Molecular Subtypes of Metastatic Castration-Resistant Prostate Cancer.
No full textPURPOSE: Although numerous biology-driven subtypes have been described previously in metastatic castration-resistant prostate cancer (mCRPC), unsupervised molecular subtyping based on gene expression has been less studied, especially using large cohorts. Thus, we sought to identify the intrinsic molecular subtypes of mCRPC and assess molecular and clinical correlates in the largest combined cohort of mCRPC samples with gene expression data available to date. EXPERIMENTAL DESIGN: We combined and batch-effect corrected gene expression data from four mCRPC cohorts from the Fred Hutchinson Cancer Research Center (N = 157), a small-cell neuroendocrine (NE) prostate cancer (SCNC)-enriched cohort from Weill Cornell Medicine (N = 49), and cohorts from the Stand Up 2 Cancer/Prostate Cancer Foundation East Coast Dream Team (N = 266) and the West Coast Dream Team (N = 162). RESULTS: Hierarchical clustering of RNA-sequencing data from these 634 mCRPC samples identified two distinct adenocarcinoma subtypes, one of which (adeno-immune) was characterized by higher gene expression of immune pathways, higher CIBERSORTx immune scores, diminished ASI benefit, and non-lymph node metastasis tropism compared with an adeno-classic subtype. We also identified two distinct subtypes with enrichment for an NE phenotype, including an NE-liver subgroup characterized by liver metastasis tropism, PTEN loss, and APC and SPOP mutations compared with an NE-classic subgroup. CONCLUSIONS: Our results emphasize the heterogeneity of mCRPC beyond currently accepted molecular phenotypes, and suggest that future studies should consider incorporating transcriptome-wide profiling to better understand how these differences impact treatment responses and outcomes
Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance.
No full textSecond-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI
PAK6 acts downstream of IQGAP3 to promote contractility in triple negative breast cancer cells.
No full textBreast cancer is a heterogeneous disease that remains the most common malignancy among women worldwide. During genomic analysis of breast tumours, mRNA levels of IQGAP3 were found to be upregulated in triple negative tumours. IQGAP3 was subsequently found to be expressed across a panel of triple negative breast cancer (TNBC) cell lines. Depleting expression levels of IQGAP3 delivered elongated cells, disrupted cell migration, and inhibited the ability of cells to form specialised invasive adhesion structures, termed invadopodia. The morphological changes induced by IQGAP3 depletion were found to be dependent on RhoA. Indeed, reduced expression of IQGAP3 disrupted RhoA activity and actomyosin contractility. Interestingly, IQGAP3 was also found to interact with p-21 activated kinase 6 (PAK6); a protein already associated with the regulation of cell morphology. Moreover, PAK6 depletion phenocopied IQGAP3 depletion in these cells. Whereas PAK6 overexpression rescued the IQGAP3 depletion phenotype. Our work points to an important PAK6-IQGAP3-RhoA pathway that drives the cellular contractility of breast cancer cells promoting both cell migration and adhesive invasion of these cells. As this phenotype is relevant to the process of metastasis and re-seeding of metastasis, the pharmacological targeting of PAK6 could lead to clinical benefit in TNBC patients
ESMO Resilience Task Force recommendations to manage psychosocial risks, optimise well-being, and reduce burnout in oncology.
No full textBACKGROUND: Burnout in health care professionals (HCPs) results from exposure to psychosocial risks at work. Left unaddressed, burnout can lead to chronic health problems, increased staff turnover, reduced work hours, absenteeism, and early retirement from clinical practice, thus impacting patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force (RTF) was established in December 2019 to support the well-being of oncology HCPs globally. This ESMO RTF position paper aims to provide a set of recommendations to optimise well-being and mitigate burnout in oncology, and to help individuals and institutions maintain the delivery of optimal cancer care. DESIGN: Recommendations were developed by a diverse multinational panel of interprofessional experts based on the key findings from three previously reported ESMO RTF surveys. RESULTS: Several recurrent work-related psychosocial risks in oncology were identified; in particular, concerns about workload and professional development. The need for flexible work patterns, continued use of virtual resources, well-being resources, and targeted support for at-risk groups were highlighted as key considerations to safeguard HCPs' health and prevent burnout. In total, 11 recommendations relating to three priority themes were developed: (i) information and training; (ii) resources; (iii) activism and advocacy. CONCLUSION: Optimising the well-being of oncology HCPs is essential for the provision of high-quality, sustainable care for patients globally. The ESMO RTF will continue its mission and is rolling out several initiatives and activities to support the implementation of these recommendations
Surgical Management of Primary Anorectal Melanoma: Is Less More?
No full textPURPOSE: Ano-uro-genital (AUG) Mucosal Melanoma UK guidelines recommended a less radical surgical strategy for anorectal melanoma (ARM) where possible. We report our experience of ARM consistent with that approach including clinical presentation, intervention undertaken and prognosis. METHODS: We present a retrospective study of 15 consecutive patients with ARM surgically treated between November 2014 and April 2023. Patients were divided into the two surgery types: wide local excision (WLE, n = 9) and abdominoperineal resection (APR, n = 6). Data on demographics, diagnosis, treatment and oncological outcomes were assessed between the groups. RESULTS: The mean age was 65.3 ± 17.4 years and 6 (40.0%) were female patients. Nine patients (60.0%) were diagnosed with stage I and six patients (40.0%) with stage II disease. R0 margins were achieved in all cases. The overall mean length of stay was lower following WLE compared to APR (2.6 ± 2.4 days versus 14.0 ± 9.8 days, p = 0.032). Two complications were observed in the WLE group compared to four complications after APR (p = 0.605). Five patients (55.5%) developed local/distant recurrence in the WLE group compared to three patients (50.0%) in the APR group (p = 0.707), with a median overall survival of 38.5 (12-83) months versus 26.5 (14-48) months, respectively. CONCLUSIONS: Achieving clear margins by the least radical fashion may have equivalent oncological outcomes to radical surgery, potentially reducing patient morbidity and preserving function. In our experience, the surgical management of ARM consistent with the 'less is more' approach adhering to AUG guidelines has acceptable outcomes
Simultaneous implementation of unrelated tumour sites on the MR Linac: A review of the commissioning process from a radiographer perspective and lessons learned.
No full textINTRODUCTION: This work reports on a systematic approach to select MRI sequences, quantify inter-observer image registration variation and determine patient positioning for the clinical implementation of MR-guided adaptive radiotherapy (MRgRT) in patients with oropharyngeal (H&N) and lung cancer. METHODS: A total of 30 participants (N=10 H&N and N=10 lung cancer patients and N=10 healthy participants) were scanned on the Elekta Unity Magnetic Resonance Linear Accelerator (MRL). Participant experience questionnaires were used to determine the most appropriate positioning device for lung treatments and tolerability of H&N immobilization devices within the confined MR Linac environment. Visual guided assessments (VGAs) completed by three observers (one oncologist and two radiographers) were used to determine the most suitable tissue weighting (using vendor-provided 3D T1w and T2w sequences) for online image registration. Offline MRI to CT and MRI to MRI rigid registrations were undertaken by nine radiographers using bony and soft tissue matching. Single-factor ANOVA and paired t-tests were utilized to determine the interobserver variation. RESULTS: Based on oncologist and patient feedback, lung cancer patients would be treated in a vac-bag with their arms by their sides, while H&N cancer patients would be immobilized using a 5-point fixation device and 5-point personalized thermoplastic shell. There was no clear preference for T1w or T2w images in the H&N cohort. However, observers preferred T2w sequences for tumour and organ at risk (OAR) visualization in the lung images. When a bony match was conducted, single-factor ANOVA tests showed no statistically significant differences between all H&N image registration types (p=0.09). For the soft-tissue registrations, T1w-CT and T1w-T1w registrations showed a statistically significant (p=0.01) reduction in inter-observer variability over T2w-CT registrations. Paired t-tests showed no statistically significant differences for bony or soft tissue matches using T1w or T2w sequences to the planning CT in the lung cohorts (p=0.63 and p=0.52, respectively). CONCLUSION: We describe the systematic approach to the selection of strategies for imaging, immobilization, and online image registration we used for H&N and lung cancer treatments on the MRL. This has facilitated the selection of the most appropriate adaptive MRgRT strategies for treating these sites at our institution
Imaging PD-L1 in the brain-Journey from the lab to the clinic.
No full textBACKGROUND: Immune checkpoint inhibitors (ICPIs) have proven to restore adaptive anti-tumor immunity in many cancers; however, no noteworthy therapeutic schedule has been established for patients with glioblastoma (GBM). High programmed death-ligand 1 (PD-L1) expression is associated with immunosuppressive and aggressive phenotypes in GBM. Presently, there is no standardized protocol for assessing PD-L1 expression levels to select patients and monitor their response to ICPI therapy. The aim of this study was to investigate the use of 89Zr-DFO-Atezolizumab to image the spatio-temporal distribution of PD-L1 in preclinical mouse models and in patients with newly diagnosed GBM treated with/without neoadjuvant Pembrolizumab. METHODS: The immunoreactivity, binding affinity, and specificity of 89Zr-DFO-Atezolizumab were confirmed in vitro. Mice-bearing orthotopic GBM tumors or patients with newly diagnosed GBM treated with/without Pembrolizumab were intravenously injected with 89Zr-DFO-Atezolizumab, and PET/CT images were acquired 24, 48, and 72 hours in mice and at 48 and 72 post-injection in patients. Radioconjugate uptake was quantified in the tumor and healthy tissues. Ex vivo immunohistochemistry (IHC) and immunophenotyping were performed on mouse tumor samples or resected human tumors. RESULTS: 89Zr-DFO-Atezolizumab was prepared with high radiochemical purity (RCP > 99%). In vitro cell-associated radioactivity of 89Zr-DFO-Atezolizumab corroborated cell line PD-L1 expression. PD-L1 in mouse GBM tumors was detected with high specificity using 89Zr-DFO-Atezolizumab and radioconjugate uptake correlated with IHC. Patients experienced no 89Zr-DFO-Atezolizumab-related side effects. High 89Zr-DFO-Atezolizumab uptake was observed in patient tumors at 48 hours post-injection, however, the uptake varied between patients treated with/without Pembrolizumab. CONCLUSIONS: 89Zr-DFO-Atezolizumab can visualize distinct PD-L1 expression levels with high specificity in preclinical mouse models and in patients with GBM, whilst complementing ex vivo analysis
Robotic MRI/CT Guided Multiregional 'smart' Biopsy for Characterization of Tumor Heterogeneity: A Prospective Development Study.
No full textRATIONALE AND OBJECTIVES: Intratumoral heterogeneity means single site tumor biopsy might not be representative. Here we develop and optimize an MRI-informed robotic multiregional 'smart' biopsy technique in retroperitoneal and pelvic sarcomas (RPS). We also explore the relationship between imaging and histological biomarkers. MATERIALS AND METHODS: Participants with suspected RPS underwent multiparametric (mp)MRI within a week prior to biopsy. Three target regions with differing MRI characteristics were contoured. Robotic or freehand multiregional biopsy was performed, collecting samples from each target region in separate specimen pots. CT/MRI fusion extracted quantitative imaging biomarkers for correlation with histological biomarkers at precise biopsy sites. The primary endpoint was feasibility and safety. Spearman's correlation explored the relationship between imaging and histological biomarkers. RESULTS: Twelve participants (7 women), median age 58.6 years interquartile range [IQR]: 52 - 75 years underwent biopsy. All procedures were technically successful with same-day discharge. The within-tumor range of Apparent Diffusion Coefficeint correlated very strongly with the within-tumor range of Ki-67 proliferation index; Spearman's ρ = 0.91 (95% CI 0.68 to 0.98). Ranges represent intratumoral heterogeneity uniquely obtained by multiregional biopsy. CONCLUSION: Multiregional robotic MRI-informed, CT-guided biopsy is feasible and safe in RPS. Sampling three distinct regions within tumors provides a more comprehensive and accurate representation of tumor biology than standard biopsy. The close relationship between imaging and histological heterogeneity biomarkers has broader implications for pancancer biopsy techniques, imaging characterization, and personalized treatment selection
A good decision is the one that feels right for me': Codesign with patients to inform theoretical underpinning of a decision aid website
No full textAbstractIntroductionPatient decision aids (PtDA) complement shared decision‐making with healthcare professionals and improve decision quality. However, PtDA often lack theoretical underpinning. We are codesigning a PtDA to help people with increased genetic cancer risks manage choices. The aim of an innovative workshop described here was to engage with the people who will use the PtDA regarding the theoretical underpinning and logic model outlining our hypothesis of how the PtDA would lead to more informed decision‐making.MethodsShort presentations about psychological and behavioural theories by an expert were interspersed with facilitated, small‐group discussions led by patients. Patients were asked what is important to them when they make health decisions, what theoretical constructs are most meaningful and how this should be applied to codesign of a PtDA. An artist created a visual summary. Notes from patient discussions and the artwork were analysed using reflexive thematic analysis.ResultsThe overarching theme was: It's personal. Contextual factors important for decision‐making were varied and changed over time. There was no one ‘best fit’ theory to target support needs in a PtDA, suggesting an inductive, flexible framework approach to programme theory would be most effective. The PtDA logic model was revised based on patient feedback.ConclusionMeaningful codesign of PtDA including discussions about the theoretical mechanisms through which they support decision‐making has the potential to lead to improved patient care through understanding the intricately personal nature of health decisions, and tailoring content and format for holistic care.Patient ContributionPatients with lived experience were involved in codesign and coproduction of this workshop and analysis as partners and coauthors. Patient discussions were the primary data source. Facilitators provided a semi‐structured guide, but they did not influence the patient discussions or provide clinical advice. The premise of this workshop was to prioritise the importance of patient lived experience: to listen, learn, then reflect together to understand and propose ideas to improve patient care through codesign of a PtDA.</jats:sec