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Standardization of Radiation Therapy to Inguinal and Pelvic Lymph Nodes in Locally Advanced Cancer of the Penis, as Defined by the International Penile Advanced Cancer Trial (InPACT).
No full textPURPOSE: InPACT addresses the optimal management of locally advanced penile cancer, aiming to prospectively evaluate the relative benefits and sequencing of surgery, chemotherapy, and chemoradiotherapy. At trial inception, radiation therapy protocols for this rare cancer lacked consistency and standardization, necessitating multicenter, international collaboration to develop comprehensive radiation therapy planning, delivery, and quality assurance guidelines. METHODS AND MATERIALS: InPACT has 2 main aims; to establish the efficacy of neoadjuvant chemotherapy or chemoradiotherapy in patients with macroscopically-involved inguinal nodes. Second, to compare prophylactic pelvic lymph node dissection plus chemoradiation to the inguinal and pelvic fields versus chemoradiation alone in patients whose inguinal node histology predicts a high risk of occult pelvic node involvement. The primary outcome measure for the trial is survival time. An international group was convened to achieve consensus on radiation therapy contouring, planning, dose, fractionation, and delivery for this rare cancer. These guidelines have been used throughout the conduct of the trial to date and form part of the radiation therapy quality assurance for each participating center. RESULTS: International consensus radiation therapy guidelines were established, encompassing risk status assessment and indications for each treatment region based on radiological and pathologic risk status of nodal basins. Guidance provides a nodal contouring atlas, addresses prepubic fat coverage, and specifies dose fractionation for both neoadjuvant and adjuvant settings, including recommendations for macroscopic disease. Trial recruitment is ongoing. Oncological and toxicity outcomes will be reported in due course. CONCLUSIONS: The InPACT radiation therapy guidelines offer a step toward international consensus on contouring for inguino-pelvic radiation therapy in penile cancer
Partial breast radiotherapy for women with early breast cancer (UK IMPORT LOW Trial): 10-year outcomes from a multicentre, randomised, controlled, phase 3, non-inferiority trial
No full textThe NHS England Jewish BRCA Testing Programme: overview after first year of implementation (2023-2024).
Get PDFBACKGROUND: The NHS Jewish BRCA Testing Programme is offering germline BRCA1 and BRCA2 genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population.Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline. A first-of-its-kind in the United Kingdom (UK) for population genetic testing, outside of research. METHODS: We reviewed data from germline testing of 5389 people who registered during the soft-launch phase (January 2023-January 2024) and their families to observe trends in uptake and outcomes of testing. RESULTS: Of the 5389 self-referrals, 4339 (80.5%) consented to testing. Of those with results returned, 2.3% (98/4,274) had a gPV (89.8% AJ founder and 10.2% non-AJ founder).Notably, the detection rate was higher in men (42/790, 5.3%) compared with women (56/3484, 1.6%), with the proportion reporting known BRCA variants within the family prior to consent also significantly increased (13.1% compared with 9.2%, respectively). CONCLUSION: Overall detection rates of gPVs are similar to those reported elsewhere from Jewish population testing. The pathway, particularly for males, may attract uptake of testing by those previously aware of familial gPVs
Factors associated with longitudinal progression of the cumulative burden of morbidity and overall mortality after cisplatin-based chemotherapy for testicular cancer.
No full textBACKGROUND: To comprehensively evaluate the longitudinal progression of cumulative burden of morbidity (CBM) in testicular cancer survivors (TCS) following standard-dose cisplatin-based chemotherapy and the impact of modifiable risk factors on morbidity and early mortality. METHODS: Participants completed first-line chemotherapy at or longer than 6 months before baseline assessments with comprehensive questionnaires and physical examinations. Based on follow-up assessments (median: 7 years later), longitudinal progression of adverse health outcomes (AHOs) and CBM score (encompassing AHO number and severity) were examined. Baseline health behaviors and AHOs were evaluated for associations with mortality using mixed-effects parametric proportional-hazards regression to identify modifiable risk factors. RESULTS: Among 616 TCS longitudinally assessed, 23% experienced worsening CBM postchemotherapy (median = 11 years, interquartile range = 7-15). Declines were driven by worsening treatment-related AHOs: tinnitus (29.7%), hearing loss (24.4%), Raynaud's disease (22.6%), neuropathy (18.5%), and neuropathic pain (10.7%). Baseline factors associated with worsening neuropathy included lack of aerobic physical activity (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.06 to 3.72), and obesity (OR = 1.85, 95% CI = 1.17 to 2.92). These were also related to worsening neuropathic pain (OR = 2.82, P = .009 and OR = 2.29, P = .023). Twenty-nine deaths occurred among 1830 5-year TCS (4.2% cumulative hazard) (median age = 48 years, range = 22-74). Participants reporting neuropathic pain (hazard ratio [HR] = 3.64, 95% CI = 1.45 to 9.10), no aerobic (HR = 6.56, 95% CI = 2.73 to 15.8), or no low-impact physical activity (HR = 3.96, 95% CI = 1.40 to 11.2) had significantly higher mortality, as did TCS indicating fair (HR = 9.23, 95% CI = 3.08 to 27.8) or poor (HR = 18.5, 95% CI = 3.30 to 103) health. Relationships between pain and mortality were mediated through lowered physical activity (P = .036). CONCLUSIONS: Clinically actionable factors associated with early mortality identify high-risk TCS in need of closer monitoring and targeted interventions. The significant relationship between neuropathic pain and mortality, mediated by low physical activity, is the first to our knowledge in TCS
Intensity-modulated moderately hypofractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-C): early toxicity results from a randomised, open-label, phase 3, non-inferiority trial.
No full textBACKGROUND: Moderately hypofractionated radiotherapy (MHRT) is a standard treatment for prostate cancer. Stereotactic body radiotherapy (SBRT) is also effective, and has been shown to be non-inferior to MHRT in a lower-risk group of patients who did not require hormone therapy (PACE-B), but randomised data on toxicity for higher-risk patients are lacking. We aimed to compare the early toxicity of MHRT and SBRT. METHODS: The randomised, open-label, phase 3, non-inferiority PACE-C trial, conducted at 53 hospitals across the UK, Republic of Ireland, and New Zealand, recruited men aged at least 18 years with intermediate-risk or high-risk histologically confirmed prostate adenocarcinoma (T1-T3a, Gleason 7-8, and prostate specific antigen 10-30 ng/mL) and with WHO performance status of 0-2. Participants were centrally randomly assigned (1:1; non-masked; permuted block size of four and six; stratified by centre and risk group) to MHRT (60 Gy; 20 daily fractions over 4 weeks) or SBRT (36·25 Gy; five daily or alternate day fractions; over 1-2 weeks) with an additional mandatory clinical target volume dose target of 40 Gy (no margin) to the prostate, and proximal 1 cm of seminal vesicles. 6 months of androgen deprivation therapy was planned and was started before commencement of radiotherapy. The primary outcome of PACE-C is freedom from biochemical or clinical failure, the data for which are not yet mature. The co-primary endpoints for this preplanned safety analysis were the percentages of Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicities at any point during or within 12 weeks of completion of radiotherapy (the early or acute period). Analyses are by treatment received, with participants included if they had one or more fractions of MHRT or SBRT, regardless of their allocated treatment. Late toxicity and efficacy data are awaited as the trial remains in follow-up. The study was prospectively registered with ClinicalTrials.gov, NCT01584258. FINDINGS: Between Nov 13, 2019, and June 24, 2022, 1208 participants were randomly assigned (601 to MHRT and 607 to SBRT). 608 patients received MHRT and 584 received SBRT, and thus were included in the study analysis. 1136 (95%) of 1192 patients were White, 20 (2%) were Black or Black British, 17 (1%) were Asian or Asian British, and seven (1%) were Chinese or other. During the early period (within 12 weeks of treatment), the co-primary endpoint of RTOG grade 2 or worse genitourinary toxicity was observed in 166 (27%) of 608 patients (95% CI 23·8 to 31·1) receiving MHRT and 162 (28%) of 582 patients (24·3 to 31·7) after SBRT (absolute difference 0·5%, 95% CI -4·7 to 5·7; p=0·89). For grade 2 or worse genitourinary Common Terminology Criteria for Adverse Events (CTCAE), 170 (28%) of 604 patients had events after MHRT and 195 (34%) of 581 patients had events after SBRT (p=0·050). Grade 3 CTCAE genitourinary toxicity was observed in three (<1%) patients receiving MHRT and three (1%) patients receiving SBRT. For grade 2 or worse gastrointestinal CTCAE, 60 (10%) of 604 patients had an event after MHRT and 96 (17%) of 581 patients had an event after SBRT (p=0·0011). Grade 3 CTCAE gastrointestinal toxicity was observed in three (<1%) patients receiving MHRT and four (1%) patients receiving SBRT. During the early period, the co-primary endpoint of RTOG grade 2 or worse gastrointestinal toxicity was observed in 69 (11%) of 608 patients (95% CI 9·0 to 14·2) receiving MHRT and 74 (13%) of 584 patients (10·2 to 15·8) receiving SBRT (absolute difference 1·4%, 95% CI -2·5 to 5·2; p=0·53). There were no treatment-related deaths. INTERPRETATION: Despite an accelerated treatment schedule and a larger treated volume than PACE-B, SBRT and MHRT had similar rates of early RTOG toxicity. FUNDING: The Royal Marsden Cancer Charity
Strategies to reverse treatment resistance in castration resistant prostate cancer (CRPC)
No full textProstate cancer (PC) growth and progression is usually dependent on androgens and androgen receptor (AR) signalling. Much research to date on metastatic castrate resistant prostate cancer (mCRPC) has focused on mechanisms of deregulated AR signalling. AR targeted therapies increase overall survival from aggressive PC, however, resistance is usually inevitable. PC cells are believed to be dependent on the tumour microenvironment (TME) to support tumour progression. Myelomonocytic cells, including a cell type described as myeloid-derived suppressor cells (MDSCs), have emerged as important players in prostate cancer biology, arguably supporting tumourigenesis. MDSCs have been reported to fuel AR signalling and drive castration resistance by releasing interleukin-23 (IL-23) and neuregulin-1 (NRG-1) in a paracrine fashion; IL-23 is implicated in may act directly on tumour cells to promote their growth. Myelomonocytic cells also generate the HER3 ligand NRG1; preclinical findings indicate that HER3 activation by NRG-1 generated by myelomonocytic cells is a therapeutic target in advanced PC. The gastrointestinal (GI) microbiota are also implicated in carcinogenesis, perhaps impacting myelomonocytic inflammation and PC progression. In preclinical mouse models, gut microbial composition is linked to the development of endocrine resistance. Nevertheless, the mechanisms by which microbiota impact prostate carcinogenesis and PC growth remain underexplored, although it has been reported that GI microbiota can synthesise androgenic steroids and carcinogens. This MD (Res) thesis brings together translational and clinical research to systematically dissect how MDSCs and GI microbiota contribute to PC growth, mechanisms of resistance, and how it can be modulated to prevent and treat PC, validating and qualifying a multiplex biomarker assay that can then be utilized in therapeutic and prevention studies. These findings will be of direct therapeutic relevance since mechanistic elucidation of the interaction between MDSCs, host microbiota and prostate tumours will facilitate the design of interventions to improve outcome from PC
Patient and public involvement in the SPRUCE methodology study investigating electronic patient reported outcomes in oncology clinical trials.
No full textBACKGROUND: Patient reported outcomes (PRO) provide crucial insight into trial participants' experience of oncology treatments. At the Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU), these are completed by participants on paper. The SPRUCE study within a trial (SWAT) investigates the impact of PRO questionnaire modality (paper or electronic) on the data received. To ensure SPRUCE is acceptable and appropriately patient-focused, we involved Patient and Public Involvement (PPI) partners throughout development and oversight. BODY: A survey was developed with PPI input, to assess public attitudes to electronic completion of healthcare questionnaires. We advertised in local papers to reach respondents without internet access; other avenues were limited due to the COVID-19 pandemic. Survey respondents were invited to virtual discussion groups to review the proposed SWAT design and provide feedback on its relevance and acceptability to potential study participants. Discussion group contributors were invited to join the SPRUCE Patient and Public Oversight Committee, providing PPI input throughout the study. Committee members were given a document explaining clinical trials, the SPRUCE study, and the committee itself. The first committee meeting saw PPI members testing the electronic PRO (ePRO) system and giving feedback on this and the patient-facing documents, for which we provided structured feedback forms. Members also provided feedback on the meeting itself. Of the fifty survey respondents, eight joined a discussion group. Six subsequently joined the Patient and Public Oversight Committee, along with one patient advocate who had been involved in the initial study design and funding application. Each committee member had access to the internet and would prefer to complete PRO questionnaires electronically. Six committee members tested the online ePRO completion system using various personal devices, resulting in changes including the addition of a free text box for participants to leave comments. Patient and public input also shaped patient-facing study documentation, including wording of the patient information sheet and correspondence to participants. CONCLUSIONS: Despite challenges faced in accessing a diverse demographic, PPI input has improved SPRUCE by ensuring the patient viewpoint is central to study oversight, helping identify ways to improve participant experience and streamlining study processes
Understanding the homeostatic response to PARP inhibitors in breast cancer
No full textPARPi show significant antitumor activity in BRCA1/2 mutant tumours, but many patients develop
resistance, and the underlying causes are often unknown. Predominantly our understanding of
resistance to PARPi has originated from studies utilising genetic approaches, and relatively little is
understood about the protein expression changes induced by PARPi, and how these changes could
give rise to PARPi resistance. In this thesis, I used mass spectrometry based proteomic profiling of
both tumour cell lines and patient derived tumour organoids to define the proteomic response to
PARPi exposure. I integrated the information gained from this proteomic profiling with genetic
perturbation screens, particularly CRISPR activation screens, to identify candidate gain of function
mechanisms of PARPi resistance. I identified upregulation of the cohesin loader NIPBL as a
candidate driver of PARP inhibitor resistance. Examination of tumour RNA-seq data from advanced
breast cancer patients with PARPi resistance indicated that NIPBL might be upregulated in the PARPi
resistant state. By conducting functional studies in in vitro models, I confirmed that upregulation of
NIPBL confers PARPi resistance, and likely does so by restoring the localisation of RAD51 to the site
of DNA damage in BRCA1/2 mutant cells that otherwise have a RAD51 defect. Together, the data
presented in this thesis offers a foundation for understanding the homeostatic responses to PARPi
exposure which could drive PARPi resistance in BRCA1/2 mutant tumours
Is pathological response an adequate surrogate marker for survival in neoadjuvant therapy with immune checkpoint inhibitors?
No full textPathological response (PR) is an oncological outcome measure that indicates the therapeutic response to neoadjuvant therapy. In clinical trials involving neoadjuvant or perioperative interventions, overall survival and disease/event-free survival are typically the primary outcome measures. Although some evidence suggests that pathological complete response (pCR) can serve as a surrogate marker for the primary endpoint in prospective trials, it remains uncertain whether pCR is a true surrogate marker for patients with cancer undergoing curative resection across all solid tumours. Here, we review the role of PR as a surrogate marker and its associated methodological issues in the era of perioperative immune checkpoint inhibitors
The Effects of Ultrasound-Stimulated Microbubbles Combined with Radiotherapy in Cancer Models
No full textApproximately 50% of all cancer patients are treated with radiotherapy during the course of their illness. Although progress has been made in treatment planning and delivery over recent decades, issues of normal tissue toxicities and radioresistance remain, particularly for patients with head and neck cancer (HNC). For these patients, there is a clinical unmet need for radiosensitising agents. Ultrasound-stimulated microbubbles (USMB) modulate the tumour microenvironment (TME) in a highly localised manner by targeting the microvasculature, inducing biological effects such as vessel disruption, vasodilation, immune cell activation and infiltration, and enhanced vessel permeability. Investigations into the use of USMB as an adjunct therapy for radiotherapy have reported enhanced tumour control in several preclinical xenograft models, however the mechanism responsible for the additive effects remains indeterminate. The aim of this thesis was to study the therapeutical potential of USMB as radiosensitisation agents in HNC using syngeneic preclinical models, and to explore the mechanism responsible for the radioenhancement effects. In vivo studies combining USMB and radiotherapy to treat two murine HNC models (MOC1 and MOC2) demonstrated the potential of the combination to enhance tumour growth control in this cancer indication. To evaluate the molecular and immunological effects and determine the mechanisms responsible for the radiosensitisation effect, multimodality imaging, histological analysis, immune profiling, and in vitro assays were carried out. The novel results from this thesis have the potential to optimise USMB use clinically to improve the quality of life of HNC patients following radiotherapy