Malignant ascites presents a considerable clinical challenge to the management of ovarian cancer, but also provides a wealth of opportunities for translational research. The accessibility of ascitic ...fluid and its cellular components make it an excellent source of tumour tissue for the investigation of prognostic and predictive biomarkers, pharmacodynamic markers and for molecular profiling analysis. In this Opinion article, we discuss recent advances in our understanding of its pathophysiology, the development of new methods to characterize its molecular features and how these findings can be used to improve the treatment of malignant ascites, particularly in the context of ovarian cancer.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options ...are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan.
Background
Re‐designing services and processes to meet growing demands in chemotherapy services is necessary with increasing treatments. There is little evidence guiding the timing and thresholds to ...be attained of pre‐chemotherapy blood assessments, namely neutrophils.
Methods
A survey was developed and distributed to health professionals in the United Kingdom (UK) to examine current practice in timing and threshold values of neutrophils and platelets before treatment administration. This was followed by a retrospective cohort study, using data from electronic patient record systems; including patients initiating treatment between January 2013 and December 2018, to determine a safe timeframe for blood assessments; comparing neutrophil, platelet, creatinine and bilirubin levels at different time points.
Results
The survey captured 25% of hospitals in the UK and variations were apparent in both the timing of assessments and thresholds needed, particularly for neutrophils. 616 (6.5%) of 4007 patients included had neutrophil levels measured twice within 7 days of treatment (with the first level taken beyond 3 days and the second test being within 3 days of treatment‐ the UK standard). Of the patients that attained an acceptable neutrophil level at their first test, five of the 616 (0.8%) became ineligible for administration from the test 2 level. 23% of patients improved their grade and became eligible for treatment. Little difference was observed for platelets.
Conclusions
We have demonstrated that extending the timeframe for blood tests can be safe, however, this practice may cause unnecessary delays for patients if only an early test is relied on for eligibility.
There is a dearth of evidence supporting the correct timing of blood tests prior to chemotherapy, leading to patients receiving numerous unnecessary tests. We aimed to provide this evidence, utilising data from electronic prescribing systems and showed that extending periods were safe but in the case of neutrophil assessments could lead to unwarranted delays.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of ...different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2.
In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008–17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013–16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I–III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1–6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred.
Across England in 2013–16, an average of 6281 patients with stage I–III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1–3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3–8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14 873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22 635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type.
Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer.
None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Background: Sentinel lymph node biopsy (SLNB) has traditionally been used to stage the axilla in early breast cancer (EBC) to guide adjuvant treatment recommendations. Following advances in ...genomic testing and tumor biology understanding, its role may be less critical especially in selected groups of women. The aim was to evaluate clinical utility of SLNB in adjuvant treatment recommendations for women ≥ 70 years with EBC in a tertiary unit in the United Kingdom. Methods: Retrospective cohort study of women ≥ 70 years with cT1-2N0 EBC undergoing primary surgery and SLNB between 01/2018-12/2022. Simple descriptive statistics and non-parametric tests were performed, including cost analysis of the SLNB procedure. Results: A total of 528 patients were included. The median age was 75 (IQR 72-79) years. Most cancers were invasive ductal (84.7%), grade 2 (66.9%), hormone receptor (HR) positive/HER2 negative (84.4%) with a median tumor size of 17 (IQR 4-50) mm. SLNB was positive in 64 (12.1%) patients. Of these 64 patients, 13 (20.3%) had completion ALND and 39 (60.9%) had adjuvant locoregional nodal radiotherapy (RT) including levels 1 & 2 of the axilla; adjuvant RT to levels 3 & 4 after ALND was given to 5/13. As per ACOSOG Z0011 criteria, 2/13 could have been spared ALND and 31/39 axillary RT. The multidisciplinary team (MDT) recommended adjuvant chemotherapy (AC) in 72 (13.6%) patients and 45 received it. Of those with a positive SLNB (n = 64), AC was recommended in 15, and received by 11. Recommendation for AC was significantly associated with age (p = 0.006), tumor grade (p < 0.0001), size (p = 0.001), receptor status (p < 0.0001) and positive SLNB status (p = 0.02) but not with comorbidities (p = 0.06). A subgroup analysis of 294 patients with cT1N0, HR+/HER2- EBC, representing a more favorable prognosis group, was performed. Here, 31/294 (10.5%) patients had positive SLNB, of whom 5 underwent ALND and 16 regional nodal RT, where 2/5 could have been spared ALND and 13/16 axillary RT as per ACOSOG Z0011 criteria. AC was recommended in 11/294 (3.7%) women and 9 received it. AC was not recommended in 20/31 (64.5%) cases, despite a positive SLNB. MDT recommendation for AC was associated with SLNB status (p = 0.02), grade 3 (p = 0.002) and multifocal disease (p = 0.02), while AC receipt was only associated with grade 3 (p = 0.017) and multifocal disease (p = 0.009) but not SLNB status (p = 0.058). Given an average cost of $6504.95 / £5359.38 per SLNB procedure in this unit, avoiding routine SLNB in the subgroup population may have potentially saved $1,912,493.95 / £1,575,657.72 in this 5 year period. Conclusions: Only a small proportion of women ≥ 70 years with EBC had positive SLNB that may influence adjuvant treatment recommendations, especially with favorable prognosis tumors. In such cases, where clinical morbidity and financial burden of SLNB may outweigh the benefits, a nuanced discussion for opting in SLNB rather than routine performance should be considered.
Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anticancer drug development. Three ...selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are FDA and European Medicines Agency (EMA) approved for hormone receptor-positive/HER2-negative advanced breast cancer. A major emerging appreciation is that these inhibitors not only are cytostatic, but also play critical roles in the interaction between tumor cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell-cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anticancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anticancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immunotherapy.
To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent ...from the COVID-19 pandemic.
We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval.
Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%.
Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.
Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy - immunotherapy has until recently been the standard of care for advanced disease. ...Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors - sorafenib sunitinib, temsirolimus and everolimus - are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease.
The UK National Institute for Health and Care Excellence guideline DG27 recommends universal testing for Lynch syndrome (LS) in all newly diagnosed colorectal cancer (CRC) patients. However, DG27 ...guideline implementation varies significantly by geography. This quality improvement project (QIP) was developed to measure variation and deliver an effective diagnostic pathway from diagnosis of CRC to diagnosis of LS within the RM Partners (RMP) West London cancer alliance.
RM Partners includes a population of 4 million people and incorporates nine CRC multidisciplinary teams (MDTs), overseen by a Pathway Group, and three regional genetic services, managing approximately 1500 new CRC cases annually. A responsible LS champion was nominated within each MDT. A regional project manager and nurse practitioner were appointed to support the LS champions, to develop online training packages and patient consultation workshops. MDTs were supported to develop an 'in-house' mainstreaming service to offer genetic testing in their routine oncology clinics. Baseline data were collected through completion of the LS pathway audit of the testing pathway in 30 consecutive CRC patients from each CRC MDT, with measurement of each step of the testing pathway. Areas for improvement in each MDT were identified, delivered by the local champion and supported by the project team.
Overall, QIP measurables improved following the intervention. The Wilcoxon signed rank test revealed significant differences with strong effect sizes on the percentile of CRC cases undergoing mismatch repair (MMR) testing in endoscopic biopsies (p = 0.008), further testing with either methylation or BRAF V600E (p = 0/03) and in effective referral for genetic testing (from 10% to 74%; p = 0.02). During the QIP new mainstreaming services were developed, alongside the implementation of systematic and robust testing pathways. These pathways were tailored to the needs of each CRC team to ensure that patients with a diagnosis of CRC had access to testing for LS. Online training packages were produced which remain freely accessible for CRC teams across the UK.
The LS project was completed by April 2022. We have implemented a systematic approach with workforce transformation to facilitate identification and 'mainstreamed' genetic diagnosis of LS. This work has contributed to the development of a National LS Transformation Project in England which recommends local leadership within cancer teams to ensure delivery of diagnosis of LS and integration of genomics into clinical practice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
To describe the tolerability and efficacy of neratinib as a monotherapy and in combination with capecitabine in advanced HER2-positive breast cancer in a real-world setting.
Methods
Patients ...who received neratinib for advanced HER2-positive at the Royal Marsden Hospital NHS Trust between August 2016 and May 2020 were identified from electronic patient records and baseline characteristics, previous treatment and response to treatment were recorded. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety.
Results
Seventy-two patients were eligible for the analysis. Forty-five patients received neratinib in combination with capecitabine and 27 patients received monotherapy. After a median duration of follow-up of 38.5 months, the median PFS for all patients was 5.9 months (95% confidence interval (CI) 4.9–7.4 months) and median OS was 15.0 months (95% Cl 10.4–22.2 months). Amongst the 52.7% (38/72) patients with confirmed brain metastases at baseline, median PFS was 5.7 months (95% CI 2.9–7.4 months) and median OS was 12.5 months (95% CI 7.7–21.4 months). Despite anti-diarrhoeal prophylaxis, diarrhoea was the most frequent adverse event, reported in 64% of patients which was grade 3 in 10%. There were no grade 4 or 5 toxicities. Seven patients discontinued neratinib due to toxicity.
Conclusions
Neratinib monotherapy or in combination with capecitabine is a useful treatment for patients with and without brain metastases. PFS and OS were found to be similar as previous trial data. Routine anti-diarrhoeal prophylaxis allows this combination to be safely delivered to patients in a real-world setting.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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