The impact of inter-cycle treatment delays on overall survival in patients with advanced-stage ovarian cancer.

INTRODUCTION: Chemotherapy forms the cornerstone of systemic treatment for advanced ovarian cancer, extending overall survival; however, drug-related toxicity can lead to treatment delays, potentially diminishing treatment efficacy. This study evaluated the impact of treatment delays on all-cause mortality of patients with ovarian cancer, to better inform decisions on patient management. METHODS: This retrospective, population-based cohort study included 1517 women with advanced-stage ovarian cancer, receiving first-line adjuvant or neoadjuvant chemotherapy in 2014 and 2015. The frequency of inter-cycle delays >7 days was calculated using drug administration dates. Kaplan-Meier estimates were used to compare 2-year overall survival (OS) between patients who were delayed and those treated to schedule. Cox proportional hazards regression was used to investigate the impact of treatment delay on all-cause mortality. Inverse probability of treatment weighting propensity scores were used to adjust for confounding variables. RESULTS: Delays >7 days occurred in 35.3% of patients. Two-year OS probability was 62.7% in patients who experienced treatment delays >7 days (95% CI, 58.7-66.9) compared to 69.1% in those treated to schedule (95% CI, 66.2-72.0). Delays were not significantly associated with all-cause mortality when adjusted for confounders (HR 1.00 95% CI, 0.83-1.20, P = .9). CONCLUSIONS: Delays to chemotherapy treatment were not significantly associated with worsened survival in patients with advanced-stage ovarian cancer. These results can inform clinical decision making that prioritize toxicity management and quality of life for those treated with chemotherapy.

The impact of inter-cycle treatment delays on 5-year all-cause mortality in early-stage breast cancer: A retrospective cohort study.

BACKGROUND: Inter-cycle delays to chemotherapy are often required to manage drug toxicity. The impact of delays on mortality is poorly characterised. This retrospective cohort study examined the association of treatment delay with all-cause mortality in early-stage breast cancer. METHODS: This real-world analytical study included adult women with stage 2 or 3 breast cancer receiving first-line (neo-)adjuvant chemotherapy between 01/01/2014 and 31/12/2015 in England. Inter-cycle delays > 7 days during the treatment period were calculated, and the association of treatment delay with 5-year all-cause mortality was investigated. Survival was compared between patients experiencing treatment delay and those completing treatment to schedule using landmark methodology and Kaplan-Meier (KM) estimator. Cox proportional hazards regression was used to investigate the impact of delay on survival, using inverse probability of treatment weighting to adjust for confounding variables. RESULTS: 8567 patients were included. 17 % (1448) experienced inter-cycle delay > 7 days during the treatment period. 1120 (13 %) women had died at the end of the 5-year follow up period. Median follow-up time was 5.5 years. Survival probability was significantly lower in patients experiencing treatment delay by KM estimator analysis (p < 0.0001). Cox proportional hazards regression demonstrated a significant positive association between delay and 5-year all-cause mortality (HR 1.33 95 % CI 1.12-1.61, p < 0.001). CONCLUSIONS: This is the largest study of its kind demonstrating an association between treatment delay and all-cause mortality. These findings support interventions to improve toxicity management allowing completion of chemotherapy to schedule where patients experience treatment delay due to treatment-related toxicity or hospital capacity pressures.

The Clinical Features and Outcomes of Pseudocirrhosis in Breast Cancer.

Pseudocirrhosis is a diffuse nodularity of the liver that radiologically mimics cirrhosis but is a distinct pathological process. It is seen almost exclusively in patients with liver metastases and may represent a response to systemic treatment. Data on the risk factors for pseudocirrhosis and outcomes are limited. In total, 170 patients with a diagnosis of breast cancer and pseudocirrhosis in a 10-year period were identified and retrospectively analysed. Data were collected on baseline patient characteristics, treatments received, and outcomes. Median time between diagnosis of liver metastases and diagnosis of pseudocirrhosis was 17.1 months (range, 0-149 months). In total, 89.4% of patients received chemotherapy between their diagnosis of breast cancer liver metastases and their diagnosis of pseudocirrhosis, most commonly a taxane (74.7%) or capecitabine (67.1%), and the median treatment lines received was 3. Median OS from first diagnosis of pseudocirrhosis was 7.6 months (95% CI: 6.1-9.6 months) and was longer in patients with HER2+ disease at 16.7 months (95% CI: 6.4-32.9 months), which was statistically significant. In our study, pseudocirrhosis occurred in the presence of liver metastases and was associated with a poor prognosis. HER2+ patients with pseudocirrhosis had a better prognosis than other subtypes, but we did not identify other significant predictors of survival. Chemotherapy was not a prerequisite for pseudocirrhosis development, although the majority of patients had received at least one line of chemotherapy before pseudocirrhosis was diagnosed.

Implementation of a geriatric oncology service at the Royal Marsden Hospital.

INTRODUCTION: Despite significant evidence supporting the benefits of comprehensive oncogeriatric assessment in the management of older patients with cancer, the adoption of specialised geriatric oncology programs in the United Kingdom remains limited. Descriptions of clinic structure and models, patient demographics and baseline characteristics, resource utilisation, and predictors of resource utilisation are lacking in this population, which may complicate or impede the planning, resourcing, and development of further services in this subspecialty on a national and regional basis. MATERIALS AND METHODS: Between November 2021 and April 2023, 244 patients commencing systemic anticancer treatment at the Royal Marsden Hospital, London underwent geriatric screening using the Senior Adult Oncology Programme-3 (SAOP3) screening tool. Baseline clinical factors (sex, age, Charlson Comorbidity Index score, Cumulative Illness Rating Scale-Geriatric [CIRS-G] score, Katz Index score, Barthel Index score, treatment intent, and Eastern Cooperative Oncology Group Performance Status [ECOG-PS]) were assessed as predictors of geriatric impairments and need for multidisciplinary referral and intervention using a negative binomial regression analysis. Referral rates to multidisciplinary teams were assessed against ECOG-PS score using point-biserial correlation, as well as against a historical control using descriptive statistics. RESULTS: The median age of participants was 77; 75.8% were female. Breast cancer was the most prevalent diagnosis (61.9%). Most patients (67.6%) were undergoing treatment in the palliative setting. Two hundred eleven (86.5%) patients were identified as having at least one geriatric impairment. Six hundred forty-nine multidisciplinary referrals were made, of which 583 (86.7%) were accepted by the referred patient. Higher ECOG PS was positively associated with geriatric impairments in physiotherapy, occupational therapy, dietetics, pharmacy, and welfare rights domains, as well as with the overall number of geriatric impairments. DISCUSSION: The Royal Marsden Senior Adult Oncology Programme represents the first geriatric oncology service in a tertiary cancer centre in the United Kingdom. Following implementation of SAOP3 screening, we observed a substantial increase in referrals to all multidisciplinary teams, suggestive of previously underrecognized needs among this population. The need for multidisciplinary intervention was strongly correlated with baseline ECOG-PS score, but not with other measured clinical variables, including comorbidity or functional indices.

From diagnosis of colorectal cancer to diagnosis of Lynch syndrome: The RM Partners quality improvement project.

AIM: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Neratinib in advanced HER2-positive breast cancer: experience from the royal Marsden hospital.

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.

Vinorelbine After Prior Treatment With Eribulin for Advanced Breast Cancer: A Single-Centre Experience Suggesting Cross-Resistance.

INTRODUCTION: The tubulin inhibitor, eribulin, improves survival for previously treated advanced breast cancer (ABC) compared to chemotherapy of physician's choice, including vinorelbine, an older anti-tubulin. Vinorelbine is commonly still used after eribulin, but potentially risks cross-resistance and its efficacy in this setting is unproven. MATERIALS AND METHODS: A retrospective analysis of all patients who received vinorelbine after prior eribulin (VAE) 2011-2015 and a parallel cohort of consecutive patients who received vinorelbine without prior eribulin (VWE) for previously treated ABC between 2005 and 2011. Patient demographics, histopathological features, treatment duration and responses were recorded. The primary endpoint was progression-free survival from date of first vinorelbine for each cohort. Secondary endpoints included radiological response rate, and overall survival (OS). RESULTS: Thirty-five VAE and 103 VWE patients were identified, all female, 71.4% and 78.6% were ER positive/HER2 negative, 8.6% and 6.8% HER2 positive, and 20.0% and 14.6% triple negative for VAE and VWE cohorts, respectively. The median number of lines of chemotherapy lines prior to vinorelbine was 4 (range 2-6) and 2 (range 0-4), respectively. Fifteen VAE patients (42.9%) received ≥1 line of chemotherapy between eribulin and vinorelbine. VAE and WWE Patients received a median of 3 cycles of vinorelbine (range 1-9 and 1-12, respectively). The median progression-free survival for VAE patients was 2.1 months and 2.0 months for VWE patients. No VAE patients were progression-free at 24 weeks, compared to 15.5% of VWE patients. Median OS from commencing vinorelbine was 4.3 months for VAE and 6.4 months for VWE patients. CONCLUSION: Vinorelbine was of limited benefit after prior eribulin in our study, suggesting cross-resistance. Even without prior eribulin, only 15% of patients experienced clinical benefit from vinorelbine monotherapy.

Palliative chemotherapy for breast cancer: A population-based cohort study of emergency hospital admissions and place of death.

OBJECTIVE: Patients with incurable breast cancer may be treated with chemotherapy to improve cancer-related symptoms, quality of life and survival. We examined the association between use of palliative chemotherapy towards the end of life in breast cancer patients and outcomes including unplanned hospital admission and place of death. METHODS: A total of 10,966 women, treated with palliative chemotherapy for breast cancer (diagnosed 1995-2017 in England) within the 2 years prior to death (death between 2014 and 2017), were analysed. Logistic regression (outcome = emergency hospital admission in last 90 days of life yes/no; outcome = place of death hospital/other) was performed, adjusting for line of palliative chemotherapy in the last 90 days of life and patient demographics. RESULTS: The odds of hospital admission reduced with increasing line of chemotherapy received (1st line odds ratio [OR] = 2.7, 2nd line OR = 2.1, 3rd line OR = 1.9, 4th+ line OR = 1.7; baseline chemotherapy) in last 90 days of life. A similar relationship was observed for hospital death (1st line OR = 2.4, 2nd line OR = 2.1, 3rd line OR = 1.7, 4th+ line OR = 1.5). CONCLUSION: This study finds palliative chemotherapy towards the end of life to be associated with increased odds of unplanned hospital admissions and hospital death. These findings can be used to inform discussions between patients and healthcare professionals towards the end of life.

Evidence to guide the optimal timing for pre-chemotherapy blood tests for early breast, colorectal cancer and diffuse large B-cell lymphoma.

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.

Impact of timing of adjuvant chemothapy for early breast cancer: the Royal Marsden Hospital experience.

BACKGROUND: The optimal time to deliver adjuvant chemotherapy has not been defined. METHODS: A retrospective study of consecutive patients receiving adjuvant anthracycline and/or taxane 1993-2010. Primary endpoint included 5-year disease-free survival (DFS) in patients commencing chemotherapy <31 versus ≥31 days after surgery. Secondary endpoints included 5-year overall survival (OS) and sub-group analysis by receptor status. RESULTS: We identified 2003 eligible patients: 1102 commenced chemotherapy <31 days and 901 ≥31 days after surgery. After a median follow-up of 115 months, there was no difference in 5-year DFS rate with chemotherapy <31 compared to ≥31 days after surgery in the overall population (81 versus 82% hazard ratio (HR) 1.15, 95% confidence interval (95% CI) 0.92-1.43, p = 0.230). The 5-year OS rate was similar in patients who received chemotherapy <31 or ≥31 days after surgery (90 versus 91%, (HR 1.21, 95% CI 0.89-1.64, p = 0.228). For 250 patients with triple-negative breast cancer OS was significantly worse in patients who received chemotherapy ≥31 versus <31 days (HR = 2.18, 95% CI 1.11-4.30, p = 0.02). DISCUSSION: Although adjuvant chemotherapy ≥31 days after surgery did not affect DFS or OS in the whole study population, in TN patients, chemotherapy ≥31 days after surgery significantly reduced 5-year OS; therefore, delays beyond 30 days in this sub-group should be avoided.

The 'hub and spoke model' for the management of surgical patients during the COVID-19 pandemic.

During the on-going COVID-19 pandemic a number of key public health services have been severely impacted. These include elective surgical services due to the synergetic resources required to provide both perioperative surgical care whilst also treating acute COVID-19 patients and also the poor outcomes associated with surgical patients who develop COVID-19 in the perioperative period. This article discusses the important principles and concepts for providing important surgical services during the COVID-19 pandemic based on the model of the RMCancerSurgHub which is providing surgical cancer services for a population of approximately 2 million people across London during the pandemic. The model focusses on creating local and regional hub centres which provide urgent treatment for surgical patients in an environment that is relatively protected from the burden of COVID-19 illness. The model extensively utilises the extended multidisciplinary team to allow for a flexible approach with core services delivered in 'clean' sites which can adapt to viral surges. A key requirement is that of a clinical prioritisation process which allows for equity in access within and between specialties ensuring that patients are treated on the basis of greatest need, while at the same time protecting those whose conditions can safely wait from exposure to the virus. Importantly, this model has the ability to scale-up activity and lead units and networks into the recovery phase. The model discussed is also broadly applicable to providing surgical services during any viral pandemic.

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study.

OBJECTIVE: 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. DESIGN: 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. RESULTS: 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%. CONCLUSIONS: 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.

Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: None.

Patient factors and their impact on neutropenic events: a systematic review and meta-analysis.

BACKGROUND: Neutropenia is associated with an increased risk of mortality and hospitalisation. Strategies, including the prescribing of colony-stimulating growth factors (CSFs), are adopted when a high risk (> 20%) of neutropenic complications are seen in the clinical trial setting. With a diverse treatment population that may differ from the patient groups recruited to studies, appropriate prescribing decisions by clinicians are essential. At present, results are conflicting from studies evaluating the risks of certain patient attributes on neutropenic events; we aimed to aggregate these associations to guide future management. DESIGN: A systematic review with a meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Studies were identified through a literature search using MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to December 1, 2017. Studies were included into a meta-analysis if they adjusted for confounders; analyses were conducted in STATA v 15.1 SE. RESULTS: A total of 4415 articles were retrieved by the search with 37 meeting the inclusion criteria and 12 eligible for meta-analysis. Meta-analysis was conducted for increasing age and yielded a pooled odds ratio of 1.39 (1.11, 1.76, I2 = 24.1%), in our subgroup analysis of 4814 patients. Odds ratios for studies were pooled that reported associations for one co-morbidity compared to none and resulted in an overall odds of 1.54 (CI 1.09-2.09, I2 = 13.1%), including 9189 patients in total. CONCLUSIONS: Results can enhance current guidance in prescribing primary prophylaxis for treatments that either fall marginally under the internationally recognised 20% neutropenia risk.

To Cycle or Fight-CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity.

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.

Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy.

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.

Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research.

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.

The association of PI3 kinase signaling and chemoresistance in advanced ovarian cancer.

Evidence that the phosphoinositide 3-kinase (PI3K) pathway is deregulated in ovarian cancer is largely based on the analysis of surgical specimens sampled at diagnosis and may not reflect the biology of advanced ovarian cancer. We aimed to investigate PI3K signaling in cancer cells isolated from patients with advanced ovarian cancer. Ascites samples were analyzed from 88 patients, of whom 61 received further treatment. Cancer cells were immunomagnetically separated from ascites, and the signaling output of the PI3K pathway was studied by quantifying p-AKT, p-p70S6K, and p-GSK3ß by ELISA. Relevant oncogenes, such as PIK3CA and AKT, were sequenced by PCR-amplified mass spectroscopy detection methods. In addition, PIK3CA and AKT2 amplifications and PTEN deletions were analyzed by FISH. p-p70S6K levels were significantly higher in cells from 37 of 61 patients who did not respond to subsequent chemotherapy (0.7184 vs. 0.3496; P = 0.0100), and this difference was greater in patients who had not received previous chemotherapy. PIK3CA and AKT mutations were present in 5% and 0% of samples, respectively. Amplification of PIK3CA and AKT2 and deletion of PTEN was seen in 10%, 10%, and 27% of samples, respectively. Mutations of PIK3CA and amplification of PIK3CA/AKT2 or deletion of PTEN did not correlate with levels of p-AKT, p-p70S6K, and p-GSK3ß. In patients with advanced ovarian cancer, there is an association between levels of p-p70S6K and response to subsequent chemotherapy. There is no clear evidence that this is driven specifically by PIK3CA or AKT mutations or by amplifications or deletion of PTEN.

Current treatment and clinical trials in ovarian cancer.

Although platinum chemotherapy remains the standard treatment for ovarian cancer, recent advances in novel targeted drugs have generated anticipation and excitement. In addition, alternate administration schedules of already established cytotoxics have shown promise in both front line and recurrent disease settings. In this review, we outline the seminal trials that influenced our current management as well as introduce recent trials that have provided intriguing results to aid the understanding of ovarian tumour biology.

Systemic therapy for advanced renal cell carcinoma.

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.