Publications by authors named "Anna Minchom"

31 Publications

Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-small Cell Lung Cancer in the Phase 1/2 LIBRETTO-001 Trial.

Oncologist 2021 Sep 15. Epub 2021 Sep 15.

University of California at San Francisco, USA.

Background: LIBRETTO-001 is an ongoing, global, open-label, phase 1/2 study of selpercatinib in patients with advanced or metastatic solid tumors. We report interim patient-reported outcomes in patients with RET fusion-positive non-small-cell lung cancer (NSCLC).

Patients And Methods: Patients completed the EORTC QLQ-C30 version 3.0 at baseline (Cycle 1, Day 1), approximately every other 28-day cycle until Cycle 13, and every 12 weeks thereafter. Data were evaluated through Cycle 13 as few patients had reached later timepoints. A change of ≥10 points from baseline in domain scores was considered clinically meaningful.

Results: Among 253 selpercatinib-treated patients, 239 were categorized into subgroups by prior therapy: treatment-naïve (n=39), 1 prior line of therapy (n=64), or ≥2 prior lines of therapy (n=136). The QLQ-C30 was completed by >85% of patients at each timepoint. Most patients overall and in each subgroup maintained or improved in all health-related quality of life (HRQoL) domains during treatment. The percentage of patients who experienced clinically meaningful improvements ranged from 61.1%-66.7% for global health status, 33.3%-61.1% for dyspnea, and 46.2%-63.0% for pain. The 61.1% of patients with improved dyspnea had ≥2 prior lines of therapy; median time-to-first improvement was 3.4 months. At the first post-baseline evaluation (Cycle 3), 45.9% of all patients reported a ≥10-point reduction in pain.

Conclusion: In this interim analysis, the majority of patients with RET fusion-positive NSCLC remained stable or improved on all QLQ-C30 subscales at each study visit, demonstrating the favorable HRQoL as measured by the QLQ-C30 during treatment with selpercatinib.

Implications For Practice: Patients with non-small cell lung cancer (NSCLC) generally experience greater symptom burden and lower health-related quality of life (HRQoL) as disease progresses. In a phase 1/2 trial, improvements in HRQoL were observed in over 60% of patients with advanced RET fusion-positive NSCLC who received selpercatinib, a highly selective RET inhibitor. More than one-third of patients reported a reduction in dyspnea during study participation and nearly half reported a reduction in pain by the first-follow up assessment.
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http://dx.doi.org/10.1002/onco.13976DOI Listing
September 2021

Study protocol for a randomised controlled trial of enhanced informed consent compared to standard informed consent to improve patient understanding of early phase oncology clinical trials (CONSENT).

BMJ Open 2021 09 6;11(9):e049217. Epub 2021 Sep 6.

Institute of Cancer Research, London, UK.

Introduction: Early phase cancer clinical trials have become increasingly complicated in terms of patient selection and trial procedures-this is reflected in the increasing length of participant information sheets (PIS). Informed consent for early phase clinical trials has been contentious due to the potential ethical issues associated with performing experimental research on a terminally ill population which has exhausted standard treatment options. Empirical studies have demonstrated significant gaps in patient understanding regarding the nature and intent of these trials. This study aims to test whether enhanced informed consent for patient education can improve patient scores on a validated questionnaire testing clinical trial comprehension.

Methods And Analysis: This is a randomised controlled trial that will allocate patients who are eligible to participate in one of four investigator-initiated clinical trials at the Royal Marsden Drug Development Unit to either a standard arm or an experimental arm, stratified by age and educational level. The standard arm will involve the full length trial PIS, followed by electronic or paper administration of the Quality of Informed Consent Questionnaire Parts A and B (QuIC-A and QuIC-B). The experimental arm will involve the full length trial PIS, exposure to a two-page study aid and 10 online educational videos, followed by administration of the QuIC-A and QuIC-B. The primary endpoint will be the difference (using a one-sided two-sample t-test) in the QuIC-A score, which measures objective understanding, between the standard and experimental arm. Accrual target is at least 17 patients per arm to detect an 8 point difference (80% power, alpha 0.05).

Ethics And Dissemination: Ethics approval was granted by the National Health Service Health Research Authority on 15 June 2020-IRAS Project ID 277065, Protocol Number CCR5165, REC Reference 20/EE/0155. Results will be disseminated via publication in a relevant journal.

Trial Registration Number: NCT04407676; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2021-049217DOI Listing
September 2021

HER3 expression and MEK activation in non-small-cell lung carcinoma.

Lung Cancer Manag 2021 Apr 9;10(2):LMT48. Epub 2021 Apr 9.

Drug Development Unit, Royal Marsden Hospital, Downs Road, Sutton, London, SM2 5PT, UK.

Aim: We explore HER3 expression in lung adenocarcinoma (adeno-NSCLC) and identify potential mechanisms of HER3 expression.

Materials & Methods: Tumor samples from 45 patients with adeno-NSCLC were analyzed. HER3 and HER2 expression were identified using immunohistochemistry and bioinformatic interrogation of The Cancer Genome Atlas (TCGA).

Results: HER3 was highly expressed in 42.2% of cases. copy number did not account for HER3 overexpression. Bioinformatic analysis of TCGA demonstrated that MEK activity score (a surrogate of functional signaling) did not correlate with HER3 ligands. RNA expression levels were significantly correlated with MEK activity after adjusting for expression.

Conclusion: HER3 expression is common and is a potential therapeutic target by virtue of frequent overexpression and functional downstream signaling.
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http://dx.doi.org/10.2217/lmt-2020-0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162178PMC
April 2021

Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial.

Clin Cancer Res 2021 Aug 2;27(15):4205-4220. Epub 2021 Jun 2.

MediCity Research Laboratory, University of Turku, Turku, Finland.

Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment.

Patients And Methods: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both and in patients with heavily pretreated metastatic cancer ( = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer.

Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8 T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients.

Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4862DOI Listing
August 2021

Safety monitoring of two and four-weekly adjuvant durvalumab for patients with stage III NSCLC: implications for the COVID-19 pandemic and beyond.

Lung Cancer 2021 06 30;156:147-150. Epub 2021 Apr 30.

Lung Unit, Department of Medical Oncology, The Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, UK; The Drug Development Unit, The Royal Marsden Hospital/Institute of Cancer Research, Downs Road, Sutton, SM2 5PT, UK. Electronic address:

Durvalumab is the first approved adjuvant immunotherapy agent for patients with stage III NSCLC treated with concurrent chemoradiotherapy and is associated with improved overall survival. In order to minimise the number of hospital visits for patients receiving durvalumab during the COVID-19 pandemic we implemented 4-weekly (20 mg/kg) durvalumab in place of 2-weekly infusions at The Royal Marsden Hospital. We assessed the potential impact of the safety of a 4-weekly schedule in patients receiving adjuvant durvalumab. We carried out a retrospective study of 40 patients treated with 2-weekly and 4-weekly infusions of durvalumab prior to and during the COVID-19 pandemic. Clinical documentation was analysed from 216 consultations across 40 patients receiving 2-weekly durvalumab and 66 consultations of 14 patients who switched from 2-weekly to 4-weekly durvalumab during the COVID-19 pandemic. In patients receiving 2-weekly durvalumab, the rate of grade 3 and 4 toxicities was 15 % compared to 7% in patients receiving 4-weekly durvalumab. Pre-existing autoimmune disease was considered a risk factor for the development of grade 3 or 4 toxicities. We did not observe any difference in the rate of grade 1 and 2 toxicities between the two groups. Our findings support the use of 4-weekly durvalumab during the COVID-19 pandemic and beyond, obviating the need for 2-weekly face-to-face consultations and blood tests, relevant given the current pandemic and the need to re-structure cancer services to minimise patient hospital visits and exposure to SARS-CoV-2.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086258PMC
June 2021

Research Related Tumour Biopsies in Early-Phase Trials with Simultaneous Molecular Characterisation - a Single Unit Experience.

Cancer Treat Res Commun 2021 11;27:100309. Epub 2021 Jan 11.

Drug Development Unit, Royal Marsden Hospital/The Institute of Cancer Research, Downs Road, Sutton, SM2 5PT. Electronic address:

Early-phase cancer clinical trials are becoming increasingly accessible for patients with advanced cancer who have exhausted standard treatment options and later phase trial options. Many of these trials mandate research tissue biopsies. Research biopsies have been perceived as ethically fraught due to the perception of potential coercion of vulnerable human subjects. We performed an audit of two years of practice to assess the safety of ultrasound (US)-guided research biopsies, and to look at the yield of a simultaneous tumour next-generation sequencing (NGS) and immunohistochemistry (IHC) molecular characterisation programme. We show that in our institution, US-guided research biopsies were safe, produced adequate tumour content and in a selected subset who underwent in-house NGS sequencing, showed a high rate of actionable mutations with 30% having a Tier 1 variant. Nevertheless, these research biopsies may only provide direct benefit for a minority of patients and we conclude with a reflection on the importance of obtaining truly informed consent.
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http://dx.doi.org/10.1016/j.ctarc.2021.100309DOI Listing
January 2021

Moving beyond epidermal growth factor receptor resistance in metastatic non-small cell lung cancer - a drug development perspective.

Crit Rev Oncol Hematol 2021 Mar 20;159:103225. Epub 2021 Jan 20.

Drug Development Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom. Electronic address:

Epidermal Growth Factor Receptor (EGFR) mutations are the most common targetable oncogenic driver mutation in metastatic non-small lung cancer (NSCLC). There have been significant advances in the management of metastatic EGFR-mutant NSCLC from the advent of first and second generation EGFR inhibitors to, more recently, the third-generation inhibitor osimertinib. Osimeritinib is now established as first-line therapy on the basis of improved outcomes compared to first and second generation agents. However, despite excellent initial response rates, responses may not be durable due to the development of acquired resistance. Understanding these mechanisms of resistance is critical to the development of rational drug and drug combinations capable of circumventing them. We discuss the major mechanisms of resistance to first, second and third generation EGFR TKIs. The potential of drug combinations utilising chemotherapy, immunotherapy and anti-angiogenic drugs are explored. We examine strategies to aid drug development, including circulating tumour DNA and novel trial designs.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103225DOI Listing
March 2021

Real-world outcomes in thoracic cancer patients with severe Acute respiratory syndrome Coronavirus 2 (COVID-19): Single UK institution experience.

Cancer Treat Res Commun 2020 2;25:100261. Epub 2020 Dec 2.

Lung Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom; Thoracic Oncology, Institute of Cancer Research, London, United Kingdom. Electronic address:

Background: UK COVID-19 mortality rates are amongst the highest globally. Controversy exists on the vulnerability of thoracic cancer patients. We describe the characteristics and sequelae of patients with thoracic cancer treated at a UK cancer centre infected with COVID-19.

Methods: Patients undergoing care for thoracic cancer diagnosed with COVID-19 (RT-PCR/radiology/clinically) between March-June 2020 were included. Data were extracted from patient records.

Results: Thirty-two patients were included: 14 (43%) diagnosed by RT-PCR, 18 (57%) by radiology and/or convincing symptoms. 88% had advanced thoracic malignancies. Eleven of 14 (79%) patients diagnosed by RT-PCR and 12 of 18 (56%) patients diagnosed by radiology/clinically were hospitalised, of which four (29%) and 2 (11%) patients required high-dependency/intensive care respectively. Three (21%) patients diagnosed by RT-PCR and 2 (11%) patients diagnosed by radiology/clinically required non-invasive ventilation; none were intubated. Complications included pneumonia and sepsis (43% and 14% respectively in patients diagnosed by RT-PCR; 17% and 11% respectively in patients diagnosed by radiology/clinically). In patients receiving active cancer treatment, therapy was delayed/ceased in 10/12 (83%) and 7/11 (64%) patients diagnosed by RT-PCR and radiology/clinically respectively. Nine (28%) patients died; all were smokers. Median time from symptom onset to death was 7 days (range 3-37).

Conclusions: The immediate morbidity from COVID-19 is high in thoracic cancer patients. Hospitalisation and treatment interruption rates were high. Improved risk-stratification models for UK cancer patients are urgently needed to guide safe cancer-care delivery without compromising efficacy.
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http://dx.doi.org/10.1016/j.ctarc.2020.100261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709731PMC
January 2021

Radiological evaluation of malignant pleural mesothelioma - defining distant metastatic disease.

BMC Cancer 2020 Dec 9;20(1):1210. Epub 2020 Dec 9.

Drug Development Unit, Royal Marsden Hospital/ Institute of Cancer Research, Down Rd, Sutton, SM2 5PT, UK.

Background: Malignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking.

Methods: In this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes.

Results: 67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without.

Conclusions: This report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms.
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http://dx.doi.org/10.1186/s12885-020-07662-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724793PMC
December 2020

Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study.

Lancet Oncol 2020 11 28;21(11):1478-1488. Epub 2020 Oct 28.

Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Background: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations.

Methods: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509.

Findings: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses.

Interpretation: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation.

Funding: Chugai Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30464-2DOI Listing
November 2020

A risk-based approach to experimental early phase clinical trials during the COVID-19 pandemic.

Lancet Oncol 2020 07;21(7):889-891

Phase I Drug Development Unit, The Royal Marsden Hospital and The Institute of Cancer Research, Sutton, UK. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30339-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324104PMC
July 2020

Systemic treatment of brain metastases in non-small cell lung cancer.

Eur J Cancer 2020 06 4;132:187-198. Epub 2020 May 4.

Royal Marsden NHS Trust, UK. Electronic address:

Brain metastases (BrMs) are associated with significant morbidity and are found in up to 50% of patients with advanced non-small cell lung cancer (NSCLC). Most of the literature focuses on symptomatic BrMs, with a lack of baseline brain imaging in asymptomatic patients. Unfortunately, much of the data on local treatments with or without systemic treatment is retrospective. Clinical trials of systemic treatments largely exclude patients with BrMs. Chemotherapy is an active treatment for BrM with response rates in the brain similar to other sites of disease. Targeted systemic treatments in patients with driver mutations (EGFR and ALK-MET to date) have impressive central nervous system (CNS) penetrance and response rates. Unfortunately, no prospective data can currently guide the timings or modality of local therapies with systemic treatments in these patients who have a high incidence of CNS disease, but retrospective data suggest that early local therapies may give better intracranial progression-free survival (ICPFS). Recent immunotherapy trials have included patients with BrMs. These patients have largely been pre-treated with local therapies and are asymptomatic. Thus, the current standard is becoming, early local therapies before or in conjunction with immunotherapy agents. The approach seems to be safe. Prospective studies are needed in NSCLC BrMs patients to make sure any benefit from local therapies on the ICPFS and quality of life is not overlooked. Here we report what we think are reasonable conclusions from the available data and make suggestions for future clinical trials in the management of NSCLC BrMs.
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http://dx.doi.org/10.1016/j.ejca.2020.03.006DOI Listing
June 2020

Radiological Patterns of Drug-induced Interstitial Lung Disease (DILD) in Early-phase Oncology Clinical Trials.

Clin Cancer Res 2020 09 24;26(18):4805-4813. Epub 2020 Apr 24.

Phase I Drug Development Unit, The Royal Marsden Hospital and The Institute of Cancer Research, Sutton, United Kingdom.

Purpose: Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described.

Patients And Methods: A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed.

Results: Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14-336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19-1.81; < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38-90.26; = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01-0.35; = 0.01).

Conclusions: DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0454DOI Listing
September 2020

Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab.

J Immunother Cancer 2020 03;8(1)

Drug Development Unit, Royal Marsden Hospital/ Institute of Cancer Research, Sutton, UK.

Background: This case represents an exceptional response to pembrolizumab in a patient with epithelioid mesothelioma with a further response on rechallenge.

Case Presentation: A 77-year-old woman with advanced epithelioid mesothelioma extensively pretreated with chemotherapy demonstrated a prolonged response of 45 months to 52 cycles of pembrolizumab. On rechallenge with pembrolizumab, further disease stability was achieved. Serial biopsies and analysis by immunohistochemistry and immunofluorescence demonstrated marked immune infiltration and documented the emergency of markers of immune exhaustion. Whole exome sequencing demonstrated a reduction in tumor mutational burden consistent with subclone elimination by immune checkpoint inhibitor (CPI) therapy. The relapse biopsy had missense mutation in BTN2A1.

Conclusion: This case supports rechallenge of programme death receptor 1 inhibitor in cases of previous CPI sensitivity and gives molecular insights.
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http://dx.doi.org/10.1136/jitc-2020-000713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069263PMC
March 2020

A prospective observational study of on-treatment plasma homocysteine levels as a biomarker of toxicity, depression and vitamin supplementation lead-in time pre pemetrexed, in patients with non-small cell lung cancer and malignant mesothelioma.

PLoS One 2019 25;14(11):e0225509. Epub 2019 Nov 25.

Lung Cancer Unit, Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.

Objectives: Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity.

Material And Methods: Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities.

Results: Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities.

Conclusion: On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225509PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877184PMC
March 2020

Outcomes of Patients with Early Onset Colorectal Cancer Treated in a UK Specialist Cancer Center.

Cancers (Basel) 2019 Oct 14;11(10). Epub 2019 Oct 14.

Department of Medicine, The Royal Marsden Foundation Trust, London and Surrey SM2 5PT, UK.

The incidence of early onset colorectal cancer (EOCRC) is rapidly increasing, but there remains paucity of outcome data for young CRC patients. We reviewed the characteristics and outcomes of 241 adults, age <50, who were diagnosed with EOCRC between January 2009 and December 2014. Median age was 42, 56% were male, and 7% had hereditary etiology. Seventy percent had left-sided primaries. At diagnosis, 11%, 50%, and 39% had stage II, III, and IV CRC. Of the patients with stage II and III CRC who underwent curative surgery, 60% and 88% had adjuvant chemotherapy, with 5-year relapse free survival of 82% and 74% respectively. Of the 123 patients with metastatic (m) EOCRC, 93%, 63%, 33%, and 12% had 1st, 2nd, 3rd, and 4th line systemic anticancer therapy (SACT) respectively. For first line SACT, 99% had doublet chemotherapy, with bevacizumab or an anti-EGFR antibody in 57%. Median overall survival (mOS) of mEOCRC patients was 20.1 months (95% C.I: 15.9-23.2). Younger age and signet cells were associated with shorter mOS, whereas more lines of SACT and curative metastasectomy with longer mOS. Metastatic EOCRC patients had poorer outcomes than expected, despite optimal multimodality treatment. This suggests an aggressive disease biology that warrants further research and therapy development.
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http://dx.doi.org/10.3390/cancers11101558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826435PMC
October 2019

Challenging the recalcitrant disease-developing molecularly driven treatments for small cell lung cancer.

Eur J Cancer 2019 09 21;119:132-150. Epub 2019 Aug 21.

Drug Development Unit, Royal Marsden/Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK. Electronic address:

Small cell lung cancer (SCLC) has been described as a 'recalcitrant' disease characterised by poor survival and with little progress made in developing novel treatments in the last decades. However, recent drug developments have opened some potential therapeutic avenues. In this review, the genomic landscape of SCLC is explored, in particular the Notch pathway and attempts to target the key node DLL3. The likely primary importance of MYC to SCLC subtype transformation and recent attempts to drug MYC are discussed. Bcl-2 is a druggable protein, highly expressed in SCLC, and relevant Bcl-2 targeting drugs are reviewed. None of these drug targets are, however, as advanced their development as the field of immunotherapy for SCLC. The key developments in single agent PD-L1 and PD-1 inhibitors and in combination with chemotherapy have led to the only recent licencing approvals for SCLC in recent years and will likely pave the way for future rational drug combinations. Drug development in SCLC poses its own challenges with rapid clinical deterioration often precluding trial entry. Effective drug development in a biomarker-driven approach depends on early patient screening and use of circulating biomarkers. Given recent developments, we may hope to be at the start of an era of greater progress in the treatment of SCLC.
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http://dx.doi.org/10.1016/j.ejca.2019.04.037DOI Listing
September 2019

Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in -Mutant Cancers.

Mol Cancer Ther 2019 08 1;18(8):1396-1404. Epub 2019 Jul 1.

Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.

It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in rewiring of signal transduction. We aimed to study differences in dynamic signaling changes within mutant ( ), non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC) cells. We used an antibody-based phosphoproteomic platform to study changes in 50 phosphoproteins caused by seven targeted anticancer drugs in a panel of 30 cell lines and cancer cells isolated from 10 patients with cancers. We report for the first time significant differences in dynamic signaling between colorectal cancer and NSCLC cell lines exposed to clinically relevant equimolar concentrations of the pan-PI3K inhibitor pictilisib including a lack of reduction of p-AKTser473 in colorectal cancer cell lines ( = 0.037) and lack of compensatory increase in p-MEK in NSCLC cell lines ( = 0.036). Differences in rewiring of signal transduction between tumor types driven by cancers exist and influence response to combination therapy using targeted agents.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679718PMC
August 2019

Multidisciplinary interventions in a specialist Drug Development Unit to improve family history documentation and onward referral of patients with advanced cancer to cancer genetics services.

Eur J Cancer 2019 06 16;114:97-106. Epub 2019 May 16.

Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, Fulham Road, London, UK. Electronic address:

Background: Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, 600-700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing. We aimed to assess the impact of different multidisciplinary interventions on family history taking and referral rates from DDU to Cancer Genetics Unit (CGU).

Methods: Over 42 months, three interventions were undertaken at different intervals: (1) embedding a genetics provider in the DDU review clinic, (2) 'traffic light' system flagging cancers with a heritable component and (3) virtual multidisciplinary meeting (MDM). Comparative analyses between intervals were undertaken, including referral rates to CGU, investigations and patient outcomes. Family history taking in a sample of 20 patients managed in each interval was assessed by a retrospective chart review.

Results: Frequency of family history taking and referral to CGU, increased with each intervention, particularly, the virtual MDM (40% vs 85%). Referral rates increased over the study period, from 0.1 referral/week (5/year, 0.36% total referrals) to 1.2/week (projected 63/year, 3.81%). Forty-four (52%) patients referred required germline testing; in three of whom, variants were identified. Non-attendance rates were low (6, 7%).

Conclusion: Patients in the DDU are unique, with long cancer histories and often short estimated life expectancy. Multidisciplinary working between CGU and DDU facilitates germline testing of those patients who may otherwise miss the opportunity.
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http://dx.doi.org/10.1016/j.ejca.2019.04.009DOI Listing
June 2019

Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies.

Ther Adv Med Oncol 2018 13;10:1758835918786658. Epub 2018 Jul 13.

Drug Development Unit at Royal Marsden Hospital/Institute of Cancer Research, Downs Rd, Sutton, SM2 5PT, UK.

Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit - for example, the PARP inhibitor olaparib has shown benefit in -mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.
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http://dx.doi.org/10.1177/1758835918786658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047242PMC
July 2018

A study of PD-L1 expression in KRAS mutant non-small cell lung cancer cell lines exposed to relevant targeted treatments.

PLoS One 2017 5;12(10):e0186106. Epub 2017 Oct 5.

The Drug Development Unit, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.

We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor (trametinib) and an AKT inhibitor (AZD5363) for 3 weeks. Only 3/5 (H23, H2030 and A549) and 2/5 cell lines (H441 and H23) showed functionally significant increases in PD-L1 expression when exposed to trametinib or AZD5363 respectively. PD-L1 overexpression is not consistent and is unlikely to be an early mechanism of resistance to KRAS mutant adeno-NSCLC treated with MEK or AKT inhibitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186106PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628934PMC
November 2017

Characterisation of the Phosphatidylinositol 3-Kinase Pathway in Non-Small Cell Lung Cancer Cells Isolated from Pleural Effusions.

Oncology 2016 16;90(5):280-8. Epub 2016 Apr 16.

The Institute of Cancer Research, London, UK.

Objectives: We hypothesised that it was possible to quantify phosphorylation of important nodes in the phosphatidylinositol 3-kinase (PI3K) pathway in cancer cells isolated from pleural effusions of patients with non-small cell lung cancer (NSCLC) and study their correlation to somatic mutations and clinical outcomes.

Materials And Methods: Cells were immunomagnetically separated from samples of pleural effusion in patients with NSCLC. p-AKT, p-S6K and p-GSK3β levels were quantified by ELISA; targeted next-generation sequencing was used to characterise mutations in 26 genes.

Results: It was possible to quantify phosphoproteins in cells isolated from 38/43 pleural effusions. There was a significant correlation between p-AKT and p-S6K levels [r = 0.85 (95% confidence interval 0.73-0.92), p < 0.0001], but not p-AKT and p-GSK3β levels [r = 0.19 (95% confidence interval -0.16 to 0.5), p = 0.3]. A wide range of mutations was described and p-S6K was higher in samples that harboured at least one mutation compared to those that did not (p = 0.03). On multivariate analysis, p-S6K levels were significantly associated with poor survival (p < 0.01).

Conclusion: Our study has shown a correlation between p-AKT levels and p-S6K, but not GSK3β, suggesting differences in regulation of the distal PI3K pathway by AKT. Higher p-S6K levels were associated with adverse survival, making it a critically important target in NSCLC.
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http://dx.doi.org/10.1159/000444928DOI Listing
December 2016

A phase 1b trial of the combination of an all-oral regimen of capecitabine and erlotinib in advanced non-small cell lung cancer in Caucasian patients.

Cancer Chemother Pharmacol 2016 Feb 26;77(2):375-83. Epub 2015 Dec 26.

Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.

Purpose: Erlotinib is active in advanced non-small cell lung cancer (aNSCLC) particularly in patients with EGFR-sensitizing mutations. The thymidylate synthase inhibitors are active in NSCLC, but capecitabine is not well studied. This study explored the safety and activity of this oral combination.

Methods: This phase Ib trial used a 3 + 3 escalation design with a combination of erlotinib (100 mg daily) with increasing doses of capecitabine (500, 750 and 1000 mg/m(2) BD, 14/21 days), in first- and second-line aNSCLC of adenocarcinoma histology. The DLT was any drug-induced toxicity ≥grade (G)2 causing dose interruption or dose delay during the first 2 cycles.

Results: Forty patients were recruited, and 1 patient had an EGFR mutation. Dose escalation stopped at capecitabine 1000 mg/m(2) with expansion to 6 patients due to unpredicted DLTs in 2/6 patients: G2 creatinine rise, G2 anaemia, G3 atrial fibrillation and G3 pneumonia. MTD was capecitabine 750 mg/m(2). First-line dose escalation at the MTD led to unpredicted DLTs in 3/4 patients (G3 troponin rise, G2 rash and G2 hyperbilirubinaemia). MTD expansion in the second-line setting was well tolerated. The most common drug toxicities were gastrointestinal (35 %), followed by skin disorders (28 %). The response rate was 3 % with a disease control rate of 34 %. Median progressive-free survival was 1.6 months (95 % CI 1.4-3.5), and median overall survival was 6.1 months (95 % CI 5.1-10.1).

Conclusion: The MTD for the combination of capecitabine and erlotinib is 750 mg/m(2) BD, 14/21 days, and 100 mg daily, respectively, which is lower than predicted. Capecitabine did not improve the efficacy of erlotinib in aNSCLC unselected for EGFR mutation.
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http://dx.doi.org/10.1007/s00280-015-2950-1DOI Listing
February 2016

The diagnosis and treatment of brain metastases in EGFR mutant lung cancer.

CNS Oncol 2014 May;3(3):209-17

Royal Marsden Hospital, Sutton, SM2 5PT, UK.

The epidemiology of non-small-cell lung cancer (NSCLC) has changed with a new pattern of disease emerging - a form of adenocarcinoma in mostly younger female patients, who are never or light smokers and more frequently in East Asian populations. Description of EGF receptor (EGFR) mutations has allowed new management strategies to evolve. Oral targeted therapies have broadened the treatment options in the advanced setting with the potential for periods of long term response. The brain is a common site of metastases with EGFR mutated lung cancer typically displaying asymptomatic, small volume, multiple lesions that respond to treatment. We explore the role of local and system therapies for brain metastases in this disease including the role of EGFR inhibitors.
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http://dx.doi.org/10.2217/cns.14.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124369PMC
May 2014

BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation.

Future Oncol 2012 May;8(5):499-507

The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.

Following Phase I and II studies revealing vemurafenib to be a safe potent inhibitor of mutated BRAF in patients with metastatic melanoma, a multicenter randomized Phase III trial was carried out to compare vemurafenib with dacarbazine in treatment-naive patients. The interim analysis results from this trial, BRIM-3, were sufficient for an independent data and safety monitoring board to recommend crossover from dacarbazine to vemurafenib, vemurafenib being associated with a relative risk reduction of 63% in the risk of death and 74% in the risk of death or disease progression compared with dacarbazine (p < 0.001 for both comparisons) with an acceptable toxicity profile. Such striking results have prompted analysis of our approach to the classification and treatment of metastatic melanoma in an age of molecular markers and targeted therapy.
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http://dx.doi.org/10.2217/fon.12.43DOI Listing
May 2012

Ipilimumab: showing survival benefit in metastatic melanoma.

Future Oncol 2011 Nov;7(11):1255-64

The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.

Ipilimumab is a fully humanized monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4. Data from preclinical and clinical studies have shown that ipilimumab can cause tumor regression in patients with metastatic melanoma with response rates of 5.8-22%. Phase III trials have demonstrated a benefit in median overall survival in the first-line setting in combination with dacarbazine versus dacarbazine alone (11.2 vs 9.1 months) and in the second-line setting in combination with gp100 versus gp100 alone (10.1 vs 6.4 months). The main toxicities of ipilimumab are immune related, most commonly skin and gastrointestinal. Bowel perforation and treatment-related deaths have occurred, although prompt use of steroids and other immunosuppressive agents can minimize this risk.
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http://dx.doi.org/10.2217/fon.11.105DOI Listing
November 2011

Clinical benefit of second-line palliative chemotherapy in advanced soft-tissue sarcoma.

Sarcoma 2010 20;2010:264360. Epub 2010 May 20.

Sarcoma Unit, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

Background. This paper aimed to assess the utility of second-line chemotherapy in patients with advanced soft-tissue sarcoma. Materials and Methods. A retrospective search of a prospectively maintained database identified patients treated between 1991 and 2005. Patients with gastrointestinal stromal tumours, small round cell tumours, and Ewing's sarcoma were excluded. Response was assessed using WHO and RECIST. Patients who achieved stable disease for 6 months or more were classified as having disease control. Results. Three hundred and seventy-nine patients received second-line chemotherapy. Eighty-six (22.7%) achieved disease control. Median duration of response was 11 months (95% CI: 9-13). On multivariate analysis, pathological subtype, absence of lung metastases, and the use of combination chemotherapy were independent predictors of disease control. Twenty-eight (16.1%) patients who failed to respond to first-line therapy achieved disease control. Eight (2.1%) patients had sufficient downstaging to enable complete surgical resection. Progression-free survival was 23% at 6 months. Median overall survival was 8 months (95% CI: 7-10 months). On multivariate analysis, synovial histology and absence of lung metastases were associated with improved survival. Conclusion. Second-line chemotherapy can provide clinical benefit in over 20% of soft-tissue sarcoma patients.
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http://dx.doi.org/10.1155/2010/264360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874927PMC
July 2011

An unusual case of pancreatic cancer with leptomeningeal infiltration.

J Gastrointest Cancer 2010 Jun;41(2):107-9

Kent Oncology Centre, Maidstone Hospital, Maidstone, ME16 9QQ, UK.

Introduction: Pancreatic cancer is a common malignancy and often presents at an advanced stage. Metastases are common but neurological involvement is rare. We aim to describe an unusual case of leptomeningeal involvement from pancreatic cancer.

Case Report: A 59-year-old man presented with a several-year history of abdominal pain, weight loss and anaemia, which had been extensively investigated. Four years after initial presentation, he presented with left leg weakness and sensory disturbance. He was observed to suffer intermittent complex seizures. CT scan of the abdomen showed subtle narrowing of the common bile duct and pancreatic ducts. Endoscopic ultrasound showed a 5-cm lesion in the head of the pancreas with adenocarcinoma cells on fine needle aspiration. Serum CA19.9 was 2,293 U/ml. MRI study of the brain and spinal cord showed widespread leptomeningeal enhancement. Cytological examination of cerebrospinal fluid revealed epithelial cells staining positive for MNF116 and EMA. He started on a weekly regimen of intrathecal combination chemotherapy of hydrocortisone 50 mg, methotrexate 12.5 mg and cytarabine 50 mg. He was also treated synchronously with palliative systemic gemcitabine. His clinical condition continued to deteriorate, cytotoxic therapy was withdrawn after 2 weeks and he died the following month.

Discussion: This case represents the unusual presentation of advanced leptomeningeal carcinomatosis in a locally early stage pancreatic adenocarcinoma. Other reported cases have been in patients with advanced metastatic disease. In the case of significant neurological symptoms and signs, clinicians should have a low threshold for performing investigations to exclude neurological involvement.
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http://dx.doi.org/10.1007/s12029-009-9120-9DOI Listing
June 2010
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