Welcome to The Christie Research Publications Repository

The repository contains the research outputs from staff and students at The Christie NHS Foundation Trust and Cancer Research UK Manchester Institute.

Current Repository Content:

Over 7000 peer reviewed articles, reviews and selected publications from 1933 onwards.

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  • Advanced small intestine well-differentiated neuroendocrine tumors (WD-SiNET): A survey of practice on 3rd line treatment

    Lamarca, Angela; Cives, M.; de Mestier, L.; Crona, J.; Spada, F.; Oberg, K.; Pavel, M.; Alonso-Gordoa, T.; The Christie NHS Foundation Trust, Manchester, (2021)
    Introduction: Selection of third-line treatment after somatostatin analogues (SSA) and Peptide Receptor Radionuclide Therapy (PRRT) for WD-SiNETs remains challenging. Aim(s): Understand current practice and rationale for decision-making in the 3rd-line setting after SSA and PRRT. Materials and methods: An online survey (replies collected between 5/8/2020 and 21/9/2020) was built. Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. Results: A total of 28 replies; medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from ENETS CoE (57.1%), who followed ENETS guidelines (82.1%). Overall, 3rd-line treatment for WD-SiNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%) or personal experience (22.2%). EVE was likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); irrespective of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was chosen if rapid progression (within 6 months) (WA 3.35/4), Ki-67 10-20% (WA 2.77/4), negative SSTR2 imaging (WA 2.65/4) or high tumor burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-FU (57.7%), FOLFOX (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). Conclusion: Selection of 3rd line therapy is based on multiple factors mainly Ki-67, rate of progression, CS and tumor burden; decisions should be made within a multidisciplinary setting
  • Systemic and intracranial efficacy of brigatinib vs.crizotinib: updated results from the ALTA-1L Trial

    Popat, S.; Kim, H. R.; Ahn, M. J.; Yang, J. C. H.; Han, J. Y.; Hochmair, M.; Lee, K. H.; Delmonte, A.; Campelo, M. R. G.; Kim, D. W.; et al. (2021)
    Background: At ALTA-1L (NCT02737501) first interim analysis (IA1), brigatinib demonstrated superior BIRC-assessed PFS and iPFS vs crizotinib. We report IA2 results, planned at w75% of 198 expected PFS events. Methods: Patients with TKI-naive advanced ALK+ NSCLC were randomized 1:1 to brigatinib 180 mg qd (7-day lead-in at 90 mg) or crizotinib 250 mg bid. Endpoints: Primary, BIRC-assessed PFS (RECIST v1.1); secondary included confirmed ORR and iORR, and iPFS (BIRC). Results: 275 patients were randomized (brigatinib/crizotinib, n¼137/ 138); median age, 58/60 years; prior chemotherapy, 26%/27%; baseline brain metastases (BIRC), 34%/36%; brain radiotherapy, 13%/ 14% (WBRT/SRS balanced across arms). At data cutoff (28 June 2019, median follow-up [brigatinib/crizotinib], 24.9/15.2 months, 150 PFS events): BIRC-assessed PFS HR, 0.49 (95% CI, 0.35e0.68, log-rank P<0.0001); brigatinib mPFS, 24.0 months (95% CI, 18.5eNE) vs crizotinib 11.0 months (9.2e12.9). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31e0.61, median 29.4 vs 9.2 months). OS was immature (total events: 33/37, brigatinib/crizotinib). In patients with baseline brain metastases, PFS HR was 0.25; data were less mature in brigatinib patients without brain metastases. Additional results in Table. Radiological overall disease progression occurred in (brigatinib vs crizotinib) 54 (39%) vs 74 (54%) patients (BIRC) and 50 (36%) vs 84 (61%) (investigator); of these, brain was first site of progression more frequently with crizotinib vs brigatinib: 31 (42%) vs 17 (31%) patients (BIRC); 22 (26%) vs 7 (14%) (investigator). Most common TEAEs grade 3: brigatinib: increased CPK (24.3%) and lipase (14.0%), hypertension (11.8%); crizotinib: increased ALT (10.2%), AST (6.6%), lipase (6.6%). Brigatinib significantly delayed median time to deterioration vs crizotinib for global health score/QoL (log-rank P¼0.0485), emotional and social functioning, fatigue, nausea and vomiting, appetite loss, constipation. Conclusions: Brigatinib demonstrated superior systemic and intracranial efficacy vs crizotinib in all patients with TKInaive ALK+ NSCLC and in patients with baseline brain metastases.
  • Molecular profiling of well-differentiated neuroendocrine tumors: Role of ctDNA

    Lamarca, Angela; Frizziero, Melissa; Barriuso, Jorge; Kapacee, Zainul Abedin; Mansoor, Was; McNamara, Mairead G; Hubner, Richard A; Valle, Juan W; The Christie NHS Foundation Trust, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, (2021)
    Introduction: Tumor molecular profiling has proven relevant for the clinical management of cancer. Circulating tumor DNA (ctDNA) may be a useful surrogate of tumor tissue when this is insufficient for analysis. Aim(s): Aims: Rate of test failure, detection rate of pathological alterations (PAs) and impact on management. Materials and methods: Patients (pts) with well-differentiated neuroendocrine tumors (WdNETs) underwent ctDNA-based molecular profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly differentiated neuroendocrine carcinoma) were used for comparison. Results: Fifteen pts with WdNET (18 ctDNA samples) included: 8 female (53.33%), median age 63.2 years (range 23.5-86.8). Primary: small bowel (8;53.3%); pancreas (5;33.3%); gastric (1;6.7%) and unknown primary (1;6.7%); grade (G)1 (n=5;33.3%); G2 (9;60.0%) and G3 (1;6.7%); median Ki-67: 5% (range 1-30). Thirty pts with non-WdNETs pts (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs 17.65% in non-WdNETs; p 0.395). Of 13 WdNET samples with successful ctDNA, PAs were detected in 6 (46.15%) (vs 82.14% in non-WdNETs; p 0.018). In WdNETs, PA rate was independent of anti-cancer systemic therapy (2/7;28.57% vs 4/6;66.67%; p 0.286) at time of ctDNA: 4, 1 and 1 samples had 1, 2 and 3 PAs, respectively; these were: CDKN2A mutation (m) (1 sample), CHEK2m (1), TP53m (2), FGFR2amplif (1), IDH2m (1), CTNNB1m (1), NF1m (1), PALB2m (1); nontargetable (0%) or impacted management (0%). There was a trend towards lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs non-WdNETs (mean 26.99); p 0.0584. Conclusion: Although feasible, ctDNA molecular profiling was of limited clinical utility for advanced WdNETs. Identification of PAs and mMAF seem higher in non-WdNETs.
  • Incidence of brain metastases (BMs) and outcomes in patients (pts) with extrapulmonary neuroendocrine neoplasms (EP-NENs)

    Kapacee, Zainul Abedin; Dawod, Mohammed; Allison, Jennifer; Frizziero, Melissa; Chakrabarty, Bipasha; Manoharan, Prakash; McBain, Catherine A; Mansoor, Was; Lamarca, Angela; Hubner, Richard A; et al. (2021)
    Introduction: The incidence, management and outcomes of pts with EP-NENs and BMs are unclear. Aim(s): To investigate outcomes in pts with EP-NENs ± BMs. Materials and methods: A retrospective study of consecutive pts with EP-NENs and BMs treated at a single ENETS CoE was performed. Median (med) overall survival (OS)/survival from BM diagnosis were estimated (Kaplan Meier). Results: Between Aug 04-Feb 20, 730 pts with an EP-NEN diagnosis were identified: med age 64 yrs (15-90); 56% male, 67% had advanced disease (ADVD). In pts with ADVD, the primary NEN site were: small bowel 42%, pancreas 22%, unknown 14%, large bowel 10%, other 5%, stomach 4% and appendix <1%; 37%, 30% and 30% pts had grade (G)1, 2 and 3 EP-NENs respectively (no grading 3%). Med OS for pts with ADVD G1, 2 and 3 EP-NENs without BMs were 95.8 (95% C.I 77.0-177.1), 61.7 (95% C.I 50.1-124.4) and 11.3 (95% C.I 9.3-14.4) months (mo) respectively. 17 pts (2.3%) developed BMs; 2 at initial diagnosis, 15 metachronously; 5 pts (29%) had a solitary BM, 12 (71%) had multiple BMs. The primary sites of origin were: unknown 41%, oesophagus 18%, pancreas 17%, small bowel 12%, cervix 6% and bladder 6%; 6%, 24% and 70% had G1, G2 and G3 EP-NENs respectively. Most common presenting symptoms of pts with BMs were limb weakness and cognitive impairment. Pts with BMs received high dose steroids and best supportive care (35%), whole brain radiotherapy with steroids (29%), surgery (18%) and localised radiotherapy (6%). Med OS for pts with G1+2 EP-NENs and BMs was not reached. Med OS in pts with G3 EP-NENs and BMs was 9.0 mo (95% CI 6.0-12.1); med survival from BM diagnosis was 2.0 mo (95% CI 0.0-4.4). Conclusion: BMs in pts with EP-NENs are rare, predominant in G3 NENs, and have a poor prognosis. Improved therapeutic options are needed.
  • Assessing the management of bone metastases in patients diagnosed with neuroendocrine neoplasms: Re-audit of clinical practice

    Garcia-Torralba, E; Lim, Kok Haw Jonathan; Barriuso, Jorge; McNamara, Mairead G; Hubner, Richard A; Mansoor, Was; Valle, Juan W; Lamarca, Angela; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, (2021)
    Introduction: There remains no global consensus on the optimal management of bone metastases in patients with neuroendocrine neoplasms (BM-NEN). Aim(s): To re-audit the clinical management of BM-NEN following the incorporation of institutional guidelines (TC-BM Guid) established in 2018 (PMID: 31639796). Materials and methods: Retrospective study of all patients with BM-NEN diagnosed from Jan-Dec 2019 following TC-BM Guid. Characteristics of BM-NEN and treatment received were evaluated against TC-BM Guid. Statistical analysis was performed using STATA v14. Results: Of 354 patients, 40 (11%) had BM (gastrointestinal: 53%, N=21; lung: 15%, N=6; unknown primary: 12%, N=5; other: 20%, N=8). BM were “widespread” in 80% (N=32). Compared to the cohort prior to TC-BM Guid implementation (2002-2018, N=85), incidence of symptoms (any), pain/hypercalcemia, and skeletal-related events were lower (45%, N=18 vs 78%, N=66; 40%, N=16 vs 64%, N=54; 13%, N=5 vs 20%, N=17, respectively). Use of analgesia for symptomatic BMs (80%, N=32 vs 44%, N=37) and use of bisphosphonates (33%, N=13 vs 22%, N=19) were higher. Use of radiotherapy and surgery were similar (23%, N=9 and 3%, N=1 respectively). The re-audit showed that management adhered to TC-BM Guid in the majority of patients (95%, N=38), including 4 patients who received best supportive care due to poor performance status (PS) and short prognosis (<3 months), which was not previously detailed in the guidelines. Conclusion: TC-BM Guid are deliverable, and current management of BM-NEN mostly adhered to these. Following this, TC-BM Guid were updated to reflect recommendations for symptomatic management only (best supportive care) for patients with poor PS/short life-expectancy.

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