• Long-term outcomes of bladder preservation in muscle-invasive bladder cancer patients

      Satiti, AD; Mistry, H; Song, Yee Pei; Choudhury, Ananya; Faculty of Biology, Medicine, and Health, University of Manchester, Manchester (2019)
    • Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status.

      Evans, D Gareth R; Moran, Anthony; Hartley, Roger; Dawson, J; Bulman, B; Knox, F; Howell, Anthony; Lalloo, Fiona; Manchester Academic Health Science Centre, Genetic Medicine, St Mary's Hospital, Central Manchester Hospitals Foundation Trust, Manchester M13 9WL, UK. gareth.evans@cmft.nhs.uk (2010-03-30)
      BACKGROUND: There are relatively few articles addressing long-term follow-up in women with breast cancer at very young ages. METHODS: We have updated and extended our population-based analysis of breast cancer diagnosed at the age < or =30 years in North-west England to include an extra 15 patients with mutation testing in BRCA1, BRCA2 and TP53, with 115 of 288 consecutive cases being tested. Kaplan-Meier curves were generated to assess overall survival, contralateral breast cancer and other second primaries. RESULTS: Survival analysis of all 288 patients showed poor overall survival, although this improved from a 15-year survival of only 46% in those diagnosed between 1980 and 1989 to 58% in those diagnosed between 1990 and 1997 (P=0.05). Contralateral breast cancer rates were at a steady rate of 0.6 per 1000, although the rates in mutation carriers were approximately 2 per 1000. Altogether, 16 BRCA1, 9 BRCA2 and 6 TP53 mutations have now been found among the 115 cases on whom DNA analysis has been performed. BRCAPRO accurately predicted the number of carriers for BRCA1 and BRCA2 and was sensitive and specific at the 10 and 20% threshold, respectively. However, BRCAPRO did not seem to give any weight to DCIS, which accounted for two BRCA1 carriers and three TP53 carriers and overpredicted mutations at the high end of the spectrum, with only 6 of 11 (54%) with a >90% probability having identifiable BRCA1/2 mutations. INTERPRETATION: Rates of new primaries are predicted to some extent by mutation status. BRCAPRO is useful at determining those patients aged < or =30 years to be tested.
    • Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study.

      van der Valk, M; Hilling, D; Bastiaannet, E; Meershoek-Klein Kranenbarg, E; Beets, G; Figueiredo, N; Habr-Gama, A; Perez, R; Renehan, Andrew G; Van de Velde, C; et al. (2018-06-23)
      The strategy of watch and wait (W&W) in patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy is new and offers an opportunity for patients to avoid major resection surgery. However, evidence is based on small-to-moderate sized series from specialist centres. The International Watch & Wait Database (IWWD) aims to describe the outcome of the W&W strategy in a large-scale registry of pooled individual patient data. We report the results of a descriptive analysis after inclusion of more than 1000 patients in the registry.
    • Long-term outcomes of hypoxia modification in bladder preservation: update from BCON trial

      Song, Yee Pei; Mistry, Hitesh; Choudhury, Ananya; Hoskin, Peter J; The University of Manchester, Manchester (2019)
    • Long-term prospective clinical follow-up after BRCA1/2 presymptomatic testing: BRCA2 risks higher than in adjusted retrospective studies.

      Evans, D G; Harkness, E; Lalloo, F; Howell, Anthony; Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester NHS Trust, Manchester, UK Manchester Centre for Genomic Medicine, Central Manchester Foundation Trust, St. Mary's Hospital, Manchester, UK Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, Christie Hospital, Manchester, UK The University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK. (2014-07-22)
      The risks of breast cancer associated with BRCA1 and BRCA2 mutations vary considerably across studies but few have assessed prospective risks, which are likely to provide more reliable risk estimates for women undergoing presymptomatic testing.
    • Long-term quality of life after cytoreductive surgery and heated intraperitoneal chemotherapy for pseudomyxoma peritonei: a prospective longitudinal study.

      Stearns, Adam T; Malcomson, Lee; Punnett, Grant; Abudeeb, Haytham; Aziz, Omer; Selvasekar, Chelliah; Fulford, Paul E; Wilson, Malcolm S; Renehan, Andrew G; O'Dwyer, Sarah T; et al. (2018-01-08)
      Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are an established treatment for pseudomyxoma peritonei (PMP), but it is a major surgical procedure and may be associated with long-term morbidity. To date, health-related quality-of-life (HRQL) data among survivors are lacking.
    • Long-term responders to palliative chemotherapy for advanced biliary tract cancer.

      Doherty, M; McNamara, Mairéad G; Aneja, P; Horgan, A; Jang, H; Dhani, N; Headly, D; Knox, J; Department of Medical Oncology, University College Hospital Galway, Galway (2016)
    • Long-term results and GvHD after prophylactic and preemptive donor lymphocyte infusion after allogeneic stem cell transplantation for acute leukemia

      Schmid, C.; Labopin, M.; Schaap, N.; Veelken, H.; Brecht, A.; Stadler, M.; Finke, J.; Baron, F.; Collin, M.; Bug, G.; et al. (2021)
      We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell transplantation (alloSCT). DLI were applied preemptively (preDLI) for minimal residual disease (MRD, n = 23) or mixed chimerism (MC, n = 169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n = 126). Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II-IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age ≥60 years (p = 0.046), advanced stage at transplantation (p = 0.003), shorter interval from transplantation (p = 0.018), and prior aGvHD ≥II° (p = 0.036) were risk factors for DLI-induced GvHD. GvHD did not influence CRI, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders. The study describes response and outcome of DLI in CHR and helps to identify candidates without increased risk of severe GvHD.
    • Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1). United Kingdom Children's Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma Working Party.

      Craft, A W; Cotterill, S J; Bullimore, J A; Pearson, D; Department of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne, U.K. (1997-06)
      The aim of this study was to evaluate multimodal chemotherapy and radiotherapy in patients with Ewing's sarcoma. 142 (74 male, 68 female) patients were entered into the ET-1 study between 1978 and 1986. They were treated with vincristine, doxorubicin, actinomycin D, and cyclophosphamide with radiotherapy plus or minus surgery to the primary tumour. Of the 120 who had no metastases at diagnosis, 45 remain alive with a median follow-up of 11.2 years. Only 2 of those with metastases at diagnosis remain alive. The major prognostic factor was site of disease, but age and serum lactic dehydrogenase at diagnosis also had an influence on outcome. 45 of the 61 patients who survived 4 years or more had late effects documented. The type and extent were dependent on tumour site, type of local therapy, volume and dose of radiotherapy. 4 patients had second malignancies. Prospects for long-term survival have improved in patients treated for Ewing's sarcoma. However, late sequelae are present in the majority of patients.
    • The long-term safety and efficacy of autologous haematopoietic stem cell transplantation for relapsing-remitting multiple sclerosis indirectly compared to alemtuzumab: a systematic review

      Greaves, O.; Patel, Amit; University of Liverpool, Liverpool, (2020)
      Background: Multiple Sclerosis (MS) is a chronic, progressive, central neurological disease mediated by autoimmunity. Despite availability of anti-inflammatory drugs such as alemtuzumab, disease progression still occurs with minimal initial reversal of symptoms. Autologous haematopoietic stem cell transplantations (aHSCT) for treatment of MS has seen more dramatic reversal in symptoms but have not been previously directly compared to alemtuzumab. Methods: Systemic review of cohort studies and randomised control trials (RCTs) of Relapsing Remitting MS (RRMS) patients treated with alemtuzumab or aHSCT. Results: aHSCT. A total of 144 studies met the search criteria. After application of eligibility criteria and removal of duplicate data, six studies including 277 patients with RRMS, who failed initial DMTs, were included in the review. All patients were initially alemtuzumab naïve. Mean baseline EDSS was 1.5-6.3. Three studies used myelo- and lympho-ablative BEAM-ATG conditioning; the others used lympho-ablative cyclophosphamide (50mg/kg/day for 3-5 days) with ATG (or alemtuzumab in a minority of patients). Both rabbit and horse ATG were used with dosing between 2.5-10mg/kg/day for 2 days or 0.5-1.5mg/ kg/day for 5 days. The available data showed a mean EDSS reduction from a baseline of 3.89 (3sf) to 2.96 at five-year follow-up. Studies with lower pre-aHSCT EDSS experienced the greatest reduction in EDSS. Event-free survival (EFS) to five years was variable between studies ranging from 0% if high pre-aHSCT EDSS, to 85% if low EDSS preaHSCT. Studies with the lowest initial EDSS experienced higher progression-free survival (PFS) to five years, around 90%. All-cause mortality across the studies was 2.6%; treatment related mortality (TRM) was 0.7%. The percentage of patients retained in the studies after five years stood at only 28.9% compared to the alemtuzumab arm where retention stood at 83.0% (p< 0.001). Comparison of EDSS at five-year follow-up between the two study arms may therefore be misleading due to survivorship bias in the aHSCT arm. Alemtuzumab. A total of 39 studies met the search criteria. After application of eligibility criteria and removal of duplicate data, three studies included 759 patients treated with alemtuzumab: CAM MS223, CARE-MSII, and CAREMSI, were used in the study. Both CAM MS223 and CARE-MSI included treatment naïve patients; CAREMSII (357 patients) included previously DMT exposed patients. Mean EDSS pre-alemtuzumab was 1.9-2.7; only 6 patients had an EDSS >5.0. Peak post-alemtuzumab EDSS reduction occurred at 2 years with the CAM MS223 study; the best mean EDSS reduction was 0.3. The improvements at two years were negated by five years. Mean EDSS across the studies progressed from a baseline of 2.31 (3sf) to 2.34 at five-year follow-up representing a mean increase of 0.03. All-cause mortality across studies was 0.5%; TRM was 0.1%. Conclusions: While it is imperfect to indirectly compare treatments from different studies, EDSS outcome patterns between aHSCT and alemtuzumab differed remarkably. aHSCT, in contrast to alemtuzumab, was associated with the largest magnitude of fall in EDSS that was sustained in the long-term to five years. A direct comparison of aHSCT with alemtuzumab in a RCT seems warranted to confirm these observations of long-term benefit with aHSCT.
    • Long-term safety of growth hormone replacement after CNS irradiation.

      Mackenzie, S; Craven, T; Gattamaneni, Rao; Swindell, Ric; Shalet, Stephen M; Brabant, Georg E; Department of Endocrinology, The Christie, Manchester Academic Health Science Centre, Wilmslow Road, Manchester M20 4BX, United Kingdom. (2011-09)
      Radiotherapy is a central component in the treatment of many brain tumors, but long-term sequelae include GH deficiency and increased risk of secondary neoplasms. It is unclear whether replacement therapy with GH (GHRT) further increases this risk.
    • Long-term survival and symptom palliation in small primary bronchial carcinomas following treatment with intraluminal radiotherapy alone.

      Gollins, Simon W; Burt, Paul A; Barber, Philip V; Stout, Ronald; Department of Clinical Oncology, Christie Hospital, Manchester, UK. (1996)
      Between April 1988 and December 1992, 37 patients with small, previously unirradiated, primary non-small cell carcinomas of the bronchus causing symptoms due to endobronchial disease were treated at the Christie Hospital, Manchester, with a single fraction of high dose rate intraluminal radiotherapy (ILT) using the microSelectron-HDR machine. Small primary (SP) lesions were defined as being less than 2 cm in diameter in a direction perpendicular to the central axis of the iridium-192 treatment source. Fifteen patients (41%) were treated to a dose of 15 Gy and 22 patients (59%) to 20 Gy at a distance of 1 cm from the central axis of the source. At 6 weeks following ILT, improvement in symptoms was seen in the following percentages of patients: haemoptysis 96%, pulmonary collapse 69%, cough 55% and dyspnoea 52%. The magnitude of improvement in these symptoms was largely maintained in patients surviving to 4 months and then 12 months post-ILT. Median actuarial survival was 709 days, 2-year survival 49.4% and 5-year survival 14.1%. Overall, there was no significant difference in survival after treatment with 20 Gy compared with 15 Gy at 1 cm. At the close of study, there were four patients still alive without disease recurrence with survivals of 38, 48, 49 and 63 months. All had had biopsy-proven squamous cell carcinomas and all had been treated with 20 Gy at 1 cm. Five patients died from massive haemoptysis as a terminal event at 4, 9, 9, 10 and 11 months post-ILT, well below the median survival for this group of patients. Again, all had been treated with 20 Gy as opposed to 15 Gy at 1 cm. Over the same time period, 287 patients with non-small cell carcinomas of more than 2 cm in diameter (large primary lesions, LP), were treated with a single fraction of ILT only, as their initial treatment. A consistently greater percentage of patients with SP lesions showed an improvement in the symptoms of haemoptysis and pulmonary collapse when compared with patients with LP lesions. Patients with LP lesions demonstrated a decreased actuarial survival when compared with SP lesions, with median survival being 156 days, 2-year survival 3.1% and no survivors beyond 39 months. This study demonstrates that, in patients with small endobronchial carcinomas a single fraction of ILT can give efficient palliation of symptoms and lead to long term disease-free survival, but that a dose of 20 Gy may be at the limit of bronchial radiation tolerance for a single dose technique employing a high dose rate source.
    • Long-term survival from pembrolizumab (pembro) completion and pembro retreatment: Phase III KEYNOTE-006 in advanced melanoma

      Long, G. V.; Schachter, J.; Arance, A.; Grob, J. J.; Mortier, L.; Daud, A.; Carlino, M. S.; Ribas, A.; McNeil, C. M.; Lotem, M.; et al. (2020)
      Background: 5-year follow-up of the phase 3 KEYNOTE-006 study (NCT01866319) showed pembro improved OS vs ipilimumab (ipi) in patients (pts) with advanced melanoma. 3-y OS rate from pembro completion for pts who completed 2 y of pembro was 93.8%. Results with 8 mo of additional follow-up are presented to inform clinical care. Methods: Eligible pts with ipi-naive advanced melanoma, ?1 prior therapy for BRAF-mutant disease, and ECOG PS 0 or 1 were randomized to pembro 10 mg/kg Q2W or Q3W for ?2 y or ipi 3 mg/kg Q3W for 4 doses. Pts discontinuing pembro with CR, PR, or SD after ?94 weeks were considered pts with 2-y pembro. Pts who stopped pembro with SD, PR or CR could receive ?12 mo of additional pembro (2nd course) upon disease progression if still eligible. ORR was assessed per immune-related response criteria by investigator review. OS was estimated using the Kaplan-Meier method. Pembro arm data were pooled. Post hoc ITT efficacy analyses are shown. Results: Median follow-up from randomization to data cutoff (Jul 31, 2019) was 66.7 mo in the pembro and 66.9 mo in the ipi arms. OS outcomes are shown in Table. For the 103 pts with 2-y pembro (30 CR, 63 PR, 10 SD), median follow-up from completion was 42.9 mo (95% CI, 39.9-46.3).Median DOR was not reached. 36-mo OS from pembro completion was 100% (95% CI, 100.0-100.0) for pts with CR, 94.8% (95% CI, 84.7-98.3) for pts with PR, and 66.7% (95% CI, 28.2-87.8) for pts with SD. 15 pts received 2nd-course pembro; BOR in 1st course was 6 CR, 6 PR, and 3 SD. Median time from end of 1st course to start of 2ndcourse was 24.5 mo (range, 4.9-41.4). Median follow-up in pts who received 2nd-course pembro was 25.3 mo (range, 3.5-39.4). Median duration of 2nd-course pembro was 8.3 mo (range, 1.4-12.6). BOR on 2ndcourse was 3 CR, 5 PR (ongoing responses, 7 pts), 3 SD (ongoing, 2 pts), and 2 PD (1 death); 2 pts pending. Conclusions: Pembro improves the long-term survival vs ipi in pts with advanced melanoma, with all pts who completed therapy in CR still alive at 5 years. Retreatment with pembro at progression in pts who stopped at SD or better can provide additional clinical benefit in a majority of pts.
    • Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.

      Van der Lely, A J; Hutson, R K; Trainer, Peter J; Besser, G M; Barkan, Ariel L; Katznelson, L; Klibanski, Anne; Herman-Bonert, V; Melmed, Shlomo; Vance, Mary Lee; et al. (2001-11-24)
      BACKGROUND: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS: Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION: Pegvisomant is an effective medical treatment for acromegaly.
    • Long-term treatment with telotristat ethyl (TE) in patients with carcinoid syndrome (CS) symptoms: results from TELEPATH study

      Horsch, D; Anthony, L; Gross, D; Valle, Juan W; Welin, S; Benavent, M; Kassler-Taub, K; Binder, P; Banks, P; Jackson, S; et al. (2019)
    • Long-term treatment with telotristat ethyl in patients with carcinoid syndrome symptoms: results from the TELEPATH study

      Horsch, D.; Anthony, L.; Gross, D. J.; Valle, Juan W; Welin, S.; Benavent, M.; Caplin, M.; Pavel, M.; Bergsland, E.; Oberg, K.; et al. (2021)
      Introduction: Telotristat ethyl is indicated for use in combination with somatostatin analogs (SSAs) to treat carcinoid syndrome (CS) diarrhea uncontrolled by SSAs alone in adults, but long-term safety and efficacy data beyond 48 weeks are needed. Objectives: The aims of the study were to evaluate the long-term safety and tolerability of telotristat ethyl and its effect on quality of life (QOL) in patients with CS. Methods: In this phase 3, nonrandomized, multicenter, open-label, long-term extension study (TELEPATH), patients who participated in phase 2 or 3 trials of telotristat ethyl continued treatment at their present dose level (250 or 500 mg thrice daily) for 84 weeks. Safety and tolerability, the primary endpoint, were assessed by monitoring adverse events (AEs), serious AEs, AEs of special interest (AESIs; including liver-related AEs, depression, and gastrointestinal AEs), and deaths. The secondary objective was to evaluate changes in patients� QOL using validated cancer questionnaires and a subjective global assessment of CS symptoms. Results: In 124 patients exposed to telotristat ethyl for a mean of 102.6 � 53.2 weeks, the type and frequency of AEs were consistent with those reported in previous trials. The occurrence of AESIs was not related to dosage or duration of therapy. Most AEs were mild to moderate in severity, and no deaths were related to telotristat ethyl. QOL scores remained stable, and the majority of patients reported adequate symptom relief throughout the study. Conclusions: Safety results of TELEPATH support the long-term use of telotristat ethyl in patients with CS diarrhea. Telotristat ethyl was well-tolerated and associated with sustained improvement in QOL scores
    • Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: updated results from the EORTC 1325-MG/KEYNOTE-054 trial

      Eggermont, A. M. M.; Blank, C. U.; Mandala, M.; Long, G. V.; Atkinson, V. G.; Dalle, S.; Haydon, A. M.; Meshcheryakov, A.; Khattak, A.; Carlino, M. S.; et al. (2020)
      Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. Patients and methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors. Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.
    • Longitudinal analysis of biochemical and haematological features of cancer patients with COVID-19

      Tivey, Ann; Shotton, R.; Lee, Rebecca J; Zhou, Cong; Banfill, Kathryn; Hague, Christina; Gomes, Fabio; Weaver, Jamie M; Armstrong, Anne C; Cooksley, Timothy J; et al. (2020)
      Background: Cancer patients (pts) are at increased risk of severe COVID-19 infection and death. Older pts, men and those with haematological malignancies and receiving anti-tumour therapy within 14 days appear to be at highest risk for poor outcomes. In general populations, severe COVID-19 infection has been associated with neutrophilia, raised lactate dehydrogenase (LDH) and C-reactive protein (CRP). Cancer and its treatment affect many haematological and biochemical parameters.We examined whether COVID-19 infection affected these compared to pts’ baseline parameters by longitudinal tracking. We also investigated whether changes were associated with poor outcome. Methods: Consecutive pts with solid or haematological malignancies presenting with index symptoms and testing positive for SARS-CoV-2 at a tertiary oncology centre were identified following institutional board approval. Clinical and laboratory data were extracted from the pt record. Paired T-tests were used for longitudinal sampling and ANOVA/Chi squared for outcomes. Results: 52 pts tested positive (27 male, 25 female; median age 63). 80.5% had solid cancers, and 19.5% haematological. 31/52 pts were lymphopenic prior to infection. Comparing mean pre-infection counts (6 months-14 days¼PRE) with mean counts from the 5 days following positive test (DURING) lymphocyte counts significantly decreased during infection (p<0.0001). Platelets were significantly reduced DURING vs. PRE COVID-19 (p¼0.0028). 17/52 pts developed transient (median 2 days) neutropenia (<2x109/L) DURING infection (6 pts <1x109/L, 2 pts <0.5x109/L), 8/17 attributed to cancer/cancer therapy, the rest had no underlying cause. 8/17 pts received growth factor support. Reduced lymphocytes/neutrophils/platelets at diagnosis were not associated with oxygen requirement (O2) or death. Different CRP trajectories were observed when comparing pts grouped by discharge/ O2/death. Higher CRP and LDH at diagnosis were associated with admission (p¼0.02 CRP/0.2 LDH), O2 (p¼0.0002 CRP/p<0.01 LDH) and death (p¼0.069 CRP/p¼0.04 LDH). Updated analysis will be presented. Conclusions: Infection with SARS-CoV-2 commonly affects haematological parameters in cancer pts. High CRP and LDH are associated with poor outcomes.
    • Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome

      Lee, Rebecca J; Wysocki, O; Bhogal, T.; Shotton, R; Tivey, Ann; Angelakas, A.; Aung, T.; Banfill, K.; Baxter, M.; Boyce, H.; et al. (2020)
      Background: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. Patients and methods: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. Results: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. Conclusion: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.
    • Longitudinal evaluation of quality of life (QoL) in patients (Pts) with FGFR2-driven cholangiocarcinoma (CCA) treated with pemigatinib

      Valle, Juan W; Bibeau, K.; Cho, Y. H.; Ren, H. B.; Feliz, L.; Lihou, C. F.; Abou-Alfa, G. K.; University of Manchester and Christie Hospital NHS Foundation Trust, Manchester (2021)
      Background: CCA is associated with poor prognosis and reduced QoL. In the phase 2 FIGHT-202 study (NCT02924376) of the selective oral FGFR1–3 inhibitor pemigatinib, 35.5% and 46.7% of pts with previously treated advanced CCA and FGFR2 fusions/rearrangements (RE) had a complete or partial response (CR/PR) and stable disease (SD), respectively; 14.9% had progressive disease (PD) [Abou-Alfa et al., Lancet Oncology 2020;21:671-684]. QoL was an exploratory endpoint. Methods: Pts received pemigatinib 13.5 mg once daily (21-day cycle; 2 weeks on, 1 week off). QoL was assessed longitudinally by best overall response (BOR) per RECIST with the EORTC-QLQ-C30 and the biliary tract cancer-specific EORTC-QLQ-BIL21 questionnaires. QoL scores and longitudinal changes from baseline (BL) were analyzed using descriptive statistics. Treatment-related changes in QoL were a priori expected to be evident by cycle 6 day 1 (week 16). Results: Of 107 pts with FGFR2 RE, 100 (93%) were evaluable for QoL, including36, 48, and 15 with CR/PR, SD, and PD, respectively. From BL to week 16, QLQ-C30 overall health status was maintained in pts with CR/PR and SD and worsened in pts with PD (Table). Emotional functioning remained stable and similar in pts with CR/PR and SD but worsened in pts with PD. All subgroups showed decline in role and social functioning. Pts with CR/PR and SD experienced decreases in QLQ-BIL21 pain and anxiety; all subgroups showed increases in QLQ-BIL21 treatment side effects. Conclusions: In these pts with advanced CCA, those with an SD as BOR had a similar pattern of changes in QoL as those with CR/PR to pemigatinib. Changes in QoL were directionally more favorable in pts with CR/PR or SD than pts with PD.