• I shared my experiences of sarcoma to benefit others

      Onasanya, Maria; The Christie NHS Foundation Trust, Manchester (2019)
    • IAPs as a target for anticancer therapy.

      Danson, Sarah; Dean, Emma J; Dive, Caroline; Ranson, Malcolm R; Christie Hospital NHS Trust and Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, United Kingdom. s.danson@sheffield.ac.uk (2007-12)
      The avoidance of apoptosis is one of the hallmarks of cancer cells. In addition, failure to induce apoptosis by anticancer agents, either due to limitations of the drug or the tumour cell evading apoptosis, is a reason for chemotherapeutic failure. Two general pathways for apoptotic cell death have been characterised, the extrinsic and intrinsic pathways which merge in the final common pathway. X-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein in the final common pathway that inhibits caspases and suppresses apoptosis. XIAP is over-expressed in many cancer cell lines and cancer tissues. High XIAP expression has been correlated with resistance to chemotherapy and radiotherapy and to poor clinical outcome by some investigators. Manipulation of apoptosis is an attractive therapeutic concept. Much effort has been spent on inhibiting the anti-apoptotic protein, B cell lymphoma gene 2 (Bcl-2) which is part of the intrinsic pathway. Now attention is turning to inhibition of XIAP as a cancer drug target. It has been argued that it is more effective to block the final common pathway rather than just the intrinsic arm. Inhibition of XIAP can be with either antisense oligonucleotides (ASO) or small molecule inhibitors. In vitro, XIAP antagonists produce XIAP knockdown and apoptosis which is associated with sensitisation of tumour cells to radiotherapy and cytotoxic drugs. In vivo, XIAP antagonists have antitumour effects and sensitise tumours to the effects of chemotherapy. This review will summarise the preclinical data for both ASO and small molecule inhibition of XIAP and discuss emerging Phase I data. Future strategies for manipulation of XIAP and the clinical development of XIAP inhibitors will be discussed.
    • The iBRA-2 (immediate breast reconstruction and adjuvant therapy audit) study: protocol for a prospective national multicentre cohort study to evaluate the impact of immediate breast reconstruction on the delivery of adjuvant therapy.

      Dave, R; O'Connell, R; Rattay, T; Tolkien, Z; Barnes, N; Skillman, J; Williamson, P; Conroy, E; Gardiner, M; Harnett, A; et al. (2016-10-07)
      Immediate breast reconstruction (IBR) is routinely offered to improve quality of life for women with breast cancer requiring a mastectomy, but there are concerns that more complex surgery may delay the delivery of adjuvant oncological treatments and compromise long-term oncological outcomes. High-quality evidence, however, is lacking. iBRA-2 is a national prospective multicentre cohort study that aims to investigate the effect of IBR on the delivery of adjuvant therapy.
    • Ibrutinib and obinutuzumab in CLL: improved MRD response rates with substantially enhanced MRD depletion for patients with > 1 year prior ibrutinib exposure

      Munir, T; Rawstron, A; Brock, K; Vicente, S; Yates, F; Bishop, R; Cramp, S; DeTute, R; Dalal, S; Webster, N; et al. (2019)
    • Ibrutinib and obinutuzumab in CLL: improved MRD response rates with substantially enhanced MRD depletion for patients with > 1 year prior ibrutinib exposure

      Rawstron, A; Munir, T; Brock, K; Webster, N; Vicente, M; Yates, F; Cramp, S; Bishop, R; Dalal, S; De Tute, M; et al. (2018)
    • Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study.

      Gopal, A; Schuster, S; Fowler, N; Trotman, J; Hess, G; Hou, J; Yacoub, A; Lill, M; Martin, P; Vitolo, U; et al. (2018-05-31)
      Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 ( P = .02), and Th1-promoting (antitumor) cytokines interferon-γ and interleukin-12 increased ( P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.
    • Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study

      Hillmen, P; Rawstron, A; Brock, K; Munoz-Vicente, S; Yates, F; Bishop, R; Boucher, R; MacDonald, D; Fegan, C; McCaig, A; et al. (2019)
      PURPOSE: The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS: CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS: In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION: The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.
    • Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the Bloodwise TAP Clarity study

      Munir, T; Rawstron, A; Brock, K; Vicente, S; Yates, F; Bishop, R; Macdonald, D; Fegan, C; McCaig, A; Schuh, A; et al. (2019)
    • Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the Bloodwise TAP CLARITY study

      Hillmen, P; Rawstron, A; Brock, K; Vicente, M; Yates, F; Bishop, R; Macdonald, D; Fegan, C; McCaig, A; Schuh, A; et al. (2018)
    • Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.

      Byrd, J; Brown, J; O'Brien, S; Barrientos, J; Kay, N; Reddy, N; Coutre, S; Tam, C; Mulligan, S; Jaeger, U; et al. (2014-07-17)
      In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.
    • ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen.

      Howell, Anthony; Osborne, C Kent; Morris, Charles; Wakeling, Alan E; Department of Medical Oncology, Christie Hospital National Health Service Trust, Manchester, United Kingdom. (2000-08-15)
      BACKGROUND: The nonsteroidal antiestrogen tamoxifen is well established as an effective treatment for patients with breast carcinoma, both for the treatment of metastatic disease and as an adjuvant to surgery for patients with primary breast carcinoma. In addition to exerting antagonistic effects on the estrogen receptor, tamoxifen and its derivatives act as partial agonists on certain tissues. These agonistic effects, for example, endometrial stimulation and stimulation of tumor growth after previous response to tamoxifen, may limit their clinical efficacy. ICI 182,780 (Faslodex) from AstraZeneca (Cheshire, United Kingdom) is a novel, steroidal estrogen antagonist that was designed to be devoid of estrogen agonist activity in preclinical models. METHODS: ICI 182,780 was tested in a large number of in vitro and in vivo preclinical models, and its value was assessed clinically when administered before surgery for breast carcinoma and hysterectomy for benign conditions and after failure of tamoxifen in patients with advanced breast carcinoma. RESULTS: All data indicated that ICI 182,780 is devoid of agonist activity in preclinical models and in clinical trials. It inhibits growth of the breast and endometrium. In animal models, it does not cross the blood-brain barrier and appears to be neutral with respect to lipids and bone. ICI 182,780 down-regulates the estrogen receptor and is active in tamoxifen-resistant breast carcinoma. In a small, Phase II study, durable responses were seen: Phase III clinical trials are in progress comparing ICI 182,780 with anastrozole and tamoxifen in the treatment of patients with advanced breast carcinoma. CONCLUSIONS: ICI 182,780 specifically down-regulates the estrogen receptor and, thus, represents the first of a new class of therapeutic agents. In this report, the authors present the current evidence that distinguishes ICI 182,780 from tamoxifen and related nonsteroidal compounds and establishes ICI 182,780 as the first in a new class of therapeutic agents.
    • ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy

      Elyashiv, O.; Ledermann, J.; Parmar, G.; Farrelly, L.; Counsell, N.; Feeney, A.; El-Khouly, F.; Macdonald, I.; Neto, A.; Arthur-Darkwa, E.; et al. (2020)
      Background: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. Primary objective: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. Study hypothesis: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. Trial design: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). Major inclusion criteria: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. Primary endpoints: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type.
    • ICON8 stage 1A and 1B analysis: safety and feasibility of weekly carboplatin and paclitaxel regimens in first-line ovarian cancer.

      James, E; Hook, J; Stenning, S; Cook, A; Coyle, C; Petrie, J; Kaplan, R; McNeish, I; Perren, T; Naik, R; et al. (2016-10-01)
    • ICON8: Overall survival results in a GCIG phase III randomised controlled trial of weekly dose-dense chemotherapy in first line epithelial ovarian, fallopian tube or primary peritoneal carcinoma treatment

      Clamp, Andrew R; James, E. C.; McNeish, I.; Dean, A.; Kim, J. W.; O'Donnell, D. M.; Hook, J.; Gallardo-Rincon, D.; Coyle, C.; Blagden, S.; et al. (2020)
      Background: ICON8 investigated the safety and efficacy of weekly dose dense chemotherapy (q1w) in patients with epithelial ovarian cancer (EOC) compared to standard three weekly chemotherapy (q3w). ICON8 had co-primary outcomes of progression free (PFS) and overall survival (OS). Mature OS and updated PFS results are reported here. Methods: Eligible women with FIGO stage IcG3-IV EOC were randomised 1:1:1 to arm 1 standard chemotherapy (q3w carboplatin AUC5/6 + q3w paclitaxel 175mg/m2); arm 2 weekly paclitaxel (q3w carboplatin AUC5/6 + q1w paclitaxel 80mg/m2); arm 3 weekly carboplatin-paclitaxel (q1w carboplatin AUC2 + q1w paclitaxel 80mg/m2). Patients received immediate primary surgery (IPS) prior to entering ICON8 or neo-adjuvant chemotherapy with planned delayed primary surgery (DPS) during chemotherapy. Analyses are performed on an intention to treat basis, comparing arms 2v1 and 3v1. Results: From Jun 2011 - Nov 2014, 1566 patients were randomised, 522, 523, 521 in arms 1, 2, 3 respectively. Baseline characteristics were well-balanced e median age 62 years; serous histology 72%; stage Ic-II 19%, IIIa-IIIb 10%, IIIc-IV 72%. 48% patients had IPS, 50% planned DPS and 2% inoperable. At 1st Oct 2019, 923 deaths had been reported, arm 1 319 (61%); arm 2 300 (57%); arm 3 304 (58%). No significant improvement in OS was observed in either comparison: arm 2v1 log rank p¼0.14, hazard ratio (HR) ¼ 0.88 (97.5% confidence interval (CI) 0.74, 1.06); arm 3v1 log rank p¼0.27, HR ¼ 0.91 (97.5% CI 0.76, 1.09). Median OS was 47.4, 54.1 and 53.4 months in arms 1, 2, 3 respectively. No heterogeneity in treatment effect was noted on subgroup analysis by surgical approach (IPS vs DPS). Updated PFS was also analysed. As in the primary analysis, no significant difference in PFS was observed with either weekly treatment (log-rank arm 2v1 p¼0.37, arm 3v1 p¼0.48; restricted mean PFS time 25, 25.5, 25.9 months in arms 1, 2, 3 respectively). Conclusions: The final analysis for ICON8 confirms that, although weekly dose-dense chemotherapy is a safe alternative to q3w chemotherapy and can be delivered successfully in first-line EOC treatment, it does not significantly improve PFS or OS.
    • ICRP Publication 131: Stem cell biology with respect to carcinogenesis aspects of radiological protection.

      Hendry, Jolyon H; Niwa, O; Barcellos-Hoff, M; Globus, R; Harrison, J; Martin, M; Seed, T; Shay, J; Story, M; Suzuki, K; et al. (2016-03-08)
    • The ICRU recommendations for reporting intracavitary therapy in gynaecology and the Manchester method of treating cancer of the cervix uteri.

      Wilkinson, James M; Ramachandran, T P; Christie Hospital, Manchester, UK. (1989-04)
      The recommendations of the International Commission on Radiation Units and Measurements for reporting intracavitary therapy have been considered with particular regard to the Manchester method of treating cancer of the cervix uteri. The total reference air kerma is calculated and tabulated as a function of prescription for the standard Manchester applicator arrangements. Furthermore, it is shown that the volume contained within a particular isodose surface may be determined, with very acceptable accuracy, from the total reference air kerma by the use of a simple empirical expression.
    • Idelalisib-rituximab induces durable remissions in TP53 disrupted B-PLL but results in significant toxicity: updated results of the UK-wide compassionate use programme.

      Eyre, T; Fox, C; Boden, A; Bloor, Adrian; Dungawalla, M; Shankara, P; Went, R; Schuh, A; Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK (2018-02-22)
    • Identical chemotherapy schedules given on and off trial protocol in small cell lung cancer: response and survival results.

      Burgers, J A; Arance, Ana; Ashcroft, Linda; Hodgetts, Jackie; Lomax, Lyn; Thatcher, Nick; University Hospital Rotterdam, Department of Pulmonary Diseases. P.O. Box 5201, 3008 AE Rotterdam, The Netherlands. (2002-08-27)
      Patients who are treated within clinical trials may have a survival benefit dependent on being a trial participant. A number of factors may produce such beneficial outcome including more rigorous adherence to a peer reviewed trial protocol, management by an experienced treatment team, being treated in a specialist centre etc. The current investigation compared patients treated on and off trial with the same standard arm treatment regimen. The results could then be interpreted without the confounding factors of differing treatment regimens, treatment teams or treatment hospitals. The results demonstrated given these circumstances that survival was no different for patients participating in a randomised trial compared with a group of patients similarly treated who were not eligible for trial entry or who declined randomisation. These results were obtained by the rigorous adherence to a defined protocol with the invaluable assistance of designated lung cancer staff.
    • Identification and evaluation of clinically significant prostate cancer: a step towards personalized diagnosis.

      Ali, Adnan; Hoyle, Alex P; Baena, Esther; Clarke, Noel W; Prostate Oncobiology The Christie NHS Foundation Trust, Manchester (2017-02-16)
      Prostate cancer (PCa) diagnostics are evolving rapidly. The quest to differentiate 'clinically significant' from 'clinically insignificant' disease has gathered momentum, leading to substantial change in traditional diagnostic approaches. Herein, we review the relevant information on currently available biomarkers and assess their ability to help physicians and patients in making a shared and personalized decision based on their individual risk of harbouring clinically significant disease.