Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs (2021)

Type of publication:
Journal article

Author(s):
Joharatnam-Hogan N, Alexandre L, Yarmolinsky J, *Lake B, *Capps N, Martin RM, Ring A, Cafferty F, Langley RE

Citation:
Current Oncology Reports, 13 Feb 2021, 23(3):29

Abstract:
Purpose of review: Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here.
Recent findings: In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with “target” trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.

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Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial (2021)

Type of publication:
Journal article

Author(s):
Morgan, Robert D; McNeish, Iain A; Cook, Adrian D; James, Elizabeth C; Lord, Rosemary; Dark, Graham; Glasspool, Rosalind M; Krell, Jonathan; Parkinson, Christine; Poole, Christopher J; Hall, Marcia; Gallardo-Rincón, Dolores; Lockley, Michelle; Essapen, Sharadah; Summers, Jeff; Anand, Anjana; *Zachariah, Abel; Williams, Sarah; Jones, Rachel; Scatchard, Kate; Walther, Axel; Kim, Jae-Weon; Sundar, Sudha; Jayson, Gordon C; Ledermann, Jonathan A; Clamp, Andrew R

Citation:
The Lancet. Oncology; February 2021, 22(2). p. 277-288

Abstract:
BACKGROUNDPlatinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial.METHODSICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146.FINDINGSBetween June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29·5 months (IQR 15·6-54·3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14·4 months (95% CI 9·2-28·0; 297 events) for patients with a RECIST complete or partial response and 13·3 months (8·1-20·1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13·8 months (95% CI 8·8-23·4; 544 events) and 9·7 months (5·8-14·5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response.INTERPRETATIONThe RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient’s clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response.FUNDINGCancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Coronavirus Disease 2019: the Pivotal Role of UK Clinical Oncology and the UK Coronavirus Cancer Monitoring Project (2021)

Type of publication:
Journal article

Author(s):
*Best ; Starkey, T.; *Chatterjee, A.; Fackrell, D.; *Pettit, L.; *Srihari, N.; Tween, H.; Olsson-Brown, A.; Cheng, V.; Hughes, D.J.; Lee, A.J.X.; Purshouse, K.; Arnold, R.; UK Coronavirus Cancer Monitoring Project Team; Sivakumar, S.; Cazier, J.-B.; Lee, L.Y.W.

Citation:
Clinical Oncology; Jan 2021; vol. 33 (no. 1)

Abstract:

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Using the Glasgow Benefit Inventory questionnaire to quantify the health benefits of lymphoedema treatment in patients with head and neck cancer (2020)

Type of publication:
Journal article

Author(s):
*Halliday E.; *Ahsan S.F.; Gittins J.

Citation:
Applied Cancer Research; Dec 2020; vol. 40 (no. 1)

Abstract:
Background: Lymphoedema is a common side effect after treatment for head and neck cancer. Our treatment protocol involves staging the degree of lymphoedema and then offering treatment comprising skin care, manual lymphatic drainage, simple lymphatic drainage, compression and elastic therapeutic tape. The Glasgow Benefit Inventory is a validated post-interventional questionnaire applicable to otorhinolaryngology interventions which measures changes in health status. The aim of this study was to quantify the health benefits of lymphoedema treatment using the Glasgow Inventory Benefit questionnaire, in patients with a history of treated head and neck cancer. Method(s): Any patient who had undergone treatment with curative intent of a primary head and neck malignancy who had been referred for lymphoedema treatment within a 6 month period was eligible for inclusion. Patients completed a questionnaire after finishing the course of lymphoedema treatment. Result(s): A total of 15 patients completed the questionnaire. Ten patients (67%) demonstrated some level of improvement in quality of life, while two (13%) reported no benefit and three (20%) reported negative improvements. The average score for the total Glasgow Benefit Inventory scale was + 7.2. The greatest benefit was demonstrated with the physical benefit subscale (+ 13.1). The average general benefit score was + 9.0. Conclusion(s): Lymphoedema treatment involves techniques which can fairly easily be taught to patients to complete at home. In this study, there were mild improvements in patient reported quality of life using the Glasgow Benefit Inventory in the majority of patients. Clinical interest has increased in lymphoedema recently, but there is still limited information about the effectiveness of treatments and future research should look to address these issues.

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Selection of endogenous control genes for normalising gene expression data derived from formalin-fixed paraffin-embedded tumour tissue (2020)

Type of publication:
Journal article

Author(s):
Smith T.A.D.; AbdelKarem O.A.; Irlam-Jones J.J.; Lane B.; Valentine H.; Bibby B.A.S.; Choudhury A.; West C.M.L.; *Denley H.

Citation:
Scientific reports; Oct 2020; vol. 10 (no. 1)

Abstract:
Quantitative real time polymerase chain reaction (qPCR) data are normalised using endogenous control genes. We aimed to: (1) demonstrate a pathway to identify endogenous control genes for qPCR analysis of formalinfixed paraffin-embedded (FFPE) tissue using bladder cancer as an exemplar; and (2) examine the influence of probe length and sample age on PCR amplification and co-expression of candidate genes on apparent expression stability. RNA was extracted from prospective and retrospective samples and subject to qPCR using TaqMan human endogenous control arrays or single tube assays. Gene stability ranking was assessed using coefficient of variation (CoV), GeNorm and NormFinder. Co-expressed genes were identified from The Cancer Genome Atlas (TCGA) using the on-line gene regression analysis tool GRACE. Cycle threshold (Ct) values were lower for prospective (19.49+/-2.53) vs retrospective (23.8+/-3.32) tissues (p<0.001) and shorter vs longer probes. Co-expressed genes ranked as the most stable genes in the TCGA cohort by GeNorm when analysed together but ranked lower when analysed individually omitting co-expressed genes indicating bias. Stability values were<1.5 for the 20 candidate genes in the prospective cohort. As they consistently ranked in the top ten by CoV, GeNorm and Normfinder, UBC, RPLP0, HMBS, GUSB, and TBP are the most suitable endogenous control genes for bladder cancer qPCR.

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Human immunodeficiency disease in new diagnoses of head and neck squamous cell cancer: are we testing? (2019)

Type of publication:
Journal article

Author(s):
*McNamara K.J.; Saunders T.F.C.; *Ahsan F.; *Fernandez C.

Citation:
Journal of Laryngology and Otology; Vol. 133(12) p. 1038-1040

Abstract:
BACKGROUND: Human immunodeficiency virus infected patients have a three-fold increased risk of head and neck squamous cell carcinoma. The British HIV Association recommends human immunodeficiency virus testing in all new diagnoses of head and neck squamous cell carcinoma.
OBJECTIVE(S): This observational study aimed to examine the current routine practice of human immunodeficiency virus testing in patients with newly diagnosed head and neck squamous cell carcinoma, and to address the importance of this test in promoting the early diagnosis and treatment of human immunodeficiency virus.
METHOD(S): All head and neck cancer multidisciplinary teams in England were questioned on their protocol for human immunodeficiency virus testing in new diagnoses of head and neck squamous cell carcinoma.
RESULT(S): Only 1 out of 30 hospitals leading head and neck multidisciplinary teams (3.3 per cent) routinely offered human immunodeficiency virus testing in this high-risk patient group.
CONCLUSION(S): This observational study highlights that head and neck specialists are not aware of, and are consequently not complying with, routine human immunodeficiency virus testing as recommended by the British HIV Association guidelines.

Patients’ and partners’ views of care and treatment provided for metastatic castrate‐resistant prostate cancer in the UK (2019)

Type of publication:
Journal article

Author(s):
Catt S, Matthews L, May S, Payne H, Mason M, Jenkins V.

Citation:
European Journal of Cancer Care. 2019 Nov;28(6):e13140.

Note:
14 of the 37 participants were recruited from the Royal Shrewsbury Hospital

Abstract:
OBJECTIVE: Documentations of the experiences of patients with advanced prostate cancer and their partners are sparse. Views of care and treatment received for metastatic castrate-resistant prostate cancer (mCRPC) are presented here.
METHODS: Structured interviews conducted within 14 days of a systemic therapy for mCRPC starting and 3 months later explored the following: treatment decisions, information provision, perceived benefits and harms of treatment, and effects of these on patients’ and partners’ lives.
RESULTS: Thirty-seven patients and 33 partners recruited from UK cancer centres participated. The majority of patients (46%) reported pain was their worst symptom and many wanted to discuss its management (baseline-50%; 3 months-33%). Patients and partners believed treatment would delay progression (>75%), improve wellbeing (33%), alleviate pain (≈12%) and extend life (15% patients, 36% partners). At 3 months, most men (42%) said fatigue was the worst treatment-related side effect (SE), 27% experienced unexpected SEs and 54% needed help with SEs. Most patients received SE information (85% written; 75% verbally); many additionally searched the Internet (33% patients; 55% partners). Only 54% of patients said nurse support was accessible.
CONCLUSION: Pain and other symptom management are not optimal. Increased specialist nurse provision and earlier palliative care links are needed. Dedicated clinics may be justified.

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Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial (2019)

Type of publication:
Journal article

Author(s):
Clarke, N W; Ali, A; Ingleby, F C; Hoyle, A; Amos, C L; Attard, G; Brawley, C D; Calvert, J; Chowdhury, S; Cook, A; Cross, W; Dearnaley, D P; Douis, H; Gilbert, D; Gillessen, S; Jones, R J; Langley, R E; MacNair, A; Malik, Z; Mason, M D; Matheson, D; Millman, R; Parker, C C; Ritchie, A W S; Rush, H; Russell, J M; Brown, J; Beesley, S; Birtle, A; Capaldi, L; Gale, J; Gibbs, S; Lydon, A; Nikapota, A; Omlin, A; O’Sullivan, J M; Parikh, O; Protheroe, A; Rudman, S; *Srihari, N N; Simms, M; Tanguay, J S; Tolan, S; Wagstaff, J; Wallace, J; Wylie, J; Zarkar, A; Sydes, M R; Parmar, M K B; James, N D

Citation:
Annals of Oncology; Dec 2019 30(12) p. 1992-2003

Abstract:
BACKGROUND STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients.
METHODS We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional.
RESULTS Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression).
CONCLUSIONS The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

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See Erratum – The authors regret that Fig.2F has been incorrectly titled. The correct title is “Failure-free survival high burden M1”.

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Establishing a large prospective clinical cohort in people with head and neck cancer as a biomedical resource: head and neck 5000 (2015)

Type of publication:
Journal article

Author(s):
Ness A.R., Waylen A., Hurley K., Jeffreys M., Penfold C., Pring M., Leary S., Allmark C., Toms S., Ring S., Peters T.J., Hollingworth W., Worthington H., Nutting C., Fisher S., Rogers S.N., Thomas S.J., Rogers S., Thiruchelvam J.K., Abdelkader M., Anari S., Mehanna H., Sheehan T., Dyker K., McCaul J., Benson R., Stewart S., Hall C., Lester J., Homer J., Hamid A., Lamont A., Fresco L., Lester S., Cogill G., Roy A., Foran B., Bisase B., Balfour A., Evans A., Gollins S., Conway D., Gunasekaran S.P., Lees L., Lowe R., England J., Scrase C., Wight R., Sen M., Doyle M., Moule R., Goodchild K., Rowell N., Beaumont-Jewell D., Loo H.W., Jankowska P., Paleri V., Casasola R., Roques T., Tierney P., Hwang D., Dyson P., Andrade G., Tatla T., Christian J., Winter S., Baldwin A., Davies J., King E., Barnes D., Repanos C., Kim D., Richards S., Dallas N., McAlister K., Berry S., Cole N., Moss L., Palaniappan N., Evans M., Siva M., *Hari C. , Wood K., Simcock R., Waldron J., Hyde N., Ahmed I., Gahir D., O’Hara J., Carr R., Forster M., Thomas S., Wagstaff L., Mano J., Brammer C., Tyler J., Coatesworth A.

Citation:
BMC Cancer, December 2014, vol./is. 14/1, 1471-2407 (December 17, 2014)

Abstract:
Background: Head and neck cancer is an important cause of ill health. Survival appears to be improving but the reasons for this are unclear. They could include evolving aetiology, modifications in care, improvements in treatment or changes in lifestyle behaviour. Observational studies are required to explore survival trends and identify outcome predictors. Methods: We are identifying people with a new diagnosis of head and neck cancer. We obtain consent that includes agreement to collect longitudinal data, store samples and record linkage. Prior to treatment we give participants three questionnaires on health and lifestyle, quality of life and sexual history. We collect blood and saliva samples, complete a clinical data capture form and request a formalin fixed tissue sample. At four and twelve months we complete further data capture forms and send participants further quality of life questionnaires. Discussion: This large clinical cohort of people with head and neck cancer brings together clinical data, patient-reported outcomes and biological samples in a single co-ordinated resource for translational and prognostic research.

Link to full-text: http://europepmc.org/articles/PMC4301458