Cancer

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

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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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Cauda equina compression in metastatic prostate cancer (2020)

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Type of publication:
Journal article

Author(s):
*Siddiqui R.S.; *Cheruvu M.S.; *Ansari H.; *Van Liefland M.

Citation:
BMJ Case Reports; Dec 2020; vol. 13 (no. 12)

Abstract:
A 67-year-old man presented to his general practitioner with intermittent episodes of unilateral sciatica over a 2-month period for which he was referred for an outpatient MRI of his spine. This evidenced a significant lumbar vertebral mass that showed tight canal stenosis and compression of the cauda equina. The patient was sent to the emergency department for management by orthopaedic surgeons. He was mobilising independently, pain free on arrival and without neurological deficit on assessment. Clinically, this patient presented with no red flag symptoms of cauda equina syndrome or reason to suspect malignancy. In these circumstances, National Institute for Health and Care Excellence guidelines do not support radiological investigation of the spine outside of specialist services. However, in this case, investigation helped deliver urgent care for cancer that otherwise may have been delayed. This leads to the question, do the current guidelines meet clinical requirements?

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

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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)

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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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An audit of the Shrewsbury and Telford two week wait CNS malignancy pathway referrals over six months (2015)

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Type of publication:
Poster presentation

Author(s):
*Metcalfe R, *Bowen J

Citation:
West Midlands Regional Neuroscience Meeting, 13 Nov 2015

Abstract:

An audit of the Shrewsbury and Telford two week wait CNS malignancy pathway referrals
over six months. By Metcalfe R*, Bowen J**
*Final year medical student, Keele University Medical School.
**Consultant Neurologist, Shrewsbury and Telford Hospital NHS trust (SaTH).
Word Count: 232 words.

Introduction:

  • The overall incidence of brain tumours in the U.K. is around 7/100,001
  • To promote early diagnosis a fast track “2 week wait” pathway exists for prompt diagnosis and initiation of management of brain/CNS tumours
  • In SaTH standardised suspected CNS malignancy referral proformas2 are faxed to meet 2 week targets appointments

Aim:

To undertake an audit to address the following:

  • Did referrals adhere to proforma criteria?
  • What proportion was seen within two weeks?
  • Is the process fit for purpose?

Methodology:

  • Case note review of all patients referred via the two week CNS Cancer pathway over a sixth month period from 1st July 2014 to 1st January 2015

Results:

  • Over the 6 months >98 % (120/122) referred via the two week wait pathway fulfilled the
    criteria on the proforma
  • Only 5.7% (7/122) were not seen within two weeks
  • 2 patients were diagnosed with brain metastases
  • No patients were diagnosed with a primary brain tumour

Conclusions:

  • Despite adherence of over 98% no case of primary brain tumour was detected over the six month period and 2 (1.6%) of patients referred had brain metastases
  • The current system is not effective at picking up brain tumours

Suggestions:

  • These results will be shared with local primary care groups and the referral criteria refined
  • A reaudit to assess impact of changes will be undertaken

References:
1. McKinney PA. J Neurol Neurosurg Psychiatry 2004;75:ii12-ii17
2. Shrewsbury and Telford Hospital NHS trust. Brain and CNS Cancer Two Week Wait
Referral Proforma. [internet] 2012 [Cited 6th October 2015] Available from:
www.sath.nhs.uk/Library/Documents/gpconnect/gpinfo/Brain%20and%20CNS
%20Cancer%20TWW%20Referral%20Proforma%20_V1_.pdf

BerEP4 and CD34 immunostaining distinguishes basaloid tricholemmoma from basal cell carcinoma (2014)

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Type of publication:
Conference abstract

Author(s):
Turnbull N., Ghumra W., *Mudaliar V., Vella J., Sanders S., Taibjee S., Carr R.

Citation:
American Journal of Dermatopathology, February 2014, vol./is. 36/2(e54-e55), 0193-1091 (February 2014)

Abstract:
Aim: To study of the utility of an immunopanel comprising BerEP4, EMA and CD34 in the differential diagnosis of basaloid tricholemmoma and basal cell carcinoma. Method: An immunopanel comprising BerEP4, EMA and CD34 was applied to 48 tricholemmomas (TL) diagnosed and collected over a 12 year period including 10 tumours with a prominent basaloid component (BTL). Patterns of immunostaining were compared with BCC from our extensive database. Positive immunostaining was defined as moderate to strong intensity in a minimum of 10% of the tumour area. Results: Positivity for BerEP4, EMA and CD34 respectively was as follows: TL – 1/24 (4.1%), 4/21 (19%), 34/34 (100%), BTL- 2/9 (22%), 1/7 (14%), 10/10 (100%) and BCC – 218/219 (99.5%), 10/199 (5%), 0/14 (0%). CD34 in TL was often only focally positive (10% in 5/ 10 cases of BTL). BerEP4 was expressed in at most 20% of the tumour area in basaloid tricholemmomas, but in at least 40% of the tumour area in 95.4% of BCC. Conclusion: Immunostaining for CD34 in combination with BerEP4 helps distinguish BTL from BCC.

Link to more details or full-text: http://gsia.tums.ac.ir/images/UserFiles/12030/Forms/306/XXXIV_Symposium_of_the_International_Society_of_25.pdf

Epidermal growth factor receptor copy number gain (EGFR CNG) and response to gefitinib in esophageal cancer (EC): Results of a biomarker analysis of a phase III trial of gefitinib versus placebo (TRANS-COG) (2014)

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Type of publication:
Conference abstract

Author(s):
Petty R.D., Dahle-Smith A., Miedzybrodzka Z., Dutton S.J., Murray G.I., Stevenson D., *Massie D., Osbourne A., Clark C., Mansoor W., Thompson J., Harrison M., Chatterjee A., Falk S., Elyan S., Garcia-Alonso A., Fyfe D.W., Chau I., Collinson D., Ferry D.

Citation:
Journal of Clinical Oncology, May 2014, vol./is. 32/15 SUPPL. 1, 0732-183X (20 May 2014)

Abstract:
Background: The Cancer Oesophagus Gefitinib (COG) trial randomised (1:1) 450 patients(pts) with advanced EC who had progressed after 1-2 lines of chemotherapy to gefitinib (G) or placebo (P). Improved disease control rates- DCR= RECIST CR+PR+SD at 8 weeks (P 15.6%, G 24.1%, p = 0.016), improved patient reported outcomes, and progression free survival (HR = 0.80, 95%CI 0.66, 0.96, p = 0.020) were seen with G-indicative of rapid and durable responses that were observed in a subset. We hypothesised that EGFR CNG in ECs would identify a subgroup responsive to G. Methods: EGFR CNG was determined by FISH on FFPE tumour specimens(all subject to central pathology review) and performed blind to treatment allocation and outcome. Disomy, low and high trisomy and low polysomy were classified as negative (No CNG) and high polysomy and amplification as positive(CNG). Primary endpoint was OS for G versus P in EGFR CNG and no CNG groups. Secondary endpoints were PFS, DCR and HRQL and outcomes in EGFR amplified patients only. Results: EGFR FISH results were available for 295 patients. Clinical features were not different from the COG trial . EGFR CNG was found in 46/295 (15.6%). There was no significant correlation with EGFR CNG and any clinical features which were also balanced in G and P groups. In EGFR CNG Pts OS was improved with G compared to P (HR=0.53 95%CI 0.28, 0.98 p=0.042), with survival for G vs P 71 vs 64% ,38 vs 14% , 25 vs 5% and 13 vs 0% at 3 ,6, 9, and 12 months respectively. There was no difference in OS for G vs P in EGFR No CNG pts (HR=0.892 95%CI 0.69, 1.16 p=0.395). For PFS EGFR CNG pts, HR=0.58, 95%CI 0.30, 1.07 p=0.080 for G vs P and HR=0.83 95% CI 0.64, 1.07,p=0.144 for EGFR No CNG pts. DCR was improved for G in EGFR CNG pts(42 vs 13%, p=0.035), and less so for EGFR No CNG (24 vs 14 %, p=0.053). EGFR amplification(6%) pts gained greatest benefit from G ( OS, HR=0.19 95%CI 0.05, 0.65 p=0.007). Conclusions: EGFR CNG identified a subgroup of EC who benefit from Gefitinib as a second line treatment and is a useful predictive biomarker for the first stratified treatment approach in this setting and also a subgroup that may be responsive to other anti-EGFR therapies.

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A prospective observational study of real-world treatment patterns and treatment outcomes in patients with advanced or metastatic renal cell carcinoma (mRCC) receiving pazopanib (2014)

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Type of publication:
Conference abstract

Author(s):
Bamias A., Bono P., Procopio G., Herrmann E., Vazquez-Estevez S., Rodriguez Sanchez A., *Srihari N., Schrijvers D.L., Hawkins R.E., Vogelzang N.J., Sapunar F.J., Kothari D., Khan S., Mehmud F., Jonasch E., Schmidinger M.

Citation:
Journal of Clinical Oncology, May 2014, vol./is. 32/15 SUPPL. 1, 0732-183X (20 May 2014)

Abstract:
Background: Pazopanib is an oral, selective, multikinase inhibitor of VEGF receptors 1/2/3, PDGF receptors alpha/s, and stem cell factor receptor (c-Kit) that is approved for first-line treatment of patients with advanced renal cell carcinoma (RCC) and for patients who received prior cytokine therapy. The COMPARZ study of pazopanib versus sunitinib as first-line treatment demonstrated noninferiority of pazopanib for progression-free survival (PFS) in the intention-to-treat population, and pazopanib statistically favored health-related quality of life (HRQoL) in 11 of the 14 domains measured (NEJM 2013;369:722-31). The PISCES patient preference study demonstrated that significantly more patients preferred pazopanib over sunitinib due to overall better HRQoL and less fatigue (JCO 2012;30 suppl 15:CRA4502). The purpose of the PRINCIPAL study is to evaluate the real-world effectiveness and safety of pazopanib in patients with advanced or mRCC. Methods: This is a global, multicenter, prospective, observational study (VEG115232, NCT01649778 ) designed to enrol up to 700 patients. Primary endpoints include PFS, overall response rate, overall survival, relative dose intensity data, HRQoL data, and safety data. Additional treatment strategies for RCC will be obtained post-progression. Key inclusion criteria include a clinical decision to initiate treatment with pazopanib (before enrolment in the study), no prior systemic therapy for advanced or mRCC, and no participation in an interventional trial. The study has enroled 339 patients to date and is currently recruiting in 15 countries, including Europe, Asia, Latin America, and the United States. This study will determine patient outcomes with pazopanib in a real-world setting in terms of efficacy, safety, and patient compliance outside the normal parameters of a controlled trial. PRINCIPAL will also provide further data in patient groups that were under-represented in the controlled clinical trials to date, such as the elderly and patients with co-morbidities.

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Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial (2014)

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Type of publication:
Randomised Controlled Trial

Author(s):
Dutton SJ,Ferry DR,Blazeby JM,Abbas H,Dahle-Smith A,Mansoor W,Thompson J,Harrison M,*Chatterjee A,Falk S,Garcia-Alonso A,Fyfe DW,Hubner RA,Gamble T,Peachey L,Davoudianfar M,Pearson SR,Julier P,Jankowski J,Kerr R,Petty RD

Citation:
Lancet Oncology, 07 2014, vol./is. 15/8(894-904), 1470-2045;1474-5488 (2014 Jul)

Abstract:
BACKGROUND: Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer.METHODS: For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179.FINDINGS: Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 373 months, 95% CI 323-450, for gefitinib vs 367 months, 95% CI 297-437, for placebo; hazard ratio 090, 95% CI 074-109, p=029). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -861, 95% CI -1449 to -273; n=227; p=0004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (269, 95% CI -233 to 772, n=231, p=0293), dysphagia (-318, 95% CI -836 to 200, n=231, p=0228), and eating (-411, 95% CI -996 to 175, n=229, p=0168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (157 months, 95% CI 123-190 in the gefitinib group vs 117 months, 95% CI 107-137 in the placebo group; HR 080, 95% CI 066-096, p=0020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0023).INTERPRETATION: The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients.FUNDING: Cancer Research UK. Copyright 2014 Elsevier Ltd. All rights reserved.

Link to more details or full-text: http://www.sciencedirect.com/science/article/pii/S1470204514700245