Publications by authors named "Thomas Geldart"

6 Publications

  • Page 1 of 1

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy.

Eur Urol Focus 2020 09 6;6(5):999-1005. Epub 2019 Feb 6.

Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK; Department of Oncology, Royal Free NHS Foundation Trust, London, UK. Electronic address:

Background: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH).

Objective: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC).

Design, Setting, And Participants: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions.

Intervention: The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition.

Outcome Measurements And Statistical Analysis: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria.

Results And Limitations: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design.

Conclusions: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required.

Patient Summary: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.
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September 2020

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind, randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss.

Eur J Cancer 2017 12 10;87:75-83. Epub 2017 Nov 10.

Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom; Poole Hospital NHS Foundation Trust, Poole, United Kingdom. Electronic address:

Background: Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy.

Methods: A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears.

Results: Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL.

Conclusions: Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.
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December 2017

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer.

Eur Urol 2016 Mar 11;69(3):450-6. Epub 2015 Sep 11.

St. James's University Hospital, University of Leeds, Leeds, UK.

Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2).

Objective: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC.

Design, Setting, And Participants: Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial.

Intervention: Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom.

Outcome Measurements And Statistical Analysis: Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients.

Results And Limitations: Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02).

Conclusions: The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles.

Patient Summary: There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.
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March 2016

SUCCINCT: an open-label, single-arm, non-randomised, phase 2 trial of gemcitabine and cisplatin chemotherapy in combination with sunitinib as first-line treatment for patients with advanced urothelial carcinoma.

Eur Urol 2015 Apr 20;67(4):599-602. Epub 2014 Nov 20.

Wales Cancer Trials Unit, School of Medicine, Cardiff University, Cardiff, UK; University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, UK.

Unlabelled: Gemcitabine and cisplatin chemotherapy (GC regimen) represents a standard treatment for advanced urothelial carcinoma. We performed an open-label, single-arm, non-randomised, phase 2 trial evaluating the addition of sunitinib to standard GC chemotherapy (SGC regimen). Overall, 63 treatment-naïve participants were recruited and received up to six 21-d cycles of cisplatin 70 mg/m2 (intravenously [IV], day 1) and gemcitabine 1000 mg/m2 (IV, days 1 and 8) combined with sunitinib 37.5 mg (orally, days 2-15). Following review of toxicity after the first six patients, the sunitinib dose was reduced to 25 mg for all patients. Overall response rate was 64%, with response noted in 37 of 58 patients. At 6 mo, 30 of 58 assessable patients (52%; 90% confidence interval [CI], 40-63%) were progression free. Median overall survival was 12 mo (95% CI, 9-15) and was heavily influenced by Bajorin prognostic group. Grade 3-4 toxicities were predominantly haematologic and limited the deliverability of the triple SGC regimen. The trial did not meet its prespecified primary end point of >60% patients progression free at 6 mo. Cumulative myelosuppression led to treatment delays of gemcitabine and cisplatin and dose reduction and/or withdrawal of sunitinib in the majority of cases. The triple-drug combination was not well tolerated. Phase 3 evaluation of the triple SGC regimen in advanced transitional cell carcinoma is not recommended.

Patient Summary: The addition of sunitinib to standard cisplatin and gemcitabine chemotherapy was poorly tolerated and did not improve outcomes in advanced urothelial carcinoma. Treatment delivery was limited by myelotoxicity.
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April 2015

Late relapse of metastatic testicular nonseminomatous germ cell cancer: surgery is needed for cure.

BJU Int 2006 Aug;98(2):353-8

Medical Oncology Unit, Southhampton University Hospitals NHS Trust, Southhampton, UK.

Objective: To identify patients with late relapse of metastatic, nonseminomatous germ cell tumour (NSGCT) and to evaluate the patterns of relapse, treatment and outcome, as such relapse at >2 years after complete remission to treatment for metastatic disease (late relapse) is uncommon, but with prolonged follow-up is becoming increasingly recognized.

Patients And Methods: Between 1980 and 2004, 1405 patients with testicular GCTs were identified who presented to Southampton University Hospital; 742 had NSGCTs or combined testicular GCTs, of whom 405 received primary chemotherapy for metastatic disease. In all, 329 (81%) patients achieved a complete response (CR) to initial treatment, with 101 of them (31%) requiring surgical resection of residual masses after chemotherapy. Any patient relapsing at >2 years after a CR to initial treatment (late relapse) was assessed in detail.

Results: In all, 20 patients had a late relapse, 17 of whom received initial treatment locally and three of whom were initially treated elsewhere. Most (65%) late relapses were asymptomatic and detected by routine cross-sectional imaging or rising levels of tumour markers. Late relapse occurred at a median (range) of 108 (26-217) months (approximately 9 years) after CR. Fifteen (75%) patients underwent only surgery for late relapse, including five who had invasive malignant germ cell cancer within the resected specimens. Fourteen of 15 surgically treated patients remained alive at a median of 44 (9-184) months from initial treatment for late relapse; one had died with progressive recurrent germ cell/epithelial malignancy. Five (25%) patients were initially treated with chemotherapy for late relapse; three of them died from progressive germ cell cancer and the two survivors both had surgical excision of residual abnormalities after salvage chemotherapy. Overall, 15 of 20 (75%) men remain alive with no evidence of disease; one further patient is currently undergoing salvage treatment for his third relapse.

Conclusion: Late relapse is uncommon after modern therapy for metastatic GCTs. Surgical treatment for localized disease, where possible, is associated with prolonged disease-free and overall survival. By contrast, chemotherapy is associated with a low response rate and a poor outcome.
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August 2006

Phase I study of vinflunine administered as a 10-minute infusion on days 1 and 8 every 3 weeks.

Invest New Drugs 2006 May;24(3):223-31

Cancer Research UK Oncology Unit, Southampton University Hospitals, Southampton, United Kingdom.

Vinflunine is a novel vinca alkaloid developed through the selective modification of vinorelbine using super-acidic chemistry. In preclinical testing, vinflunine demonstrated significantly enhanced anti-tumour activity in human tumour xenograft models when compared to its parent compound. A phase I study was conducted to evaluate the safety and toxicity of vinflunine administered as a 10 minute intravenous infusion on days 1 and 8 every three weeks. Sixteen patients with advanced solid tumours were treated. Two of four patients experienced dose limiting toxicities (DLT) at 190 mg/m2 and this was established as the maximum tolerated dose (MTD). At the MTD, the DLT of vinflunine consisted of constipation and neutropenia. Fatigue was notable but not dose limiting. No objective responses were observed. A dose of 170 mg/m2 given on a day 1 and 8 schedule every three weeks would be suitable for future studies.
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May 2006