Publications by authors named "Matthew Wheater"

18 Publications

  • Page 1 of 1

The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis.

Eur Urol 2020 03 1;77(3):344-351. Epub 2020 Jan 1.

Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.

Background: Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m), and cisplatin (BEP) chemotherapy, or surveillance.

Objective: To test whether one cycle of BEP achieves similar recurrence rates to two cycles of BEP.

Design, Setting, And Participants: A total of 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study.

Intervention: One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m on days 1-3, and cisplatin 50 mg/m on days 1-2, plus antibacterial and granulocyte colony stimulating factor prophylaxis.

Outcome Measurements And Statistical Analysis: The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr.

Results And Limitations: The median follow-up was 49 mo (interquartile range 37-60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3-3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3-4 febrile neutropenia occurred in 6.8% of participants.

Conclusions: BEP is safe and the 2-yr MR rate is consistent with that seen following two BEP cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BEP in high-risk stage 1 NSGCTT. Adoption of one cycle of BEP as standard would reduce overall exposure to chemotherapy in this young population.

Patient Summary: Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles.
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http://dx.doi.org/10.1016/j.eururo.2019.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026695PMC
March 2020

Outcome of Men With Relapses After Adjuvant Bleomycin, Etoposide, and Cisplatin for Clinical Stage I Nonseminoma.

J Clin Oncol 2020 04 26;38(12):1322-1331. Epub 2019 Dec 26.

Cantonal Hospital St Gallen, Department of Medical Oncology and Hematology, St. Gallen, Switzerland.

Purpose: Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment.

Patients And Methods: Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses.

Results: Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes.

Conclusion: Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).
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http://dx.doi.org/10.1200/JCO.19.01876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164488PMC
April 2020

Salvage Chemotherapy With Gemcitabine, Paclitaxel, Ifosfamide, and Cisplatin for Relapsed Germ Cell Cancer.

Clin Genitourin Cancer 2018 12 17;16(6):458-465.e2. Epub 2018 Jul 17.

University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom.

Background: Metastatic germ cell tumors remain potentially curable when treated with salvage chemotherapy at first relapse. In the present phase I/II study, we sought to improve on the response rate and duration of the TIP (paclitaxel, ifosfamide, cisplatin) regimen by adding gemcitabine (Gem-TIP).

Materials And Methods: Twenty patients were recruited after failure of first-line cisplatin-containing chemotherapy. The primary objectives were to determine the maximum tolerated dose of gemcitabine when combined with TIP and to establish the dose intensity of the TIP drugs in this combination. The secondary objectives were the response rates, failure-free survival, and overall survival.

Results: The maximum tolerated dose of gemcitabine was 1200 mg/m. The mean relative dose intensity was 95% (95% confidence interval [CI], 90.2%-99.2%) for gemcitabine, 96% (95% CI, 92.9%-98.7%) for paclitaxel, 92% (95% CI, 84.5%-98.8%) for ifosfamide, and 94% (95% CI, 89.3%-99.0%) for cisplatin. The overall complete response rate was 50%; another 30% of the patients achieved a partial response. The 1-year failure-free survival and overall survival rates were 68% (95% CI, 43%-84%) and 89.5% (95% CI, 64%-97%), respectively.

Conclusion: Gemcitabine can be added to TIP chemotherapy at the full dose, with manageable toxicity and no detrimental effect on the dose intensity of the TIP drugs. The response rate and duration were improved compared with those reported from the Medical Research Council TIP trial; further evaluation is warranted.
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http://dx.doi.org/10.1016/j.clgc.2018.07.006DOI Listing
December 2018

Successful use of adalimumab in immune checkpoint inhibitor-associated inflammatory arthritis.

Rheumatol Adv Pract 2018 30;2(1):rky001. Epub 2018 Jan 30.

Rheumatology Department, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, UK.

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http://dx.doi.org/10.1093/rap/rky001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649903PMC
January 2018

Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease.

J Surg Oncol 2018 May 28;117(6):1170-1178. Epub 2017 Dec 28.

Cancer Sciences Academic Unit, University of Southampton, Southampton, United Kingdom.

Background: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy.

Methods: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively.

Results: A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9).

Conclusions: M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.
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http://dx.doi.org/10.1002/jso.24956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033148PMC
May 2018

Outcome of Men With Relapse After Adjuvant Carboplatin for Clinical Stage I Seminoma.

J Clin Oncol 2017 Jan 28;35(2):194-200. Epub 2016 Nov 28.

Stefanie Fischer and Silke Gillessen, Cantonal Hospital St Gallen, St Gallen; Dirk Klingbiel, SAKK Coordinating Center, Bern; Jörg Beyer, Universitätsspital Zürich, Zürich, Switzerland; Torgrim Tandstad, St Olavs University Hospital, Trondheim, Norway; Matthew Wheater, Caroline Chau, and Edurne Arriola, University Hospital Southampton, Southampton; Emilio Porfiri, Kalena Marti, and Paul Hutton, Birmingham University Hospital, Birmingham; Jonathan Shamash, St Bartholomew's Hospital, London, United Kingdom; Aude Fléchon, Centre Léon Bérard, Lyon; Brigitte Laguerre, Centre Eugène Marquis, Rennes, France; Jorge Aparicio, Hospital Universitari i Politècnic La Fe, Valencia; Pablo Maroto, Hospital Sant Pau, Barcelona, Spain; Breda Skrbinc, Institute of Oncology, Ljubljana, Slovenia; Umberto Basso, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy; Anja Lorch, Universitätsklinikum Düsseldorf, Düsseldorf; Klaus-Peter Dieckmann, Klinik für Urologie, Hamburg, Germany; Gabriella Cohn-Cedermark, Karolinska Institute; Gabriella Cohn-Cedermark, Karolinska University Hospital, Stockholm; and Olof Ståhl, Skane University Hospital, Lund, Sweden.

Purpose Adjuvant carboplatin is one of three management strategies that may follow inguinal orchiectomy in clinical stage I seminoma. However, little is known about the outcome of patients who experience a relapse after such treatment. Patients and Methods Data from 185 patients who relapsed after adjuvant carboplatin between January 1987 and August 2013 at 31 centers/groups from 20 countries were collected and retrospectively analyzed. Primary outcomes were disease-free survival and overall survival. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results With a median follow-up of 53 months (95% CI, 48 to 60 months) the 5-year disease-free survival was 82% (95% CI, 77% to 89%), and the 5-year overall survival was 98% (95% CI, 95% to 100%). The median time from orchiectomy to relapse was 19 months (95% CI, 17 to 23 months); 15% (95% CI, 10% to 21%) of relapses occurred > 3 years after treatment. The majority of relapses were detected by computed tomography scan during routine follow-up, 98% in the International Germ Cell Cancer Collaborative Group good prognosis group. Chemotherapy was administered to 92% of patients, mostly as standard first-line treatment corresponding to stage; 8% of patients had additional local treatments. Only 28 patients experienced a second relapse. At last follow-up, 174 (94%) of 185 patients were alive without disease, and four patients with disease. Seven patients died, three of whom due to progressive disease. Conclusion Within the limitations of a retrospective analysis, the results suggest that the majority of patients who experience a relapse after adjuvant carboplatin for clinical stage I seminoma can be successfully treated with a cisplatin-based chemotherapy regimen adequate for stage. Because 15% of the relapses occurred > 3 years after adjuvant treatment, a minimum of 5 years follow-up is recommended.
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http://dx.doi.org/10.1200/JCO.2016.69.0958DOI Listing
January 2017

Evaluation of immune infiltration in the colonic mucosa of patients with ipilimumab-related colitis.

Oncoimmunology 2016;5(9):e1209615. Epub 2016 Jul 15.

Southampton NIHR Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK; University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Approximately 30% of patients treated with ipilimumab will develop gastrointestinal toxicity. The immunological drivers that underpin the clinical observations in human tissues are poorly understood. We report here on the immune consequences of ipilimumab treatment in the colorectal mucosa of patients with treatment-related colitis. Using immunohistochemistry, we evaluated the immune infiltrate by CD8, FoxP3, and granzyme B (GzmB) in colonic biopsies from 20 patients with ipilimumab-related colitis. We assessed 10 cases with normal colon biopsies for comparison. In eight cases (four on steroids only, four on steroids and infliximab), we evaluated two sequential biopsies. We observed that CD8, FoxP3, and GzmB T cell counts were significantly higher in patients with ipilimumab-related colitis compared to normal colon ( < 0.0001). Patients who required infliximab for the resolution of their colitis had a significantly higher CD8/FoxP3 ratio than those treated only with steroids and this correlated with clinical severity. The analysis of repeat samples revealed that resolution of the colitis was associated with a decrease in CD8 and FoxP3 cells both in patients treated with steroids and infliximab. Our data suggest that counts of cytotoxic T cells and Tregs in the colonic mucosa from patients with ipilimumab-related colitis correlate with clinical findings and may predict severity and guide management.
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http://dx.doi.org/10.1080/2162402X.2016.1209615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048766PMC
July 2016

Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma.

Oncoimmunology 2016 May 18;5(5):e1143997. Epub 2016 Feb 18.

Cancer Sciences Academic Unit, University of Southampton , Southampton, United Kingdom.

Background: Untreated metastatic uveal melanoma (UM) carries a grave prognosis. Unlike cutaneous melanoma (CM), there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1-PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab.

Methods: To assess the efficacy and safety of pembrolizumab, we retrospectively analyzed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access program (EAP) who received pembrolizumab at 2 mg/kg 3 weekly. Tumor assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (irRC) by CT scanning. Toxicity was recorded utilizing Common Terminology Criteria for Adverse Events ("CTCAE") v4.03.

Results: Twenty-five patients were identified receiving a median of six cycles of treatment. Two patients achieved a partial response and six patients stable disease. After a median follow-up of 225 d median progression free survival (PFS) was 91 d and overall survival (OS) was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. Five patients experienced grade 3 or 4 adverse events (AEs); there were no treatment related deaths.

Conclusions: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities.
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http://dx.doi.org/10.1080/2162402X.2016.1143997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910726PMC
May 2016

Systemic immune-inflammation index predicts the clinical outcome in patients with metastatic renal cell cancer treated with sunitinib.

Oncotarget 2016 08;7(34):54564-54571

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Background: In this retrospective analysis, we explored the prognostic and predictive value of the systemic immune-inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, at baseline and changes at week 6 during first-line sunitinib in patients with metastatic renal cell cancer (RCC).

Results: Patients were stratified into high SII (≥ 730) and low SII (< 730) groups. SII was associated with objective response, p < 0.0001. The median PFS was 6.3 months (95% CI 5.5-8.9) in patients with SII ≥ 730 and 18.7 months (95% CI 14.7-22.8) in those with SII < 730, p < 0.0001. The median OS was 43.6 months (95% CI 35.3-52.1) in patients with SII < 730, and 13.5 months (95% CI 9.8-18.5) in those with SII ≥ 730, p < 0.0001. In multivariate analysis, performance status, IMDC score and SII were able to predict OS (HR = 3.29, HR = 1.71 and HR = 1.79, respectively).

Materials And Methods: We included 335 consecutive RCC patients treated with first-line sunitinib. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion at week 6 of treatment on PFS and OS was evaluated by Cox regression analyses.

Conclusions: The SII and its changes during treatment represent a powerful prognostic indicator of clinical outcome in patients with metastatic RCC.
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http://dx.doi.org/10.18632/oncotarget.10515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342364PMC
August 2016

Outcome and Biomarker Analysis from a Multicenter Phase 2 Study of Ipilimumab in Combination with Carboplatin and Etoposide as First-Line Therapy for Extensive-Stage SCLC.

J Thorac Oncol 2016 09 11;11(9):1511-21. Epub 2016 Jun 11.

University of Southampton, Southampton, United Kingdom.

Objectives: Our aim was to evaluate the safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive-stage SCLC.

Methods: Patients with chemotherapy-naive extensive-stage SCLC were treated with carboplatin and etoposide for up to six cycles. Ipilimumab, 10 mg/kg, was given on day 1 of cycles 3 to 6 and every 12 weeks. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and immune-related response criteria. The primary end point was 1-year progression-free survival (PFS) according to RECIST. Secondary end points included PFS according to immune-related PFS and overall survival. Autoantibody serum levels were evaluated and correlated with clinical outcomes.

Results: A total of 42 patients were enrolled between September 2011 and April 2014; 39 were evaluable for safety and 38 for efficacy. Six of 38 patients (15.8% [95% confidence interval (CI): 7.4-30.4]) were alive and progression-free at 1-year by RECIST. Median PFS was 6.9 months (95% CI: 5.5-7.9). Median immune-related PFS was 7.3 months (95% CI: 5.5-8.8). Median overall survival was 17.0 months (95% CI: 7.9-24.3). Of the patients evaluable for response, 21 of 29 (72.4%) achieved an objective response by RECIST and 28 of 33 (84.8%) achieved an objective response by the immune-related response criteria. All patients experienced at least one adverse event; at least one grade 3 or higher toxicity developed in 35 of 39 patients (89.7%); in 27 patients (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. Positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity.

Conclusions: Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation.
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http://dx.doi.org/10.1016/j.jtho.2016.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063510PMC
September 2016

Infliximab for IPILIMUMAB-Related Colitis-Letter.

Clin Cancer Res 2015 Dec;21(24):5642-3

Southampton NIHR Experimental Cancer Medicine Centre, Faculty of Medicine, University of Southampton Tremona Road, Southampton, United Kingdom. University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, United Kingdom.

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http://dx.doi.org/10.1158/1078-0432.CCR-15-2471DOI Listing
December 2015

Immunosuppression for ipilimumab-related toxicity can cause pneumonia but spare antitumor immune control.

Oncoimmunology 2015 Oct 27;4(10):e1040218. Epub 2015 May 27.

Cancer Sciences Unit; University of Southampton and University Hospital Southampton NHS Foundation Trust ; Southampton, UK ; University Hospital Southampton NHS Foundation Trust ; Southampton, UK ; Southampton Experimental Cancer Medicine Center; University of Southampton and University Hospital Southampton NHS Foundation Trust ; Southampton, UK.

Ipilimumab is a standard therapy for advanced melanoma. Severe immune related adverse events occur in up to 30% of patients and require treatment with immunosuppressants such as steroids or the anti-TNFα antibody, infliximab. We describe two patients with advanced melanoma treated with ipilimumab. Both suffered from severe immune related side effects and required prolonged immunosuppression with steroids and/or infliximab. Both patients recovered and in spite of the immune suppression, demonstrate clinical evidence of tumor control. This argues that distinct immunological effector functions control nosocomial infection and tumor, respectively. To our knowledge, these are also the first two case reports of pneumocystis pneumonia in this setting.
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http://dx.doi.org/10.1080/2162402X.2015.1040218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589063PMC
October 2015

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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http://dx.doi.org/10.1016/j.eururo.2015.08.035DOI Listing
March 2016

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

Melanoma Res 2015 Oct;25(5):432-42

aDepartment of Oncology bCambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer Theme, Cambridge University Hospitals NHS Foundation Trust, Cambridge cSouthampton Experimental Cancer Medicine Center, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton dDepartment of Medical Oncology, The Christie, Manchester eDepartment of Medicine, Royal Marsden NHS Foundation Trust, London fOxford NIHR Biomedical Research Centre, Oxford gDepartment of Medical Oncology, Mount Vernon Hospital, Northwood hDepartment of Medical Oncology, Velindre Cancer Centre, Cardiff iNorthern Centre for Cancer Care, Newcastle upon Tyne jDirectorate of Haematology and Oncology, Guy's and St. Thomas' NHS Foundation Trust, London kDepartment of Medical Oncology, Royal Wolverhampton Hospitals lDepartment of Medical Oncology, Royal Preston Hospital mClinical Oncology, Norfolk and Norwich University Hospital nDivision of Clinical Sciences, St George's Hospital Medical School, London oDepartment of Oncology, Castle Hill Hospital, Hull pSheffield Experimental Cancer Medicine Centre, University of Sheffield, Weston Park Hospital, Sheffield qClinical Oncology Department, Royal Cornwall Hospitals rSt. James's Institute of Oncology, St. James's University Hospital, Leeds, UK.

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.
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http://dx.doi.org/10.1097/CMR.0000000000000185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560270PMC
October 2015

The clinical features and management of testicular germ cell tumours in patients aged 60 years and older.

BJU Int 2011 Dec 31;108(11):1794-9. Epub 2011 May 31.

Department of Medical Oncology, Southampton University Hospitals NHS Trust, UK.

Unlabelled: What's known on the subject ? and What does the study add? The treatment of younger men with testicular germ cell cancers is well documented with established intensive chemotherapy regimens for those with advanced disease. Although the majority of patients present in the third or fourth decade, men also present in later life. These patients are typically excluded from clinical trials and there are no contemporary published series describing their management. This series describes the management of older patients with testicular germ cell tumours at both early and advanced stages of disease. Patients with stage I seminoma can be safely managed with all recognised treatment strategies and state I non-seminomas were managed with surveillance. Cure can still be achieved in older patients with advance germ cell tumours however chemotherapy regimens developed in younger patients must be tailored to the presence of co-morbidity.

Objectives: • To review the practice of a large referral centre for the management of older patients with testicular germ cell cancer (GCC). • There are few published data available on the management of testicular GCC in elderly patients, who often have medical comorbidities and have been excluded from clinical trials.

Patients And Methods: • We reviewed our prospectively collected database for patients presenting with GCC who were aged ≥60 years. • Details of presentation, management and outcome were recorded.

Results: • In total, 60 patients aged ≥60 years were identified from 1461 patients treated with GCC from 1979-2005, representing 4% of the total population. • Median age was 67 years, 44 had seminoma (73%) and 16 had non-seminoma histology (27%). • Stage I seminoma patients were managed with surveillance, adjuvant radiotherapy and adjuvant carboplatin. All stage I non-seminomas underwent surveillance. • In total, 15 patients received systemic chemotherapy for metastatic disease with modified bleomycin, etoposide and cisplatin; etoposide and cisplatin; carboplatin-based regimens; or other combinations. Toxicity was manageable, with no toxic deaths. • In total, four patients (6.7%) died of GCC.

Conclusions: • In elderly patients, GCC should be managed with curative intent. • Conventional therapies are tolerable for most men with stage I seminoma. In metastatic disease, comorbidity may necessitate treatment modifications. • Most patients are cured with manageable toxicity.
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http://dx.doi.org/10.1111/j.1464-410X.2011.10252.xDOI Listing
December 2011

Late relapse (>2 years) on surveillance in stage I non-seminomatous germ cell tumours; predominant seminoma only histology.

BJU Int 2010 Dec 24;106(11):1648-51. Epub 2010 Aug 24.

Cancer Research UK Clinical Centre, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

Objectives: Surveillance is a standard management approach following orchidectomy for stage I non-seminomatous and mixed germ cell tumours. Patients who relapse following this approach are treated with cisplatin-based chemotherapy, with retroperitoneal lymph node dissection considered for patients with post-chemotherapy residual masses.

Patients And Methods: We reviewed the clinicopathological data for all patients who relapse greater than 24 months after commencing our surveillance programme.

Results: Between 1989 and 2008, 453 patients with a median age of 30 years were entered into our surveillance program for stage I non-seminomatous germ cell tumours (NSGCTs) after orchidectomy alone. All primary tumour specimens contained NSGCT, with seminomatous elements identified in 168 cases (37%). One-hundred patients (22%) relapsed and the majority of relapses occurred within the first 2 years (76 ≤ 12 months, 15 ≥ 12 months ≤ 2 years). Nine patients relapsed after more than 2 years of surveillance. We found a high incidence of pure seminoma (56%) at sites of metastatic disease in this group. All late-relapsing patients were alive and disease free at a median follow up of 45 months from relapse.

Conclusions: We recommend that late-relapsing patients with normal serum alpha fetoprotein levels undergo biopsy to define histologically the nature of recurrent disease. In those with pure seminoma retroperitoneal lymph node dissection for post chemotherapy residual masses can be avoided.
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http://dx.doi.org/10.1111/j.1464-410X.2010.09471.xDOI Listing
December 2010

The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival.

Cancer Biol Ther 2010 Oct 1;10(7):728-35. Epub 2010 Oct 1.

Southampton Cancer Research UK Centre, University of Southampton School of Medicine, MP824 Southampton General Hospital, UK.

eIF4E is over-expressed in many tumours, including a high proportion of breast cancers. eIF4E is an oncogene, and signalling pathways which promote eIF4E activity represent potential targets for therapeutic intervention in cancer. MNKs phosphorylate eIF4E on serine 209, a modification that can be required for eIF4E-dependent cell transformation. There is therefore a clear requirement to determine the role of MNKs in the proliferation and survival of cells from the major human tumours, such as breast cancer. Phosphorylated eIF4E protein was readily detectable in some breast tumour samples, but was below the limits of detection in others. Of 6 breast cancer cell lines representing the major sub-types of breast cancer, phosphorylated eIF4E was readily detectable in 5 of them, with MCF-7 cells displaying markedly lower levels. Long term colony forming assays demonstrated that all the five lines with high levels of phosphorylated eIF4E were highly sensitive to a MNK inhibitor. In short term assays, a range of responses was revealed. MCF-7 cells were insensitive in both assays. The anti-proliferative effects of the MNK inhibitor in breast cancer cells are primarily cytostatic, rather than cytotoxic, and are potentially due to the inhibition of cyclin D1 synthesis. Our data provide evidence that the sensitivity of breast cancer cells to MNK inhibition may correlate with baseline levels of eIF4E phosphorylation, and suggest that a proportion of breast cancers could be sensitive to inhibiting MNK kinase activity, and that the presence of phosphorylated eIF4E could provide a biomarker for the identification of responsive tumours.
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http://dx.doi.org/10.4161/cbt.10.7.12965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093812PMC
October 2010

Recombinant factor VIIa in the management of pulmonary hemorrhage associated with metastatic choriocarcinoma.

J Clin Oncol 2008 Feb;26(6):1008-10

Department of Medical Oncology, Southampton General Hospital, Southampton, United Kingdom.

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http://dx.doi.org/10.1200/JCO.2007.14.8486DOI Listing
February 2008
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