Now showing items 1-20 of 9872

    • Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial

      Parker, CC; James, ND; Brawley, CD; Clarke, Noel W; Hoyle, Alex, P; Ali, Adnan; Ritchie, AWS; Attard, G; Chowdhury, S; Cross, W; Dearnaley, DP; Gillessen, Silke; Gilson, C; Jones, RJ; Langley, RE; Malik, ZI; Mason, MD; Matheson, D; Millman, R; Russell, JM; Thalmann, GN; Amos, CL; Alonzi, R; Bahl, A; Birtle, A; Din, O; Douis, H; Eswar, C; Gale, J; Gannon, MR; Jonnada, S; Khaksar, S; Lester, JF; O'Sullivan, JM; Parikh, OA; Pedley, ID; Pudney, DM; Sheehan, DJ; Srihari, NN; Tran, Anna, T; Parmar, MKB; Sydes, MR; Academic Urology Unit, Royal Marsden Hospital, London, UK (2018)
    • Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.

      Rhost, S; Hughes, E; Harrison, Hannah; Rafnsdottir, S; Jacobsson, H; Gregersson, P; Magnusson, Y; Fitzpatrick, P; Andersson, D; Berger, K; Stahlberg, A; Landberg, Goran; Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden (2018)
      BACKGROUND: Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has been linked to malignant properties. Within a screen, using in vivo like growth conditions, we identified progranulin as a highly secreted cytokine affecting cancer stem cells in breast cancer. This cytokine is known to play a role in numerous biological and tumour-related processes including therapy resistance in a range of cancer types. METHODS: Different in vitro and in vivo relevant conditions were used to validate breast cancer stem cell expansion mediated by progranulin and its receptor sortilin. Small interfering ribonucleic acid (siRNA) and pharmacological inhibition of sortilin were used to elucidate the role of sortilin as a functional receptor during progranulin-induced breast cancer stem cell propagation, both in vitro and in vivo, using breast cancer xenograft models. In addition, single-cell gene expression profiling as well as a Sox2 reporter breast cancer cell line were used to validate the role of dedifferentiation mediated by progranulin. RESULTS: In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ER?-negative breast cancer as well as in ER?-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin. CONCLUSION: The collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences. KEYWORDS: Breast cancer; Cancer stem cells; Dedifferentiation; Differentiation; Hypoxia; Metastasis; Secretion
    • The p38 alpha stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1 alpha.

      Simoes-Sousa, Susana; Littler, Samantha; Thompson, Sarah L; Minshall, Paul; Whalley, Helen J; Bakker, B; Belkot, Klaudyna; Moralli, D; Bronder, Daniel; Tighe, Anthony; Spierings, DCJ; Bah, Nourdine; Graham, Joshua; Nelson, Louisa; Green, CM; Foijer, F; Townsend, Paul A; Taylor, Stephen S; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4QL (2018)
      Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1? and that inhibiting Hif-1? restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.
    • Intercomparison exercises: why is it important to calibrate radionuclide calibrators for different radionuclides.

      Ferreira, KM; Fenwick, AJ; Robinson, Andrew P; Denis-Bacelar, AM; Wevrett, J; Keightley, JD; National Physical Laboratory,Teddington (2018)
    • A novel method for accurate activity measurements of emerging Th-227-labelled conjugates.

      Fenwick, AJ; Keightley, JD; Denis-Bacelar, AM; Ferreira, KM; Wevrett, JL; Robinson, Andrew P; National Physical Laboratory,Teddington (2018)
    • Impact of prostate cancer hypofractionation on patient reported outcomes: baseline to 5 years change in the CHHIP Trial.

      Staffurth, J; Haviland, J; Wilkins, A; Syndikus, I; Khoo, V; Bloomfield, D; Parker, C; Logue, John P; Scrase, C; Birtle, A; Malik, Z; Panades, M; Eswar, C; Graham, J; Russell, M; Kirkbride, P; O'Sullivan J; Cruickshank, C; Dearnaley, D; Hall, E; Velindre Cancer Centre, Cardiff, United Kingdom, (2018)
    • The effect of target shape, size, and partial volume correction on Voxel dosimetry for molecular radiotherapy.

      Calvert, Nicholas; Baldachin, E; Burguete, L; Cullen, D; Hamilton, David; Page, Emma; Pells, S; Pietras, B; Price, E; Tipping, Jill; Christie NHS Foundation Trust, Manchester, (2018)
    • Impact of tumour morphology on routine clinical dosimetry calculations in molecular radiotherapy.

      Denis-Bacelar, AM; Fenwick, AJ; Ferreira, KM; Robinson, Andrew P; Wevrett, JL; National Physical Laboratory,Teddington (2018)
    • Direct Monte Carlo simulations for accurate diagnostic and therapeutic dosimetry calculations.

      Denis-Bacelar, AM; Fenwick, AJ; Ferreira, KM; Robinson, Andrew P; Wevrett, JL; National Physical Laboratory,Teddington (2018)
    • Meta-analysis of Genome-Wide Association Studies (GWAS) of late toxicity in 3,874 men treated with radiation for prostate cancer.

      Kerns, SL; Fachal, L; Dorling, L; Barnett, G; Burnet, N; Sydes, M; Dearnaley, D; Dunning, A; Pharoah, P; Parliament, MB; Usmani, NH; De Ruyck, K; Ostrer, H; Rosenstein, BS; CaamaNo, AG; Carballo, A; Higuero, PMP; Vega, A; West, Catharine M L; Hall, E; University of Rochester Medical Center, Rochester, NY, (2018)
    • Magnetic resonance-based response assessment and dose adaptation in human papilloma virus positive tumors of the oropharynx treated with radiotherapy (MR-ADAPTOR): An R-IDEAL stage 2a-2b/Bayesian phase II trial.

      Bahig, H; Yuan, Y; Mohamed, ASR; Brock, KK; Ng, SP; Wang, J; Ding, Y; Hutcheson, K; McCulloch, M; Balter, PA; Lai, SY; Al-Mamgani, A; Sonke, JJ; van der Heide, UA; Nutting, C; Li, XA; Robbins, J; Awan, M; Karam, I; Newbold, K; Harrington, K; Oelfke, U; Bhide, S; Philippens, MEP; Terhaard, CHJ; McPartlin, Andrew J; Blanchard, P; Garden, AS; Rosenthal, DI; Gunn, GB; Phan, J; Cazoulat, G; Aristophanous, M; McSpadden, KK; Garcia, JA; van den, Berg, CAT; Raaijmakers, CPJ; Kerkmeijer, L; Doornaert, P; Blinde, S; Frank, SJ; Fuller, CD; University of Texas MD Anderson Cancer Center, Houston, TX, USA (2018)
      Background: Current standard radiotherapy for oropharynx cancer (OPC) is associated with high rates of severe toxicities, shown to adversely impact patients' quality of life. Given excellent outcomes of human papilloma virus (HPV)-associated OPC and long-term survival of these typically young patients, treatment de-intensification aimed at improving survivorship while maintaining excellent disease control is now a central concern. The recent implementation of magnetic resonance image - guided radiotherapy (MRgRT) systems allows for individual tumor response assessment during treatment and offers possibility of personalized dose-reduction. In this 2-stage Bayesian phase II study, we propose to examine weekly radiotherapy dose-adaptation based on magnetic resonance imaging (MRI) evaluated tumor response. Individual patient's plan will be designed to optimize dose reduction to organs at risk and minimize locoregional failure probability based on serial MRI during RT. Our primary aim is to assess the non-inferiority of MRgRT dose adaptation for patients with low risk HPV-associated OPC compared to historical control, as measured by Bayesian posterior probability of locoregional control (LRC). Methods: Patients with T1-2?N0-2b (as per AJCC 7th Edition) HPV-positive OPC, with lymph node <3?cm and <10 pack-year smoking history planned for curative radiotherapy alone to a dose of 70?Gy in 33 fractions will be eligible. All patients will undergo pre-treatment MRI and at least weekly intra-treatment MRI. Patients undergoing MRgRT will have weekly adaptation of high dose planning target volume based on gross tumor volume response. The stage 1 of this study will enroll 15 patients to MRgRT dose adaptation. If LRC at 6?months with MRgRT dose adaptation is found sufficiently safe as per the Bayesian model, stage 2 of the protocol will expand enrollment to an additional 60 patients, randomized to either MRgRT or standard IMRT. Discussion: Multiple methods for safe treatment de-escalation in patients with HPV-positive OPC are currently being studied. By leveraging the ability of advanced MRI techniques to visualize tumor and soft tissues through the course of treatment, this protocol proposes a workflow for safe personalized radiation dose-reduction in good responders with radiosensitive tumors, while ensuring tumoricidal dose to more radioresistant tumors. MRgRT dose adaptation could translate in reduced long term radiation toxicities and improved survivorship while maintaining excellent LRC outcomes in favorable OPC. Trial registration: ID: NCT03224000; Registration date: 07/21/2017
    • Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.

      Kandolf, SL; Guo, J; Agarwala, S; Hauschild, A; McArthur, G; Cinat, G; Wainstein, A; Caglevic, C; Lorigan, Paul C; Gogas, H; Alvarez, M; Duncombe, Robert; Lebbe, C; Peris, K; Rutkowski, P; Stratigos, A; Forsea, AM; De La Cruz, ML; Kukushkina, M; Dummer, R; Hoeller, C; Gorry, C; Bastholt, L; Herceg, D; Neyns, B; Vieira, R; Arenberger, P; Bylaite-Bucinskiene, M; Babovic, N; Banjin, M; Putnik, K; Todorovic, V; Kirov, K; Ocvirk, J; Zhukavets, A; Ymeri, A; Stojkovski, I; Garbe, C; Department of Dermatology, Faculty of Medicine, Military Medical Academy, Belgrade, Serbia (2018)
      According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.
    • Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis

      McNamara, Mairead G; Slagter, Astrid E; Nuttall, Christina; Frizziero, Melissa; Pihlak, Rille; Lamarca, Angela; Tariq, Noor-ul-ain; Valle, Juan W; Hubner, Richard A; Knox, JJ; Amir, E; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK (2018)
      BACKGROUND: Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS: A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS: Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION: CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).
    • Absolute calibration of the elekta unity MR Linac using the UK code of practice for high-energy photon dosimetry.

      Budgell, Geoff J; Gohil, Pooja; Agnew, James Paul; Berresford, Joe; Billas, I; Duane, S; The Christie NHS Foundation Trust, Manchester, UK (2018)
      Absolute dosimetry for MR Linacs is complicated by non-standard reference conditions, the non-suitability of the UK secondary standard chamber for use in water and the effects of the magnetic field on the response of Farmer field chambers. Measurements were made on a pre-clinical 7 MV Elekta Unity MR Linac. Reference conditions were chosen as isocentre (143.5 cm SAD), 10 cm deep, 10?×?10 cm2 field and gantry angle 90° to avoid output variation from liquid helium levels dropping in the surrounding annulus. TPR 20/10 was measured as 0.698 at isocentre. Measurements on a conventional linac demonstrated that TPR 20/10 does not vary between SAD 100 cm and 143.5 cm. The UK National Physical Laboratory (NPL) provides calibration factors, ND, for the secondary standard NE 2611A thimble chamber in terms of absorbed dose to water. ND was taken for the value of the measured TPR 20/10. Independent intercomparisons were made at 6 MV on a conventional linac between the NE2611A and two PTW waterproof Farmer 30013 chambers. The response of these chambers varies very slowly with energy hence it is reasonable to assume this introduces minimal uncertainty. Ion recombination and polarity correction factors measured on the MR Linac were unchanged by the magnetic field. An additional correction factor to account for the 1.5 T magnetic field on the Farmer chambers was measured as 0.986 taking the ratio of TP corrected readings before and after ramp-up of the magnetic field. An orientation parallel to the magnetic field (along the bore of the MR Linac) was chosen to minimise the magnitude of this factor. An independent audit was performed by the NPL using alanine pellets and Farmer chambers calibrated via a water calorimeter from the Netherlands primary standards laboratory which operates within the MR Linac. This gave agreement with our calibration to within 1.0%.
    • The impact of training and professional collaboration on the interobserver variation of lung cancer delineations: a multi-institutional study

      Mercieca, S; Belderbos, JSA; van BA; Delorme, S; van Herk, Marcel; Faculty of Health Science , University of Malta . Msida , Malta (2018)
      BACKGROUND: To assess the impact of training and interprofessional collaboration on the interobserver variation in the delineation of the lung gross tumor volume (GTVp) and lymph node (GTVln). MATERIAL AND METHODS: Eight target volume delineations courses were organized between 2008 and 2013. Specialists and trainees in radiation oncology were asked to delineate the GTVp and GTVln on four representative CT images of a patient diagnosed with lung cancer individually prior each course (baseline), together as group (interprofessional collaboration) and post-training. The mean delineated volume and local standard deviation (local SD) between the contours for each course group were calculated and compared with the expert delineations. RESULTS: A total 410 delineations were evaluated. The average local SD was lowest for the interprofessional collaboration (GTVp?=?0.194?cm, GTVln?=?0.371?cm) followed by the post-training (GTVp?=?0.244?cm, GTVln?=?0.607?cm) and baseline delineations (GTVp?=?0.274?cm, GTVln: 0.718?cm). The mean delineated volume was smallest for the interprofessional (GTVp?=?4.93?cm3, GTVln?=?4.34?cm3) followed by the post-training (GTVp?=?5.68?cm3, GTVln?=?5.47?cm3) and baseline delineations (GTVp?=?6.65?cm3, GTVln?=?6.93?cm3). All delineations were larger than the expert for both GTVp and GTVln (p?<?.001). CONCLUSION: Our findings indicate that image interpretational differences can lead to large interobserver variation particularly when delineating the GTVln. Interprofessional collaboration was found to have the greatest impact on reducing interobserver variation in the delineation of the GTVln. This highlights the need to develop a clinical workflow so as to ensure that difficult cases are reviewed routinely by a second radiation oncologist or radiologist so as to minimize the risk of geographical tumor miss and unnecessary irradiation to normal tissue.
    • The role of aspirin following treatment for early stage gastro-oesophageal cancer: adherence and tolerability data from the Add-Aspirin Trial.

      Underwood, T; Cafferty, F; Joharatnam, N; Hubner, Richard A; Thomas, A; Petty, R; Jankowski, J; Bridgewater, J; Pramesh, CS; Gadgil, D; Henson, V; Crossley, A; Sothi, S; Patel, K; Swinson, D; Kunene, V; Sridhar, T; Warner, N; Hewish, M; Falk, S; Langley, R; University of Southampton, Southampton, (2018)
    • Evaluation of a novel atlas to reduce variability of contouring masticatory muscles in head and neck cancer patients.

      Hague, Christina; Beasley, William J; Green, Andrew; Garcez, Kate; Lee, Lip W; Maranzano, M; McPartlin, Andrew J; Mullan, Damian; Sykes, Andrew J; Thomson, David J; van Herk, Marcel; West, Catharine M L; Slevin, Nicholas J; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, (2018)
    • Genetic variants predict optimal timing of radiotherapy to reduce side-effects in breast cancer patients

      Johnson, K; Chang-Claude, J; Critchley, AM; Kyriacou, C; Lavers, S; Rattay, T; Seibold, P; Webb, A; West, Catharine M L; Symonds, RP; Talbot, CJ; Leicester Cancer Research Centre, University of Leicester, Leicester (2018)
      The retinal cones of teleost fish contract at dawn and elongate at dusk. We have previously reported that we can selectively induce detergent-lysed models of cones to undergo either reactivated contraction or reactivated elongation, with rates and morphology comparable to those observed in vivo. Reactivated contraction is ATP dependent, activated by Ca2+, and inhibited by cAMP. In addition, reactivated cone contraction exhibits several properties that suggest that myosin phosphorylation plays a role in mediating Ca2+-activation (Porrello, K., and B. Burnside, 1984, J. Cell Biol., 98:2230-2238). We report here that lysed cone models can be induced to contract in the absence of Ca2+ by incubation with trypsin-digested, unregulated myosin light chain kinase (MLCK) obtained from smooth muscle. This observation provides further evidence that MLCK plays a role in regulating cone contraction. We also report here that lysed cone models can be induced to contract in the absence of Ca2+ by incubation with high concentrations of MgCl2 (10-20 mM). Mg2+-induced reactivated contraction is supported by inosine triphosphate (ITP) just as well as by ATP. Because ITP will not serve as a substrate for MLCK, this finding suggests that Mg2+-activation of contraction does not require myosin phosphorylation. Although Ca2+-induced contraction is completely blocked by cAMP at concentrations less than 10 microM, cAMP has no effect on cone contraction activated by unregulated MLCK or by high Mg2+ in the absence of Ca2+. Because trypsin digestion of MLCK cleaves off not only the Ca2+/calmodulin-binding site but also the site phosphorylated by cAMP-dependent protein kinase, and because Mg2+ activation of cone contraction circumvents MLCK action altogether, both these observations would be expected if cAMP inhibits reactivated cone contraction by catalyzing the phosphorylation of MLCK and thus reducing its affinity for Ca2+, as has been described for smooth muscle. Together our results suggest that in lysed cone models, myosin phosphorylation is sufficient for activating cone contraction, even in the absence of other Ca2+-mediated events, that cAMP inhibition of contraction is mediated by cAMP-dependent phosphorylation of MLCK, and that 10-20 mM Mg2+ can activate actin-myosin interaction to produce contraction in the absence of myosin phosphorylation.
    • Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials.

      Vergote, I; Coens, C; Nankivell, M; Kristensen, GB; Parmar, MKB; Ehlen, T; Jayson, Gordon C; Johnson, N; Swart, AM; Verheijen, R; McCluggage, WG; Perren, T; Panici, PB; Kenter, G; Casado, A; Mendiola, C; Stuart, G; Reed, NS; Kehoe, S; University Hospitals Leuven, Department of Obstetrics and Gynaecology, Leuven, Belgium. (2018)
      BACKGROUND: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. METHODS: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. FINDINGS: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0-9·6; EORTC, 9·2 years [IQR 7·3-10·4]; CHORUS, 5·9 years [IQR 4·3-7·4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8-13·0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1-51·3] and 26·9 months [12·7-50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86-1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7-53·7) and 23·6 months (10·5-46·9), respectively (HR 1·20, 95% CI 1·06-1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1-47·6] and 21·2 months [10·0-36·4], respectively; HR 0·76, 95% CI 0·58-1·00; p=0·048; median progression-free survival 10·6 months [7·9-15·0] and 9·7 months [5·2-13·2], respectively; HR 0·77, 95% CI 0·59-1·00; p=0·049). INTERPRETATION: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status.
    • RIVA - a phase IIa study of rituximab and varlilumab in relapsed or refractory B-cell malignancies: study protocol for a randomized controlled trial.

      Lim, SH; Linton, Kim M; Collins, GP; Dhondt, J; Caddy, J; Rossiter, L; Vadher, K; Fines, K; Rogers, LE; Fernando, D; Stanton, L; Davies, AJ; Johnson, PWM; Griffiths, G; Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton, Southampton, UK (2018)
      BACKGROUND: Over 12,000 new cases of B-cell malignancies are diagnosed in the UK each year, with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) being the most common subtypes. Standard frontline therapy consists of immunochemotherapy with a CD20 monoclonal antibody (mAb), such as rituximab, delivered in combination with multi-agent chemotherapy. Despite being considered a treatable and potentially curable cancer, approximately 30% of DLBCL cases will relapse after frontline therapy. Advanced stage FL is incurable and typically has a relapsing and remitting course with a frequent need for re-treatment. Based on supportive preclinical data, we hypothesised that the addition of varlilumab (an anti-CD27 mAb) to rituximab (an anti-CD20 mAb) can improve the rate, depth and duration of the response of rituximab monotherapy in patients with relapsed or refractory B-cell malignancies. METHODS/DESIGN: Combination treatment of varlilumab plus rituximab, in two different dosing regimens, is being tested in the RIVA trial. RIVA is a two-stage open-label randomised phase IIa design in up to 40 patients with low- or high-grade relapsed or refractory CD20+ B-cell lymphoma. The study is open to recruitment in the UK. Enrolled patients are randomised 1:1 to two different experimental varlilumab to rituximab combinations. The primary objective is to determine the safety and tolerability of the combination and the anti-tumour activity (response) in relapsed or refractory B-cell malignancies. Secondary objectives will include an evaluation of the duration of the response and overall survival. Tertiary translational objectives include assessment of B-cell depletion, changes in immune effector cell populations, expression of CD27 as a biomarker of response and pharmacokinetic properties. Analyses will not be powered for formal statistical comparisons between treatment arms. DISCUSSION: RIVA will determine whether the combination of rituximab and varlilumab in relapsed or refractory B-cell malignancies is active and safe prior to future phase II/III trials. TRIAL REGISTRATION: EudraCT, 2017-000302-37. Registered on 16 January 2017. ISRCTN, ISRCTN15025004 . Registered on 16 August 2017.