• Prospective subgroup analyses of the randomized MCL-002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma.

      Arcaini, L; Lamy, T; Walewski, J; Belada, D; Mayer, J; Radford, John A; Jurczak, W; Morschhauser, F; Alexeeva, J; Rule, S; et al. (2018-01)
      In the mantle cell lymphoma (MCL)-002 study, lenalidomide demonstrated significantly improved median progression-free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long-term follow-up data and results of preplanned subgroup exploratory analyses from MCL-002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL-002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1-21; 28-day cycles) or single-agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent-to-treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single-agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history.
    • Prospective technical validation and assessment of intra-tumour heterogeneity of a low density array hypoxia gene profile in head and neck squamous cell carcinoma.

      Betts, Guy N J; Eustace, Amanda; Patiar, S; Valentine, Helen R; Irlam, Joely J; Ramachandran, A; Merve, Ashriwad; Homer, Jarrod J; Möller-Levet, Carla S; Buffa, F; et al. (2012-08-27)
      BACKGROUND AND PURPOSE: Tumour hypoxia is associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC), however there is no accepted method for assessing hypoxia clinically. We aimed to conduct a technical validation of a hypoxia gene expression signature using the TaqMan Low Density Array (TLDA) platform to investigate if this approach reliably identified hypoxic tumours. MATERIALS AND METHODS: Tumour samples (n=201) from 80 HNSCC patients were collected prospectively from two centres. Fifty-three patients received pimonidazole prior to surgery. TaqMan Low Density Array-Hypoxia Scores (TLDA-HS) were obtained by quantitative real-time PCR (qPCR) using a 25-gene signature and customised TLDA cards. Assay performance was assessed as coefficient of variation (CoV). RESULTS: The assay was sensitive with linear reaction efficiencies across a 4log(10) range of inputted cDNA (0.001-10ng/μl). Intra- (CoV=6.9%) and inter- (CoV=2.0%) assay reproducibility were excellent. Intra-tumour heterogeneity was lower for TLDA-HS (23.2%) than for pimonidazole (67.2%) or single gene measurements of CA9 (62.2%), VEGFA (45.0%) or HIG2 (39.4%). TLDA-HS in HNSCC cell lines increased with decreasing pO(2). TLDA-HS correlated with Affymetrix U133 Plus 2.0 microarray HS (p<0.01) and positive pimonidazole scores (p=0.005). CONCLUSIONS: Gene expression measurements of hypoxia using a 25-gene signature and TLDA cards are sensitive, reproducible and associated with lower intra-tumour heterogeneity than assaying individual genes or pimonidazole binding. The approach is suitable for further assessment of prognostic and predictive capability in clinical trial material.
    • Prospective validation of a hypoxia gene signature biomarker in the NIMRAD trial.

      Irlam, Joely J; Bibby, B; Thiruthaneeswaran, N; Williamson, A; Betts, G; Yang, Lingjian; Valentine, Helen R; Roberts, Darren L; Choudhury, Ananya; West, Catharine M L (2018)
    • Prospective validation of prognostic score in high-grade gastrointestinal neuroendocrine carcinomas (GI-NECs).

      Lamarca, Angela; Barriuso, Jorge; McNamara, Mairéad G; Hubner, Richard A; Valle, Juan W; Medical Oncology Department, The Christie NHS (2016)
    • Prospects for personalised treatment of patients with radioiodine-avid locally recurrent or metastatic thyroid cancer

      Beasley, M.; Garcez, Kate; Bristol Cancer Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, (2021)
      Although most patients with metastatic or inoperable locally recurrent differentiated thyroid cancer have radioiodine-avid disease, the outcome for patients who do not achieve remission with radioiodine therapy is poor. Most centres use fixed empirical activities of radioiodine to treat these patients, which is in contrast to other areas of oncology, where there is a shift to more individualised treatment. The use of dosimetry techniques to calculate a more appropriate activity of radioiodine for each patient may increase the effectiveness of radioiodine therapy but is more complex, time-consuming and of unproven benefit. This review addresses some of the limitations of empirical radioiodine therapy, discusses existing dosimetry-based approaches to individualising therapy and proposes further work in this area. A prospective randomised controlled trial comparing empirical activities of radioiodine with activities guided by a combination of lesional dosimetry and maximum safe dose has not been carried out previously. Although considerable challenges in the design of such a study remain, a network of centres in the UK now has the potential to take this forward.
    • Prospects for the development of long-acting formulations of human somatropin.

      Jostel, Andreas; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. (2006)
      In healthy humans, growth hormone (GH) is secreted in distinct pulses with an underlying nyctohemeral pattern. Current forms of somatropin replacement are unable to closely mimic such a release pattern, but are still able to exert the beneficial action of GH. A limited number of short-term studies in rodents and humans suggest that longitudinal growth may be superior when somatropin is given with a pulsatile mode of administration, whereas hepatic insulin-like growth factor-I generation and beneficial changes in body composition appear to be equal or even enhanced with continuous somatropin administration.Recent developments in drug delivery technology have allowed the use of slow-release preparations of somatropin in humans. The most successful technology so far has been the encapsulation of somatropin molecules in poly(D,L-lactic-co-glycolic acid) biodegradable microspheres. Pharmacokinetic and pharmacodynamic data have been published on two such preparations; Nutropin Depot((R)) and hGH-Biosphere((R)). The latter has a superior release profile, but outcomes data from multicenter trials in both children and adults have been presented for the former: catch-up growth was observed in children, although to a lesser degree than historic comparative data obtained with the use of daily somatropin injections and the effects on metabolic derangements in GH-deficient patients appeared similar to those observed with daily injections. Improved sustained-release somatropin preparations will need further study of their long-term efficacy, but, if successful, will be highly attractive in terms of patient compliance and convenience.
    • Prospects for the secondary prevention of colorectal cancer: screening by flexible sigmoidoscopy?

      Woodman, Ciaran B J; Prior, Pat; Joseph, R; Watson, A; Centre for Cancer Epidemiology, Christie Hospital NHS Trust, Withington, Manchester, United Kingdom. (1995)
      It may be useful to draw an analogy between the proposed screening programme for colorectal cancer and the cervical cancer screening programme. Both tumours show a spectrum of histological abnormalities consistent with a premalignant phase. The natural history of these premalignant lesions is poorly understood and although some will progress, if untreated, to invasive disease, most will not. Light microscopy cannot confidently distinguish which cases will progress and which will regress, and clinicians are therefore obliged to treat all. This will result in the destruction of many lesions of uncertain malignant potential. The secondary prevention of cervical cancer, although therapeutically efficacious, is inefficient. A lack of understanding of the natural history of intraepithelial neoplasia has frustrated attempts to develop rational referral criteria, and it is only now that the appropriate trials are being undertaken. The development of outpatient investigative and therapeutic procedures has resulted in many more women being referred for investigation and treatment, with predictable pressure on other services offered by gynaecologists, but no demonstrable saving of life. Similar uncertainties surround a screening programme for colorectal cancer. The principal concerns are not about the efficacy of polypectomy in interrupting the polyp cancer sequence, although uncertainties about the frequency with which cancer arises de novo do require that the effectiveness of this intervention is formally tested. Our major concerns are with compliance, and the management of the individual who tests positive--that is, who is found to have a distal polyp. Technological advances and operator enthusiasm may, as has happened with the cervical screening programme, lead to a relaxation in the indications for further investigation and treatment. Such a development would affect resources substantially if a population screening programme were in place. Nevertheless, there are grounds for believing that a screening programme for colorectal cancer, using sigmoidoscopy, might be successful in certain age groups if compliance was satisfactory. The scale of benefits may be comparable with those achieved by the breast screening programme. Our limited cost analysis, which relates to only to specific items of clinical activity, suggest that the mean cost for each case of cancer prevented will be about 8000 pounds sterling. These conclusions suggest that screening by flexible sigmoidoscopy merits serious consideration. It is also imperative, however, that consideration should be given to resolving some of the uncertainties about the clinical management and surveillance of those found to have distal polyps.
    • PROSPERO: A study to determine the utility of focused genomic profiling to guide selection of drug therapy in salivary gland cancer

      Rack, Samuel; Li, Yonghan; McKay, Craig; Wallace, Andrew; Metcalf, Robert; University of Manchester, Manchester (2019)
    • Prostate cancer awareness survey to proud postcards

      Heyworth, Ben; Gilliver, A; Ralph, S; Hewitt, P; Mackereth, Peter A; The Christie NHS FT, Manchester (2016-07-15)
    • Prostate cancer radiotherapy recommendations in response to COVID-19

      Zaorsky, Nicholas G; Yu, James B; McBride Sean M; Dess, Robert T; Jackson, William C; Mahal, Brandon A; Chen, Ronald; Choudhury, Ananya; Henry, A; Syndikus, I; et al. (2020)
    • Prostate cancer: Can I have a PSA test please nurse?

      Johnson, Helen; The Christie NHS FT, Manchester, M20 4BX (2016-01-02)
    • Prostate cancer: evaluation of vascular characteristics with dynamic contrast-enhanced T1-weighted MR imaging--initial experience.

      Buckley, David L; Roberts, Caleb; Parker, Geoff J M; Logue, John P; Hutchinson, Charles E; Imaging Science and Biomedical Engineering, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, England. (2004-12)
      PURPOSE: To use contrast material-enhanced magnetic resonance (MR) imaging and a distributed-parameter tracer kinetics model for prospectively evaluating the vascular characteristics of prostate cancer. MATERIALS AND METHODS: Twenty-two patients between 57 and 76 years of age (mean age, 67 years) with histologically proved adenocarcinoma of the prostate were examined by using three-dimensional dynamic contrast-enhanced T1-weighted MR imaging at 1.5 T. The local research ethics committee approved this study, and written consent was obtained from all patients. Data from regions of interest drawn in tumor, normal-appearing peripheral zone tissue, and muscle were analyzed to provide estimates of perfusion, blood volume, interstitial volume, and microvascular permeability-surface area product. These estimates were compared by using the nonparametric Wilcoxon signed rank test. RESULTS: Mean blood flow was significantly (P < .001) higher in 22 prostate tumors than in 20 contralateral peripheral zones (66 vs 32 mL/100 mL/min). Similarly, the interstitial distribution volume in tumors was enlarged compared with the interstitial distribution volume in normal peripheral zones (42 vs 27 mL/100 mL). Blood volume and microvascular permeability-surface area product values in tumors (1.0 mL/100 mL and 22 mL/100 mL/min, respectively) were similar to estimated values in peripheral zone tissue (1.5 mL/100 mL and 21 mL/100 mL/min, respectively). CONCLUSION: These findings show considerable promise for isolating vascular characteristics of prostate cancer.
    • Prostate radiotherapy for men with metastatic disease: a new comparison in the STAMPEDE trial.

      Parker, C; Sydes, M; Mason, M; Clarke, Noel W; Aebersold, D; de Bono, J; Dearnaley, D; Ritchie, A; Russell, J; Thalmann, G; et al. (2013-05)
    • Prostate radiotherapy for men with metastatic disease: a new comparison in the systemic therapy in advancing or metastatic prostate cancer: evaluation of drug efficacy (STAMPEDE) trial.

      Parker, C; Sydes, M; Mason, M; Clarke, Noel W; Aebersold, D; de Bono, J; Dearnaley, D; Ritchie, A; Russell, J; Thalmann, G; et al. (2013-05)
    • Prostate radiotherapy for metastatic hormone-sensitive prostate cancer: a STOPCAP systematic review and meta-analysis

      Burdett, S; Boeve, M; Ingleby, C; Fisher, J; Rydzewska, H; Vale, L; van, G; Clarke, Noel W; Hulshof, C; James, D; et al. (2019)
      BACKGROUND: Many trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC). OBJECTIVE: To systematically review trials of prostate radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: Using a prospective framework (framework for adaptive meta-analysis [FAME]), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators. INTERVENTION: We included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Hazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis. RESULTS AND LIMITATIONS: We identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval [CI] 0.81-1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84-1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67-0.82, p=0.94×10-8) and FFS (HR=0.76, 95% CI 0.69-0.84, p=0.64×10-7), equivalent to ?10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden-a pattern consistent across trials and outcome measures, including survival (<5, ?5; interaction HR=1.47, 95% CI 1.11-1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases. CONCLUSIONS: Prostate radiotherapy should be considered for men with mHSPC with a low metastatic burden. PATIENT SUMMARY: Prostate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered.
    • Prostate radiotherapy in newly diagnosed metastatic prostate cancer

      Ali, Adnan; Parker, CC; Clarke, Noel W; Genito-Urinary Cancer Research Group and the FASTMAN Prostate Cancer Centre for Excellence, Division of Cancer Sciences, Manchester Cancer Research Centre, The University of Manchester, Manchester (2019)
    • Prostate zones and cancer: lost in transition?

      Ali, Amin; Du Feu, Alexander; Oliveira, Pedro; Choudhury, Ananya; Bristow, Robert G; Baena, Esther; Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester (2021)
      Localized prostate cancer shows great clinical, genetic and environmental heterogeneity; however, prostate cancer treatment is currently guided solely by clinical staging, serum PSA levels and histology. Increasingly, the roles of differential genomics, multifocality and spatial distribution in tumorigenesis are being considered to further personalize treatment. The human prostate is divided into three zones based on its histological features: the peripheral zone (PZ), the transition zone (TZ) and the central zone (CZ). Each zone has variable prostate cancer incidence, prognosis and outcomes, with TZ prostate tumours having better clinical outcomes than PZ and CZ tumours. Molecular and cell biological studies can improve understanding of the unique molecular, genomic and zonal cell type features that underlie the differences in tumour progression and aggression between the zones. The unique biology of each zonal tumour type could help to guide individualized treatment and patient risk stratification.
    • ProtecTing low-risk prostate cancer.

      Choudhury, Ananya; The Christie NHS FT and University of Manchester, Manchester (2017-11)
    • Protecting the heart: a practical approach to account for the full extent of heart motion in radiotherapy planning

      Vasquez Osorio, Eliana; McCallum, H.; Bedair, A.; Faivre-Finn, Corinne; Haughey, A.; van Herk, Marcel; Iqbal, M. S.; McWilliam, Alan; Price, Gareth J; Byrne, J.; et al. (2020)
      Purpose: Emerging evidence suggests that the heart is more radio-sensitive than previously assumed; therefore accounting for heart motion in radiotherapy planning is becoming more critical. In this study, we determined how much heart delineations based on 3D CT, 4D average projection (AVG) and maximum intensity projection (MIP) images should be extended to represent the full extent of heart motion during 4D imaging acquisition. Materials and methods: 3D and 4D CT scans of ten lung cancer patients treated with stereotactic ablative radiotherapy (SABR) were used. Median surfaces were derived from heart delineations of three observers on the 3D CT, AVG, MIP and 25% exhale scans. Per patient, the 25% exhale contour was propagated on every phase of the 4D scan. The union of all 4D phase delineations (U4D) represented the full extent of heart motion during imaging acquisition. Surface distances from U4D to 3D, AVG, MIP volumes were calculated. Distances in the most extreme surface points (1.5cm most superior/inferior, 10% most right/left/anterior/posterior) were used to derive margins accounting only for systematic (delineation) errors. Results: Heart delineations on the MIP were the 'closest' to the full extent of motion, requiring only ?2.5 mm margins. Delineations on the AVG and 3D scans required margins up to 3.4 and 7.1 mm, respectively. The largest margins were for the inferior, right and anterior aspects for the delineations on the 3D, AVG and MIP scans, respectively. Conclusion: Delineations on either 3D, AVG or MIP scans required extensions to represented the heart's full extent of motion; the MIP requiring the smallest margins. Research including daily imaging, to determine the random components for the margins, and dosimetric measurements, to determine the relevance of creating a planning organ at risk volume (PRV) of the heart, is required.
    • Protection of spermatogenesis in rats from the cytotoxic procarbazine by the depot formulation of Zoladex, a gonadotropin-releasing hormone agonist.

      Ward, J A; Robinson, J; Furr, B J; Shalet, Stephen M; Morris, Ian D; Department of Physiological Sciences, University of Manchester Medical School, United Kingdom. (1990-02-01)
      The hypothesis that adjuvant treatment designed to produce testicular atrophy would preserve fertility in males receiving cancer chemotherapy was examined in the rat. Testicular atrophy was induced by a depot formulation of Zoladex [D-Ser(Bu(t))6-Aza-Gly10-GnRH], a gonadotropin-releasing hormone (GnRH) analogue. The experiments were conducted in albino Wistar as well as in the piebald variegated rat. Rats received the depot Zoladex formulation 2 weeks before and immediately prior to being treated with four weekly doses of procarbazine (200 mg/kg). Testicular function was evaluated 50 and 90 days after the last procarbazine dose. Procarbazine induced testicular atrophy concomitant with marked germinal cell aplasia in both strains of rat. In the Wistar rat adjuvant treatment with Zoladex caused slight but not significant alleviation of the testicular toxicity of procarbazine. The testicular toxicity of procarbazine was more extensive in the piebald variegated rat, and 50 days after the last procarbazine treatment the testes were small, sperm were absent, and the stem cell index was close to zero. Serum luteinizing hormone (LH) concentrations were raised and testicular LH receptor binding was low in the presence of normal serum and testicular testosterone concentrations, indicating compensated Leydig cell failure. Testicular weight and sperm content, as well as LH receptor binding, were still decreased in rats which received both Zoladex and procarbazine, suggesting that the analogue offered no protection. However, the stem cell index of the seminiferous tubules in the procarbazine-Zoladex-treated rats was not significantly different from vehicle-treated rats, which suggested that recovery from the effects of procarbazine was in progress. Ninety days after the end of procarbazine treatment alone the testes of rats were still atrophied and there was little evidence of active spermatogenesis. Leydig cell failure appeared to have progressed as, in addition to the low testicular LH receptor content and raised serum LH concentration, the prostate and seminal vehicle weights were decreased. The combination of Zoladex treatment with procarbazine was successful in preserving testicular function in the piebald variegated rats as virtually all the functional and morphological parameters of both the seminiferous tubule and the Leydig cell were not significantly different from those of vehicle-treated rats. This study demonstrates for the first time that effective gonadal protection from the toxic effects of procarbazine chemotherapy can be achieved by administration of the depot formulation of the gonadotropin-releasing hormone analogue Zoladex. The results show clearly that complete suppression of spermatogenesis is not a prerequisite for the successful outcome of treatments designed to protect the gonad from cytotoxic chemotherapy.