• Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment.

      Badie, Christophe; Dziwura, S; Raffy, C; Tsigani, Theodora; Alsbeih, G; Moody, J; Finnon, Paul; Levine, Edward; Scott, David A; Bouffler, Simon; et al. (2008-06-03)
      Normal tissue reactions to radiation therapy vary in severity among patients and cannot be accurately predicted, limiting treatment doses. The existence of heritable radiosensitivity syndromes suggests that normal tissue reaction severity is determined, at least in part, by genetic factors and these may be revealed by differences in gene expression. To test this hypothesis, peripheral blood lymphocyte cultures from 22 breast cancer patients with either minimal (11) or very severe acute skin reactions (11) have been used to analyse gene expression. Basal and post-irradiation expression of four radiation-responsive genes (CDKN1A, GADD45A, CCNB1, and BBC3) was determined by quantitative real-time PCR in T-cell cultures established from the two patient groups before radiotherapy. Relative expression levels of BBC3, CCNB1, and GADD45A 2 h following 2 Gy X-rays did not discriminate between groups. However, post-irradiation expression response was significantly reduced for CDKN1A (P<0.002) in severe reactors compared to normal. Prediction of reaction severity of approximately 91% of individuals sampled was achieved using this end point. Analysis of TP53 Arg72Pro and CDKN1A Ser31Arg single nucleotide polymorphisms did not show any significant association with reaction sensitivity. Although these results require confirmation and extension, this study demonstrates the possibility of predicting the severity of acute skin radiation toxicity in simple tests.
    • Addition of novel degenerate electrical waveform stimulation with photodynamic therapy significantly enhances its cytotoxic effect in keloid fibroblasts: first report of a potential combination therapy.

      Sebastian, A; Allan, Ernest; Allan, Donald; Colthurst, J; Bayat, A; Plastic & Reconstructive Surgery Research, School of Translational Medicine, Manchester Interdisciplinary Biocentre (MIB), The University of Manchester, UK. (2011-12)
      We recently reported use of photodynamic therapy (PDT) for treating keloid disease (KD). However, in view of high recurrence rates post any treatment modality, adjuvant therapies should be considered. Additionally, we previously demonstrated the effect of a novel electrical waveform, the degenerate wave (DW) on differential gene expression in keloid fibroblasts.
    • Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (SCOUT) in metastatic colorectal cancer.

      Sheikh, Hamid Y; Valle, Juan W; Waddell, Thomas K; Palmer, Karen; Wilson, Gregory; Sjursen, Ann-Marie; Craven, Olive; Swindell, Ric; Saunders, Mark P; Department of Clinical Oncology, Christie Hospital, Manchester, UK. (2008-08-19)
      Tegafur-uracil (UFT) plus leucovorin (LV, folinic acid) with alternating irinotecan and oxaliplatin were effective and well tolerated in patients with metastatic colorectal cancer (mCRC) in a phase I study. This study expanded the maximum tolerated dose group. Patients aged >or=18 years had histologically confirmed, inoperable, previously untreated, measurable mCRC. Patients received irinotecan 180 mg m(-2) on day 1, oxaliplatin 100 mg m(-2) on day 15 and UFT 250 mg m(-2) plus LV 90 mg on days 1-21 every 28 days. The phase I/II study comprised 45 patients, 29 at the maximum tolerated dose (MTD). The response rate in 38 evaluable patients was 63% (95% confidence interval (CI): 49-80). Median time to progression and overall survival were 8.7 months (95% CI: 7.9-10.4) and 16.8 months (95% CI: 9.6-25.3), respectively. In the MTD group, one patient had grade 3 leucopenia; one had grade 3 neutropaenia; three had grade 3 diarrhoea; and one had grade 3 neurotoxicity. No hand-foot syndrome grade >1 was seen. In total, 67% of eligible patients received second-line therapy. UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for mCRC, with minimal neurotoxicity and hand-foot syndrome.
    • Analysis of prostate-specific antigen bounce after I(125) permanent seed implant for localised prostate cancer.

      Mitchell, Darren M; Swindell, Ric; Elliott, Tony; Wylie, James P; Taylor, Cathy M; Logue, John P; Department of Clinical Oncology, Christie NHS Trust, Manchester, UK. dmmitchell@doctors.org.uk (2008-07)
      BACKGROUND AND PURPOSE: To report on the incidence of benign prostate-specific antigen bounce following permanent I(125) prostate brachytherapy, to describe the associations in our population and review the relationship of bounce to subsequent biochemical failure. MATERIALS AND METHODS: From February 2000 to May 2005, 374 patients with localised prostate cancer were treated with I(125) permanent prostate brachytherapy at a single institution. A prospectively collected database was used to identify cases of prostate-specific antigen (PSA) bounce, defined as a rise of 0.2 ng/ml above an initial PSA nadir with subsequent decline to or below that nadir without treatment. The patients who received neo-adjuvant or adjuvant hormone manipulation were excluded. Biochemical failure was determined using the both the ASTRO consensus definition and Phoenix (nadir +2 ng/mL) definition. RESULTS: Two hundred and five patients were identified with a median follow-up of 45 months (24-85). PSA bounce was noted in 79 (37%) men, occurring at a median of 14.8 months (1.7-40.6) following implant. The median peak PSA was 1.8 ng/ml (0.4-7.4) with a bounce magnitude of 0.91 ng/ml (0.2-5.8). When pre- and post-implant factors were assessed for association to bounce, only younger age was statistically significant (p=0.002). The threshold for biochemical failure as defined by the ASTRO consensus definition (1997) was met in 4 (5%) patients after experiencing bounce as opposed to 19 (15%) non-bounce patients (p=0.01). The threshold for Phoenix (nadir +2 ng/mL) was met in 6 (7.5%) patients following bounce versus 22 (17%) of non-bounce patients (p=0.003). Both definitions are prone to false positive calls during bounce. Median PSA velocity during the bounce was 0.08 ng/mL/month (0.02-0.98) and was statistically significantly lower than the median velocity prior to the Phoenix biochemical failure at 0.28 ng/mL/month (0.07-2.04) (p=0.0005). CONCLUSION: PSA bounce is a common finding in our population and is associated with a lower rate of subsequent biochemical failure. The noted differences in PSA velocity will require verification in a future analysis to reduce the influence of median follow-up on this finding. Patients should be advised of the potential of bounce in PSA follow-up after permanent I(125) prostate brachytherapy and physicians involved in follow-up of prostate brachytherapy patients should be aware of this phenomenon, allowing them to commit to appropriate PSA surveillance, avoiding the premature and inappropriate initiation of salvage therapy during PSA bounce.
    • Benign schwannoma in paranasal sinuses: a clinico-pathological study of five cases, emphasising diagnostic difficulties.

      Sheikh, Hamid Y; Chakravarthy, R P; Slevin, Nicholas J; Sykes, Andrew J; Banerjee, Saumitra S; Department of Clinical Oncology, Christie Hospital NHS Trust, Manchester, UK. hamid.sheikh@christie-tr.nwest.nhs.uk (2008-06)
      OBJECTIVES: To highlight the difficulty in making a correct diagnosis of benign schwannoma in the paranasal region, to raise awareness of this rare condition, and to suggest the most appropriate treatment. METHOD: Retrieval of cases retrospectively from archives of the histopathology department of a major UK cancer centre with central review of all cases. RESULTS: Five cases were identified since 1990 and clinical and pathological features are summarised. Median follow up of patients was 8.1 years. Radiological appearances of local bone invasion and histological features of tumour unencapsulation and hypercellularity could give the mistaken impression of malignant disease and lead to unnecessary over-treatment. CONCLUSION: Central pathological review and clinical awareness is required. Although local recurrence can occur, the prognosis is excellent. The treatment of choice is local excision. Radiotherapy can be considered, but in most cases it would incur unnecessary morbidity.
    • CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma.

      McRonald, Fiona E; Morris, Mark R; Gentle, Dean; Winchester, Laura; Baban, Dilair; Ragoussis, Jiannis; Clarke, Noel W; Brown, Michael D; Kishida, Takeshi; Yao, Masahiro; et al. (2009)
      BACKGROUND: Renal cell carcinoma (RCC) is histopathologically heterogeneous with clear cell and papillary the most common subtypes. The most frequent molecular abnormality in clear cell RCC is VHL inactivation but promoter methylation of tumour suppressor genes is common in both subtypes of RCC. To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC). RESULTS: 43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) suggesting that a subset of RCC displayed a CpG Island Methylator Phenotype. Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC. Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling. CONCLUSION: These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.
    • Cribriform-morular variant of papillary thyroid carcinoma: molecular characterization of a case with neuroendocrine differentiation and aggressive behavior.

      Cameselle-Teijeiro, José; Menasce, Lia P; Yap, Beng K; Colaco, Rovel J; Castro, Patricia; Celestino, Ricardo; Ruíz-Ponte, Clara; Soares, Paula; Sobrinho-Simões, Manuel; Department of Pathology, Clinical University Hospital, Galician Health Service, University of Santiago de Compostela, Santiago de Compostela, Spain. (2009-01)
      We describe an especially aggressive case of cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) in a 42-year-old man with familial adenomatous polyposis who died with lung and brain metastases 17 months after thyroidectomy. The angioinvasive neoplasm combined a mixture of trabecular, solid, cribriform, and follicular patterns of growth with CD10+ morules. Follicles were devoid of colloid, and the nuclear features typical of PTC were present in some areas and missing in others. Tumor cells were positive for thyroid transcription factor-1 and, in 40% of the tumoral mass, also were positive for chromogranin and synaptophysin and were negative for thyroglobulin and calcitonin. Strong nuclear staining for beta-catenin was found in all tumor cells, as was positivity for p53 and cyclin D1. In addition to the germline heterozygous APC Ex 2-3 duplication mutation, a somatic homozygous silent p. Thr1493Thr gene variant was found in the neoplastic cells along with RET/PTC rearrangement. This tumor represents the first case of C-MV of PTC showing neuroendocrine differentiation.
    • Development and validation of a nomogram for prediction of survival and local control in laryngeal carcinoma patients treated with radiotherapy alone: a cohort study based on 994 patients.

      Egelmeer, A G T M; Velazquez, E R; de Jong, J M A; Oberije, C; Geussens, Y; Nuyts, S; Kremer, B; Rietveld, D; Leemans, C R; de Jong, M; et al. (2011-07)
      To advise laryngeal carcinoma patients on the most appropriate form of treatment, a tool to predict survival and local control is needed.
    • Effect of epoetin alfa on survival and cancer treatment-related anemia and fatigue in patients receiving radical radiotherapy with curative intent for head and neck cancer.

      Hoskin, Peter J; Robinson, Martin; Slevin, Nicholas J; Morgan, David; Harrington, Kevin; Gaffney, Christopher; Marie Curie Research Wing for Oncology, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, UK. peterhoskin@nhs.net (2009-12-01)
      PURPOSE: To evaluate the effect of epoetin alfa on local disease-free survival (DFS), overall survival (OS), and cancer treatment-related anemia and fatigue in patients with head and neck cancer receiving radical radiotherapy with curative intent. PATIENTS AND METHODS: Patients (N = 301) with hemoglobin (Hb) less than 15 g/dL were randomly assigned in a ratio of 1:1 to receive radiotherapy plus epoetin alfa (10,000 U subcutaneously [SC] three times weekly if baseline Hb was < 12.5 g/dL; 4,000 U SC three times weekly if baseline Hb > or = 12.5 g/dL) or radiotherapy alone. Hb levels were monitored weekly. The primary end point was local DFS, defined as the time from random assignment to local disease recurrence or death. Secondary efficacy end points included OS, local tumor response, and local tumor control. Patients were followed at 1, 4, 8, and 12 weeks postradiotherapy and annually for 5 years. Cancer treatment-related anemia and fatigue were evaluated with the Functional Assessment of Cancer Therapy-Anemia and Functional Assessment of Cancer Therapy-Head and Neck. Adverse events were recorded up to 12 weeks postradiotherapy. RESULTS: Hb levels increased from baseline with epoetin alfa. The median duration of local DFS was not statistically different between groups (observation, 35.42 months; epoetin alfa, 31.47 months; hazard ratio, 1.04; 95% CI, 0.77 to 1.41). Groups did not significantly differ in DFS, OS, tumor outcomes, or cancer treatment-related anemia or fatigue. No new or unexpected adverse events were observed. CONCLUSION: Addition of epoetin alfa to radical radiotherapy did not affect survival, tumor outcomes, anemia, or fatigue positively or negatively in patients with head and neck cancer.
    • Effectiveness of a home care nursing program in the symptom management of patients with colorectal and breast cancer receiving oral chemotherapy: a randomized, controlled trial.

      Molassiotis, Alexander; Brearley, Sarah; Saunders, Mark P; Craven, Olive; Wardley, Andrew M; Farrell, Carole; Swindell, Ric; Todd, Chris; Luker, Karen; University of Manchester, School of Nursing, University Place, Manchester, M13 9PL, United Kingdom. alex.molassiotis@manchester.ac.uk (2009-12-20)
      PURPOSE: To assess the effectiveness of a symptom-focused home care program in patients with cancer who were receiving oral chemotherapy in relation to toxicity levels, anxiety, depression, quality of life, and service utilization. PATIENTS AND METHODS: A randomized, controlled trial was carried out with 164 patients with a diagnosis of colorectal (n = 110) and breast (n = 54) cancers who were receiving oral capecitabine. Patients were randomly assigned to receive either a home care program by a nurse or standard care for 18 weeks (ie, six cycles of chemotherapy). Toxicity assessments were carried out weekly for the duration of the patients' participation in the trial, and validated self-report tools assessed anxiety, depression, and quality of life. RESULTS: Significant improvements were observed in the home care group in relation to the symptoms of oral mucositis, diarrhea, constipation, nausea, pain, fatigue (first four cycles), and insomnia (all P < .05). This improvement was most significant during the initial two cycles. Unplanned service utilization, particularly the number of inpatient days (57 v 167 days; P = .02), also was lower in the home care group. CONCLUSION: A symptom-focused home care program was able to assist patients to manage their treatment adverse effects more effectively than standard care. It is imperative that patients receiving oral chemotherapy are supported with such programs, particularly during initial treatment cycles, to improve their treatment and symptom experiences.
    • Endometrial adenocarcinoma: an analysis of treatment and outcome.

      Byrd, Louise M; Swindell, Ric; Webber-Rookes, Daniel; Hannon, Robert; Hunter, Robin D; Livsey, Jacqueline E; Davidson, Susan E; Department of Obstetrics and Gynaecology, St Mary's Hospital for Women and Children, Manchester, UK. louise.byrd@cmmc.nhs.uk (2008-11)
      This study aims to review the survival and morbidity in patients treated for endometrial cancer, at a single centre and analyses the effects of co-morbidity on these outcomes. Case notes of all patients referred to the Christie Hospital with endometrial carcinoma from January 1, 1993 to December 31, 1995 (n=499) were reviewed. Twenty patients presented with recurrence and were not included in this analysis. Three hundred and seventy-five patients had previously undergone a total abdominal hysterectomy and bilateral salpingoophorectomy (+/- pelvic lymphadenectomy). Of these, 175 received adjuvant external beam radiotherapy (XRT) only, 49 received XRT and brachytherapy, 30 received brachytherapy alone and 121 patients had no further therapy. One hundred and four patients were referred for primary treatment. Radical radiotherapy was administered to 63 patients who were unfit for surgery, with 10 of these receiving XRT + brachytherapy and 53 receiving brachytherapy alone. Thirteen patients received palliative XRT and 28 supportive care only. The overall 5-year survival for those treated radically was 73.3%. There was no significant survival difference between patients who underwent surgery and adjuvant radiotherapy, in whatever form (p=0.115). Patients who did not undergo surgery did less well as a group, although there was no significant survival difference between those treated with combination therapy or brachytherapy alone (p=0.33). Survival was significantly associated with FIGO stage, tumour grade, age (especially those >75 years) and co-morbidity (ACE-27 score). Late morbidity occurred in 46 patients, with severe toxicity affecting 12 (3.8%). Toxicity was associated with ACE-27 score (p=0.0019), treatment dose and modality, with 50% (n=6) of severe toxicity seen in patients receiving adjuvant XRT + ICT. These data demonstrate that survival in patients with endometrial carcinoma treated radically remains good, with the stage and grade of tumour being significant factors for overall survival. The incidence of severe morbidity related to radiotherapy of any modality was 3.8%. A high co-morbidity (ACE-27) score was significantly associated with poorer survival (p<0.0055) and increased late treatment morbidity (p=0.0019).
    • Estimation of renal function -- what is appropriate in cancer patients?

      Barraclough, Lisa H; Field, Catherine; Wieringa, Gilbert E; Swindell, Ric; Livsey, Jacqueline E; Davidson, Susan E; Department of Clinical Oncology, Christie Hospital, Manchester, UK. lisahelenbone@hotmail.com (2008-12)
      AIMS: To compare the accuracy of renal assessment in patients with cancer using radioisotope glomerular filtration rate (GFR), urine collection for creatinine clearance, Cockroft-Gault, Modification of Diet in Renal Disease (MDRD) and Wright formulae. MATERIALS AND METHODS: Measurements of isotope GFR from 367 patients were compared with estimates from the described methods (Cockroft-Gault, MDRD, Wright). An analysis including a further 252 patients with an isotope GFR < or = 50 ml/min was also carried out. RESULTS: The Wright formula was the most accurate form of estimating renal function for the first study group. The formulae were similar in accuracy in the second study group. CONCLUSIONS: The Wright formula is the most accurate form of estimation of renal function in comparison with the isotope GFR for cancer patients. When there is a large proportion of patients with a low isotope GFR (< or = 50 ml/min), the formulae have similar accuracy.
    • European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.

      Rafnar, T; Vermeulen, S H; Sulem, P; Thorleifsson, G; Aben, Katja K H; Witjes, J A; Grotenhuis, A J; Verhaegh, G W; Hulsbergen-van de Kaa, C A; Besenbacher, S; et al. (2011-11-01)
      Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.
    • Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay.

      Hoefig, C S; Köhrle, J; Brabant, Georg E; Dixit, Kashinath C S; Yap, Beng K; Strasburger, C J; Wu, Z; Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany. (2011-06)
      Thyronamines are thyronergic metabolites of thyroid hormones. Lack of reliable and sensitive detection methods for endogenous 3-iodothyronamine (3-T(1)AM) has so far hampered progress in understanding their physiological action and role in endocrine homeostasis or pathophysiology of diseases.
    • External beam boost for cancer of the cervix uteri when intracavitary therapy cannot be performed.

      Barraclough, Lisa H; Swindell, Ric; Livsey, Jacqueline E; Hunter, Robin D; Davidson, Susan E; Department of Clinical Oncology, Christie Hospital, Manchester, UK. lisahelenbone@hotmail.com (2008-07-01)
      PURPOSE: To assess the outcome of patients treated with radical radiotherapy for cervical cancer who received an external beam boost, in place of intracavitary brachytherapy (ICT), after irradiation to the whole pelvis. METHODS AND MATERIALS: Case notes were reviewed for all patients treated in this way in a single center between 1996 and 2004. Patient and tumor details, the reasons why ICT was not possible, and treatment outcome were documented. RESULTS: Forty-four patients were identified. The mean age was 56.4 years (range, 26-88 years). Clinical International Federation of Gynecology and Obstetrics or radiologic stage for Stages I, II, III, and IV, respectively, was 16%, 48%, 27%, and 7%. A total radiation dose of 54-70 Gy was given (75% received > or =60 Gy). Reasons for ICT not being performed were technical limitations in 73%, comorbidity or isolation limitations in 23%, and patient choice in 4%. The median follow-up was 2.3 years. Recurrent disease was seen in 48%, with a median time to recurrence of 2.3 years. Central recurrence was seen in 16 of the 21 patients with recurrent disease. The 5-year overall survival rate was 49.3%. The 3-year cancer-specific survival rate by stage was 100%, 70%, and 42% for Stages I, II, and III, respectively. Late Grades 1 and 2 bowel, bladder, and vaginal toxicity were seen in 41%. Late Grade 3 toxicity was seen in 2%. CONCLUSION: An external beam boost is a reasonable option after external beam radiotherapy to the pelvis when it is not possible to perform ICT.
    • Irinotecan+5-fluorouracil with concomitant pre-operative radiotherapy in locally advanced non-resectable rectal cancer: a phase I/II study.

      Iles, S M; Gollins, Simon W; Susnerwala, Shabbir; Haylock, B; Myint, A Sun; Biswas, A; Swindell, Ric; Levine, Edward; Department of Clinical Oncology, The Christie Hospital NHS Trust, Manchester M20 4BX, UK. (2008-04-08)
      In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n=12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m(-2) to 60 mg m(-2) to 70 mg m(-2) to identify the maximum tolerated dose (60 mg m(-2)). In phase II, 31 patients with non-resectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m(-2) per day) for 5 weeks. Irinotecan (60 mg m(-2)) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity.
    • MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer.

      Choudhury, Ananya; Nelson, L D; Teo, M T W; Chilka, S; Bhattarai, S; Johnston, C F; Elliott, F; Lowery, J; Taylor, C F; Churchman, M; et al. (2010-09-15)
      Radical radiotherapy and surgery achieve similar cure rates in muscle-invasive bladder cancer, but the choice of which treatment would be most beneficial cannot currently be predicted for individual patients. The primary aim of this study was to assess whether expression of any of a panel of DNA damage signaling proteins in tumor samples taken before irradiation could be used as a predictive marker of radiotherapy response, or rather was prognostic. Protein expression of MRE11, RAD50, NBS1, ATM, and H2AX was studied by immunohistochemistry in pretreatment tumor specimens from two cohorts of bladder cancer patients (validation cohort prospectively acquired) treated with radical radiotherapy and one cohort of cystectomy patients. In the radiotherapy test cohort (n = 86), low tumor MRE11 expression was associated with worse cancer-specific survival compared with high expression [43.1% versus 68.7% 3-year cause-specific survival (CSS), P = 0.012] by Kaplan-Meier analysis. This was confirmed in the radiotherapy validation cohort (n = 93; 43.0% versus 71.2%, P = 0.020). However, in the cystectomy cohort (n = 88), MRE11 expression was not associated with cancer-specific survival, commensurate with MRE11 being a predictive marker. High MRE11 expression in the combined radiotherapy cohort had a significantly better cancer-specific survival compared with the high-expression cystectomy cohort (69.9% versus 53.8% 3-year CSS, P = 0.021). In this validated immunohistochemistry study, MRE11 protein expression was shown and confirmed as a predictive factor associated with survival following bladder cancer radiotherapy, justifying its inclusion in subsequent trial designs. MRE11 expression may ultimately allow patient selection for radiotherapy or cystectomy, thus improving overall cure rates.
    • A phase I study of the safety and pharmacokinetics of the combination of pertuzumab (rhuMab 2C4) and capecitabine in patients with advanced solid tumors.

      Albanell, Joan; Montagut, Clara; Jones, Eileen T; Pronk, Linda; Mellado, Begoña; Beech, Janette; Gascon, Pere; Zugmaier, Gerhard; Brewster, Michael; Saunders, Mark P; et al. (2008-05-01)
      PURPOSE: To study the safety, pharmacokinetics, and recommended dose of the combination of pertuzumab, a humanized monoclonal antibody HER2-dimerization inhibitor, and capecitabine in patients with advanced malignancies. EXPERIMENTAL DESIGN: Patients that had progressed to standard treatment were treated with pertuzumab at a fixed dose of 1,050 mg given i.v. on day 1 plus capecitabine at doses of 825-1,000-1,250 mg/m(2), twice daily orally on days 1 to 14 of each 21-day treatment cycle, in three sequential cohorts. The pharmacokinetics of capecitabine and pertuzumab were studied. Patients received a single dose of capecitabine in a pretreatment phase (day -7) followed by serum sampling for capecitabine and its metabolites. RESULTS: Nineteen patients were accrued and 18 were assessable. The combination of capecitabine and pertuzumab was well tolerated at all dose levels and no dose-limiting toxicities were observed. The most frequent adverse event was asthenia, which was grade 3 in two patients. One asymptomatic pulmonary embolism occurred. No other grade 3 or 4 adverse events or cardiac or left ventricular ejection fraction events were reported. There was no apparent change in the pharmacokinetics of capecitabine and its metabolites when combined with pertuzumab. The pharmacokinetics of pertuzumab was apparently not modified when administered with capecitabine. Disease stabilization was observed in 11 patients. CONCLUSIONS: Pertuzumab and capecitabine were well tolerated at all dose levels. Escalation beyond the highest dose level tested was not planned, as this included the recommended doses of monotherapy for both drugs. In conclusion, this combination is ready for phase II testing.
    • A phase II study evaluating the use of concurrent mitomycin C and capecitabine in patients with advanced unresectable pseudomyxoma peritonei.

      Farquharson, Adam L; Pranesh, Nagarajan; Witham, Gary; Swindell, Ric; Taylor, Malcolm B; Renehan, Andrew G; Rout, Shantanu; Wilson, Malcolm S; O'Dwyer, Sarah T; Saunders, Mark P; et al. (2008-08-19)
      Pseudomyxoma peritonei (PMP) is a rare neoplastic process characterised by progressive intra-abdominal dissemination of mucinous tumour, and generally considered resistant to systemic chemotherapy. A phase II study in patients with advanced unresectable PMP was undertaken to evaluate the combination of systemic concurrent mitomycin C (7 mg m(-2) i.v. on day 1) and capecitabine (1250 mg m(-2) b.d. on days 1-14) in a 3-weekly cycle (MCap). Response was determined by semiquantitative assessment of disease volume on serial computed tomographic (CT) scans and serum tumour marker (CEA, CA125, CA19-9) changes at 12 weeks. Between 2003 and 2006, 40 patients were recruited through a national centre for the treatment of peritoneal surface tumours. At baseline, 23 patients had progressive disease and 17 had stable disease. Of 39 assessable patients, 15 (38%, 95% confidence intervals (CIs): 25, 54%) benefited from chemotherapy in the form of either reductions in mucinous deposition or stabilisation of progressive pretreatment disease determined on CT scan. Notably, two patients, originally considered unresectable, following MCap and re-staging underwent potentially curative cytoreductive surgery. Grade 3/4 toxicity rates were low (6%, 95% CIs: 4, 9%). Twenty out of 29 assessed patients (69%, 95% CIs: 51, 83%) felt that their Global Health Status improved during chemotherapy. This is the first trial to demonstrate an apparent benefit of systemic chemotherapy in patients with advanced unresectable PMP.
    • Phase II study of cisplatin and imatinib in advanced salivary adenoid cystic carcinoma.

      Ghosal, N; Mais, Kathleen L; Shenjere, Patrick; Julyan, Peter J; Hastings, David L; Ward, Timothy H; Ryder, W David J; Bruce, I; Homer, Jarrod J; Slevin, Nicholas J; et al. (2011-10)
      Patients with adenoid cystic carcinoma of the salivary glands show over-expression of KIT in a high proportion of cases. Options for systemic treatment are limited in locally advanced and metastatic disease. We explored the efficacy of imatinib and cisplatin combined in this group of patients. A Gehan's two-stage, phase II trial was conducted on 28 patients. Those with progressive, locally advanced, and metastatic disease with an over-expression of KIT were treated with single agent imatinib 800 mg daily for two months, followed by a combination of imatinib 400mg daily and cisplatin 80 mg/m(2) at four-weekly intervals for six cycles. This was followed by maintenance single agent imatinib 400mg daily until the disease progressed. Response was monitored using fluorodeoxyglucose positron emission tomography (FDG-PET) and morphological imaging using computed tomography, magnetic resonance, and chest radiographs (CT/MRI/CXR). Morphological imaging showed partial response in three of 28 patients, and five patients showed a response on FDG-PET. In addition, 19 patients had useful stabilisation of disease. The median time to progression and overall survival was 15 months (range 1-43) and 35 months (range 1-75), respectively. The combination of imatinib and cisplatin was reasonably well tolerated. This combination may provide stabilisation in locally advanced and metastatic adenoid cystic carcinoma of the salivary glands.