• Omitting elective nodal irradiation during thoracic irradiation in limited-stage small cell lung cancer - Evidence from a phase II trial.

      Colaco, Rovel J; Sheikh, Hamid Y; Lorigan, Paul C; Blackhall, Fiona H; Hulse, Paul; Califano, Raffaele; Ashcroft, Linda; Taylor, Paul; Thatcher, Nick; Faivre-Finn, Corinne; et al. (2012-04)
      Omitting elective nodal irradiation (ENI) in limited-stage disease small cell lung cancer (LD-SCLC) is expected to result in smaller radiation fields. We report on data from a randomised phase II trial that omitted ENI in patients receiving concurrent chemo-radiotherapy for LD-SCLC. 38 patients with LD-SCLC were randomised to receive once-daily (66Gy in 33 fractions) or twice-daily (45Gy in 30 fractions) radiotherapy (RT). 3D-conformal RT was given concurrently with cisplatin and etoposide starting with the second cycle of a total of four cycles. The gross tumour volume was defined as primary tumour with involved lymph nodes (nodes ≥1cm in short axis) identifiable with CT imaging. ENI was not used. Six recurrence patterns were identified: recurrence within planning target volume (PTV) only, recurrence within PTV+regional nodal recurrence and/or distant recurrence, isolated nodal recurrence outside PTV, nodal recurrence outside PTV+distant recurrence, distant metastases only and no recurrence. At median follow-up 16.9 months, 31/38 patients were evaluable and 14/31 patients had relapsed. There were no isolated nodal recurrences. Eight patients relapsed with intra-thoracic disease: 2 within PTV only, 4 within PTV and distantly and 2 with nodal recurrence outside PTV plus distant metastases. Rates of grade 3+ acute oesophagitis and pneumonitis in the 31 evaluable patients were 23 and 3% respectively. In our study of LD-SCLC, omitting ENI based on CT imaging was not associated with a high risk of isolated nodal recurrence, although further prospective studies are needed to confirm this. Routine ENI omission will be further evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563).
    • A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker.

      Khoja, Leila; Backen, Alison C; Sloane, Robert; Menasce, Lia P; Ryder, W David J; Krebs, Matthew G; Board, Ruth E; Clack, G; Hughes, A; Blackhall, Fiona H; et al. (2012-01-31)
      Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study.
    • Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours.

      Dean, Emma J; Middleton, M R; Pwint, T; Swaisland, H; Carmichael, J; Goodege-Kunwar, P; Ranson, Malcolm R; Clinical Trials Unit, Department of Medical Oncology, The Christie NHS Foundation Trust, The University of Manchester, Wilmslow Road, Manchester M20 4, BX, UK. emma.dean@christie.nhs.uk (2012-01-31)
      Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase inhibitor with anti-tumour activity and acceptable toxicity as monotherapy in patients with BRCA-deficient cancers. The vascular endothelial growth factor receptor inhibitor bevacizumab has been incorporated into standard of care with chemotherapy in various tumours. This phase I study established the safety, tolerability and clinical pharmacokinetics of olaparib alone and in combination with bevacizumab.
    • Targeted agents in non-small cell lung cancer (NSCLC): Clinical developments and rationale for the combination with thoracic radiotherapy.

      Koh, Pek K; Faivre-Finn, Corinne; Blackhall, Fiona H; De Ruysscher, D; Department of Clinical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. (2011-12-22)
      In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions.
    • Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells.

      Sabharwal, A; Waters, R; Danson, Sarah; Clamp, Andrew R; Lorigan, Paul C; Thatcher, Nick; Margison, Geoffrey P; Middleton, Mark R; Department of Medical Oncology, University of Oxford, Oxford, UK. (2011-12-21)
      To assess the value of pretreatment O-methylguanine-DNA methyltransferase (MGMT) expression in peripheral blood mononuclear cells (PBMCs) in predicting haematological toxicity with O-alkylating agent chemotherapy, we explored this relationship retrospectively in melanoma patients. Ninety-three patients treated with temozolomide or dacarbazine in four clinical trials were assessed, and a model of the interaction between MGMT expression and haematological toxicity was constructed. Nadir white-cell and platelet counts were related to, and hence could be predicted from, pretreatment MGMT. Leucopenia and thrombocytopenia were more prevalent amongst patients with low pretreatment MGMT, according to the highest grades of toxicity experienced and/or the dose intensity patients could sustain. Addition of interferon to chemotherapy or compression of the temozolomide schedule increased the toxicity. The model also predicts significant myelotoxicity where PBMC MGMT is inactivated, consistent with the experience in the clinic with lomeguatrib and O-benzylguanine. Determination of MGMT in PBMC can identify patients at greatest risk of toxicity or who are suitable for dose intensification.
    • Biomarkers for small cell lung cancer: Neuroendocrine, epithelial and circulating tumour cells.

      Stovold, Rachel; Blackhall, Fiona H; Meredith, S; Hou, Jian-Mei; Dive, Caroline; White, A; Faculty of Life Sciences, Manchester Academic Health Sciences Centre, University of Manchester, AV Hill Building, Manchester, M13 9PT, UK; Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, UK. (2011-12-15)
      Small cell lung cancer (SCLC) is characterised by an aggressive clinical course with invariable resistance to chemotherapy despite initially high response rates. There has been little improvement in outcome over the past few decades, with no breakthrough yet in targeted therapies. Recent preclinical data and studies of circulating tumour cells (CTCs) highlight distinct cellular heterogeneity within SCLC. Better understanding of how these phenotypes contribute to metastasis and tumour progression might pave the way for development of more successful targeted therapies. Here we review these studies, their implications for future research and for the incorporation of biomarkers reflecting neuroendocrine, epithelial and mesenchymal phenotypes in clinical studies.
    • R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study.

      Pappo, A; Patel, S; Crowley, J; Reinke, D; Kuenkele, K; Chawla, S; Toner, G; Maki, R; Meyers, P; Chugh, R; et al. (2011-12-01)
      The type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). We conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT.
    • Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis.

      Calman, L; Beaver, K; Hind, D; Lorigan, Paul C; Roberts, C; Lloyd-Jones, M; School of Nursing, Midwifery and Social Work, Jean McFarlane Building, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. (2011-12)
      The burden of lung cancer is high for patients and carers. Care after treatment may have the potential to impact on this. We reviewed the published literature on follow-up strategies intended to improve survival and quality of life.
    • Sunitinib for advanced pancreatic neuroendocrine tumors.

      Hubner, Richard A; Valle, Juan W; Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK. (2011-12)
      Recent recognition of the high prevalence of neuroendocrine tumors in combination with a sustained failure to improve outcomes for patients with advanced disease has elevated their priority for research and drug development. Sunitinib (SU11248, Sutent; Pfizer Inc. NY, USA) potently inhibits multiple-receptor tyrosine kinases, resulting in antiangiogenic effects. A growing body of evidence indicates angiogenesis is a clinically relevant therapeutic target in pancreatic neuroendocrine tumors, culminating in a Phase III randomized study of sunitinib in patients with advanced progressive pancreatic neuroendocrine tumors. Sunitinib has recently gained regulatory approval as a single agent in this setting, and future studies will investigate most appropriate patient selection, and sequencing and combination with other targeted and cytotoxic agents. Here, we discuss in detail the molecular properties, clinical efficacy and safety of sunitinib in the context of pancreatic neuroendocrine tumors.
    • Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer.

      Soria, J-C; Márk, Z; Zatloukal, P; Szima, B; Albert, I; Juhász, E; Pujol, J L; Kozielski, J; Baker, N; Smethurst, D; et al. (2011-11-20)
      To evaluate the efficacy and safety of dulanermin combined with paclitaxel and carboplatin (PC) and bevacizumab (PCB) as first-line treatment for advanced or recurrent non-small-cell lung cancer (NSCLC).
    • Anti-estrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells.

      Martinez-Outschoorn, U E; Goldberg, A; Lin, Z; Ko, Y H; Flomenberg, N; Wang, C; Pavlides, S; Pestell, R; Howell, Anthony; Sotgia, F; et al. (2011-11-15)
      Here, we show that tamoxifen resistance is induced by cancer-associated fibroblasts (CAFs). Coculture of estrogen receptor positive (ER+) MCF7 cells with fibroblasts induces tamoxifen and fulvestrant resistance with 4.4 and 2.5-fold reductions, respectively, in apoptosis compared with homotypic MCF7 cell cultures. Treatment of MCF7 cells cultured alone with high-energy mitochondrial "fuels" (L-lactate or ketone bodies) is sufficient to confer tamoxifen resistance, mimicking the effects of coculture with fibroblasts. To further demonstrate that epithelial cancer cell mitochondrial activity is the origin of tamoxifen resistance, we employed complementary pharmacological and genetic approaches. First, we studied the effects of two mitochondrial "poisons," namely metformin and arsenic trioxide (ATO), on fibroblast-induced tamoxifen resistance. We show here that treatment with metformin or ATO overcomes fibroblast-induced tamoxifen resistance in MCF7 cells. Treatment with the combination of tamoxifen plus metformin or ATO leads to increases in glucose uptake in MCF7 cells, reflecting metabolic uncoupling between epithelial cancer cells and fibroblasts. In coculture, tamoxifen induces the upregulation of TIGAR (TP53-induced glycolysis and apoptosis regulator), a p53 regulated gene that simultaneously inhibits glycolysis, autophagy and apoptosis and reduces ROS generation, thereby promoting oxidative mitochondrial metabolism. To genetically mimic the effects of coculture, we next recombinantly overexpressed TIGAR in MCF7 cells. Remarkably, TIGAR overexpression protects epithelial cancer cells from tamoxifen-induced apoptosis, providing genetic evidence that increased mitochondrial function confers tamoxifen resistance. Finally, CAFs also protect MCF7 cells against apoptosis induced by other anticancer agents, such as the topoisomerase inhibitor doxorubicin (adriamycin) and the PARP-1 inhibitor ABT-888. These results suggest that the tumor microenvironment may be a general mechanism for conferring drug resistance. In summary, we have discovered that mitochondrial activity in epithelial cancer cells drives tamoxifen resistance in breast cancer and that mitochondrial "poisons" are able to re-sensitize these cancer cells to tamoxifen. In this context, TIGAR may be a key "druggable" target for preventing drug resistance in cancer cells, as it protects cancer cells against the onset of stress-induced mitochondrial dys-function and aerobic glycolysis.
    • Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer.

      Cuzick, J; Dowsett, M; Pineda, S; Wale, C; Salter, J; Quinn, E; Zabaglo, L; Mallon, E; Green, A R; Ellis, I O; et al. (2011-11-10)
      We recently reported that the mRNA-based, 21-gene Genomic Health recurrence score (GHI-RS) provided additional prognostic information regarding distant recurrence beyond that obtained from classical clinicopathologic factors (age, nodal status, tumor size, grade, endocrine treatment) in women with early breast cancer, confirming earlier reports. The aim of this article is to determine how much of this information is contained in standard immunohistochemical (IHC) markers.
    • Influence of comorbidities and age on risk of death without recurrence: a retrospective analysis of the Arimidex, Tamoxifen Alone or in Combination trial.

      Ring, A; Sestak, I; Baum, M; Howell, Anthony; Buzdar, A; Dowsett, M; Forbes, J F; Cuzick, J; Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, BN2 5BE, United Kingdom. (2011-11-10)
      The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a double-blind randomized trial in which postmenopausal women with early-stage breast cancer were assigned to receive anastrozole, tamoxifen, or the combination. We have conducted a retrospective analysis to examine the effects of comorbidities and age on treatment received, breast cancer-related mortality, and competing causes of mortality.
    • Second cancer risk after chemotherapy for Hodgkin's lymphoma: a collaborative British cohort study.

      Swerdlow, A J; Higgins, C D; Smith, P; Cunningham, D; Hancock, B W; Horwich, A; Hoskin, P J; Lister, T A; Radford, John A; Rohatiner, A Z S; et al. (2011-11-01)
      We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge.
    • VEGF inhibitors and advanced ovarian cancer.

      Jayson, Gordon C; Christie Hospital and University of Manchester, Academic Health Sciences Centre, Manchester, UK. (2011-11)
    • A patient with a metastatic gastroenteropancreatic endocrine carcinoma causing hyperinsulinaemic hypoglycaemia and the carcinoid syndrome.

      Hinchliffe, E; Allcock, R L; Mansoor, Was; Myers, M A; Department of Clinical Biochemistry, University Hospital of South Manchester, Wythenshawe, Manchester M23 9LT, UK. (2011-11)
      We present the case of a 57-year-old patient who initially presented with a constellation of symptoms including intense pruritis, flushing and diarrhoea. Following several months clinical deterioration, the patient was investigated radiologically, where multiple hepatic tumours were identified. Liver biopsy confirmed the presence of a well-differentiated metastatic gastroenteropancreatic endocrine carcinoma with biochemical evidence of serotonin secretion. Over a period of six months, the clinical course of the patient's disease progressed whereby severe hypoglycaemia became the major manifestation. Subsequent biochemical investigations confirmed the diagnosis of an insulinoma. Extensive radiological investigation revealed a solitary primary pancreatic tumour, indicating the presence of a metastatic pancreatic endocrine tumour (PET) secreting both insulin and serotonin. The patient was treated with a chemotherapy regimen consisting of 12 cycles of 5-fluorouracil/oxaliplatin, responding clinically - improved World Health Organization performance score from 3 to 1, biochemically - significantly reduced plasma chromogranin A and cancer antigen 19-9 concentrations and improved liver function tests, and radiologically - reduced pancreatic and hepatic tumour size. This is the first report of a primary PET secreting insulin and serotonin. Due to the association of serotonin-secreting gastroenteropancreatic endocrine tumours (GEP-ETs) with multiple endocrine neoplasia type-1 (MEN1) and biochemical evidence of an insulinoma, MEN1 should also be considered in such cases. The case provides further evidence for the biological heterogeneity of GEP-ETs and the myriad secretory humoral products and resultant clinical syndromes arising from such tumours.
    • A phase II trial evaluating two schedules of sagopilone (ZK-EPO), a novel epothilone, in patients with platinum-resistant ovarian cancer.

      Rustin, G; Reed, N; Jayson, Gordon C; Ledermann, J A; Adams, M; Perren, T; Poole, C; Lind, M; Persic, M; Essapen, S; et al. (2011-11)
      Sagopilone, the first fully synthetic epothilone, has shown promising preclinical activity in tumour models. This open-label randomised phase II study investigated two infusion schedules of sagopilone in women with ovarian cancer.
    • Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.

      Regan, M; Neven, P; Giobbie-Hurder, A; Goldhirsch, A; Ejlertsen, B; Mauriac, L; Forbes, J; Smith, I; Láng, I; Wardley, Andrew M; et al. (2011-11)
      Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up.
    • Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial.

      Gridelli, C; Bennouna, J; de Castro, J; Dingemans, A; Griesinger, F; Grossi, F; Rossi, A; Thatcher, Nick; Wong, E K; Langer, C; et al. (2011-11)
      We present the treatment rationale and study design of the AvaALL (MO22097; ClinicalTrials: NCT01351415) trial, a multicenter, open-label, randomized, two-arm, phase IIIb study. Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) whose disease has progressed after four to six cycles of first-line treatment with bevacizumab plus a platinum-based doublet and a minimum of two cycles of bevacizumab (monotherapy) maintenance treatment will be randomized in a 1:1 ratio to one of two study arms. Patients treated on arm A will receive bevacizumab 7.5 or 15 mg/kg intravenously (I.V.) on day 1, every 21 days plus, investigator's choice of agents indicated for use in second-line (limited to pemetrexed, docetaxel, or erlotinib) and subsequent lines of treatment. Patients treated on arm B, will receive investigator's choice of agents alone indicated for use in second-line and subsequent lines of treatment, but no further bevacizumab treatment. The primary endpoint of this study is overall survival (OS). Secondary endpoints include the 6-month, 12-month, and 18-month OS rates, progression-free survival, and time to progression at second and third progressive disease (PD), response rate, disease control rates, and duration of response at second and third PD. Additionally, efficacy in the subgroup of patients with adenocarcinoma, and the safety of bevacizumab treatment across multiple lines of treatment will be assessed. Exploratory objectives include assessment of the quality of life through multiple lines of treatment, comparison of the efficacy between Asian and non-Asian patients, and correlation of biomarkers with efficacy outcomes, disease response, and adverse events.
    • Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer.

      Ledermann, Jonathan A; Hackshaw, Allan; Kaye, Stan B; Jayson, Gordon C; Gabra, Hani; McNeish, Iain; Earl, Helena; Perren, Timothy J; Gore, Martin; Persic, Mojca; et al. (2011-10-01)
      Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease.