• A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands.

      Chanudet, E; Ye, Hongtao; Ferry, J; Bacon, C M; Adam, P; Müller-Hermelink, H K; Radford, John A; Pileri, S A; Ichimura, K; Collins, V P; et al. (2009-02)
      The genetic basis of MALT lymphoma is largely unknown. Characteristic chromosomal translocations are frequently associated with gastric and pulmonary cases, but are rare at other sites. We compared the genetic profiles of 33 ocular adnexal and 25 pulmonary MALT lymphomas by 1 Mb array-comparative genomic hybridization (CGH) and revealed recurrent 6q23 losses and 6p21.2-6p22.1 gains exclusive to ocular cases. High-resolution chromosome 6 tile-path array-CGH identified NF-kappaB inhibitor A20 as the target of 6q23.3 deletion and TNFA/B/C locus as a putative target of 6p21.2-22.1 gain. Interphase fluorescence in situ hybridization showed that A20 deletion occurred in MALT lymphoma of the ocular adnexa (8/42=19%), salivary gland (2/24=8%), thyroid (1/9=11%) and liver (1/2), but not in the lung (26), stomach (45) and skin (13). Homozygous deletion was observed in three cases. A20 deletion and TNFA/B/C gain were significantly associated (p<0.001) and exclusively found in cases without characteristic translocation. In ocular cases, A20 deletion was associated with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis (p=0.007), a higher proportion of relapse (67% versus 37%) and a shorter relapse-free survival (p=0.033). A20 deletion and gain at TNFA/B/C locus may thus play an important role in the development of translocation-negative MALT lymphoma.
    • Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma.

      Greystoke, Alastair; O'Connor, James P B; Linton, Kim M; Taylor, M Ben; Cummings, Jeffrey; Ward, Timothy H; Maders, Fran; Hughes, Anthony; Ranson, Malcolm R; Illidge, Timothy M; et al. (2011-02-15)
      Treatment efficacy and toxicity are difficult to predict in lymphoma patients. In this study, the utility of circulating biomarkers in predicting and/or monitoring treatment efficacy/toxicity were investigated.
    • Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer.

      Krebs, Matthew G; Sloane, Robert; Priest, Lynsey; Lancashire, Lee J; Hou, Jian-Mei; Greystoke, Alastair; Ward, Timothy H; Ferraldeschi, Roberta; Hughes, Andrew; Clack, Glen; et al. (2011-04-20)
      Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) lacks validated biomarkers to predict treatment response. This study investigated whether circulating tumor cells (CTCs) are detectable in patients with NSCLC and what their ability might be to provide prognostic information and/or early indication of patient response to conventional therapy.
    • Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy.

      Hou, Jian-Mei; Greystoke, Alastair; Lancashire, Lee J; Cummings, Jeffrey; Ward, Timothy H; Board, Ruth E; Amir, Eitan; Hughes, Sarah; Krebs, Matthew G; Hughes, Andrew; et al. (2009-08)
      Serological cell death biomarkers and circulating tumor cells (CTCs) have potential uses as tools for pharmacodynamic blood-based assays and their subsequent application to early clinical trials. In this study, we evaluated both the expression and clinical significance of CTCs and serological cell death biomarkers in patients with small cell lung cancer. Blood samples from 88 patients were assayed using enzyme-linked immunosorbent assays for various cytokeratin 18 products (eg, M65, cell death, M30, and apoptosis) as well as nucleosomal DNA. CTCs (per 7.5 ml of blood) were quantified using Veridex CellSearch technology. Before therapeutic treatment, cell death biomarkers were elevated in patients compared with controls. CTCs were detected in 86% of patients; additionally, CD56 was detectable in CTCs, confirming their neoplastic origin. M30 levels correlated with the percentage of apoptotic CTCs. M30, M65, lactate dehydrogenase, and CTC number were prognostic for patient survival as determined by univariate analysis. Using multivariate analysis, both lactate dehydrogenase and M65 levels remained significant. CTC number fell following chemotherapy, whereas levels of serological cell death biomarkers peaked at 48 hours and fell by day 22, mirroring the tumor response. A 48-hour rise in nucleosomal DNA and M30 levels was associated with early response and severe toxicity, respectively. Our results provide a rationale to include the use of serological biomarkers and CTCs in early clinical trials of new agents for small cell lung cancer.
    • Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study.

      Valle, Juan W; Wasan, H; Johnson, P; Jones, Eileen T; Dixon, L; Swindell, Ric; Baka, Sofia; Maraveyas, A; Corrie, P; Falk, S; et al. (2009-08-18)
      BACKGROUND: We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. METHODS: Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. RESULTS: In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). CONCLUSION: Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.
    • Influence of co-morbidity on renal function assessment by Cockcroft-Gault calculation in lung cancer and mesothelioma patients receiving platinum-based chemotherapy.

      Hubner, Richard A; Goldstein, R; Mitchell, S; Jones, A; Ashley, S; O'Brien, M E R; Popat, S; Dept Medical Oncology, Christie Hospital, Manchester M20 4BX, UK. (2011-09)
      Creatinine clearance (CrCl) estimation by Cockcroft-Gault calculation (CG) often replaces measurement of glomerular filtration rate (GFR) by [(51)Cr]-ethylenediaminetetraacetic acid clearance (EDTA). Co-morbidity, age, and renal impairment influence the accuracy of CG, whilst the relationship between CG and EDTA has been poorly assessed in lung cancer patients, a population significantly affected by these covariates.
    • Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer.

      Lin, Nancy U; Diéras, Véronique; Paul, Devchand; Lossignol, Dominique; Christodoulou, Christos; Stemmler, Hans-Joachim; Roché, Henri; Liu, Minetta C; Greil, Richard; Ciruelos, Eva; et al. (2009-02-15)
      PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. EXPERIMENTAL DESIGN: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
    • No study left behind: a network meta-analysis in non-small-cell lung cancer demonstrating the importance of considering all relevant data.

      Hawkins, Neil; Scott, David A; Woods, Beth S; Thatcher, Nick; Oxford Outcomes Ltd., Oxford, UK. neil.hawkins@oxfordoutcomes.com (2009-09)
      OBJECTIVE: To demonstrate the importance of considering all relevant indirect data in a network meta-analysis of treatments for non-small-cell lung cancer (NSCLC). METHODS: A recent National Institute for Health and Clinical Excellence appraisal focussed on the indirect comparison of docetaxel with erlotinib in second-line treatment of NSCLC based on trials including a common comparator. We compared the results of this analysis to a network meta-analysis including other trials that formed a network of evidence. We also examined the importance of allowing for the correlations between the estimated treatment effects that can arise when analysing such networks. RESULTS: The analysis of the restricted network including only trials of docetaxel and erlotinib linked via the common placebo comparator produced an estimated mean hazard ratio (HR) for erlotinib compared with docetaxel of 1.55 (95% confidence interval [CI] 0.72-2.97). In contrast, the network meta-analysis produced an estimated HR for erlotinib compared with docetaxel of 0.83 (95% CI 0.65-1.06). Analyzing the wider network improved the precision of estimated treatment effects, altered their rankings and also allowed further treatments to be compared. Some of the estimated treatment effects from the wider network were highly correlated. CONCLUSIONS: This empirical example shows the importance of considering all potentially relevant data when comparing treatments. Care should therefore be taken to consider all relevant information, including correlations induced by the network of trial data, when comparing treatments.
    • Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: risks of breast/ovarian cancer quoted should reflect the cancer burden in the family.

      Evans, D Gareth R; Shenton, Andrew; Woodward, Emma; Lalloo, Fiona; Howell, Anthony; Maher, Eamonn R; Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital Manchester M13 0JH, UK. gareth.evans@cmmc.nhs.uk (2008)
      BACKGROUND: The identification of a BRCA1 or BRCA2 mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation. METHODS: We reviewed 385 unrelated families (223 with BRCA1 and 162 with BRCA2 mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers - 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort. RESULTS: Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7-71.3%) and 79.5% (95%CI 75.5-83.5%) respectively for BRCA1 and 75% (95%CI 71.7-78.3%) and 88% (95%CI 85.3-91.7%) for BRCA2. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65-71%) and 65% (95%CI 75-84%) for BRCA1 and 30% (95%CI 25.5-34.5%) and 37% (95%CI 31.5-42.5%) for BRCA2. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005). CONCLUSION: In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.
    • A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.

      Jonker, D J; Rosen, L S; Sawyer, M B; de Braud, F; Wilding, G; Sweeney, C J; Jayson, Gordon C; McArthur, G A; Rustin, G; Goss, G; et al. (2011-06)
      This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.
    • 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.
    • Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma.

      Kirkwood, John M; Lorigan, Paul C; Hersey, Peter; Hauschild, Axel; Robert, Caroline; McDermott, David F; Marshall, Margaret A; Gomez-Navarro, Jesus; Liang, Jane Q; Bulanhagui, Cecile A; et al. (2010-02-01)
      PURPOSE: This phase II study assessed the antitumor activity of tremelimumab, a fully human, anti-CTL-associated antigen 4 monoclonal antibody, in patients with melanoma. EXPERIMENTAL DESIGN: Patients with refractory/relapsed melanoma received 15 mg/kg tremelimumab every 90 days. After 4 doses, patients with tumor response or stable disease were eligible to receive < or =4 additional doses. Primary endpoint was best overall tumor response assessed by an independent endpoint review committee, and secondary endpoints included duration of response, overall survival, progression-free survival, and safety. RESULTS: Of 251 patients enrolled, 246 (241 response-evaluable) received tremelimumab. Objective response rate was 6.6% (16 partial responses); duration of response was 8.9 to 29.8 months. Eight (50%) objective responses occurred in patients with stage IV M(1c) disease, and 11 (69%) were ongoing at last tumor assessment. Eight (3.3%) patients achieved responses in target lesions (Response Evaluation Criteria in Solid Tumors) despite progressive disease within the first cycle. All 8 survived for >20 months; 5 (63%) remained alive. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at 6 months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. Common treatment-related adverse events were generally mild to moderate, and grade 3/4 adverse events included diarrhea (n = 28, 11%), fatigue (n = 6, 2%), and colitis (n = 9, 4%). There were 2 (0.8%) treatment-related deaths. CONCLUSIONS: Tremelimumab showed an objective response rate of 6.6%, with all responses being durable > or =170 days since enrollment, suggesting a potential role for tremelimumab in melanoma.
    • Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer.

      Baka, Sofia; Califano, Raffaele; Ferraldeschi, Roberta; Ashcroft, Linda; Thatcher, Nick; Taylor, Pat; Faivre-Finn, Corinne; Blackhall, Fiona H; Lorigan, Paul C; Department of Medical Oncology, Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. (2008-08-05)
      This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and
    • Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer.

      Cunningham, D; Chau, I; Stocken, D; Valle, Juan W; Smith, David; Steward, William P; Harper, P; Dunn, J; Tudur-Smith, C; West, J; et al. (2009-11-20)
      PURPOSE: Both gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly assigned to GEM alone or GEM plus capecitabine (GEM-CAP). PATIENTS AND METHODS: Patients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status
    • Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors.

      O'Connor, James P B; Naish, Josephine H; Parker, Geoff J M; Waterton, John C; Watson, Yvonne; Jayson, Gordon C; Buonaccorsi, Giovanni A; Cheung, Susan; Buckley, David L; McGrath, Deirdre M; et al. (2009-11-15)
      PURPOSE: There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS: Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS: DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS: These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.
    • Primary diffuse large B-cell lymphoma of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma Study Group.

      Ryan, G; Martinelli, Giovanni; Kuper-Hommel, M; Tsang, R; Pruneri, G; Yuen, K; Roos, D; Lennard, A; Devizzi, L; Crabb, S; et al. (2008-02)
      BACKGROUND: Primary diffuse large B-cell lymphoma (DLBCL) of breast is rare. We aimed to define clinical features, prognostic factors, patterns of failure, and treatment outcomes. PATIENTS AND METHODS: A retrospective international study of 204 eligible patients presenting to the International Extranodal Lymphoma Study Group-affiliated institutions from 1980 to 2003. RESULTS: Median age was 64 years, with 95% of patients presenting with unilateral disease. Median overall survival (OS) was 8.0 years, and median progression-free survival 5.5 years. In multifactor analysis, favourable International Prognostic Index score, anthracycline-containing chemotherapy, and radiotherapy (RT) were significantly associated with longer OS (each P < or = 0.03). There was no benefit from mastectomy, as opposed to biopsy or lumpectomy only. At a median follow-up time of 5.5 years, 37% of patients had progressed--16% in the same or contralateral breast, 5% in the central nervous system, and 14% in other extranodal sites. CONCLUSIONS: The combination of limited surgery, anthracycline-containing chemotherapy, and involved-field RT produced the best outcome in the pre-rituximab era. A prospective trial on the basis of these results should be pursued to confirm these observations and to determine whether the impact of rituximab on the patterns of relapse and outcome parallels that of DLBCL presenting at other sites.
    • A qualitative exploration of a respiratory distress symptom cluster in lung cancer: cough, breathlessness and fatigue.

      Molassiotis, A; Lowe, M; Blackhall, Fiona H; Lorigan, Paul C; School of Nursing, Midwifery & Social Work, University of Manchester, University Place, Manchester M13 9PL, UK. alex.molassiotis@manchester.ac.uk (2011-01)
      There is a growing awareness that symptoms frequently co-occur in 'symptom clusters' and that understanding these clusters may improve the management of unrelieved symptoms in patients. In-depth longitudinal exploration of lung cancer patients' symptom experiences is used to examine patient symptom experiences and distress across the disease trajectory of lung cancer.
    • Randomised phase II trial of 4 dose levels of single agent docetaxel in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): DOC PS2 trial. Manchester lung cancer group.

      Califano, Raffaele; Griffiths, Richard W; Lorigan, Paul C; Ashcroft, Linda; Taylor, Paul; Burt, Paul A; Lee, Lip W; Chittalia, Abbas; Harris, Maggie A; Faivre-Finn, Corinne; et al. (2011-09)
      The role of chemotherapy for advanced NSCLC patients and ECOG PS2 remains controversial. We evaluated 4 doses of 3-weekly docetaxel to identify a less toxic, clinically effective dose.
    • 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.
    • Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study.

      Crinò, Lucio; Dansin, Eric; Garrido, Pilar; Griesinger, Frank; Laskin, Janessa; Pavlakis, Nick; Stroiakovski, Daniel; Thatcher, Nick; Tsai, Chun-Ming; Wu, Yi-long; et al. (2010-08)
      BACKGROUND: Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous non-small-cell lung cancer (NSCLC). The SAiL (MO19390) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice. METHODS: Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB-IV); an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7.5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00451906. FINDINGS: At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade > or = 3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients [1%]). Bevacizumab was temporarily interrupted after 28 (2%) of 1347 bleeding events and 72 (7%) of 1025 hypertension events, and permanently discontinued after 110 (8%) bleeding events and 40 (4%) hypertension events. No new safety signals were reported. INTERPRETATION: Our results confirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC. FUNDING: F Hoffmann-La Roche Ltd.