• Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study.

      Colleoni, Marco; Giobbie-Hurder, Anita; Regan, Meredith M; Thürlimann, Beat; Mouridsen, Henning; Mauriac, Louis; Forbes, John F; Paridaens, Robert; Láng, István; Smith, Ian; et al. (2011-03-20)
      Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy.
    • Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial.

      Rustin, G; Van der Burg, M; Griffin, C; Guthrie, D; Lamont, A; Jayson, Gordon C; Kristensen, G; Mediola, C; Coens, C; Qian, W; et al. (2010-10-02)
      BACKGROUND: Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. METHODS: Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. FINDINGS: 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4-81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80-1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0-27·9) for patients on early treatment and 27·1 months (22·8-30·9) for those on delayed treatment. INTERPRETATION: Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. FUNDING: UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.
    • First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial.

      Hagenbeek, Anton; Gadeberg, Ole; Johnson, Peter W; Pedersen, Lars Møller; Walewski, Jan; Hellmann, Andrzej; Link, Brian K; Robak, Tadeusz; Wojtukiewicz, Marek; Pfreundschuh, Michael; et al. (2008-06-15)
      Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.
    • Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma.

      Clamp, Andrew R; Ryder, W David J; Bhattacharya, Soumo; Pettengell, Ruth; Radford, John A; Department of Medical Oncology, Cancer Research UK, University of Manchester, Christie Hospital, Wilmslow Rd., Manchester M20 4BX, UK. Andrew.clamp@christie.nhs.uk (2008-07-22)
      The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.
    • Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1.

      Danson, Sarah; Johnson, P; Ward, Timothy H; Dawson, M; Denneny, Olive; Dickinson, G; Aarons, Leon; Watson, A; Jowle, Debra; Cummings, Jeffrey; et al. (2011-07)
      This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours.
    • 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
    • Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer.

      Rosell, Rafael; Robinet, G; Szczesna, A; Ramlau, R; Constenla, M; Mennecier, B C; Pfeifer, W; O'Byrne, Kenneth J; Welte, T; Kolb, R; et al. (2008-02)
      BACKGROUND: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. PATIENTS AND METHODS: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m(2), day 1) and vinorelbine (25 mg/m(2) on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m(2), followed by 250 mg/m(2) weekly thereafter). RESULTS: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. CONCLUSION: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.
    • 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.
    • 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.
    • Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial.

      Ellis, Paul A; Barrett-Lee, P J; Johnson, Lindsay; Cameron, David; Wardley, Andrew M; O'Reilly, Susan; Verrill, Mark W; Smith, Ian; Yarnold, John; Coleman, Robert E; et al. (2009-05-16)
      BACKGROUND: Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. METHODS: In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. FINDINGS: All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). INTERPRETATION: This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. FUNDING: Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.
    • Use of G-CSF during concurrent chemotherapy and thoracic radiotherapy in patients with limited-stage small-cell lung cancer safety data from a phase II trial.

      Sheikh, Hamid Y; Colaco, Rovel J; Lorigan, Paul C; Blackhall, Fiona H; Califano, Raffaele; Ashcroft, Linda; Taylor, Paul; Thatcher, Nick; Faivre-Finn, Corinne; Dept of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK. (2011-10)
      There is paucity of data in the literature regarding the safety of combining granulocyte colony stimulating factor (G-CSF) during chemo-radiotherapy (CTRT) in lung cancer patients. The ASCO 2006 recommendations advise against use of CSFs during concomitant mediastinal CTRT. The only randomised study evaluating CSFs in this context showed significant increase in grade 3/4 thrombocytopenia and an excess of pulmonary toxic deaths. In the context of a phase II trial, 38 patients with limited-stage small cell lung cancer were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy. Radiotherapy (RT) was given concurrently with cisplatin and etoposide. G-CSF was given as primary or secondary prophylaxis or as a therapeutic measure during an episode of febrile neutropenia according to local protocols. Common terminology criteria for adverse events (CTCAE) v3.0 was used to record toxicity. Thirteen (34%) of 38 patients received G-CSF concurrently with RT. With a median follow-up of 16.9 months, there were no treatment related deaths reported. Seven (54%) patients experienced grade 3/4 thrombocytopenia and 5 (38%) experienced grade 3/4 anaemia. Thirty-one percent required platelet transfusions. No episodes of bleeding were observed. There were no cases of grade 3/4 acute pneumonitis. These data suggests that with modern three-dimensional (3D) conformal RT, G-CSF administration concurrently with CTRT does not result in the increase risk of pulmonary toxicity, but does increase the risk of thrombocytopenia. Whether the risks of thrombocytopenia are outweighed by the outcome of timely early concurrent CTRT is being evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563) in which G-CSF is permitted during thoracic irradiation.
    • YY1 expression predicts favourable outcome in follicular lymphoma.

      Naidoo, Khimara; Clay, V; Hoyland, J A; Swindell, Ric; Linton, Kim M; Illidge, Timothy M; Radford, John A; Byers, RJ; School of Cancer and Enabling Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK. (2011-02)
      Follicular lymphoma is the second most common type of non-Hodgkin's lymphoma worldwide. The majority of patients diagnosed as having follicular lymphoma have an indolent form of the disease, but a subset of patients have aggressive disease with a shorter survival interval. Optimal treatment stratification requires a distinction between these two groups, though there are presently few prognostic biomarkers available. The transcription factor YY1 has been shown to play an important role in cancer biology. The authors have previously reported a correlation of Yin Yang 1 (YY1) mRNA levels with survival in FL. This study aimed to validate these findings at the protein level.