• 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer.

      Stahel, R; Thatcher, Nick; Früh, M; Le Péchoux, C; Postmus, P E; Sorensen, J B; Felip, E; Faivre-Finn, Corinne; Blackhall, Fiona H; Department of Oncology, University Hospital Zurich, Zurich, Switzerland. (2011-09)
      The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference, the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through discussion at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement in SCLC is reported in this article. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update.
    • Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine.

      Dangoor, A; Lorigan, Paul C; Keilholz, U; Schadendorf, D; Harris, A; Ottensmeier, C; Smyth, J; Hoffmann, K; Anderson, R; Cripps, M; et al. (2010-06)
      BACKGROUND: Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens. METHODS: Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-gamma ELISPOT assays. Safety and clinical responses were monitored. RESULTS: Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions. CONCLUSIONS: DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation.
    • 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.
    • A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection.

      Wong, R; Cunningham, D; Barbachano, Y; Saffery, C; Valle, Juan W; Hickish, T; Mudan, S; Brown, G; Khan, A; Wotherspoon, A; et al. (2011-09)
      Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection.
    • A phase 2 study of SP1049C, doxorubicin in P-glycoprotein-targeting pluronics, in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction.

      Valle, Juan W; Armstrong, Anne C; Newman, C; Alakhov, V; Pietrzynski, G; Brewer, Julie; Campbell, S; Corrie, P; Rowinsky, E K; Ranson, Malcolm R; et al. (2011-10)
      To evaluate the antitumor activity of SP1049C, a novel P-glycoprotein targeting micellar formulation of doxorubicin, consisting of doxorubicin and two non-ionic block copolymers (pluronics), in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). Patients and
    • Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

      Eisen, Tim; Thatcher, Nick; Leyvraz, Serge; Miller, Wilson H; Couture, Felix; Lorigan, Paul C; Lüthi, François; Small, David; Tanovic, Adnan; O'Brien, M; et al. (2009-04)
      OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n = 13) or limited-stage disease (n = 7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.
    • 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
    • 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.
    • 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 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.
    • Systemic treatment for advanced (stage IIIb/IV) non-small cell lung cancer: more treatment options; more things to consider. Conclusion.

      Bunn, Paul A; Thatcher, Nick; University of Colorado Cancer Center, Aurora, Colorado, USA. (2008)
      Chemotherapy for non-small cell lung cancer (NSCLC) can prolong survival and improve quality of life, but the majority of advanced stage patients succumb to disease within 2 years, meaning that there is room for improvement. The standard chemotherapy for NSCLC involves one of a number of chemotherapy doublets that have been shown to improve survival when compared with single agents or best supportive care. These doublets are generally comparable in terms of efficacy, differing primarily in their toxicity profiles. However, encouraging new options may be approaching, including therapies targeted to specific patient subpopulations, and the use of combinations of current and new drugs to produce synergistic effects. Targeted therapies include the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, EGFR monoclonal antibody cetuximab, and vascular endothelial growth factor (VEGF) inhibitors such as sorafenib, a small molecule TKI, and bevacizumab, a recombinant monoclonal VEGF antibody. Most attempts to combine EGFR-targeted therapies with standard chemotherapy in NSCLC have produced poor results, possibly as a result of antagonism between EGFR TKIs and chemotherapy. Positive results with bevacizumab suggest that VEGF-rather than EGFR-targeted therapies may produce better results when combined with chemotherapy. Other new drugs being tested include enzastaurin, an oral serine threonine kinase inhibitor; vinflunine, a vinca alkaloid; dihydrofolate reductase inhibitors; and thymidylate synthase inhibitors. Combinations of therapies, especially those acting via different mechanisms, hold promise for improvements in survival, but careful testing is required to determine optimum combinations of available drugs and where new drugs fit into the armamentarium.
    • Systemic treatment for advanced (stage IIIb/IV) non-small cell lung cancer: more treatment options; more things to consider. Introduction.

      Bunn, Paul A; Thatcher, Nick; University of Colorado Cancer Center, Aurora, Colorado, USA. (2008)
      Lung cancer is the most common cancer and a highly lethal disease, with improvements in survival rates being dependent on advances in early detection and improved systemic therapies applied to surgery and/or irradiation in early-stage disease. Non-small cell lung cancer (NSCLC) represents around 80% of all lung cancers, and unfortunately at diagnosis most patients have advanced unresectable disease with a very poor prognosis. Indeed, 30%-40% of patients treated with first-line therapy will subsequently be candidates for second-line treatment. Current U.S. Food and Drug Administration-approved second-line treatments are docetaxel (a taxane), pemetrexed (a folate antimetabolite), and erlotinib (an epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]). Gefitinib, another EGFR TKI, currently has only limited use in North America and is not available in Europe. These and other new molecular-target-specific agents may have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Overexpression of EGFR is reported to occur in 40%-80% of NSCLC cases, and EGFR mutations are associated with a significantly higher response rate and longer duration of response following treatment with EGFR TKIs. Another option is antiangiogenesis: the growth and persistence of solid tumors and their metastases are angiogenesis dependent, and so antiangiogenic therapies have been developed, such as the use of TKIs that block the vascular endothelial growth factor receptor. In fact, many commonly used chemotherapeutic drugs have antiangiogenic activity. Ongoing studies are focusing on patient selection and targeted therapies, and there are many new agents undergoing clinical trials.
    • 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.