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Background The DREAMtherapy (Dual REctal Angiogenesis MEK inhibition radiotherapy) trial is a novel intertwined design whereby two tyrosine kinase inhibitors (cediranib and selumetinib) were independently evaluated with rectal chemoradiotherapy (CRT) in an efficient manner to limit the extended follow-up period often required for radiotherapy studies. Patients and methods Cediranib or selumetinib was commenced 10 days before and then continued with RT (45 Gy/25#/5 wks) and capecitabine (825 mg/m2 twice a day (BID)). When three patients in the cediranib 15-mg once daily (OD) cohort were in the surveillance period, recruitment to the selumetinib cohort commenced. This alternating schedule was followed throughout. Three cediranib (15, 20 and 30 mg OD) and two selumetinib cohorts (50 and 75 mg BID) were planned. Circulating and imaging biomarkers of inflammation/angiogenesis were evaluated. Results In case of cediranib, dose-limiting diarrhoea, fatigue and skin reactions were seen in the 30-mg OD cohort, and therefore, 20 mg OD was defined as the maximum tolerated dose. Forty-one percent patients achieved a clinical or pathological complete response (7/17), and 53% (9/17) had an excellent clinical or pathological response (ECPR). Significantly lower level of pre-treatment plasma tumour necrosis factor alpha (TNFα) was found in patients who had an ECPR. In case of selumetinib, the 50-mg BID cohort was poorly tolerated (fatigue and diarrhoea); a reduced dose cohort of 75-mg OD was opened which was also poorly tolerated, and further recruitment was abandoned. Of the 12 patients treated, two attained an ECPR (17%). Conclusions This novel intertwined trial design is an effective way to independently investigate multiple agents with radiotherapy. The combination of cediranib with CRT was well tolerated with encouraging efficacy. TNFα emerged as a potential predictive biomarker of response and warrants further evaluation.

There are conflicting associations between growth factor expression and clinicopathological variables in colorectal cancer. This study aimed to define the expression of members of the VEGF family and the receptor, VEGFR2, in primary and metastatic sites of colorectal cancer and their relationship to metastatic potential. Thirty colorectal cancers, 12 lymph node metastases and 9 liver metastases were immunostained for VEGF-A, VEGF-C, VEGF-D and VEGFR2. VEGFR2 was expressed by endothelial cells and by the malignant epithelium. VEGF-C and VEGFR2 were co-expressed in the same territory and correlated throughout the primary tumour and in metastatic lymph nodes, but not in liver metastases. Their expression at the invasive tumour edge correlated with expression in metastatic nodes. The benefit of anti-VEGF antibodies might be increased by directing additional therapies against VEGF-C or against the kinase receptors to target redundancy in the system. A component of the therapeutic benefit might be due to a direct anti-tumour effect as well as an anti-angiogenic effect.

We assessed the tolerability, safety, pharmacokinetics and dose-limiting toxicity (DLT) of the recombinant humanized IgG4 anti-vascular endothelial growth factor (VEGF) monoclonal antibody, HuMV833, in patients with advanced cancer. Cohorts of patients with progressive solid tumours received escalating doses of HuMV833 as a 1-h intravenous (I.V.) infusion on days 1, 15, 22, and 29. Twenty patients (median Eastern Cooperative Oncology Group (ECOG) score 1) were accrued. HuMV833 infusions were well tolerated and there were no grade III or IV toxicities definitely related to the antibody. Grade I or II toxicities probably related to the antibody included fatigue, dyspnoea and rash. There were two episodes of asymptomatic hypocalcaemia, one at grade III and one grade IV, which were recorded in early follow-up. There were eight grade I episodes of asymptomatic elevation of activated partial thromboplastin time (APTT) and two grade III events; one in a patient receiving 1 mg/kg and the other receiving extended doses of 10 mg/kg. Pharmacokinetic analysis revealed a non-linear kinetic and an elimination half-life of between 8.2 (0.3 mg/kg) and 18.7 (10 mg/kg) days. One patient with ovarian cancer experienced a partial response (PR) of 9 months duration and eight had disease stabilisation (SD) including one patient with colorectal carcinoma whose disease was stable for 14 months. In 13 of the 14 samples taken from 12 patients, the plasma concentration of hepatocyte growth factor (HGF) was reduced 24 h after drug administration. HuMV833 is safe and lacked DLT at doses up to 10 mg/kg on this schedule. Multiple doses were well tolerated, despite occasional asymptomatic elevations in APTT. By combining pharmacokinetic, pharmacodynamic and toxicity data, we can identify doses of 1 and 3mg/kg for further investigation. HuMV833 appears to possess some clinical activity.

Early drug development at EORTC has always been subject to structural changes to adapt to the rapid changes that occur in oncological drug development. The expertise of early drug developers has always been cross-fertilised with disease-/tumour-oriented groups and also backwards to the laboratory research groups. This results in the establishment of a solid and dedicated network of medical oncologists with focused expertise in cancer drug development. The EORTC Data Center is fully equipped with all expertise to support clinical research activities and includes regulatory, safety, and quality assurance desks. The EORTC New Drug development Programme (NDDP) provides methodological expertise to early clinical trials and coordinates phase I and phase II studies addressing various approaches. Through NDDP, the early clinical groups and the disease-/tumour-oriented groups have created specific networks to address early drug development in specific tumour types. This results in very efficient networks which have the resources and the patients to address and conduct challenging clinical trials in a standardised fashion ensuring the highest standards in cancer treatment.

We conducted a retrospective immunohistochemical evaluation of the prognostic significance of the expression of p53 and the related proteins Bax, Bcl-2, growth arrest and DNA damage (Gadd45), murine double minute 2 (Mdm2) and p21(WAF1/CIP1) in chemonaive tumours taken from 66 patients with ovarian cancer. Ki-67 expression (a marker of cell proliferation) was also evaluated immunohistochemically, while apoptosis within malignant cells was determined with the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) assay. The expression of each of the following proteins was significantly associated in the tumours (P < 0.05 unless otherwise stated): Bax with Bcl-2 (P < 0.01); Bax with Mdm2; p21(WAF1/CIP1) with Gadd45 (P < 0.01); p21(WAF1/CIP1) with p53; p53 with Mdm2. Univariate analysis showed that expression of p53, Bax, bulk residual disease and International Federation of Gynecology and Obstetricians (FIGO) stage were all strongly correlated with response to chemotherapy (P < 0.01). Similarly, the FIGO stage and Ki-67 expression (P < 0.01), as well as pathological subtype and bulk residual disease (P < 0.05), were prognostic factors for disease progression. The FIGO stage and Ki-67 expression were significant prognostic factors for overall survival (P < 0.01), with Gadd45 expression and pathological subtype also significant (P < 0.05) in a univariate analysis. Multivariate analysis for response to chemotherapy showed that expression of p53, Bax and FIGO stage were all independent prognostic factors (P < 0.01). The FIGO stage was the most important independent prognostic factor for progression and survival on multivariate analysis (P < 0.01). However, Ki-67 expression was also an independent prognostic factor for disease progression (P < 0.05) and approached significance for survival (P = 0.055). Taken together, these data suggest that determination of Ki-67 expression could supplement established prognostic factors.