Dual inhibition of epidermal growth factor and insulin-like 1 growth factor receptors reduce intestinal adenoma burden in the Apc(min/+) mouse.

BACKGROUND: Identification of early molecular pathway changes may be useful as biomarkers for tumour response/resistance prediction, and here we provide direct in vivo proof of this concept. The type 1 insulin-like growth factor receptor (IGF1R) has been implicated in various aspects of adenoma development and metastasis. We show here that, in murine intestinal adenomas acutely exposed to a small molecular inhibitor of EGFR (gefitinib), there is concurrent suppression of EGFR downstream signalling and induction of IGF signalling. We therefore tested the hypothesis that blockade of EGFR signalling was being tempered by compensatory activation of the IGF pathway by examining the effect of chronic suppression of IGF1R using AZ12253801, a small molecular tyrosine kinase inhibitor of IGF1R. METHODS: Male Apc(min/+) mice with an intestinal tumour burden were exposed to a single dose of an inhibitor against EGFR (gefitinib), IGF1R (AZ12253801), 0.5% Tween 80 or combined EGFR/IGF1R inhibitor and culled 4 h post dosing. Tumour tissue was analysed to detect the early molecular pathways induced and anti-tumour phenotypic changes. Cohorts of male Apc(min/+) mice (n=15-17) were subsequently treated with gefitinib for a period of 8 weeks and subsequently exposed to single (either gefitinib or AZ12253801) or combined (gefitinib and AZ12253801) therapy. We also included a vehicle-treated cohort, which was never exposed to gefitinib and became symptomatic of the disease by day 150. RESULTS: Both single treatments delayed the onset of disease symptoms. Combined dosing with gefitinib and AZ12253801 similarly delayed the onset of symptoms, and at 200 days suppressed small intestinal tumourigenesis more effectively than either treatment alone (median small intestinal adenoma volume (47 mm(3) (comb) vs 248 mm(3) (AZ12253801), P=0.0003 and 47 mm(3) (comb) vs 123 mm(3) (gefitinib), P=0.0042, Mann-Whitney (two-sided) test). CONCLUSION: Our data provide evidence in support of the use of combinatorial therapy, and establishes the need to further define the precise benefit in vivo.

A clinical review of the investigation and management of carcinoma of unknown primary in a single cancer network.

AIMS: Carcinoma of unknown primary (CUP) is a common encounter in oncological practice and represents 2.0-6.0% of all invasive malignancies. Evidence to support particular therapeutic strategies in this patient population is scarce, and empirical therapies are frequently derived from research on patients where the primary tumour site is known. MATERIALS AND METHODS: This retrospective study reviewed the management of all patients recorded to have a diagnosis of CUP in a single cancer centre over a period of 12 months. Health records were reviewed documenting the CUP subtype, the investigations carried out both in the referring cancer unit and subsequently at the cancer centre and the recommended treatment (type and regimen), together with survival. The outcomes were examined in respect to a number of prognostic factors. Statistical tests were considered significant at P < 0.05. RESULTS: One hundred and sixty-six patients were recorded to have a diagnosis of CUP, representing 3.7% of all referrals to the cancer centre. The median age of patients was 68 years (range 32-94 years), and 52.0% were women. The three most common CUP subgroups were CUP-liver/multiple sites (25.0%), CUP-bone (21.0%) and CUP-brain (16.0%). The remaining subgroups occurred at frequencies of less than 10% each. Histological confirmation was only obtained in 55.0% of cases. Even within a single subtype, 41 patients with CUP-liver/multiple sites underwent a total of 19 different investigations before any treatment being given. Forty-seven (28.0%) patients received radiotherapy, 30 (18.0%) received chemotherapy and 58 (35.0%) received supportive care alone. Nine different 5-fluorouracil-containing regimens were used in 11 patients treated with chemotherapy for CUP-liver. The overall median survival for all patients was 4.0 months. Survival was better in patients with a good performance status (0-1) and absent liver metastases (median survival 15.0 months; 95% confidence interval 8.0-22.1) and those who received chemotherapy (median survival 13.0 months; 95% confidence interval 7.4-18.6). Multivariate analysis confirmed female gender (P = 0.006), a good performance status (0/1) (P < 0.0001) and absent liver metastases (P = 0.002) as favourable prognostic indicators. CONCLUSIONS: The appropriate management of patients with CUP is unclear and this study revealed a high degree of variation in clinical practice. This area is in urgent need of clinical research to ensure that the treatment of CUP is evidence based. Until such time, clinical recommendations are suggested for the investigation and treatment of such patients. Therapeutic progress will be facilitated by designating a clinical lead for CUP in each clinical network.