No abstract

Angiogenesis is essential for tumor growth and metastasis. It is controlled by multiple factors, one of the most important being vascular endothelial growth factor (VEGF). VEGF and p53 expression were evaluated in 16 hyperplastic polyps, 35 solitary tubular and tubulovillous adenomas, and 47 cases of sporadic colorectal carcinomas arising on the basis of preexisting adenomas, using immunohistochemistry. In parallel, angiogenesis was assessed by the Chalkley score (CS) method. VEGF positivity was detected in 19/47 carcinoma cases (40%). In the respective adenomatous part of the tumor, VEGF positivity was detected in 11/47 cases (23%). Carcinomas arising from VEGF-positive adenomas were mostly VEGF positive (10/11, 91%), whereas in 28/36 (78%) carcinomas arising from VEGF-negative adenomas VEGF expression was not detected. CS was higher in VEGF-positive compared with VEGF-negative carcinomas (9.1 +/- 1.8 and 7.8 +/- 2.3, respectively, p < 0.05), whereas there was no statistically significant difference between the CS in the VEGF-negative and VEGF-positive adenomatous part of the tumor (3.3 +/- 1.8 and 4.3 +/- 2.3, respectively). Nuclear p53 positivity was detected in 26/47 (55%) cases in the cancerous part and in 14/47 (29%) cases in the adenomatous part of the tissue, and no significant correlation with VEGF expression was observed. We conclude that VEGF associates with angiogenesis in colorectal cancer, and its pattern of expression in adenomas is maintained in the arising carcinomas. Further investigation is warranted to clarify whether these findings could be used as indicators of prognosis in screening programs or in patients with limited stage disease where the usefulness of adjuvant therapies with either cytotoxic drugs or inhibitors of angiogenesis is still unclear.

Objective: Pegylated liposomal doxorubicin (PLD) and capecitabine (CAP) have separately shown significant antitumor activity in a wide range of solid tumors. A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of their combination in patients with refractory solid tumors. Patients and Methods: Fifteen patients with histologically confirmed inoperable solid neoplasms were enrolled. The patients’ median age was 65 years, 10 were male, and 12 had a performance status score (WHO) of 0–1. PLD was administered on day 1 as a 1-hour intravenous infusion at escalated doses ranging from 35 to 40 mg/m². CAP was administered on days 1–14 per os, at escalated doses ranging from 1,600 to 1,800 mg/m², given as two daily divided doses. Treatment was repeated every 3 weeks. Results: At the dose of PLD 40 mg/m² and CAP 1,800 mg/m², all 3 enrolled patients presented DLTs [2 patients grade 3 palmar-plantar erythrodysesthesia (PPE) and 1 patient grade 3 asthenia] and thus, the recommended MTD for future phase II studies is PLD 40 mg/m² and CAP 1,700 mg/m². A total of 57 treatment cycles were administered. Grade 2/3 neutropenia complicated 9 (17%) cycles and 1 patient was hospitalized for febrile neutropenia. There was no septic death. The main nonhematologic toxicity was PPE grade 2 in 3 (19%) patients and grade 3 in 4 (27%). PPE was the reason of treatment interruption for 3 patients. Other toxicities were mild and easily manageable. Two patients (16%) with partial response suffering from gastric cancer and 5 patients with (42%) stable disease were observed among 12 evaluable patients. Conclusions: The results of this phase I study demonstrate that PLD and CAP can be combined at clinically effective and relevant doses. However, PPE is a common side effect and further investigation is warranted to define its precise role in the treatment of solid malignancies.