Capecitabine in combination with oxaliplatin and bevacizumab (AXELOX) as 1st line treatment for fit and vulnerable elderly patients (aged >70 years) with metastatic colorectal cancer (mCRC): a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

BACKGROUND: Colorectal cancer (CRC) is a disease of the elderly. However, geriatric patients are often excluded from clinical trials. The combination of capecitabine, oxaliplatin and bevacizumab (XELOX/BEV) has not been assessed in an elderly population. METHODS: We conducted a phase II study of XELOX plus bevacizumab combination as first line treatment in elderly patients with metastatic CRC. Treatment consisted of capecitabine 750 mg/m2 twice a day during days 1-7, oxaliplatin 85 mg/m2 and bevacizumab 5 mg/kg on day 1. Treatment was repeated every 14 days. The primary endpoint was overall response rate. RESULTS: In the 48 enrolled patients response rate according was 46.8% (95% CI: 32.54%-61.07%), while 13 patients had stable disease, for an overall disease control rate of 74.4% (95% CI: 57.8-91.2). Progression free survival was 7.9 months (95% CI: 5.9-9.8 months) and the median overall survival 20.1 months (95% CI: 15.6-25.7 months). Response rate and progression free survival has been correlated with baseline albumin and haemoglobin levels. There was one treatment-related death. Grade 3-4 toxicities were asthenia (4.2%), neurotoxicity (2.1%) and diarrhea 6.3%). CONCLUSIONS: The combination of capecitabine, oxaliplatin and bevacizumab is an effective and safe combination for the treatment of elderly patients with metastatic CRC. TRIAL REGISTRATION: Clinical trials NCT01024504, 26 November 2010.

Pooled analysis of elderly patients with non-small cell lung cancer treated with front line docetaxel/gemcitabine regimen: the Hellenic Oncology Research Group experience.

INTRODUCTION: Thirty to 40% of patients with non-small cell lung cancer (NSCLC) are older than 70 years and rarely are enrolled in clinical trials. Moreover, in clinical practice, > 75% of patients older than 65 years with metastatic NSCLC never receive any kind of chemotherapy. PURPOSE: To retrospectively evaluate the impact of age on efficacy and toxicity of chemotherapy regimens in patients with advanced NSCLC treated with the docetaxel-gemcitabine combination. PATIENTS AND METHODS: Pooled data from six clinical trials of the Hellenic Oncology Research Group were analyzed. According to their age, patients were divided into two groups: those with age < 70 years and those with > or = 70 years. RESULTS: A total of 858 patients were included in this analysis. Six hundred sixty-six (77.6%) patients were younger than 70 years, whereas 192 (22.4%) patients where > or = 70-year-old. Overall response rate was 30.3% and 30.2% for patients < 70 years and > or = 70 years, respectively (p = 0.974). The median time to tumor progression was 4.1 and 4.5 months for patients < 70 years and > or = 70 years, respectively (p = 0.948). Median overall survival was 9.9 and 9.2 months for patients < 70 and > or = 70, respectively (p = 0.117). The multivariate analysis revealed performance status (PS) (p = 0.0001) and stage (p = 0.0001) as independent factors with significant impact on the hazard of death. Chemotherapy was well tolerated, but the incidence of grade III/IV mucositis was significantly higher in elderly patients (0.2% versus 1.5% for patients < 70 versus > or = 70 years, respectively; p = 0.011). CONCLUSION: The docetaxel/gemcitabine regimen has a comparable efficacy and tolerance in young (< 70 years) and elderly (> or = 70 years) patients.

VEGF expression in the colorectal adenoma-carcinoma sequence.

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.

Assessment of highly angiogenic and disseminated in the peripheral blood disease in breast cancer patients predicts for resistance to adjuvant chemotherapy and early relapse.

The assessment of tumor molecular features in combination with the detection of occult malignant cells may provide important clinical information, beyond the standard staging of breast cancer. Using a nested RT-PCR technique, we assessed prospectively the presence of cytokeratin-19 (CK19) mRNA positive cells in the blood of 100 operated patients with breast cancer before the initiation of adjuvant chemotherapy and local radiotherapy. Tissue samples were prospectively collected and analyzed for estrogen (ER) and progesterone (PgR) receptor, c-erbB-2 overexpression, mutant-p53 and bcl-2 protein accumulation, proliferation index and microvessel density (MVD). CK-19 mRNA-positive cells were detected in the peripheral blood of 33% of patients. Simultaneous display of high intratumoral MVD and of CK-19 mRNA-positive cells, which characterized highly angiogenic and disseminated in the peripheral blood (HAD) disease was noted in 25% of patients. Detection of CK-19 positive cells was significantly associated with increased MVD (p = 0.002). In univariate analysis (median follow-up 30 months) CK19 mRNA detection and MVD were the most significant factors related to a short relapse-free survival (RFS), (p < 0.0001). In multivariate analysis, CK19 positivity, high MVD and c-erbB-2 overexpression were the only significant and independent variables associated with relapse (p = 0.0005, 0.03 and 0.04, respectively). Patients with HAD had an expected relapse rate close to 70% vs. <5% in the remaining patients irrespectively of the used chemotherapy regimen. The simultaneous presence of high MVD and CK19-positive cells in the blood of patients with early breast is linked with poor prognosis, which cannot be improved with standard chemotherapy regimens.

Hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC): a short, safe, and effective postoperative regimen for high-risk breast cancer patients.

PURPOSE: Although the role of radiotherapy (RT) after mastectomy in reducing the local relapse rate is well established, its impact on overall survival is strongly questioned. Up to 70% of patients will not benefit from additional RT, and a "wait and see" policy is often adopted. Establishment of short, still safe, and effective RT regimens would render adjunctive radiotherapy more appealing. We evaluated the toxicity and efficacy of a Hypofractionated and intensively Accelerated RT regimen supported with amifostine Cytoprotection (HypoARC) in a cohort of 72 high-risk breast cancer patients treated with modified mastectomy or conservative surgery and FEC (5-fluorouracil/epirubicin/cyclophosphamide) chemotherapy. PATIENTS AND METHODS: A high dose of amifostine, 1,000 mg, was given as a 5-min i.v. infusion before each of the 12 consecutive fractions of RT (4 x 3.5 Gy/fraction and 8 x 4 Gy/fraction, 1 fraction/day, 5 fractions/week). The breast or chest wall, as well as supraclavicular and axillary area, was included in the RT fields. The follow-up of patients ranged from 18 to 42 months (median, 28 months). Alkaline phosphatase (AF) expression was assessed immunohistochemically in normal and cancerous breast tissues. RESULTS: Ninety-two percent of patients successfully completed the regimen, the only side effects being mild nausea and asthenia. In 7% of patients, amifostine was interrupted because of a rash/fever reaction. A dramatic reduction in acute skin toxicity was noted (p < 0.0001). Acute pneumonitis, as well as late toxicity in breast, chest wall, axillary, and lung tissue, was lower with the HypoARC regimen, although not significantly, than with the standard fractionation regimen used to treat two matched control cohorts. Both HypoARC and standard RT significantly reduce the local relapse rate (p < 0.0001), although the local relapse-free and overall survival times were marginally better for the HypoARC group of patients (p > 0.09). AF showed a mixed nuclear/cytoplasmic pattern of expression in the epithelial, endothelial, and stromal component of the normal breast and benign lesions, whereas an impressive loss of AF expression was noted in in situ and invasive breast cancer and tumoral stroma. CONCLUSIONS: The HypoARC regimen is convenient for both patients and radiotherapy departments. The regimen is well tolerated and shows a significantly better profile in terms of early toxicity; a reduced rate of late sequel may be expected. The local relapse rate is as low as that expected from conventional RT. The absence of AF expression in cancer cells and tumoral stroma is probably a major reason for the selective protection of normal breast tissue by amifostine.

A multicenter phase II study of docetaxel and carboplatin combination as front-line treatment in advanced non-small cell lung cancer.

BACKGROUND: To evaluate the efficacy and safety of docetaxel in combination with carboplatin as first-line treatment of patients with inoperable, locally advanced or metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB and IV NSCLC, age < 75 years, performance status (WHO) 0-2, were enrolled onto the study. Docetaxel was given at a dose of 100 mg/m2 over an 1-hour i.v. infusion. Carboplatin dosed to an area under the time-concentration curve (AUC) of 6 mg/ml.minute, using the Calvert's formula, was administered over a 30-minute i.v. infusion. The regimen was repeated every 3 weeks. RESULTS: Thirty-eight patients received a total of 155 chemotherapy cycles (median 4 cycles/patient). All patients were assessable for toxicity and 34 for response. There was one (2.6%) complete and nine (23.7%) partial responses; in an intention-to-treat analysis the overall response rate was 26.6% (95% CI: 12.3%-40.3%). The median duration of response was 7 months (range: 3-29), the median time to tumor progression 7 months (range: 3.5-31), and the median overall survival 9 months (range: 0.5-31.5). The probability for 1-year survival was 44%. Grade 3-4 neutropenia was the main hematological toxicity of the regimen occurring in 19 (50%) patients. Four (10.5%) neutropenic episodes were complicated with fever but there was no septic death. Non-hematological toxicity was generally mild. CONCLUSION: These results indicate that the docetaxel-carboplatin combination is a relatively active and well-tolerated front-line regimen for the treatment of patients with advanced or metastatic NSCLC.