Everolimus as second-line therapy for metastatic renal cell carcinoma: a 'real-life' study.

AIMS: This study, conducted in a 'field-practice' scenario, investigates the effectiveness and safety of everolimus in the second-line treatment of metastatic renal cell carcinoma (mRCC) patients. PATIENTS & METHODS: mRCC patients, who started everolimus 10 mg/day after failure of first-line VEGF receptor-targeted tyrosine kinase inhibitor, were included in this study. Study end points were treatment response, progression-free survival and tolerability. RESULTS: In total, 100 patients were assessed; the median duration of everolimus treatment was 7.1 months (95% CI: 5.7-8.5). A total of 19% of patients experienced a partial response and 62% of patients reached a stable disease. Median progression-free survival was 8 months (95% CI: 6.7-9.3). A total of 75% of patients experienced adverse events; no grade 4 adverse events were reported. CONCLUSION: These findings, obtained in a 'field-practice' scenario, support the use of everolimus for mRCC patients who failed one VEGF receptor-targeted tyrosine kinase inhibitor.

Significance of erb-B2 immunoreactivity in cervical cancer.

C-erbB2 is over-expressed or amplified in many carcinomas. We assessed the relationship between erb-B2 immunoreactivity, and its predictive role in progression-free survival and treatment outcome in patients with cervical carcinoma. Sections from 65 cervical carcinoma were immunostained with antibody to p185 erbB2. Immunoreactive ErbB2 was found in 25 patients (38%) [+ 15 pts. (23%); ++ 10 pts. (15%)]. There were no correlation with age, performance status, grading and histology. Erb-B2 immunoreactivity significantly correlated with stage of the disease. Positive immunoreactivity was found in 63%, 44%, 14% and 0% of stage I, II, III and IV carcinomas, (p = 0.0045). Progression-free survival was longer in erb-B2 positive patients without reaching significance. No correlation was found between erbB2 and response to radiotherapy or chemotherapy. In conclusion, a significant proportion of stage I and II cervical cancer express erb-B2 compared to more advanced stages. Expression of the oncogene does not appear to be related to prognosis or treatment outcome.

Real-time contrast-enhanced specific ultrasound in staging and follow-up of splenic lymphomas.

From January 2003 to April 2005 we studied 25 lymphoma patients (10 with HD, 4 with low-grade NHL, 6 with high-grade NHL and 5 with chronic lymphatic leukaemia; 14 men, 11 women, age range 28-79 years). After a baseline US study we rapidly injected 4.8 mL of the second-generation microbubble contrast agent SonoVue (Bracco, Italy). Contrast enhanced studies were carried out with the contrast-specific software named Contrast Tuned Imaging (Esaote, Italy) using a continuous, harmonic acquisition and a low acoustic pressure. The CS-US findings were correlated with results of standard tools, including CT, MRI, US follow up. CS-US revealed correctly 47 out of the 52 lesions identified by CT scan, in the absence of false positive findings (sensitivity = 90%; Specificity = 100%, in comparison to CT scan). Complete concordance in evaluating the lesion extension of the CS-US in respect to CT was 88%, while underestimate occurred in 9% and overestimate in 3% of cases. On the contrary, basic sonography defined correctly the dimensional alteration in 52% of the cases, underestimated in 35% and overestimated in 13%, thus showing significantly lower accuracy (chi-square = 30.0, p < 0.001). In our experience, CS-US was superior to conventional sonography even from a qualitative point of view.

Phase I/II study of gemcitabine and epirubicine in stage IIIB-IV non small cell lung cancer.

Platinum-based chemotherapy currently represents standard treatment for advanced non-small cell lung cancer (NSCLC). Gemcitabine is one of the most promising agents currently in use in advanced NSCLC. As a single-agent, epirubicin, showed tumour response rates ranging from 17% to 36% in NSCLC. The aim of the present study was to evaluate the combination of gemcitabine and epirubicin in a phase I-II study. Thirty chemotherapy-naive patients with stage III B-IV NSCLC received gemcitabine at a fixed dose of 1000 mg/m2 on days 1 and 8 every 3 weeks; epirubicin was administered every 21 days on day 1 at the initial dose of 80 mg/m2 which was subsequently escalated. Neutropenia was dose-limiting toxicity since it occurred in 3 out of five patients receiving epirubicin at the dose of 110 mg/m2. An objective response was observed in 14/30 patients, including 2 (7%) complete responses and 12 (40%) partial responses. Median duration of response was 12 months (range: 3 to 53 + months). Median overall survival was 16 months (range: 4 to 55 + months). The combination of gemcitabine and epirubicin is well tolerated. While the observed activity of this combinated treatment matches that of platinum-based regimens, the duration of response and survival have been sufficiently promising to initiate a phase II trial which is currently under way.

Stop Flow in abdominal and pelvic cancer relapses.

To determinate MTD, DLT and safe doses for phase II study, a dose finding study with Mitomycin and Adriamycin Stop-Flow administration was carried out. A phase II study focused on resectability of pelvic colorectal relapses is in progress. From November 1995, 84 pts, 52 male and 32 female (94 treatments), with advanced not resectable abdominal (14 pts) or pelvic (70 pts) relapses, and resistant to previous systemic chemotherapy, were enrolled in the study. 46 pts entered the phase I-early phase II study, while subsequently 38 pts were recruited in ongoing phase II study. Safe dose were: MMC 20 mg/mq and ADM 75 mg/mq. The phase II study focused on colorectal relapses registered very promising responses: 90% pain control, 1 pCR and 26 PR / 63 (OR 43%), 8 NC (13%) 9/27 responder patients (33%) obtained a complete resectability of colorectal relapses. Stop-Flow is a safe and feasible technique very useful as a palliation treatment.

The prognostic role of pre-chemotherapy hemoglobin level in patients with ovarian cancer.

Anemia significantly affects quality of life of cancer patients, but the impact of hemoglobin levels on survival is still unclear. The aim of this retrospective study was to assess the prognostic role of pre-chemotherapy hemoglobin levels in patients with ovarian cancer. Two hundred twenty-two patients were divided in 3 groups based on baseline hemoglobin levels (< 10 gr/dl (54 pts., 24%); 10-11.9 gr/dl (87 pts., 39%), > or = 12 gr/dl (82 pts., 37%)). Correlations among baseline characteristics (age, ECOG performance status, stage, grading, histology, residual disease after primary surgery) and baseline hemoglobin level were analyzed. Poor performance status (p = 0.03), more advanced stage (p = 0.01), and sub-optimal residual disease (p = 0.002) were more frequent in patients with lower hemoglobin values. There was no significant correlation between baseline hemoglobin level and response rate to subsequent chemotherapy. Based on univariate analysis, hemoglobin categories were statistically significant predictors for time to progression (p = 0.0002) and overall survival (p < 0.0001). Based on multivariate analysis, patients with hemoglobin between 10 and 12 g/dl had a 1.45 hazard ratio (HR) for recurrence and a 1.35 HR of death compared with patients with normal hemoglobin. Patients with hemoglobin < 10 g/dl had a 2.02 HR of recurrence and a 2.49 HR of death compared with patients with normal hemoglobin. These findings show that hemoglobin level prior to chemotherapy is an independent predictor of progression-free survival and overall survival in patients treated for ovarian carcinoma.

Phase I study of temozolomide and lomustine in the treatment of high grade malignant glioma.

Systematic reviews and meta-analysis have demonstrated an improved prognosis by chemotherapy of malignant glioma patients. The effects of clinical research therefore have the aim to find more active drugs or new combination therapies. The combination of Temozolomide (TMZ) and nitrosoureas was evaluated preclinically with an evidence of therapeutic synergy. Based on these findings, we have carried out a phase I study with TMZ administered in low, prolonged doses of 75 mg/m2 per day, once a day for 21 days, escalated in cohorts of 3 patients, in combination with a fixed dose of Lomustine (CCNU) 100 mg/m2 orally on day 1. MTD was evident. The treatment was generally well tolerated. We did not observe bleeding or severe infections, as described for several combination chemotherapies with TMZ and other agents. In this study, for the first time in high grade malignant glioma, two orally administrated drugs were associated .TMZ 75 mg/m2 for 28 consecutive days and CCNU 100 mg/m2 on day 1 of every 6 weeks could be recommended as a safe treatment dosage. One of the ten patients evaluated for clinical response showed a partial response, while nine showed stability of disease, with a median duration of from 5 to 6 months.

Second-line intra-arterial chemotherapy in advanced pancreatic adenocarcinoma.

The present study was conducted to evaluate activity and toxicity of the FLEC (folinic acid 100 mg/m2; 5-fluorouracil 1000 mg/m2; carboplatin 300 mg/m2; epirubicin 60 mg/m2) schedule as second-line treatment for progressive locally advanced or metastatic pancreatic cancer (LAMPC). FLEC was administered every 3 weeks with an angiographic catheter introduced into the tumor vascular bed. Thirty-two patients were enrolled. Twenty patients had a PS of 2. Twenty-five patients had metastatic disease to liver. Seven (21.9%) partial responses were observed (WHO criteria). Fifteen patients (46.9%) had stable disease and ten patients (31.2%) had progressive disease. The median OS from the diagnosis was 11.8 months. PS (p=0.0308) and pain (WHO scale, p=0.0222; analogic scale, p=0.0446) significantly improved after therapy. No patient discontinued treatment because of toxicity (NCI-CTC criteria). The current study shows that intraarterial chemotherapy is a good therapeutic option in second-line treatment of LAMPC.

Activity of chemotherapy in mucinous epithelial ovarian cancer: a retrospective study.

OBJECTIVE: Mucinous ovarian carcinoma has a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of first-line and second-line chemotherapy in patients with mucinous ovarian cancer in a mono-institutional series. PATIENTS AND METHODS: In the period under survey (1996-2003), 225 new patients with ovarian cancer were treated. Twenty-one out of these patients (9.3%) received a diagnosis of mucinous ovarian cancer. The median age, performance status, stage at diagnosis and residual disease after surgery were similar in the mucinous compared to the other histological groups (P=NS). RESULTS: In mucinous ovarian cancer the grading of the tumors was 2 in 76% of the cases, while grade 3 was more frequent in the other subtypes (p<0.002). Eighty-five % of the patients had received carboplatin/paclitaxel, while the remaining cases had been treated with a cisplatin-based chemotherapy not containing paclitaxel. Two patients with early stage were treated with adjuvant chemotherapy and were not evaluable for response while 19 patients had measurable disease (12 pts) or were assessed at second-look (7 pts). Forty-seven % of the 19 patients experienced disease progression during first-line, while 31.5% and 10.5% complete and partial responses were recorded, respectively. Fifteen out of the 21 patients had progressed at the time of the analyses. Sixty % of the progressed patients were platinum-refractory, 3 cases were platinum-sensitive and 3 platinum-resistant. The 3 platinum-sensitive patients were treated with single agent carboplatin without any response. No response was recorded with topotecan or liposomal doxorubicin when given as second- or third-line treatment in platinum-refractory/resistant patients. CONCLUSION: Mucinous ovarian cancer has a poor response to chemotherapy both in the first-line and in the recurrence settings. Studies with alternative chemotherapy combinations are mandatory in this histological subgroup.

Monoclonal antibodies targeting epidermal growth factor receptor and vascular endothelial growth factor with a focus on head and neck tumors.

PURPOSE OF REVIEW: To provide an overview of recent clinical trials with monoclonal antibodies targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) in head and neck cancer (HNC) and in other tumors. To discuss future therapeutic strategies. RECENT FINDINGS: Cetuximab, a chimeric monoclonal antibody targeting EGFR, has induced improved locoregional control and survival in combination with radiotherapy in a phase III study in locally advanced inoperable HNC. The recent Bowel Oncology with Cetuximab Antibody (BOND) study has shown that the combination of irinotecan and cetuximab yields a better response rate and a longer time to progression with respect to cetuximab monotherapy in irinotecan-refractory metastatic colorectal cancer, pointing to both a cetuximab single-agent activity and a cetuximab potential for reversal of irinotecan resistance. Non-small cell lung cancer and pancreatic cancer represent further areas for cetuximab development. Bevacizumab is a humanized monoclonal antibody that targets VEGF. It is the first antiangiogenic drug to have induced a survival advantage in cancer therapy, within a randomized trial of irinotecan, 5-fluorouracil, leucovorin (IFL) combined with bevacizumab or placebo in metastatic colorectal cancer. The use of bevacizumab in HNC is supported by preclinical evidence of an angiogenic loop; a few clinical trials are exploring the feasibility and the therapeutic potential of a combination of bevacizumab and EGFR-targeted drugs. SUMMARY: Monoclonal antibodies targeting EGFR and VEGF represent exciting therapeutic strategies that should be further evaluated both in combination with drugs acting on the same target at a different level and in combination with other antisignaling agents acting on different pathways.