Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial.

BACKGROUND: Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid AN d TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. RESULTS: The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. PATIENTS AND METHODS: Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50 mg/m(2)) in combination with a fixed dose of ZOL (2 mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. CONCLUSIONS: The bi-weekly combination of DTX (50 mg/m(2)) followed by ZOL was feasible and show promising anti-tumor activity.

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.

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.

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.

Single agent vinorelbine as first-line chemotherapy in elderly patients with advanced breast cancer.

BACKGROUND: Breast cancer arises in about 48% of patients (pts) older than 65 years. Chemotherapy is administered to elderly pts with advanced breast cancer (ABC) resistant to hormonal treatment or with visceral metastases. Vinorelbine (VNR), a semisynthetic vinca alkaloid, is active and well-tolerated in ABC reporting, as a single agent, an objective response (OR) rate of 41%-60%. The ELVIS (Elderly Lung cancer Vinorelbine Italian Study) trial demonstrated the tolerability and efficacy of VNR in elderly pts with advanced non-small cell lung cancer (JNCI 91: 66-72, 1999). MATERIALS AND METHODS: From January 1999 to December 2000, we analysed, retrospectively, our data about single-agent VNR as a first-line chemotherapy in elderly pts (> or = 70 years) with ABC. Twenty-four pts were analysed. VNR was administered at the dose of 30 mg/m2, i.v., days 1 and 8, every 3 weeks for a maximum of 6 cycles. RESULTS: The main toxicity was (% of pts): grade (G) 3-4 neutropenia 25%; G 2 thrombocytopenia 4.1%; G 2 asthenia 25%; G 2-3 constipation 16.6%; and G 1 neurotoxicity 25%. No cycles of chemotherapy were omitted or postponed. Granulocyte colony-stimulating factor was administered in 12.5% of a total of 112 cycles. Nine (37.5%) objective responses (2 complete and 7 partial responses) were observed. The median duration of response and survival were 7 and 11 months, respectively. CONCLUSION: These results suggest that single agent VNR is active and well-tolerated in elderly pts with ABC. Further prospective trials are warranted.