N. Gebbia

Treatment of advanced adenocarcinomas of the exocrine pancreas and the gallbladder with 5‐fluorouracil, high dose levofolinic acid and oral hydroxyurea on a weekly schedule: Results of a multicenter study of the Southern Italy Oncology Group (G.O.I.M.)

To date there is no established chemotherapeutic treatment for patients with unresectable locally advanced and/or metastatic carcinomas of the exocrine pancreas or the gallbladder. A multicenter Phase II trial has been performed by the Southern Italy Oncology Group with the aim of evaluating the clinical effectiveness and tolerability of weekly 5‐fluorouracil (5‐FU) in modulation with intravenous (i.v.) high dose levofolinic acid and oral hydroxyurea.

5-Fluorouracil and folinic acid with or without CPT-11 in advanced colorectal cancer patients: A multicenter randomised phase II study of the Southern Italy Oncology Group

PURPOSE The combination regimen CPT-11 plus bolus and infusion 5-fluorouracil (5-FU) with high-dose leucovorin (hybrid regimen LV5FU2) has been tested for activity and toxicity against advanced colorectal carcinoma in a randomised, multicenter phase II trial. PATIENTS AND METHODS A total of 102 chemotherapy-naïve patients were randomised in a 1:2 fashion to receive: leucovorin 100 mg/m2 administered as a two-hour infusion before 5-FU 400 mg/m2 as an intravenous bolus, and FU 600 mg/m2 as a 22-hour infusion immediately after 5-FU bolus injection repeated on days 1 and 2 (LV5FU2 regimen, arm A, 34 patients) or CPT-11 at 180 mg/m2 (150 mg/m2 for patients of age > or = 70 and < 75 years) only on day 1 immediately before LV5FU2 therapy (LV5FU2 + CPT-11 regimen, arm B 68 patients). Both treatments were repeated every two weeks. The presence of a calibration arm assured consistency and more realistic evaluation of results achieved with the LV5FU2 + CTP-II regimen. RESULTS Thirty-three and sixty-four patients were evaluable in arm A and B, respectively. The overall response rate was 18% in arm A (95% CI: 7%-34%) and 40% in arm B (95% CI: 28%-52%). Median time to progression, median duration of response and survival were similar in both groups. Responders (CR + PR) survived statistically longer than non-responders only in arm B (20 vs. 10 months, P = 0.0016). All patients were evaluable for toxicity which was mild in both groups; gastrointestinal disturbances were the most common. There were no treatment-related deaths. Grade 3-4 toxicity was uncommon in both arms. CONCLUSIONS The addition of CPT-11 to the hybrid LV5FU2 regimen provided a significant overall response rate (40%) with relatively mild toxicity. The overall response rate was 18% in patients treated with LV5FU2 alone in the calibration arm. Thus, considering other encouraging data from the literature, the CPT-11 + FU-LV combination therapy can be regarded as a new, very effective treatment option for first-line treatment of advanced colorectal cancer patients.

Oral granisetron with or without methylprednisolone versus metoclopramide plus methylprednisolone in the management of delayed nausea and vomiting induced by cisplatin‐based chemotherapy. A prospective randomized trial

Background. A single‐institution, randomized open trial was prospectively performed to compare orally administered granisetron with or without intramuscularly administered methylprednisolone to metoclopramide plus methylprednisolone in the prevention of delayed nausea and vomiting induced by cisplatin‐based chemotherapy. The effects of antiemetic treatments were evaluated from days 2 to 5 of the first cycle after cisplatin administration among patients who had never before received chemotherapy.

The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers

Abstract Zoledronic acid is a bisphosphonate that is effective in the treatment of complications of metastatic bone disease. We have carried out a perspective study on 24 consecutive patients with prostate cancer metastatic to bone to verify the effect of zoledronic acid on analgesic response and a possible relationship with the levels of bone metabolism biomarkers. Eligibility for this study required prostate cancer patients with metastatic bone disease and pain not controlled by analgesics. Patients were excluded from the study if they were receiving cytotoxic chemotherapy or radiation therapy within three months. Eighteen patients (75%) were considered responder to acid zoledronic, only 6 patients did not respond. Before starting treatment (T0) mean Visual Analogue Scale was 7.8 (SE +/− 0.29), after 1 month therapy (T1) was 3.6 (SE +/− 0.3) and after three months (T2) was 3.1 (SE +/− 0.4) with a significant difference between T0 and T1 (p<0.0005) and between T0 and T2 (p<0.0005). Visual Analogue Scale improvement was positively correlated with decrease of C-telopeptide and bone phosphatase alkaline (p<0.05) serum levels.

Primary extranodal non-Hodgkin lymphomas of the uterus and the breast: report of three cases

The authors describe one case of a rare primitive non-Hodgkin lymphoma of the uterus, and two cases of primary non-Hodgkin lymphoma of the breast. Histologically, the uterine lymphoma, although clinically confined to the uterus, was a diffuse large cell lymphoma, group G according to the Working formulation for Clinical Usage. The two cases of breast lymphoma were a centrocytic-centroblastic and a lymphoplasmocytoid non-Hodgkin lymphoma, respectively. All cases were initially treated with radical surgery plus radiotherapy, but the first patient showed an early recurrence at distant sites, which required systemic cytotoxic chemotherapy. The patient with uterine non-Hodgkin lymphoma received a very intense regimen--i.e. the ProMACE-Cytabom--because of the unfavourable histology, while the two patients with primary breast non-Hodgkin lymphoma received less aggressive CHOP and CVP chemotherapy. All patients are still alive and free of disease 3 to 6 years after initial diagnosis. These cases stress the systemic nature of non-Hodgkin lymphomas even if apparently localized to a single extranodal organ. Thus, although a definitive therapeutic strategy cannot be drawn from the rare and occasional reports in the medical literature, primary extranodal lymphomas require integrated multimodality therapy with radiotherapy and/or chemotherapy.

Vinorelbine plus cisplatin versus cisplatin plus vindesine and mitomycin C in stage IIIB-IV non-small cell lung carcinoma: A prospective randomized study

PURPOSE To compare a regimen of vinorelbine and cisplatin (VC) to the combination of mitomycin, vindesine, and cisplatin (MVP) in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC). The main endpoits were analysis of objective response rates, toxicity, time to progression, and overall survival. PATIENTS AND METHODS 247 eligible patients were randomized to receive (a) vinorelbine 25 mg/m(2) intravenous bolus on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 every 4 weeks, or (b) mitomycin c 8 mg/m(2) i.v. on day 1, vindesine 3 mg/m(2) i.v. on days 1, 8, 15 and 22, plus cisplatin 100 mg/m(2) on day 1 every 4 weeks. In subsequent cycles vindesine was given every other week. For both treatments a maximum of six cycles was planned. Patients with performance status 0-2 according to the ECOG scale were enrolled. Response and toxicity were evaluated according to the WHO criteria. Analysis of clinical efficacy was performed according to an intent-to-treat analysis. RESULTS No statistically significant differences in clinical efficacy were observed between the two chemotherapy regimens. The overall objective response rates were 39% (95% CL, 31-49%) in the VC arm and 42% (95% CL, 33-51%) in the MVP arm (P=0.13). Median time to progression was 4.2 and 4.5 months for the MVP arm and the VC arm, respectively. Median overall survival was 7 months in the VC arm and 8 months in the MVP one (log-rank test, P=0.898). These differences were not statistically significant. However, leukopenia and thrombocytopenia were significantly higher in the MVP arm than in the VC (P=0.0001; P=0.0002). Grade 3 alopecia was more frequent in the MVP arm than in the VC one (P<0.001), which was associated with higher rate of phlebitis (P=0.037). CONCLUSION Data achieved in this study suggest that the vinorelbine-cisplatin doublet is similar to the three-drug MVP regimen in term of overall response rate, time to progressive disease, and overall survival. However, hematological toxicity and alopecia are more frequent and severe in the MVP regimen which therefore appears to be less tolerable than the VC regimen. The combination of vinorelbine and cisplatin may be considered as a reference treatment for future studies on the treatment of advanced NSCLC.

A prospective evaluation of the activity of human granulocyte-colony stimulating factor on the prevention of chemotherapy-related neutropenia in patients with advanced carcinoma

After informed consent, 86 patients with advanced cancer undergoing potentially myelosuppressive cytotoxic chemotherapy were randomized to receive placebo or subcutaneous granulocyte-colony stimulating factor (G-CSF) 5 micrograms/Kg/day in order to prevent severe neutropenia and its related morbidity. The incidence of neutropenia (absolute neutrophil count < 1,000/mm3) was significantly reduced in patients receiving G-CSF than in controls (18% versus 42%; P < 0.05). The duration of neutropenia was also shortened by the administration of G-CSF (4.8 versus 8.2 days; P < 0.05). Therapy with G-CSF has also a positive impact on the dose-intensity of employed regimens. Patients treated with G-CSF showed oral fungal disease in 9% of cases, while control patients had a 21% incidence (NS). Patients treated with G-CSF received 91% of the programmed dose-intensity as compared to 71% of control patients (P < 0.05). These data strengthen the clinical usefulness of G-CSF in the prevention of chemotherapy-related neutropenia, infections, and reduction in dose-intensity. Further studies are required to establish if the increase in dose-intensity allowed by G-CSF treatment may positively influence the outcome of cancer patients.

Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM).

Lonidamine (LND) is a unique antineoplastic drug derived from indazole-3-carboxylic acid which inhibits oxygen consumption and aerobic glycolysis, interfering with energy metabolism of neoplastic cells. LND has been experimentally shown to potentiate the cytotoxic effects of epirubicin (EPI) in human breast cancer cell lines, cisplatin activity in both platinum-sensitive and -resistant human ovarian carcinoma cell lines, and EPI antineoplastic activity in some recent phase III trials carried out in advanced breast cancer. A multicenter phase II trial was carried out with the combination of cisplatin 60 mg/m2, EPI 100 mg/m2 and LND 450 mg/day p.o. in three refracted doses/day starting 2 days before cisplatin and EPI (day -2 and -1), stopping 2 days after chemotherapy (day 0, +1 and +2). Thirty patients with metastatic breast cancer were enrolled into the study. Twenty-nine patients were evaluable for objective response. The overall response rate accordingly to an intent-to-treat analysis was 73% (95% CL 54-88%). Four patients achieved complete response (13%; 95% CL 4-31%) with a median duration of 9.5 months (range 4-16) and 18 patients had partial response (60%; 95% CL 41-77%) with a median duration of 9.8 months. Stable disease was obtained in five cases (17%) and progressive disease was recorded in three patients. One patient died of progressive cancer before restaging. The overall median survival of the whole series of patients was 14+ months. The most frequent toxicities were represented by gastrointestinal and hematological side effects. The combination of cisplatin + EPI plus oral LND is active against metastatic breast carcinoma. The antineoplastic activity of the cisplatin + EPI + LND regimen is as high as that reported for more aggressive regimens such as the fluorouracil + doxorubicin + cyclophosphamide combinations without an increase in toxic effects.

Bortezomib: A New Pro-Apoptotic Agent in Cancer Treatment

Bortezomib is a proteasome inhibitor. It targets the ubiquitin-proteasome pathway with subsequent inhibition of the degradation of proteins involved in cell cycle regulation and cancer cell survival. The best known molecular mechanism concerns the inhibition of IkappaB breakdown and the related stabilization of NFkappaB, thus preventing its translocation to the nucleus for the activation of downstream pathways. Bortezomib is the only drug in this class which has been approved for clinical use. It has shown an efficient antitumor effect in a phase III clinical trial (APEX) involving relapsed multiple myeloma patients. Response rate, time to progression and overall survival have been improved in patients treated with bortezomib and dexamethasone compared to dexamethasone alone. These results have induced several researchers to suggest preclinical and clinical studies for the application of bortezomib in solid tumors. Preclinical data have proved useful in the identification of several of the biological processes implicated, including cell cycle arrest at the G2/M phase, upregulation of p21, apoptosis regulation, microvessel density reduction, overcoming chemotherapy resistance. The clinical results obtained so far with the use of bortezomib in patients with solid malignancies are still not sufficient for the introduction of the drug into clinical practice. Furthermore, the results obtained with the use of bortezomib combined with cytotoxic drugs have not proved any more satisfactory than those obtained with bortezomib used as a single agent. Other preclinical studies are required in order to reach a clearer understanding of the relevance of bortezomib in the therapy of solid tumors.

Anti-endothelin drugs in solid tumors

Importance of the field: The endothelin (ET) axis, which includes the biological functions of ETs and their receptors, has played a physiological role in normal tissue, acting as a modulator of vasomotor tone, tissue differentiation and development, cell proliferation and hormone production. Interestingly, it also functions in the growth and progression of various tumors. Several researchers have identified the blockade of the ET-1 receptor as a promising therapeutic approach. Areas covered in this review: The clinical investigation of an orally bioavailable ET antagonist, atrasentan, in prostate cancer, is encouraging. In this neoplasia, it has shown antitumor activity, bone metastasis control and amelioration of cancer-related pain but improvement in time to progression and overall survival has still not been demonstrated. The clinical trials of other ET antagonists are reported. Literature research was performed by Pubmed and Pharmaprojects. What the reader will gain: A comprehensive view about the use of atrasentan in the treatment of castration-resistant prostate cancer (CRPC) is provided together with the scientific rationale based on the function of ET and its receptor in various cancer development mechanisms. Take home message: Atrasentan seems to be active in CRPC, although strong scientific evidence is still to be found. Interesting clinical findings regard zibotentan.