Bone metastasis in breast cancer is treated by high-dose tamoxifen.

PURPOSE: Bone metastases in breast cancer are quite common, and some patients may have no other site of metastasis. An effective treatment is often endocrine agents administration (tamoxifen or antiaromatases), given mainly to postmenopausal women. Radiation treatment is also effective, although difficult to perform in cases of extensive skeletal disease. Chemotherapy does not help. The purpose of this study was to investigate the effectiveness of high-dose tamoxifen in female patients with breast cancer and bone metastasis. METHODS: 28 patients with breast cancer were treated with high-dose tamoxifen. All of them had been pretreated with hormonal therapy including low-dose tamoxifen. RESULTS: The results were extremely positive with clinical amelioration and also disappearance of osteolysis in some patients. Twenty six out of 28 patients responded to the treatment, the criteria being mainly pain reduction and body mobilization (an amelioration which lasted 8 months-4 years). CONCLUSION: Tamoxifen is efficient when readministered at high dose to breast cancer patient with bone metastasis.

The role of Ki-67 in the proliferation and prognosis of breast cancer molecular classification subtypes.

The Ki-67 antigen was identified in the early steps of polymerase I-dependent ribosomal RNA synthesis. Although it seems that this protein has an important function in cell division, its exact role is still unclear and there is little published work on its overall function. The aim of the present study was to evaluate the contribution of the level of Ki-67 with respect to tumor recurrence in molecularly classified groups of breast cancer patients. Ki-67 was divided into the percentage levels up to and including 20% and over 20%. Immunohistochemistry and fluorescence in-situ hybridization are described for the results of estrogen receptor, progesterone receptor, c-erb-B2, and Ki-67 biomarkers. Formaldehyde-fixed breast samples were paraffin wax embedded and processed for paraffin sections. The protocol of the present study started in 1995 and finished in 2010. Nine hundred and sixteen patients with breast cancer were examined: 291 were grouped as luminal A, 228 as luminal B, 221 as the Her-2 subtype, and 107 as basal cell (triple negative). Follow-up ranged from 3 to 15 years following diagnosis. It was found that in luminal A patients, only one had a Ki-67 level higher than 20%. In luminal B, the Ki-67 was higher than 20% in 51.16% of the patients and recurrence occurred in 23.68%. In the Her-2 subtype, the Ki-67 level was more than 20% in 48.63%. In basal cell triple-negative patients, Ki-67 was more than 20% in 63.86%. The data presented here indicate that the level of Ki-67 may be considered one of the valuable biomarkers in breast cancer patients with respect to process and recurrence.

Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial.

To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.

Topotecan and pegylated liposomal doxorubicin combination as palliative treatment in patients with pretreated advanced malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive disease with poor or modest responses to chemotherapy and dismal prognosis. In most of the cases the scope of the treatment is only palliative. In the current study, the combination of i.v. topotecan and pegylated liposomal doxorubicin (PLD) in advanced multi-treated MPM was tested. Primary objective was palliation of the symptoms, with the secondary ones being the establishment of the regimen's safety and efficacy. PATIENTS AND METHODS: Nine patients were enrolled (7 males/2 females, median age 57.5 years, ECOG performance status ≤ 2), having progressed after 2 or 3 lines of chemotherapy including pemetrexed and cisplatin. Main symptoms were dyspnea, cough, chest pain, fatigue, and anorexia. The treatment included topotecan 1.2 mg/m2 i.v. on Days 1 - 3 and PLD 40 mg/m2 on Day 4, every 28 days. The patients received 4 - 8 chemotherapy cycles (median 5.8). RESULTS: In all cases, symptoms were significantly improved after the 2nd treatment cycle. Respiratory function tests showed considerable enhancement, while cough and pain were drastically reduced. All patients had objective clinical benefit, 1 patient achieving partial response and 8 stable disease. Median time to progression and overall survival was 7 and 9 months, respectively. The chosen dose of the topotecan/ PLD combination was well-tolerated with no Grade 3/4 toxicities. Quality of life, as it was evaluated by the QLQ-C30 and QLQLC13 questionnaires, had improved scores especially the ones referring symptomatology. CONCLUSION: The current study shows a significant palliative effect of the topotecan/ PLD combination in pretreated patients with advanced MPM.

Liposomal cisplatin: a new cisplatin formulation.

Over the last three decades, cisplatin has been one of the most effective cytotoxic agents, but its administration has been hindered by its nephrotoxicity, neurotoxicity and myelo toxicity. Recently, liposomal cisplatin, lipoplatin, has been formulated and tested thoroughly in preclinical (in vitro) and phase I, II and III trials, as documented in the literature. Experiments in animals showed that lipoplatin is less toxic than cisplatin and that it produces tumour reduction. The histological examination of treated tumours from mouse xenografts was consistent with apoptosis in the tumour cells in a mechanism similar to that of cisplatin. Lipoplatin infusion in patients and measurements of platinum levels in tumour specimens showed 10-50 times higher levels in tumours and metastases than in the adjacent normal specimens. A phase I-II study using a combination of lipoplatin and gemcitabine in pretreated patients (with disease progression or stable disease) with advanced pancreatic cancer was conducted. No nephrotoxicity was observed. With lipoplatin monotherapy the dose-limiting toxicity was determined to be 350 mg/m and the maximum tolerated dose 300 mg/m; when used in combination with paclitaxel the dose-limiting toxicity for lipoplatin was 250 mg/m and for paclitaxel 175 mg/m, and the maximum tolerated dose was 200 and 175 mg/m, respectively. In two phase II randomized studies comparing the lipoplatin combination versus the cisplatin combination, it was found that the former was statistically significantly less toxic than the latter, whereas the response rate and survival were similar. Up to now, the data on lipoplatin treatment in malignant tumours are quite impressive, because of the negligible toxicity and because it is equal if not superior to cisplatin with regard to response rate. This review aims to chronologically document publications relevant to liposomal cisplatin to date.

Myelotoxicity of oral topotecan in relation to treatment duration and dosage: a phase I study.

Oral topotecan has been recently brought into clinical practice at a dose of 2.3 mg/m(2) for 5 days, every 3 weeks. Published data show quite high myelotoxicity. The aim of this trial was to define the daily dose and treatment duration, which permits safe toxicity. The study was designed to begin at a low daily dosage of 1.5 mg/m(2) and was escalated by increasing the topotecan dose and the day-treatment duration. The plan was to end up with 2.3 mg/m(2) daily for 5 days. In cases of tolerability with the last dosage given, we would then continue testing a higher daily dosage. Treatment repetition was planned to be every 21 days. Dosage levels were 1.5, 2.0 and 2.3 mg/m(2) for 3 days, 2.0 and 2.3 mg/m(2) for 4 days, and 2.3 mg/m(2) for 5 days. Toxicity was scored according to the Common Toxicity Criteria. Thirty-two patients (27 male, five female, median age 60 years, range 46-77 years) with small-cell lung cancer were included. The patients on 1.5 and 2 mg/m(2) for 3 days showed no myelotoxicity. Four (25%) patients on 2.3 mg/m(2) 3-day treatment developed grade 3-4 neutropenia. Three of five patients (60%) treated for 4 days at a dose of 2.3 mg/m(2) developed grade 3-4 neutropenia and less than half (two of five, 40%) of these patients had thrombocytopenia. Eight patients (66.7%) on the 5-day treatment presented with serious grade 3-4 myelotoxicity. Two treatment-related deaths were observed in the 5-day group and one in the 4-day group. Granulocyte growth factor was applied in over 60% of the patients. In conclusion, a dose of 2.3 mg/m(2) for 5 days was intolerable. Dose-limiting toxicity was 2.3 mg/m(2) for 4 days without prophylactic granulocyte colony-stimulating factor administration. The safe duration of oral topotecan treatment and the maximum tolerated dose seem to be not longer than 3 days at a dose of 2.3 mg/m(2).

Survival after cytotoxic chemotherapy in patients with advanced hormone-resistant prostate cancer: a phase II study.

In the past, it was believed that when advanced-stage prostate cancer became resistant to hormonal management, no chemotherapy should be administered, as survival was not prolonged. Mitoxanthrone and prednisone were mostly administered, while recently, other agents such as docetaxel or paclitaxel have been tested both with and without hormonal treatment. The objective of the present phase II study was to determine the survival and the response rate of patients after the chemotherapy was administered. Sixty-five patients with advanced prostate cancer were included. The inclusion criteria involved histological confirmation of adenocarcinoma and resistance to hormonal therapy. The majority of the patients had stage IVa or IVb disease and a performance status of 0-1 to 2. The treatment involved chemotherapy in combination with a luteinizing hormone-releasing hormone (LHRH) or dexamethasone or estramustine. The hormone treatment preceded the cytotoxic administration and no amelioration in the patients nor prostate serum antigen (PSA) reduction was observed. The initial cytotoxic agents administered were docetaxel 75 mg/m(2) in 25 patients, mitoxanthrone 10 mg/m(2) in 15 patients, epirubicin 75 mg/m(2) in 15 patients and paclitaxel 175 mg/m(2) in 10 patients, all repeated every 3 weeks. The response rate was documented by bone scan, CT scan of the abdomen (and occasionally of the chest) and by the PSA serum value. Clinical benefit was also estimated. Thirty-three (50.77%) patients achieved a partial response; stable disease was observed in 24 (36.92%) patients and disease progression in 8 (12.31%). Twenty-two (33.85%) experienced clinical benefit. A significant PSA reduction was seen in 35 (53.85%) patients. The median survival was 18 months and the range 3-84 months. One, 2, 3 and five-year survival was 75.38, 23.07, 12.30 and 4.66%, respectively. Toxicity was well-tolerated. Patients with hormone-resistant advanced prostate cancer do have good prospects for receiving substantial benefit with the addition of chemotherapy, as observed in the present trial.

Metastatic renal cancer and patient survival as a criterion of treatment response.

Advanced metastatic renal cancer is an incurable disease, unless a successful excision of metastatic lesions can be performed. No effective treatment has yet been found. In the last few years, targeting therapies have been developed. In the past, the main treatment was based on cytokines (interferon-alpha or interleukin-2). Our objective was to determine the median and overall survival in the 66 patients who were studied and reviewed. All had histologically confirmed advanced renal cancer. There were 41 male and 25 female patients, with a median age of 60 years. In 68.18% of the patients, the treatment was mainly interferon-alpha (IFN-alpha) given 3 times a week for a median time duration of 6 months (range 3-12 months). Four patients received interleukin-2 (IL-2) and 17 patients received chemotherapy, 15 of whom had hormonal treatment. Eleven patients underwent palliative radiation therapy (in the bone or brain). Seven patients received no treatment apart from supportive care. A partial response was achieved in 11.11% of the patients treated with IFN-alpha. No response was observed in patients treated with chemotherapy or hormonal therapy. The median survival of all the patients was 20 months (95% CI 14.96-25.04). These results are discussed in comparison with the survival results of modern targeting treatment studies. In the latter studies, despite the high response rates (31-40%), the survival was 16.4 months. Our data indicate that the response rate as a criterion is not adequate in determining drug effectiveness.

Comparison of cisplatin-paclitaxel combination versus cisplatin-etoposide in patients with small-cell lung cancer: a Phase III study.

Cisplatin-paclitaxel and cisplatin-etoposide combination therapies were compared in limited and extensive disease in patients with small-cell lung cancer. The primary objectives were to determine median and overall survival, time to tumor progression and tolerance and the secondary objective, the response rate. From January 2003 till July 2007, 108 patients were enrolled in the study. All patients had histologically- or cytologically-confirmed small-cell lung cancer. All patients were chemotherapy and radiotherapy naive. The patients were designated to receive six cycles: in the investigational Arm A, cisplatin, 80 mg/m(2) and paclitaxel 175 mg/m(2) were infused on day 1 (1 cycle) and repeated every 3 weeks. In the control Arm B, cisplatin, 80 mg/m(2) was administered on day 1 and etoposide, 120 mg/m(2) per day was given on days 1-3 (1 cycle), every 3 weeks. In Arm A, 6 (11.3%) patients achieved a complete response and 32 (58.1%), a partial response; in Arm B, 7 (12.7%) patients achieved a complete response and 32 (58.2%) a partial response. The median survival time in Arm A patients was 12 months and in Arm B, 13 months, p=0.354. The time to tumor progression (TTP) was 8 and 6 months for Arms A and B, respectively (p=0.060). Toxicity, although common in both Arms, was acceptable. Neutropenia, anemia and diarrhea were higher in the control Arm. The cisplatin-paclitaxel combination is not superior to cisplatin-etoposide with respect to survival, TTP, toxicity and response rate. The former combination could be applied as an alternative chemotherapy regimen for patients with limited or advanced small-cell lung cancer.

Present treatment and future expectations in advanced pancreatic cancer.

Advanced or metastatic pancreatic cancer is an incurable disease. The main treatment is chemotherapy with cytotoxic agents. On the basis of our experience in clinical trials, the objectives have been to determine response rate, life prolongation and clinical benefit. In our trials and in those of other authors, all of these objectives have been met. Responses remain low; 5-25% of patients have a partial response, life prolongation is significantly achieved versus best supportive care, and clinical benefit is observed in 40-60% of patients. Rarely do patients survive for over 2 years and no patient is cured. The standard cytotoxic treatment is the agent gemcitabine. The addition of other agents, such as cisplatin, irinotecan, oxaliplatin and taxanes, in combination with gemcitabine, has shown higher response rates but overall survival has not significantly increased. Research related to monoclonal or gene therapies for pancreatic cancer has created hope. The horizon has been broadened by a recent report on a tyrosine kinase inhibitor, erlotinib (EGFR inhibitor) which has shown significantly longer median survival, when combined with gemcitabine versus gemcitabine alone. Other anti-angiogenic agents, such as cetuximab and the anti-Her-2, herceptin, are now being tested in ongoing trials. Farnesyl transferase inhibitors represent another direction which research is taking; this is related to the Ras-oncogenes (K-, H- and N-ras) which are known to be involved in signal transduction pathways regulating cell growth and differentiation in many human cancers including pancreatic. Trials of these and other targeting therapies have not produced the expected effectiveness. The combination of monoclonal and/or gene therapies with cytotoxic agents suggests there is hope for the future.

Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

A phase I-II study of bi-weekly gemcitabine and irinotecan as second-line chemotherapy in non-small cell lung cancer after prior taxane + platinum-based regimens.

PURPOSE: Treatment options in patients with recurrent non-small cell lung cancer (NSCLC) remain limited as a result of poor activity of most agents after failure of platinum-based therapy. In the present phase I-II study, we evaluated the feasibility and efficacy of bi-weekly gemcitabine (GEM) + irinotecan (CPT-11) in patients with relapsed NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC, WHO-performance status (PS)

A retrospective open-label uncontrolled study of Epoetin zeta on the treatment of chemotherapy-induced anemia in solid tumors.

PURPOSE: This is a single-center uncontrolled retrospective study to evaluate the efficacy and safety of the biosimilar epoetin zeta after approval in chemotherapy-induced anemia (CIA). METHODS: Patients screened were >18 years old suffering from solid malignancies and CIA with Hg ≤10 or <11 g/dl if symptomatic anemia. Patients had measurable disease by TNM and Eastern Cooperative Oncology Group (ECOG). Patients were treated for at least 12 weeks and the primary endpoint was to determine the incidence of blood transfusions, and secondarily, the overall safety and efficacy defined as ≥1 g/dl rise in Hb concentration or ≥40,000 cells/µl rise in reticulocyte count. Quality of life was assessed with ECOG performance status (PS) and functional assessment of cancer therapy-anemia (FACT-An) score. RESULTS: 1287 patients with median Hb 9.3 g/dl (range 8.3-10.6) were enrolled and included in the evaluation. Median age was 63 years (range 33-78). 74% of patients were stage III/IV. Patients received epoetin zeta subcutaneously at fixed 40,000-IU once weekly. Blood transfusions were given in 178 patients (13.8%; 95% CI 11.9-15.6%). Appropriate response was observed in 79% patients by week 4, 87% by week 8, and 91% by week 12. A mean Hb increase of 2.5 g/dl was observed by week 12 which correlated with an improvement in PS and Fact-An score. Thrombotic events occurred in 5.2% (95% CI 3.4-7.1%) of patients. CONCLUSIONS: Epoetin zeta is effective in palliation and treatment of CIA in patients with solid tumors. Overall, it is well tolerated and safe even in patients with increased disease burden.

Predictive value of D-dimer plasma levels in response and progressive disease in patients with lung cancer.

Patients with cancer may present with one or more circulatory markers of haemostatic activation which may be associated with tumor growth and cancer cell dissemination. In our clinical practice we observed haemostatic abnormalities with or without thrombotic episodes in cancer patients. The aim of the present study was to detect the D-dimer plasma levels in advanced-stage lung cancer patients before, during and after chemotherapy, and to determine whether there is a correlation with response rate, disease recurrence and survival, in order to estimate the possible predictive value of D-dimer plasma levels. Forty-seven/52 patients were evaluable and analysed; 38 patients had non-small-cell lung cancer (NSCLC) and 9 small-cell lung cancer (SCLC) and all were at an advanced stage or inoperable. Two (4.3%) achieved complete response (CR), 17 (36.2%) partial response (PR), and 16 (34%) had progressive disease (PD). We found that 14/19 (73.7%) patients with CR or PR showed a reduction in D-dimer plasma values and 11/16 (68.8%) with PD showed increased values; also, in patients with recurrent disease (12/13, 92.3%), D-dimer plasma levels were increased. All of the above values were statistically significant. D-Dimer plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the evolution of the disease.

A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer.

PURPOSE: To evaluate the efficacy and tolerance of the docetaxel/gefitinib combination as second-line treatment in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-six patients pretreated with gemcitabine-based chemotherapy were enrolled in the study. Docetaxel (75 mg/m(2), i.v.) was administered every 3 weeks for a maximum of 6 cycles and gefitinib (250 mg/day, p.o.) was given continuously. RESULTS: Five (19.2%) patients achieved stable disease. The median duration of disease control was 4.8 months (range 1-13.2), the median time to disease progression 2.1 months (range 1-7.3) and the median survival time 2.9 months (range 1-13.9). Grade 3/4 neutropenia was recorded in 9 (34.6%) patients, although only 1 (3.8%) developed grade 2 febrile neutropenia. One (3.8%) patient experienced grade 3 fatigue and 2 (7.7%) grade 3 diarrhea. Grade 1/2 rash was observed in 13 (50%) patients. There were no treatment-related deaths. CONCLUSION: The docetaxel/gefitinib combination, although safe, has no activity as salvage treatment for advanced pancreatic cancer after failure of gemcitabine-based chemotherapy.

Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study.

The present trial is a phase I-II study based on a new liposomal cisplatin (lipoplatin). Previous preclinical and clinical data (phase I pharmacokinetics) led to the investigation of a combined treatment modality involving lipoplatin and gemcitabine. The gemcitabine dose was kept standard at 1000 mg/m2 and the lipoplatin dose was escalated from 25 mg/m2 to 125 mg/m2. The treatment was administered to advanced pretreated pancreatic cancer patients who were refractory to previous chemotherapy which included gemcitabine. Lipoplatin at 125 mg/m2 was defined as dose limiting toxicity (DLT) and 100 mg/m2 as the maximum tolerated dose (MTD) in combination with 1000 mg/m2 of gemcitabine. Preliminary objective response rate data showed a partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%). Liposomal cisplatin is a non-toxic alternative agent to bare cisplatin. In combination with gemcitabine, it has an MTD of 100 mg/m2 and shows promising efficacy in refractory pancreatic cancer.

Liposomal oxaliplatin in the treatment of advanced cancer: a phase I study.

BACKGROUND: Lipoxal is a liposomal oxaliplatin, which reduces the cytotoxic agent's adverse reactions without reducing effectiveness. Our objectives were to determine the adverse reactions, dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of lipoxal. PATIENTS AND METHODS: Twenty-seven patients with advanced disease of the gastrointestinal system were included in the study. All patients had been pretreated with standard chemotherapy according to established guidelines. At entry, all patients had recurrent or progressive disease (stage IV gastrointestinal cancers: colorectal, gastric and pancreatic). Six lipoxal dose levels (100 mg/m2, 150 mg/m2, 200 mg/m2, 250 mg/m2, 300 mg/m2 and 350 mg/m2) were set and at least 3 patients were included at each level. Eight patients were treated at 300 mg/m2 (MTD). The treatment was given once weekly for 8 weeks. RESULTS: No serious side-effects were observed at the first 4 dose levels (100-250 mg/m2). At levels 5 and 6, mild myelotoxicity and nausea were observed. The most common adverse reaction was grade 2-3 peripheral neuropathy, observed in all 4 patients treated at 350 mg/m2. The 350 mg/m2 dose level was therefore considered as DLT and the 300 mg/m2 level as the MTD. Of the 27 patients, 3 achieved partial response and 18 had stable disease for 4 months, (range 2-9 months). CONCLUSION: The most common toxicity was peripheral neuropathy at the 300 and 350 mg/m2 dose levels. Lipoxal was well-tolerated and greatly reduced all the other side-effects of oxaliplatin, especially myelotoxicity and gastrointestinal tract toxicities. These preliminary results showed adequate effectiveness in pretreated patients.

Phase II study of bevacizumab plus irinotecan on the treatment of relapsed resistant small cell lung cancer.

PURPOSE: This phase II study investigates the efficacy and safety of DNA topoisomerase I inhibitor irinotecan plus bevacizumab a monoclonal antibody against VEGF (BEVIRI) in patients with relapsed chemo-resistant SCLC. METHODS: Patients who previously completed treatment with cisplatin-etoposide who relapsed within 3 months, had measurable extensive-stage SCLC, ECOG performance status 0-2 and adequate hematologic, renal and hepatic function, were given intravenous irinotecan 175 mg/m(2) plus intravenous bevacizumab 7.5 mg/kg on day 1 and 15 in 30 day cycles for a target of at least four cycles. No patients had received prophylactic intracranial irradiation. Treatment response was assessed with computer tomography scans with the completion of two consecutive cycles. Primary endpoint was overall response rate (ORR). RESULTS: Thirty-two patients were enrolled and 28 of them were eligible for evaluation of response, toxicity and survival. The median age was 63.5 years (range 48-73). The ORR (CR and PR) was 25 % (95 % CI 8.9-41.0) and including patients with stable disease overall disease control rate at 2 months was 89 % (95 % CI 77.41-100). The median duration of response was 6 months, median progression-free survival was 3 months (mean PFS: 3.2, 95 % CI 2.7-3.7), and median overall survival was 6 months (mean OS: 6.3, 95 % CI 5.4-7.1). The PFS rate at 6 months was 3.6 %, and 1-year OS rate was 3.6 %. The median number of cycles received was 4.5 (range 1-6). There were two (7.1 %) hematologic (neutropenia) and one (3.5 %) non-hematologic (proteinuria) serious grades 3-4 adverse reactions without necessitating treatment discontinuation. CONCLUSION: BEVIRI combination in relapsed chemo-resistant SCLC patients demonstrates promising efficacy and low toxicity compared to historical controls. Further investigation is warranted.

Phase II trial of biweekly administration of vinorelbine and gemcitabine in pretreated advanced breast cancer.

PURPOSE: To determine the efficacy of gemcitabine (GEM) plus vinorelbine (VRL) administered biweekly in pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Advanced breast cancer patients without response, with stable disease, or with recurrence within 6 months of prior treatment were given GEM 1,000 mg/m(2) and VRL 25 mg/m(2), once every 2 weeks for at least six cycles. RESULTS: Of the 51 patients enrolled, 50 (median, age 58 years; range, 34 to 76 years) were assessable. All patients had prior chemotherapy with an anthracycline-related regimen that included taxanes in 50% of the cases. Four patients (8%) had a complete response (CR) and 23 (46%) had a partial response (PR), for an overall response rate of 54%; 16 (32%) had stable disease and 7 (14%) experienced disease progression. Response occurred mainly in patients with soft tissue (83.3%) and lung metastasis (66.7%). Response duration was 4 to 8+, 4 to 9+, and 4 to 9 months for those with CR, PR, and stable disease, respectively. The regimen was well tolerated, with grade 1 to 2 myelotoxicity and asthenia reported. No patient required a dose reduction. Gastrointestinal side effects were negligible. Patients received 99.7% (range, 93.0% to 100.0%) of the planned dose-intensity of each drug. CONCLUSION: GEM in combination with VRL is an active regimen for advanced breast cancer patients, and biweekly administration significantly reduces myelotoxicity.

Paclitaxel and gemcitabine combination in a biweekly schedule in patients with advanced non small-cell lung cancer: a phase I study.

PURPOSE: This phase I study was designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the paclitaxel-gemcitabine combination in a biweekly schedule in chemotherapy-naive patients with advanced non small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Treatment was administered on an outpatient basis every 2 weeks: paclitaxel over a 1-h IV infusion and gemcitabine as a 30-min IV infusion immediately following paclitaxel. RESULTS: Twenty-nine patients were treated at six different dose levels, ranging from paclitaxel 135-175 mg/m2 and gemcitabine 1,500-3,000 mg/m2. A total of 198 cycles were administered (median 7, range 1-13). DLTs in the first two cycles were grade 4 neutropenia and myocardial ischemia at the dose level paclitaxel/gemcitabine 150/2,000 mg/m2, febrile neutropenia and grade 4 neutropenia at the dose level paclitaxel/gemcitabine 175/2,500 mg/m2, fatal pneumonitis, sudden death and grade 3 neutropenia at the dose level paclitaxel/gemcitabine 175/3,000 mg/m2. The MTD was paclitaxel 175 mg/m2 and gemcitabine 2,500 mg/m2. The average dose intensity at this dose level was 98%. The overall intent-to-treat response rate was 35.7% (95% confidence interval [CI] 17.97%-53.47%). Overall median survival was 36 weeks (95% CI, 24-48). CONCLUSION: Paclitaxel and gemcitabine can be safely administered at a high dose intensity on an every-other-week schedule. The recommended phase II dose is paclitaxel 175 mg/m2 and gemcitabine 2,500 mg/m2.