Final results of a phase II study of paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

BACKGROUND: Efficacy and safety data for combining bevacizumab, gemcitabine, and paclitaxel for locally advanced/metastatic breast cancer are limited. PATIENTS AND METHODS: AVALUZ trial evaluates the combination of bevacizumab 10 mg/kg, gemcitabine 2,000 mg/m(2) plus paclitaxel 150 mg/m(2), on days 1 and 15 of each 28-day course in previously untreated HER-2 negative patients. RESULTS: Median progression-free survival (PES): 12.3 months. The overall response and clinical benefit rate (CR + PR + SD) were 72 % (95 % CI 60.9-82.0 %) and 89 % (95 % CI 80.3-95.3 %), respectively. Median overall survival: 27.4 mo. Baseline circulating tumor cell (CTCs) ≥2 versus CTCs <2 was associated with lower PFS, p = 0.046. Overall response was significantly greater in patients with intense angiotensin type 1 receptor (AGTR1) expression (99 vs. 60 % [p = 0.021]). The most frequent grade 3/4 adverse events were: neutropenia (10 %); febrile neutropenia (1 %); sensory neuropathy (13 %); and asthenia (6 %). Grade 3 adverse events of interest with bevacizumab included bleeding (1 %) and hypertension (4 %). One patient developed cardiac ischemia (1 %). CONCLUSIONS: Adding bevacizumab to chemotherapy appeared feasible and well tolerated, producing toxicity comparable to other effective combined first-line regimens. Baseline circulating endothelial cells and AGTR1 expression are predictive of PFS and response.

Pegylated liposomal doxorubicin in combination with cyclophosphamide and trastuzumab in HER2-positive metastatic breast cancer patients: efficacy and cardiac safety from the GEICAM/2004-05 study.

BACKGROUND: In order to determine the feasibility of substituting pegylated liposomal doxorubicin (PLD) for doxorubicin in combination with cyclophosphamide and trastuzumab as adjuvant therapy, we conducted a phase II study of the combination as first-line therapy in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic breast cancer (MBC). METHODS: PLD 50 mg/m(2) and cyclophosphamide 600 mg/m(2) were administered every 4 weeks for six cycles; trastuzumab (4 mg/kg loading dose, then 2 mg/kg) was administered weekly for 24 weeks. The primary end point was objective response rate (ORR), and the secondary end points included time to progression (TTP), overall survival (OS), and safety. RESULTS: Among the 48 evaluable patients, ORR was 68.8% [95% confidence interval (CI) 55.69% to 81.91%], with 6 patients (12.5%) achieving a complete response and 27 (56.2%) a partial response. The median TTP was 12 months (95% CI 9-15.1 months), and the median OS was 34.2 months (95% CI 27.2-41.2 months). Febrile neutropenia was seen in three patients, grade 3 hand-foot syndrome in 29.2% of patients, and grade 3-4 mucositis in 22.9% of patients. Symptomatic congestive heart failure was not observed, and 16.7% of patients experienced grade 2 asymptomatic left ventricular systolic dysfunction. CONCLUSION: The combination of PLD-cyclophosphamide-concurrent trastuzumab is a feasible, safe, and effective first-line regimen for HER2-overexpressing MBC.

A phase II randomized trial of gemcitabine-docetaxel versus gemcitabine-cisplatin in patients with advanced non-small cell lung carcinoma.

PURPOSE: To test efficacy and tolerability of non-platinum regimens for advanced non-small-cell lung cancer (NSCLC). METHODS: Chemonaive patients with measurable stage IIIB/IV NSCLC treated with gemcitabine and cisplatin (GC), or gemcitabine and docetaxel (GD), maximumsix cycles in a phase IIB trial. RESULTS: A total of 108 patients were randomized. Response rates (GC vs. GD, respectively): complete 3.6/2.0%, Partial 30.9/38.0%. Median Overall Survival (OS): 8.9 months in both groups (P = 0.53); and median time to progression (TTP): 6.2/5.5 months respectively (P = 0.61). Toxicities included (GC vs. GD, respectively): grade 3-4 neutropenia 49.1/41.2%; grade 3 thrombocytopenia 30.9/3.9%; grade 3 anemia 14.5/3.9%. Non-haematological toxicity was similar, except for nausea and vomiting, (16.3/2%); renal toxicity (3.7/0%) and hepatic toxicity (5.6/12.7%). CONCLUSIONS: With a higher overall response rate and lower toxicity, GD is a good first treatment option for advanced NSCLC.

A prospective observational study of the effectiveness, safety, and effect on fatigue of darbepoetin alfa for the treatment of chemotherapy-induced anaemia.

OBJECTIVE: Anaemia is common in cancer patients treated with chemotherapy. Darbepoetin alfa (DA) is the only erythropoiesis-stimulating protein approved for administration at weekly and every-three-week intervals in cancer patients receiving chemotherapy. This article investigates the effectiveness, tolerability and effect on fatigue of DA. METHODS: Prospective, observational study performed in 30 Spanish centres. Eligible patients were > or = 18 years of age, anaemic (haemoglobin [Hb] < or = 11 g/dL), with non-myeloid malignancies, receiving chemotherapy. DA (150 mug) was administered weekly for a maximum of 16 weeks (dosage doubled if Hb increased < 1 g/dL after 4 weeks). MAIN OUTCOME MEASURES: Haematopoietic response (Hb increase > or = 2 g/dL or Hb > or = 12 g/dL in the absence of transfusions in the previous 28 days), transfusion required between Weeks 5 and 16 and fatigue measured by the Fatigue subscale of the Functional Assessment of Cancer Therapy. RESULTS: 293 adults were recruited (56.4% women), with lymphoproliferative malignancies (44.3%) or solid tumours (55.7%). Baseline Hb was 9-11 g/dL in 83.7% of patients. Sixty-four per cent (95% CI: 58.1-69.4%) had a haematopoietic response and 12% required transfusions. After adjusting for performance status, concomitant diseases and chemotherapy type, an increase in Hb level was significantly associated with an improvement in Fatigue subscale (+1.9 points per 1 g/dL). Only 2% of patients had treatment-related adverse events: thromboembolic pulmonary disease (0.3%); hypersensitivity reaction (0.3%); local pain following DA administration (0.3%); insomnia (0.3%); thrombocytosis (0.3%) and deep vein thrombosis (0.3%). CONCLUSIONS: Fixed-dose DA administered once weekly seems to be an effective, well-tolerated treatment for chemotherapy-induced anaemia in patients with non-myeloid malignancies, and there is an indication of a possible benefit on fatigue in the clinical practice.

Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen.

BACKGROUND: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). PATIENTS AND METHODS: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). RESULTS: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2-4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P<0.03). CONCLUSIONS: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment.

Phase II randomised trial of raltitrexed-oxaliplatin vs raltitrexed-irinotecan as first-line treatment in advanced colorectal cancer.

The purpose of this phase II randomised trial was to determine which of two schemes, raltitrexed-irinotecan or raltitrexed-oxaliplatin, offered better activity and less toxicity in patients with advanced colorectal cancer (CRC). A total of 94 patients with previously untreated metastatic CRC were included and randomised to receive raltitrexed 3 mg m(-2) followed by oxaliplatin 130 mg m(-2) on day 1 (arm A), or CPT-11 350 mg m(-2) followed by raltitrexed 3 mg m(-2) (arm B). In both arms treatment was repeated every 3 weeks. Intent-to-treat (ITT) analysis showed an overall response rate of 46% (95% CI, 29.5-57.7%) for arm A, and 34% (95% CI, 19.8-48.4%) for arm B. Median time to progression was 8.2 months for arm A and 8.8 months for arm B. After a median follow-up of 14 months, 69% of patients included in arm A were still alive, compared to 59% of those included in arm B. Overall, 31 patients (65%) experienced some episode of toxicity in arm A and 32 patients (70%) in arm B, usually grade 1-2. The most common toxicity was hepatic, with 29 patients (60%) in arm A and 24 patients (62%) in arm B, and was grade 3-4 in four (8%) and four (9%) patients, respectively. In all, 14 patients (29%) from arm A and 24 patients (52%) from arm B had some grade of diarrhoea (P<0.03). Neurologic toxicity was observed in 31 patients (64%) in arm A, and was grade 3-4 in five patients (10%), while a cholinergic syndrome was detected in nine patients (19%) in arm B. There were no differences in haematologic toxicity. One toxic death (2%) occurred in arm A and three (6.5%) in arm B. In conclusion, both schemes have high efficacy as first-line treatment in metastatic CRC and their total toxicity levels are similar. Regimens with raltitrexed seem a reasonable alternative to fluoropyrimidines.

Docetaxel and high-dose epirubicin as neoadjuvant chemotherapy in locally advanced breast cancer.

PURPOSE: Epirubicin and docetaxel are two of the most active drugs against breast carcinoma. As the achievement of a pathological complete response (pCR) is important for survival of patients with locally advanced disease, we used both drugs as neoadjuvant chemotherapy. PATIENTS AND METHODS: Women with locally advanced or inflammatory breast cancer received epirubicin 120 mg/m2 followed by docetaxel 75 mg/m2, both on day 1, every 21 days for four cycles. Lenograstim was administered for 10 days in all cycles. RESULTS: Of 51 patients included, 50 received a total of 188 cycles, with a median of 4 per patient. The median age was 47 years, tumour stage was IIIA in 14 patients and IIIB in 36. Oestrogen receptors were positive in 65% of tumours. There were 10 clinical complete responses (20%) and 29 partial responses (58%). Surgery consisted of mastectomy in 40 patients and tumorectomy in 6. After surgery, 9 pCR were recorded (18%). One patient progressed and died soon after the end of chemotherapy. After a median follow-up of 22 months, the median disease-free survival was 33.7 months. Grade 3/4 neutropenia was observed in 32% of patients, anaemia in 6%, and thrombocytopenia in 4%. Five patients had febrile neutropenia. There were no toxic deaths or grade 4 nonhaematological toxicities. CONCLUSIONS: Docetaxel plus high-dose epirubicin showed promising activity in patients with locally advanced and inflammatory breast cancer, at the cost of moderate toxicity.

Phase II study of carboplatin and 1-h intravenous etoposide and paclitaxel in a novel sequence as first-line treatment of patients with small-cell lung cancer.

PURPOSE: To evaluate the efficacy and tolerability of paclitaxel, carboplatin and etoposide when administered in combination to previously-untreated small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Patients (n=95) with limited-stage disease (LSD; n=45) or extensive-stage disease (ESD; n=50) from 14 Spanish hospitals were entered into the study. Etoposide was administered 80 mg/m(2)/day intravenous (i.v.) on days 1, 2 and 3, paclitaxel 175 mg/m(2) i.v. on day 3 and carboplatin area-under-the-concentration-time-curve=6; i.v. on day 3, of a 3-week cycle, and repeated for up to 6 cycles. RESULTS: The overall response (OR) rate was 74% (n=70; 32 complete, 38 partial). Although the OR in LSD and ESD patients was similar (73 vs 74%, respectively), the percentage complete response was significantly higher among the former (49 vs 20%). The main toxicities were grade 3-4 neutropenia and febrile neutropenia (62 and 18%, respectively) and there were 3 toxic deaths. Other toxicities were rare or easily manageable. Disease-free survival and overall survival rates at 1 year were 53 and 70% in LSD and 18 and 39% in ESD patients, respectively. CONCLUSION: The results indicate that the combination of paclitaxel, etoposide and carboplatin has an anti-tumour activity in SCLC that is comparable to other combination regimens, and is well tolerated.

Raltitrexed in the treatment of elderly patients with advanced colorectal cancer: an active and low toxicity regimen.

In spite of the high prevalence of advanced colorectal cancer in the elderly, we have little data on the efficacy and toxicity of chemotherapy in this age group. Raltitrexed is a thymidylate synthetase inhibitor with known activity in the treatment of advanced colorectal cancer. The objective of this study was to analyse the efficacy and tolerance of raltitrexed in elderly patients with advanced colorectal cancer. 92 patients diagnosed with advanced colorectal cancer aged >or=70 years were entered into the study. Raltitrexed was given at a dose of 3 mg/m(2) once every 3 weeks for a minimum of three cycles. A total of 511 cycles were given with a median of five cycles per patient. 20 out of the 90 patients evaluable for response achieved a partial response (PR) (22%, 95% Confidence Interval (CI): 17-36%), 43 (48%) remained stable and 27 showed progression (30%). The mean duration of response was 24 weeks and the progression-free interval was 15 weeks. The overall median survival was 41 weeks. 31 patients (39%, 95% CI: 28-50%) experienced a clinical benefit (improvement of the performance status without a worsening of symptoms or relief of symptoms without a worsening of the performance status). The main toxicities were gastrointestinal and haematological. 12 patients (13%) developed grade 3-4 side-effects: 7 had nausea/vomiting (8%), 6 a transaminase increase (7%), 4 asthenia (4%), 3 diarrhoea (3%), 2 neutropenia (2%), 2 anaemia (2%) and 1 thrombocytopenia (1%). Three toxic deaths occurred (3%). The group of patients with a creatinine clearance