Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy.

To evaluate the predictive value of genes involved in resistance to platinum-taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR. Most of the patients (172 out of 187) received front-line carboplatin-paclitaxel regimen. Expression levels were correlated with overall (OS) and progression-free (PFS) survival by multivariate analysis. Patients with high TXN and THBS1 expression presented longer PFS (P=0.001 and P<0.001, respectively) and OS (P=0.024 and P<0.001, respectively). High TXR1 expression was associated with decreased PFS (P<0.001) and OS (P<0.001). Multivariate analysis demonstrated that high PRR13/low THBS1 expression was an independent factor for decreased PFS (hazards ratio: 1.94; 95% confidence interval (CI): 1.48-2.92; P=0.008) and OS (hazard ratio: 3.89; 95% CI: 2.16-6.87; P<0.001), whereas low TXN expression was correlated with decreased PFS (hazard ratio: 1.44; 95% CI: 1.05-2.84; P=0.043) and OS (hazard ratio: 2.38; 95% CI: 1.78-2.77; P=0.009). These findings indicate that PRR13/THBS1 and TXN expression could be used for the prediction of resistance to treatment of EOC patients and, therefore, merit to be further evaluated.

Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG).

BACKGROUND: Sequential administration of anthracycline and taxane is the current standard of care adjuvant regimen for node-positive early breast cancer. Due to long-term toxicity concerns, anthracycline-free regimens have been developed. We compared a sequential dose-dense anthracycline and taxane regimen with the anthracycline-free regimen of docetaxel and cyclophosphamide. PATIENTS AND METHODS: In this randomized, non-inferiority, phase III trial, women with HER2-negative invasive breast cancer and at least one positive axillary lymph node were randomized to receive either epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) every 2 weeks for four cycles, followed by four cycles of docetaxel (75 mg/m(2)) every 2 weeks with prophylactic G-CSF support (FEC → D) or docetaxel (75 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 21 days for six cycles (TC). The primary end point of the study was the 3-year disease-free survival (DFS) rate. RESULTS: Six hundred and fifty women were randomized to either FEC → D (n = 326) or TC (n = 324). After a median follow-up of 46 and 47 months, the 3-year DFS rate was 89.5% and 91.1% for the FEC → D and TC arm, respectively (hazard ratio = 1.147, 95% confidence interval 0.716-1.839, P = 0.568). Grade 3-4 neutropenia was higher in the TC arm (32.4% versus 10.5%, P = 0.0001). The incidence of neutropenic fever was low (<1%). Nausea, vomiting, hand-foot syndrome and fatigue (grade 3-4) were more common with FEC → D. Acute cardiotoxicity was rare (1 event in each group). There were no toxic deaths. CONCLUSIONS: This trial did not clearly demonstrate that TC is non-inferior to dose-dense FEC → D. However, 3-year DFS rates were excellent in both arms for women with node-positive, HER2-negative early breast cancer. CLINICALTRIALSGOV: NCT01985724.

Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG).

BACKGROUND: Adjuvant trastuzumab in combination with chemotherapy improves survival of women with HER2-positive early breast cancer. In this study, we compared 12 versus 6 months of adjuvant trastuzumab. PATIENTS AND METHODS: Axillary node-positive or high-risk node-negative women with HER2-positive early breast cancer were randomized to receive 12 or 6 months of adjuvant trastuzumab concurrently with dose-dense, granulocyte colony-stimulating factor (G-CSF)-supported docetaxel (75 mg/m(2) every 14 days for four cycles). All patients received upfront dose-dense, G-CSF-supported FEC (5-fluorouracil 700 mg/m(2), epirubicin 75 mg/m(2), cyclophosphamide 700 mg/m(2) every 14 days for four cycles). Randomization was carried out before commence of chemotherapy. The primary end point was the 3-year disease-free survival (DFS). RESULTS: A total of 481 patients were randomized to receive 12 months (n = 241) or 6 months (n = 240) of adjuvant trastuzumab. Chemotherapy was completed in 99% and 98% of patients, while trastuzumab therapy in 100% and 96% of patients in the 12- and 6-month groups, respectively. After 47 and 51 months of median follow-up, there were 17 (7.1%) and 28 (11.7%) disease relapses in the 12- and 6-month groups (P = 0.08). The 3-year DFS was 95.7% versus 93.3% in favor of the 12-month treatment group (hazard ratio = 1.57; 95% confidence interval 0.86-2.10; P = 0.137). There was no difference in terms of overall survival and cardiac toxicity between the two groups. CONCLUSIONS: Our study failed to show noninferiority for the 6-month arm. The results further support the current standard of care that is administration of adjuvant trastuzumab for 12 months.

A multicenter phase I-II study of docetaxel plus epirubicin plus bevacizumab as first-line treatment in women with HER2-negative metastatic breast cancer.

PURPOSE: To assess the efficacy and toxicity of docetaxel (D) plus epirubicin (E) in combination with bevacizumab (B) [DEB regimen] as front-line treatment in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with previously untreated HER2-negative MBC received B (15 mg/kg), E (75 mg/m2) and D (75 mg/m2) with prophylactic G-CSF support every 3 weeks (q3w) for up to 9 cycles followed by B (15 mg/kg q3w) until disease progression. Primary endpoint was the overall response rate (ORR). Circulating tumor cells (CTCs) were evaluated using the CellSearch system at different time points during therapy. RESULTS: Eighty-three women were enrolled with median age 62 years, performance status 0-1 in 93%, triple negative disease in 12% and liver metastases in 47%. In an intention to treat analysis, complete response was achieved in 13 (15.7%) and partial response in 42 (50.6%) (overall response rate 66.3%; 95% CI 56.09-76.44%). The median time to progression was 20.1 months and the 1-year overall survival rate 82.3%. Grade 3-4 neutropenia occurred in 37%, febrile neutropenia in 10%, anemia in 4%, thrombocytopenia in 2% and diarrhea in 2% of patients. There were two deaths possibly related to study treatment (sigmoid perforation n = 1; sudden death n = 1). Moreover, one patient developed pulmonary embolism and another one myocardial infarction while on treatment. Although DEB administration significantly reduced the proportion of patients presenting CTCs, the detection of ≥5 or ≥1 CTCs before treatment initiation was significantly associated with worse progression-free survival (p = 0.001 and p = 0.004) and overall survival (p = 0.001 and p = 0.027), respectively. CONCLUSIONS: The DEB regimen is a very active but also potentially toxic combination in MBC. Detection of CTCs before treatment is associated with worse outcome. CLINICALTRIALSGOV: NCT00705315.

A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer.

BACKGROUND: The Breast Cancer Study Group of the Hellenic Oncology Research Group conducted a phase III trial of single-agent capecitabine versus the vinorelbine/gemcitabine doublet in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. The primary objective was to demonstrate superiority of combination treatment in terms of progression-free survival (PFS). PATIENTS AND METHODS: Women with MBC were randomly assigned to receive either capecitabine (Cap arm: 1250 mg/m(2) twice daily, on days 1-14) or vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m(2); gemcitabine 1000 mg/m(2); both drugs on days 1 and 15). RESULTS: Seventy-four women were treated on each arm and median PFS was 5.4 versus 5.2 months (P = 0.736), for VG and Cap, respectively. Median overall survival was 20.4 months for the VG arm and 22.4 months for the Cap arm (P = 0.319). Overall response rate was 28.4% in the VG arm and 24.3% in the Cap arm (P = 0.576). Both regimens were generally well tolerated. Neutropenia and fatigue were more common with VG arm and hand-foot syndrome with Cap arm. CONCLUSIONS: This trial failed to demonstrate superiority of vinorelbine/gemcitabine doublet over single-agent capecitabine in terms of PFS. Given the favorable toxicity and convenience of oral administration, single-agent capecitabine is recommended for compliant patients.

Maintenance chemotherapy or not in ovarian cancer stages IIIA, B, C, and IV after disease recurrence.

PURPOSE: Ovarian cancer may have a high percentage of residual disease after chemotherapy. It is questionable whether second or more lines of chemotherapy are needed in patients with slow-growing residual disease. In the present trial we compared the median survival of patients with residual or recurrent disease who received 1-2 lines of chemotherapy with those who received 3-9 lines. METHODS: Two hundred and five patients with advanced stage IIIA, B, C and IV ovarian cancer were divided into two groups based on the number of chemotherapy lines they received. All patients had prior first-line chemotherapy; the criteria for recruitment in the study were: a) residual or recurrent disease and b) failure to respond to first-line therapy. Group A included patients who received 1 or 2 lines of chemotherapy and group B, 3-9 lines. RESULTS: The median survival of group A was 76 months and of group B 53 months (p<0.001). Complete response (CR) was observed in 80 out of the 193 7lpar;41.45%) evaluable patients, partial response (PR) in 37 (19.17%), stable disease (SD) in 54 (27.987percnt;) and progressive disease (PD) in 22 (11.40%) patients. CONCLUSION: In ovarian cancer patients with advanced disease, multiple chemotherapy lines (3=9) offer no advantage over 1 or 2 lines, with respect to overall survival.

Depression, anxiety and general psychopathology in breast cancer patients: a cross-sectional control study.

OBJECTIVE: A significant proportion of breast cancer patients experience psychiatric morbidity. The present study compared the psychopathological profile (depression, anxiety and general psychopathology) of Greek women with breast cancer with a group of healthy controls. MATERIALS AND METHODS: Patients (n=109) were recruited from a specialized oncology breast cancer department and healthy controls (n=71) from a breast outpatient clinic. General psychopathology was assessed by the SCL-90-R. The Montgomery-Asberg Depression Rating Scale (MADRS) and the Spielberger State-Trait Anxiety Inventory (STAI) were used for assessing depression and anxiety. Demographics and clinical characteristics were also recorded. Data were modeled using multiple regression analysis. RESULTS: The mean age was 54.7±18.1 years for the control group and 51.2±9.5 years for the patient group (p=0.288). Mean scores on SCL-90-R, MADRS and STAI were significantly higher in the cancer group compared to controls (p<0.05). Multiple regression analysis revealed that breast cancer was independently and positively associated with all psychological measures (p<0.05). Regression coefficients ranged from 0.19 (SCL-90-R, psychotism) to 0.33 (MADRS). Lower anger/aggressiveness and anxiety were found in highly educated women; divorced/widowed women scored higher on obsessionality and MADRS compared to married women. Psychiatric treatment was associated with higher scores on somatization, depression, phobic anxiety and general psychopathology. CONCLUSION: Anxiety, depression, and overall psychopathology are more frequent in breast cancer patients compared to controls. Disease makes a larger independent contribution to all psychopathological measures than any other investigated variable. Therefore, breast cancer patients should be closely followed up in order to identify and timely treat any mental health problems that may arise.

Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer.

BACKGROUND: The purpose of this study was to compare docetaxel plus epirubicin versus docetaxel plus capecitabine combinations as front-line treatment in women with advanced breast cancer (ABC). PATIENTS AND METHODS: Previously untreated patients with ABC were randomly assigned to receive docetaxel 75 mg/m(2) plus epirubicin 75 mg/m(2) (DE) on day 1 or docetaxel 75 mg/m(2) on day 1 plus capecitabine 950 mg/m(2) orally twice daily on days 1-14 (DC) in 21-day cycles. Previous anthracycline-based (neo)-adjuvant chemotherapy was allowed if completed >1 year before enrollment. The primary objective of the study was to compare time to disease progression (TTP). RESULTS: One hundred and thirty-six women were treated on each arm and median TTP was 10.6 versus 11.0 months (P = 0.7), for DE and DC, respectively. According to RECIST criteria we observed 15 (11%) versus 11 (8%) complete responses and 55 (40%) versus 61 (45%) partial responses (P = 0.8), with DE and DC, respectively. Severe toxicity included grade 3-4 neutropenia (57% versus 46%; P = 0.07), febrile neutropenia (11% versus 8%; P = 0.4), hand-foot syndrome (0% versus 4%; P = 0.02), grade 2-3 anemia (20% versus 7%; P = 0.001) and asthenia (12% versus 6%; P = 0.09) with DE and DC, respectively. CONCLUSIONS: The DE and DC regimens have similar efficacy but different toxicity. Either regimen can be used as front-line treatment of ABC.

Evaluation of the paclitaxel-ifosfamide-cisplatin (TIP) combination in relapsed and/or metastatic cervical cancer.

BACKGROUND: Recurrent or metastatic cervical cancer represents an aggressive malignancy with a high rate of locoregional and distant failure. Therefore, we evaluated the three-drug combination of paclitaxel-ifosfamide-cisplatin (TIP). METHODS: Systemic chemotherapy-naive patients with advanced metastatic/relapsed cervical cancer and a World Health Organization (WHO) performance status (PS) of 0-2 were eligible. TIP chemotherapy doses were paclitaxel 175 mg m(-2) on day 1, ifosfamide 2.5 g m(-2) on days 1+2, and cisplatin 40 mg m(-2) on days 1+2, with prophylactic granulocyte-colony stimulating factor. RESULTS: A total of 42 patients with recurrent/metastatic cervical cancer are evaluable for response and toxicity: median age: 56 (25-74) years; PS: 1 (0-2); histologies - squamous: 35, adenosquamous: 5, and adenocarcinoma: 2. Responses were overall response rate (RR): 62% (95% confidence interval (CI): 47.3-76.7%), with complete response (CR): 26% (95% CI: 12.7-39.3%), and partial response (PR): 36% (95% CI: 21.5-49.9%). Responses according to the relapse site were overall RR: 32% (95% CI: 13.7-50.3%) within previously irradiated pelvis vs 75% (95% CI: 57.7-92.3%) in extra-pelvic sites. Median time to progression (TTP) was 7 (range, 2-34+) months and median overall survival (OS) was 16.5 (range, 3-36+) months. Toxicities included grade 3-4 neutropenia: 83% (21% febrile neutropenia), grade 3-4 thrombocytopenia: 9%, no grade 3 neuropathy (35% grade 2), grade 2 asthenia/fatigue 15%, and no treatment-related deaths. CONCLUSION: TIP is an active regimen with acceptable toxicity in advanced/relapsed cervical cancer.

Docetaxel-ifosfamide combination in patients with advanced breast cancer failing prior anthracycline-based regimens: results of a phase I-II study.

The established clinical activity of docetaxel and ifosfamide as single agents in anthracycline pre-treated breast cancer, led us to conduct a phase I-II study to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and clinical activity of the docetaxel+ifosfamide combination in this setting. Patients with histologically confirmed metastatic breast cancer, after failure on prior anthracycline-based chemotherapy, were treated at successive dose levels (DLs) in cohorts of 3-6 with escalated doses of docetaxel 70-100 mg/m(2) over 1 h on day 1 followed by ifosfamide 5-6 g/m(2) divided over days 1+2 (2.5-3.0 g/m(2)/day over 1 h), every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. Between March 1997 and December 2002, 65 patients with a median age of 57 years (range, 32-72) and performance status (WHO) of 1 (range, 0-2) were treated at 5 DLs as follows; 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were: 56%; (95% CI, 42.2-69.7%); 4 CRs, 24 PRs, 10 SD and 12 PD. The median response duration was 7 mo (3-24 mo), median TTP 6.5 mo (0.1-26 mo), and median OS 13 mo (0.1-33 mo). Grade 3/4 toxicities included: neutropenia in 72% of patients, with 60% developing grade 4 neutropenia (

Weekly administration of topotecan-paclitaxel as second-line treatment in ovarian cancer.

PURPOSE: To investigate the weekly administration of topotecan combined with paclitaxel in pretreated advanced ovarian cancer patients; our objectives were to determine efficacy, toxicity and survival. METHODS: The chemotherapy agents, topotecan and paclitaxel were administered on a weekly basis for 3 consecutive weeks, every 28 days. The plan was to give three courses (each course included three once-weekly infusions). The dose of topotecan was 1.75 mg/m(2) and of paclitaxel 70 mg/m(2). RESULTS: From January 2004 until January 2006, 45 patients were enrolled in this multicenter trial; 44 patients were evaluable for response and toxicity. The median age was 60 years old (range 39-82 years) and performance status was 0-2. Thirty-nine patients were in stage III and 5 in stage IV. All patients had been pretreated with carboplatin or cisplatin in combination with paclitaxel. Complete and partial responses were seen in 39% of the patients, stable disease in 43% and progressive disease in 18%; median survival time was 9 months, range 2-24+ months, (95% CI: 7.9-10.2). There was a notable absence of grade 3 toxicity except for neutropenia in 11% of the patients. CONCLUSION: The combination of topotecan and paclitaxel administered on a weekly basis is a well-tolerated chemotherapy schedule. The response rate of 39% is quite high for patients with pretreated ovarian cancer.

Salvage chemotherapy with gemcitabine and oxaliplatin in heavily pretreated patients with metastatic breast cancer: a multicenter phase II study.

PURPOSE: It was the aim of this study to evaluate the activity and tolerance of gemcitabine and oxaliplatin in pretreated metastatic breast cancer patients. METHODS: Thirty-one patients who had disease relapse or progression after completion of an anthracycline- and/or taxane-based front-line regimen were treated with gemcitabine 1,500 mg/m(2) on days 1 and 8 as a 30-min intravenous infusion and oxaliplatin 130 mg/m(2) on day 8 as a 4-hour intravenous infusion, in cycles of 21 days. RESULTS: Complete response occurred in 1 patient (3%) and partial response in 4 patients (13%) (overall response rate 16%; 95% confidence interval 3.2-29.1). Nine patients (29%) had stable disease and 17 (55%) progressive disease. Three partial responses (13%) were achieved among 23 patients receiving the regimen as third-line treatment. The median duration of response was 6 months (range 3-44.8), the median time to tumor progression 4.6 months (range 0.8-43.8), and the median survival 14.4 months (range 2.1-44.8). Grade 3 and 4 neutropenia occurred in 14 patients (45%), grade 3 and 4 thrombocytopenia in 6 patients (20%), and grade 2 and 3 asthenia in 4 patients (13%). There was no episode of febrile neutropenia. CONCLUSION: The gemcitabine-oxaliplatin combination is a relatively active and well-tolerated salvage regimen in patients with heavily pretreated metastatic breast cancer.

Irinotecan combined with docetaxel in pre-treated metastatic breast cancer patients: a phase II study.

PURPOSE: This is a phase II study where a novel chemotherapy combination was tested in pre-treated breast cancer patients: docetaxel and irinotecan have already been established as agents for breast and colorectal cancer, respectively. METHODS: Forty-eight (median age 54 years, range 26-77 year) patients, all evaluable, were enrolled. All patients had been pre-treated with anthracycline-combined chemotherapy, 30 of whom were also treated with paclitaxel and 2 with docetaxel. World Health Organization (WHO) performance status was 0-2. The dominant metastasis was in the liver (54.17%), in the lungs (27.08%), in soft tissues (12.50%) and in the skeleton (6.25%). Treatment involved irinotecan infusion 200 mg/m(2) for 90 min and docetaxel infusion 80 mg/m(2) for 90 min, repeated once every 3 weeks. RESULTS: Twenty-five (52.08%, 95% confidence interval [CI] 37.95-66.21) patients showed responses: 3 complete (6.25%, 95% CI 0-13.05) and 22 (45.83%, 95% CI 31.74-59.92) partial; the most responsive metastases were observed at the liver site (53.85%). Grade 3 and 4 neutropenia was observed in 18 patients (37.50%); 14 (29.17%) patients developed anaemia and three (6.25%), thrombocytopenia. Concerning non-haematologic toxicity, alopecia and fatigue were common; grade 3 diarrhea was observed in only one (2.08%) patient. CONCLUSION: The irinotecan-docetaxel combination produces quite a high response rate in pre-treated advanced breast cancer patients.

Dose escalation of docetaxel and ifosfamide in patients with advanced breast cancer failing prior anthracyclines: mature results of a phase I-II study.

PURPOSE: Single-agent docetaxel and ifosfamide are clinically active in anthracycline-pretreated advanced breast cancer. We conducted a phase I-II study aiming to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the activity of the docetaxel-ifosfamide combination in this setting. PATIENTS AND METHODS: Cohorts of 3-6 patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel (70-100 mg/m(2) over 1 h on day 1), followed by ifosfamide 5-6 g/m(2) divided over days 1 and 2 (2.5-3.0 g/m(2)/day over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. RESULTS: Sixty-five patients (median age 57 years, range 32-72) and performance status (PS) (World Health Organization-WHO) of 1 (range 0-2) were treated at 5 DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were evaluable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were 56% (95% CI 42.2-69.7): complete remission (CR) 4, partial remission (PR) 24, stable disease (SD) 10 and progressive disease (PD) 12. The median response duration was 7 months (range 3-24), the median time to progression (TTP) 6.5 months (range 0.1-26), and the median overall survival (OS) 13 months (range 0.1-33). Grade 3/4 toxicities included neutropenia in 72% of patients-with 60% developing grade 4 neutropenia (

Front-line chemotherapy with docetaxel and gemcitabine administered every two weeks in patients with metastatic breast cancer: a multicenter phase II study.

OBJECTIVE: To evaluate the docetaxel-gemcitabine combination administered every 2 weeks in women with untreated metastatic breast cancer (MBC). METHODS: Fifty-two patients with MBC received docetaxel 65 mg/m2 as front-line chemotherapy intravenously over 1 h followed by gemcitabine 1,500 mg/m2 intravenously over 30 min on days 1 and 14. Cycles were repeated every 28 days without prophylactic growth factor support. Twenty-eight (54%) patients had previously received chemotherapy as adjuvant or neoadjuvant treatment. Thirty-six (69%) patients had visceral disease including 20 (38%) with liver metastases. All patients were evaluated for toxicity and 45 for response. RESULTS: In an intention-to-treat analysis, a complete response occurred in 7 (13%) patients and partial response in 24 (46%) for an overall response rate of 59% (95% CI: 46.3-73.0%). The response rate was 68% for the 28 patients who had previously received adjuvant or neoadjuvant chemotherapy and 67% for the 36 patients with visceral metastases. The median duration of response was 6.1 months and the median time to disease progression 10.9 months. A total of 254 cycles were administered with dose reduction in 26 (10%) cycles and no lethal toxicity. Grade III-IV neutropenia occurred in 17 (33%) patients and thrombocytopenia in 3 (6%). Febrile neutropenia developed in 3 (6%) patients. Nonhematological toxicity was generally mild. CONCLUSION: The docetaxel-gemcitabine combination is an active and well-tolerated front-line treatment for patients with MBC. This regimen represents a suitable option especially for women relapsing after anthracycline-based adjuvant chemotherapy.

Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer.

BACKGROUND: The purpose of this study was to evaluate the prognostic significance of the molecular detection of cytokeratin 19 (CK-19) mRNA-positive cells in the peripheral blood of women with operable breast cancer after the completion of adjuvant chemotherapy. PATIENTS AND METHODS: Blood from 161 patients with stage I and II breast cancer, obtained after the completion of adjuvant chemotherapy, was tested by nested RT-PCR for CK-19 mRNA detection. Using univariate and multivariate analyses possible interactions with other prognostic factors and association of CK-19 mRNA detection with risk of relapse, disease-free interval (DFI) and overall survival were investigated. RESULTS: After completion of adjuvant chemotherapy, 27.3% of patients had peripheral blood CK-19 mRNA-positive cells; there was no association of this finding with any other prognostic factors or the type of chemotherapy regimen used. For patients with less than four involved axillary lymph nodes the risk of relapse was 3.81 [95% confidence interval (CI) 1.06-13.71] times higher, and the DFI was significantly reduced (P = 0.028) if CK-19 mRNA-positive cells were detectable in the blood after the completion of adjuvant chemotherapy. In contrast, for patients with four or more involved lymph nodes, the presence of CK-19 mRNA-positive cells after adjuvant chemotherapy did not significantly affect the risk of relapse or DFI. Furthermore, the risk of relapse was higher (hazards ratio 3.70; 95% CI 1.09-13.89) and the DFI was reduced (P = 0.022) for patients with detectable CK-19 mRNA-positive cells following adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as compared with epirubicin, cyclophosphamide and 5-fluorouracil (FEC) or sequential taxotere-epirubicin and cyclophosphamide (T/EC) chemotherapy. CONCLUSIONS: The detection of CK-19 mRNA-positive cells in the peripheral blood after adjuvant chemotherapy may be of clinical relevance for patients with early breast cancer and less than four involved axillary lymph nodes.

Salvage treatment of metastatic breast cancer with docetaxel and carboplatin. A multicenter phase II trial.

OBJECTIVES: To evaluate the efficacy and safety of docetaxel in combination with carboplatin as salvage treatment in women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Chemotherapy-pretreated women with MBC were treated with docetaxel 75 mg/m(2) as 1-hour i.v. infusion followed by carboplatin AUC 6 mg/ml.min, using the Calvert's formula, as 30-min i.v. infusion. Cycles were repeated on an outpatient basis every 3 weeks. RESULTS: Thirty-six patients received a total of 210 chemotherapy cycles (median 6 cycles/patient). All but one patient had previously received anthracyclines for the treatment of metastatic disease and half of the patients had failed to respond to front-line treatment. Twenty-eight (78%) patients had visceral disease. On an intention-to-treat analysis there were three (8%) complete and 19 (53%) partial responses for an overall response rate of 61% (95% CI: 45.2-77.0%). The response rate was 44% (2 CRs, 6 PRs) among 18 patients who had progressive or stable disease as best response to front-line treatment. The median duration of response was 8 months, the median time to tumor progression 10 months, and the probability of 1-year survival 66%. Grade 3-4 neutropenia was the main hematologic toxicity occurring in 16 (45%) patients or 36 (17%) cycles. Seven (19%) patients developed 8 (4%) febrile neutropenic episodes. Grade 3 thrombocytopenia occurred in 4 (11%) patients or 6 (3%) cycles. Non-hematologic toxicity was generally mild. G-CSF was used in 19 (53%) patients or 134 (64%) cycles. There was one sudden death possibly related to the treatment. CONCLUSION: The docetaxel-carboplatin combination is an active outpatient salvage regimen for the treatment of women with MBC relapsing or not responding to anthracycline-based front-line therapy.

Phase I-II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer.

Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I-II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel-ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70-100 mg x m(-2) over 1 h on day 1 followed by ifosfamide 5-6 g x m(-2) divided over days 1 and 2 (2.5-3.0 g x m(-2) day(-1) over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32-72) years and performance status (WHO) of 1 (range, 0-2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3-68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3-24 months), median time to progression 6.5 month (0.1-26 month), and median overall survival 13 months (0.1-33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients-with 63% developing grade 4 neutropenia (