FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG).

A randomized multicenter phase III study was conducted to compare the sequential docetaxel followed by epirubicin/cyclophosphamide combination with that of FEC regimen as adjuvant chemotherapy in women with axillary node-positive early breast cancer. Seven hundred and fifty-six women with axillary lymph node-positive breast cancer were randomized to receive either 4 cycles of docetaxel (100 mg/m(2)) followed by 4 cycles of epirubicin (75 mg/m(2)) plus cyclophosphamide (700 mg/m(2)) (experimental arm) or 6 cycles of FEC (epirubicin 75 mg/m(2), cyclophosphamide 700 mg/m(2), and 5-fluorouracil 700 mg/m(2); control arm). All regimes were administered every 3 weeks. The primary end point was five-year disease-free survival (DFS). After a median follow-up period of 5 years, 233 (30.8%) relapses had occurred (108 and 125 in the experimental and control arms, respectively; P = 0.181). The five-year DFS was 72.6% (95% CI 63.8-81.3%) and 67.2% (95% CI 58.0-76.4%) for women randomized in the experimental and control arms, respectively (P = 0.041; log rank test). There was no difference in the overall survival between the two arms (83.8 and 81.4% in the experimental and control arms, respectively; P = 0.533). The experimental arm was associated with increased neutropenia requiring administration of granulocyte colony-stimulating factor in 90.5% of the patients as compared with 74.1% in the control arm (P = 0.0001). The sequential docetaxel followed by epirubicin/cyclophosphamide adjuvant chemotherapy regimen resulted in improved five-year DFS in women with axillary node-positive early breast cancer at the expense of increased but manageable myelotoxicity.

Detection of circulating tumor cells in prostate cancer patients: methodological pitfalls and clinical relevance.

Disseminated malignancy is the major cause of prostate cancer-related mortality. Circulating tumor cells (CTCs) are essential for the establishment of metastasis. Various contemporary and molecular methods using prostate-specific biomarkers have been applied to detect extraprostatic disease that is undetectable by conventional imaging techniques, assessing the risk for disease recurrence after therapy of curative intent. However, the clinical relevance of CTC detection is still controversial. We review current literature regarding molecular methods used for the detection of CTCs in the peripheral blood and bone marrow biopsies of patients with prostate cancer, and we discuss the methodological pitfalls that influence the clinical significance of molecular staging.

Clinical features of hypersensitivity reactions to oxaliplatin: a 10-year experience.

BACKGROUND: Oxaliplatin has become one of the major cytotoxic agents for the treatment of gastrointestinal tumors. As a result, several cases of the so-called oxaliplatin-associated hypersensitivity reaction have been documented. PATIENTS AND METHODS: We have retrospectively evaluated and characterized these reactions in our patient group by reviewing the files of 1,224 patients exposed to an oxaliplatin-containing regimen in order to provide useful clinical information for diagnosis and management. RESULTS: Three hundred and eight (308) patients who have never been exposed to platinum compounds developed symptoms compatible with a reaction to oxaliplatin that was verified by manifestation of at least similar symptoms on rechallenging. The reactions occurred after the first 5 courses, with a median course number of 9 (range 1-24). These reactions could be distinguished as (1) mild reactions occurring in 195 (63%) patients manifesting with itching and small area erythema either during treatment or within the next hours, and (2) severe reactions occurring in 113 (37%) patients within minutes of drug infusion manifesting with diffuse erythroderma, facial swelling, chest tightness, bronchospasm and changes in blood pressure. Oxaliplatin withdrawal was not required in patients with a mild reaction. Forty-eight (42%) patients having a severe reaction with appropriate premedication and prolongation of the infusion duration could tolerate 2-4 subsequent courses. For the remaining 65 (58%) patients, oxaliplatin withdrawal was inevitable because of the very severe reactions occurring on rechallenging. In addition, 3 patients presented with thrombocytopenia and 3 others with hemolytic anemia, all reversible upon oxaliplatin discontinuation. CONCLUSIONS: Hypersensitivity reactions to oxaliplatin are underestimated. Although the reactions are not frequent during first courses, in extensively pretreated patients, they may become a serious problem. In the majority of patients, drug discontinuation might not be necessary. In patients manifesting a severe reaction, re-exposure to oxaliplatin should be considered only if the patient can tolerate the reaction and there has been clinical benefit from this therapy. Physicians and nursing staff should be aware of the risk and be well prepared.

Paclitaxel-ifosfamide-cisplatin as salvage chemotherapy in ovarian cancer patients pretreated with platinum compounds and paclitaxel.

BACKGROUND: The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors previously exposed to platinum compounds and paclitaxel has not yet been defined. The present phase II study evaluated the activity and toxicity of a paclitaxel-ifosfamide-cisplatin combination in the aforementioned group of patients. Given the in vitro and in vivo synergism between these three agents, it was believed that using a three drug combination would overcome tumor resistance to cisplatin. PATIENTS AND METHODS: Thirty-five patients were enrolled in the study. The median age was 55 and the median performance status 1. Thirteen (37%) had potentially platinum sensitive, 12 (35%) had primary platinum-resistant and 10 (28%) patients had secondary platinum-resistant tumors. Treatment consisted of paclitaxel 175 mg/m2 as a 3 h i.v. infusion on day 1, cisplatin 75 mg/m2 i.v. over 2 h fractionated over days 1 and 2, and ifosfamide 5 mg/m2 i.v. over 1 h fractionated on days 1-2 with mesna uroprotection. Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulation factor (G-CSF) was given at a dose of 5 microg/kg/day on days 4-10. A median of 4 cycles were administered with the delivered dose intensity at 85% of the planned dose for the three agents. RESULTS: Among 35 patients evaluable for response and toxicity, there were 10 partial responses with a response rate of 28.6% (95% confidence interval 12%-45%). Stable disease was recorded in 9 (25.7%) and progressive disease in 16 (45.7%) patients. Subgroup analysis revealed a response rate of 38.5% in potentially platinum-sensitive, 16.5% in primary platinum-resistant and 30% in secondary platinum-resistant tumors. The median response duration was 5 months (range 3-14 months), the median time to progression 6 months (range 3-18 months) and the median survival 12 months (range 3-44 months). Myelotoxicity was significant with neutropenia grade 3 and 4 occurring in 35% and 45% of patients, respectively. Eight episodes (5% of all cycles) of febrile neutropenia were documented and well managed with oral or i.v. antibiotics and G-CSF continuation until complete recovery. Grade 1, 2 and 3 peripheral neuropathy developed in 30%, 30% and 10% of patients, respectively. In conclusion, the three drug combination demonstrated a significant effectiveness in potentially platinum-sensitive tumors and a moderate efficacy in platinum-resistant tumors. The regimen, although myelotoxic, is tolerable with G-CSF support. Further investigation via comparative studies is required to define any superiority of the present regimen over doublets of the three agents in this group of patients.

Subsets of patients with advanced gastric cancer responding to second-line chemotherapy with docetaxel-cisplatin.

The role of docetaxel in combination with cisplatin in the management of gastric cancer resistant to first-line chemotherapy has not yet been defined. This multicenter prospective phase II study evaluated the activity and toxicity of the docetaxel-cisplatin combination in gastric cancer patients, whose tumors were primarily resistant to first-line chemotherapy or had tumor recurrence after chemotherapy. Treatment consisted of docetaxel 70 mg/m2 i.v. followed by cisplatin 70 mg/m2 both administered on day one, every three weeks. Thirty-two patients were enrolled in the study. The median age was 60 years and the median performance status (ECOG) was 1. Six (19%) patients had tumor progression during adjuvant chemotherapy, 19 (59%) had tumor recurrence after primary chemotherapy and 7 (22%) had tumor progressing while on first-line chemotherapy. Twenty (62%) patients had received non-platinum agents as first-line chemotherapy, while the rest had received the so-called "new generation" regimen that contained cisplatin. Among 32 patients evaluable for response, there were 5 (16%) (CI 95%-8%-35%) partial responses, all in patients that had received non-platinum agents as first-line chemotherapy. Stable disease was recorded in 8 (25%) and progressive disease in 19 (59%) patients. The median response duration was 4 (range 3-6) months, the median time to progression was 5 (range 3-6) months, the median survival after second-line chemotherapy was 6 (range 2-24) months and the median survival after first-line chemotherapy was 12 (range 4-36) months. Myelotoxicity was the main toxicity with grade 3-4 neutropenia occurring in 19 (59%) of the patients and febrile neutropenia in 4 (12%) patients. G-CSF support was given to 25 (78%) patients. Grade 3-4 thrombocytopenia was recorded in 4 (12%) patients. In conclusion, the combination of docetaxel plus cisplatin appears to be a moderately effective regimen with acceptable toxicity when G-CSF support is provided. According to our results, it seems that patients, whose tumors were not exposed to cisplatin during first-line chemotherapy, were more likely to respond to this regimen.

Phase I trial of weekly docetaxel with a 4-weekly cisplatin administration in patients with advanced gastric carcinoma.

The docetaxel-cisplatin combination is active against several tumors including gastric cancer but it is followed by severe myelosuppression. Recent experience with weekly taxanes has demonstrated a mild myelotoxicity with high dose intensity. We investigated in a phase I study a weekly schedule of docetaxel on days 1, 8 and 15 and cisplatin on day 1 every 4 weeks in 19 patients with advanced gastric cancer with no prior chemotherapy. Cohorts of patients were treated with escalating doses of docetaxel (starting dose 30 mg/m(2) per week and increments of 10 mg/m(2) per week) and cisplatin (starting dose 70 mg/m(2) and increments of 5 mg/m(2)). Febrile neutropenia was the only dose-limiting event occurring in four (20%) patients; the dose-limiting toxicity was reached at dose level three (docetaxel 40 mg/m(2) per week and cisplatin 75 mg/m(2)). The maximum-tolerated dose was 40 mg/m(2) per week for docetaxel and 70 mg/m(2) every 4 weeks for cisplatin. Grade 3/4 neutropenia occurred in six patients (30%); early death occurred in one patient with septic shock because of neutropenia and another with acute coronary ischemia. Two (11%) complete and two (11%) partial responses were documented (ORR 22%; 95% CI 3-39%), with a median response duration of 5 months and median time to progression of 7 months. In conclusion, the combination of weekly docetaxel plus cisplatin is feasible with moderate toxicity and merits further investigation in phase II studies in advanced gastric cancer.

Docetaxel in combination with irinotecan (CPT-11) in platinum-resistant paclitaxel-pretreated ovarian cancer.

The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors resistant to platinum compounds has not yet been defined. This multicenter prospective phase II study evaluated the activity and toxicity of the docetaxel-plus-irinotecan combination in ovarian cancer patients whose tumors were resistant to platinum compounds and who had been exposed to paclitaxel. Treatment consisted of docetaxel 60 mg/m2 i.v. followed by irinotecan 200 mg/m2 i.v. both on day 1 followed by prophylactic recombinant human granulocyte-colony stimulating factor (rhG-CSF) support from days 2 to 6, every 3 weeks. Thirty-one patients were enrolled in the study. The median age was 60 years, and the median performance status (ECOG) was 1. Eight (26%) patients had primary tumors resistant to platinum, while the rest of the population had tumor recurrence within 6 months from the last cisplatin treatment. Four chemotherapy cycles per patient were administered, with the delivered dose intensity at 75% of the planned dose for both agents. Among 30 patients evaluable for response, there were 2 (7%) complete and 4 (14%) partial responses (overall response rate 20%; (95% confidence interval, CI, 11%-33%). Stable disease was recorded in 8 (28%) patients and progressive disease in 15 (51%). The median response duration was 4.5 months (range, 3-12), the median time to progression 5 months (range, 2-17) and the median survival 11 months (range, 1-40); the 1-year survival was almost 50%. Myelotoxicity was moderate, with grade 3 and 4 neutropenia occurring in 23% of the patients, grade 3-4 thrombocytopenia in 6% and febrile neutropenia in 13%. Grade 3 diarrhea was observed in 2% of the patients. There was one treatment-related death due to sepsis. In conclusion, the combination of docetaxel plus irinotecan with rhG-CSF support, appears to be a moderately effective regimen with acceptable toxicity for platinum-resistant, paclitaxel-pretreated ovarian cancer patients. Further investigation in comparative studies is required to define the role of combination versus single agent chemotherapy in this group of patients.

Docetaxel and epirubicin supported by granulocyte colony-stimulating factor first-line in advanced breast cancer.

This phase II trial studied the efficacy and toxicity of docetaxel-epirubicin, supported by granulocyte colony-stimulating factor, as first-line chemotherapy in metastatic breast cancer. Patients received epirubicin (60 mg/m2) followed 1 hour later by docetaxel (80 mg/m2) every 3 weeks for a maximum of 8 cycles or until disease progression. Prophylactic granulocyte colony-stimulating factor (5 micrograms/kg) was administered daily for 5 days. Sixty-nine patients were evaluable for efficacy and toxicity. Objective responses occurred in 45 patients (65%; 95% confidence interval: 53-76%), with 11 (16%) complete responses and 34 (49%) partial responses. Responses were observed at all metastatic sites. The median response duration was 8 months (range 4-68), median time to progression was 10 months (range 4-68) and median overall survival was 24 months (range 7-68): neutropenia was dose limiting (46% grade 3-4 toxicity). The left ventricular ejection, fraction measured in 50 patients, fell below normal in 14 patients (28%), 8 patients had grade 1 and 6 grade 2 cardiotoxicity, but none developed congestive cardiac failure. The docetaxel-epirubicin regimen is extremely effective in poor prognosis breast cancer patients with visceral metastases, with significant overall and complete responses, followed by prolonged survival in responders. Although myelosuppression remains the major toxicity, prophylactic GCSF administration was associated with a small percentage of neutropenic fever.

Weekly Gemcitabine plus Fluorouracil-Folinic Acid Given Weekly for Two Days in Patients with Advanced Pancreatic Cancer : A Phase II Study.

OBJECTIVE: To investigate the efficacy and toxicity of gemcitabine administration followed by the combination of fluorouracil (5-FU) modulated by folinic acid in patients with advanced, symptomatic pancreatic cancer. The main objective was to estimate tumour response and any improvement in patients' quality of life. PATIENTS: The study included 48 evaluable patients with metastatic disease with no prior chemotherapy. The study duration was 3 years. INTERVENTIONS: Gemcitabine 1000 mg/m(2) intravenously was given on days 1 and 8 followed by fluorouracil 350 mg/m(2) intravenously as a bolus biologically modulated by folinic acid 350 mg/m(2) intravenously given on days 1, 2, 8 and 9 in order to develop the conditions for any potential drug synergism. The regimen was administered every 3 weeks for 1 year or until disease progression. RESULTS: Objective partial responses were documented in ten (21%) patients (95% CI 10.5, 35). Twenty-two (46%) patients had stable disease while 16 (33%) patients had progressive disease. The median response duration was 8 months (range 4-20). The median time to progression was 6 months (range 2-24), while the median survival of the group was 7 months (range 3-36) and the probability of surviving beyond 12 months was 20%. Of the 44 patients with tumour-related symptoms who were considered evaluable for clinical-benefit response, 28 (70%) patients had pain improvement, 25 (52%) patients had improvement of their performance status, and nine (28%) patients experienced weight gain during treatment. Serum concentrations of cancer antigen (Ca-19-9) were decreased by more than 50% in 14 (37%) of the 38 assessable patients. Chemotherapy was well tolerated, with mild myelotoxicity. Gastrointestinal toxicity was moderate with mild mucositis. CONCLUSION: The regimen of gemcitabine and fluorouracil administered in this study was well tolerated and showed a moderate antitumour activity and a significant palliative effect on tumour-related symptoms. Because fluorouracil is a low toxicity combination agent for gemcitabine, other forms of the two-drug combination warrant further investigation.

A phase I trial of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer.

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTD) of oral metronomic vinorelbine with capecitabine in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Escalated doses of oral metronomic vinorelbine (starting dose 30 mg) every other day continuously and capecitabine (starting dose 800 mg/m(2) bid) on days 1-14 every 21 days were administered. DLTs were evaluated during the first cycle. RESULTS: Thirty-six women were enrolled at eight escalating dose levels. For twenty-four patients, treatment was first line, for eight second line, and for four third line. The DLT level was reached at oral metronomic vinorelbine 70 mg and capecitabine 1,250 mg/m(2), and the recommended MTD doses are vinorelbine 60 mg and capecitabine 1,250 mg/m(2). DLTs were febrile neutropenia grade 3 and 4, diarrhea grade 4, and treatment delays due to unresolved neutropenia. There was no treatment-related death. The main toxicities were grade 2-3 neutropenia in 16.6% of patients each, grade 2-3 anemia 16.5%, grade 2-4 fatigue 27.5%, grade 2-3 nausea/vomiting 11%, and grade 3-4 diarrhea 8.2%. Two complete and 10 partial responses were documented. CONCLUSION: Oral metronomic vinorelbine with capecitabine is a well-tolerated and feasible regimen that merits further evaluation in MBC.

Modified docetaxel-cisplatin in combination with capecitabine as first-line treatment in metastatic gastric cancer. a phase II study.

The combination of docetaxel, cisplatin and fluorouracil is considered to be one of the reference regimens for advanced gastric cancer, but due to its major myelotoxicity, its use in clinical practice has become limited. This prospective phase II study evaluated the activity and toxicity of a modified regimen with lower doses of docetaxel and cisplatin combined with oral capecitabine instead of fluorouracil for patients with advanced gastric cancer. Treatment consisted of docetaxel at 60 mg/m(2) i.v. followed by cisplatin at 60 mg/m(2), both administered on day one, every three weeks. Capecitabine at 2 g/m(2) per day was administered in two divided doses for 14 days (days 2-15). Thirty six patients were enrolled in the study. The median age was 64 years and performance status (ECOG) was 0-1. All patients had advanced disease, 78% with liver metastases, 100% with intra-abdominal lymph node metastases and 67% with peritoneal implants. Out of the 36 patients, 13 had undergone gastric resection, 13 had received adjuvant chemotherapy with irinotecan-leucovorin-fluorouracil, while seven patients had undergone adjuvant radiotherapy. The remaining 23 patients presented with advanced inoperable disease. Among 36 evaluable for response cases, there were 16 (44.4%) (Confidence Internal (CI) 95%=28-60%), partial responses. Stable disease was recorded in 12 (33.3%), resulting in an overall disease control rate of 78% (CI 95%=69-87%), while 8 (22.3%) patients progressed on chemotherapy. The median response duration was 6 (range=3-8) months. The median time-to-progression was 5 (range=3-6) months and the median survival (after the administration of a second-line chemotherapy in 12 patients), was 12 (range=5-24) months. Myelotoxocity was the main toxicity, with grade 3-4 neutropenia occurring in 18 (50%) and febrile neutropenia in six (16%) patients. Granulocyte-Colony Stimulating Factor (G-CSF) support was given to 16 (44.4%) patients, while grade 3 thrombocytopenia was recorded in two (6%). In conclusion, this modified regimen of docetaxel-cisplatin-capecitabine appears to have comparable efficacy with that reported for the reference regimen, with acceptable toxicity when G-CSF support is provided. However, because due to the small size of the study, further investigation is warranted.

Salvage chemotherapy with oxaliplatin and capecitabine for breast cancer patients pretreated with anthracyclines and taxanes.

There is no standard treatment for breast cancer patients whose tumors have been exposed both to anthracyclines and taxanes. Oxaliplatin shows synergism with 5-fluorouracil (5-FU) and capecitabine is an oral prodrug of 5-FU with known efficacy in pretreated patients. This phase II trial studied the efficacy and toxicity of the oxaliplatin-capecitabine combination as salvage treatment in breast cancer patients pretreated with anthracyclines and taxanes. Patients received oxaliplatin 80 mg/m(2) on day 1 followed by oral capecitabine 1800 mg/m(2) divided in two doses for 7 days every two weeks for a maximum of twelve courses or until disease progression. Twenty-eight patients were evaluable for efficacy and toxicity. Objective responses (all partial) were documented in 9 patients [32%; 95% confidence interval (CI): 13-51.2%]. Responses were documented at all metastatic sites. The median response duration was 5 months (range 3-9), median time to progression was 4.5 months (range 2-10) and median overall survival was 10 months (range 2-18). Myelotoxicity was minimal with grade 3 thrombocytopenia as the main toxicity. Hand-foot syndrome was well tolerated. The present regimen was well tolerated with a rather moderate effectiveness but very significant for this group of patients. Further studies where the combination could be compared with single agent capecitabine are warranted.

Cisplatin-Ifosfamide-gemcitabine as salvage chemotherapy in ovarian cancer patients pretreated with platinum compounds and Paclitaxel.

BACKGROUND: The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors previously exposed to platinum compounds and paclitaxel has not yet been defined. The present phase II study evaluated the activity and toxicity of a gemcitabine-ifosfamide-cisplatin combination in the aforementioned group of patients. Given the in vitro and in vivo synergism between the three agents, it was believed that using a three-drug combination would overcome tumor resistance to cisplatin. PATIENTS AND METHODS: Twenty-four patients were enrolled in the study. The median age was 56 years and the median performance status 1. Eight (34%) had potentially platinum-sensitive, 6 (24%) had primary platinum-resistant and 10 (42%) patients had secondary platinum-resistant tumors. Treatment consisted of gemcitabine 1 g/m(2) i.v. on days 1 and 8, cisplatin 75 mg/m(2) i.v. over 2 h fractionated over days 8 and 9, and ifosfamide 5 mg/m(2) i.v. over 1 h fractionated on days 8-9 with mesna uroprotection. Courses were administered every 3 weeks on an outpatient basis. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 microg/kg/day on days 10-14. A median of 4 cycles were administered with the delivered dose intensity at 85% of the planned dose for the three agents. RESULTS: Among 24 patients evaluable for response and toxicity, there were 8 partial responses with a response rate of 33% (95% confidence interval 16.4-55%). Stable disease was recorded in 6 (25.7) and progressive disease in 10 (42%) patients. Subgroup analysis revealed a response rate of 50% in potentially platinum-sensitive, 16.5% in primary platinum-resistant and 30% in secondary platinum-resistant tumors. The median response duration was 5 months (range 3-12 months), the median time to progression 6 months (range 3-16 months) and the median survival 12 months (range 3-24 months). Myelotoxicity was significant, with neutropenia grade 3 and 4 occurring in 35% and 20% of patients, respectively. Four episodes (3.5% of all cycles) of febrile neutropenia were documented and were well managed with oral antibiotics and G-CSF continuation until complete recovery. Grade 1, 2 and 3 peripheral neuropathy developed in 40%, 30%, and 10% of patients, respectively. CONCLUSION: The three-drug combination demonstrated a significant effectiveness in potentially platinum-sensitive tumors and a moderate efficacy in platinum-resistant tumors. The regimen, although myelotoxic, is tolerable with G-CSF support. Further investigation via comparative studies is required to define any superiority of the present regimen over doublets of the three agents in this group of patients.