Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO.

BACKGROUND: Patients with recurrent/metastatic endometrial cancer that progresses after chemotherapy have limited treatment options and poor outcomes. Preclinical data suggest the oral mammalian target of rapamycin inhibitor everolimus may provide clinical benefit in these patients. METHODS: In this multicenter, open-label, phase 2 study, patients with advanced or metastatic endometrial cancer refractory to one or two previous chemotherapy regimens received everolimus 10 mg per day until progression or unacceptable toxicity. Primary end point was the non-progressive disease rate at 3 months. Secondary end points included duration of response, progression-free, and overall survival (OS), and safety. RESULTS: Forty-four patients were enrolled (median age, 65 years); 66% received one previous chemotherapy regimen. The 3-month non-progressive disease rate was 36% (95% confidence interval 22-52%), including two patients (5%) with partial response (PR). At 6 months, two additional patients experienced PR. Median duration of response was 3.1 months. Median progression-free and OS were 2.8 months and 8.1 months, respectively. The most common adverse events were anaemia (100%), fatigue (93%), hypercholesterolaemia (81%), and lymphopenia (81%). CONCLUSION: Everolimus demonstrated efficacy and acceptable tolerability in patients with chemotherapy-refractory advanced or metastatic endometrial cancer. These results support the further development of phosphatidylinositol 3-kinase-targeted therapies in endometrial cancer.

Targeting SKCa channels in cancer: potential new therapeutic approaches.

Many studies have reported changes in potassium channel expression in many cancers and the involvement of these channels in various stages of cancer progression. By contrast, data concerning SKCa channels (small conductance calcium-activated potassium channels) have only recently become available. This review aims i) to present the structure and physiology of SKCa channels, ii) to provide an overview of published data concerning the SKCa proteins produced in tumor cells, and, whenever possible, the biological function assigned to them and iii) to review previous and novel modulators of SKCa channels. SKCa channels are activated by low concentrations of intracellular calcium and consist of homo- or heteromeric assemblies of α-subunits named SK1, SK2 and SK3. SK2-3 channels are expressed in tumors and have been assigned a biological function in cancer cells: the enhancement of cell proliferation and cell migration by hijacking the functions of SK2 and SK3 channels, respectively. Two major classes of SKCa modulators have been described: toxins (apamin) and small synthetic molecules. Most SKCa blockers are pore blockers, but some modify the calcium sensitivity of SKCa channels without interacting with the apamin binding site. In this review, we present edelfosine and ohmline as atypical anticancer agents and novel SK3 inhibitors. Edelfosine and ohmline are synthetic alkyl-lipids with structures different from all previously described SKCa modulators. They should pave the way for the development of a new class of migration-targeted anticancer agents. We believe that such blockers have potential for use in the prevention or treatment of metastasis.

New alkyl-lipid blockers of SK3 channels reduce cancer cell migration and occurrence of metastasis.

Edelfosine is an inhibitor of SK3 channel mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, (125)I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC(50) of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-antimetastatic agent.

The SK3/K(Ca)2.3 potassium channel is a new cellular target for edelfosine.

BACKGROUND AND PURPOSE: The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (edelfosine) is an ether-linked phospholipid with promising anti-cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function. EXPERIMENTAL APPROACH: Using cell migration-proliferation assays, patch clamp, spectrofluorimetry and ¹²5I-Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA-MB-435s cells, mediated by the small conductance Ca²(+) -activated K(+) channel, SK3/K(Ca)2.3. KEY RESULTS: Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/K(Ca)2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit ¹²5I-Apamin binding to this SK(Ca) channel; rather, it reduced the calcium sensitivity of SK3/K(Ca)2.3 channel and dramatically decreased intracellular Ca²(+) concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SK(Ca) channel blockers. In contrast, K+ channel openers prevented edelfosine-induced anti-migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA-MB-435s cell migration. In contrast, transient expression of SK3/K(Ca)2.3 protein in a SK3/K(Ca)2.3-deficient cell line increased cell migration and made these cells responsive to edelfosine. CONCLUSIONS AND IMPLICATIONS: Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/K(Ca)2.3 channels and provide insights into the future development of a new class of migration-targeted, anti-cancer agents.

Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial.

BACKGROUND: Breast cancer becomes lethal when visceral metastases develop. At this stage, anti-cancer treatments aim at relieving symptoms and delaying death without resulting in additional toxicity. On the basis of their differential anti-oxidant defence level, tumour cells can be made more sensitive to chemotherapy than non-tumour cells when membrane lipids are enriched with docosahexaenoic acid (DHA), a peroxidisable and oxidative-stress-inducing lipid of marine origin. METHODS: This open-label single-arm phase II study evaluated the safety and efficacy (response rate), as primary end points, of the addition of 1.8 g DHA daily to an anthracycline-based chemotherapy (FEC) regimen in breast cancer patients (n = 25) with rapidly progressing visceral metastases. The secondary end points were time to progression (TTP) and overall survival (OS). RESULTS: The objective response rate was 44%. With a mean follow-up time of 31 months (range 2-96 months), the median TTP was 6 months. Median OS was 22 months and reached 34 months in the sub-population of patients (n = 12) with the highest plasma DHA incorporation. The most common grade 3 or 4 toxicity was neutropaenia (80%). CONCLUSION: DHA during chemotherapy was devoid of adverse side effects and can improve the outcome of chemotherapy when highly incorporated. DHA has a potential to specifically chemosensitise tumours.

All-oral combination of oral vinorelbine and capecitabine as first-line chemotherapy in HER2-negative metastatic breast cancer: an International Phase II Trial.

BACKGROUND: This multicentre, international phase II trial evaluated the efficacy and safety profile of a first-line combination of oral vinorelbine plus capecitabine for women with metastatic breast cancer (MBC). METHODS: Patients with measurable, HER2-negative disease received, as a first line in metastatic setting, 3-weekly cycles of oral vinorelbine 80 mg m(-2) (after a first cycle at 60) on day 1 and day 8, plus capecitabine 1000 mg m(-2) (750 if >or=65 years of age) twice daily, on days 1-14. Treatment was continued until progression or unacceptable toxicity. RESULTS: A total of 55 patients were enrolled and 54 were treated (median age: 58.5 years). Most (78%) had visceral involvement and 63% had received earlier (neo)adjuvant chemotherapy. The objective response rate (RECIST) in 49 evaluable patients was 51% (95% confidence interval (CI), 36-66), including complete response in 4%. The clinical benefit rate (response or stable disease for >or=6 months) was 63% (95% CI, 48-77). The median duration of response was 7.2 months (95% CI, 6.4-10.2). After a median follow-up of 41 months, median progression-free survival was 8.4 months (95% CI, 5.8-9.7) and median overall survival was 29.2 months (95% CI, 18.2-40.1). Treatment-related adverse events were manageable, the main grade 3-4 toxicity was neutropaenia (49%); two patients experienced febrile neutropaenia and three patients had a neutropaenic infection (including one septic death). A particularly low rate of alopaecia was observed. CONCLUSION: These results show that the all-oral combination of oral vinorelbine and capecitabine is an effective and well-tolerated first-line regimen for MBC.

A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients.

PURPOSE: A multicentric, phase II study to evaluate the efficacy and safety of the combination paclitaxel and oxaliplatin in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: Patients received 175 mg/m(2) paclitaxel (over 3 h) followed by 130 mg/m(2) oxaliplatin (over 2 h) every 21 days for up to nine cycles without hydration or primary granulocyte colony-stimulating factor prophylaxis. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2 and to have received no more than one prior cisplatin- and/or carboplatin-containing chemotherapy regimen with a platinum-progression-free interval > or =6 months. RESULTS: Of the 105 patients enrolled and treated, 98 were eligible. An overall response rate of 81% (79 of 98 patients) (95% confidence interval 71% to 88%) was observed according to RECIST criteria (third party reviewed), and 88% (86 of 98) when this was complemented with CA-125 response. With a median follow up of 43.6 months (range 30.2-64.2) the median progression-free survival was 10.2 months (range 0.3-21.4) and the overall survival 32.4 months. Seven hundred and eight cycles were administered (median seven per patient; range one to nine). A total of 67% of patients experienced National Cancer Institute Common Toxicity Criteria grade 3-4 neutropenia, including 8% with concomitant febrile episode, without treatment-related deaths. Ninety-three per cent of patients experienced neuropathy of grade 1 or more, including 25% with cumulative reversible peripheral neuropathy of grade 3-4. Oxaliplatin doses were reduced in 30 patients due to neurotoxicity. CONCLUSIONS: The oxaliplatin/paclitaxel combination can be administered in an outpatient setting every 3 weeks without specific measures. The high level of activity and its duration observed warrants further evaluation of this combination in pretreated platinum-sensitive advanced ovarian cancer patients.

Tumor parameters, clinical and pathological responses, medical management, and survival through time on 710 operable breast cancers.

The aim of the current study is an analysis of tumor parameters, clinical and pathological responses, medical management, and survival on 710 operable breast cancer patients who received neoadjuvant chemotherapy from 1982 to 2004 and were grouped into four successive periods according to diagnosis date: (1) 1982-1989; (2) 1990-1994; (3) 1995-1999; and (4) 2000-2004. Patients were treated by different neoadjuvant chemotherapies combinations: AVCF/M, TNCF, NEM, NET, TAXOTERE, FEC 50, 75, 100, FAC 50, and TAXOTERE-TNCF, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1-9). After primary chemotherapy, patients underwent a surgery and a radiotherapy. In case of significant residual disease, some patients received additional courses of chemotherapy. In addition, menopausal patients with hormonal receptor-positive tumors received tamoxifen for 5 yr. Clinical factors had some remarkable variations with time. The median age of the patients was 49.5 yr (range, 26-81). The size of the tumor was significantly greater from 1995; conversely, clinical lymph-node involvement was lower in period 4 than in the first period. The percentage of invasive ductal carcinoma and of SBR III tumors increased about 20% from 1982-1989 to 2000-2004. The number of positive hormonal receptors increased from 38.3% in period 1 to 74% in period 4. The clinical response rate improved recently from before 1990. The pathological response rate was greater in periods 2 and 3 than in periods 1 and 4. An adjuvant hormonotherapy became progressively more frequently given (44.7 for period 1 and 73.3% for period 4). Finally, no significant difference was found when we compared overall and disease-free survival through the four periods. It appears that the progressive increase of tumor burden was compensated by more effective treatments.

Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer.

The purpose of the study was to evaluate the efficacy and safety of docetaxel plus epirubicin (ET) and of 5-fluorouracil plus epirubicin and cyclophosphamide (FEC) as first-line chemotherapy for metastatic breast cancer. A total of 142 patients (intent-to-treat (ITT)) with at least one measurable lesion were randomised to receive docetaxel 75 mg m(-2) plus epirubicin 75 mg m(-2) or 5-fluorouracil 500 mg m(-2) plus epirubicin 75 mg m(-2) and cyclophosphamide 500 mg m(-2) intravenously once every 3 weeks for up to eight cycles. Prophylactic granulocyte-colony-stimulating factor was only permitted after the first cycle, if required. Per-protocol analysis (n=132) gave an overall response rate for ET of 63.1% (95% confidence interval (CI), 50-78%) and for FEC 34.3% (95% CI, 23-47%) after a median seven and six cycles, respectively. Intent-to-treat population (n=142) gave an overall response rate for ET of 59% (95% CI, 47-70%) and for FEC 32% (95% CI, 21-43%) after a median seven and six cycles, respectively. The median response duration for ET was 8.6 months (95% CI, 7.2-9.6 months) and for FEC 7.8 months (95% CI, 6.5-10.4 months). The median time to progression (ITT) for ET was 7.8 months (95% CI, 5.8-9.6 months) and for FEC 5.9 months (95% CI, 4.6-7.8 months). After a median follow-up of 23.8 months, median survival (ITT) for ET and FEC were 34 and 28 months, respectively. Nonhaematologic grade 3-4 toxicities were infrequent in both arms. Haematologic toxicity was more common with ET and febrile neutropenia was reported in 13 patients (18.6%) in the ET group. Two deaths in the ET group were possibly related to study treatment. In conclusion, both ET and FEC were associated with acceptable toxicity. ET is a highly active first-line therapy for metastatic breast cancer.

Neoadjuvant docetaxel for operable breast cancer induces a high pathological response and breast-conservation rate.

Docetaxel (Taxotere), alone or in combination with other anticancer agents, has proven efficacy in the first- and second-line treatment of metastatic breast cancer. This phase II study investigated the efficacy and tolerability of docetaxel as neoadjuvant chemotherapy in women with stage II-III primary operable breast cancer. Patients (n=88) were treated with six cycles of docetaxel at 100 mg m(-2) every 21 days, followed by definitive surgery and radiotherapy. After six cycles of docetaxel, the overall clinical response rate was 68.4% (CI 95%: 58.1-78.7%), including 19.0% complete remissions. Breast conservation was achieved in 72.4% of patients. A high pathological complete response (pCR) rate in breast was confirmed in 15 patients (19.8% (CI 95%: 10.8-28.8%)) on Chevallier's classification restricted to breast and in 27 patients (35.5% (CI 95%: 24.7-46.3%)) on Sataloff's classification. After a median follow-up of 30.8 months, 19 recurrences were documented with a median time to first recurrence of 17.3 months. Patients with stage III tumours had more recurrences than patients with stage II tumours (P=0.02). The principal toxicity of docetaxel is myelosuppression and 70.5% of patients developed grade III or IV neutropenia with 13.6% developing neutropenic sepsis. There was no case of severe cardiac toxicity, thrombocytopenia or any other serious adverse events. In conclusion, neoadjuvant docetaxel induces a high pCR and breast-conservation rate. Docetaxel monotherapy is a highly effective regimen that merits formal comparison with currently used combination regimens in a randomised phase III study.

Phase II multicentre study of docetaxel plus 5-fluorouracil in patients with anthracycline-pretreated metastatic breast cancer.

The purpose of the study was to determine the efficacy and safety of docetaxel plus continuous infusion of 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracyclines. A total of 41 patients with histologically proven metastatic breast cancer and performance status 0-2, who had received at least one anthracycline-containing regimen, received docetaxel 85 mg m(-2) followed by continuous infusion of 5-FU 750 mg m(-2) day(-1) for 5 days every 3 weeks for up to eight cycles. All patients received corticosteroid premedication, but there was no prophylactic colony-stimulating factor support. The most frequent metastatic sites were the liver (61%), bone (29%), and lung (29%). All 41 patients were assessable for toxicity and 30 were eligible and assessable for efficacy. The objective response rate was 70.0% (95% CI: 53.6-86.4%) for the per protocol group and 53.7% (95% CI: 38.4-68.9%) for the intent-to-treat (ITT) population. For the ITT population, median duration of response was 8.4 months (95% CI: 6.7-12.2 months), median time to progression was 6.7 months (95% CI 5.5-8.6 months), and median survival was 17 months (95% CI: 12.3-not recorded months). Grade 3/4 neutropenia occurred in 54% of patients, with febrile neutropenia in 24% of patients and 5% of cycles, but infections were rare. Stomatitis was frequent, grade 3 in 24% of patients and grade 4 in one patient (2%), but manageable. Diarrhoea was rare, grade 3 in 7% of patients and 1% of cycles. Other grade 3/4 nonhaematological toxicities were infrequent. In conclusion, this docetaxel/5-FU regimen is highly active and well tolerated in patients with anthracycline-pretreated metastatic breast cancer. The efficacy is particularly promising, as one-third of patients were either second-line and/or anthracycline-resistant/refractory.

Anthracycline-induced cardiac toxicity is not increased by dietary omega-3 fatty acids.

Exogenous n-3 polyunsaturated fatty acids (PUFA) and specially docosahexaenoic acid (DHA) have been previously reported to potentiate the efficacy of anticancer agents that generate an oxidative stress, such as anthracyclines, by enhancing the susceptibility of cell membranes to lipid peroxidation. Since lipid peroxidation has also been suggested to mediate anthracycline-induced heart failure, we designed a study aimed at investigating whether a DHA-enriched diet coupled with controlled oxidative conditions prevents or aggravates this serious side effect in vivo. Female Sprague-Dawley rats were submitted for at least 3 weeks to diet enriched in DHA, which was provided either as natural oil (sardine oil, experiment 1) or in a purified form (DHASCO, experiment 2). At the same time, to constrain the nutritional oxidative status, the anti-oxidant Vitamin E or the pro-oxidant menadione/sodium ascorbate redox mixture was added. Then, epirubicin was administered weekly at two cumulative doses, 9 mg x kg(-1) (experiment 1) or 15 mg x kg(-1) (experiment 2). Cardiotoxicity was assessed by electrocardiographic (ECG) and hemodynamic measurements, completed with histological examination. Epirubicin-induced dose-dependent mortality, alterations of hemodynamic parameters and histological damages, all features characterizing the occurrence of congestive heart failure. Moreover, the addition of anti- or pro-oxidant did not change the hemodynamics either at the lowest (experiment 1) or the highest dose (experiment 2). Similarly, the ECG measurements and histological examinations did not reveal any difference. DHA was actually incorporated, as evaluated through the adipose tissue fatty acid composition. All these observations indicated that the DHA-enriched diet, placed under controlled oxidative conditions, did not appear to prevent but neither to aggravate epirubicin-induced cardiotoxicity. These findings support the idea that DHA improves the anthracycline therapeutic index.

Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy.

PURPOSE: A phase II trial was performed to evaluate the efficacy, tolerance, and pharmacokinetic profiles of oral vinorelbine (Navelbine). Oral Navelbine (NVB; Pierre Fabre Médicament, Boulogne, France) was given as first-line chemotherapy for locally advanced or metastatic breast carcinoma (ABC). PATIENTS AND METHODS: Sixty-four patients were entered to receive oral NVB on a weekly basis for a total of 8 weeks unless progression or toxicity occurred. Oral NVB was given at 60 mg/m(2) weekly for the first three administrations and was increased to 80 mg/m(2) for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Patients with objective response or stable disease continued treatment up to a total of 12 weeks or more. RESULTS: Fifty-eight evaluable patients were included in our study. Four patients (6.9%) had complete responses, and 14 (24.1%) had partial responses, for an overall response rate of 31% (95% CI, 19% to 43%). Median progression-free survival was 17.4 weeks. Median overall survival is not yet reached. There were no treatment-related deaths. The main toxicity was neutropenia: grade 4 in 17.2% of the patients, and 1.8% of administrations and associated clinical serious events in 4 patients (6.2%). Grade 3 and 4 nausea and/or vomiting were noted in 3.1% and 4.6% of the patients, respectively. Only one patient developed grade 3 neuroconstipation. An analysis of Quality of Life Questionnaire C30 forms revealed no significant alteration between baseline and weeks 8 and 16 in global quality of life. CONCLUSION: Oral NVB at this schedule is an effective and well-tolerated agent in the treatment of ABC and offers a promising alternative to the intravenous route. Combination studies are ongoing.

A phase II trial of ZD0473 in platinum-pretreated ovarian cancer.

The primary aim of this phase II trial was to assess the antitumour activity of ZD0473 in ovarian cancer patients who had failed initial platinum-based therapy. Patients (n=94) were classified as either platinum-sensitive (n=35) or platinum-resistant (n=59) depending on whether they had relapsed or progressed within 26 weeks of completing first-line platinum-based chemotherapy. Patients initially received 120 mg/m(2) ZD0473 as a 1-h intravenous (i.v.) infusion on day 1 of a 3-week cycle. If well tolerated, the dose could be escalated to 150 mg/m(2). Few patients (9%) withdrew because of treatment-related adverse events and no clinically significant oto-, nephro- or neurotoxicity was observed. Objective response rates for platinum-resistant and sensitive patients were 8.3 and 32.4%, respectively, and clinical benefit was observed in 76.5% of the sensitive patients. Median time to progression was 57 and 180 days, and median time to death was 242 and 402 days, for resistant and sensitive patients, respectively. In conclusion, ZD0473 has a manageable toxicity profile and encouraging activity in platinum-sensitive ovarian cancer patients.

Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin +/- taxane-pretreated ovarian cancer patients.

BACKGROUND: This multicentre phase II open-label study evaluated safety and antitumour activity of oxaliplatin in cisplatin or carboplatin (cis/carboplatin) +/- taxane-pretreated advanced ovarian cancer (AOC) patients. PATIENTS AND METHODS: Forty-eight patients received oxaliplatin 130 mg/M2 intravenously every 3 weeks, 94% having a performance status (PS) 0-1. All were pretreated with cis/carboplatin and 21 (44%) with paclitaxel. The median number of involved organs was two, 18 (38%) had liver metastasis, 23 (48%) were platinum-resistant and 14 (29%) were taxane-resistant. Forty-two patients were evaluable for a response, 18 (43%) were platinum-resistant and 11 (26%) were taxane-resistant. RESULTS: A total of 253 cycles was administered (median: 5.5/patient). Median cumulative oxaliplatin dose was 666 mg/m2. National Cancer Institute-Common Toxicity Criteria toxicity analysis showed that seven patients (15%) had grade 3/4 thrombocytopenia, two patients (4%) had grade 3 neutropenia, and one patient had grade 3 anaemia. Eleven patients (23%) experienced grade 3 neurosensory toxicity. Of the 29 patients with peripheral neuropathy at the end of treatment, 55% had recovered or improved 1 month later. Eleven objective responses (two complete) were obtained in the 42 evaluable patients [ORR 26%, 95% confidence interval (CI) 14% to 42%], with 10/24 (42%, 95% CI 22% to 63%) in platinum-sensitive, and 1 of 18 (5.6%, 95% CI 0% to 27%) in platinum-resistant patients. Median response duration was 9.2 months (95% CI 6.6% to 11.8%), and median progression-free and overall survival in all treated patients were 4.3 months (95% CI 3.0% to 5.7%) and 15.0 months (95% CI 11.1% to 18.8%), respectively. CONCLUSION: Oxaliplatin has a good safety profile and is active in cis/carboplatin +/- paclitaxel-pretreated AOC patients.

Sequential or alternating administration of docetaxel (Taxotere) combined with FEC in metastatic breast cancer: a randomised phase II trial.

The aim of this study, using a Fleming single-stage design, was to explore the efficacy and safety of Taxotere 100 x mg x m(-2) docetaxel and FEC 75 cyclophosphamide 500 mg x m(-2), fluorouracil 500 x mg x m(-2) and epirubicin 75 mg x m(-2), in alternating and sequential schedules for the first-line treatment of metastatic breast cancer. One hundred and thirty-six women were randomly allocated, to one of three treatment regimens: DTX 100 plus FEC 75, alternated for eight courses (ALT); four courses of DTX 100 followed by four courses of FEC 75 (SEQ T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ F). One hundred and thirty-one women were evaluable for tumour response. Although the treatment outcome was equivalent in the two sequential arms and the alternating regimen (P=0.110, not significant), the response rate was less encouraging in the SEQ F arm (52.3%) than in the other two arms (71.1% for ALT and 70.5% for SEQ T), in which docetaxel was administered first. Time to progression was similar in the ALT, SEQ T and SEQ F arms (9.5, 9.3 and 10.4 months respectively). Grade 3-4 neutropenia was observed in nearly all patients; febrile neutropenia occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of patients. Few patients (< or =9%) developed grade 3-4 non-haematological toxicities. Relative dose intensity was 97-99% for all regimens. All treatment regimens were active and well tolerated.

Results of ZD0473 in platinum-pretreated ovarian cancer: analysis according to platinum free interval.

Resistance to platinum-containing regimens can develop in many women with ovarian cancer and may lead to relapse in > 80% of patients. ZD0473 is a new-generation platinum agent that, in preclinical studies, shows evidence of antitumour activity and overcomes platinum-resistance mechanisms. This Phase II trial has evaluated the efficacy and tolerability of ZD0473 in second-line ovarian cancer patients. Patients received ZD0473 120 mg/m2 (1-h iv infusion, day 1 q 3-weeks); the starting dose was increased to 150 mg/m2 after a safety review. We report here on results when patients are divided into four cohorts depending upon whether they were considered platinum-resistant or -sensitive. Patients were placed into one of 3 cohorts if they were platinum resistant (relapsed/progressed < or = 26 weeks after completion of prior platinum-based chemotherapy) or cohort 4 if this period was > 26 weeks (sensitive). Ninety-four patients were recruited to the trial (59 resistant, 35 sensitive; median age 58 [range 27-75] years; 86 with performance status [PS] < or = 1). Forty-nine patients received a starting dose of 120 mg/m2, of which 15 escalated to 150 mg/m2, and 45 received a starting dose of 150 mg/m2. Overall, the median number of treatment cycles received was 3 (range 1-8). Grade 3/4 thrombocytopenia was the most common haematological adverse event occurring in 62% of patients overall. Grade 3/4 lethargy, vomiting and nausea were the most common non-haematological toxicities. No clinically significant oto-, nephro- or neurotoxicity was observed. Overall response rates for all platinum-resistant and -sensitive patients were 8.3% and 32.4%, respectively. Stable disease occurred in 17 resistant and 15 sensitive patients.