Quality-of-life analysis of the MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG study comparing platinum-based versus non-platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer.

Background: MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods: Ovarian cancer patients recurring or progressing 6-12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intention-to-treat. Results: Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P = 0.001) and objective response rate (51.6% versus 19.4%, P = 0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand-foot skin reaction, rash/desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion: MITO-8 QoL analysis shows that deterioration of some functioning and symptom scales is lower with PBC, with improvement of emotional functioning and pain, despite worsening of toxicity-related items. ClinicalTrials.gov: NCT00657878.

Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial.

BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EUDRACT NUMBER: 2011-001298-17.

A Phase II, randomized, double-blind study of zibotentan (ZD4054) in combination with carboplatin/paclitaxel versus placebo in combination with carboplatin/paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy (AGO-OVAR 2.14).

BACKGROUND: In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer. METHODS: In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10mg or placebo once-daily, plus paclitaxel 175 mg/m(2) iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability. RESULTS: A total of 120 patients were randomized (zibotentan: n=59; placebo: n=61). Addition of zibotentan 10mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR=1.46, [80% CI: 1.10-1.94]; P=0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: -16%; paclitaxel: -14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43-48% of patients). CONCLUSIONS: Zibotentan 10mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.

A phase I-II study of elacytarabine (CP-4055) in the treatment of patients with ovarian cancer resistant or refractory to platinum therapy.

PURPOSE: Treatment of patients with recurrent ovarian cancer remains a challenge, and there is a need for new and more effective agents. A phase I-II study was designed to determine the recommended dose (RD) and the anti-tumour effect of a prolonged administration of elacytarabine, the elaidic ester of cytarabine, in patients with refractory/resistant recurrent ovarian cancer. EXPERIMENTAL DESIGN: The primary objective of the dose escalation phase I part was to determine the RD for elacytarabine when given twice for five consecutive days in a 4-week schedule, D1-5 and D8(+2)-12(+2) q4w. Three to six patients were to be enrolled at each dose level. The start dose was elacytarabine 75 mg/m(2)/day. The phase II part was designed as a two-step study based on response. RESULTS: A total of 28 patients entered the study, 17 patients in the phase I part and 11(#) patients in phase II. Three dose levels were tested: 75 mg/m(2)/day in 3 patients, 100 mg/m(2)/day in 7 + 11(#) patients, and 125 mg/m(2)/day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m(2)/day dose level, establishing the lower dose of 100 mg/m(2)/day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI). CONCLUSIONS: The RD for elacytarabine was 100 mg/m(2)/day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of elacytarabine in the ovarian cancer indication are not warranted.

Carboplatin-paclitaxel-induced leukopenia and neuropathy predict progression-free survival in recurrent ovarian cancer.

BACKGROUND: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin-paclitaxel (CP) or carboplatin-liposomal doxorubicin (CPLD). METHODS: We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell <4.0 × 10(9) per litre or severe infection) during cycle 1 of chemotherapy with progression-free survival (PFS). Using time-dependent proportional-hazards models, we also investigated the association between neuropathy and PFS. RESULTS: Of 608 patients with nadir blood and did not receive growth factors, 72% (CP=70%, CPLD=73%) had leukopenia. Leukopenia was prognostic for PFS in those receiving CP (adjusted hazard ratio (aHR) 0.66, P=0.01). Carboplatin-liposomal doxorubicin was more effective than CP in patients without leukopenia (aHR 0.51, P=0.001), but not those experiencing leukopenia (aHR 0.93, P=0.54; interaction P=0.008).Of 949 patients, 32% (CP=62%, CPLD=28%) reported neuropathy during landmark. Neuropathy was prognostic for PFS in the CP group only (aHR 0.77, P=0.02). Carboplatin-liposomal doxorubicin appeared to be more effective than CP among patients without neuropathy (aHR 0.70, P<0.0001), but not those with neuropathy (aHR 0.96, P=0.81; interaction P=0.15). CONCLUSION: First-cycle leukopenia and neuropathy were prognostic for patients treated with CP. Efficacy of CP treatment was similar to CPLD in patients who developed leukopenia. These findings support further research to understand the mechanisms of treatment-related toxicity.

Multimodality approach in extra cervical locally advanced cervical cancer: chemoradiation, surgery and intra-operative radiation therapy. A phase II trial.

BACKGROUND: The goal of this study was to determine the rational of radical surgery with intra-operative high-dose radiotherapy after chemoradiation (RT-CT) in extra cervical locally advanced cervical cancer (LACC) patients. METHODS: Between 2000 and 2007, 42 LACC (stage IIA bulky-IVA) patients were treated at the Gynecologic Oncology Unit of the C.R.O. of Aviano in a Phase II Clinical Trial. Radiotherapy was administered to the whole pelvic region (50.4 Gy in 28 fractions) in combination with cisplatin (60 mg/mq) plus 5FU (750 mg/mq for 4 days) on first and fifth week of RT. Radical surgery with Intra-Operative Radiation Therapy (IORT) was performed 6-8 weeks after the end of RT-CT treatment. RESULTS: After RT-CT, 35/42 patients (83%) underwent radical surgery and IORT treatment. At pathologic examination 8/35 (23%) patients showed complete response, while the rest (27/35) had residual disease either microscopic (17/27) or gross (10/27). The 5-year disease free survival (DFS) and the 5-year overall survival (OS) were 46% and 49% respectively. There were significant better DFS and OS when residual tumor was absent or limited to the cervix, respectively 78% versus 16% and 81% versus 20% (p < 0.001). All recurrences occurred within 24 months from treatment. CONCLUSIONS: RT-CT followed by surgery and IORT in LACC patients seems to be active in a subgroup of patients with pathological complete response to treatment or partial response with residual tumor limited to the cervix.

Carboplatin and pegylated liposomal doxorubicin for advanced ovarian cancer: preliminary activity results of the MITO-2 phase III trial.

BACKGROUND: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. PATIENTS AND METHODS: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m(2) or PLD 30 mg/m(2) every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). CONCLUSIONS: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.

Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer.

The purpose of this study was to compare long-term survival in first-line chemotherapy with and without platinum in advanced-stage ovarian cancer. From July 1987 to November 1992, 161 untreated patients with FIGO stage III-IV epithelial ovarian cancer were randomized: 81 patients received no platinum and 80 received platinum combination. Residual disease after surgery was <2 cm in 61 patients without platinum, 59 with platinum. Median age was 58 years in nonplatinum arm and 55 years in platinum arm (range: 15-73). Complete and partial responses were 51% and 10% for nonplatinum arm and 51% and 8% for platinum arm, respectively (P= 0.7960). Stable disease was observed in 18% of patients in nonplatinum arm and 15% of patients in platinum arm and progression in 20% of nonplatinum- and 21% of platinum-treated cases. Ten-year disease-free survival was 37% for therapy without platinum and 31% for platinum combination (P= 0.5679); 10-year overall survival was 23% without platinum and 31% with platinum combination (P= 0.2545). Fifteen-year overall survival showed a trend of short duration in favor of platinum (P= 0.0678). Relapses occurred after 60 months in ten patients (seven with and three without platinum). The overall and disease-free survivals at 5, 10, and 15 years show no statistically significant long-term advantage from the addition of cisplatin; however, there is a slight trend in its favor.

Gemcitabine and anthracyclines in platinum-resistant ovarian cancer.

BACKGROUND: Most of the patients with advanced ovarian cancer will recur after first-line platinum-based chemotherapy and need additional treatment. Gemcitabine (G) and Anthracyclines are active in this setting and their combination has shown synergistic antiproliferative activity in vitro, due to different mechanisms of action and non-overlapping toxicities. PATIENTS AND METHODS: In 2002 we began a phase II study with G 1000 mg/m(2) (day 1,8) combined to Epirubicin (E) 60 mg/m(2) (day 1), every 3 weeks for 6 cycles, in Platinum resistant/refractory ovarian carcinoma patients. RESULTS: Among 30 patients enrolled so far (27 evaluable), receiving 149 cycles (median 6), 1 complete and 12 partial responses (48%), 9 stabilizations (33%) and 5 progressions (18%) were observed, with a good correlation with serological responses. Median time to progression was 8 months, while median time to response was 10 weeks and median duration 8 months. Grade 3-4 toxicities consisted of neutropenia (58%), thrombocytopenia (3%), anemia (10%), liver toxicity (13%), and mucositis (7%). Eight patients (27%) received G-CSF and 3 (10%) blood transfusions. No febrile neutropenia nor cardiotoxicity were observed. CONCLUSIONS: Although our results are preliminary, G/E combination appears particularly effective and safe in these platinum resistant/refractory patients.

Oral etoposide in elderly patients with advanced non small cell lung cancer: a clinical and pharmacological study.

Seventeen elderly patients with advanced progressive non small cell lung cancer (NSCLC) were treated with oral etoposide at the daily dose of 100 mg for 14 days every 3-4 weeks with pharmacokinetic monitoring. One partial response and 6 stabilizations were documented with a median overall duration of 13 weeks (range 8-32). The median survival was 24 weeks with an apparent advantage for non-progressive patients (40 weeks vs. 18 weeks). The treatment was well tolerated especially by those patients without concomitant illness, suggesting the crucial role of a careful selection of the geriatric population. Toxicity was not related to the etoposide plasma level, but was clearly dependent on comorbidity. A geriatric assessment rather than chronological age therefore appears to be more reliable in the selection of elderly patients for clinical trials. The easy self-management, favorable toxicity profile and synergy with other compounds makes oral etoposide suitable for further clinical-pharmacological studies in elderly patients.

Innovative schedule of oral idarubicin in elderly patients with metastatic breast cancer: comprehensive results of a phase II multi-institutional study with pharmacokinetic drug monitoring.

BACKGROUND: To determine if protracted low-dose oral idarubicin (IDA), feasible in a previous dose-finding study, would result in similar activity and a better toxicity profile in patients with metastatic breast cancer. PATIENTS AND METHODS: Elderly women (> or=65 years) with metastatic breast carcinoma were treated with 7.5 mg/day for 21 consecutive days, every 4 weeks. After the first fourteen patients, due to excessive toxicity, the protocol was amended to 5 mg/day. IDA and Idarubicinol (IDOL) plasma concentrations (C(trough)) were investigated in all patients. RESULTS: Between April 1999 and June 2004, 47 elderly patients were accrued in this two-part study (14 and 33 patients respectively). The median age was 74 and 75 years respectively. Visceral involvement was present in most patients. A partial response was noted in 7/31 patients (22%; 95% CI, 9.6-41.1%). Eleven patients had stable disease (33%). At the dose of 5 mg/day the treatment was well tolerated. Neutropenia grade 4 was present in only 6% of patients; alopecia > grade 1 and cardiotoxicity did not occur. The median time to progression was 3 months and the median overall survival was 17 months. IDA C(trough) and IDOL C(trough) levels were significantly associated with haematologic toxicity. CONCLUSION: This study shows that idarubicin at the dose of 5 mg/day for 21 consecutive days is feasible and effective in elderly breast cancer patients but do not demonstrate an improvement in efficacy. A determination of the IDA and IDOL plasma levels (C(trough)) is predictive for toxicity.

A study from the EORTC new drug development group: open label phase II study of sabarubicin (MEN-10755) in patients with progressive hormone refractory prostate cancer.

Sabarubicin (MEN-10755), a new synthetic anthracycline analogue, was evaluated for safety and efficacy in a multicentre phase II study in patients with advanced hormone refractory prostate cancer (HRPC). Thirty seven patients were included, of which 34 were evaluable for PSA response according to Bubley's criteria. Sabarubicin was administered as a short (30 min) intravenous infusion at a dose of 80 mg/m(2) every 3 weeks. The main toxicity consisted of grade 3/4 neutropenia in 24 patients (64.9%), with grade 3/4 febrile neutropenia occurring in one patient only. Grade 3/4 cardiotoxicity was observed in 4 patients including one ineligible. Other toxicities were mild. Nine patients achieved a PSA response (26.5%), 10 patients had stable disease (29.4%) and 14 patients disease progression (41.2%). One patient (2.9%) had a PSA response that was not confirmed by repeat PSA testing. The objective response rate according to RECIST criteria was 6.7% in 15 patients with measurable disease. The median duration of PSA responses was relatively long 7.1 months (95% CI 4.9-20.7) as was the median time to treatment progression in patients with stable disease. The median overall survival was 18.7 months (95% CI 9.1-N), comparable to results recently observed in taxotere-containing regimens. To confirm and extend these results, further testing of sabarubicin in larger trials is warranted.

Pharmacokinetic comparison of 120-hour infusion versus hyperfractionated oral administration of idarubicin.

The aim of this study was to compare the pharmacokinetics of idarubicin (IDA) and its active metabolite idarubicinol (IDOL) after chronic oral and continuous intravenous (i.v.) IDA administration in order to establish the oral doses needed to reach the i.v. equiactive plasma drug exposure. The pharmacokinetic profile of IDA and IDOL was investigated in 23 patients receiving 12 mg/m2 IDA by 120-h i.v. infusion (2.4 mg/m2/day) combined with cyclophosphamide, etoposide and prednisone in comparison to 28 patients receiving oral IDA doses ranging from 2 to 10 mg/day for 21 days in a phase I study. We found that IDA AUC24h/dose/m2 was 4.7-fold greater during i.v. than oral administration, whereas IDOL AUC24h/dose/m2 was only about 2-fold higher after i.v. administration. The metabolic ratio between IDOL AUC24h and IDA AUC24h in plasma was about 3-fold higher after oral administration. Based on these results we were able to estimate that equiactive plasma drug exposure was reached with an approximately 2.5-fold greater oral dose/m2 of IDA than the corresponding i.v. dose.

Ifosfamide in advanced/disseminated breast cancer.

Ifosfamide is an alkylating agent active in various tumor types including breast cancer. The availability of mesna (sodium 2-mercaptoethanesulfonate) has increased its safety, avoiding the main dose-limiting side effect, urotoxicity. Interesting activity as a single agent, with response rates ranging from 7 to 30%, is reported in pretreated patients; more attractive data derived from phase II studies on ifosfamide combined with drugs known to be active in advanced breast cancer show response rates always over 35%. This review has taken in consideration papers published after 1995 and available on PubMed medline: the data indicate a potential usefulness of ifosfamide in the clinical management of advanced breast cancer, even if the exact therapeutic role of the drug in this setting should be derived from randomized studies not yet available.

Treatment of older breast cancer patients with high recurrence risk.

Adjuvant treatment of elderly women affected by breast cancer who have a high risk of recurrence is one of the most questionable issues in clinical oncology. The use of tamoxifen in women with hormone receptor-positive tumors is a relatively simple therapeutic option considering the favourable toxicity profile, whereas the administration of adjuvant chemotherapy is more complicated and a variety of aspects need to be considered. The estimated life expectancy, the presence and degree of comorbid conditions, the geriatric assessment and estimated benefit from treatment should be taken into account. Due to the lack of data from clinical trials in women over the age of 70, the approach is still experimental. Clinical trials evaluating the role of adjuvant chemotherapy in high risk patients are currently being developed and hopefully in the near future, more convincing data on the best drugs, regimens and benefits for the treatment of elderly breast cancer patients will become available.

Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme.

BACKGROUND: XR5000 is a tricyclic carboxamide that intercalates DNA and inhibits both topoisomerase I and II. The aim of this study was to evaluate the efficacy and tolerability of XR5000 in patients with recurrent glioblastoma multiforme previously untreated with chemotherapy at relapse. PATIENTS AND METHODS: Patients received XR5000 at a dose of 3010 mg/m2 as a 120-h central venous infusion every 3 weeks. An independent panel assessed response every two cycles using McDonald's criteria (tumour size, steroid intake and neurological status); toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Sixteen patients were enrolled (one ineligible patient was excluded from efficacy evaluation). Performance status was zero (five patients), one (nine patients) or two (one patient). They received 30 cycles of XR5000 (median 2, range 1-5). Haematological toxicity was mild, with only one patient experiencing grade 3 neutropenia. Other related grade 3/4 adverse events included chest pain (one patient), axillary vein thrombosis (one patient) and rigors/fever in the absence of neutropenia (one patient). There were no objective responses, 14 patients progressing on XR5000 and one having stable disease. CONCLUSIONS: Although XR5000 was generally well tolerated, these results do not support further evaluation in patients with glioblastoma multiforme using this dose and schedule.

Population pharmacokinetics and pharmacodynamics of oral etoposide.

AIMS: To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours. METHODS: A prospective, open label, cross-over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P-Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints. RESULTS: Mean clearance was 1.14 l h(-1) (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r(2) = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l(-1) h; CV 64%; range 0.4-9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l(-1) h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l(-1) h) than in patients with stable (2.1 mg l-1 h) or progressive disease (2.3 mg l-1 h) (P = 0.01). CONCLUSIONS: Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.

Phase II study of sequential administration of docetaxel followed by doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m(2) every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m(2) every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel). RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m(2) (range, 150 to 543 mg/m(2)), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months). CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.