A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and oxaliplatin in patients with advanced solid tumors

PURPOSE: To evaluate the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of the combination of pegylated liposomal doxorubicin (PEG-LD), paclitaxel and oxaliplatin (L-OHP) administered every 2 weeks in patients with advanced solid tumors. METHODS: Thirty-nine pretreated patients with advanced solid tumors received escalated doses of PEG-LD (10-16 mg/m(2)), paclitaxel (100-120 mg/m(2)) and L-OHP (50-70 mg/m(2)) every 2 weeks. As one cycle of treatment was considered the administration of both drugs on days 1 and 15 of a 4-week cycle. RESULTS: The MTDs were PEG-LD 14 mg/m(2), paclitaxel 120 mg/m(2) and L-OHP 70 mg/m(2). Neutropenia was the DLT in all but one case with only one episode of febrile neutropenia and no toxic deaths. Four (4%) and 13 (12%) cycles were complicated by grades 4 and 3 neutropenia, respectively. Grades 2-3 fatigue and neurotoxicity occurred in 13 and 12% of cycles, respectively. Responses were observed in patients with breast, endometrial and ovarian carcinomas. CONCLUSIONS: This is a quite well-tolerated regimen which merits further evaluation in phase II studies.     

Phase II study of pegylated liposomal doxorubicin (Caelyx) and docetaxel as first-line treatment in metastatic breast cancer.

BACKGROUND: The aim of this study was to determine the activity and safety of pegylated liposomal doxorubicin (PLD; Caelyx) and docetaxel combination as first-line treatment in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-four patients with a median age of 63 years were treated with PLD 30 mg/m(2) (day 1) and docetaxel 75 mg/m(2) (day 2) every 3 weeks for six cycles. Recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) could be used in patients with grade > or =3 neutropenia after the first cycle. RESULTS: Forty-two of 44 patients were assessable for response. The response rate (RR) was 64.3% (95% confidence interval 49.8% to 78.8%). Six patients (14.3%) achieved complete response (complete disappearance of all measurable and assessable disease lasting at least 4 weeks, no new lesions, no disease-related symptoms), partial response was observed in 21 patients (50%) > or =50% decrease of measureable disease lasting at least 4 weeks, no progression of assessable disease, no new lesions, no disease-related symptoms), eight patients had stable disease and seven patients progressive disease. Median disease-free and overall survival were not reached, but were in excess of 17 months (range 6-17 months). Twenty of the patients had received previous adjuvant chemotherapy (10 with epirubicin-containing regimen with a median cumulative dose of 400 mg/m(2)). Grade > or =3 neutropenia occurred in 18.4% and neutropenic fever in 9% of patients. Palmar-plantar erythrodysesthesia was observed in four patients. Dose reduction was necessary in seven patients. Two patients discontinued treatment: one due to prolonged grade 3-4 neutropenia and one due to neurotoxicity. No treatment-related deaths occurred. CONCLUSIONS: The combination of PLD and docetaxel achieved high RRs with acceptable toxicity as first-line treatment in MBC.     

Metastatic breast cancer: the role of pegylated liposomal doxorubicin after conventional anthracyclines

Anthracyclines demonstrate significant disease activity in breast cancer and are a key component of therapy in both early and advanced disease. It has been long recognized that these agents are associated with cumulative dose-related cardiotoxicity that often limits their utility at the time of disease recurrence. The risk of anthracycline-associated cardiotoxicity appears to be highest in women with HER2-overexpressing breast cancer previously having received an adjuvant anthracycline-trastuzumab regimen. Clinical trials have demonstrated that pegylated liposomal doxorubicin (PLD) is equally active but associated with a significantly lower risk of cardiotoxicity compared with conventional doxorubicin whether administered as monotherapy or in combination with trastuzumab. Thus, PLD can be effectively and safely substituted for conventional doxorubicin, allowing retreatment with an anthracycline in the metastatic setting. PLD has also been shown to improve time to tumor progression when used as maintenance therapy. These data, when coupled with the need to maintain efficacy and reduce cardiotoxicity in the management of metastatic breast cancer, support the use of PLD in the metastatic setting, as well as support the rationale for evaluating PLD as adjuvant therapy.     

Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: Results from a subset analysis of the CALYPSO phase III trial

AimTo perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial.Patients and methodsThe international non-inferiority trial enrolled women with ROC that relapsed >6 months following first- or second-line platinum- and paclitaxel-based therapies. Patients were randomised to CD [carboplatin–pegylated liposomal doxorubicin (PLD)] or CP (carboplatin–paclitaxel) and stratified by treatment-free interval (TFI). In this analysis, patients with a TFI > 24 months were analysed separately for progression free survival (PFS), the primary endpoint of CALYPSO, overall survival (OS) and safety.ResultsA total of 259 very platinum-sensitive patients were included (n = 131, CD; n = 128, CP). Median PFS was 12.0 months for the CD arm and 12.3 months for CP [HR = 1.05 (95% CI, 0.79–1.40); P = 0.73 for superiority] and median OS was 40.2 months for CD and 43.9 for CP [HR = 1.18 (95% CI 0.85–1.63); P = 0.33 for superiority]. Overall response rates were 42% and 38%, respectively (P = 0.46). Toxicities were more common with CP versus CD, including grade 3/4 neutropenia (40.8% versus 27.5%; P = 0.025), nausea (4.8% versus 3.1%; P = 0.47), allergic reaction (8% versus 3.1%; P = 0.082) sensory neuropathy (4.8% versus 2.3%; P = 0.27) and grade 2 alopecia (88% versus 9.2%; P < 0.001). Grade 3/4 thrombocytopenia (12.2% versus 3.2%; P = 0.007) and mucositis (2.3% versus 0%; P = 0.089) were more common with CD. Grade 3/4 hand-foot syndrome occurred rarely with CD (3 patients versus 0 in CP arm; P = 0.089).ConclusionCP and CD were equally effective treatment regimens for patients with very platinum-sensitive ROC. The favourable risk–benefit profile suggests carboplatin–PLD as treatment of choice for these patients.     

Chemotherapy with pegylated liposomal doxorubicin and cisplatin in recurrent platinum-sensitive epithelial ovarian cancer

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is the only nonplatinum agent to significantly improve survival in patients with platinum-sensitive recurrent ovarian cancer. The present study was designed to assess the efficacy and safety of PLD plus cisplatin combination therapy in these patients. METHODS: Twenty-two women (median age, 57 years) with ovarian cancer that recurred 6 months or more after standard carboplatin and paclitaxel therapy were eligible for enrollment. Cisplatin was administered intravenously as a 60-min infusion on day 1, at a single dose of 60 mg/m(2), and PLD was given intravenously as a 1-h infusion on day 2, at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. RESULTS: Hematological toxicity was mainly leucopenia/neutropenia, and this was the principal dose-limiting toxicity. Severe (grade III-IV) leucopenia/neutropenia was observed in 7 (32%) and 9 (41%) patients, respectively. Only 2 (9%) patients were complicated by febrile neutropenia. Grade III-IV anemia occurred in only 4 (18%) patients. Severe thrombocytopenia was not noted; only 5 patients (23%) had grade I-II toxicity. NO toxicity in biochemical parameters was noted. Several severe nonhematological adverse effects were managed according to standard protocols and were transient, as well as being well-tolerated. Twenty-one patients were evaluated for response. The overall response rate was 62% (13 of 21; 95% confidence interval [CI], 38%-82%), with four (19%) complete and nine (43%) partial responses. At the time of last follow-up, all of the 22 patients were alive. The median follow-up period was 8.5 months (range, 2 to 22 months). CONCLUSION: PLD combined with cisplatin at the schedule and dosage used in this study is an active and safe second-line chemotherapy regimen with acceptable and easily manageable toxicities in women with platinum-sensitive recurrent ovarian cancer.     

Pegylated liposomal doxorubicin/carboplatin combination in ovarian cancer,progressing on single-agent pegylated liposomal doxorubicin

AIM: To assess the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) and carboplatin in patients with recurrent epithelial ovarian carcinoma (ROC), following disease progression on single agent PLD.METHODS: An analysis of the medical records of 10 patients with ROC, treated in our institution with a combination of PLD and carboplatin following progression on single-agent PLD therapy was performed. The median age was 59.1 years (range, 45 to 77 years). All diagnoses were histological-proven. Eight of the 10 patients were platinum-resistant. Following disease progression on single-agent PLD treatment, carboplatin area under the curve (AUC)-5 was added to PLD in all 10 patients. In order to assess disease status, Ca-125 was assessed before each PLD/carboplatin treatment. Relative changes in Ca-125 values were calculated, and response defined as a greater than 50% reduction in Ca-125 from baseline. Radiographic studies were re-evaluated and responses to therapy based on computer tomography (CT) scans carried out on a regular basis every 2-3 mo in each patient. Statistical analysis was performed using SPSS (V19).RESULTS: A median of 10 cycles (range, 2-26) of the carboplatin-PLD combination was given. Of the 10 treated patients, 6 had > 50% reduction in Ca-125 levels from baseline, 4 of these had a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the other 2 patients had no measurable disease. In a further 2 patients with a best response of disease stabilization and < 50% reduction of Ca-125 levels, one had progression of disease after 26 cycles, and the second progressed with brain metastases following 12 cycles. Seven of the eight patients who were platinum-resistant showed evidence of clinical benefit on carboplatin-PLD combination therapy; 5 of these had > 50% reduction in Ca-125 level, 4 also showed a partial response on CT scan. The treatment was generally well-tolerated by the patients.CONCLUSION: Addition of carboplatin to PLD, after disease progression on single-agent PLD therapy, is both effective and safe in patients with ROC, even in those with Platinum-resistant disease.     

Phase 1 clinical study of pegylated liposomal doxorubicin (JNS002) in Japanese patients with solid tumors

BACKGROUND: Pegylated liposomal doxorubicin (PLD, JNS002) is a formulation of doxorubicin encapsulated polyethylene-glycol coated liposomes with prolonged circulation time and unique toxicity profile. This phase 1 study was aimed at investigating the maximum tolerated dose (MTD), recommended dose, toxicity, pharmacokinetics, and antitumor activity in Japanese patients with solid tumors. METHODS: Patients with solid tumors not amenable to standard forms of treatment were eligible. PLD was administered as an intravenous infusion every 4 weeks. Dose escalation of PLD was planned from 30 to 60 mg/m(2) in 10 mg/m(2) increments. The pharmacokinetics of total doxorubicin (encapsulated plus non-encapsulated) in plasma were examined for the first cycle of treatment. RESULTS: Fifteen patients, aged 49-69 (median; 56) years with advanced solid tumors were enrolled. The major non-hematological toxicities were hand-foot syndrome (HFS), rash and stomatitis. Myelosuppression, especially leukopenia and neutropenia were major hematological toxicities. Although HFS was not severe, a delay of doses for subsequent cycles was required with multiple dosing. The peak plasma concentration and the area under the concentration time curve of PLD increased proportionally to the dose. Objective response was observed in one patient and the normalization of tumor marker values in another. These two patients had been diagnosed with ovarian cancer. CONCLUSION: The recommended dose for phase 2 clinical studies of PLD in Japanese patients was 50 mg/m(2) every 4 weeks. The encouraging results prompted us to plan a subsequent clinical study of PLD against ovarian cancer.     

Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group.

BACKGROUND: To determine the activity and safety of the combination of paclitaxel and pegylated liposomal doxorubicin (Caelyx) in patients with locally advanced breast cancer. PATIENTS AND METHODS: This was a multicenter phase II study. Thirty-five newly diagnosed patients with locally advanced breast cancer were included in the study. Histological or cytological diagnosis was necessary for inclusion. Median age was 54 years (range 26-73 years). Fifteen patients were premenopausal and 20 postmenopausal. Paclitaxel was administered at a dose of 175 mg/m(2) and pegylated liposomal doxorubicin 35 mg/m(2) every 3 weeks for six cycles. RESULTS: Twenty-five patients (71%) responded. Six (17%) had a complete response, 19 (54%) had a partial response, four remained stable, two progressed and four were not evaluated for response due to discontinuation of chemotherapy. Three patients had a pathologically complete response. A total of 173 cycles were administered. The primary toxicity observed was skin toxicity. Grade 3 skin toxicity was noted in four patients (11%). Palmar-plantar erythrodysesthesia (PPE) grade 3 was experienced by three (9%). Two patients presented with PPE and skin toxicity. Hematological toxicities included grade 3 leukopenia in four patients (3%). Other grade 3 toxicities were uncommon and included only alopecia in 29 patients (83%). Grade 3 or 4 neurotoxicity was not observed in any patient. Dose reduction was necessary in seven patients; in six due to skin toxicity and in one due to neutropenia. Four patients discontinued treatment due to skin toxicity. There were no treatment-related deaths. CONCLUSIONS: The combination of pegylated liposomal doxorubicin and paclitaxel was active in locally advanced breast cancer. The primary toxicity was cutaneous toxicity and it was manageable.     

含聚乙二醇脂质体多柔比星的R-CDOP方案治疗弥漫性大B细胞淋巴瘤的临床应用评价

目的 评价将R-CHOP方案(利妥昔单抗+环磷酰胺+长春新碱+多柔比星+泼尼松)中的多柔比星改为含聚乙二醇脂质体多柔比星的R-CDOP方案治疗弥漫性大B细胞淋巴瘤患者的疗效和安全性.方法 回顾性收集76例弥漫性大B细胞淋巴瘤患者的临床资料,其中39例使用标准的R-CHOP方案化疗(R-CHOP组),37例使用含多柔比星...     

Pilot study with pegylated liposomal doxorubicin for advanced or unresectable hepatocellular carcinoma.

We performed a pilot-study on pegylated liposomal doxorubicin (PLD) for advanced hepatocellular carcinoma. Seventeen patients received 40 mg/m(2) PLD intravenously every 4 weeks. A clinical benefit response was achieved in 50% (complete remission 7%, minor remission 7%, stable disease 36%). Toxicities were moderate. In view of these encouraging findings, further studies appear warranted.     

A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma

BACKGROUND: Despite a decreased incidence of AIDS-related Kaposi's sarcoma (KS) due to the advent of highly active antiretroviral therapy, approximately 15% of AIDS patients still develop AIDS-related KS. This study evaluated the clinical benefit, tumor response, and safety of pegylated liposomal doxorubicin for the treatment of AIDS-related KS. METHODS. This was a double-blind, multicenter study that randomized patients with AIDS-related KS to six cycles of pegylated liposomal doxorubicin (20 mg/m2; n = 60) or liposomal daunorubicin (40 mg/m2; n = 19) every 2 weeks. Clinical benefit was assessed using patient questionnaires and monitoring of KS-associated symptoms. Tumor responses were assessed using imaging techniques, direct measurement of skin lesions, and photographs, when possible. RESULTS. Clinical benefit was observed in 48/60 patients (80%) receiving pegylated liposomal doxorubicin and was maintained for a median of 62 days (range, 28-107 days). Clinical benefit was achieved by 12/19 patients (63.2%) receiving liposomal daunorubicin and was maintained for a median of 55 days (range, 28-84 +days). Clinical benefit correlated with tumor response. Tumor responses were achieved by 55.0% of patients receiving pegylated liposomal doxorubicin and 31.6% of patients receiving liposomal daunorubicin. Response rates were similar within each treatment group when only those patients without changes in antiretroviral therapy during treatment were considered. Adverse events associated with pegylated liposomal doxorubicin were neutropenia (30%), nausea (28.3%), and asthenia (16.7%). CONCLUSIONS. Pegylated liposomal doxorubicin is safe and effective for the treatment of AIDS-related KS, with most patients experiencing clinical benefit, tumor response, or both.     

High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours

The blood-brain barrier is a major obstacle for the chemotherapeutic drugs to effectively reach primary or secondary brain tumours. Stealth liposomal drugs are highly accumulated in tumoural tissues. In the present study we investigated the relative accumulation of(99m)Tc-DTPA radiolabelled stealth liposomal doxorubicin (Caelyx) in 10 patients with metastatic brain tumours and five patients with brain glioblastoma undergoing radiotherapy. Patients with metastatic brain lesions were treated with 10 consecutive fractions of radiotherapy (whole brain, 3 Gy/fraction, day 1-12) followed by a booster dose of 9 Gy (3 Gy/fraction, day 21-23). Caelyx, at a dose of 25 mg mg(-2)was given on day 1 and on day 21. Radiolabelled Caelyx accumulation was 13-19 times higher in the glioblastomas and 7-13 times higher in the metastatic lesions, as compared to the normal brain. The drug accumulation in the tumoural areas was 40-60% of the accumulation in the bone marrow of the skull bones. The normal brain radioactivity was <4% of the bone marrow, confirming an important shielding effect of the blood-brain barrier in the normal but not in the tumoural tissue. Four of 10 patients with metastatic lesions showed a complete response in CT-scan performed 2 months following therapy. There was no severe toxicity related to radiotherapy or to chemotherapy noted. It is concluded that stealth liposomal drugs selectively overcome the blood-brain barrier in the tumoural areas. The clinical importance of this observation is now under investigation.     

Unexpected low efficacy of stealth liposomal doxorubicin (Caelyx) and vinorelbine in metastatic breast cancer

In this phase II study, 23 patients with metastatic breast cancer were treated with a combination of Caelyx (40 mg/m² on day 1) and vinorelbine (20 mg/m² on days 1 and 8) every 4 weeks. According to the statistical design, enrollment was closed after the first stage due to the low response rate observed (four partial remissions, 12 stabilizations). Toxicity was acceptable, however, grade 3–4 neutropenia was not negligible. Our study does not support the development of this combination in advanced breast cancer.     

A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors

Purpose  Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors. Methods  Patients received bortezomib, 0.9–1.5 mg/m², on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m², on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination. Results  A total of 37 patients with four median prior therapies were treated. Frequent grade 1–2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib at 1.2 mg/m², and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m². Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m² levels, bortezomib at 1.3 mg/m² and PLD at 30 mg/m² are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs. Conclusions  A regimen of bortezomib, 1.3 mg/m² on days 1, 4, 8, and 11 with PLD, 30 mg/m², on day 4 of a 21-day cycle, was safe in this study, and merits further investigation. Supported in part by grants from the following: Millennium Pharmaceuticals, Inc., General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health(RR00046), National Cancer Institute SPORE in Breast Cancer (5-P50-CA58223-09A1 H.S. Earp), National Inst. of Health (K23-RR16536 ECD), Leukemia and Lymphoma Society (6096-07 RZO), and National Cancer Institute (RO1 CA102278 RZO).     

A pilot study evaluating the efficacy and toxicity of biweekly gemcitabine and pegylated liposomal doxorubicin in recurrent platinum-resistant epithelial ovarian cancer

Background Both gemcitabine and pegylated liposomal doxorubicin (PLD) are antineoplastic drugs with clinical activity in patients with platinum-resistant ovarian cancer. The present study was designed to assess the efficacy and safety of biweekly scheduled gemcitabine and PLD combination therapy in such patients. Methods Eighteen women with ovarian cancer that had recurred within 6 months after standard carboplatin and paclitaxel therapy were eligible for enrollment. Gemcitabine 2000 mg/m² and PLD 20 mg/m² were administered intravenously on days 1 and 15 of a 28-day cycle. Results Hematological toxicity was mild. No severe (grade III/IV) leucopenia/neutropenia or thrombocytopenia was observed. Severe anemia was seen in only 3 (17%) patients. Several other severe nonhematological adverse effects were well tolerated and easily managed. The overall response rate was 28% (5 of 18; 95% confidence interval [CI], 10%–54%) with 2 (11%) complete and 3 (17%) partial responses. The median overall survival time was 17 months (range, 1 to 25 months). The median survival for patients with clinical benefit including disease response or stabilization was 17 months (range, 3 to 26 months) compared to that of patients with progressive disease, which was 2 months (range, 1 to 11 months; P = 0.04). Conclusion A biweekly schedule of gemcitabine combined with PLD is an active and safe chemotherapy regimen with acceptable and easily manageable toxicities in women with recurrent platinum-resistant ovarian cancer.     

A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer

Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m(-2); doxil 20, 30, 40 and 50 mg m(-2). Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m(-2) and doxil 30 mg m(-2) q 21. Reducing the paclitaxel dose to 135 mg m(-2) did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m(-2) also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m(-2), doxil 30 mg m(-2) q 28 or carboplatin AUC 5, paclitaxel 175 mg m(-2), doxil 20 mg m(-2) q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome.     

Weekly paclitaxel combined with pegylated liposomal doxorubicin (CaelyxTM) given every 4 weeks: dose-finding and pharmacokinetic study in patients with advanced solid tumors.

BACKGROUND: We aimed to define the maximum tolerated dose (MTD) and characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Caelyx trade mark ) and weekly paclitaxel (wPTX), and to investigate pharmacokinetics of PLD in this combination. METHODS: A phase I study was performed with an initial dose of 50 mg/m(2) wPTX and 30 mg/m(2) PLD. The paclitaxel dose was escalated in increments of 10 mg/m(2) and PLD in increments of 5 mg/m(2) until the MTD was reached. The pharmacokinetics of PLD were studied at the highest achieved dose levels. RESULTS: Forty-four cancer patients were enrolled. The MTD was 30/90 and 35/80 mg/m(2) for PLD/wPTX. Dose-limiting toxicities included treatment delay for neutropenia grade 3, febrile neutropenia, palmar-plantar erythrodysesthesia and deep venous thrombosis. Toxicity below the MTD was mild: skin toxicity grade 1-2 developed at high cumulative doses and vascular thrombotic events occurred in two patients with predisposing factors. No cardiotoxicity or clinically relevant peripheral neuropathy was seen. Nausea/vomiting and alopecia were negligible. Three complete responses and nine partial responses were documented among 34 evaluable cases. PLD plasma concentrations were evaluated in seven patients treated at subMTD. Paclitaxel produced a median 53.5% increase of PLD area under the concentration curve (range 4.4%-219%). CONCLUSIONS: The combination of PLD/wPTX constitutes an active chemotherapy regimen with mild toxicity that merits investigation in phase II at 30/80 or 35/70 mg/m(2). Patients should be monitored for a potentially increased risk of thromboembolic events.     

Early changes in CA125 after treatment with pegylated liposomal doxorubicin or topotecan do not always reflect best response in recurrent ovarian cancer patients

PURPOSE: To examine early changes in CA125 relative to objective response in patients with recurrent ovarian cancer treated with pegylated liposomal doxorubicin (PLD) or topotecan and to compare the CA125 trends between the two chemotherapeutics. PATIENTS AND METHODS: Patients with recurrent ovarian cancer, all of whom had measurable or evaluable disease, were randomized to receive 50 mg/m2 PLD every 28 days (n = 239) or 1.5 mg/m2 topotecan for 5 days every 21 days (n = 235) as part of a previously reported multicenter study. CA125 measurements were obtained prior to therapy and with each cycle of administration. Assessable patients underwent radiographic evaluation for response after two cycles of therapy. Objective responses were compared to trends in CA125 values at the end of cycles 1 and 2. CA125 changes were categorized as baseline (+/-10%), +/- 10%-25% variance, and > 25% variance. RESULTS: Among patients treated with PLD, 50% of complete responders (CR) and 41% of partial responders (PR) had increases in CA125 from baseline to cycle 1. Increases in CA125 were also seen in topotecan-treated patients; however, fewer patients had increases (20% and 8%, respectively). Overall, 15% of responding patients (CR + PR) receiving PLD and 6% receiving topotecan had elevated CA125 after two cycles of therapy. For those patients achieving a partial response, 19% of PLD-treated patients and 8% of topotecan-treated patients had CA125 levels above baseline at cycle 2. CONCLUSIONS: Considerable intrapatient variation in CA125 values is present among responding patients. Early increases in CA125 may not predict ultimate outcome, especially in PLD-treated patients.     

Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin (PLD): results of a phase II study

Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m(-2), although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.     

Myotax: a phase II trial of docetaxel plus non-pegylated liposomal doxorubicin as first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines

Aim

Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumour activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as a single agent or in combination with cyclophosphamide. This phase II trial was performed to evaluate the efficacy and the safety of NPLD and docetaxel combination in patients with metastatic breast cancer previously exposed to adjuvant anthracyclines.

Patients and methods

Thirty-four patients received NPLD 60 mg/m² and docetaxel 75 mg/m² in a 21-day cycle as first-line therapy of metastatic breast cancer. Treatment was planned for six cycles and was continued until progression or toxicity.

Results

Objective response rate among response-assessable patients was 79% (95% CI (confidence interval), 64–94%) and 27% (95% CI, 11–43%) presented a complete response. Median progression free survival was 11.3 months (95% CI, 6.2–13.3 months) and median overall survival was 28.2 months (95% CI, 16–36.4 months). Symptomatic grade 3 cardiotoxicity occurred in 15% of cases and febrile neutropenia in 47% of the patients.

Conclusions

The combination of NPLD and docetaxel demonstrated high antitumour activity in a population of metastatic breast cancer patients exposed to adjuvant anthracyclines and showed an unexpected and unexplained 15% symptomatic left ventricular systolic dysfunction rate.