Dose Of Liposomal Doxorubicin Research Articles

Preclinical evaluation of early multi-organ toxicity induced by liposomal doxorubicin using 67Ga-citrate

Although liposomal doxorubicin (LPD) is widely used for cancer treatment, knowledge concerning the toxicity induced by this drug in healthy organs and tissues is limited. LPD-induced toxicity studies relative to free doxorubicin (DOX) have focused on cardiotoxicity in tumor-bearing animals. On the other hand, the results on DOX-induced cardiotoxicity depending on gender are controversial. One of the manifestations of toxicity is tissue inflammation. 67Ga-citrate has been used for decades to assess inflammation in various pathologies. In this work, the ex vivo biodistribution of 67Ga-citrate is used to evaluate induced multi-organ toxicity in healthy 10-week-old male and female CD1 mice treated for 5 weeks with LPD. Toxicity in males, determined by 67Ga-citrate, was evident only in the target organs of liposomes (spleen, liver, kidneys, and lungs); the average weight loss was 11% and mortality was 14%. In female mice, 67Ga-citrate revealed a cytotoxic effect in practically all organs, the average weight loss was 37%, and the mortality after the last dose of LPD was 66%. These results confirm the usefulness of 67Ga-citrate and the importance of stratifying by sex in the toxicological evaluation of drugs.

Predictors of new-onset heart failure and overall survival in metastatic breast cancer patients treated with liposomal doxorubicin

Cardiovascular diseases (CVDs) are the major cause of morbidity/mortality among breast cancer (BC) patients. Observation of the daily practice in eight experienced Polish oncology centers was conducted to find all possible predictors of new cases of heart failure (HF) and overall survival (OS) of metastatic BC patients treated with liposomal doxorubicin, taking into account the impact of pre-existing CVDs. HF was the cause of premature discontinuation of liposomal doxorubicin therapy in 13 (3.2%) of 402 patients. The probability of developing HF was higher in women with pre-existing CVDs (HR 4.61; 95%CI 1.38–15.38). Independent of CVDs history, a lower risk of HF was observed in those treated with a cumulative dose of liposomal doxorubicin > 300 mg/m2 (HR 0.14; 95% CI 0.04–0.54) and taxane-naive (HR 0.26; 95% CI 0.07–0.96). Multivariate analysis including the presence of pre-existing CVDs and occurrence of new HF, revealed a liposomal doxorubicin in cumulative doses of > 300 mg/m2 as a beneficial predictor for OS (HR 0.61; 95% CI 0.47–0.78) independently of subsequent chemotherapy (HR 0.72; 95% CI 0.57–0.92) or endocrine therapy (HR 0.65; 95% CI 0.49–0.87). Higher doses of liposomal doxorubicin can decrease mortality in metastatic BC without increasing the risk of HF. The clinical benefit is achieved regardless of pre-existing CVDs and subsequent anticancer therapy.

Effects of immunisation against PCSK9 in mice bearing melanoma

IntroductionInhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an established modality for the treatment of hypercholesterolaemia. However, the impact of PCSK9 inhibition in other situations such as cancer remains largely unknown. The current study was conducted to study the effects of PCSK9 inhibition on cancer endpoints in mice bearing melanoma.Material and methodsTo generate antiPCSK9 antibody in vivo, a nanoliposomal antiPCSK9 vaccine adsorbed to 0.4% Alum adjuvant was subcutaneously injected in C57BL/6 mice four times with bi-weekly intervals. Two weeks after the last immunisation, mice were subcutaneously inoculated with B16F0 melanoma cells. After a tumour mass was palpable (approximately 10 mm3), the mice were randomly divided into four groups and subjected to different treatment protocols: (1) PBS (untreated control), (2) vaccine group, (3) the combination of vaccine and a single dose of liposomal doxorubicin (Doxil®), and (4) liposomal doxorubicin (positive control) group. To determine therapeutic efficacy, mouse body weight, tumour size, and survival were monitored every three days for 36 days.ResultsThe nanoliposomal antiPCSK9 vaccine was found to efficiently induce specific antibodies against PCSK9 in C57BL/6 mice, thereby reducing plasma levels and function of PCSK9. Tumour volumes in the vaccinated group were not significantly different from those in the liposomal doxorubicin, combination, and control groups. The time to reach endpoint (TTE) values of the vaccine (28 ±5 days), combination (30 ±6 days), liposomal doxorubicin (34 ±2 days), and control (31 ±2 days) groups were not significantly different, either. Furthermore, the tumour growth delay (TGD) values of the vaccine (–11.5 ±15.4%), liposomal doxorubicin (7.75 ±6.5%), combination (–6 ±20.77%), and control (0 ±7.5) groups were not significantly different. Finally, there was no significant difference between the median survival time and lifespan of the vaccinated versus other tested groups.ConclusionsThe nanoliposomal PCSK9 vaccine did not adversely affect the growth of melanoma tumour nor the survival of tumour-bearing mice.

Interstitial pneumonia in patients with diffuse large B-cell lymphoma receiving RCHOP and RCDOP regimens

目的比较RCHOP和RCDOP方案治疗弥漫大B细胞淋巴瘤（DLBCL）后间质性肺炎的发生情况。方法回顾性分析2013年1月至2018年8月上海交通大学医学院附属瑞金医院血液科收治的DLBCL患者836例，其中接受RCDOP方案者114例，根据年龄、性别、IPI评分等因素1∶1配对，选出114例接受RCHOP方案的患者作为对照组。收集患者的基础疾病状况、性别、年龄、有无B症状、IPI评分、疾病分期、血LDH、血β2-微球蛋白等相关临床资料，进一步分析间质性肺炎发生的危险因素。结果RCHOP方案和RCDOP方案治疗DLBCL后间质性肺炎的发生率分别为2.60％和28.95％，差异有统计学意义（P<0.01）。RCDOP方案中，随着脂质体阿霉素剂量自25～30 mg/m2增加至35~40 mg/m2，患者的完全缓解率自76.90％增至85.50％（P>0.05），间质性肺炎的发生率也自17.30％增至38.71％（P<0.05）。多因素回归分析显示，应用RCDOP方案、治疗前Ann Arbor分期高是患者预后不良的独立危险因素。结论应用RCDOP方案治疗DLBCL时需加强对间质性肺炎的预防和监测。

Kaposi's Sarcoma in Lung Transplantation: A Decade's Single-Centre Case Series

Purpose Human herpes virus 8 (HHV8) is associated with Kaposi's sarcoma, multicentric Castleman's disease and Primary Effusion Lymphoma. Behaving as an opportunistic virus, immune-compromised patients, including solid organ transplant recipients, are disproportionately affected. The aim of our study was to review all the cases of HHV8 related disease in our lung transplant population. Methods We retrospectively evaluated the incidence of KS and HHV8 associated lymphoproliferative disorders among all lung transplant recipients at our centre, from January 2008 to December 2017. Clinical data of these patients were collected, taking into account time of onset, donor/recipient HHV8 serology, treatments and outcomes. Results Four out of 203 (2%) patients developed KS (Table 1). Disseminated forms of KS occurred through HHV8 infection from a seropositive donor (D+/R-); both patients initially complained of aspecific symptoms (fever and malaise) and presented with pancytopenia and very high HHV8 DNAemia. We observed a very aggressive progression of KS, and patient 3 died 4 weeks after the fourth dose of liposomal doxorubicin due to an untreatable mycotic infection. By contrast, KS due to viral reactivation (i.e., D-/R+) was milder, limited to the skin and responded to modifications in the immunosuppressive regimens. Interestingly, the recipient of the liver harvested from patient 4’s donor developed another serious HHV8 related disease (i.e., Castelman's disease, investigation currently ongoing at another transplant centre). Conclusion We suggest implementation of D/R serological screening for HHV-8 before transplantation, in order to identify patients at risk of developing HHV-8 related diseases, improve clinical and virological surveillance and possibly individualize immune-suppressive therapy. For the time being, in the absence of a systematic screening, we strongly recommend to report index cases as soon as possible to regional allocation systems in order to identy other recipients potentially at risk.

Liposomal Coencapsulation of Doxorubicin with Listeriolysin O Increases Potency via Subcellular Targeting.

Liposomal doxorubicin is a clinically important drug formulation indicated for the treatment of several different forms of cancer. For doxorubicin to exert a therapeutic effect, it must gain access to the nucleus. However, a large proportion of the liposomal doxorubicin dose fails to work because it is sequestered within endolysosomal organelles following endocytosis of the liposomes due to the phenomenon of ion trapping. Listeriolysin O (LLO) is a pore-forming protein that can provide a mechanism for endosomal escape. The present study demonstrates that liposomal coencapsulation of doxorubicin with LLO enables a significantly larger percentage of the dose to colocalize with the nucleus compared to liposomes containing doxorubicin alone. The change in intracellular distribution resulted in a significantly more potent formulation of liposomal doxorubicin as demonstrated in both the ovarian carcinoma cell line A2780 and its doxorubicin-resistant derivative A2780ADR.

Therapy with liposomal doxorubicin in patients with advanced breast cancer after treatment with classical doxorubicin

Breast cancer is the most common female cancer in the world and in Poland. The improvement of diagnostic and therapeutic methods has led to patients’ longer life expectancy. It has also made breast cancer a chronic disease, increasing the risk of late side effects of oncological therapy. More cardiovascular diseases are diagnose in patients over 65 with an oncological history than in those without it and therefore much effort must be made to maximise effectiveness of the therapy with as few side effects as possible. The article presents two breast cancer patients treated with big doses of liposomal doxorubicin with a good response and almost no side effects.

A dose‐finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma

There are few effective therapies for high-risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose-finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose-limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m(2) monthly with temsirolimus 20 mg/m(2) weekly. Hematologic toxicity was common but manageable. Dose-limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co-administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.

Evaluation of Pegylated Liposomal Doxorubicin Dose on the Adverse Drug Event Profile and Outcomes in Treatment of Recurrent Endometrial Cancer

This study aims to determine factors that may increase the likelihood of adverse drug events (ADEs) in patients with recurrent endometrial cancer treated with pegylated liposomal doxorubicin (PLD) as well as this agent's impact on clinical outcomes. The treatment records of patients with endometrial cancer who received PLD at The University of Texas, MD Anderson Cancer Center, from 1996 to 2006 were reviewed. Patient demographics, PLD dose, ADEs, use of supportive care interventions, disease progression, and survival were extracted. Logistical regression analysis was used to identify factors that were associated with higher incidence of ADEs and that influenced survival. A total of 60 patients with recurrent endometrial cancer were identified who experienced 122 ADEs. The most commonly reported ADEs were nausea (18.9%), palmar-plantar erythrodysesthesia (PPE; 16.4%), muscle weakness (12.3%), mucositis (10.7%), and peripheral neuropathy (9.8%). Seventeen patients (28%) required a dose reduction because of ADEs. However, only 5 (8.3%) patients discontinued therapy because of toxicity. Cooling mechanisms were used in 19 patients to prevent PPE, although 9 of these patients still experienced PPE. Treatment with 6 or more cycles of PLD was associated with increased incidence of neutropenia (P = 0.045), peripheral neuropathy (P = 0.004), and PPE (P < 0.001). No differences in progression-free survival or time to progression were found between the doses of PLD; however, there was an assessable trend toward increased survival with doses of 40 mg/m(2). Although there was no association with dose level and ADEs, more cycles received increased the incidence of toxicities, including PPE and neuropathy. There was no association between different doses of PLD and progression-free survival or time to progression.

A 4-Drug, Weekly Combination Regimen of Bortezomib, Cyclophosphamide, Liposomal Doxorubicin, and Dexamethasone for Initial Treatment of Multiple Myeloma

AbstractAbstract 5038 Background:Combination regimens have been highly effective in multiple myeloma. Based on our results with the combination of bortezomib, cyclophosphamide, dexamethsone (Bensinger et al Br J Haematol 2010), we added liposomal doxorubicin to assess whether we could improve response as well as evaluate a weekly combination regimen at our academic center and network affiliated sites in the community. The trial is registered as NCT00849251. Methods:We initially evaluated the regimen in the relapsed setting for toxicity and found it to be well tolerated in 6 patients, then moved to newly diagnosed patients, with the intent that the regimen would serve as induction chemotherapy in preparation for autologous stem cell transplant for transplant-eligible patients. The dosing was bortezomib 1. 6 mg/m2 IV, cyclophosphamide 300 mg/m2 IV, and dexamethasone 40 mg po, days 1, 8, 15, and a single dose of liposomal doxorubicin 30 mg/m2 on day 8 per 28 day cycle. Patients received a maximum of 4 cycles of therapy and the primary endpoints were safety and response at the end of treatment. Results:A total of 31 out of the planned 45 patients (both newly diagnosed and relapsed) were enrolled, as the trial was ended early due to inability to obtain liposomal doxorubicin (Doxil®) for a period of 6 months. One of the relapsed patients was administratively withdrawn after the cycle 1 day 1 treatment. For the remaining 5 relapsed patients who received 2–4 cycles of treatment, the responses were 1 VGPR that was only immunofixation positive, 1 PR and 3 stable disease (SD). For the 24 patients with newly diagnosed MM who completed 1–4 cycles of treatment, there were 2 complete remissions (CRs), 5 VGPRs (2 of which were only immunofixation positive), 11 PRs, and 6 SD for an overall (CR+VGPR+PR) response rate of 75%. Five patients did not complete 4 cycles of therapy, one due to massive pulmonary embolism, one because of need for radiation for intractable back pain during cycle 2 despite marked serological response, and 3 due to stable disease with plateau in response. Of the 25 patients who received BCDD as initial therapy, there have been 3 deaths to date, one due to massive pulmonary embolism on day 13 of the first cycle of treatment, without known history of hypercoagulable risk, one at 7. 7 months of unknown cause, and one at 15. 3 months of progressive disease, resulting in an estimated overall survival of 86% at 2 years from start of therapy. Median follow-up among the 22 survivors is 16. 6 months (range, 8. 1 to 26. 8 months). One patient with a known central line associated deep venous thrombosis in the relapsed group did not exhibit progression of thrombosis off warfarin during therapy. After enrollment of the first 9 patients, an amendment was filed for subsequent patients to receive aspirin prophylaxis, or if at high risk by criteria suggested by Palumbo et al for prophylaxis for MM patients on imids, with low molecular weight heparin or warfarin. Other adverse events that were attributed to investigational regimen include grade 3 hand/foot syndrome (2), infection without neutropenia (1), urinary tract infection (1), and gastrointestinal hemorrhage due to Mallory-Weiss tear (1). Twenty-one patients who completed therapy went on to successful mobilization and collection of peripheral blood stem cells, and autologous or tandem autologous (2) or tandem autologous-minimal myeloablative allogeneic stem cell transplant (7). Two of the 21 patients have died (one at 2. 1 months after first autologous transplant from unknown cause, and one at 9. 8 months from progressive disease). Median follow-up after first autologous transplant among the 19 survivors is 13. 4 months (range, 1. 1 to 20. 4 months). Summary:The 4 drug BCDD regimen exhibited a 75% overall response rate after 4 cycles, with no progression during treatment, was able to be administered weekly in an outpatient setting of both academic and community hematologists and oncologists, and successfully prepared patients for autologous stem cell transplant. Disclosures:Becker:Millennium: Research Funding. Bensinger:Millennium: Research Funding.

Anti-tumor efficacy of interventional chemotherapy with liposomal doxorubicin for hepatic metastasis of pancreatic cancer in nude mouse model

To investigate the anti-tumor effect of interventional chemotherapy with liposome doxorubicin for hepatic metastasis of pancreatic tumor in nude mice. After the establishment of hepatic metastatic model of pancreatic tumor, the nude mice received various formulations via a spleen injection to imitate the interventional chemotherapy. In each of two following experiments, 42 nude mice were randomly divided into 6 groups. They received liposomal doxorubicin (including high, intermittent and low-dose), free doxorubicin, gemcitabine plus cisplatin and control respectively. In the first experiment, the doses were 6, 3, 1.5, 3, 3 mg/kg and 100 µl 10% glucose for each group respectively. And in the second experiment, 9, 6, 3, 6, 6 mg/kg, and 100 µl 10% glucose respectively. The efficacies of interventional injection of liposomal doxorubicin with different doses were examined in terms of tumor growth retardation for the hepatic metastatic foci of pancreatic tumor. In the first experiment, the difference of median hepatic tumor volume was significant among the three groups of mice receiving liposomal doxorubicin with incremental doses in a dose-dependent manner [high dose: (3 ± 1) mm(3), middle dose: (55 ± 18) mm(3), low dose: (90 ± 23) mm(3), P < 0.05]. The liposomal doxorubicin led to a substantial delay of tumor growth as compared to the free drug or gemcitabine plus cisplatin at the same dose (both P < 0.05). In addition, all animals were well-tolerated with no obvious acute toxicity. In the second experiment, significant difference was obtained for the mice injected with different doses of liposomal doxorubicin [(11 ± 4) mm(3), (13 ± 4) mm(3), (50 ± 18) mm(3), P < 0.05]. It was correlated with tumor growth delay. The mice administered with either 9 mg/kg or 6 mg/kg were more efficacious to retard tumor growth than those given 3 mg/kg (P < 0.05). Despite its enhanced effectiveness as compared to mice in gemcitabine plus cisplatin group (P < 0.05), the liposomal doxorubicin at a dose of 6 mg/kg resulted in a marginally delayed tumor growth compared to those of free doxorubicin at the same dose (P > 0.05). No evident acute toxic response was observed for each group of mice receiving liposomal doxorubicin. In contrast, approximately half of the animals receiving either free doxorubicin or gemcitabine plus cisplatin died of toxic responses. Liposomal doxorubicin may be a potential interventional chemotherapeutic agent for hepatic metastasis of pancreatic tumor because of improved anti-tumor efficacy and reduced toxicity in comparison to free doxorubicin and gemcitabine plus cisplatin.

Phase I trial of liposomal doxorubicin and ZD1839 in patients with refractory gynecological malignancies or metastatic breast cancer

Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer. Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed. Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease. Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.

CONCOMITANT LIPOSOMAL DOXORUBICIN AND DAILY PALLIATIVE RADIOTHERAPY IN ADVANCED FELINE SOFT TISSUE SARCOMAS

Local recurrence of feline soft tissue sarcomas is common despite aggressive treatment. Liposomal doxorubicin might serve as a depot radiosensitizer if administered concomitantly with daily radiotherapy and thus improve tumor control. In this pilot study, the feasibility of concomitant liposomal radiochemotherapy was evaluated in a palliative setting in 10 cats with advanced soft tissue sarcomas. Cats were treated with median number of 5 (range 5-7) daily fractions of radiotherapy and a median total dose of 20 Gy (range 20-31.5 Gy). One dose of liposomal doxorubicin was administered at the beginning of radiotherapy. Seven cats received further free or liposomal doxorubicin after completion of the liposomal doxorubicin/radiation protocol. Seven of the treated 10 cats (70%) achieved a partial (n=5) or complete (n=2) response with a median response duration of 237 days. The median progression free interval in all 10 cats was 117 days and the median overall survival time was 324 days. Concomitant liposomal radiochemotherapy was tolerated well in nine cats, one cat experienced temporary anorexia. Although the number of patients is too small to make definitive conclusions, results appear promising enough to investigate the role of liposomal doxorubicin as a radiosensitizer further.

The treatment of limb soft tissue sarcoma with TNF-alfa and pegylated liposomal doxorubicin (PLD): Phase I-II study

10583 Background: Hyperthermic isolation perfusion (HILP) has been employed for STS as limb salvage procedure. Fifty-eight patients affected with unresectable STS have been treated with doxorubicin and 1 mg of TNF-alfa. The CR and PR were 34% and 48% respectively, with a limb salvage rate of 84%. Unfortunately, the limb toxicity was quite high, therefore we decided to employ PLD. Methods: Fourteen patients have been treated with escalating dose of liposomal doxorubicin, starting from 10 mg/L of limb volume up to 18 mg/L, at mean muscle temperature of 41.5C. During HILP blood samples were taken from both systemic and perfusional circulation at 10 minutes intervals. At the end of HILP a tumor and muscle biopsy was carried out in order to evaluate the doxorubicin concentration. A total of 18 STS patients have been treated with PLD. All the patients were monitored in terms of grade of limb toxicity (Wieberdink classification) and systemic toxicity (WHO classification). Eleven patients have been later treated ...

Liposomal doxorubicin-associated acute hypersensitivity despite appropriate preventive measures

Liposomal doxorubicin is becoming popular as a chemotherapeutic agent in the treatment of multiple malignancies. This paper describes an episode of hypersensitivity reaction associated with the infusion of liposomal doxorubicin in an ovarian cancer patient, despite preventive measures being undertaken during her first cycle of chemotherapy. Clinicians may overlook the possibility of hypersensitivity reactions associated with liposomal doxorubicin because routine prophylaxis is not provided and reactions are infrequently observed in practice. Close monitoring during the first 15 min of infusion for signs of hypersensitivity should be mandatory for patients receiving their first dose of liposomal doxorubicin. Further research should identify patients who are at risk of experiencing such hypersensitivity.

A Bacterial Protein Enhances the Release and Efficacy of Liposomal Cancer Drugs

Clostridium novyi-NT is an anaerobic bacterium that can infect hypoxic regions within experimental tumors. Because C. novyi-NT lyses red blood cells, we hypothesized that its membrane-disrupting properties could be exploited to enhance the release of liposome-encapsulated drugs within tumors. Here, we show that treatment of mice bearing large, established tumors with C. novyi-NT plus a single dose of liposomal doxorubicin often led to eradication of the tumors. The bacterial factor responsible for the enhanced drug release was identified as a previously unrecognized protein termed liposomase. This protein could potentially be incorporated into diverse experimental approaches for the specific delivery of chemotherapeutic agents to tumors.

Paclitaxel, carboplatin and pegylated liposomal doxorubicin in ovarian and peritoneal carcinoma: A phase I study of the Gynecologic Oncology Group

Based on the activity and tolerability of liposomal doxorubicin in platinum- and paclitaxel-resistant ovarian carcinoma, we conducted a phase I trial of pegylated liposomal doxorubicin with paclitaxel and carboplatin to determine the maximum tolerated dose (MTD) in chemotherapy naive ovarian, peritoneal and tubal carcinoma patients. Three schedules were studied: paclitaxel, carboplatin and pegylated liposomal doxorubicin every 28 days; paclitaxel and carboplatin every 21 days with liposomal doxorubicin every 42 days; and weekly paclitaxel, carboplatin (AUC=5) every 21 days and liposomal doxorubicin every 42 days. The paclitaxel dose was 175 mg/m(2) over 3 h on an every 3-4 week schedule and 60 mg/m(2) when administered weekly. Based on the frequency of neutropenic sepsis, grade 4 thrombocytopenia and > or =grade 3 non-hematologic toxicity, the starting dose of liposomal doxorubicin of 20 mg/m(2) was escalated to determine the MTD. A total of 210 (21-day) cycles were administered to 37 patients. Dose-limiting toxicity (DLT) occurred when liposomal doxorubicin was administered at 40 mg/m(2). Because of treatment-related delays resulting in decreased paclitaxel/carboplatin dose intensity, administration was modified to be given every 21 days, with liposomal doxorubicin given every 42 days. Since neutropenia was the DLT of this schedule, the schema was further modified to administer paclitaxel weekly; however, weekly administration was inconsistent because of toxicity. Paclitaxel 175 mg/m(2), carboplatin (AUC=5) and pegylated liposomal doxorubicin 30 mg/m(2) are tolerable without supportive therapy. The usual dose intensity of paclitaxel/carboplatin was maintained by administering liposomal doxorubicin every other cycle.

Liposomal doxorubicin (M) plus gemcitabine (G) as first line treatment in metastatic breast carcinoma: A phase I-II study

10651 Background: We designed a phase I-II trial to determine the combination dose of liposomal doxorubicin (Myocet) plus gemcitabine (Gemzar), and to evaluate the safety and feasibility of the regimen Methods: Patients with histologically confirmed breast cancer, untreated distant metastasis, age &gt;18 years old, left ventricular ejection fraction (LVEF) &gt;50% and adequate bone marrow, renal and hepatic function were included in the study. Patients received up to six cycles of treatment. No G-CSF support was used prophylactically. LVEF was repeated at 3, and 6 months, and every 6 months thereafter. Results: Phase I: After 6 patients, the recommended dose was M (55 mg/m2) D1 and G (900 mg/m2) D1 and 8, administered every 21 days. Phase II: 53 patients have been enrolled; 52 are included in the safety analysis and 42 in the efficacy analysis. The median age of the population was 61 years of age (32–79). ECOG PS was 0 in 55%, 1 in 41%, 2 in 4%. Postmenopausal status in 87%. Main histology was ductal carcinoma (85%). Prior adjuvant anthracyclines had been administered in 19 cases (median dose of doxorubicin: 300 mg/m2, or epirubicin: 425 mg/m2). Metastasic lesions were in liver (25), lung (17), bone (16), and lymph nodes (25). Patients received a median number of 5 cycles (range 1–6). Median relative dose intensity was 83% for M and 75% for G. Grade III-IV hematologic toxicity per administered cycles was: leukopenia (21.9%), neutropenia (31.2%), febrile neutropenia (4 %), and thrombocytopenia (7.4%). Grade III-IV non-hematologic toxicities were stomatitis (4.8%), nausea (1.7%), vomiting (2.2%), asthenia (2.6%) and diarrhea (0.8%). Thirteen of 52 pts (25%) had alopecia grade III-IV. No signs or symptoms of cardiac impairment have been seen. An objective response rate of 62% was obtained (95% CI: 45.6- 76.4%). Two patients had complete response (4.8%), 24 partial response (57.1%), 10 stable disease and 6 progressive disease. The response rate was similar in patients with or without previous adjuvant anthracyclines (68.5% and 61%, respectively). Conclusions: The combination of liposomal doxorubicin plus gemcitabine has high efficacy and low toxicity in advanced breast cancer patients, and may be a valuable option in patients that have received adjuvant anthracyclines. [Table: see text]

A phase II study of the combination of liposomal doxorubicin (LD) and gemcitabine (G) in patients with relapsed ovarian cancer after chemotherapy containing platinum compounds

5154 Background: Treatment of choice for patients (pts) with platinum-resistant ovarian cancer (OC) is to be defined. LD is active in relapsed OC with a response rate of 25%. G has shown activity as second line chemotherapy. Our purpose was to evaluate the activity and safety of the LD and G combination chemotherapy in relapsed OC pts, previously treated with at least one platinum containing regimens. Methods: Between Apr 2002 and November 2004, 20 pts with recurrence of histologically proven epithelial OC entered the study and were treated with G 700 mg/m2 (30 min i.v.) on day 1,8 and LD 30 mg/m2 (120 min i.v.) on day 1, every 28 days. The study is still ongoing, so 5 pts are not yet evaluable for response. Results: Characteristics of the pts were the following: median age of 56 years (range 31–74); ECOG PS 0; histology: serous 12 pts, clear cell 3 pts, endometrioid 2 pts, poorly differentiated 2 pts, mucinous 1 pt, mucinous borderline 1pt; initial FIGO stage: III in 16 pts, II in 2 pts, IC in 1 pt, IV in 1 pt. All pts were pretreated with at least one platinum containing chemotherapy. Toxicity consisted of: grade 3–4 (NCI-CTC) neutropenia in 60% of pts, palmo-plantar erythrodysesthesia (PPE) in 40% of pts (grade 1 in 30% of pts, grade 2 in 10%), mucositis in 15% of pts. Doses of LD were reduced by 10–25% in 3 pts due to haematological toxicity or PPE. Filgrastim was administered in 7 pts with neutropenia and EPO was administered in 1 pt with anemia. No neutropenic fever nor unespected toxicity or treatment-related deaths were observed. A total of 145 cycles were administered, with a median of 7 cycles for pt (range 2–14). Objective responses were observed in 40% of pts (6/15 pts) after 2 to 7 cycles (median 3): 4 pts had complete response, 2 pts had partial response. The mean duration of response was 21.3 weeks (range 8–44). The other 9 pts had a stable disease for a mean duration of 25.7 weeks (range 4–52). The mean progression free survival for all pts was 22.9 months (range 4–52). At follow up 7 pts were AWD, 8 were DOD. Conclusions: In this patient population the LD and G combination, with schedule and doses described, is active, with mild and manageable toxicity. No significant financial relationships to disclose.

Cardiac Safety of Pegylated Liposomal Doxorubicin (Doxil®/Caelyx®) Demonstrated by Endomyocardial Biopsy in Patients with Advanced Malignancies

Although conventional doxorubicin demonstrates broad activity, its clinical use is limited by cardiotoxicity. A more recent analysis suggests conventional doxorubicin-related cardiotoxicity occurs more frequently and at lower cumulative doses than previously reported. Pegylated liposomal doxorubicin, designed to maintain or improve conventional doxorubicin activity while reducing toxicities, has demonstrated improved cardiac safety versus conventional doxorubicin. In this prospective study, we evaluated endomyocardial biopsies to determine the cardiac effects of pegylated liposomal doxorubicin in patients with advanced malignancies receiving doxorubicin-equivalent doses ≥ 550 mg/m2 (including pegylated liposomal doxorubicin) or ≥ 400 mg/m2 pegylated liposomal doxorubicin alone. Eight patients were enrolled, and 10 biopsy scores were obtained (two patients had two biopsies). Median biopsy score (Billingham scale) was 0.75 (range, 0–1.5) after a median pegylated liposomal doxorubicin dose of 707.5 mg/m2 and median total anthracycline exposure of 908.5 mg/m2. These results suggest that pegylated liposomal doxorubicin minimizes doxorubicin-related cardiotoxicity, even at doses exceeding the recommended lifetime cumulative conventional dose (450–550 mg/m2).