Extravasation of oxaliplatin: an infrequent and irritant toxicity

Oxaliplatin has been classified as an irritant drug. Less than 10 cases of oxaliplatin extravasation through a central venous access have been described to date. We present a case of extravasation through a central venous access, of the highest dose (165 mg) of oxaliplatin reported to date. We confirmed the irritant effect, and full recovery from toxicity was achieved. We describe the treatment administered and offer a review of literature.     

Extravasation of doxorubicin from vascular access devices

An assessment was made of 36 extravasations of Adriamycin (doxorubicin) in which vascular access devices had been used. Of these, 25 (69%) were sufficiently severe to warrant removal of the device. Physical manifestations were frequently of delayed onset. Edema and/or erythema often involved extensive areas around the catheter or access device and in several cases were accompanied by pain, discomfort or paresthesia. In 20 patients (59%), spontaneous resolution without ulceration occurred in spite of occasional extravasation of large amounts of doxorubicin. Most extravasations were caused by a limited number of technical errors and equipment problems. These were equally divided by site into injection port extravasations and catheter-related extravasations (18 patients each). The two most frequent causes were needle and catheter tip dislodgements. Procedures are suggested for minimizing the opportunities for extravasation of doxorubicin administered through vascular access devices.     

Lyso-thermosensitive liposomal doxorubicin for treatment of bladder cancer

Purpose: To evaluate lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox^®) in combination with loco-regional mild hyperthermia (HT) for targeted drug delivery to the bladder wall and potential treatment of bladder cancer.

Material and methods: Porcine in vivo studies were performed with the following groups: (i) intravenous (IV) LTLD with hyperthermia (LTLD?+?HT); (ii) IV doxorubicin (DOX) with hyperthermia (IV DOX?+?HT) and (iii) IV LTLD without hyperthermia (LTLD – HT). Drug formulations were delivered via 30?min IV infusion coinciding with 1-h bladder irrigation (45?°C water for HT groups, 37?°C for non-HT group), followed by immediate bladder resection. DOX concentrations were measured in consecutive sections parallel to the bladder lumen by liquid chromatography following drug extraction. Computer models were developed to simulate tissue heating and drug release from LTLD.

Results: Comparing mean DOX concentrations at increasing depths from the lumen to outer surface of the bladder wall, the ranges for LTLD?+?HT, IV DOX?+?HT and LTLD – HT, respectively, were 20.32–3.52?μg/g, 2.34–0.61?μg/g and 2.18–0.51?μg/g. The average DOX concentrations in the urothelium/lamina and muscularis, respectively, were 9.7?±?0.67 and 4.09?±?0.81?μg/g for IV LTLD?+?HT, 1.2?±?0.39 and 0.86?±?0.24?μg/g for IV DOX?+?HT, and 1.15?±?0.38 and 0.62?±?0.15?μg/g for LTLD – HT. Computational model results were similar to measured DOX levels and suggest adequate temperatures were reached within the bladder wall for drug release from LTLD.

Conclusions: Doxorubicin accumulation and distribution within the bladder wall was achieved at concentrations higher than with free IV doxorubicin by mild bladder hyperthermia combined with systemic delivery of LTLD.     

多柔比星脂质体在乳腺癌治疗中的安全性分析

目的探讨多柔比星脂质体治疗乳腺癌的安全性。 方法回顾性分析解放军第九六〇医院甲状腺乳腺外科2018年10月至2021年9月使用含多柔比星脂质体药物方案的乳腺癌患者的临床资料,分析患者选择使用多柔比星脂质体的原因,评价心脏毒性以及其他不良反应。 结果共收集215例病例资料。患者选择使用多柔比星脂质体具有主、客观原因。客观原因包括：既往心脏疾病病史(5例,2.3%)、高龄(≥65岁)(11例,5.1%)、心血管病史或心脏疾病遗传因素(15例,7.0%)及合并左乳放射治疗(75例,34.9%)。主观原因包括：对脱发、骨髓抑制、消化道等不良反应特别关注(57例,26.5%),以及年轻患者重视日后生活质量、关注药物的远期心脏毒性(52例,24.2%)。共5例(2.3%,5/215)患者发生心功能损害。其他不良反应为白细胞减少(34.9%,75/215)、脱发59例(27.4%,59/215)、恶心及呕吐41例(19.1%,41/215)、手足麻木15例(7.0%,15/215)、血小板减少41例(19.1%,41/215)。特有的不良反应中手足综合征共11例(5.1%,11/215),并且,在使用本药物的前30例患者中有15例第1次化疗期间发生急性输液反应,其中1例第2次化疗时仍然发生,临床表现为潮红、呼吸困难,给予停药、扩充血容量后缓解,之后降低输液速度完成了治疗。 结论多柔比星脂质体在临床上应用有降低心脏毒性的客观原因和患者意愿选择的主观原因。其在临床上应用是安全的,但应注意不良反应发生,特别应注意其特有的手足综合征和输液反应。     

Long-term chemotherapy of HIV-associated Kaposi's sarcoma with liposomal doxorubicin

The aim of this study was to examine the outcome, adverse events and clinical complications of long-term chemotherapy with pegylated liposomal doxorubicin (PegLiposomal DOX) for human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS) in the pre-highly active antiretroviral therapy (HAART) era. A phase II study over a 4-year period in a tertiary care university hospital was carried out. 52 acquired immunodeficiency syndrome (AIDS)-patients with advanced KS received long-term chemotherapy (71+/-51 weeks) with a mean of 22.8+/-18.2 cycles and a mean cumulative liposomal doxorubicin dose of 456+/-364 mg/m(2) (120-1040 mg/m(2)). Tumour burden, duration and dosage of PegLiposomal DOX, adverse events, opportunistic infections, immunological parameters and HIV load were measured. A complete (10%) or partial response (56%) was achieved while on chemotherapy. 10 patients (19%) showed stable disease. Tumour progression was observed in 8 patients (15%). Importantly, chemotherapy with PegLiposomal DOX was also successful after previous cytostatic therapy with bleomycin and vincristine. The most common adverse events included leucopenia, neutropenia, anaemia, and increased liver function tests. 34 patients (65%) developed new opportunistic infections and 29 patients (56%) died during the study period. To conclude, pegylated liposomal doxorubicin is a safe and effective drug for long-term chemotherapy of advanced (AIDS) KS without adverse effects on CD4 cell counts and HIV viral load.     

Pegylated liposomal doxorubicin in the treatment of breast cancer

Anthracyclines, particularly conventional doxorubicin, play an important role in the treatment of breast cancer, both in the adjuvant and metastatic settings. However, the benefits of conventional doxorubicin in terms of antitumor activity are limited by its therapeutic index. Liposomal formulations were developed to increase the therapeutic index of conventional doxorubicin. Pegylated liposomal doxorubicin, the most widely studied liposomal doxorubicin formulation in breast cancer, has been evaluated in > 20 clinical trials. Pegylated liposomal doxorubicin provides tumor-targeted efficacy without many of the toxicities associated with conventional doxorubicin, including myelosuppression, alopecia, nausea and vomiting, and most importantly, cardiac toxicity. As a single agent, pegylated liposomal doxorubicin has demonstrated similar efficacy to that of conventional doxorubicin in patients with metastatic breast cancer. It has also demonstrated efficacy in combination with other agents or modalities, including cyclophosphamide, paclitaxel, docetaxel, gemcitabine, vinorelbine, and hyperthermia. Response rates in patients with metastatic breast cancer receiving pegylated liposomal doxorubicin either alone or in combination regimens range from 27% to 83%, with median survival estimated at 7-20 months. Small studies also suggest a role for pegylated liposomal doxorubicin in the treatment of locally advanced breast cancer. Preliminary results suggest that pegylated liposomal doxorubicin may be safely administered in combination with docetaxel and trastuzumab in patients with HER2-positive disease. Owing to its comparable efficacy and favorable safety profile, pegylated liposomal doxorubicin may be a useful alternative to conventional doxorubicin, as well as other agents commonly used in the treatment of breast cancer.     

Response of progressive fibromatosis to therapy with liposomal doxorubicin

BACKGROUND: Patients with fibromatosis not amenable to surgery may suffer from high morbidity. Various chemotherapeutic regimens have been tried in these patients with limited success. Here, we report on the successful use of pegylated liposomal doxorubicin in the treatment of 4 patients with unresectable fibromatosis in unfavorable localizations. PATIENTS AND METHODS: 3 children and 1 adult with progressive fibromatosis were treated with 3-weekly cycles of chemotherapy with liposomal doxorubicin (dose range 20-50 mg/m2 per day every 21 days). Tumors were located at the nasal cavity, fossa infratemporalis, oral cavity, abdomen, and fossa supraclavicularis and were unresectable. 3 of the 4 patients had been heavily pretreated with various chemotherapeutic agents. Objective tumor response was monitored by magnetic resonance imaging and possible cardiotoxicity by echocardiography at regular intervals. RESULTS: A tumor response was obtained in all 4 patients. All patients showed normal cardiac function after completion of chemotherapy as evaluated by left ventricular shortening fraction. Severe neutropenia was not observed. CONCLUSION: Pegylated liposomal doxorubicin is a therapeutic option in patients with progressive unresectable fibromatosis in unfavorable localizations.     

Enhancement of antitumor activity of polyethylene glycol-coated liposomal doxorubicin with soluble and liposomal interleukin 2.

Polyethylene glycol-coated liposomal doxorubicin (Doxil) has a sustained release profile and a mild myelosuppressive effect that may enable a beneficial interaction with lymphocyte-activating cytokines, such as interleukin 2 (IL-2). Previous studies have shown that liposome entrapment of IL-2 potentiates its immunomodulatory effects and reduces the need for frequent dosing. We assessed the therapeutic effect of Doxil (8 mg/kg) followed by free or liposomal IL-2 (50,000 Cetus Units x 3) in mice bearing M109 lung adenocarcinoma transplanted i.v. or i.p. Doxil was always administered i.v., whereas IL-2 was given i.v. in the i.v. M109 model and i.p. in the i.p. M109 model. The optimal combined treatment was significantly more effective than liposomal chemotherapy alone, producing tumor-free, long-term survivors in 100% (i.v. M109) and 94% (i.p. M109) of the mice, compared with 50% and 56%, respectively, for Doxil alone. The efficacy boost of IL-2 appeared to be formulation dependent, with free IL-2 and IL-2 in small unilamellar vesicles most active in the i.v. tumor model, and IL-2 in multilamellar vesicles most active in the i.p. tumor model. The combination of Doxil with free or liposomal IL-2 was devoid of any conspicuous toxicity. Cytokine treatment without chemotherapy was completely ineffective. Liposome-based chemoimmunotherapy is a synergistic and highly efficacious approach to eradicate metastatic and regionally spread tumors.     

Convection-enhanced delivery of liposomal doxorubicin in intracranial brain tumor xenografts

We previously reported that convection-enhanced delivery (CED) of liposomes into brain tissue and intracranial brain tumor xenografts produced robust tissue distribution that can be detected by magnetic resonance imaging. Considering image-guided CED of therapeutic liposomes as a promising strategy for the treatment of brain tumors, we evaluated the efficacy of pegylated liposomal doxorubicin delivered by CED in an animal model. Distribution, toxicity, and efficacy of pegylated liposomal doxorubicin after CED were evaluated in a U251MG human glioblastoma intracranial xenograft model. CED of pegylated liposomal doxorubicin achieved good distribution in brain tumor tissue and surrounding normal brain tissue. Distribution was not affected by the particle concentration of pegylated liposomal doxorubicin, but tissue toxicity increased at higher concentrations. CED of pegylated liposomal doxorubicin, at a dose not toxic to normal rat brain (0.1 mg/ml doxorubicin), was significantly more efficacious than systemic administration of pegylated liposomal doxorubicin at the maximum tolerated dose. CED of pegylated liposomal doxorubicin resulted in improved survival compared to CED of free doxorubicin at the same dose. Outcomes of this study suggest that CED of liposomal drugs is a promising approach for the treatment of glioblastoma.     

Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation

Antitumor drugs such as doxorubicin have been encapsulated into liposomes as a means of enhancing activity and reducing toxicity. The present study was initiated to determine whether chronically administered liposome-encapsulated doxorubicin would be less toxic than the free drug. Doxorubicin was prepared in positively charged cardiolipin liposomes, and 1.75 mg/kg was given i.v. to each of five beagles. A second group received the free drug at 1.75 mg/kg. Additional animals received i.v. injections of either doxorubicin-free liposomes or 0.9% NaCl solution. All substances were given at 3-week intervals, and the experiment ended 1 week after the seventh injection (total dose, 12.25 mg/kg). A temporary reduction in food consumption was noted during the first few days after the administration of either form of doxorubicin. The effect was more severe in the dogs given free doxorubicin, and body weight decreased significantly only in this group of animals. Three dogs given free doxorubicin died or were killed before the end of the study because they were in poor condition. Lesions consisting mainly of vacuolization and myofibrillar loss were noted in the hearts of all five dogs given free doxorubicin. The severity of the lesions ranged from 2 to 4 (average, 3.4). In contrast, no abnormalities were found in any of the hearts from dogs given the liposomal doxorubicin. The most obvious general toxic effect caused by administration of free doxorubicin was alopecia, which was entirely prevented when doxorubicin was encapsulated into liposomes. At the dosage regimen utilized, liposomal doxorubicin and free doxorubicin exerted comparable degrees of bone marrow suppression. Thus, liposomal encapsulation of doxorubicin decreased cardiac and other toxic effects elicited by free doxorubicin. Whether this advantage can be translated into effective antineoplastic activity will need further evaluation.     

Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients

Purpose  

There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD.     

Phase I clinical trial of topotecan and pegylated liposomal doxorubicin

Background: The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors. Patients and Methods: Patients were treated with intravenous topotecan (0.75-1.25 mg/m²) for 3 days followed by PLD (25-40 mg/m²) on Day 4. The following dose combinations (topotecan/PLD, mg/m²) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days. Results: Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m² every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m² every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer. Conclusions: This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m² on Days 1-3 followed by PLD 40 mg/m² on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m² on Days 1-3 and PLD 30 mg/m² on Day 4 of a 21-day cycle.     

多柔比星脂质体联合达卡巴嗪治疗不可手术切除硬纤维瘤的疗效初探

  目的  硬纤维瘤是一种交界性肿瘤,易复发,不转移。对于不可手术切除的硬纤维瘤患者可以考虑药物治疗。本研究探讨使用多柔比星脂质体联合达卡巴嗪方案治疗不可手术切除硬纤维瘤患者的临床效果。  方法  选取2015年1月至2019年12月北京大学肿瘤医院收治的35例不可手术切除的硬纤维瘤患者作为研究对象,其中男性11例,女性24例;发病年龄3～53岁,平均年龄27.5岁;肿瘤大小:T2（5～10 cm）6例,T3（10～15 cm）11例,T4（>15 cm）12例,6例多发,无T1（<5 cm）。所有患者均接受多柔比星脂质体联合达卡巴嗪方案化疗,每2个周期进行影像学评效,若有效,至少化疗6个周期,最长12个周期。  结果  化疗结束时评效,部分缓解（partial response,PR）10例,疾病稳定（stable disease,SD）24例,疾病进展（progressive disease,PD）1例,无完全缓解（complete response,CR）病例;客观反应率（objective response rate,ORR）为28.6%,疾病控制率（disease control rate,DCR）为97.1%。无进展生存时间（progression-free survival,PFS）2～50个月,中位无进展生存期（median progression- free survival,mPFS）为13个月,平均PFS为14.4 个月,23例完成计划化疗患者PFS超过12个月,在5例患者中观察到结束化疗后肿瘤仍持续缩小。  结论  对于不可手术切除的硬纤维瘤患者,多柔比星脂质体联合达卡巴嗪方案化疗是一种安全有效的药物治疗方法。      

Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancer

Anthracyclines, including doxorubicin, are the mainstay of therapy for breast cancer. However, doxorubicin can cause dose-dependent cardiotoxicity, limiting the cumulative dose. Liposomal conjugation of doxorubicin results in preferential distribution of doxorubicin in the tumor compared with normal tissues. Nonpegylated liposomal doxorubicin (NPLD) has demonstrated reduced cardiac toxicity, with anti-tumor responses comparable to those of conventional doxorubicin. The substitution of NPLD for conventional anthracyclines significantly reduces the cumulative cardiotoxicity, while allowing a higher cumulative dose. This allows patients who have already received the maximum cumulative dose of doxorubicin to receive further doxorubicin, as well as those with risk factors for anthracycline-induced cardiotoxicity. The favorable cardiac safety profile of NPLD may allow it to be combined with newer therapies, such as trastuzumab.