Conventional Anthracyclines Research Articles

Neoadjuvant pegylated liposomal doxorubicin-containing chemotherapy in combination with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer: A randomized phase II study (METIS).

596 Background: In the neoadjuvant phase, anti-HER2 therapy is usually delayed when combined with anthracycline-containing chemotherapy regimens, since conventional anthracycline and anti-HER2 agents cannot be given simultaneously. Pegylated liposomal doxorubicin (PLD) is a modified form of doxorubicin that can lower the risk of heart damage while preserving its anticancer activity. In this study, we aimed to explore whether PLD could replace conventional anthracycline and be used earlier with anti-HER2 agents to enhance neoadjuvant efficacy without increasing cardiotoxicity. Methods: The METIS study was an investigator-initiated, multicenter, open-label, randomized, phase II study conducted at 11 centers in China. Patients aged 18 to 70 years old with previously untreated stage II–III histologically documented HER2-positive breast cancer were randomly assigned (1:1) to receive PLD-containing or epirubicin-containing neoadjuvant chemotherapy. The PLD-containing regimen consisted of 4 cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by 4 cycles of a taxane of the investigator's choice (docetaxel, paclitaxel, or nab-paclitaxel). The epirubicin-containing regimen consisted of 4 cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by 4 cycles of a taxane of the investigator's choice. Both regimens included trastuzumab (8 mg/kg loading dose, then 6 mg/kg maintenance dose) and pertuzumab (840 mg loading dose, then 420 mg maintenance dose) every 3 weeks. Trastuzumab and pertuzumab were given with all chemotherapy cycles in the PLD-containing group, and with the taxane cycles only in the epirubicin-containing group. The primary end point was investigator-assessed total pathological complete response (tpCR) rate in the intention-to-treat population. Results: From August 2019 to March 2023, 156 were enrolled and randomly assigned to receive PLD-containing (n=80) or epirubicin-containing (n=76) treatment. At date of data analysis, the median follow-up duration was 16.3 months. The PLD-containing treatment group had a higher rate of pathological complete response (67.5%, 95% CI 56.1-77.6) than the epirubicin-containing group (48.7%, 95% CI 37.0-60.4), with a rate difference of 18.8% (p=0.033). Only one patient in the epirubicin-containing group experienced a grade 3 decrease in left ventricular ejection fraction, while none did in the PLD-containing group. Other adverse events were similar in both groups. Conclusions: A combination of PLD and cyclophosphamide with trastuzumab and pertuzumab, followed by a taxane, trastuzumab, and pertuzumab, significantly increased the rate of tpCR without more cardiotoxicity in neoadjuvant treatment for early-stage HER2-positive breast cancer patients. Clinical trial information: NCT04172259 .

A Novel Anticancer Quinolone, ( R)-Wac-224 Monotherapy or Combination with Cytarabine/Venetoclax Confers Promising Activities Against Acute Myeloid Leukemia

Introduction Approximately 60%-80% of patients with acute myeloid leukemia (AML) who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances of novel anticancer agents. Targeting topoisomerase 2 (Top2) is important to treat patients with AML, as anthracycline is widely used in general practice. However, anthracycline-induced cardiotoxicity or anthracycline resistance due to P-glycoproteinoverexpression often becomes major obstacles to successful treatment. Therefore, continuing development of more effective novel treatments for AML is necessary. Quinolones, antibacterials that attack DNA gyrase and topoisomerase IV (functional analog of mammalian Top2), possess a broad spectrum chemotherapeutic activities including anti-leukemic effects (e.g. vosaroxin). In this study, we developed and characterized a novel quinolone that demonstrates promising activities against human AML as a single agent and in combination with other agents. Methods and Results We developed 5-methyl-7-{3-[(oxan-2-ylmethyl) carbamoyl] azetidin-1-yl}-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid [racemic WAC-224 (WAC) or (R)-WAC-224 (R-WAC), which is a novel anticancer quinolone, targeting Top 2. WAC inhibited Top2α comparable with vosaroxin (a known Top2 inhibitor) in a topoisomerase relaxation assay. IC 50 of vosaroxin and WAC were 1.10 μM and 2.26 μM, respectively. R-WAC significantly inhibited the human AML cell line proliferation (MV4-11, HL60, and KG1a), which was comparable to daunorubicin and cytarabine, in a manner not affected by P-glycoprotein overexpression. WAC also elicited cell apoptosis against MV4-11 cells comparable with vosaroxin. Whereas, WAC did neither increase serum troponin-T nor decrease the crypt numbers in the small intestine, indicating WAC was less toxic than doxorubicin. R-WAC monotherapy demonstrated prolonged survival in the AML mice model and inhibited tumor growth in the MV4-11 xenograft mice model. Moreover, the combination of R-WAC and cytarabine demonstrated more active anti-leukemia effects than daunorubicin and cytarabine in the AML mice model. R-WAC and cytarabine or daunorubicin and cytarabine did not exhibited decreased body weight in mice. Next, we investigated R-WAC combination with venetoclax, selective BCL-2 inhibitor, for anti-leukemia effects. R-WAC and venetoclax exhibited increased cell apoptosis against MV4-11 and KG1a cells in vitro, and more active anti-leukemia effects in xenotranplant MV4-11 mouse model than each monotherapy. These results suggest that R-WAC and combination with cytarabine or venetoclax has strong anti-leukemia effects without increased toxicities. Finally, R-WAC significantly suppressed the colony-forming capacity of bone marrow CD34 + stem/progenitor cells in refractory AML patients, indicating R-WAC depleted AML stem cells. Conclusion R-WAC has promising anti-leukemia effects with less toxicities compared with conventional anthracycline possibly due to the different inhibitory mechanisms of Top2 isoform (anthracycline inhibits Top2β). These results indicate that R-WAC is a promising therapeutic agent for AML and support its clinical development, especially as a combination of R-WAC with cytarabine or venetoclax.

Pegylated liposomal doxorubicin combined with ifosfamide for advanced soft tissue sarcomas: A phase I dose-escalation study.

e23525 Background: Doxorubicin combined with ifosfamide (IFO) is one of the preferred treatment options for non-specific soft tissue sarcomas (STS), but is limited by cumulative cardiotoxicity and severe myelosuppression. Pegylated liposomal doxorubicin (PLD) provides an effective alternative to conventional anthracyclines with reduced toxicity. However, there is no standard dose recommendation for PLD combined with IFO for STS. The present study aimed to investigate the maximum tolerated dose (MTD) of PLD combined with IFO in advanced STS patients. Methods: This was a phase I, open-label, single-center, dose-escalation study. Patients with locally advanced or metastatic STS were enrolled, except for gastrointestinal stromal tumors, Ewing's sarcomas, embryonal rhabdomyosarcomas, and alveolar rhabdomyosarcomas. We used a standard 3 + 3 dose-escalation design with progressively increasing PLD and IFO (3 g/m2 per day for 3 days, q3w) for one cycle, with a dose escalation ranged from 30 to 70 mg/m2 (5mg/m2 increment per step). The primary endpoint was determination of the MTD, and the secondary endpoint was the incidence/severity of adverse events (AEs). Results: From January 2020 to September 2022, 23 patients were enrolled in this study, including 3 patients at doses 30-45 mg/m2, 6 patients at dose 50 mg/m2, and 5 patients at 55 mg/m2. The median age was 49 years (ranges from 30 to 68 years), the male/female ratio was 12/11, and 22 (95.65%) patients had stage IV disease (AJCC staging system). Initially, no DLT was observed at doses of 30-50 mg/m2, with 3 patients in each dose phase. Two patients developed DLTs at the 55 mg/m2 dose, resulting in the 50 mg/m2 dose extending to a total of 6 patients who completed treatment without DLT. The DLTs at dose 55 mg/m2 of the first patient were grade 4 neutropenia lasting ≥ 5 days and grade 3 thrombocytopenia with hemorrhage tendency; the second patient had grade 4 neutropenia lasting ≥ 5 days, grade 4 thrombocytopenia relapsed after platelet transfusion, and grade 3 increased alanine aminotransferase. Therefore, the MTD of PLD was 50 mg/m2. The most common (≥ 10%) grade 3-4 AEs in all patients were lymphopenia (56.52%), neutropenia (82.61%), leukopenia (86.96%), and thrombocytopenia (13.04%). Conclusions: For patients with locally advanced or metastatic STS, single cycle PLD combined with IFO had a tolerable AE profile, with an MTD of 50 mg/m2 for PLD. Further researches are needed to confirm the multi-cycle recommendation. Clinical trial information: ChiCTR1900028270 .

Cardiac Safety in Breast Cancer Patients Receiving Pegylated Liposome Doxorubicin Sequential Anti-HER2 Monoclonal Antibody Therapy.

Background: Cardiotoxicity associated with the sequential use of anthracyclines followed by trastuzumab is common in adjuvant therapy of patients with HER2-positive early breast cancer (eBC). However, the cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) is relatively less studied. Method: Clinical data of patients with HER2-positive eBC treated with PLD and cyclophosphamide (PLD-C) followed by taxanes plus trastuzumab ± pertuzumab (TH or TPH) who then completed standard anti-HER2 treatment for 12 months from June 2012 to August 2021 were retrospectively collected. The primary endpoints were clinical and subclinical cardiotoxicity. Result: In total, 70 eligible patients were enrolled. Among them, 55 patients (78.6%) received PLD-C → TH and 15 patients (21.4%) received PLD-C → TPH. The median follow-up time was 41.8 months. Until August 2021, only two patients had recurrent or metastatic diseases, with 2-year and 5-year disease-free survivals of 98.6% and 96.8%, respectively. Clinical cardiotoxicity occurred in six patients (8.6%), and all of them had an absolute decline of ≥16% from baseline left ventricular ejection fraction (LVEF) but not below the lower limit of normal (LLN = 50%). Subclinical cardiotoxicity events occurred in 17 patients (24.3%), and all of them had absolute declines of ≥10% and <16% from baseline LVEF but not below the LLN. No patients were interrupted from treatment, and all patients completed anti-HER2 treatment for 12 months. The sharpest decrease in LVEF was observed at 18 months after the start of PLD treatment. The cumulative incidences of clinical and subclinical cardiotoxicity were 9.8% and 28.3%, respectively. In the univariate analysis, body mass index, age, left chest wall radiotherapy, and ongoing cardiovascular risk factors were not significantly associated with clinical or subclinical cardiotoxicity (p > 0.05). No patients had congestive heart failure or death caused by PLD or anti-HER2 treatment. Conclusion: The sequential use of PLD and trastuzumab showed a lower incidence of clinical cardiotoxicity, presented as asymptomatic decreased LVEF, compared with the results obtained in previous clinical studies using conventional anthracycline, taxanes and trastuzumab. The study regimen demonstrated good cardiac tolerance and is an alternative strategy for cardioprotection in patients with HER2-positive eBC.

Abstract 375: SR-B1-targeted nanoparticle delivery of novel anthracyclines to Ewing's Tumors

Abstract Purpose: Anthracyclines effectively treat many pediatric cancers, but their use is limited by cardiotoxicity and new approaches to mitigate anthracycline-induced cardiac damage are urgently needed. Nanoparticle drug delivery is one solution to maintain anticancer efficacy while mitigating both acute and long-term cardiac complications. Additionally, novel treatments are needed to improve cure rates in certain cancer diagnoses that have not seen advancements in decades, particularly Ewing Sarcoma (EWS). Experimental Design: We investigated the use of a self-assembling micelle structure composed of myristic acid conjugated to an Apo-A1 mimetic 5A peptide, termed Myr5A nanoparticles (Myr5A NPs). These nanoparticles are transported into cells via the cholesterol scavenger receptor class B type-1 (SR-B1). Doxorubicin (DOX) and the Myr5A NP cannot form a stable micelle due to the hydrophilic nature of DOX, which results in preferential binding to the peptide shell, as opposed to the hydrophobic core. To favor micelle stability, we opted to use the novel, highly hydrophobic anthracyclines valrubicin and AD198 to test the nanoparticle delivery system. The potency of these anthracyclines encapsulated in Myr5A NPs were evaluated in human EWS cell lines with high and low SR-B1 expression via MTT assay. Additionally, 5 mg/kg intraperitoneal injections were administered weekly to 4-week-old wild type C57BL6/J mice and immune compromised homozygous null forkhead box N1 mice (Foxn1null/null mice) over 5 weeks, to assess by echocardiography, acute and long-term cardiac dysfunction. Results: Treatment with Myr5A-encapsulated AD198 and Myr5A-encapsulated valrubicin significantly inhibited EWS cell proliferation at concentrations comparable to conventional anthracyclines. Moreover, compared to unencapsulated valrubicin and AD198, encapsulation resulted in a lower IC50 in EWS lines with higher SR-B1 surface expression. By 19 weeks of age, DOX-treated C57BL6/J mice exhibited significantly decreased ejection fraction (EF) compared to PBS control and Myr5A-encapsulated anthracyclines (p&amp;lt;0.05). Additionally, an increase in Left Ventricular Mass (LVM) was observed in all groups except DOX by 19 weeks (p&amp;lt;0.05). Lastly, DOX-treated Foxn1null/null mice showed diminished survival rate compared to all treatment groups, and similar results to C57BL6/J mice in EF and LVM. Conclusions: Our results indicate that AD198 and valrubicin, when encapsulated in Myr5A NPs, induce minimal cardiac dysfunction while maintaining antitumor efficacy in EWS tumors. Myr5A NP drug delivery may be a viable option for the treatment of high SR-B1 expressing tumors with a decreased risk of acute and long-term cardiac complications. Future studies will evaluate the drug potency in non-cancer cell lines, such as cardiac fibroblasts and myocytes, and the effects of Myr5A-encaspulated anthracyclines on EWS xenografts and other pediatric tumors. Citation Format: Kathryn Crouch, Logan Davis, Nirupama Sabnis, Alexander Pertsemlidis, Laura Rutledge, James Graham, Jason Yustein, Gregory J. Aune. SR-B1-targeted nanoparticle delivery of novel anthracyclines to Ewing's Tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 375.

Thyroid Dysfunction Following Conventional Anthracycline- and Taxane-based Chemotherapy for Breast Cancer

Thyroid Dysfunction Following Conventional Anthracycline- and Taxane-based Chemotherapy for Breast Cancer

Effectiveness and safety of pegylated liposomal doxorubicin versus epirubicin as neoadjuvant or adjuvant chemotherapy for breast cancer: a real-world study

BackgroundPegylated liposomal doxorubicin (PLD) is an improved formulation of doxorubicin with comparable effectiveness but significantly lower cardiotoxicity than conventional anthracycline. This study aimed to evaluate the real-world effectiveness and safety of PLD versus epirubicin as neoadjuvant or adjuvant treatment for breast cancer.MethodsClinical data of invasive breast cancer patients who received neoadjuvant or adjuvant chemotherapy with PLD or epirubicin were retrospectively collected. Propensity score matching (PSM) was performed to reduce the risk of selection bias. The molecular typing of these patients included Luminal A, Luminal B, HER2-positive, and basal-like/triple-negative. The primary outcome was pathological complete response (pCR) rate for neoadjuvant chemotherapy and 3-year disease-free survival (DFS) rate for adjuvant chemotherapy. Noninferiority was suggested if the lower limit of the 95% CI for the 3-year DFS rate difference was greater than − 10%. The secondary outcome was adverse reactions.ResultsA total of 1213 patients were included (neoadjuvant, n = 274; adjuvant, n = 939). pCR (ypT0/Tis ypN0) rates of patients who received neoadjuvant chemotherapy were 11.6% for the PLD group and 7.0% for the epirubicin group, but the difference was not statistically significant (P = 0.4578). The 3-year DFS rate of patients who received adjuvant chemotherapy was 94.9% [95%CI, 91.1–98.6%] for the PLD group and 95.4% [95%CI, 93.0–97.9%] for the epirubicin group (P = 0.5684). Rate difference between the two groups and its 95% CI was - 0.55 [− 5.02, 3.92]. The lower limit of the 95% CI was − 5.0% > − 10.0%, suggesting that PLD is not be inferior to epirubicin in adjuvant chemotherapy for breast cancer. The incidences of myelosuppression, decreased appetite, alopecia, gastrointestinal reactions, and cardiotoxicity were lower in the PLD group than in the epirubicin group, while the incidence of nausea was higher in the PLD group.ConclusionsIn the neoadjuvant and adjuvant treatment of breast cancer, effectiveness is similar but toxicities are different between the PLD-containing regimen and epirubicin-containing regimen. Therefore, further study is warranted to explore PLD-based neoadjuvant and adjuvant chemotherapy for breast cancer.

Pegylated Liposomal Doxorubicin Versus Epirubicin as Adjuvant Therapy for Stage I-III Breast Cancer.

Background: Conventional anthracyclines, like epirubicin, are cornerstone drugs for breast cancer treatment of all stages, but their cumulative toxicity could cause life-threatening side effects. Pegylated liposomal doxorubicin (PLD), an effective anti-breast cancer drug, has lower toxicity than conventional anthracyclines. This retrospective study compared the efficacy and toxicity profiles between PLD and epirubicin as adjuvant therapy for breast cancer.Patients and Methods: A total of 1,471 patients diagnosed with stage I–III breast cancer between 2000 and 2018 were included in this study, among which 661 were treated with PLD and 810 with epirubicin, with 45.9 months as the median follow-up time. Anti-breast cancer efficacy was assessed with overall survival (OS) and disease-free survival (DFS), while cardiac toxicity was assessed with left ventricular ejection fraction (LVEF) and electrocardiogram (ECG).Results: The Kaplan–Meier method and Cox proportional hazards model revealed that there was no statistical difference in OS or DFS between patients treated with PLD and epirubicin, regardless of cancer stages or molecular subtypes (all p-values > 0.05). In addition, patients had significantly better LEVF and ECG data after adjuvant therapy with PLD (both p-values < 0.05).Conclusion: Based on the large sample size and the long follow-up time of this study, we conclude that PLD has a similar anti-breast cancer efficacy as epirubicin while inducing lower level of cardiac toxicity in Han Chinese. This study suggests that PLD-based adjuvant chemotherapy could be a better option than epirubicin for breast cancer patients especially with existing cardiac disease.

Higher efficacy and reduced adverse reactions in neoadjuvant chemotherapy for breast cancer by using pegylated liposomal doxorubicin compared with pirarubicin

The present study aimed to investigate the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) in preoperative neoadjuvant chemotherapy for patients with breast cancer by comparing with conventional anthracycline. This study is a non-randomized controlled trial. Prospective analysis was conducted after matching as required. A total of 146 patients with confirmed diagnosis of breast cancer by histopathological examinations were enrolled into the observation group and control group in 1:1 ratio. Each of the cases in the observation group was required to correspond to another in the control group according to the requirements including age, molecular subtype, axillary node status, and regimen of the preoperative neoadjuvant chemotherapy. The chemotherapy was based on regimens consisting of anthracyclines, paclitaxel or docetaxel, and/or platinum. PLD was used at least twice in the observation group, with traditional anthracycline as a contrast in the control group. Clinical responses as well as cardiac side effects and other adverse reactions were evaluated by clinical and imaging examinations such as electrocardiogram (ECG) and color Doppler ultrasound during the chemotherapy. Pathologic examinations were performed following the surgeries after preoperative neoadjuvant chemotherapy. All the patients in both groups completed the preoperative neoadjuvant chemotherapy according to their original regimens. The postoperative pathological evaluation revealed a higher pathologic complete response (PCR) rate and significantly more patients of grade V of the Miller-Payne grading system in the observation group as compared to the control group (p = 0.047). In addition, the observation group recorded an evidently lower occurrence of the adverse cardiac events (p = 0.014), ECG changes (p = 0.048), and the relatively severe adverse reactions such as myelosuppression. Compared with conventional anthracycline drugs, PLD has a better pathologic response and safety performance, as well as a similar clinical effectiveness in preoperative neoadjuvant chemotherapy for breast cancer.

High Efficacy of Liposomal Annamycin (L-ANN) in Combination with Cytarabine in Syngeneic p53-Null AML Mouse Model

High Efficacy of Liposomal Annamycin (L-ANN) in Combination with Cytarabine in Syngeneic p53-Null AML Mouse Model

Rechallenge with dabrafenib plus trametinib in anaplastic thyroid cancer: A case report and review of literature

Introduction: Anaplastic thyroid carcinoma (ATC) is a highly aggressive, undifferentiated rare tumor. Median overall survival is usually between 8 and10 months, with a 1-year survival rate of 20%. Conventional anthracycline based chemotherapy regimens demonstrate low response rates with short duration. Novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape of ATC have been investigated. Case presentation: We herein report the rechallenge of a 52-year-old ATC patient with BRAF V600E mutation with dabrafenib plus trametinib. She presented with recurrent and progressive disease despite surgery, radiation therapy, 3 different chemotherapy regimens, and combination of dabrafenib-trametinib in different settings. She was rechallenged with dabrafenib-trametinib, and had a good response. Conclusion: To our knowledge, this is the first ATC case who responded to dabrafenib-trametinib rechallenge, reported in the literature. We want to emphasize that combination of dabrafenib and trametinib might be a good choice for resistant locoregional and metastatic ATC patients with BRAF V600E mutation, particularly in whom rapid clinical response is urgently needed. Moreover, rechallenge with this combination should be kept in mind in selected cases.

The Efficacy of Pegylated Liposomal Doxorubicin-Based Neoadjuvant Chemotherapy in Breast Cancer: A Retrospective Case-Control Study in Taiwan.

Breast cancer is a global issue regarding women's health, and high incident rates remain in the Taiwanese female population. Chemotherapy, using anthracycline-based chemotherapeutic agents in neoadjuvant settings, has been introduced as a promising new therapeutic option for treatment of invasive breast cancer. Set apart from conventional anthracycline regimens such as epirubicin, pegylated liposomal doxorubicin (Lipo-Dox®, PLD) was introduced for providing a justifiable treatment effect, while offering a favorable toxicity profile for breast cancer patients in a metastatic setting. However, the efficacy of PLD in neoadjuvant settings for breast cancer patients has not yet been sufficiently reported. This study aims to investigate the efficacy of PLD-based neoadjuvant chemotherapy in breast cancer patients using a retrospective matched case-control study. A total of 183 PLD cases and 183 epirubicin-based controls were included after a 1 : 1 ratio case-control matching procedure was held, according to the matching criteria. These criteria included the patient's preoperative clinical stage, molecular subtype, chemotherapy regimen with taxanes prior to surgery, and histological grade. All data were collected according to an institutional review board approved protocol. The study results reported that the PLD and epirubicin groups both obtained similar outcomes in pathologic complete response (pCR), recurrence, and overall survival rate with no statistically significant differences. Overall, the study results demonstrate that PLD-based neoadjuvant chemotherapy offers a similar effect of treatment with a favorable toxicity profile within the study follow-up duration, when compared with conventional epirubicin-based neoadjuvant chemotherapy.

Pegylated liposomal doxorubicin as neoadjuvant therapy for stage II–III locally advanced breast cancer

Conventional anthracyclines represent a cornerstone drug in the treatment of breast cancer. Pegylated liposomal doxorubicin (PLD) has similar efficacy to anthracyclines with reduced toxicity. This study was to compare the efficacy and safety of PLD-based neoadjuvant chemotherapy (NAC) with epirubicin-based treatment for breast cancer. 81 breast cancer patients were enrolled in this retrospective study. The objective response rate (ORR) in the PLD group was 74.1%, the 3-year disease-free survival(DFS) and overall survival(OS) were 81.5% and 88.9%. The PLD group achieved similar efficacy to the EPI group. The PLD group showed a low rate of neutropenia , nausea and vomiting, but a higher rate of mucositis and hand-foot syndrome. In neoadjuvant chemotherapy for invasive breast cancer, PLD provides comparable efficacy to epirubicin with a safe cardiac toxicity profile and manageable adverse effects.

Cardiac Safety with High Cumulative Dose of Pegylated Liposomal Doxorubicin in Patients with Metastatic Breast Cancer Previously Treated with Conventional Anthracyclines

Introduction: The treatment of metastatic breast cancer (MBC) is still challenging. Many studies documented the efficacy of pegylated liposomal doxorubicin (PLD) in patients with MBC, but there is a limited data about the cardiac safety with high cumulative dose (HCD) of PLD. Aim of the work: We conducted this trial to outline the cardiac safety of HCD of PLD in patients with MBC who previously received conventional anthracyclines. Methods: During the period of nine years (January 2011 to December 2019). We extracted the data of the patients with MBC receiving PLD at Medical Oncology Department, South Egypt Cancer Institute, Assiut University. These included patients’ demographics and therapeutic data including the full data of PLD, prior conventional anthracyclines, prior trastuzumab, and prior radiotherapy. Also, data about comorbidities as well as cardiac and other toxicities of PLD were obtained. The data was analysed using SPSS v. 21. Results: For all 81 eligible patients, the mean age was 43.9 years (±standard deviation (SD) 13.2). The mean cumulative dose of PLD was 378.4 mg/m2 (± SD of 250.2) and a range of 100 - 1200 mg/m2. About thirty-one (38.3%) patients received high cumulative dose (400 mg/m2 or more), while the remaining 50 patients did not. The decline in left ventricular ejection fraction (LVEF) was relatively rare; and of low grade. Grade 2 decline in LVEF occurred in only two patients who received high cumulative dose of PLD, and only one patient who did not reach HCD (p = 0.555). Grade 3 or 4 decline in LVEF did not occur in patients either with or without HCD. Regarding other toxicities, there was a significant increase in incidence of all grades palmar plantar erythrodysesthesia (PPE) in patients who received HCD of PLD when compared to those who did not reach the HCD (38.7% versus 16% respectively; p = 0.021). Conclusion: Our study concluded that the use of PLD seems to be a justified agent in the treatment of MBC who previously treated by conventional anthracyclines in the adjuvant, metastatic or both settings, even in patients reaching the cumulative dose of conventional anthracycline.

Ecteinascidins – new antineoplastic drugs from the depths of the seas

Trabectedin, also known as ecteinascidin 743 (Et-743), is a tetrahydroisoquinoline alkaloid that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata. Trabectedin is one of the first anticancer drugs of marine origin that has been approved in the European Union. The compound is used to treat patients with advanced soft tissue sarcoma in case of failure of conventional anthracyclines and ifosfamide therapy and in the treatment of recurrent platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. The mechanism of action of trabectedin is based on interaction with the minor groove of DNA double helix. It triggers a cascade of events that interfere with several transcription factors, DNA binding proteins and DNA repair pathways, resulting in G2/M cell cycle arrest and ultimately apoptosis. Moreover, emerging evidence indicates that Et-743 has dual effects. In addition to induce direct growth inhibition, cell death and differentiation of malignant cells it also affects the tumor microenvironment by reducing the production of key inflammatory mediators. A multifaceted mechanism of action may explain positive results when trabectedin is used in the treatment of cancer that exhibits resistance to conventional chemotherapeutics. The widespread use of ecteinascidins in therapy as well as in clinical trials is, however, limited by the high price of these compounds. Therefore, intensive work is being carried out on the search for synthetic analogues of ecteinascidins with equally high activity against tumor cells.

Extravasation accidents with liposomal/liposomal pegylated anthracyclines treated with dexrazoxane: an overview and outcomes.

The extravasation of chemotherapeutic agents is a challenge for oncologic care teams. The management of nonliposomal (conventional) anthracyclines is well established in clinical practice guidelines, including general measures and specific antidotes, such as dexrazoxane. However, there is little scientific evidence on the management of liposomal and pegylated liposomal anthracyclines. The aim of this paper was to review the scientific literature on the extravasation of liposomal and pegylated liposomal anthracyclines and determine the clinical impact of this type of extravasation, focusing on dexrazoxane. The literature was searched using two databases: PubMed and Embase. Three searches were conducted, using liposomal anthracycline extravasation, pegylated liposomal anthracycline extravasation, and liposomal doxorubicin extravasation as keywords, respectively. Seven articles fulfilled the study eligibility criteria and included seventeen cases in humans. Extravasation occurred with three drugs: liposomal doxorubicin in nine (53%) patients, liposomal daunorubicin in four (23.5%) patients, and pegylated liposomal doxorubicin in four (23.5%) patients. General measures for extravasations were applied in all patients, but only three patients received dexrazoxane. All cases were completely resolved at 2-3 months, except for one patient, in whom dexrazoxane was not used. In animals, dexrazoxane decreased both the frequency of wounds produced by pegylated liposomal doxorubicin and their extent. The pharmacokinetic profiles of liposomal and pegylated liposomal anthracyclines differ from those of conventional anthracyclines, modifying their effectiveness and safety. General measures may be inadequate to heal areas affected by extravasation, which may require the administration of dexrazoxane. However, each case should be evaluated individually for the administration of dexrazoxane in off-label use until scientific evidence is available on its effectiveness and safety as an antidote for these formulations of anthracyclines.

Nanomedicine in Cancer Treatment: Efficacy and Toxicity Profile of PEGylated Liposomal Doxorubicin Compared to Conventional Doxorubicin: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials

BackgroundCancer [CA] has a major impact on society in the United States (U.S.) and worldwide. as one of the leading causes of morbidity and mortality in all continents, accounting for 8.8 million deaths in 2015. As indicated by the World Health Organization (WHO), there will be 15 million new cases of CA worldwide in 2020. In developed countries, CA represents the second leading cause of death, exceeded only by heart disease. Current interventions for CA incorporate a combination of radiation, chemotherapy and surgery. Conventional CA drugs display distinctive toxicity and adverse effects compared to nanoformulated CA drugs (nanomedicines). Nanotechnology offers an enhanced technique for delivering anti‐CA drugs at molecular level in neoplasms while avoiding any harm to the normal rapidly proliferating cells in the body.AimTo facilitate the benefits, efficacy and safety assessment of nanomedicines, this research aimed to gain insight into the effects specific for the nanomedicine PEGylated Liposomal Doxorubicin (PLD) by systematically reviewing and analyzing the available data utilizing published research articles discussing randomized controlled trials [RCT] PLD to conventional CA drugs or treatments. In addition, by comparing Doxorubicin, the same active pharmaceutical ingredient in a conventional formulation versus a nanoformulation, this research aimed to identify any adverse effects specific for the nano aspect PLD.MethodsA systematic review and analysis of research articles published on nanotechnology and nanomedicine in CA treatment and therapy was performed utilizing different online databases and indexes available. This research focused on identifying research articles discussing nanomedicine in CA treatment with special emphasis on RCT comparing PEGylated Liposomal Doxorubicin(PLD) to conventional CA drugs. Restrictive exclusion and inclusion criteria were defined leading to a selection of relevant articles that used comparable experimentaldesigns. Critical appraisal of those studies was performed and the results were summarized in a table of evidence.ResultsThe objective was to investigate whether particular toxicity could be related to PLD and whether a nanoformulation of an active pharmaceutical ingredient altered the nature of adverse effects of the product in humans compared to a conventional formulation. The study of toxicity information did not reveal nanospecific toxicity that could be related to PLD.ConclusionCompared to conventional CA therapies, nanomedicine have the following advantages: it may increase the bioavailability of poorly soluble drugs, may prolongs drug circulation times in vivo, and permits multiple drug loading, all of which could improve drug efficacy and reduce toxicity. Furthermore, nanomedicine can maintain the synergistic ratio of the drugs; deliver the drugs to the tumor at the same time, such that two or more drugs of tumor treatment achieve synchronization in time and space; and alter the pharmacokinetics and distribution profile in vivo such that these are dependent on nanocarrier properties (rather than being dependent on the drugs themselves). This research has demonstrated that PEGylated Liposomal Doxorubicin (PLD) is highly effective and associated with a significantly lower risk of toxicity and an improved therapeutic index [TI] compared to conventional doxorubicin without any compromise in efficacy, and makes it a favorable choice over conventional anthracyclines,Support or Funding InformationSupported by Institutional Resources of USAT Montserrat and the Einstein Medical Instiute, N. Palm Beach, FL. USAThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P6-15-06: SOLTI-0702 CAPRICE: Final results of a phase II study of pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as neoadjuvant chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: 5-year overall survival disease free survival and late cardiac safety

Abstract Background: Anthracycline and taxane-based chemotherapy is the standard treatment for high-risk breast cancer. However, conventional anthracyclines are not commonly used in elderly patients or those patients prone to cardiotoxicity and there is a potential risk leaving them undertreated. Pegylated liposomal doxorubicin (PLD) has comparable efficacy, but significantly less cardiotoxicity than conventional anthracyclines. We conducted a phase II trial to assess the efficacy and safety of a neoadjuvant chemotherapy (NC) based on PLD and paclitaxel (PTX) in this group of patients. The pathological complete response, breast conservative surgery (BCS) and safety data at a 35-month follow-up were published (Gil-Gil et al. Breast Cancer Res Treat 2015). Here we present the final analysis of 5-year overall survival (OS) and 5-year disease-free survival (DFS) and cardiac safety after 60 months of follow-up. Methods: Fifty patients with stage II (48%) and III (52%) breast cancer (seven cases were T4d) and with at least one risk factor for developing cardiotoxicity were included. NC schedule: PLD 35 mg/m2 plus cyclophosphamide 600 mg/m2 every 4 weeks for four cycles, followed by 80 mg/m2 weekly PTX for 12. Median age was 73 years old (84% were older than 65 years). Forty-eight (96%) of tumors were triple negative (TN). Secondary objectives included 5-year DFS, 5year OS and cardiac safety measured by a decrease in left ventricular ejection fraction (LVEF), electrocardiogram (ECG) anda cardiac questionnaire performed every 3 months during the first year, every 6 months year 2-3 and every 12 months year 4-5 of follow-up. Results: Forty-eight patients (96%) completed the 4 cycles of PLD plus CPM, while only 26 patients (52%) could complete the 12 weeks of PTX. Forty-six patients (92%) underwent surgery. After surgery: 27 patients received radiotherapy, 2 letrozole and 1 trastuzumab. The 5-year OS was 56% (95% CI 41.2-68.4) and the 5-year DFS was 54.4% [95% CI: 38.3-67.9].No significant decrease in LVEF was seen (mean baseline LVEF was 66.6 (52-86) and mean LVEF after 60 months was 66 (54.5-73). Four patients (8%) developed cardiotoxicity (in 2 cases G3). There were 5 non-cancer deaths (10%): 3 during treatment (all in patients &amp;gt; 80 years: a sudden death one month after surgery, a haemorrhagic stroke 30 days after completing chemotherapy and a non-neutropenic pneumonia); and 2 during follow-up (1 Amyotrophic Lateral Sclerosis and 1 intestinal ischemia). Conclusions: PLD followed by PTX as NC was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. The 5 year DFS and 5 year OS in elderly patients with bulky TN tumors were similar tothe reported in the literature. This regimen could be an option for the neoadjuvant treatment of cardiotoxicity-prone patients or elderly patients who present high-risk breast cancer. Citation Format: Gil-Gil M, Bellet M, Morales S, Barnadas A, Manso L, Morilla Ruiz I, Azaro A, Ciruelos Gil E, Garcia Martínez E, Marínez N, Melé M, Soler T, Villagrasa P, Pernas S. SOLTI-0702 CAPRICE: Final results of a phase II study of pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as neoadjuvant chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: 5-year overall survival disease free survival and late cardiac safety [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-15-06.

Efficacy and safety of non-pegylated liposomal doxorubicin in metastatic breast cancer therapy

Breast cancer is the most frequently diagnosed female cancer in Poland (over 17,500 women). Anthracyclines have become one of the most important drugs in breast cancer systemic treatment. In the treatment of metastatic disease combination chemotherapy with doxorubicin provides the objective response rate of 60–85%, and the median time of progression-free survival is about 12 months. Non-pegylated liposomal doxorubicin (NPLD) in combination with cyclophosphamide is associated with a lower risk of cardiotoxicity, higher efficacy and more favourable toxicity profile as compared with conventional anthracycline regimes. Two cases of females patients treated with NPLD described in this article demonstrate the importance of the choice of chemotherapy, professional monitoring, early detection and treatment of adverse effects. Non-pegylated liposomal doxorubicin ordained in systemic treatment of stage IV breast cancer prolongs survival and enhances the quality of life. It is a reasonable option for palliative therapy.

Efficacy and toxicity of pegylated liposomal doxorubicin-based chemotherapy in early-stage breast cancer: a multicenter retrospective case-control study.

PEGylated liposomal doxorubicin (PLD) has comparable efficacy and differing toxicity from conventional anthracyclines used to treat advanced breast cancer. This study compared disease-free survival and toxicity between PLD-based and conventional anthracycline-based regimens as adjuvant treatments for early-stage breast cancer. We analyzed disease-free survival (DFS) rates, and adverse events in 102 women with early-stage (I-IIIa) breast cancer who received adjuvant PLD-based chemotherapy from 2002 to 2008. Each patient was matched for age, stage at diagnosis, HER-2 expression and hormone therapy use to a patient treated with an epirubicin-based regimen. Fisher's exact and Pearson's chi-square tests were used for categorical data analysis. Kaplan-Meier analysis and Cox regression models were used to analyze DFS. DFS at 5 years was 81.3% for PLD-based regimen and 82.3% for epirubicin-based regimen. This difference was not significant (p = 0.939). Stage IIIa disease was associated with a shorter DFS in univariate analysis (p = 0.048). In multivariate analysis that controlled for adjuvant treatment, age at diagnosis, stage, HER-2 expression, type of surgery and hormone and radiation therapy, stage IIIa disease (P = 0.023) and lack of hormone therapy (P = 0.024) were each independently associated with shorter DFS. Adverse events were evaluated, and with the exception of hand-foot syndrome, more grade 3 and 4 toxicities occurred in patients who received epirubicin-based regimens than in those given PLD-based regimens. For patients with early-stage breast cancer who received PLD-based adjuvant chemotherapy, 5-year DFS was comparable and toxicity was acceptable, yet different from those of patients who received epirubicin-based regimens.