Dataset Information

Pegylated Liposomal Doxorubicin (Caelyx^®) as Adjuvant Treatment in Early-Stage Luminal B-like Breast Cancer: A Feasibility Phase II Trial.

ABSTRACT:

Background

Adjuvant chemotherapy for Luminal B-like breast cancers usually includes anthracycline-based regimens. However, some patients are reluctant to receive chemotherapy because of side-effects, especially alopecia, and ask for a "less intensive" or personalized approach.

Patients and methods

We conducted a phase II feasibility trial to evaluate pegylated liposomal doxorubicin (PLD, Caelyx^®) as adjuvant chemotherapy. Patients who received surgery for pT1-3, any N, and luminal B-like early-stage breast cancer (EBC) candidates for adjuvant chemotherapy were included. PLD was administered intravenously at 20 mg/m² biweekly for eight courses. Endocrine therapy was given according to menopausal status. Trastuzumab was administered in HER2-positive disease. The primary endpoint was to evaluate the feasibility of this regimen, defined as the ability of a patient to achieve a relative dose intensity (RDI) of at least 85% of the eight cycles of treatment. Secondary endpoints included adverse events (AEs), tolerability, breast cancer-free survival, disease-free survival, and overall survival.

Results

From March 2016 to July 2018, 63 patients were included in the trial. Median age was 49 years (range: 33-76), with mostly pre- and peri-menopausal (65%) and stage I-II (94%). Only 5% of patients had HER2-positive EBC. Median RDI was 100% (range: 12.5-100%; interquartile range, IQR: 87.5-100%). The proportion of patients meeting the primary endpoint was 84% (95% confidence interval, CI: 73-92%). Overall, 55 out of 63 enrolled patients completed treatment (87%, 95% CI: 77-94%). Most common AEs were palmar-plantar erythrodysesthesia (12.2%), fatigue (10.4%), and mucositis (8.5%). Only 13% of patients had G3 AEs. None had alopecia. After a median follow-up of 3.9 years (range: 0.3-4.7) two distant events were observed, and all patients were alive at the date of last visit.

Conclusions

The trial successfully met its primary endpoint: the regimen was feasible and well tolerated and could be considered for further evaluation as a treatment option for patients with contraindications to standard anthracyclines or requiring a personalized, less intensive approach.

SUBMITTER: Dellapasqua S

PROVIDER: S-EPMC8700739 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Peritoneal carcinomatosis is a common metastatic pattern in ovarian, gastric, colorectal, and appendiceal cancer; systemic chemotherapy is the current standard of care for peritoneal metastatic disease; however, in a subset of patients its beneficial effect remains questionable. More effective perioperative chemotherapy is needed. Materials and methods: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new treatment that applies chemotherapeutic drugs into the peritoneal cavity as an aerosol under pressure. It's a safe and feasible approach that improves local bioavailability of chemotherapeutic drugs as compared with conventional intraperitoneal chemotherapy. Till now the drugs used in PIPAC for the treatment of the peritoneal carcinomatosis (PC) are cisplatin, doxorubicin, and oxaliplatin; as of yet, there are no in vivo data comparing different drug formulations and dosage schedules of PIPAC. Pegylated liposomal doxorubicin 1.5 mg/sm was aerosolized in PIPAC procedures. Results: Pharmacokinetics analysis of 10 procedures performed with conventional doxorubicin solution at the dose of 1.5 mg/m2 were compared to 15 procedures with the same dose of pegylated liposomal doxorubicin (PLD). Significant differences between experimental groups were detected by one-way ANOVA followed by Bonferroni correction; a p value < 0.05 was considered statistically significant. A statistically different doxorubicin tissue concentration was observed for the doxorubicin solution compared to pegylated liposomal doxorubicin in the right parietal peritoneum and right diaphragm. In the Caelyx® series a mean tissue concentration of 1.27 ± 1.33 mg/g was reported, while in the second one we registered a mean concentration of 3.1 ± 3.7 mg/g. Conclusions: The delivery of nano-particles in PIPAC was feasible, but pegylated liposomal concentrations are lower than standard doxorubicin formulation. Probably mechanical and physical properties of pressurized aerosol chemotherapy might alter their stability and cause structural disintegration.

Project description:AimsAcute myeloblastic leukemia (AML) is the most common type of acute leukemia in adults. Despite numerous treatment strategies including chemotherapy and radiotherapy, a large number of patients do not respond to treatment and experience relapse. The main problem of these patients is the development of resistance to anti-cancer drugs. Therefore, any endeavor to reduce drug resistance in these patients is of high priority. In general, several mechanisms such as changes in drug metabolic pathways, drug inactivation, drug target alterations and reduced drug accumulation in the cells contribute to drug resistance of cancer cells. In this context, evidence suggests that exosomes could reduce drug resistance by removing drugs from their parent cells. In the present study, we aimed to investigate the effects of exosome release inhibition on the resistance of U937 cells to PEGylated liposomal doxorubicin (PLD).Main methodsIn order to find a suitable ABCG2 (ATP-binding cassette sub-family G member 2) transporter substrate, virtual screening was performed among a list of drugs used in leukemia and PLD was selected. U937 cells were treated with PLD with/without co-treatment with the exosome release inhibitor, GW4869. Released exosomes within different study groups were isolated and characterized to determine the differences between groups. Doxorubicin presence in the isolated exosomes was also measured by high performance liquid chromatography (HPLC) to confirm drug export through the exosomes. Finally, the effect of exosome inhibition on the cytotoxicity of PLD on U937 cells was determined using different cytotoxicity assays including the standard lactate dehydrogenase (LDH) release assay and the flow cytometric analysis of apoptotic and non-apoptotic cell death.Key findingsGW4869 treatment caused a significant decrease in the exosome release of U937 cells compared to the untreated cells, as evidenced by the reduction of the protein content of the isolated exosomes (P<0.05). Co-treatment with GW4869 significantly increased cytotoxic cell death in the groups treated with 0.5 and 1 µM PLD, compared to the same groups without GW4869 co-treatment (P<0.05). Interestingly, co-treatment with GW4896 and 0.5 µM PLD was enough to induce the same cytotoxic effect as that of the sole 1 µM PLD group.SignificanceOur findings showed that U937 cells increase their resistance against the cytotoxic effects of PLD through the exosome-mediated expelling of the drug. Inhibition of exosome release could prevent PLD efflux and consequently increase the vulnerability of the U937 cells to the cytotoxic effects of PLD. Our results along with prior studies indicate that the integration of exosome release inhibitors into the common PLD-containing chemotherapy regimens could significantly lower the required concentrations of the drug and consequently reduce its associated side effects. Further studies are warranted to identify clinically safe inhibitors and investigate their clinical efficacy.

Dataset Information

Pegylated Liposomal Doxorubicin (Caelyx^®) as Adjuvant Treatment in Early-Stage Luminal B-like Breast Cancer: A Feasibility Phase II Trial.

Background

Patients and methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Pegylated Liposomal Doxorubicin (Caelyx®) as Adjuvant Treatment in Early-Stage Luminal B-like Breast Cancer: A Feasibility Phase II Trial.

Background

Patients and methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pegylated Liposomal Doxorubicin (Caelyx^®) as Adjuvant Treatment in Early-Stage Luminal B-like Breast Cancer: A Feasibility Phase II Trial.