The prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy: A systematic review and meta-analysis.

Introduction

Generally, patients with malignant diseases often have worse psychological and physical health. An estimation of 2020 cancer statistics revealed about 1,806,590 new cancer cases diagnosed and 606,520 new deaths assigned to cancer in US. [ 1 ] Although enormous progress against cancer have been made in the past decade, chemotherapy is of great importance for majority of the patients especially for the late-stage patients. However, most patients undergoing conventional chemotherapy suffer from serious side effects due to nonselective toxicity of drugs to normal cells. [ 2 ] There is an urgent need and tremendous value to develop novel chemotherapeutic drug carriers.

Advanced researches indicate that nano-sized carriers have presented an important therapeutic agents in both diagnosis and therapy of cancer because they have longer plasma half-life and may enhance chemotherapeutic drugs delivery while limiting nontumorous tissue distribution. [ 3 ] Consequently, it possesses increase anticancer efficacy and lower toxicity to normal tissue. [ 4 ] Liposomes are the most clinically established nanometer material that are used to deliver cytotoxic and antifungal drugs, genes, as well as vaccines. [ 5 ] The outstanding profile consist in its biocompatibility, biodegradability, reduced toxicity, capacity for size, and surface manipulations. Pegylated liposomal doxorubicin (PLD; Doxil/Caelyx) is unique formulation of doxorubicin, which have been used for various malignancies. It is a cytotoxic anthracycline antibiotic extracted from Streptomyces peucetius var. caesius . [ 6 – 7 ] PLD is the first FDA-approved anticancer nano-drug and has demonstrated tremendous benefits. PLD represents an improved formulation of conventional doxorubicin, with reduced cardiotoxicity and an improved pharmacokinetic profile. [ 8 ] As shown by evidence from clinical trials, intravenous PLD is a useful option in the treatment of malignancies. The possible mechanism of its antitumor has not been explained clearly. It may interfere with the DNA, RNA, and protein synthesis by blocking topoisomerase I and intercalate between adjacent base pairs of the double helix structure of DNA. [ 9 , 10 ] Survival is highly dependent on and inversely correlated with the stage of disease at the initiation of treatment. Despite the well-established role of liposomal doxorubicin-based chemotherapy in prognosis for tumor patients, these conclusions were controversial and inconsistent. Meta-analysis is a statistical software that incorporates all available data to derive a pooled and authentic result. [ 11 ] Herein, we try to perform a meta-analysis to explore whether patients treated with PLD chemotherapy is associated with cancer prognosis.

Methods

Literature search strategy

A detailed review of literature was conducted from PubMed, Embase, Cochrane Library, CBM, and CNKI, using the terms ( “liposom∗ and doxorubicin OR DOX-SL OR Lipodox OR Doxil OR Caelyx OR Lipo-Dox OR DaunoXome”) and (“cancer OR tumor OR tumour OR neoplasm OR neoplasma OR neoplasia OR carcinoma”). The literature search was last updated on March 21, 2020. We also searched the reference of the relevant review articles to seek for the potentially included studies. The PRISMA statement for reporting systematic reviews and meta-analyses was cited in this meta-analysis. [ 12 ] In addition, the ethical approval was not applied in current study because there was no patient's privacy or clinical samples.

Inclusion and exclusion criteria

In order to derive a pooled and relatively authentic result, studies should meet the following criteria before being included: the included studies focused on the associations; and the studies provided available data. As per the exclusion criteria: no survival analysis data; studies involved cell lines and animals; similar or duplicate study; and other type articles including reviews, case reports, and letters.

Data extraction and quality assessment

We extracted the data including the first author, publication year, country, no of patients, age, cancer type, treatment arms, phase, follow-up time, survival outcomes, and hazard ratio (HR) (95% confidence interval [CI]) from included study. The data were independently extracted by 2 authors. Disagreements were resolved by discussion or reviewed by a third author.

Among these data, country came from USA, UK, Greece, and others; Sample size was separated into ≥100 and <100; Cancer type included soft tissue sarcoma, multiple myeloma, acute myelogenous leukaemia, nonsmall cell lung cancer, oesophago-gastric cancer, acute lymphoblastic leukemia, metastatic breast cancer, ovarian cancer (OC). Survival outcomes contained overall survival (OS) and progression-free survival (PFS).

Statistical analysis

We explored the prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy by using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) and STATA 12.0 software (Stata Corpotation, College Station, TX). HR (95% CI) was obtained for assessing the prognosis of cancer patients. Meanwhile, the Q statistics and I 2 test were applied to calculate the heterogeneity of eligible study. P < .05 and/or I 2 > 50% were considered as statistically heterogeneous, and random effects (DerSimonian and Laird method) model was used to pool the results. [ 13 , 14 ] Otherwise, fixed effects (Mantel–Haenszel method) model was applied. [ 15 ]

One-way sensitivity analyses removed each single included studies at a time were performed to assess the pooled results’ stability. Moreover, the publication bias was assessed using Begg test. P < .05 indicated that there was a bias. [ 16 ] Additionally, different subgroups consisted of country, cancer type, and sample size were analysed in current meta-analysis.

Results

Study characteristics

Consequently, 26 studies with a total of 7943 participants were selected in our meta-analysis (Fig. 1 ). [ 17 – 42 ] The main study characteristics are provided in Table 1 . Among them, Kaye et al [ 31 ] phase II, open-label, randomized, multicenter study was performed to explore 3 different chemotherapy in OC. Therefore, we took it as 3 different studies independently. Twenty-eight studies were finally included in this analysis (Table 1 ).

Among these studies, only 1 study was conducted in China and the rest of studies came from English. The participants of each included studies ranged from 60 to 973. The cancer types contained 9 metastatic breast cancer, 10 OC, 3 nonsmall cell lung cancer, 2 multiple myeloma, 1 acute lymphoblastic leukemia, 1 acute myelogenous leukaemia, 1 oesophago-gastric cancer, and 1 soft tissue sarcoma. Meanwhile, 26 and 27 out of 28 studies reported OS and PFS, respectively. The detailed information is presented in Table 2 . However, the treatment arms differed greatly in these eligible studies.

Meta-analysis of overall survival

As a result, 26 studies were analysed the prognosis of cancer patients undergoing liposomal doxorubicin chemotherapy. We found that no significant difference was explored in OS (HR = 0.98, 95%CI: 0.93–1.04, P = .544) (Fig. 2 ). Likewise, subgroup analysis demonstrated no significant differences regarding country, cancer type, and sample sizes (Table 3 ).

Meta-analysis of progression-free survival

There were 27 studies involved with PFS. Ultimately, we found that no association of patients after liposomal chemotherapy in tumors was detected with PFS (HR = 1.00, 95%CI: 0.92–1.10, P = .945) (Fig. 3 ). A similar results were explored in subgroup analysis of sample sizes rather than country and cancer type. The details were shown in Table 4 .

Sensitivity analysis and publication bias evaluation

Sensitivity analysis demonstrated that our conclusions were relatively stable in OS (Fig. 4 ) and PFS (Fig. 5 ). Furthermore, Begg funnel plot observed no publication bias in this analysis of OS ( P = .508) (Fig. 6 A) and PFS ( P = .983) (Fig. 6 B, respectively).

Discussion

Although cancer is not completely curable by current therapies, it deserves effective treatment. Patients receiving proper chemotherapy would help to relieve the symptom, improve the quality of life, and prolong survival. However, conventional chemotherapy cannot satisfy people's demands. After persistent efforts over the recent years, many anticancer nanoplatforms have been explored and investigated in preclinical and clinical trials. Yet, only the minority has satisfied efficacy criteria for regulatory approval, and many liposomal platforms were applied. [ 43 ]

Doxorubicin is generally regarded as the most effective anticancer drugs, but its clinical practice has limitation because of a cumulative dose-dependent cardiotoxicity that could result in some potentially fatal toxicity of nontarget normal tissues. Liposomes are proven candidates for delivery of a wide range of therapeutics, since their payload can be encapsulated in their internal aqueous compartment or embedded within the phospholipid bilayer. [ 44 ] Clinicians have used liposomes, self-assembled lipid vesicles, as nanoscale systems to deliver encapsulated anthracycline molecules for cancer treatment. Stealth liposomes can passively accumulate in solid tumors due to their inherently leaky vasculature and defective lymphatic drainage. PLD is an active and unique formulation of doxorubicin, which has been proven to be a better therapeutic choice for cancer patients. In this formulation, doxorubicin-encapsulated liposomes are sterically stabilized by grafting polyethylene glycol onto the liposomal surface (Stealth Liposome). [ 45 ] Its liposomal encapsulation reduces plasma free anticancer drug level and drug delivery to normal tissues, possibly decreasing immunosuppression and cardiotoxicity of doxorubicin. [ 46 ] It confers different pharmacokinetic characteristics that results in a circulation half-life compared with conventional free doxorubicin, which has a half-life of less than 10 minutes. [ 47 ] Then prolonged circulation in cancer tissues permits higher uptake of PLD. The selective accumulation of PLD in cancer tissue led to about 10-fold higher intracellular anticancer drug concentrations than adjacent normal tissues. [ 48 ] Consequently, patients who have received PLD reduced risk of nausea or vomiting, myelosuppression, alopecia, and cardiotoxicity. [ 49 , 50 ] In addition, acquisition of drug resistance of tumor cells in patients is a major challenge in previously treated patients, which could be explained by the barrier of the chemotherapy drug transport across the cell membrane. PLD directly fused with the tumor cell membrane rather than transporting across the cell membrane. Accordingly, PLD was gradually considered the most appropriate chemotherapeutic agents for the cancer patients, especially for resistant tumors. [ 51 ]

Chemotherapy is as effective or better in the treatment of recurrent and progressive cancer therapy compared to other therapies. The advantages of PLD often include longer circulation and enhanced drug delivery to tumor tissue, however, these factors did not lead to improve prognosis in patients. Maybe it is closely linked with the dose and cycle dependent pharmacokinetic changes. [ 52 ] Another explanation for the lack of a prognostic advantage for the liposomal formulation could be the tumor immunologic milieu, which may be infiltrated with immunosuppressive leukocytes. [ 53 ] In previous study, the author pays more attention to tolerability and conclude that the choice of regimen could be based on individual patient preference on the basis of side effects. [ 54 ] To date, many clinical trials have confirmed the efficacy and cardiac safety of liposomal doxorubicin in various settings: a monotherapy or in combination with other drugs, a first-line therapy (compared with conventional doxorubicin), [ 55 ] a second-line therapy or later in patients with anthracycline- and taxanepretreated disease, [ 56 ] a maintenance therapy for patients with responding or stable disease after first-line chemotherapy. [ 57 ] However, there is no consensus for the superiority of PLD chemotherapy compared with conventional chemotherapy. The results reported in clinical trial, in some cases, failed to provide a formal proof that PLD is the best option for clinical practice. [ 58 ]

In general, PLD has substantial clinical activity of durable clinical responses in 26% of patients. [ 59 ] Recent researches have shown that PLD may prolong both PFS and OS when compared with conventional chemotherapy. Because of these relatively small sample size trials, the results cannot be considered definitive. This meta-analysis was performed to explore the prognosis of cancer patients after liposomal doxorubicin-based chemotherapy in various tumors. As results, PLD has not shown significant superiority to other approved conventional chemotherapy drugs in prognosis. No association was detected between liposomal vs conventional formulations in OS and PFS. Subgroup analysis also showed that there was no statistical difference rather than subgroups of country and cancer type in PFS. However, these results remains to be further evaluated in advanced research. The previously reported studies would suggest that we need to take dose ranges and cycle dependent pharmacokinetic changes into consideration. [ 60 ] Maybe larger single doses may be more efficacious than smaller split doses. [ 61 ] Thus, detailed studies are required to confirm our conclusions.

Our study has several limitations. First, merely published studies were included for eligible literatures. Then there were inconsistent chemotherapy regimen and dose of eligible studies, and may be influenced our conclusions. Meanwhile, the extreme heterogeneity suggested that potentially possible factors should be taken into consideration.

In conclusion, no association was explored among cancer patients after liposomal doxorubicin-based chemotherapy in prognosis in our study. However, detailed and further studies are needed to confirm our conclusion.

Author contributions

Conceptualization: Kaiping Zhang, Yin Zhang.

Data curation: Kaiping Zhang, Xiang Fang, Yin Zhang.

Software: Kaiping Zhang, Xiang Fang.

Visualization: Xiang Fang.

Writing – original draft: Kaiping Zhang, Xiang Fang.

Writing – review & editing: Kaiping Zhang, Yin Zhang, Min Chao.

Footnotes

Abbreviations: CI = confidence interval, HR = hazard ratio, OC = ovarian cancer, OS = overall survival, PFS = progression-free survival, PLD = pegylated liposomal doxorubicin.

How to cite this article: Zhang KP, Fang X, Zhang Y, Chao M. The prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy: a systematic review and meta-analysis. Medicine . 2021;100:34(e26690).

This work was supported by the Natural Science Foundation of Anhui Medical University (AHMU) (Grant nos. 2019xkj082).

The authors have no conflicts of interests to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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