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. 2021 Aug 27;100(34):e26690. doi: 10.1097/MD.0000000000026690

The prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy

A systematic review and meta-analysis

Kai-Ping Zhang 1, Xiang Fang 1, Yin Zhang 1, Min Chao 1,∗
Editor: Ahmed Salah Naser1
PMCID: PMC8389975  PMID: 34449454

Abstract

Background:

It is well known that liposome-based delivery of cytotoxic chemotherapeutics has been proposed as a putative strategy to enhance drug tolerability and efficacy compared to the conventional chemotherapy. However, its potential effect on improving prognosis remains largely unknown. The current meta-analysis is to explore the prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy.

Methods:

A detailed review of English and Chinese literature was conducted up to March 21, 2020. We evaluate its possible correlations using hazard ratios (HRs) with 95% confidence intervals (CIs). The pooled data were calculated by STATA software and Review Manager 5.3 software.

Results:

Consequently, 26 studies including 7943 patients were satisfied in current analysis. There were no significant differences between liposomal and conventional chemotherapy in OS (HR = 0.98, 95%CI: 0.93–1.04, P = .544) and PFS (HR = 1.00, 95%CI: 0.92–1.10, P = .945). Likewise, subgroup-analysis regarding country, cancer type, and sample sizes also showed the similar results of the 2 paired groups.

Conclusion:

Taken together, our finding has demonstrated that there was no association of undergoing liposomal doxorubicin-based chemotherapy with cancer prognosis. However, detailed and further studies are needed to confirm our conclusion.

Keywords: chemotherapy, doxorubicin, liposome, meta-analysis, nanomedicine, prognosis

1. 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.

2. Methods

2.1. 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.

2.2. 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.

2.3. 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).

2.4. 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 I2 test were applied to calculate the heterogeneity of eligible study. P < .05 and/or I2 > 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.

3. Results

3.1. 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).

Figure 1.

Figure 1

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Flow diagram of the study selection process in the meta-analysis.

Table 1.

Characteristics of included clinical studies.

First authors Year Country No. of patients Age, median (range) Cancer types Treatment arms Phase Follow-up Outcomes
Judson I[17] 2001 USA 50/45 52 (19–80)/52 (27–77) STS PLD 50 mg/m2 every 28 d; doxorubicin 75 mg/m2 every 21 d Phase II NA OS/PFS
Dimopoulos MA[18] 2003 Greece 132/127 65 (37–88)/66 (37–88) MM PLD 40 mg/m2 every 28 days; doxorubicin 9 mg/m2 every 28 days Phase III 40 mo OS/PFS
O’Brien ME[19] 2004 UK 254/255 59 (28–82)/58 (25–82) MBC PLD 50 mg/m2 every 28 d; doxorubicin 60 mg/m2 every 21 d Phase III NA OS/PFS
Rifkin RM[20] 2006 USA 97/95 60 (37–84)/60 (44–81) MM PLD 40 mg/m2 every 28 d; doxorubicin 9 mg/m2 every 28 d Phase III 21 mo OS/PFS
Hunault-Berger M[21] 2011 France 31/29 68 (55–77)/66 (60–80) ALL PLD 40 mg/m2 days 1 to 4; doxorubicin 12 mg/m2/day days 1 to 4 Phase II 48 mo OS/PFS
Batist G[22] 2001 Canada 142/155 55 (30–80)/54 (22–88) MBC Liposomal doxorubicin 60 mg/m2 every 21 d; doxorubicin 60 mg/m2 every 21 d Phase III 20 mo OS/PFS
Harris L[23] 2002 USA 108/116 58 (26–85)/58 (29–82) MBC Liposomal doxorubicin 75 mg/m2 every 21 d; doxorubicin 75 mg/m2 every 21 d Phase III 4 mo OS/PFS
Latagliata R[24] 2008 Rome 148/153 68.2 (61–74.8)/68 (61–74.8) AML Daunoxome 80 mg/m2 days 1 to 3; daunorubicin 45 mg/m2 days 1 to 3 Phase III 26.6 mo OS/PFS
Mylonakis N[25] 2010 Greece 47/41 64 (49–83)/66 (52–77) NSCLC Liposomal cisplatin 120 mg/m2 every 21 d; cisplatin 100 mg/m2 every 21 d Phase II 53 mo OS/PFS
Stathopoulos GP[26] 2010 Greece 114/115 65 (37–80)/66 (41–85) NSCLC Liposomal cisplatin 200 mg/m2 every 14 d; csplatin 75 mg/m2 every 14 d Phase II 15 mo OS/PFS
Yang X[27] 2012 China 50/50 55.2 (34–76)/53.2 (25–73) NSCLC Liposomal paclitaxel 150 mg/m2 every 21 d; paclitaxel 150 mg/m2 every 21 d NA 20 mo OS/PFS
Roy AC[28] 2013 UK 44/44 56 (38–81)/62 (33–79) OG cancer Liposomal irinotecan 120 mg/m2 every 21 d; irinotecan 300 mg/m2 every 21 d Phase II NA OS/PFS
Pignata S[29] 2011 Italy 410/410 57 (25–77)/57 (21–77) OC Carboplatin and PLD 30 mg/m2 every 3 wk; carboplatin and paclitaxel 175 mg/m2 every 3 wk Phase III 20 mo OS/PFS
Bafaloukos D[30] 2010 Greece 93/96 62 (38–89)/63 (37–81) OC Carboplatin and PLD 45 mg/m2 every 3 wk; carboplatin and paclitaxel 175 mg/m2 every 3 wk Phase II 43.6 mo PFS
Kaye SB-1[31] 2012 UK 33/32 53.0 (43–81)/58.5 (45–77) OC PLD 50 mg/m2 every 28 d; olaparib 200 mg every 28 d; Phase II NA OS/PFS
Kaye SB-2[31] 2012 UK 33/32 53.0 (43–81)/53.5 (35–76) OC PLD 50 mg/m2 every 28 d; olaparib 400 mg every 28 d; Phase II NA OS/PFS
Kaye SB-3[31] 2012 UK 33/64 53.0 (43–81)/NA OC PLD 50 mg/m2 every 28 d; olaparib 400 + 200 mg every 28 d; Phase II NA PFS
Alberts DS[32] 2008 USA 31/30 66.9 (43–87)/62.5 (31–80) OC Carboplatin and PLD 30 mg/m2 every 4 wk; carboplatin every 4 wk Phase III 22.4 mo OS/PFS
Pujade-Lauraine E[33] 2010 France 466/507 60.5 (24–82)/61 (27–82) OC Carboplatin and PLD 30 mg/m2 every 4 wk; carboplatin and paclitaxel 175 mg/m2 every 3 wk Phase III 22 mo OS/PFS
Mutch DG[34] 2007 USA 96/99 62 (28–83)/59 (38–85) OC PLD 50 mg/m2 every 28 d; gemcitabine 1000 mg/m2 every 21 d Phase III 29.2 mo OS
Gordon AN[35] 2001 USA 239/235 60 (27–87)/60 (25–85) OC PLD 50 mg/m2 every 28 d; topotecan 1.5 mg/m2 every 21 d Phase III NA OS/PFS
Colombo N[36] 2012 Italy 417/412 59 (23–84)/59 (25–87) OC PLD 50 mg/m2 every 4 wk; patupilone 10 mg/m2 every 3 wk Phase III 27 mo OS/PFS
Sparano JA[37] 2009 USA 378/373 52.5 (26–80)/51.8 (30–87) MBC PLD 30 mg/m2 and docetaxel 60 mg/m2 every 21 d; docetaxel 75 mg/m2 every 21d Phase III NA OS/PFS
Chan S[38] 2004 UK 80/80 54 (19–78)/54 (26–82) MBC Myocet 75 mg/m2 and cyclophosphamide 600 mg/m2; epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 wk Phase III 21 mo OS/PFS
Keller AM[39] 2004 USA 150/151 56 (33–87)/56 (30–83) MBC PLD 50 mg/m2 every 28 d; vinorelbine or mitomycin C and vinblastine every 6 to 8 wk Phase III NA OS/PFS
Baselga J[40] 2014 USA 181/182 52 (22–79)/53 (30–76) MBC NPLD 50 mg/m2 every 3 wk and trastuzumab and paclitaxel; trastuzumab and paclitaxel every 3 wk Phase III 44 mo OS/PFS
Smorenburg CH[41] 2014 Netherlands 40/38 NA MBC PLD 45 mg/m2 every 4 wk; capecitabine 1000 mg/m2 every 3 wk Phase III 39 mo OS/PFS
Harbeck N[42] 2017 Germany 105/105 62 (36–82)/63 (22–85) MBC PLD 50 mg/m2 every 28 d; capecitabine 1250 mg/m2 twice daily for 14 d every 21 d Phase III NA OS/PFS
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ALL = acute lymphoblastic leukemia, AML = acute myelogenous leukaemia, MBC = metastatic breast cancer, MM = multiple myeloma, NA = not available, NPLD = nonpegylated liposomal doxorubicin, NSCLC = nonsmall cell lung cancer, OC = ovarian cancer, OG = oesophago-gastric, OS = overall survival, PFS = Progression-free survival, PLD = pegylated liposomal doxorubicin, STS = soft tissue sarcoma.

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.

Table 2.

The survival data of the selected studies.

First authors Year Country No. of patients Cancer types Outcome HR (95%CI)
Judson I 2001 USA 50/45 STS OS 0.64 (0.38–1.10)
Judson I 2001 USA 50/45 STS PFS 1.09 (0.75–1.58)
Dimopoulos MA 2003 Greece 132/127 MM OS 1.36 (0.85–2.17)
Dimopoulos MA 2003 Greece 132/127 MM PFS 1.15 (0.80–1.64)
O’Brien ME 2004 UK 254/255 MBC OS 0.94 (0.74–1.19)
O’Brien ME 2004 UK 254/255 MBC PFS 1.00 (0.82–1.22)
Rifkin RM 2006 USA 97/95 MM OS 0.69 (0.31–1.52)
Rifkin RM 2006 USA 97/95 MM PFS 1.15 (0.67–1.98)
Hunault-Berger M 2011 France 31/29 ALL OS 0.97 (0.54–1.77)
Hunault-Berger M 2011 France 31/29 ALL PFS 1.16 (0.67–2.03)
Batist G 2001 Canada 142/155 MBC OS 1.04 (0.77–1.41)
Batist G 2001 Canada 142/155 MBC PFS 1.03 (0.80–1.33)
Harris L 2002 USA 108/116 MBC OS 0.76 (0.56–1.04)
Harris L 2002 USA 108/116 MBC PFS 0.92 (0.66–1.26)
Latagliata R 2008 Rome 148/153 AML OS 0.95 (0.72–1.26)
Latagliata R 2008 Rome 148/153 AML PFS 1.10 (0.80–1.50)
Mylonakis N 2010 Greece 47/41 NSCLC OS 0.92 (0.54–1.56)
Mylonakis N 2010 Greece 47/41 NSCLC PFS 0.91 (0.59–1.42)
Stathopoulos GP 2010 Greece 114/115 NSCLC OS 1.21 (0.87–1.68)
Stathopoulos GP 2010 Greece 114/115 NSCLC PFS 0.86 (0.64–1.16)
Yang X 2012 China 50/50 NSCLC OS 1.27 (0.81–1.97)
Yang X 2012 China 50/50 NSCLC PFS 0.76 (0.53–1.09)
Roy AC 2013 UK 44/44 OG cancer OS 1.32 (0.79–2.21)
Roy AC 2013 UK 44/44 OG cancer PFS 1.06 (0.71–1.57)
Pignata S 2011 Italy 410/410 OC OS 0.82 (0.72–1.12)
Pignata S 2011 Italy 410/410 OC PFS 0.95 (0.81–1.13)
Bafaloukos D 2010 Greece 93/96 OC PFS 1.15 (0.78–1.66)
Kaye SB-1 2012 UK 33/32 OC OS 0.66 (0.27–1.55)
Kaye SB-1 2012 UK 33/32 OC PFS 0.91 (0.48–1.74)
Kaye SB-2 2012 UK 33/32 OC OS 1.01 (0.44–2.27)
Kaye SB-2 2012 UK 33/32 OC PFS 0.86 (0.45–1.62)
Kaye SB-3 2012 UK 33/64 OC PFS 0.88 (0.51–1.56)
Alberts DS 2008 USA 31/30 OC OS 0.46 (0.22–0.95)
Alberts DS 2008 USA 31/30 OC PFS 0.54 (0.32–0.93)
Pujade-Lauraine E 2010 France 466/507 OC OS 0.99 (0.85–1.16)
Pujade-Lauraine E 2010 France 466/507 OC PFS 0.82 (0.72–0.94)
Mutch DG 2007 USA 96/99 OC OS 1.02 (0.71–1.42)
Gordon AN 2001 USA 239/235 OC OS 0.82 (0.68–1.00)
Gordon AN 2001 USA 239/235 OC PFS 0.79 (0.67–0.94)
Colombo N 2012 Italy 417/412 OC OS 1.07 (0.91–1.26)
Colombo N 2012 Italy 417/412 OC PFS 0.95 (0.8–1.12)
Sparano JA 2009 USA 378/373 MBC OS 0.98 (0.82–1.17)
Sparano JA 2009 USA 378/373 MBC PFS 1.52 (1.29–1.79)
Chan S 2004 UK 80/80 MBC OS 1.15 (0.77–1.72)
Chan S 2004 UK 80/80 MBC PFS 1.52 (1.06–2.19)
Keller AM 2004 USA 150/151 MBC OS 1.05 (0.82–1.33)
Keller AM 2004 USA 150/151 MBC PFS 1.26 (0.98–1.62)
Baselga J 2014 USA 181/182 MBC OS 1.27 (0.98–1.65)
Baselga J 2014 USA 181/182 MBC PFS 1.19 (0.92–1.53)
Smorenburg CH 2014 Netherlands 40/38 MBC OS 0.87 (0.53–1.43)
Smorenburg CH 2014 Netherlands 40/38 MBC PFS 0.68 (0.42–1.09)
Harbeck N 2017 Germany 105/105 MBC OS 1.12 (0.79–1.58)
Harbeck N 2017 Germany 105/105 MBC PFS 1.08 (0.76–1.54)
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ALL = acute lymphoblastic leukemia, AML = acute myelogenous leukaemia, CI = confidence interval, HR = hazard ratio, MBC = metastatic breast cancer, MM = multiple myeloma, NA = not available, NSCLC = nonsmall cell lung cancer, OG = oesophago-gastric, OC = ovarian cancer, OS = overall survival, PFS = progression-free survival, STS = soft tissue sarcoma.

3.2. 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).

Figure 2.

Figure 2

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Forest plot of the association between liposomal doxorubicin-based chemotherapy in various tumors and OS. CI = confidence interval, HR = hazard ratio, OS = overall survival.

Table 3.

Stratified analysis of liposomal doxorubicin-based chemotherapy and overall survival.

Categories Subgroups No. Case/control HR (95%CI) P-value I2 P h
All 26 3843/3911 0.98 (0.93–1.04) .544 15.6% .239
Country USA 9 1330/1326 0.91 (0.79–1.06) .217 51.0% .038
UK 5 331/363 1.01 (0.84–1.21) .918 0.0% .609
Greece 3 293/283 1.18 (0.93–1.50) .178 0.0% .543
Others 9 1889/1939 1.00 (0.92–1.08) .915 0.0% .670
Cancer types MBC 9 1438/1455 1.01 (0.92–1.11) .799 0.0% .443
OC 8 1692/1757 0.94 (0.86–1.02) .132 35.1% .148
NSCLC 3 211/206 1.16 (0.92–1.47) .215 0.0% .620
Others 6 502/493 0.98 (0.82–1.18) .867 22.2% .267
Sample sizes ≥100 18 3567/3620 0.99 (0.94–1.05) .819 17.0% .250
<100 8 276/291 0.86 (0.69–1.06) .152 5.2% .390
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CI = confidence interval, HR = hazard ratio, MBC = metastatic breast cancer, NSCLC = nonsmall cell lung cancer, OC = ovarian cancer, Ph = P-value of heterogeneity test, UK = The United Kingdom.

3.3. 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.

Figure 3.

Figure 3

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Forest plot of the association between liposomal doxorubicin-based chemotherapy in various tumors and PFS. CI = confidence interval, HR = hazard ratio. PFS = progression-free survival.

Table 4.

Stratified analysis of liposomal doxorubicin-based chemotherapy and progression-free survival.

Categories Subgroups No. Case/control HR (95%CI) P-value I2 P h
All 27 3840/3908 1.00 (0.92–1.10) .945 60.7% .000
Country USA 8 1234/1227 1.04 (0.83–1.31) .720 82.1% .000
UK 6 411/443 1.06 (0.91–1.22) .468 3.3% .396
Greece 4 386/379 1.00 (0.83–1.19) .964 0.0% .518
Others 9 1809/1859 0.91 (0.85–0.98) .017 12.9% .327
Cancer types MBC 9 1438/1455 1.14 (0.98–1.32) .101 64.8% .004
OC 9 1689/1754 0.87 (0.81–0.94) .000 14.1% .316
NSCLC 3 211/206 0.84 (0.68–1.03) .086 0.0% .800
Others 6 502/493 1.11 (0.94–1.31) .204 0.0% 1.000
Sample sizes ≥100 18 3564/3617 1.03 (0.93–1.15) .526 70.3% .000
<100 9 276/291 0.90 (0.77–1.06) .217 0.0% .499
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CI = confidence interval, HR = hazard ratio, MBC = metastatic breast cancer, NSCLC = nonsmall cell lung cancer, OC = ovarian cancer, Ph = P-value of heterogeneity test, UK = The United Kingdom.

3.4. 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. 6A) and PFS (P = .983) (Fig. 6B, respectively).

Figure 4.

Figure 4

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One-way sensitivity analysis of liposomal doxorubicin-based chemotherapy in various tumors with OS. CI = confidence interval, OS = overall survival.

Figure 5.

Figure 5

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One-way sensitivity analysis of liposomal doxorubicin-based chemotherapy in various tumors with PFS. CI = confidence interval, PFS = progression-free survival.

Figure 6.

Figure 6

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Begg funnel plot for publication bias test. (A) OS of liposomal doxorubicin-based chemotherapy in various tumors; (B) PFS of liposomal doxorubicin-based chemotherapy in various tumors. HR = hazard ratio, OS = overall survival, PFS = progression-free survival.

4. 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].

References

  • [1].Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:07–30. [DOI] [PubMed] [Google Scholar]
  • [2].Al-Jamal WT, Kostarelos K. Liposomes: from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine. Acc Chem Res 2011;44:1094–104. [DOI] [PubMed] [Google Scholar]
  • [3].Namiki Y, Fuchigami T, Tada N, et al. Nanomedicine for cancer: lipid-based nanostructures for drug delivery and monitoring. Acc Chem Res 2011;44:1080–93. [DOI] [PubMed] [Google Scholar]
  • [4].Leonard RC, Williams S, Tulpule A, Levine AM, Oliveros S. Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet). Breast 2009;18:218–24. [DOI] [PubMed] [Google Scholar]
  • [5].Abu Lila AS, Ishida T. Liposomal delivery systems: design optimization and current applications. Biol Pharm Bull 2017;40:01–10. [DOI] [PubMed] [Google Scholar]
  • [6].Karimi Zarchi AA, Amini SM, Salimi A, Kharazi S. Synthesis and characterisation of liposomal doxorubicin with loaded gold nanoparticles. IET Nanobiotechnol 2018;12:846–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Malla S, Niraula NP, Singh B, Liou K, Sohng JK. Limitations in doxorubicin production from Streptomyces peucetius. Microbiol Res 2010;165:427–35. [DOI] [PubMed] [Google Scholar]
  • [8].Gabizon AA, Patil Y, La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat 2016;29:90–106. [DOI] [PubMed] [Google Scholar]
  • [9].Muggia FM. Clinical efficacy and prospects for use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers. Drugs 1997;54:22–9. [DOI] [PubMed] [Google Scholar]
  • [10].Alberts DS, Garcia DJ. Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs 1997;54:30–5. [DOI] [PubMed] [Google Scholar]
  • [11].Munafo MR, Flint J. Meta-analysis of genetic association studies. Trends Genet 2004;20:439–44. [DOI] [PubMed] [Google Scholar]
  • [12].Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:e1–34. [DOI] [PubMed] [Google Scholar]
  • [13].Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58. [DOI] [PubMed] [Google Scholar]
  • [14].DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. [DOI] [PubMed] [Google Scholar]
  • [15].Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48. [PubMed] [Google Scholar]
  • [16].Begg CB, Berlin JA. Publication bias and dissemination of clinical research. J Natl Cancer Inst 1989;81:107–15. [DOI] [PubMed] [Google Scholar]
  • [17].Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001;37:870–7. [DOI] [PubMed] [Google Scholar]
  • [18].Dimopoulos MA, Pouli A, Zervas K, et al. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol 2003;14:1039–44. [DOI] [PubMed] [Google Scholar]
  • [19].O’Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440–9. [DOI] [PubMed] [Google Scholar]
  • [20].Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a phase III multicenter randomized trial. Cancer 2006;106:848–58. [DOI] [PubMed] [Google Scholar]
  • [21].Hunault-Berger M, Leguay T, Thomas X, et al. A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study. Haematologica 2011;96:245–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Batist G, Ramakrishnan G, Rao CS, et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventionaldoxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 2001;19:1444–54. [DOI] [PubMed] [Google Scholar]
  • [23].Harris L, Batist G, Belt R, et al. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 2002;94:25–36. [DOI] [PubMed] [Google Scholar]
  • [24].Latagliata R, Breccia M, Fazi P, et al. Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia. Br J Haematol 2008;143:681–9. [DOI] [PubMed] [Google Scholar]
  • [25].Mylonakis N, Athanasiou A, Ziras N, et al. Phase II study of liposomal cisplatin (Lipoplatin) plus gemcitabine versuscisplatin plus gemcitabine as first line treatment in inoperable (stage IIIB/IV) non-small cell lung cancer. Lung Cancer 2010;68:240–7. [DOI] [PubMed] [Google Scholar]
  • [26].Stathopoulos GP, Antoniou D, Dimitroulis J, et al. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann Oncol 2010;21:2227–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Yang X, Zhang H, Nong J, et al. A randomized trial of liposomal paclitaxel plus cisplatin as first-line therapy for advanced non-small cell lung cancer. Zhongguo Fei Ai Za Zhi 2012;15:208–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Roy AC, Park SR, Cunningham D, et al. A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol 2013;24:1567–73. [DOI] [PubMed] [Google Scholar]
  • [29].Pignata S, Scambia G, Ferrandina G, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin Oncol 2011;29:3628–35. [DOI] [PubMed] [Google Scholar]
  • [30].Bafaloukos D, Linardou H, Aravantinos G, et al. A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study. BMC Med 2010;8:03. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Kaye SB, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012;30:372–9. [DOI] [PubMed] [Google Scholar]
  • [32].Alberts DS, Liu PY, Wilczynski SP, et al. Randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatinversus carboplatin in platinum-sensitive (PS) patients with recurrent epithelialovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy (Southwest Oncology Group Protocol S0200). Gynecol Oncol 2008;108:90–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sentitive ovarian cancer in late relapse. J Clin Oncol 2010;28:3323–9. [DOI] [PubMed] [Google Scholar]
  • [34].Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007;25:2811–8. [DOI] [PubMed] [Google Scholar]
  • [35].Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001;19:3312–22. [DOI] [PubMed] [Google Scholar]
  • [36].Colombo N, Kutarska E, Dimopoulos M, et al. Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. J Clin Oncol 2012;30:3841–7. [DOI] [PubMed] [Google Scholar]
  • [37].Sparano JA, Makhson AN, Semiglazov VF, et al. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol 2009;27:4522–9. [DOI] [PubMed] [Google Scholar]
  • [38].Chan S, Davidson N, Juozaityte E, et al. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol 2004;15:1527–34. [DOI] [PubMed] [Google Scholar]
  • [39].Keller AM, Mennel RG, Georgoulias VA, et al. Randomized phase III trial of pegylated liposomal doxorubicin versusvinorelbine or mitomycin C plus vinblastine in women with taxane-refractoryadvanced breast cancer. J Clin Oncol 2004;22:3893–901. [DOI] [PubMed] [Google Scholar]
  • [40].Baselga J, Manikhas A, Cortés J, et al. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. Ann Oncol 2014;25:592–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Smorenburg CH, de Groot SM, van Leeuwen-Stok AE, et al. A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG. Ann Oncol 2014;25:599–605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Harbeck N, Saupe S, Jäger E, et al. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat 2017;161:63–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Viswanadh MK, Muthu MS. Targeted bioadhesive nanomedicine: an effective approach for synergistic drug delivery to cancers. Nanomedicine (Lond) 2018;13:1401–3. [DOI] [PubMed] [Google Scholar]
  • [44].Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest 2001;19:424–36. [DOI] [PubMed] [Google Scholar]
  • [45].Hu Y, Wu C, Zhu C, et al. Enhanced uptake and improved anti-tumor efficacy of doxorubicin loaded fibrin gel with liposomal apatinib in colorectal cancer. Int J Pharm 2018;552:319–27. [DOI] [PubMed] [Google Scholar]
  • [46].Farzaneh H, Ebrahimi Nik M, Mashreghi M, Saberi Z, Jaafari MR, Teymouri M. A study on the role of cholesterol and phosphatidylcholine in various features of liposomal doxorubicin: from liposomal preparation to therapy. Int J Pharm 2018;551:300–8. [DOI] [PubMed] [Google Scholar]
  • [47].Boers-Sonderen MJ, van Herpen CM, van der Graaf WT, et al. Correlation of toxicity and efficacy with pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD) (Caelyx®). Cancer Chemother Pharmacol 2014;74:457–63. [DOI] [PubMed] [Google Scholar]
  • [48].Symon Z, Peyser A, Tzemach D, et al. Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes. Cancer 1999;86:72–8. [PubMed] [Google Scholar]
  • [49].Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997;54:15–21. [DOI] [PubMed] [Google Scholar]
  • [50].van den Hurk C, Breed W, Dercksen W. Nonpegylated liposomal doxorubicin: reduction in cardiotoxicity, although still severe alopecia. Anticancer Drugs 2015;26:687. [DOI] [PubMed] [Google Scholar]
  • [51].Boulikas T. Molecular mechanisms of cisplatin and its liposomally encapsulated form, Lipoplatin™. Lipoplatin™ as a chemotherapy and antiangiogenesis drug. Cancer Ther 2007;5:351–76. [Google Scholar]
  • [52].Hong RL, Tseng YL. Phase I and pharmacokinetic study of a stable, polyethylene-glycolated liposomal doxorubicin in patients with solid tumors: the relation between pharmacokinetic property and toxicity. Cancer 2001;91:1826–33. [PubMed] [Google Scholar]
  • [53].Goswami KK, Ghosh T, Ghosh S, Sarkar M, Bose A, Baral R. Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cell Immunol 2017;316:01–10. [DOI] [PubMed] [Google Scholar]
  • [54].Gibson JM, Alzghari S, Ahn C, Trantham H, La-Beck NM. The role of pegylated liposomal doxorubicin in ovarian cancer: a meta-analysis of randomized clinical trials. Oncologist 2013;18:1022–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Jehn CF, Hemmati P, Lehenbauer-Dehm S, Kümmel S, Flath B, Schmid P. Biweekly pegylated liposomal doxorubicin (Caelyx) in heavily pretreated metastatic breast cancer: a phase 2 study. Clin Breast Cancer 2016;16:514–9. [DOI] [PubMed] [Google Scholar]
  • [56].Lorusso V, Latorre A, Giotta F. Chemotherapy options beyond the first line in HER-negative metastatic breast cancer. J Oncol 2020;2020:9645294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [57].Alba E, Ruiz-Borrego M, Margelí M, et al. Maintenance treatment with pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer: GEICAM 2001-01 study. Breast Cancer Res Treat 2010;122:169–76. [DOI] [PubMed] [Google Scholar]
  • [58].Mahner S, Meier W, du Bois A, et al. Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial. Eur J Cancer 2015;51:352–8. [DOI] [PubMed] [Google Scholar]
  • [59].Muggia FM, Hainsworth JD, Jeffers S, et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997;15:987–93. [DOI] [PubMed] [Google Scholar]
  • [60].Gabizon A, Isacson R, Rosengarten O, Tzemach D, Shmeeda H, Sapir R. An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin. Cancer Chemother Pharmacol 2008;61:695–702. [DOI] [PubMed] [Google Scholar]
  • [61].Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 2012;167:195–205. [DOI] [PMC free article] [PubMed] [Google Scholar]

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