Open Access

Effectiveness of multi-drug regimen chemotherapy treatment in osteosarcoma patients: a network meta-analysis of randomized controlled trials

  • Xiaojie Wang1,
  • Hong Zheng1,
  • Tao Shou1,
  • Chunming Tang1,
  • Kun Miao1 and
  • Ping Wang2Email author
Contributed equally
Journal of Orthopaedic Surgery and Research201712:52

https://doi.org/10.1186/s13018-017-0544-9

Received: 20 January 2017

Accepted: 28 February 2017

Published: 29 March 2017

Abstract

Background

Osteosarcoma is the most common malignant bone tumour. Due to the high metastasis rate and drug resistance of this disease, multi-drug regimens are necessary to control tumour cells at various stages of the cell cycle, eliminate local or distant micrometastases, and reduce the emergence of drug-resistant cells. Many adjuvant chemotherapy protocols have shown different efficacies and controversial results. Therefore, we classified the types of drugs used for adjuvant chemotherapy and evaluated the differences between single- and multi-drug chemotherapy regimens using network meta-analysis.

Methods

We searched electronic databases, including PubMed (MEDLINE), EmBase, and the Cochrane Library, through November 2016 using the keywords “osteosarcoma”, “osteogenic sarcoma”, “chemotherapy”, and “random*” without language restrictions. The major outcome in the present analysis was progression-free survival (PFS), and the secondary outcome was overall survival (OS). We used a random effect network meta-analysis for mixed multiple treatment comparisons.

Results

We included 23 articles assessing a total of 5742 patients in the present systematic review. The analysis of PFS indicated that the T12 protocol (including adriamycin, bleomycin, cyclophosphamide, dactinomycin, methotrexate, cisplatin) plays a more critical role in osteosarcoma treatment (surface under the cumulative ranking (SUCRA) probability 76.9%), with a better effect on prolonging the PFS of patients when combined with ifosfamide (94.1%) or vincristine (81.9%). For the analysis of OS, we separated the regimens to two groups, reflecting the disconnection. The T12 protocol plus vincristine (94.7%) or the removal of cisplatinum (89.4%) is most likely the best regimen.

Conclusions

We concluded that multi-drug regimens have a better effect on prolonging the PFS and OS of osteosarcoma patients, and the T12 protocol has a better effect on prolonging the PFS of osteosarcoma patients, particularly in combination with ifosfamide or vincristine. The OS analysis showed that the T12 protocol plus vincristine or the T12 protocol with the removal of cisplatinum might be a better regimen for improving the OS of patients. However, well-designed randomized controlled trials of chemotherapeutic protocols are still necessary.

Keywords

Osteosarcoma Chemotherapy drugs Progression-free survival Overall survival Meta-analysis

Background

Osteosarcoma is the most common type of primary malignant bone tumour. It exhibits a high metastasis rate and is frequently detected in adolescents at sites of rapid bone growth [1, 2]. Although osteosarcoma is frequently treated by surgical joint amputation or disconnection, the prognosis remains poor in patients with metastatic osteosarcoma [3]. Therefore, the ultimate treatment of this disease not only depends on primary tumour control but also the removal of small metastases. Thus, adjuvant chemotherapy combined with the surgical removal of the primary tumour is needed to reduce the size of the tumour, clear the metastases, and improve progression-free survival (PFS) and overall survival (OS).

Osteosarcoma is also a relatively drug-resistant tumour, and the treatment effect of single-drug chemotherapy is not ideal [4, 5]. Thus, multi-drug regimens are necessary to control tumour cells at various stages of the cell cycle, eliminate local or distant micrometastases, and reduce the emergence of drug-resistant cells [6]. Several systematic reviews have examined osteosarcoma chemotherapy, but the results are controversial. A previous study suggested that ifosfamide-based chemotherapy could significantly improve the PFS and OS of osteosarcoma patients [7]. However, recent traditional meta-analyses have not determined whether ifosfamide application and chemotherapy have similar histological response rates and 5-year PFS and OS in non-metastatic and primary osteosarcoma patients; thus, ifosfamide is not recommended [810]. Additionally, in a systematic review concerning the dose of chemotherapy drugs, high-dose drugs did not significantly improve the PFS and OS of patients compared to moderate-dose drugs [1113]. Thus, additional studies are needed to resolve these controversies.

From the 1970s to the present, many adjuvant chemotherapy protocols have shown various efficacy differences and controversial results. No definitive evidence exists regarding which treatment is more advantageous for clinical application [14, 15]. The aim of the present study was to analyse the existing chemotherapy protocol through direct and indirect comparisons to guide clinical application. However, an analysis of each type of chemotherapy protocol is too complex and cumbersome. Therefore, in the present study, we classified the types of drugs used in adjuvant chemotherapy and evaluated the differences between single or multi-drug chemotherapy regimens using a network meta-analysis.

Methods

This network meta-analysis was performed in accordance with Preferred Reporting Items for Systematic Reviews (PRISMA) statement [16].

Data search strategy and selection criteria

Two authors independently performed the literature search through November 2016 using electronic databases, including PubMed (MEDLINE), EmBase, and the Cochrane Library, with the keywords “osteosarcoma”, “osteogenic sarcoma”, “chemotherapy”, and “random*”, without language restriction. The bibliographies of the obtained publications and relevant reviews were also assessed to ensure that no relevant studies were inadvertently omitted. The publications included in the present study met the following criteria: (1) randomized controlled trial (RCT) design; (2) inclusion of osteosarcoma patients; (3) examination of two or more groups using different single- or multi-drug regimens; and (4) inclusion of PFS or OS as an outcome. The exclusion criteria consisted of the following: (1) non-RCT studies; (2) studies including patients with other types of sarcomas, such as Ewing sarcoma; (3) non-chemotherapy controlled studies, such as surgery or radiotherapy controlled studies; (4) studies comparing the same chemotherapeutic drug type, such as a drug dose-related study; and (5) non-desired outcome studies. Additionally, reviews, comments, case reports, basic studies, and conference reports were also excluded.

Data extraction

Two authors independently extracted the following information from eligible studies: first author’s name, publication year, location, research time, study register or abbreviation, sample size, average age, ratio of males, type of disease, experimental intervention, control, and follow-up. In the present analysis, the major outcome was PFS, and the secondary outcome was OS, as some patients changed the initial randomized treatment after disease progression. We assessed the methodological quality of the included trials using the Cochrane Collaboration’s tool, which assigns grades of “high risk”, “unclear risk”, or “unclear risk” of bias across the seven specified domains [17].

Statistics analysis

We initially conducted a pairwise meta-analysis using a random effect model, as this model is likely the most appropriate and conservative methodology accounting for between-trial heterogeneity within each comparison [18]. For dichotomous outcomes, odds ratios (ORs) or logarithm transformation with 95% confidence intervals (CIs) were calculated to determine the sizes of the effects. We also used a random effect network meta-analysis for mixed multiple treatment comparisons because this analysis fully preserves the within-trial randomized treatment comparisons in each trial [19]. To rank the treatments for each outcome, we used the surface under the cumulative ranking (SUCRA) probabilities [20]. Comparison-adjusted funnel plots were used to determine whether small-study effects were present in the analysis conducted in the present study [21]. All tests were two-tailed, and a p value of less than 0.05 was considered statistically significant. Data analyses were performed using STATA software (version 14.0; Stata Corporation, College Station, TX, USA).

Results

Literature search

In the present study, 747 articles were identified after the duplicates were removed. A total of 678 articles were excluded after the titles and abstracts were screened. The full texts of the remaining 69 articles were assessed, and the following types of studies were removed: non-randomized design (19); comparisons of the same type of chemotherapeutic drug (12); duplications or secondary studies (9); non-controlled studies (2); no desired outcomes (2); and other sarcoma studies (2). Eventually, 23 articles assessing a total of 5742 patients were included in the present systematic review [2244] (Fig. 1, Table 1).
Fig. 1

PRISMA flowchart illustrating the selection of studies included in the present analysis

Table 1

Characteristics of subjects in eligible studies

Author

Year

Location

Research time

Study register/abbreviation

Sample size

Average agea

Male/Female

Type of disease

Follow-up

Yan Zhang [22]

2013

China

2007–2008

NA

76

24.4 ± 1.7

44/32

Enneking II-III

5 years

Neyssa M. Marina [23]

2016

International

2005–2011

EURAMOS-1

2260 (618)

4–40

365/253

High grade

62–63 months

Sophie Piperno-Neumann [24]

2016

France

2007–2014

OS2006

318

15.4 (5.8–50.9)

179/136

High grade

3.9 years

Stefan S. Bielack [25]

2015

International

2005–2011

EURAMOS-1

2260 (1041)

14 (11–16)

421/295

High grade

44 months

Alessandra Longhi [26]

2014

Italy

2007–2011

EudraCT:2006-002676-18

20

34 (11–65)

11//9

Postrelapse

73 months

J.S. Whelan [27]

2012

Europe

1982–2002

EOI (BO02/80831)

179

3–40

102/77

High grade

9.4 years

    

EOI (BO03/80861)

391

3–38

261/130

High grade

9.4 years

Hui Zhao [28]

2010

China

2002–2007

NA

32

18.5 (7–68)

16/16

Lung metastasis

60 months

Alexander J. Chou [29]

2009

USA

2001–2005

CCG/POG (INT-0133)

91

<30

56/35

High-grade intramedullary metastasis

89 months

Paul A. Meyers [30]

2008

USA

2001–2005

CCG/POG (INT-0133)

662

13 (1–30)

361/301

High grade, Non-metastasis

7.7 years

Marie-Cecile Le Deley [31]

2007

France

1994–2001

SFOP-OS94 (NCT00180908)

234

13.2 (3.1–19.5)

131/103

High grade

77 months

Paul A. Meyers [32]

1998

USA

1986–1993

MSKCC (T12) protocol

73

15.8 (4.6–36.4)

42/31

High grade

91.4 months

Robert L. Souhami [33]

1997

International

1986–1991

EOI (T10) protocol

407

NA

261/130

High grade, Non-metastasis

5.6 years

Michael P. Link [34]

1993

International

1982–1984

MIOS

36

NA

NA

High grade, Non-metastasis

4–8 years

John H. Edmonson [35]

1984

USA

1976–1980

Mayo Clinic

38

17 (9–62)

24/14

Postoperation

31–74 months

K. Winkler [36]

1984

Germany

1979–1982

COSS-80

116

14 (5–24)

69/47

High grade

30 months

F. Eilber [37]

1987

USA

1981–1984

NA

112

15 (4–75)

44/15

Non-metastasis

2 years

D.R. Sweetnam [38]

1986

UK

1975–1981

NA

194

1–40

111/83

Lung metastasis

26–94 months

K. Winkler [39]

1988

Germany

1982–1984

COSS-82

125

14

73/52

Osteosarcoma

6 years

Vivien H.C. Bramwell [40]

1992

Canada

1983–1986

EOI

198

NA

114/84

High grade

5 years

John C. Ivins [41]

1976

USA

1974–1975

Mayo Clinic

26

NA

NA

Osteosarcoma

15 months

C. Jasmin [42]

1978

France

1976-

EORTC

27

18 (9–28)

13/14

Osteosarcoma

2 years

Gilchrist GS [43]

1978

USA

NA

NA

32

NA

NA

Osteosarcoma

753 days

J.M.V. Burgers [44]

1988

Netherlands

1978–1983

EORTC-SIOP03 (20781)

140

1–30

87/53

Osteosarcoma

5 years

Abbreviations: CCG Children’s Cancer Group, COSS Cooperative Osteosarcoma Study Group, EOI the European Osteosarcoma Intergroup, EORTC European Organization for Research on Treatment of Cancer, EURAMOS-1 The European and American Osteosarcoma Study Group, MIOS the Multi-institutional Osteosarcoma Study, MSKCC Memorial Sloan-Kettering Cancer Center, SFOP Societe Francaise d’Oncologie Pediatrique, SSG the Scandinavian Sarcoma Group, NA not available

aMean ± standardization; median (minimum-maximum); minimum-maximum

The included studies were published from 1976 to 2016 and were researched from 1974 to 2014. The analysis contained several multicentre large-scale studies, such as The European and American Osteosarcoma Study Group-1 (EURAMOS-1), Osteosarcoma 2006 (OS2006), and the Symposium of the Cooperative Osteosarcoma Study Group (COSS-80). Many studies contained duplicate reports. Thus, we included relatively recently published studies and referred to the outcomes of the duplicate reports. All age groups of patients were included, and slightly more men than women were included. All studies included patients with osteosarcoma defined according to a pathological diagnosis. In addition, four studies included osteosarcoma patients without metastasis, two studies included metastasis patients, and one study included relapse patients. Most studies initiated chemotherapy prior to surgery. The longest median follow-up period was 9.4 years (Table 1). All included studies had an RCT design without blinding, and most randomizations were not rigorous. However, the assessed outcome was objective; thus, the overall quality of the included studies was not ideal but was acceptable (Additional file 1: Figure S1).

For chemotherapeutic drug application, we investigated all types of drugs used in the intervention arms and classified each of the drugs of the experimental arms by alphabetical order. The present study did not include a comprehensive analysis, reflecting the characteristics of applied chemotherapeutic protocols, as most application stages, durations, and dosages of drugs were different in different protocols (Table 2). Drugs showing no chemotherapeutic effect, such as granulocyte colony-stimulating factor (G-CSF) and muramyl tripeptide, were excluded. Drugs that may be included in chemotherapy, such as mistletoe, were included in the present analysis.
Table 2

Interventions and abbreviations for eligible studies

Author

Year

Study register/short name

Intervention

Abbr.

Control

Abbr.

Yan Zhang [22]

2013

NA

Adriamycin; cisplatin; ifosfamide; recombinant human endostatin

APIR

Adriamycin; cisplatin; ifosfamide

API

Neyssa M. Marina [23]

2016

EURAMOS-1

Adriamycin; methotrexate; cisplatin

AMP

Adriamycin; methotrexate; cisplatin; ifosfamide; etoposide

AMPIE

Sophie Piperno-Neumann [24]

2016

OS2006

Methotrexate; ifosfamide; etoposide; zoledronate

MIEZ

Methotrexate; ifosfamide; etoposide

MIE

   

Adriamycin; cisplatin; ifosfamide; zoledronate

APIZ

Adriamycin; cisplatin; ifosfamide

API

Stefan S. Bielack [25]

2015

EURAMOS-1

Adriamycin; methotrexate; cisplatin; interferonα-2β

AMPF

Adriamycin; methotrexate; cisplatin

AMP

Alessandra Longhi [26]

2014

EudraCT:2006-002676-18

Viscum album

V

Etoposide

E

J.S. Whelan [27]

2012

EOI (BO02/80831)

Adriamycin; methotrexate; cisplatin

AMP

Adriamycin; cisplatin

AP

  

EOI (BO03/80861)

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate; cisplatin; vincristine

ABCDMPL

Adriamycin; cisplatin

AP

Hui Zhao [28]

2010

NA

Cisplatin; pirarubicin

PT

Ifosfamide; pirarubicin

IT

Alexander J. Chou [29]

2009

CCG/POG (INT-0133)

Adriamycin; methotrexate; cisplatin

AMP

Adriamycin; cisplatin; methotrexate; ifosfamide

AMPI

Paul A. Meyers [30]

2008

CCG/POG (INT-0133)

Adriamycin; methotrexate; cisplatin

AMP

Adriamycin; cisplatin; methotrexate; ifosfamide

AMPI

Marie-Cecile Le Deley [31]

2007

SFOP-OS94 (NCT00180908)

Adriamycin; methotrexate

AM

Methotrexate; ifosfamide; etoposide

MIE

Paul A. Meyers [32]

1998

MSKCC (T12) protocol

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate; cisplatin

ABCDMP

Bleomycin; cyclophosphamide; dactinomycin; methotrexate;

BCDM

Robert L. Souhami [33]

1997

EOI (T10) protocol

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate; vincristine

ABCDMPL

Adriamycin; cisplatin

AP

Michael P. Link [34]

1993

MIOS

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate; cisplatin

ABCDMP

Blank

Blank

John H. Edmonson [35]

1984

Mayo Clinic

Methotrexate; vincristine

ML

Blank

Blank

K. Winkler [36]

1984

COSS-80

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate; interferon

ABCDMF

Adriamycin; methotrexate; cisplatin; interferon

AMPF

   

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate;

ABCDM

Adriamycin; methotrexate; cisplatin

AMP

F. Eilber [37]

1987

NA

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate;

ABCDM

Blank

Blank

D.R. Sweetnam [38]

1986

NA

Adriamycin; methotrexate; vincristine

AML

Methotrexate; vincristine

ML

K. Winkler [39]

1988

COSS-82

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate; cisplatin; ifosfamide

ABCDMPI

Adriamycin; bleomycin; cyclophosphamide; dactinomycin; methotrexate; cisplatin;

ABCDMP

Vivien H.C. Bramwell [40]

1992

EOI

Adriamycin; methotrexate; cisplatin

AMP

Adriamycin; cisplatin

AP

John C. Ivins [41]

1976

Mayo Clinic

Transfer factor

N

Adriamycin; methotrexate; vincristine

AML

C. Jasmin [42]

1978

EORTC

Adriamycin; cyclophosphamide; methotrexate; vincristine

ACML

Adriamycin; methotrexate; cyclophosphamide; alkeran

ACMK

Gilchrist GS [43]

1978

NA

Adriamycin; methotrexate; vincristine

AML

Transfer factor

N

J.M.V. Burgers [44]

1988

EORTC-SIOP03 (20781)

Adriamycin; cyclophosphamide; methotrexate; vincristine

ACML

Blank

Blank

Abbreviations: CCG Children’s Cancer Group, COSS Cooperative Osteosarcoma Study Group, EOI the European Osteosarcoma Intergroup, EORTC European Organization for Research on Treatment of Cancer, EURAMOS-1 The European and American Osteosarcoma Study Group, MIOS The Multi-institutional Osteosarcoma Study, MSKCC Memorial Sloan Kettering Cancer Center, SFOP Societe Francaise d’Oncologie Pediatrique, SSG the Scandinavian Sarcoma Group, NA not available

For the PFS analysis, we extracted all studies of 5-year PFS or the longest follow-up period for PFS. In the present study, we analysed 16 types of multi-drug regimens. Four multi-drug regimens were directly compared to a blank control, which indicated treatment without chemotherapy. In this analysis, the nodes were weighted according to the number of studies evaluated for each treatment, and the edges were weighted according to the precision of the direct estimate for each pairwise comparison (Fig. 2a). In network pairwise comparisons, the ABCDM (all protocol abbreviations are defined in Table 2) regimen was superior to the ACML (logOR, 1.38; 95% CI, 0.09–2.68) and Blank (logOR, 1.30; 95% CI, 0.19–2.41) regimens for the PFS outcome. The ABCDMP regimen was superior to the ACML (logOR, 2.14; 95% CI, 0.45–3.84), AML (logOR, 2.13; 95% CI, 0.00–4.26), Blank (logOR, 2.06; 95% CI, 0.50–3.62), and ML regimens (logOR, 2.24; 95% CI, 0.22–4.27), and the ABCDMPI regimen, combining ABCDMP with ifosfamide, was superior to the ABCDMP regimen alone (logOR, 0.84; 95% CI, 0.09–1.59). The ABCDMPI regimen was also superior to the ACML (logOR, 2.98; 95% CI, 1.13–4.84), AML (logOR, 2.97; 95% CI, 0.71–5.23), Blank (logOR, 2.90; 95% CI, 1.17–4.63), ML (logOR, 3.08; 95% CI, 0.92–5.24), and N (logOR, 2.75; 95% CI, 0.22–5.28) regimens in the network comparisons. Moreover, the ABCDMP regimen in combination with vincristine (ABCDMPL) was superior to the ACML (logOR, 1.89; 95% CI, 0.14–3.64), AMP (logOR, 0.46; 95% CI, 0.01–0.90), AMPF (logOR, 0.64; 95% CI, 0.11–1.18), and Blank (logOR, 1.80; 95% CI, 0.19–3.42) regimens. No other significant differences were found among these regimens (Additional file 2: Table S1). Based on the SUCRA rank, the ABCDMPI regimen was the most likely treatment to improve PFS in osteosarcoma patients (94.1%), followed by the ABCDMPL (81.9%) and ABCDMP (76.9%) regimens. Additionally, the comparison-adjusted funnel plot used to assess publication bias and determine the presence of small-study effects did not suggest any publication bias (Additional file 3: Figure S2a). In addition, some regimens were not included in the network meta-analysis, reflecting a disconnection, and a traditional meta-analysis showed no significant difference between interventions, except for APIZ compared to MIE (OR, 2.27; 95% CI 1.02–5.04) (Fig. 3).
Fig. 2

Network of comparisons for all outcomes included in the analyses. a Progression-free survival. b Overall survival, part one. c Overall survival, part two. Abbreviations: A adriamycin, B bleomycin, C cyclophosphamide, D dactinomycin, E etoposide, F interferon, I ifosfamide, K alkeran, L vincristine, M methotrexate, N transfer factor, P cisplatin

Fig. 3

Forest plot of comparisons not included in the network meta-analysis. Abbreviations: A adriamycin, E etoposide, I ifosfamide, M methotrexate, P cisplatin, R recombinant human endostatin, T pirarubicin, V Viscum album, Z zoledronate

For the OS analysis, we separated the regimens into two groups, reflecting the disconnection. The first group included AMP, AMPF, AMPI, AMPIE, AP, and ABCDMPL. Four regimens were directly compared to AMP, and we directly compared AP and ABCDMPL (Fig. 2b). In the network comparisons, the ABCDMPL regimen showed a significant advantage compared to the AMP (logOR, 0.47; 95% CI, 0.02–0.92), AMPF (logOR, 0.65; 95% CI, 0.01–1.29), and AP (logOR, 0.31; 95% CI, 0.04–0.57) regimens (Additional file 4: Table S2). The results showed that ABCDMPL was most likely the best regimen for improving the OS (94.7%) of osteosarcoma patients, followed by the AP (58.3%) and AMPIE (56.8%) regimens. The second group included ABCDM, ABCDMP, ACML, BCDM, ML, and N. Four regimens were directly compared to the Blank condition (Fig. 2c). In the network comparison, the ABCDM regimen was superior to the AML (logOR, 1.99; 95% CI, 0.14–3.84), Blank (logOR, 1.54; 95% CI, 0.37–2.70), and ML (logOR, 1.76; 95% CI, 0.03–3.49) regimens, and no other significant difference was found among comparisons (Additional file 5: Table S3). Regarding rank, ABCDM (89.4%) was most likely to be the best regimen, followed by N (70.1%) and BCDM (60.9%). The comparison-adjusted funnel plot showed no obvious publication bias (Additional file 3: Figure S2b and c). A comparison of regimens not included in the network meta-analysis revealed that APIR had a significant advantage over API in improving the OS (OR, 3.48; 95% CI, 1.17–10.32) of the patients (Fig. 3). However, this result was based on a single study and lacked precision and robustness.

Discussion

In the present study, we analysed single- or multi-drug regimens of chemotherapy for the treatment of osteosarcoma using a network meta-analysis. We did not analyse the chemotherapeutic effect according to protocols because the application stage, duration, and dosage of each drug varied. The PFS analysis showed that the ABCDMPI, ABCDMPL, and ABCDMP regimens were most likely to improve PFS in osteosarcoma patients. In the present study, the ABCDMP regimen played a critical role in a treatment involving the T12 protocol (including adriamycin, bleomycin, cyclophosphamide, dactinomycin, methotrexate, cisplatin) used at the Memorial Sloan Kettering Cancer Center (MSKCC) between 1986 and 1993. This more intensive preoperative regimen comprised two courses of cisplatinum and doxorubicin in addition to a high dose of methotrexate and bleomycin, cyclophosphamide, and dactinomycin [32]; it showed a better effect on prolonging the PFS of patients when combined with ifosfamide or vincristine. However, these results are partially supported by a previous view that ifosfamide-based chemotherapy significantly improves the PFS of osteosarcoma patients [7]. In the secondary outcome analysis, we also observed that the regimens with more types of drugs showed better results, but use of a transfer factor also showed advantages. However, these results should be considered with caution, as most studies changed the initial protocol and required more active chemotherapy with metastasis or progression. Therefore, the effective gap between interventions could be reduced, resulting in bias. The practice of changing the chemotherapy regimen is common, correct, and ethical in clinical practice.

Despite the present results, it is undeniable that when the number of different types of chemotherapeutic drugs increases, the cytotoxicity and adverse effects will also simultaneously increase. Thus, a balance exists, suggesting that multi-drug regimens could significantly prolong the PFS of osteosarcoma patients but lead to more serious adverse effects. Adverse effects are common in chemotherapy and include nephrotoxicity, ototoxicity, and bone marrow suppression. Serious adverse effects will affect the application of the chemotherapy programme and even the quality of life of patients.

Thus, in clinical practice, cytoprotective agents, such as muramyl tripeptide, are also frequently and simultaneously used for chemotherapy. However, this agent is not widely used, and the literature did not show that cytoprotective agents significantly improved the PFS and OS of patients [29]. Therefore, in the present study, we did not analyse the use of cytoprotective agents. In addition, Viscum album, transfer factor, and recombinant human endostatin are non-traditional chemotherapy drugs that show a cytotoxicity effect. Although they are controversial, we still included these types of drugs in the present analysis.

In the present study, neoadjuvant chemotherapy was used in most included studies. Neoadjuvant chemotherapy includes the administration of chemotherapeutic agents prior to the main treatment, and this regimen has several advantages: (1) It can eliminate micrometastases early to avoid metastases caused by delayed surgery or low resistance. (2) It can control the primary tumour and reduce the chance of surgical tumour spread. (3) It can assess the chemotherapeutic effect and guide the postoperative chemotherapy. (4) It can assess the prognosis earlier. Although the results of RCTs suggested no significant effect on the outcome of patients when comparing preoperative chemotherapy to postoperative chemotherapy [45], neoadjuvant chemotherapy for limb salvage and the surgical process is still worthy of clinical application.

In addition, several studies compared intra-arterial or intravenous chemotherapeutic infusion. When the same regimens were applied, no significant differences were observed in the chemotherapy response between intra-arterial and intravenous infusion [46, 47]. However, some studies suggested that intra-arterial infusion has a more active effect [48, 49]. Regarding the dosage of chemotherapeutic agents, comparisons of a high or moderate dose of methotrexate have primarily been described. A high dose of methotrexate was more widely used in patients who could tolerate this drug. However, in small-sample RCTs of children with osteosarcoma, a significant difference in outcome was not observed between different dosages [5052].

We systematically analysed chemotherapeutic regimens for osteosarcoma patients using a network meta-analysis, although individual chemotherapeutic protocols could not be analysed. In the present study, multi-drug regimens, such as the T12 protocol plus ifosfamide or vincristine, had a better effect on prolonging the PFS and OS of osteosarcoma patients. Further research with well-designed, double-blinded RCTs is still necessary, as the psychological evidence might also influence patient outcomes. In addition, further trials using relatively well-developed chemotherapeutic protocols would be beneficial to analyse the differences among multiple chemotherapeutic protocols.

Limitations

There are several limitations to the present study. First, the present analysis was performed at a study level, not at an individual level. Second, for chemotherapy, cytoprotective agents might also improve the survival time of patients by reducing the chemotherapy-induced damage to normal tissue, but these drugs were not analysed in this study. Third, we did not perform the Grading of Recommendations Assessment, Development and Evaluation in the present analysis, as all included studies had an RCT design without blind concealment, and most of the results showed a low risk of imprecision.

Conclusions

In conclusion, the T12 protocol has a better effect on prolonging the PFS of osteosarcoma patients when combined with ifosfamide or vincristine. For the OS, the T12 protocol plus vincristine or the removal of cisplatinum also represents the best regimen. Further RCTs of chemotherapeutic protocols are still necessary.

Abbreviations

A: 

Adriamycin

B: 

Bleomycin

C: 

Cyclophosphamide

CCG: 

Children’s Cancer Group

COSS: 

Cooperative Osteosarcoma Study Group

CTs: 

Confidence intervals

D: 

Dactinomycin

E: 

Etoposide

EOI: 

The European Osteosarcoma Intergroup

EORTC: 

European Organization for Research on Treatment of Cancer

EURAMOS-1: 

The European and American Osteosarcoma Study Group

F: 

Interferon

G-CSF: 

Granulocyte colony stimulating factor

I: 

Ifosfamide

K: 

Alkeran

L: 

Vincristine

M: 

Methotrexate

MIOS: 

The Multi-institutional Osteosarcoma Study

MSKCC: 

Memorial Sloan Kettering Cancer Center

N: 

Transfer factor

NA: 

Not available

ORs: 

Odds ratios

OS: 

Overall survival

P: 

Cisplatin

PFS: 

Progression-free survival

PRISMA: 

Preferred Reporting Items for Systematic Reviews

R: 

Recombinant human endostatin

RCT: 

Randomized controlled trial

SFOP: 

Societe Francaise d’Oncologie Pediatrique

SSG: 

The Scandinavian Sarcoma Group

SUCRA: 

Surface Under the Cumulative Ranking

T: 

Pirarubicin

V: 

Viscum album

Z: 

Zoledronate

Declarations

Acknowledgements

We thank the authors of the included studies.

Funding

None.

Availability of data and materials

All the data of the manuscript are presented in the paper or additional supporting files.

Authors’ contributions

XjW conceived the study. XjW and HZ searched the literature and collected the data. XjW, TS, CmT, and KM performed the statistical analysis. XjW and HZ drafted the manuscript. PW reviewed the manuscript. All authors have read and approved the final paper.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Publisher's Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Medical Oncology, the First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology
(2)
Department of Thoracic Surgery, the First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology

References

  1. Dantas-Barbosa C, Brigido MM, Maranhao AQ. Construction of a human Fab phage display library from antibody repertoires of osteosarcoma patients. Genet Mol Res. 2005;4:126–40.PubMedGoogle Scholar
  2. Cai S, Zhang T, Zhang D, Qiu G, Liu Y. Volume-sensitive chloride channels are involved in cisplatin treatment of osteosarcoma. Mol Med Rep. 2015;11:2465–70.PubMedGoogle Scholar
  3. Zhang Y, Zhang L, Zhang G, Li S, Duan J, Cheng J, et al. Osteosarcoma metastasis: prospective role of ezrin. Tumour Biol. 2014;35:5055–9.View ArticlePubMedGoogle Scholar
  4. Burns BS, Edin ML, Lester GE, Tuttle HG, Wall ME, Wani MC, et al. Selective drug resistant human osteosarcoma cell lines. Clin Orthop Relat Res. 2001;383:259–67.View ArticleGoogle Scholar
  5. Chou AJ, Gorlick R. Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev Anticancer Ther. 2006;6:1075–85.View ArticlePubMedGoogle Scholar
  6. Wang Y, Teng JS. Increased multi-drug resistance and reduced apoptosis in osteosarcoma side population cells are crucial factors for tumor recurrence. Exp Ther Med. 2016;12:81–6.PubMedPubMed CentralGoogle Scholar
  7. Fan XL, Cai GP, Zhu LL, Ding GM. Efficacy and safety of ifosfamide-based chemotherapy for osteosarcoma: a meta-analysis. Drug Des Devel Ther. 2015;9:5925–32.View ArticlePubMedPubMed CentralGoogle Scholar
  8. Su W, Lai Z, Wu F, Lin Y, Mo Y, Yang Z, et al. Clinical efficacy of preoperative chemotherapy with or without ifosfamide in patients with osteosarcoma of the extremity: meta-analysis of randomized controlled trials. Med Oncol. 2015;32:481.View ArticlePubMedGoogle Scholar
  9. Jian T, Xianbiao X, Yongqian W, Lili W, Bo W, Xian Z, Xuqi S, Mengqi W, Jianqiu K, Gang H, Junqiang Y, Jingnan S. Role of ifosfamide chemotherapy for patients with non-metastatic osteosarcoma: a meta-analysis with 1724 patients. Int J Clin Exp Med. 2016;9:12574–83.Google Scholar
  10. Zhuang Y, Wang K. Efficacy and safety of chemotherapy with or without ifosfamide in primary osteosarcoma treatment: a systemic review of randomized controlled trials. Int J Clin Exp Med. 2016;9:10434–42.Google Scholar
  11. Wang W, Wang ZC, Shen H, Xie JJ, Lu H. Dose-intensive versus dose-control chemotherapy for high-grade osteosarcoma: a meta-analysis. Eur Rev Med Pharmacol Sci. 2014;18:1383–90.PubMedGoogle Scholar
  12. Zhang FY, Tang W, Zhang ZZ, Huang JC, Zhang SX, Zhao XC. Systematic review of high-dose and standard-dose chemotherapies in the treatment of primary well-differentiated osteosarcoma. Tumour Biol. 2014;35:10419–27.View ArticlePubMedGoogle Scholar
  13. Wang WG, Wan C, Liao GJ. The efficacy of high-dose versus moderate-dose chemotherapy in treating osteosarcoma: a systematic review and meta-analysis. Int J Clin Exp Med. 2015;8:15967–74.PubMedPubMed CentralGoogle Scholar
  14. Yamamoto N, Tsuchiya H. Chemotherapy for osteosarcoma—where does it come from? What is it? Where is it going? Expert Opin Pharmacother. 2013;14:2183–93.View ArticlePubMedGoogle Scholar
  15. Wang G, Zhang Z, Yang M, Xu B, Gao Q, Yang X. Comparative proteomics analysis of human osteosarcoma by 2D DIGE with MALDI-TOF/TOF MS. J Bone Oncol. 2016;5:147–52.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.View ArticlePubMedPubMed CentralGoogle Scholar
  18. Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry. 2003;160:1209–22.View ArticlePubMedGoogle Scholar
  19. White IR, Barrett JK, Jackson D, Higgins JP. Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Res Synth Methods. 2012;3:111–25.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Li D, Wang T, Shen S, Cheng S, Yu J, Zhang Y, et al. Effects of fluroquinolones in newly diagnosed, sputum-positive tuberculosis therapy: a systematic review and network meta-analysis. PLoS One. 2015;10:e0145066.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Trinquart L, Chatellier G, Ravaud P. Adjustment for reporting bias in network meta-analysis of antidepressant trials. BMC Med Res Methodol. 2012;12:150.View ArticlePubMedPubMed CentralGoogle Scholar
  22. Zhang Y, Ren LF. Clinical analysis of the recombinant human endostatin combined with DIA in the treatment of osteosarcoma. Anti-tumor Pharmacy. 2013;3:368–71.Google Scholar
  23. Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016;17:1396–408.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Piperno-Neumann S, Le Deley MC, Redini F, Pacquement H, Marec-Berard P, Petit P, et al. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1070–80.View ArticlePubMedGoogle Scholar
  25. Bielack SS, Smeland S, Whelan JS, Marina N, Jovic G, Hook JM, et al. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 good response randomized controlled trial. J Clin Oncol. 2015;33:2279–87.View ArticlePubMedPubMed CentralGoogle Scholar
  26. Longhi A, Reif M, Mariani E, Ferrari S. A randomized study on postrelapse disease-free survival with adjuvant mistletoe versus oral etoposide in osteosarcoma patients. Evid Based Complement Alternat Med. 2014;2014:210198.View ArticlePubMedPubMed CentralGoogle Scholar
  27. Whelan JS, Jinks RC, McTiernan A, Sydes MR, Hook JM, Trani L, et al. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol. 2012;23:1607–16.View ArticlePubMedGoogle Scholar
  28. Zhao H, Yao Y, Wang Z, Lin F, Sun Y, Chen P. Therapeutic effect of pirarubicin-based chemotherapy for osteosarcoma patients with lung metastasis. J Chemother. 2010;22:119–24.View ArticlePubMedGoogle Scholar
  29. Chou AJ, Kleinerman ES, Krailo MD, Chen Z, Betcher DL, Healey JH, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer. 2009;115:5339–48.View ArticlePubMedPubMed CentralGoogle Scholar
  30. Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol. 2008;26:633–8.View ArticlePubMedGoogle Scholar
  31. Le Deley MC, Guinebretiere JM, Gentet JC, Pacquement H, Pichon F, Marec-Berard P, et al. SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007;43:752–61.View ArticlePubMedGoogle Scholar
  32. Meyers PA, Gorlick R, Heller G, Casper E, Lane J, Huvos AG, et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J Clin Oncol. 1998;16:2452–8.View ArticlePubMedGoogle Scholar
  33. Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997;350:911–7.View ArticlePubMedGoogle Scholar
  34. Link MP. The multi-institutional osteosarcoma study: an update. Cancer Treat Res. 1993;62:261–7.View ArticlePubMedGoogle Scholar
  35. Edmonson JH, Green SJ, Ivins JC, Gilchrist GS, Creagan ET, Pritchard DJ, et al. A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma. J Clin Oncol. 1984;2:152–6.View ArticlePubMedGoogle Scholar
  36. Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, et al. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol. 1984;2:617–24.View ArticlePubMedGoogle Scholar
  37. Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol. 1987;5:21–6.View ArticlePubMedGoogle Scholar
  38. Sweetnam DR. A trial of chemotherapy in patients with osteosarcoma (a report to the Medical Research Council by their Working Party on Bone Sarcoma. Br J Cancer. 1986;53:513–8.View ArticleGoogle Scholar
  39. Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfurst C, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988;6:329–37.View ArticlePubMedGoogle Scholar
  40. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voute PA, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992;10:1579–91.View ArticlePubMedGoogle Scholar
  41. Ivins JC, Ritts RE, Pritchard DJ, Gilchrist GS, Miller GC, Taylor WF. Transfer factor versus combination chemotherapy: a preliminary report of a randomized postsurgical adjuvant treatment study in osteogenic sarcoma. Ann N Y Acad Sci. 1976;277:558–74.View ArticlePubMedGoogle Scholar
  42. Jasmin C. Randomized trial of adjuvant chemotherapy in osteogenic osteosarcoma: comparison of altering sequential administrations of high doses of adriamycin, methotrexate, and cyclophosphamide with a 6-month administration of high-dose adriamycin followed by a low-dose semicontinuous chemotherapy. EORTC Osteosarcoma Working Party Group. Recent Results Cancer Res. 1978;68:28–32.Google Scholar
  43. Gilchrist GS, Ivins JC, Ritts Jr RE, Pritchard DJ, Taylor WF, Edmonson JM. Adjuvant therapy for nonmetastatic osteogenic sarcoma: an evaluation of transfer factor versus combination chemotherapy. Cancer Treat Rep. 1978;62:289–94.PubMedGoogle Scholar
  44. Burgers JM, van Glabbeke M, Busson A, Cohen P, Mazabraud AR, Abbatucci JS, et al. Osteosarcoma of the limbs. Report of the EORTC-SIOP 03 trial 20781 investigating the value of adjuvant treatment with chemotherapy and/or prophylactic lung irradiation. Cancer. 1988;61:1024–31.View ArticlePubMedGoogle Scholar
  45. Goorin AM, Schwartzentruber DJ, Devidas M, Gebhardt MC, Ayala AG, Harris MB, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol. 2003;21:1574–80.View ArticlePubMedGoogle Scholar
  46. Winkler K, Bielack S, Delling G, Salzer-Kuntschik M, Kotz R, Greenshaw C, et al. Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (study COSS-86). Cancer. 1990;66:1703–10.View ArticlePubMedGoogle Scholar
  47. Bacci G, Ferrari S, Tienghi A, Bertoni F, Mercuri M, Longhi A, et al. A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity. Eur J Surg Oncol. 2001;27:98–104.View ArticlePubMedGoogle Scholar
  48. Bacci G, Ruggieri P, Picci P, Mercuri M, Ferraro A, Tella G, et al. Intra-arterial versus intravenous cisplatinum (in addition to systemic Adriamycin and high dose methotrexate) in the neoadjuvant treatment of osteosarcoma of the extremities. results of a randomized study. J Chemother. 1996;8:70–81.View ArticlePubMedGoogle Scholar
  49. Bacci G, Picci P, Avella M, Ferrari S, Casadei R, Ruggieri P, et al. Effect of intra-arterial versus intravenous cisplatin in addition to systemic adriamycin and high-dose methotrexate on histologic tumor response of osteosarcoma of the extremities. J Chemother. 1992;4:189–95.View ArticlePubMedGoogle Scholar
  50. Krailo M, Ertel I, Makley J, Fryer CJ, Baum E, Weetman R, et al. A randomized study comparing high-dose methotrexate with moderate-dose methotrexate as components of adjuvant chemotherapy in childhood nonmetastatic osteosarcoma: a report from the Childrens Cancer Study Group. Med Pediatr Oncol. 1987;15:69–77.View ArticlePubMedGoogle Scholar
  51. Makley JT, Krailo M, Ertel IJ, Fryer CJ, Baum ES, Weetman RM, et al. The relationship of various aspects of surgical management to outcome in childhood nonmetastatic osteosarcoma: a report from the Childrens Cancer Study Group. J Pediatr Surg. 1988;23:146–51.View ArticlePubMedGoogle Scholar
  52. Bacci G, Gherlinzoni F, Picci P, Van Horn JR, Jaffe N, Guerra A, et al. Adriamycin-methotrexate high dose versus adriamycin-methotrexate moderate dose as adjuvant chemotherapy for osteosarcoma of the extremities: a randomized study. Eur J Cancer Clin Oncol. 1986;22:1337–45.View ArticlePubMedGoogle Scholar

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© The Author(s). 2017

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