Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Pautier (2022)

Type of study:

RCT (LMS-04 was a multicenter, open-label, randomized,

phase 3 superiority study)

Setting and country:

Patients included from 20 centers of the French Sarcoma Group (anticancer centers or hospitals with an oncological unit) in France.

Funding and conflicts of interest:

Funding: PharmaMar.

All authors declare no competing interests.

Inclusion criteria:

- Patients included had histologically confirmed diagnosis

by experts, -18 years or older, -eastern cooperative oncology group performance status of less than 2, -adequate haematological, liver, and cardiac functions.

Exclusion criteria:

-patients history of malignancy, -who were in complete remission for less than 3 years, -who had CNS metastases

N total at baseline: 150

Intervention: 76

Control: 74

Important prognostic factors²:

For example

Median age:

I: 64 (53-69)

C: 59 (52-68)

Sex:

I: 17/76 (22%) M

C: 21/74 (28%) M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Doxorubicin alone as firstline therapy for metastatic or unresectable leiomyosarcoma

(uterine or soft tissue).

Patients received doxorubicin (75 mg/m²) alone once every 3 weeks for up to six cycles via the central venous route per slow perfusion for 10–15 min. An injection of subcutaneous lenograstim (granulocyte-colony

stimulation factor) was given every day from day 3 to day 9. No maintenance treatment was allowed in the doxorubicin alone group.

Surgery for residual disease (primary tumor or

metastasis, or both) was allowed in both groups (except for progressive disease) after six cycles according to investigator decisions;

A maximum of two dose reductions for each drug were permitted.

Describe  control (treatment/procedure/test):

doxorubicin plus trabectedin followed by trabectedin alone in patients without progression (doxorubicin plus trabectedin group) as firstline therapy for metastatic or unresectable leiomyosarcoma

(uterine or soft tissue).

In the doxorubicin plus trabectedin group, patients

received doxorubicin (60 mg/m²) for 10–15 min via central

venous perfusion followed by a 3-h central venous

perfusion of 1·1 mg/m² trabectedin on day 1. Pretreatment

with 20 mg dexamethasone was administered 30 min

before trabectedin. An injection of pegfilgrastim (6 mg;

pegylated granulocyte-colony stimulation factor) was

administered on day 2 subcutaneously. Treatment was

administered every 3 weeks for a maximum of six cycles. Patients in the doxorubicin plus trabectedin group

without progression after six cycles of doxorubicin and

trabectedin (with or without surgery) received maintenance

trabectedin (1·1 mg/m²) via central venous perfusion for

3 h (even in the case of previous dose reductions of

trabectedin in the combined phase with doxorubicin) after premedication with intravenous dexamethasone (20 mg). Maintenance trabectedin was administered every 3 weeks

until disease progression or for a maximum period of

12 months of treatment (maximum 17 cycles in

maintenance therapy), whichever occurred first.

Surgery for residual disease (primary tumor or

metastasis, or both) was allowed in both groups (except for progressive disease) after six cycles according to investigator decisions;

A maximum of two dose reductions for each drug were permitted.

Length of follow-up:

48 months

Loss-to-follow-up: not reported

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival^d

I: 26 (34.2%)

C: 32 (43.2%)

progression free survival^b

12 months:

I: 16.0% (95% CI 9.4-25.9]

C: 50.7% [95% CI 39.5-61.9]

24 months:

I: 5.3% [95% CI 2.1-12.9]

C: 30.2% [95% CI 20.9-41.5]

Median PFS:

I: 6.2 months (95 % CI, 4.1 to 7.1)

C: 12.2 months (95% CI, 10.1 to 15.6)

Response rate, N (%)^c

Complete and partial

I: 10 (13%)

C: 27 (36%)  

(difference 23% [95% CI 10–37]; p=0·0009)

quality of life

not reported

safety (adverse events^a and toxicity^e)

Stopped treatment because of toxicity

I: 3 (4%)

C: 17 (23%)

Adverse events (grade 3-4) reported

I: 39 (52%)

C: 71 (96%)

-Conclusion: LMS-04 met its primary endpoint, identifying a statistically significant improvement in progression-free-survival with

the doxorubicin plus trabectedin combination compared with standard-of-care doxorubicin alone as a first-line treatment for metastatic leiomyosarcomas. This improvement was observed both in the uterine and the soft tissue populations.

Comments

-Clinical trial number registered.

-Funding: PharmaMar.

^a= adverse events assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events.

^b= progression free survival was defined as the time from random assignment until date of progression, established on the basis of RECIST criteria, or the date of death from any cause,whichever occurred first.

^c=   The response rate was defined as the proportion of patients with all complete or partial responses according to RECIST criteria. The response taken into consideration was the best response during the six induction cycles.

^d= Overall survival was defined as the time from the date of random assignment to the date of death from any cause.

^e= Because maintenance with trabectedin after six cycles of the combined therapy was a new method, the toxicity was

monitored in the first ten patients on maintenance in

group B and was discussed with the internal data safety

monitoring board.

Bui-Nguyen

 (2015)

Type of study:

randomized multicenter prospective dose-selection ( a multicenter, phase IIB study followed by a phase III study).

Setting and country:

Multiple centers in different countries such as United States, Austria, Belgium, Denmark, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Spain, Switzerland, United Kingdom

Funding and conflicts of interests:

Nicolas Penel declares receiving funding from

Pharmamar, Novartis, Bayer Healthcare, Roche, and

Janssen Cilag and discloses a consultant or advisory role

for Pharmamar and Bayer Healthcare. Jean Yves Blay

declares receiving research funding from and having a

consultant or advisory role with Pharmamar; and

Winetter TA van der Graaf declares receiving speaker’s

bureau from GlaxoSmithKline and receiving research

funding from GlaxoSmithKline and Novartis. All other authors declare no conflicts of interest.

Inclusion criteria:

- Eligible patients were >=18 years old,

- Had one of the

following histologically-confirmed advanced and/or metastatic STS of grades II/III and with progressive disease as assessed by the local investigator, 

- Patients had the presence of measurable disease according to response

evaluation criteria in solid tumors (RECIST 1.1),

- World Health Organisation (WHO) performance

status (PS) 0 or 1,

- Having adequate bone marrow (absolute

neutrophils count (ANC) >= 1.5 X 10⁹ /L,

- Hemoglobin

(HB) >= 9 g/dL or HB >= 5.6 mmol/L,

- Platelets

(PLT) P 100 >= 10⁹/L),

- Hepatic (bilirubin 6 ULN,

alanine aminotransferase (SGPT/ALT) and aspartate

aminotransferase (SGOT/AST) =< 2.5 X ULN) and renal (serum creatinine =< 1.5 X ULN) functions,

- Normal left ventricular ejection fraction (LVEF) assessed by echocardiography or multiple gated acquisition scan (MUGA),

- Alkaline phosphatase =< 2.5 X ULN and

albumin P 25 g/L. Additionally, - For women of childbearing potential and men

the use of an effective contraception was mandatory.

Exclusion criteria:

-Patient had received any anti-cancer therapy

including other systemic therapy, radiotherapy and surgery, within 28 days prior to treatment start. Additionally, main exclusion criteria included;                              -patients with central nervous system metastases or leptomeningeal tumor spread,

- history

of malignancies other than STS,

-patients with in situ carcinoma of the cervix,     -patients with resected incidental prostate cancer staged pT2 with Gleason score 66 and postoperative prostate-specific antigen (PSA) < 0.5 ng/ml) within the past

5 years.

N total at baseline: 133

Intervention: 43

Control T3h + T24h: 90

Important prognostic factors²:

For example

Age (y): Median (range)

I: 60 (24-77)

C T3h: 60 (34-84)

C T24h: 60 (23-78)

Sex:

I: 18 (41.9%) M

C T3h: 18 (38.3%) M

C T24h: 20 (46.5%)M

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Patients with advanced/metastatic soft tissue sarcoma receiving   doxorubicin hydrochloride 75 mg/m2 infusion on day 1 every 3 weeks. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

Describe  control (treatment/procedure/test):

Patients with advanced/metastatic soft tissue sarcoma

T3h investigational arm consisting of trabectedin

1.3 mg/m2 /3-hour intravenous infusion on day 1 every 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity;

(ii) T24h investigational arm consisting of trabectedin 1.5 mg/m2/24 hour intravenous infusion on day 1 every 3 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Length of follow-up:

Not specified. In article stated that; ‘’AEs were assessed every 6 weeks during the first 3 months

and every 12 weeks thereafter. After progression,

patients were followed-up every 12 weeks for survival.’’ And,

‘’Median follow-up per arm was: 7.8 months

(interquartile range (IQR) 5.4–10.3) doxorubicin,

8.0 months (IQR 6.4–11.3) T3h, and 7.9 months (IQR

5.7–11.3) T24h.

E.g. Overall survival (start date ‘June 2011 and August 2012’-the clinical cut-off date for analysis was 15th March 2013).’’

In the phase III trial – not this study, patients complete quality of life questionnaire (EORTC QLQ-C30 version 3) at baseline, at 6, 12, 24, and 36 weeks during study, and at the end of study.

After completion of study therapy, patients are followed up at 1 month, every 6 or 12 weeks until disease progression, and every 12 weeks thereafter.

Loss-to-follow-up: not reported

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome

Outcome measures and effect size (include 95%CI and p-value if available):

For the outcome measures: T3h and T24 h were added up.

Overall survival^c (N, %)

I: 33 (76.7%).

C: 64 (71.1%)

Progression-free survival^b:  (N, %)

6 months:

I: 16 (38%)

C: 32 (37%)

12 months

I:  8 (18%)

C:  15 (17%)

Median PFS^b

I: 5.5 months

C T3H: 2.8 months

C T24H: 3.1 months

(objective) response rate^a

I: 27 (62.8%)

C: 52 (57.8%)

Quality of life

Not reported

Safety (adverse events and toxicity) (Grade 3-4)^d

Nausea (N, %):

I: 2 (5.0%)

C: 8 (8.9%)

Febrile neutropeniaI:

I: 3 (7.5%)

C: 11 (12.2%)

Thrombocytopenia

I: 1 (2.5%)

C: 14 (15.6%)

Neutropenia

I: 23 (57.5%)

C: 41 (45.6%)

Fatigue

I: 2 (5.0%)

C: 6 (6.7%)

Toxicity  (N, %)

I: 1 (2.5%)

C: 15 (16.7%)

Conclusion:  Doxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic soft-tissue sarcoma (STS).

^c= Overall survival was determined from the date of randomization to the date of death, whatever

the cause. Patients still alive at the time of analysis were

censored at the date of their last follow-up.

^b=PFS, defined as the time

from random assignment until the date of either objective progression by RECIST 1.1, discontinuation of treatment or death from any cause.

^a=  disease control rates (stabilisation or partial/complete responses)

Response duration was determined from the time when measurement criteria were first met until the first date of objectively documented progression or death. Stable disease duration was measured in the subset of patients achieving at least stable disease, from the date of randomization until the criteria for progression were met. For patients without progression, response duration and stable disease duration were censored at the date of the last tumor assessment.

^d=  The most frequent grade 3–4 AE were haematologic.

Seddon (2017)

Type of study:

RCT phase 3

Setting and country:

Between Dec 3, 2010, and Jan 20, 2014, patients were recruited in 24 UK hospitals and one Swiss

Group for Clinical Cancer Research (SAKK) hospital.

Funding and conflicts of interests:

The GeDDiS trial was funded by Cancer Research UK (C2921/A11561),

with separate funding obtained from Sarcoma UK (SUK16.2015) to

support the pharmacogenomics studies described. Funding from Cancer

Research UK supported the central coordination of the trial.

Declaration of interests

BS has received honoraria and travel grants from Novartis, Pharmamar,

Ariad, Clinigen, Daiichi, and Lilly. SJS has received honoraria and travel

grants from Lilly Oncology, Pharmamar, and Pfizer. PJW has received

honoraria from Amgen, Bristol-Myers Squibb, Lilly, and Theradex, and

research grants from AstraZeneca, Pfizer, and Virtuu. CR has received

honoraria from Pfizer, GlaxoSmithKline, Novartis, and Astellas and a

research grant from Astellas. MM has received honoraria from Pharmamar and Pierre Fabre, and sponsorship for conferences from

Roche and Bristol-Myers Squibb. NA has received sponsorship and

funding for conferences from Pharmamar and Roche. SB has received

grants from AstraZeneca and professional fees from Biocompatibles.

JW, ML, FC, ZW, CB, GJV, DJ, KK, RT, SF, SN, and H-MD declare no

competing interests

Inclusion criteria:

-at least 13 years old (with the aim to encourage participation

of the teenage and young adult population), -with

histological confirmation of high-grade advanced softtissue sarcoma (defined as Trojani grade 2 or 3), measurable disease according to the Response Evaluation

Criteria In Solid Tumors version 1.1 (RECIST 1.1), -evidence of disease progression in the previous 6 months

(defined as radiological progression when comparing current imaging to a previous disease assessment done

within the previous 6 months; clinical progression was

accepted in patients for whom there were concerns

regarding treatment delays incurred by awaiting

radiological disease progression, on discussion with the

chief investigator), -no previous chemotherapy for

sarcoma, -no previous doxorubicin for any previously

treated cancer, -WHO performance status 0–2, -a life

expectancy of at least 3 months, -patients were required to

have adequate organ function (absolute neutrophil count

≥1·0×10⁹ per L; platelet count ≥100×10⁹ per L; bilirubin

≤1·5×upper limit of normal [ULN]; aspartate transaminase, alanine transaminase, or both ≤3·0×ULN;

alkaline phosphatase ≤3·0×ULN [patients were eligible

with a higher alkaline phosphatase concentration if this

was shown to be due to bone isoenzyme]; measured or

calculated creatinine clearance ≥30 mL/min; and cardiac

ejection fraction within local normal limits), and -tumor

tissue was required to be available for central review.

Exclusion criteria:

- Patients were excluded from the trial if they had alveolar

soft part sarcoma, gastrointestinal stromal tumor, -Ewing’s sarcoma, alveolar or embryonal rhabdomyosarcoma,

desmoplastic small round cell tumor, extraskeletal myxoid

chondrosarcoma, dermatofibrosarcoma protuberans,

malignant mixed mesodermal tumor or carcinosarcoma

of the uterus, smooth muscle tumors of uncertain

malignant potential of uterus, known active or uncontrolled

brain metastases, active uncontrolled infection, or grade 3

or 4 peripheral neuropathy, -pregnant or lactating women

were excluded, -patients with a history of malignancy

other than sarcoma (exceptions included basal or squamous

cell carcinoma of the skin and carcinoma in situ of the

cervix, breast, or prostate) within 3 years before enrolment were also excluded.

N total at baseline: 257

Intervention: 129

Control: 128

Important prognostic factors²:

For example

Age±SD:

I (Dox): 56 (49.4-64.0)

C: 55 (45.6-64.0)

Sex:

I (DOX): 50 (39%) M

C: 51 (40%) M

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Patients with advanced

or metastatic soft-tissue sarcoma received six cycles of intravenous doxorubicin 75 mg/m² on day 1 every 3 weeks. Dose

capping according to sites’ local policy and dose banding to

within plus or minus 5% of the calculated dose were

permitted. Pre-treatment and post-treatment anti-emetics

were given for all trial treatments, as per local anti-emetics policy. In both groups, patients completed up to six cycles of treatment in the absence of disease progression, intolerable side-effects, or withdrawal of consent.

Describe  control (treatment/procedure/test):

Patients with advanced

or metastatic soft-tissue sarcoma received intravenous gemcitabine

675 mg/m² on days 1 and 8 and intravenous docetaxel 75 mg/m² on day 8 every 3 weeks. Pre-treatment and post-treatment anti-emetics

were given for all trial treatments, as per local anti-emetics

policy. In both groups, patients completed up to six cycles

of treatment in the absence of disease progression,

intolerable side-effects, or withdrawal of consent.

Length of follow-up:

24 weeks after date of randomization.

Loss-to-follow-up: 3

Intervention: 1

N (%)

Reasons (describe) did not start treatment after allocation to intervention group

Control: 2

N (%)

Reasons (describe)

Did not start treatment after allocation to intervention group

Incomplete outcome

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival^b

At 24 weeks:

I: 86.8% (95% CI 79.6–91.6)

C: 82.6% (95% CI 74.8–88.2)

Progression-free survival^a

At 12 weeks:

I: 72.1% [95% CI 63.5–79.0]

C: 63.8% [95%CI 54.8–71.5]

At 24 weeks:

I: 46.3% [95% CI 37.5–54.6]

C: 46.4% [95% CI 37.5–54.8]

(objective) response rate^d

I: 25 (19%)

C: 25 (20%)

Quality of life ^eInsufficient questionnaires

were returned to be able to assess quality of life at 18 weeks and 24 weeks (83 [32%] of 257 questionnaires were returned at both 18 weeks and 24 weeks, compared with

132 [51%] of 257 at 12 weeks.

Safety (adverse events^c and toxicity)

Grade 3-4 adverse events

Febrile neutropenia

I: 27 [17%]

C: 15 [12%]

Fever

I: 18 (12%)

C: 19 (15%)

Neutropenia

I: 22 (14%)

C: 10 (8%)

Comments:

-conclusion: In this randomized phase 3 trial of gemcitabine and

docetaxel compared with doxorubicin as first-line therapy

for locally advanced or metastatic soft-tissue sarcoma, we

found no significant difference between the two treatment

groups for the primary endpoint of the proportion of

patients alive and progression free at 24 weeks.

-registered clinical trial

-^a=time from randomization to date of progression or death from

any cause, whichever occurred first

-^b=time from randomization to date of death from any cause

-^c= Adverse events were assessed according to the

National Cancer Institute Common Terminology

Criteria for Adverse Events (CTCAE) version 4.03. The three most common serious adverse events were febrile neutropenia, fever, and neutropenia

-^d=Response was

assessed by local investigators according to RECIST 1.1 (complete or partial response).

-^e=Quality of life was assessed at baseline and at 12, 18,

and 24 weeks after randomization, using the EORTC QLQ-C30, and fatigue-specific FA-13 questionnaires.

Grunwald (2020)

Type of study:

RCT

Setting and country:

Between October 2012 and march 2016, a total of 120 eligible patients were enrolled.

Funding and conflicts of interests:

Conflict of interest: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.

Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. 

Funding:   sponsored by the Hanover Medical School and was executed

within the academic network of the Sarcoma Working

Group of the German Studies Group for Medical Oncology in cooperation with the German Interdisciplinary

Sarcoma Group and a site in Belgium

Inclusion criteria:

-  progressive advanced nonresectable or metastatic measurable

disease of chemotherapy-sensitive STS subtypes in patients with local histopathology and age 60 years or older.

Main eligible histologies were fibrosarcoma, pleomorphic high-grade sarcoma, leiomyosarcoma, liposarcoma,

alveolar or pleomorphic rhabdomyosarcoma, vascular

sarcoma, synovial sarcoma not otherwise specified, and

malignant peripheral nerve sheath tumors., -Adequate

organ functions, -ECOG PS 0 to 2, and -availability of archived tumor tissue were additional criteria, -brain metastases

were allowed if they were adequately treated, -previous

anthracycline-based chemotherapy with curative intent

was permitted if it had been completed more than 6 months

before recurrence.

Exclusion criteria:

N total at baseline: 120

Intervention: 39

Control: 81

Important prognostic factors²:

For example

Age (Median age, years (range)):

I: 70 (60-81)

C: 72 (60-88)

Sex:

I: 17 (43.6%) M

C: 44 (54.3%) M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Elderly patients with STS. Doxorubicin was given at

75 mg/m² once every 3 weeks intravenously for up to  6 cycles. Dose modifications consisted of decrements of doxorubicin to 60 mg/m. Concomitant medications were

used according to local standards, and granulocyte

colony-stimulating factor (G-CSF) was permitted as a  prophylactic.

Describe  control (treatment/procedure/test):

Elderly patients with STS

Pazopanib was given at 800 mg once per day until

progression or intolerance. Dose modifications consisted of 200 mg

decrements for pazopanib.  Concomitant medications were used according to local standards, and granulocyte

colony-stimulating factor (G-CSF) was permitted as a  prophylactic.

Length of follow-up:

Imaging was performed at baseline, at

weeks 6, 12, 19, and 26, and every 12 weeks thereafter.

Loss-to-follow-up:

Missing measures at baseline were

replaced by assessment on day 1 before therapy was initiated. No other imputations of data were performed.

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival (12 weeks)

I: 14.3 months (95% CI 8.3 to 25.9)

C: 12.3 (95% CI 8.7 to 19.8)

Progression-free survival ^a

12 weeks

I: 44% (95% CI 28% to 59%)

C: 53% (95% CI, 42% to 64%)

(P=.298)

26 weeks

I: 23% (95% CI 10% to 36%)

C: 26% (95% CI 16% to 35%)

(P=.738).

(objective) response rate^d

I: 6 (15.4%)

C: 10 (12.3%)

Quality of life ^b

Global health status

I: 53.6 (45.8 to 61.4)

C: 57.1 (51.7 to 62.4)

Safety (adverse events^c and toxicity)

Treatment-related severe adverse events

I: 10 (27.0%)

C: 27 (33.3%)

(p=.4933)

Any event (Grade 3-4)

I: 35 (94.6%)

C: 66 (81.5%)

Comments:

-conclusion:  Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the

first-line treatment of STS in patients age 60 years or older.

-clinical trial number registered

-^a=  PFS defined as the time from random assignment to objective tumor progression or death as a result of any cause

- ^b= using the EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire; the  (EORTC

QLQ-C30) was used to assess global HR-QoL in patients

with cancer (not specified scale scoring).

^c= the proportion of patients with at least one severe AE.   AEs were classified according to Common Terminology Criteria for Adverse Events (CTCAE 4.0).

^d= partial plus complete response rates

Martin-Broto (2016)

Type of study:

RCT (phase 2 study)

Setting and country: The study was performed within 24 Spanish centers and one Portuguese

Center. Between November 2009 and October 2012, 115 patients were enrolled in the trial.

Funding and conflicts of interests:

Authors’ disclosures of potential conflicts

of interest are found in the article online at

www.jco.org.

The study was sponsored by the Spanish Group for Research on Sarcoma. Partially supported by Grant TRA-050,

awarded by the Spanish Ministry of

Health. PharmaMar Company supported

shipping and expenses for clinical

research organization management of the trial.

Inclusion criteria:

-Patients with locally advanced nonresectable or metastatic

STS; -measurable disease according to RECIST 1.0 criteria; and histologic

subtypes including undifferentiated pleomorphic sarcoma, liposarcoma,

leiomyosarcoma, synovial sarcoma, myxofibrosarcoma, malignant peripheral nerve sheath tumor, fibrosarcoma, angiosarcoma, epithelioid

hemangioendothelioma, solitary fibrous tumors, epithelioid sarcoma, and

unclassified sarcoma, -Additional criteria were Eastern Cooperative Oncologic Group performance status (ECOG PS) of 0 to 2 (category 2 was

ruled out after an early amendment), -age older than 18 years, -and adequate

bone marrow, renal, and liver function, -Normal cardiac function with left

ventricular ejection fraction had to be >= 50% by echocardiogram or

multigated acquisition scan (using the same method at baseline and after six cycles).

Exclusion criteria:

-previous chemotherapy administration, -previous radiation therapy involving the target lesions, central

nervous system metastases, and- women with a positive pregnancy test.

N total at baseline: 113

Intervention: 59

Control: 54

Important prognostic factors²:

For example

median age, years (range):

I: 52 (20-68)

C: 53 (18-73)

Sex:

I: 30 (51% M)

C: 32 (59% M)

Groups comparable at baseline? Yes, except for some imbalances in the distribution of locally advanced tumors and leiomyosarcomas or liposarcomas which were more frequently allocated in the intervention arm.

Describe intervention (treatment/procedure/test):

Doxorubicin

was administered at 75 mg/m². Both schemes were administered for six cycles in the absence of progression or unacceptable toxicity.

Describe  control (treatment/procedure/test):

Trabectedin was

administered first, because this was considered to be the most cytotoxic

sequence observed in preclinical studies. Patients received trabectedin

as a 3-hour infusion through a central port at 1.1 mg/m²

, followed by

doxorubicin 60 mg/m2

, administered as a 20-minute infusion. In addition to routine antiemetic, patients received intravenous dexamethasone

30 minutes before the trabectedin; 4 mg of dexamethasone was administered orally 24 and 12 hours before the trabectedin. Filgrastim was administered

to all patients.

Length of follow-up:

Median follow-up lengths 13 months, further not specified.

Loss-to-follow-up: not reported

Intervention: 3

N (%)

Reasons (describe)

Control:

N (%) 1

Reasons (describe)

Incomplete outcome

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival

Median OS:

I: 13.7 months

C: 13.3 months

(HR, 1.21, 95% CI, 0.77 to 1.92).

Progression-free survival

At 1 year

I: 20% (95% CI, 9 to 30)

C: 15% (95% CI, 5 to 25)

Median PFS

I: 5.5 months

C: 5.7 months

(HR 1.16, 95 % CI, 0.79 to 1.71)

Partial response rate ^b

Partial response:

I: 10 (17%)

C: 9 (17%)

Stable disease:

I: 27 (47%)

C: 28 (53%)

Progressive disease:

I: 21 (36%)

C: 16 (30%)

Quality of life

Not reported

Safety (adverse events and toxicity)^a

Grade 3 or 4 thrombocytopenia

I: 1 (2%)

C: 10 (18%)

Neutropenia

I: 36 (61%)

C:54 (100%)

Nausea

I: 2 (3%)

C: 8 (15%)

Stomatitis;

I: 0 (0%)

C: 8 (15%)

Febrile neutropenia

I: 24 (41%)

C: 32 (59%)

Conclusion: trabectedin plus doxorubicin did not show superiority over doxorubicin alone as first-line treatment

of advanced STS.

^a= measured in accordance with the National Cancer Institute’s common Terminology Criteria for Adverse Events version 3.0.

  ^b= tumor response according to RECIST

Judson (2014)

Type of study:

RCT

Setting and country:

Between April 30, 2003, and May 25, 2010, at 38 hospitals in ten countries (Belgium, Canada,

Denmark, France, Germany, Netherlands, Slovakia, Spain,

Switzerland, UK).

Funding and conflicts of interests:

Funding: Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.

Declaration of interests:  We have no competing interests.

Inclusion criteria:

-Patients had to have

histological evidence of high-grade soft-tissue sarcoma

(grades 2–3) according to the Federation Nationale des Centres de Lutte Contre le Cancer grading system when

applicable and radiological evidence of measurable

unresectable or metastatic disease progression within 6

weeks before treatment according to RECIST (version

1.0), -patients with the following tumor

types: undifferentiated pleomorphic sarcoma, myxoid or

round cell liposarcoma, pleomorphic liposarcoma and dedifferentiated liposarcoma, pleomorphic rhabdomyosarcoma, synovial sarcoma, myxofi bro sarcoma,

fibrosarcoma, leiomyo sarcoma, angiosarcoma, malignant

peripheral nerve sheath tumor, epithelioid sarcoma,

unclassified high-grade sarcoma (not otherwise specified) were included, -patients had to be age 18–60 years, -patients had to have a WHO performance status of 0 or 1, -absolute

neutrophil count more than 2 × 10⁹ cells per L, -more than 100 × 10⁹ platelets per L, serum creatinine of 120 μmol/L or less or calculated creatinine clearance (Cockroft and Gault

method) more than 65 mL/min, - patients had to have two functioning kidneys, bilirubin 30 μmol/L or less, and albumin more than

25 g/L, -patients also had to have a normal (according to

local assessments) left ventricular ejection fraction by

multiple gated acquisition scan or echocardiogram, -women of child-bearing potential had to take adequate contraceptive measures and have a negative pregnancy test

within 7 days of study entry.

Exclusion criteria:

Patients with -gastrointestinal stromal tumor, mixed mesodermal

tumor, chondrosarcoma, malignant mesothelioma,

neuroblastoma, osteosarcoma, Ewing’s sarcoma, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, and alveolar soft part sarcoma were excluded, also having other severe illness (eg, psychosis

or previous history of cardiovascular disease), symptomatic

or known CNS metastases, previous or concurrent second

primary malignant tumors (except adequately treated insitu carcinoma of cervix or basal cell carcinoma) was an exclusion criteria, - patients who had had radiotherapy to the sole

available index lesion or those who had received

chemotherapy for advanced disease, although previous

adjuvant chemotherapy (preoperative or postoperative)

was allowed if disease progression had not occurred within

6 months of completion.

N total at baseline: 455

Intervention: 228

Control: 227

Important prognostic factors²:

For example

Age (Median (IQR; years);

I: 48 (41-55)

C: 47 (39-54)

Sex:

I: 103 (45%M)

C: 114 (505M)

Groups comparable at baseline? yes

Describe intervention (treatment/procedure/test):

Patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma. Patients assigned to receive doxorubicin alone were given doxorubicin 75 mg/m² by intravenous bolus on day 1 or 72 h continuous intravenous infusion. Treatment was repeated every 3 weeks until

disease progression or unacceptable toxic effects, up to a  maximum of six cycles.

Describe  control (treatment/procedure/test):

Patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma.

Those assigned to

receive intensified doxorubicin and ifosfamide received doxorubicin 25 mg/m² per day on days 1–3 and ifosfamide (2·5 g/m² per day, days 1–4) plus mesna (0·5 g/m² by intravenous bolus before ifosfamide, 1·5 g/m² concurrent with ifosfamide, and 1 g/m² orally

2 h and 6 h after completion of ifosfamide infusion),

followed by pegfilgrastim (6 mg subcutaneously, day 5;

appendix). Treatment was repeated every 3 weeks until disease progression or unacceptable toxic eff ects, up to a maximum of six cycles.

Length of follow-up:

After treatment progression, patients were followed up

every 12 weeks for survival.

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome

Outcome measures and effect size (include 95%CI and p-value if available):

Overall survival^b

Median overall survival

I: 12.8 months (95% CI 10.5–14.3)

C: 14.3 months (95% CI, 12.5-16.5 months)

(HR: 0.83, 95% CI 0.67-1.03).

Progression-free survival^c

Median PFS

I: 4.6 months [95% CI 2.9–5.6]

C:7.4 months [95% CI 6·6–8·3])

(HR 0.74, 95% CI 0.60–0.90).

(objective) response rate^d

I: 31 (14%)

C: 60 (26%)

Quality of life

Not reported

Safety (adverse events and toxicity^a)

Grade 3 and 4 toxic effects

Leucopenia

I: 40 (18%)

C: 97 (43%)

Neutropenia

I: 83 (37%)

C: 93 (42%)

Febrile neutropenia

I: 30 (13%)

C: 103 (46%)

Anaemia

I: 10 (4%)

C: 78 (35%)

Thrombocytopenia

I: 1 (<1%)

C: 75 (33%)

Conclusion:

We found no improvement in overall survival from the

administration of intensifi ed combination chemotherapy

with doxorubicin plus ifosfamide compared with

doxorubicin alone.

^a=side-effects of treatment were graded according to International Common Toxicity Criteria.

^b=Overall survival was computed from the date of

randomization to the date of death from any cause. Patients alive at the time of the analysis were censored at their last follow-up date.

^c= Progression-free survival was computed from the date of randomization to the first

recorded date of progression or death. Patients alive and

progression-free at the time of analysis were censored at

the date of last follow-up.

^d= complete plus partial responses

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Pautier (2022)

Definitely yes;

Reason:

Investigators identified and enrolled the patients into the

trial. Patients were randomly assigned (1:1) into the

doxorubicin alone group or the doxorubicin plus

trabectedin group by means of an interactive web response

system. Random assignment

was stratified by tumor location (uterus vs soft tissue)

and disease (locally advanced vs metastatic). Permuted

blocks of different sizes (from two to six) were used to allocate the patients to each treatment group.

Probably yes;

Reason:

The random

assignment request was signed by the investigator and

sent by fax to the data center. The data manager randomly assigned each patient using the online TENALEA randomization software version 2.2.

A report with each randomization

number and a group

assignment was then provided to the investigator. Because

of the open-label trial design, the patients, investigators,

and the study sponsor were not masked to the study treatment.

Probably yes;

Reason:

Randomization and analysis of data blinded: the tumor response was assessed by the investigator

using RECIST version 1.1 (using thoracic and abdominalpelvic

CT scans or MRI). For the primary endpoint

analysis (progression-free survival), a blinded radiographic central review, based on imaging only (using

thoracic and abdominal-pelvic CT scans or MRI), was

performed at the Gustave-Roussy hospital (before the

database was locked, ie, no further data were added) to

confirm progression.

The primary endpoint  was progression-free survival assessed by blinded independent

central review and according to Response Evaluation Criteria in Solid Tumors 1.1 criteria.

Patients, health care providers; blinding not reported

Probably yes;

Reason:

Efficacy analyses were

performed on all randomly assigned patients, based on the intention-to-treat principle.

Definitely yes;

Reason:

All relevant outcomes were reported;

Probably yes;

Reason:

Funding: PharmaMar.

overall survival

Low concerns of bias

progression free survival

Low concerns of bias

response rate

Low concerns of bias

quality of life

not reported

safety

adverse events

Low concerns of bias

toxicity

Low concerns of bias

Bui-Nguyen  (2015)

Probably yes;

Reason:

Parallel assignment to the treatment groups.

Eligible patients were randomized in a 1:1:1 ratio: (two intervention groups and one control).

The randomization was stratified by institution, age at registration (</>=60 years) and presence of liver

metastases (no/yes).

Definitely no;

Reason:

Allocation sequence not specified/reported. 

Probably no;

Reason:

Open label study;  thus no masking/blinding.

Perhaps data analysts were blinded; ‘’The results of the planned interim analysis at the end of the first step were reviewed by an independent data

monitoring committee on 4th July 2013’’.

May be assumed that patients were not aware about the type of chemotherapy they received, however unsure (not reported). ‘’All infusions were

administered with a central venous catheter’’, and ‘’The use of growth factors

was left to the discretion of the investigator’’.

Definitely no;

Reason:

Not reported.

Probably yes;

Reason:

Quality of life assessment was reported in study protocol, however findings regarding QOL not reported in this study (Bui-Nguyen, 2015).

Probably no;

Reason:

Results of step 1: none of the experimental arms fulfils expectations and the study will not continue as a phase III.

Overall survival

High concerns of risk

PFS

High concerns of risk

Response rate

High concerns of risk

QOL

Not reported

Adverse events

High concerns of risk

Seddon (2017)

Probably yes;

Reason:

Patients were randomly allocated in a 1:1 ratio to receive

either gemcitabine and docetaxel or doxorubicin.

Patients were stratified by age (≤18 years vs

>18 years) and histological subtype (uterine

leiomyosarcoma vs synovial sarcoma vs pleomorphic

sarcoma vs other eligible sarcomas). We chose these

specific histological strata on the basis of available

evidence at the time of trial design suggesting potential

differential disease response to chemotherapy in the

different strata.

Probably yes;

Reason:

Treatment was assigned centrally by computer at the

Cancer Research UK and University College London

Cancer Trials Centre (UCL CTC; London, UK) using a

minimisation algorithm incorporating a random

element. Treatment allocation was

communicated electronically to the site randomizing the

patient. Treatment allocation was not masked

Probably no;

Reason:

Not reported. Solely stated that all  pathology samples were reviewed by a single

histopathologist (RT) (before randomization). During trial, not reported whom was blinded.

Probably yes;

Reason:

ITT performed, solely for outcome measure adverse events – solely those patients  who received at least one dose of their randomly

assigned treatment (n=254) were analysed. Three were excluded due to not receiving the intervention/control.

Probably no;

Reason:

Regarding outcome measure quality of life ‘’Insufficient questionnaires

were returned to be able to assess quality of life at 18 weeks and 24 weeks (83 [32%] of 257 questionnaires were returned at both 18 weeks and 24 weeks, compared with

132 [51%] of 257 at 12 weeks.’’

Probably yes;

/

Overall survival

Some concerns of risk

PFS

Some concerns of risk

Response rate

Some concerns of risk

QOL

Not reported

Adverse events

Some concerns of risk

Grunwald (2020)

Probably yes;

Reason:

A randomization list was prepared before the study

for permuted blocks of variable sizes and a  2:1 randomization ratio for comparing pazopanib and doxorubicin. Randomization was stratified by ECOG PS of 0 to 1 versus 2

and liposarcoma histology.

Definitely no;

Reason:

Concealment of allocation not reported.

Probably no;

Reason:

Blinding not reported.

Probably no;

Reason:

Loss to follow-up not reported. 

Definitely yes;

Reason:

All relevant outcomes were reported

Probably no;

Reason:

Overall survival

High concerns of risk

PFS:

High concerns of risk

Response rate

High concerns of risk

QOL

High concerns of risk

Adverse events

High concerns of risk

Martin-Broto (2016)

Probably yes;

Reason:

Patients were stratified according to metastatic disease-free interval

(=< 12 months or > 12 months). Patients were randomly assigned to each arm, and central pathologic review was planned for all patients.

Definitely no;

Reason:

Concealment of allocation not reported.

Probably no;

Reason:

Not reported, solely stated that ‘’The participants were blindly assessed by an expert pathologist in the field of sarcoma (R.R.) for both diagnostic confirmation and translational

purposes.’’

Probably no;

Reason:

Loss to follow-up small (n=3 and n=1 in respectively the intervention and control group).

Definitely yes;

Reason:

All relevant outcomes were reported;

Probably yes;

Reason:

PharmaMar Company supported shipping and expenses for clinical research organization management of the trial.

Overall survival

High concerns of risk

PFS:

High concerns of risk

Response rate

High concerns of risk

QOL

Not reported

Adverse events

High concerns of risk

Judson (2014)

Definitely yes;

Reason:

The randomization sequence was generated

by an online randomized trial access system based on the

minimisation method. Randomization was stratified by center, performance status (0 vs 1), age (<50 years vs ≥50 years), liver metastases (present vs absent), and

histological grade (2 vs 3).

Probably no;

Reason:

Allocation sequence not reported, solely stated that ‘’A panel of specialist sarcoma pathologists did a mandatory

central pathology review but patients were enrolled on the

basis of local diagnosis.’’ And ‘’ Neither patients nor

investigators were masked to treatment allocation.’’.

Probably no;

Reason:

Not reported

Probably no;

Reason:

Eight patients did not start treatment and three did not receive the allocated

treatment (figure 1). As a result, the safety population

consisted of 447 patients and the per-protocol population

of 432 patients.

Definitely yes;

Reason:

All relevant outcomes were reported;

Probably no;

Overall survival

Some concerns of risk

PFS:

Some concerns of risk

Response rate

Some concerns of risk

QOL

Not reported

Adverse events

Some concerns of risk