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Adjuvant chemotherapy for advanced endometrial cancer

  1. Khadra Galaal1,*,
  2. Mansour Al Moundhri2,
  3. Andrew Bryant3,
  4. Alberto D Lopes1,
  5. Theresa A Lawrie4

Editorial Group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

Published Online: 15 MAY 2014

Assessed as up-to-date: 11 NOV 2013

DOI: 10.1002/14651858.CD010681.pub2


How to Cite

Galaal K, Al Moundhri M, Bryant A, Lopes AD, Lawrie TA. Adjuvant chemotherapy for advanced endometrial cancer. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD010681. DOI: 10.1002/14651858.CD010681.pub2.

Author Information

  1. 1

    Princess Alexandra Wing, Royal Cornwall Hospital, Gynaecological Oncology, Truro, UK

  2. 2

    College of Medicine and Health Sciences and Sultan Qaboos University Hospital, Medical Oncology Unit, Department of Medicine, Al-Khod, Oman

  3. 3

    Newcastle University, Institute of Health & Society, Newcastle upon Tyne, UK

  4. 4

    Royal United Hospital, Cochrane Gynaecological Cancer Group, Bath, UK

*Khadra Galaal, Gynaecological Oncology, Princess Alexandra Wing, Royal Cornwall Hospital, Truro, TR1 3LJ, UK. Khadra.Galaal@rcht.cornwall.nhs.uk. khadragalaal@yahoo.co.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 15 MAY 2014

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Characteristics of included studies [ordered by study ID]
GOG 122

MethodsMulticentre parallel RCT conducted in the USA. Recruitment between 1992 and 2000.


Participants422 women were enrolled (396 assessable).

Women with FIGO stage III or IV endometrial cancer of any histology. CRS included hysterectomy and BSO, surgical staging, and tumour resection to a maximum of 2 cm residual tumour at a single site. Nodal sampling was optional for women with stage III or IV by clinical or surgical criteria.

Women were ineligible if they had recurrent disease; liver, lung or haematogenous metastases; or a history of chemotherapy or radiotherapy.

Protocol treatment was to be started within eight weeks of CRS.


InterventionsArm 1 (194 women): doxorubicin (60 mg/m2) and cisplatin (50 mg/m2) every three weeks for seven cycles, followed by one cycle of cisplatin (AP)

Arm 2 (202 women): whole body irradiation (WAI); 30 Gy in 20 fractions with a 15 Gy boost


OutcomesPFS (5-year), OS, toxicity, QoL


NotesBaseline characteristics overall, were: 50% endometrioid tumours; 27% stage IV; 52% grade 3; 86% absent or microscopic residual disease; 95% performance status 0-1; median age 63 years. Risk factors for poorer prognosis were slightly skewed in favour of the WAI arm.

Median follow-up was 74 months. WAI group was evaluated weekly during WAI; AP group was evaluated before each AP cycle (every three weeks). After protocol treatment, women were evaluated every three months for two years, then every six months.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBalanced block randomisation in ratio 1:1; balanced assignment within each institution.

Allocation concealment (selection bias)Low riskAllocation was concealed until telephone registration with verification of eligibility.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskAn unblinded trial; however, performance bias is unlikely to have an impact on survival data.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPathology materials of primary and progressive disease were reviewed by the GOG Pathology Committee. A central review of eligibility data was conducted by the GOG Gynecologic Oncology Committee without knowledge of outcome.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data was < 10%.

Selective reporting (reporting bias)Unclear riskAll expected outcomes were reported. Adjusted results were reported which increased the magnitude of the effect in favour of chemotherapy.

Other biasLow riskA well-designed and conducted trial. ITT analyses.

GOG 184

MethodsMulticentre parallel RCT conducted in the USA. Recruitment from 2000 to 2004.


Participants659 women were enrolled.

Women with FIGO stage III/IV endometrial cancer of any histology, with disease limited to the pelvis and abdomen were eligible.Women were not eligible if they had recurrent disease, previous radiotherapy, previous malignancy within five years, serious comorbidity, and survival expected to be < three months.

All women received CRS and volume-directed radiation to pelvic lymph nodes, with or without para-aortic lymph nodes. CRS included hysterectomy and BSO. Radiotherapy was initiated within eight weeks of CRS.

After the results of GOG 122 were known, women with stage IV were no longer eligible as GOG 122 showed a significant benefit with adjuvant chemotherapy after surgery in this group, compared with adjuvant radiotherapy.


InterventionsChemotherapy was initiated within eight weeks of radiotherapy.

Arm 1 (282 women) = Day 1:cisplatin (50 mg/m2)/doxorubicin (45 mg/m2)/Day 2:paclitaxel (160 mg/m2), every 21 days for six cycles. G-CSF given to all women.

Arm 2 (270 women) = Day 1:cisplatin (50 mg/m2)/doxorubicin (45 mg/m2) every 21 days for six cycles. G-CSF initially optional, then in 2002 it was included in the control regimen for all women.


OutcomesRFS (3 year), OS, loco-regional recurrence, distant recurrence, adverse events


NotesOS data were not mature at the time of the 2009 report. We were unsuccessful in obtaining these mature data from the investigators.

Baseline characteristics overall, were: 69% endometrioid tumours; 12% stage IV; 41% grade 3; 90% absent or microscopic residual disease; 99% performance status 0-1; median age 58 years. Median follow-up was 47 and 46 months for the trial arms, respectively.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral random assignment by the GOG Statistical and Data Center after CRS and radiotherapy. Randomisation was in balanced blocks.

Allocation concealment (selection bias)Low riskRandomisation was concealed from institutions and patients until centrally allocated.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskAn unblinded trial; however, performance bias is unlikely to have an impact on survival data.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskCentral review of data and pathology materials was performed and a central review of eligibility data was conducted by the GOG Gynecologic Oncology Committee without knowledge of outcome.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data was < 10%.

Selective reporting (reporting bias)Low riskAll expected outcomes were reported.

Other biasLow riskA well-designed and conducted trial. ITT analyses.

Maggi 2006

MethodsMulticentre parallel RCT conducted in Italy. Recruitment from 1990 to 1997.


Participants345 women were randomised after surgical staging. 340 were analysed.

Inclusion criteria were high-risk endometrial cancer defined as stage IcG3 and stage IIG3 with > 50% myometrial invasion, or stage III.

All women underwent CRS as primary treatment (TAH-BSO, with or without partial colpectomy and pelvic and lumbo-aortic lymph node sampling). Protocol treatment was started within 30 days of surgery.


InterventionsArm 1: doxorubicin (45 mg/m2), cisplatin (50 mg/m2) and cyclophosphamide (600 mg/m2) every four weeks for five cycles.

Arm 2: external beam radiation therapy (45-50 Gy on a five days per week schedule).


Outcomes3, 5 and 7-year OS and PFS; toxicity.


NotesRandomisation was stratified by stage of disease with approximately 26.5% stage I, 9% stage II and 64% stage III disease.

Baseline characteristics of the groups were similar overall, including stage: 57% grade 3, 72% had myometrial invasion > 50%, median age 62.5 years; residual disease not reported.

Median follow-up was 95.5 months. For the purposes of this review, we included only the stage III survival data which we obtained from the trial investigators via email on the 23/12/2013. We did not obtain separate stage III baseline data.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was carried out centrally by telephone and patients were stratified by institution and stage of disease".

Allocation concealment (selection bias)Low riskRandomisation was concealed from institutions and patients until centrally allocated.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskAn unblinded trial (blinding not possible due to the nature of the interventions).

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnblinded. Progression was assessed or detected by pelvic examination, pathological examination of vault smears, and annual chest radiographs. If progression was suspected, other diagnostic tests were performed.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data was < 10%.

Selective reporting (reporting bias)Low riskAll expected outcomes were reported.

Other biasLow riskA well-designed and conducted trial. ITT analyses.

Susumu 2008

MethodsMulticentre RCT conducted in Japan. Recruitment from 1994 to 2000.


Participants475 women were randomised but only 385 were analysed as 41 were found to be ineligible and 49 had non-endometrioid histology.

Inclusion criteria were age < 75 years, WHO performance status of 0-3, FIGO stage IC - IIIC with myometrial invasion > 50%. All women underwent CRS as primary treatment (TAH/BSO and, ideally, pelvic and paraaortic lymphadenectomy) and had no residual tumour. Patients were excluded if previously treated with surgery, chemotherapy or radiotherapy for another cancer.


InterventionsAll women received CRS. Treatment was initiated within four weeks of surgery.

Arm 1: adjuvant doxorubicin (40 mg/m2), cisplatin (50 mg/m2) and cyclophosphamide (333 mg/m2) every four weeks for three or more cycles.

Arm 2: adjuvant external beam radiation therapy (45-50 Gy on a five days per week schedule).


OutcomesFive year OS, PFS and toxicity


NotesRandomisation was not stratified by stage, however treatment groups had similar numbers of women with stage III disease (47 and 50 women in the radiotherapy and chemotherapy groups, respectively). Baseline characteristics of the groups were similar overall, including stage: 53% grade 3, 100% had myometrial invasion > 50%, 37% lymphovascular space invasion, 0% non-endometrioid histology, mean age 59 years. We did not obtain separate baseline data for stage III women.

Median follow-up was 60 months.

Only 97 women (25%) had stage III endometrial cancer. The investigators define a high risk group of 75 women with IIIB/C, or stage IIIA with other risk factors. From the trial publication, it is not clear how many of these women were allocated to each trial group. However, we have used the survival data in our analyses in the meantime and have requested complete stage III data from the trial investigators.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSimple randomisation was performed. "Each participant was assigned by a central telephone system".

Allocation concealment (selection bias)Low riskAssigned by a central telephone system.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskAn unblinded trial (blinding not possible due to the nature of the interventions).

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMethod of detection of progression not described; however, the primary outcome (OS) is unlikely to be affected.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk49 participants (10%) were excluded after randomisation due to non-endometrioid histology (27 and 22 in RT and CT groups respectively) and 41 were deemed ineligible (18 and 23 respectively). This might be explained if randomisation was performed before surgical staging.

Selective reporting (reporting bias)Low riskAll expected outcomes were reported. We obtained unpublished subgroup data from the investigators on the 21/3/2014.

Other biasLow riskNone noted. ITT analyses.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aapro 2003RCT of chemotherapy only (CD versus doxorubicin only) in women with advanced or recurrent disease. CRS was not performed. This study is included in the Cochrane review of chemotherapy for (non-adjuvant) recurrent and metastatic endometrial cancer (Vale 2012).

Fleming 2004aRCT of CD versus DP in women with advanced or recurrent endometrial cancer. Included patients with recurrent disease which was not amenable to surgery. This study is included in the Cochrane review of (non-adjuvant) chemotherapy for advanced, recurrent and metastatic endometrial cancer (Vale 2012).

Fleming 2004bRCT of CD versus CDP in women with advanced or recurrent endometrial cancer. Included patients with recurrent disease which was not amenable to surgery. This study is included in the Cochrane review of (non-adjuvant) chemotherapy for advanced, recurrent and metastatic endometrial cancer (Vale 2012).

Gallion 2003RCT of standard timing versus circadian timing of chemotherapy (CD) in women with advanced or recurrent disease. CRS was not performed. This study is included in the Cochrane review of chemotherapy for (non-adjuvant) recurrent and metastatic endometrial cancer (Vale 2012).

Hogberg 2010RCT of high-risk endometrial cancer (HREC) participants (including 20% stage III participants) evaluating radiotherapy versus chemoradiation. This study is included in the Cochrane review of adjuvant chemotherapy for (any stage) endometrial cancer (Johnson 2011).

Kuoppala 2008RCT of 156 HREC participants (including 20 stage IIIA participants [12%]) evaluating adjuvant radiotherapy versus sequential chemoradiation. This study is included in the Cochrane review of adjuvant chemotherapy for (any stage) endometrial cancer (Johnson 2011).

Mustea 2013Feasibility study of chemoradiation in advanced disease, not a RCT.

Nomura 2011RCT of cisplatin/docetaxel versus carboplatin/docetaxel versus carboplatin/paclitaxel in women with advanced or recurrent endometrial cancer with measurable disease (non-adjuvant chemotherapy).

Wolfson 2007This RCT was conducted in women with uterine sarcomas not endometrial carcinoma.

 
Characteristics of ongoing studies [ordered by study ID]
GOG 0258

Trial name or titleCarboplatin and paclitaxel with or without cisplatin and radiation therapy in treating patients with endometrial cancer

MethodsPhase III multi-centre open label RCT

ParticipantsWomen with high risk endometrial cancer (surgical stage III/IV advanced and stage I/II clear cell or serous papillary)

InterventionsArm 1: cisplatin on days 1 and 29 + EBRT for six weeks. Thereafter, four courses of carbo/paclitaxel. ('sandwich' technique)

Arm 2: carbo/paclitaxel x six courses starting on day 1.

OutcomesRFS, OS, early and late adverse effects, QoL

Starting dateJune 2009

Contact informationDaniela Matei

NotesAdjuvant chemoradiation versus CT.

PORTEC-3

Trial name or titleRandomized phase III trial comparing concurrent chemoradiation and adjuvant chemotherapy with pelvic radiation alone in high risk and advanced stage endometrial carcinoma: PORTEC-3

MethodsPhase III multicentre, open label RCT stratified according to participating group.

ParticipantsWomen with endometrial cancer stage IB/C and IIA grade 3, stage IIB any grade, stage IIIA (grade 3 or more than just peritoneal cytology) or IIIC, or serous or clear cell histology stage IB-III. No residual tumour or uterine sarcoma. Lymphadenectomy, or full surgical staging, or both allowed.

InterventionsArm 1: cisplatin on days 1 and 22 + EBRT for six weeks (with vaginal brachytherapy for cervical involvement). Thereafter, up to four courses of carbo/paclitaxel ('sandwich' technique)

Arm 2: EBRT for six weeks (with vaginal brachytherapy for cervical involvement)

OutcomesRFS, OS, rates of pelvic and distant recurrence, severe treatment-related toxicity (G3/4), and QoL

Starting dateOct 2006

Contact informationCarien Creutzberg

NotesAdjuvant chemoradiation versus RT.

 
Comparison 1. Chemotherapy vs radiotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 OS (Stage III/IV)2Hazard Ratio (Random, 95% CI)Subtotals only

    1.1 Stage III
2514Hazard Ratio (Random, 95% CI)0.76 [0.57, 1.02]

    1.2 Stage IV
1106Hazard Ratio (Random, 95% CI)0.68 [0.44, 1.04]

    1.3 Stage III/IV
2620Hazard Ratio (Random, 95% CI)0.75 [0.57, 0.99]

 2 OS (stage III/IV) (unadjusted data)2Hazard Ratio (Random, 95% CI)0.75 [0.60, 0.94]

 3 OS (stage III/IV dichotomous)2620Risk Ratio (M-H, Random, 95% CI)0.79 [0.68, 0.93]

 4 OS (Stage III only)2Hazard Ratio (Random, 95% CI)Subtotals only

    4.1 Stage IIIA
2234Hazard Ratio (Random, 95% CI)0.61 [0.38, 0.98]

    4.2 Stage IIIC
2265Hazard Ratio (Random, 95% CI)0.76 [0.53, 1.09]

 5 OS (Stage III dichotomous)2514Risk Ratio (M-H, Random, 95% CI)0.76 [0.62, 0.93]

 6 PFS (Stage III/IV)2Hazard Ratio (Random, 95% CI)Subtotals only

    6.1 Stage III
2514Hazard Ratio (Random, 95% CI)0.81 [0.63, 1.05]

    6.2 Stage IV
1106Hazard Ratio (Random, 95% CI)0.57 [0.38, 0.86]

    6.3 Stage III/IV
2620Hazard Ratio (Random, 95% CI)0.74 [0.59, 0.92]

 7 PFS (stage III/IV dichotomous)2620Risk Ratio (M-H, Random, 95% CI)0.89 [0.77, 1.02]

 8 PFS (Stage III only)2Hazard Ratio (Random, 95% CI)Subtotals only

    8.1 Stage IIIA
2234Hazard Ratio (Random, 95% CI)0.66 [0.43, 1.01]

    8.2 Stage IIIC
2265Hazard Ratio (Random, 95% CI)0.86 [0.61, 1.21]

 9 PFS (Stage III dichotomous)2514Risk Ratio (M-H, Random, 95% CI)0.84 [0.70, 1.01]

 10 Severe adverse events (G3/4)1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    10.1 Leukopenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.2 Neutropenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.3 Thrombocytopenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.4 Gastrointestinal
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.5 Neurological
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.6 Infection
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.7 Skin
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.8 Genitourinary
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    10.9 Alopecia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 11 Treatment discontinuation due to toxicity1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 12 Treatment-related deaths2620Risk Ratio (M-H, Random, 95% CI)1.67 [0.55, 5.00]

 
Comparison 2. CDP vs CD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 OS (stage III/IV)1552Hazard Ratio (Random, 95% CI)0.0 [0.0, 0.0]

 2 PFS (stage III/IV)1Hazard Ratio (Random, 95% CI)Subtotals only

 3 Severe adverse events (G3/4)1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    3.1 Leukopenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Neutropenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.3 Anaemia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.4 Thrombocytopenia
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.5 Gastrointestinal
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.6 Neurological
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.7 Infection
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.8 Skin
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.9 Genitourinary
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.10 Pain
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 4 Treatment discontinuation1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 
Summary of findings for the main comparison.

Adjuvant chemotherapy (CT) versus adjuvant radiotherapy (RT) for women with stage III and IV endometrial cancer

Patient or population: women with stage III or IV endometrial cancer after primary cytoreductive surgery

Settings: hospital

Intervention: CT

Comparison: RT

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

RTCT

5- year OS Stage IIIHR 0.75 (0.57 to 0.99)620 women
(2)
⊕⊕⊕⊝
moderate
For OS, a consistent effect was demonstrated across trials and subgroups (IIIA, IIIC and IV). Dichotomous OS data gave similar results (two trials, RR 0.79, 95% CI 0.68 to 0.93).

For PFS, a consistent effect was demonstrated across trials and subgroups (IIIA, IIIC and IV) but the dichotomous data suggests a smaller effect size (two trials, RR 0.89, 95% CI 0.77 to 1.02). We downgraded the quality of evidence due to imprecision (wide CIs) and the possibility that salvage radiotherapy may have contributed to a greater effect size for OS.

60 women alive per 100 diagnosed75 women alive per 100 diagnosed (61 to 86)

Stage IV

30 women alive per 100 diagnosed38 women alive per 100 diagnosed (30 to 50)

5-year PFSNot estimatedHR 0.74 (0.59 to 0.92)620 women
(2)
⊕⊕⊕⊝
moderate





5-year OS (stage III)Not estimatedHR 0.76

(0.57 to 1.02)
514 women

(2)
⊕⊕⊕⊝
moderate





5-year PFS (stage III)Not estimatedHR 0.81 (0.63 to 1.05)514 women

(2)
⊕⊕⊕⊝
moderate






*The assumed risk is based on SEER survival data (SEER 2007). Use of these data assumes that the adjuvant treatment of choice from 1988 to 2001 was radiotherapy. Assumed risk varies depending on other risk factors, such as age and histology.

The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival; CT: chemotherapy; RT: radiotherapy.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 
Summary of findings 2.

Adjuvant cisplatin/doxorubicin/paclitaxel (CDP) compared with cisplatin/doxorubicin (CD) for women with advanced (stage III/IV) endometrial cancer

Patient or population: women with advanced (stage III/IV) endometrial cancer after surgery and radiotherapy

Settings: hospital

Intervention: CDP

Comparison: CD

OutcomesRelative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments

PFS (stage III/IV)

Median follow-up 46/47 months
HR 0.90 (0.69 to 1.17)552
(1)
⊕⊕⊕⊝
moderate
We considered this evidence high quality but downgraded it to moderate, as mature OS data has not yet been published, therefore we cannot exclude other differences in survival risks/benefits.

CI: Confidence interval; HR: Hazard ratio; PFS: Progression-free survival; CDP: cisplatin/doxorubicin/paclitaxel; CD: cisplatin/doxorubicin.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.