Supplementary 1 (1M, pdf) - Journal of Gynecologic Oncology

Supplementary 1. Guidelines development process in accordance with evidence-based medicine [KQ 1] 1-1.

Generation of key questions based on PICO*

[KQ 1]

Is the survival rate similar between laparoscopic staging surgery and open surgery in early-stage endometrial cancer? P :

Early-stage endometrial carcinoma

I

Laparoscopic hysterectomy

:

C :

Total abdominal hysterectomy

O :

Overall survival or progression-free survival

*PICO: Population (P), Intervention or indicator (I), Comparator (C), Outcome (O). 1-2.

Medical literature search and study identification

PubMed, EMBASE, and Cochrane were used for the literature search, and the search formula is as follows. Table 1. Procedure to identify eligible clinical trials for answering KQ1 MEDLINE

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

EMBASE

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

(“Endometrial Neoplasms”[Mesh]) OR “Uterine Neoplasms”[Mesh:NoExp] (Endometrial[tiab] OR Endometrioid[tiab] OR Endometrium[tiab] OR Uterus[tiab] OR Uterine[tiab]) AND (cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab]) 1 OR 2 (“Uterus”[Mesh:NoExp]) OR “Endometrium”[Mesh] Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] “Adenocarcinoma”[Mesh:NoExp] 5 OR 6 “Carcinoma, Endometrioid”[Mesh] (Endometrial[tiab] OR Endometrioid[tiab] OR Endometrium[tiab] OR Uterus[tiab] OR Uterine[tiab]) 4 OR 9 10 AND 7 3 OR 8 OR 11 Laparoscopy[tiab] OR Laparoscopies[tiab] OR Laparoscopic[tiab] OR “Minimally Invasive”[tiab] OR Robot*[tiab] ((“Laparoscopy”[Mesh:NoExp]) OR “Minimally Invasive Surgical Procedures”[Mesh:NoExp]) OR “Robotic Surgical Procedures”[Mesh] 77788 13 OR 14 12 AND 15 16 AND Publication date from 2010/01/01 to 2014/12/31 17 NOT “review”[Publication Type] OR “review literature as topic”[MeSH Terms] “endometrium tumor”/de OR “endometrium cancer”/de OR “endometrium carcinoma”/exp OR “uterus tumor”/de OR “uterus cancer”/de OR “uterus carcinoma”/exp (Endometrial:ab,ti OR Endometrioid:ab,ti OR Endometrium:ab,ti OR Uterus:ab,ti OR Uterine:ab,ti) AND (cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti) 1 OR 2 “uterus”/de OR “endometrium”/exp OR “uterus cavity”/exp Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti “adenocarcinoma”/de 5 OR 6 Endometrial:ab,ti OR Endometrioid:ab,ti OR Endometrium:ab,ti OR Uterus:ab,ti OR Uterine:ab,ti 8 OR 4 7 AND 9 “endometrioid carcinoma”/exp 3 OR 10 OR 11 Laparoscopy:ab,ti OR Laparoscopies:ab,ti OR Laparoscopic:ab,ti OR “Minimally Invasive”:ab,ti OR Robot*:ab,ti “laparoscopy”/exp OR “minimally invasive surgery”/exp OR “robotic surgical procedure”/exp 13 OR 14 12 AND 15 16 NOT (“article in press”/it OR “conference review”/it OR “editorial”/it OR “erratum”/it OR “letter”/it OR “note”/it OR “review”/it OR “short survey”/it) 17 NOT (“human cell”/de OR “human tissue”/de) 18 AND (2010:py OR 2011:py OR 2012:py OR 2013:py OR 2014:py)

1

Cochrane

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

(Endometrial OR Endometrioid OR Endometrium OR Uterus OR Uterine) AND (cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms):ti,ab,kw MeSH descriptor: [Endometrial Neoplasms] explode all trees MeSH descriptor: [Uterine Neoplasms] this term only 1–3/or MeSH descriptor: [Uterus] this term only MeSH descriptor: [Endometrium] explode all trees Adenocarcinoma or Adenocarcinomas:ti,ab,kw MeSH descriptor: [Adenocarcinoma] this term only 7 or 8 MeSH descriptor: [Carcinoma, Endometrioid] explode all trees Endometrial OR Endometrioid OR Endometrium OR Uterus OR Uterine 11 or 5 or 6 12 and 9 13/trial

A total of 2,834 papers were searched using the aforementioned method from January 2010 to December 2014. Inclusion and exclusion criteria were applied to these papers, as shown in Figure 1, and five papers were finally selected.

Figure 1. Flow chart of searching strategy for answering KQ1.

1-3.

Quality assessment

All of the finally-selected papers concerned randomized controlled clinical research, and, to evaluate the appropriateness of the study design, Cochrane Collaboration’s tool for assessing risk of bias was used. The results of the evaluation of the risk of bias in five papers are summarized in Table 2. Table 2. Study design characteristics based on the QUADAS tool 2

Study ID

Random sequence generation

Allocation concealment

Blinding of participants

Blinding of personnel

Blinding of outcome

Incomplete outcome data

Selective reporting

Other sources of bias

Lu, 2013

Low

Low

High

High

Low

Unclear

Unclear

Low

Walker, 2012

Low

Low

High

High

Low

Low

Unclear

Low

Malzoni, 2009

Low

Low

High

High

Unclear

Low

Low

Low

Zullo, 2009

Low

Low

High

High

Low

Low

Low

Low

Tozzi, 2005

Low

Low

High

High

Low

Low

Unclear

Low

3

1-4.

Level of evidence and grade of recommendation

Table 3. Evidence table for laparoscopy Study ID

Study design

Country

Study period

Population

Inclusion criteria

Intervention

Control

Number

Outcome

Results (5-year OS)

Intervention

Control

151

121

5-year OS

96% vs. 91%

Lu, 2013

RCT

China

Median F/U: 68 months

Laparoscopy

Laparotomy

All stages

Walker, 2012

RCT

USA (LAP2)

Median F/U: 59.3 months

Laparoscopy

Laparotomy

Clinical stages I–IIA 1,696

920

5-year OS

89.8% vs. 89.8%

Malzoni, 2009

RCT

Italy

Nov 2001–Jan 2006

Laparoscopy

Laparotomy

Clinical stage I

81

78

5-year OS

93.2% vs. 91.1%

Zullo, 2009

RCT

USA

Mar 2001–Dec 2003

Laparoscopy

Laparotomy

Clinical stage I

40

38

5-year OS

82.5% vs. 84.2%

Tozzi, 2005

RCT

Germany

Median F/U: 44 months

Laparoscopy

Laparotomy

All stages

63

59

5-year OS

82.7% vs. 86.5%

RCT, randomized controlled trial; F/U, follow-up; OS, overall survival.

The evidence for the key question was supported by the results of five randomized controlled trials. According to the research result, survival rates were not different for laparoscopic staging surgery compared with laparotomy in early-stage endometrial cancer, and therefore laparoscopic staging surgery may be conducted. (Level of evidence: high) Table 4. Estimation of grade Outcomes

KQ1 Follow-up: 5 years

Illustrative comparative risks (95% CI) Assumed risk

Corresponding risk

Control 126 per 1000

126 per 1000 (104–152)

Relative effect (95% No. of participants (studies) CI)

Quality of the evidence (grade)

RR 1.00 (0.83–1.21) 3247 (5 studies)

⊕⊕⊕⊕ High

4

Comments

1-5.

Meta-analysis

For this recommendation, a meta-analysis was conducted to identify differences in survival rates according to surgical method in early-stage endometrial cancer patients. There was no difference in 5-year survival rates between the group that underwent laparoscopic staging surgery and the group that underwent open surgery (relative risk: 1.00; 95% confidence interval: 0.83–1.21).

Figure 2. Result of meta-analysis. RR, relative risk; CI, confidence interval.

1-6.

Summary

[KQ 1]

Is the survival rate similar between laparoscopic staging surgery and open surgery in early-stage endometrial cancer? Laparoscopic staging surgery is recommended for the surgical staging of early-stage endometrial cancer. Level of evidence: A (high) Strength of recommendation: 1 (strong)

1-7.

References

1.

Lu Q, Liu H, Liu C, et al. Comparison of laparoscopy and laparotomy for management of endometrial carcinoma: a prospective randomized study with 11-year experience. J Cancer Res Clin Oncol 2013; 139(11): 1853-9.

2.

Walker JL, Piedmonte MR, Spirtos NM, et al. Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 2012; 30(7): 695-700.

3.

Malzoni M, Tinelli R, Cosentino F, et al. Total laparoscopic hysterectomy versus abdominal hysterectomy with lymphadenectomy for early-stage endometrial cancer: a prospective randomized study. Gynecol Oncol 2009; 112(1): 126-33.

4.

Zullo F, Palomba S, Falbo A, et al. Laparoscopic surgery vs laparotomy for early stage endometrial cancer: long-term data of a randomized controlled trial. Am J Obstet Gynecol 2009; 200(3): 296 e1-9.

5.

Tozzi R, Malur S, Koehler C, et al. Laparoscopy versus laparotomy in endometrial cancer: first analysis of survival of a randomized prospective study. J Minim Invasive Gynecol 2005; 12(2): 130-6.

5

[KQ 2] 2-1.


[KQ 2]

Does ovarian preservation affect survival in patients with early-stage endometrial cancer? P :

Early-stage endometrial carcinoma

I

Ovarian preservation (or ovarian saving)

:

C :

Bilateral salpingooophorectomy

O :

Overall survival or progression-free survival

*PICO: Population (P), Intervention or indicator (I), Comparator © , Outcome (O).

2-2.


PubMed, EMBASE, and Cochrane were employed for the literature search, and the search formula is as follows. Table 1. Procedure to identify eligible clinical trials for answering KQ2 MEDLINE

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

EMBASE

17. 18. 19. 20. 21. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Cochrane

20. 1. 2. 3. 4. 5. 6.

(“Endometrial Neoplasms”[Mesh]) OR “Uterine Neoplasms”[Mesh:NoExp] (Endometrial[tiab] OR Endometrioid[tiab] OR Endometrium[tiab] OR Uterus[tiab] OR Uterine[tiab]) AND (cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab]) 1 OR 2 (“Uterus”[Mesh:NoExp]) OR “Endometrium”[Mesh] Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] “Adenocarcinoma”[Mesh:NoExp] 5 OR 6 “Carcinoma, Endometrioid”[Mesh] (Endometrial[tiab] OR Endometrioid[tiab] OR Endometrium[tiab] OR Uterus[tiab] OR Uterine[tiab]) 4 OR 9 10 AND 7 3 OR 8 OR 11 (“Organ Preservation”[Mesh]) OR “Fertility Preservation”[Mesh] ((“Organ Sparing Treatments”[Mesh]) OR “Ovariectomy”[Mesh]) Ovariectomies[tiab] OR Oophorectomy[tiab] OR Oophorectomies[tiab] OR Castration[tiab] OR Castrations[tiab] OR Ovariectomy[tiab] (ovarian[tiab] OR adnexa[tiab] OR adnexal[tiab] ovary[tiab]) AND (preservation[tiab] OR Sparing[tiab] OR save[tiab] OR saving[tiab] OR removal[tiab] OR remove[tiab]) 13–16/OR 12 AND 17 18 NOT (animals[Mesh Term] NOT (humans[Mesh Term] AND animals[Mesh Term])) 19 NOT “review”[Publication Type] OR “review literature as topic”[MeSH Terms] 20 AND Publication date from 2010/01/01 to 2014/12/31 “endometrium tumor”/de OR “endometrium cancer”/de OR “endometrium carcinoma”/exp OR “uterus tumor”/de OR “uterus cancer”/de OR “uterus carcinoma”/exp (Endometrial:ab,ti OR Endometrioid:ab,ti OR Endometrium:ab,ti OR Uterus:ab,ti OR Uterine:ab,ti) AND (cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti) 1 OR 2 “uterus”/de OR “endometrium”/exp OR “uterus cavity”/exp Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti “adenocarcinoma”/de 5 OR 6 Endometrial:ab,ti OR Endometrioid:ab,ti OR Endometrium:ab,ti OR Uterus:ab,ti OR Uterine:ab,ti 8 OR 4 7 AND 9 “endometrioid carcinoma”/exp 3 OR 10 OR 11 “organ preservation”/de OR “fertility preservation”/exp OR “conservative treatment”/de OR “ovarian preservation”/exp OR “ovariectomy”/exp Ovariectomies:ab,ti OR Oophorectomy:ab,ti OR Oophorectomies:ab,ti OR Castration:ab,ti OR Castrations:ab,ti OR Ovariectomy:ab,ti (ovarian:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti ovary:ab,ti) AND (preservation:ab,ti OR Sparing:ab,ti OR save:ab,ti OR saving:ab,ti OR removal:ab,ti OR remove:ab,ti) 13–15/OR 12 AND 16 17 NOT (“article in press”/it OR “conference review”/it OR “editorial”/it OR “letter”/it OR “note”/it OR “review”/it OR “short survey”/it) 18 NOT (“animal cell”/de OR “animal experiment”/de OR “animal model”/de OR “animal tissue”/de OR “human cell”/de OR “human tissue”/de OR “in vitro study”/de OR “nonhuman”/de) 19 AND (2010:py OR 2011:py OR 2012:py OR 2013:py OR 2014:py) (Endometrial OR Endometrioid OR Endometrium OR Uterus OR Uterine) AND (cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms):ti,ab,kw MeSH descriptor: [Endometrial Neoplasms] explode all trees MeSH descriptor: [Uterine Neoplasms] this term only 1–3/or MeSH descriptor: [Uterus] this term only MeSH descriptor: [Endometrium] explode all trees

6

7. 8. 9. 10. 11. 12. 13. 14.

Adenocarcinoma or Adenocarcinomas:ti,ab,kw MeSH descriptor: [Adenocarcinoma] this term only 7 or 8 MeSH descriptor: [Carcinoma, Endometrioid] explode all trees Endometrial OR Endometrioid OR Endometrium OR Uterus OR Uterine 11 or 5 or 6 12 and 9 13/trial

A total of 1,702 papers were searched using the aforementioned method from January 2010 to December 2014. Inclusion and exclusion criteria were applied to these papers as shown in Figure 1, and three papers were finally selected.

Figure 1. Flow chart of searching strategy for answering KQ2

2-3.

Quality assessment

All three ultimately selected papers were nonrandomized studies (NRSs), and to evaluate the appropriateness of the study design, the Newcastle-Ottawa Quality Assessment Scale technique was used. The results of the evaluation of the three papers are summarized in the table below. Table 2. Study design characteristics Study ID

Representati veness of the exposed cohort

Selection of the nonexposed cohort

Ascertainment of exposure

Demonstration that outcome of interest was not present at start of study

ComparAssessment ability of of outcome cohorts on the basis of the design or analysis

Was followup long enough for outcomes to occur?

Adequacy of follow-up of cohorts

Lee, 2013

*

*

*

*

**

*

*

*

Sun, 2013

*

*

*

*

**

*

*

*

Wright, 2009

*

*

*

*

**

*

*

*

7

2-4.


Table 3. Evidence table for ovarian preservation Study ID

Study design

Country

Study period

Population

Inclusion criteria

Intervention

Control

Number Intervention

Control

Outcome

Result (5-year OS)

Lee, 2013

Retrospective cohort

Korea (multicenter)

1997–2008

Ovarian preservation


Stage I-II EC, premenopausal women

176

319

5-year OS

HR, 1.33 (95% CI, 0.43–4.09)

Sun, 2013


China

2000–2010



Early-stage EC (≤45 years)

34

169

5-year OS

HR, 1.006 (95% CI, 0.112–9.019)

Wright, 2009


SEER dataset

1988–2004



Stage I EC (≤45 years)

402

2,867

5-year OS

HR, 0.68 (95% CI, 0.34–1.35)

OS, overall survival; EC, endometrial carcinoma; HR, hazard ratio; CI, confidence interval.

The evidence for the key question was supported by the three NRS research results. There was no difference in survival rates between those whose ovary was removed and those whose ovary was not removed if the tumor was confined to the uterine corpus and there was no finding of distant metastasis. Therefore, women ≤45 years old who want preservation of their ovary may selectively undergo ovary preservation. Because there is no randomized controlled trial verifying the results, the level of evidence is low. (Level of evidence: low) Table 4. Estimation of grade Outcomes

KQ2, Follow-up: 5 years

Illustrative comparative risks* (95% CI) Assumed risk

Corresponding risk

Control See comment

See comment

Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (grade)

0.83 (0.47–1.47)

3,967 (3 studies)

⊕⊕⊝⊝ low

8

Comments

2-5.

Meta-analysis

For this recommendation, a meta-analysis was conducted to identify differences in survival rates when the ovary was preserved and not preserved in patients with early-stage endometrial cancer. The death rate in the group with ovary preservation was 0.83 times the rate in the group without ovary preservation (hazard ratio: 0.83; 95% confidence interval: 0.47–1.47).

Figure 2. Result of meta-analysis. SE, standard error; CI, confidence interval. 2-6.

Summary

[KQ 2]

Does ovarian preservation affect survival in patients with early-stage endometrial cancer? Ovarian preservation is recommended at the time of hysterectomy for young women with early-stage endometrial cancer that is confined to the uterus without evidence of extrauterine spread. Level of evidence: C (low) Strength of recommendation: 2 (weak)

2-7.

References

1.

Lee TS, Lee JY, Kim JW, et al. Outcomes of ovarian preservation in a cohort of premenopausal women with early-stage endometrial cancer: a Korean Gynecologic Oncology Group study. Gynecol Oncol 2013; 131(2): 289-93.

2.

Sun C, Chen G, Yang Z, et al. Safety of ovarian preservation in young patients with early-stage endometrial cancer: a retrospective study and meta-analysis. Fertil Steril 2013; 100(3): 782-7.

3.

Wright JD, Buck AM, Shah M, et al. Safety of ovarian preservation in premenopausal women with endometrial cancer. J Clin Oncol 2009; 27(8): 1214-9.

9

[KQ 3] 3-1.


[KQ 3]

Is progestin therapy for fertility-sparing treatment effective for young women with early-stage endometrial cancer? P :

Endometrial carcinoma

I

Progestin-based therapy

:

C :

Total hysterectomy ± bilateral salpingo-oophorectomy / or

O :

Response rate or pregnancy outcome

*PICO: Population (P), Intervention or indicator (I), Comparator © , Outcome (O). 3-2.


PubMed, EMBASE, and Cochrane were employed for the literature search, and the search formula is as follows. Table 1. Procedure to identify eligible clinical trials for answering KQ3 MEDLINE

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

EMBASE

17. 18. 19. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Cochrane

1. 2. 3.

(“Endometrial Neoplasms”[Mesh]) OR “Uterine Neoplasms”[Mesh:NoExp] (Endometrial[tiab] OR Endometrioid[tiab] OR Endometrium[tiab] OR Uterus[tiab] OR Uterine[tiab]) AND (cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab]) 1 OR 2 (“Uterus”[Mesh:NoExp]) OR “Endometrium”[Mesh] Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] “Adenocarcinoma”[Mesh:NoExp] 5 OR 6 “Carcinoma, Endometrioid”[Mesh] (Endometrial[tiab] OR Endometrioid[tiab] OR Endometrium[tiab] OR Uterus[tiab] OR Uterine[tiab]) 4 OR 9 10 AND 7 3 OR 8 OR 11 Desogestrel[tiab] OR Dydrogesterone[tiab] OR Progesterone[tiab] OR Pregnenedione[tiab] OR Megestrol[tiab] OR Gestagens[tiab] OR Progestagens[tiab] (Progestational[tiab] OR Gestagenic[tiab] OR Progestagenic[tiab] OR Progestin[tiab] OR Gestagen[tiab] OR Progestogen[tiab]) AND (Agents[tiab] OR Hormones[tiab] OR Compounds[tiab] OR drug[tiab] OR Agent[tiab] OR Hormone[tiab] OR Compound[tiab]) Fertility[tiab] AND (Preservations[tiab] OR Preservation[tiab]) ((((((“Fertility Preservation”[Mesh]) OR “Progestins”[Mesh]) OR “Desogestrel”[Mesh]) OR “Dydrogesterone”[Mesh]) OR “Progesterone”[Mesh]) OR “Megestrol Acetate”[Mesh]) OR “Megestrol”[Mesh] 13–16/OR 12 AND 17 18 NOT “review”[Publication Type] OR “review literature as topic”[MeSH Terms] “endometrium tumor”/de OR “endometrium cancer”/de OR “endometrium carcinoma”/exp OR “uterus tumor”/de OR “uterus cancer”/de OR “uterus carcinoma”/exp (Endometrial:ab,ti OR Endometrioid:ab,ti OR Endometrium:ab,ti OR Uterus:ab,ti OR Uterine:ab,ti) AND (cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti) 1 OR 2 “uterus”/de OR “endometrium”/exp OR “uterus cavity”/exp Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti “adenocarcinoma”/de 5 OR 6 Endometrial:ab,ti OR Endometrioid:ab,ti OR Endometrium:ab,ti OR Uterus:ab,ti OR Uterine:ab,ti 8 OR 4 7 AND 9 “endometrioid carcinoma”/exp 3 OR 10 OR 11 Desogestrel:ab,ti OR Dydrogesterone:ab,ti OR Progesterone:ab,ti OR Pregnenedione:ab,ti OR Megestrol:ab,ti OR Gestagens:ab,ti OR Progestagens:ab,ti (Progestational:ab,ti OR Gestagenic:ab,ti OR Progestagenic:ab,ti OR Progestin:ab,ti OR Gestagen:ab,ti OR Progestogen:ab,ti) AND (Agents:ab,ti OR Hormones:ab,ti OR Compounds:ab,ti OR drug:ab,ti OR Agent:ab,ti OR Hormone:ab,ti OR Compound:ab,ti) Fertility:ab,ti AND (Preservations:ab,ti OR Preservation:ab,ti) “fertility preservation”/exp OR “gestagen”/de OR “desogestrel”/exp OR “dydrogesterone”/exp OR “progesterone”/exp OR “megestrol”/exp OR “megestrol acetate”/exp 13–16/OR 12 AND 17 18 NOT (“article in press”/it OR “conference review”/it OR “editorial”/it OR “erratum”/it OR “letter”/it OR “note”/it OR “review”/it OR “short survey”/it) 19 NOT (“animal cell”/de OR “animal experiment”/de OR “animal model”/de OR “animal tissue”/de OR “human cell”/de OR “in vitro study”/de OR “nonhuman”/de) (Endometrial OR Endometrioid OR Endometrium OR Uterus OR Uterine) AND (cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms):ti,ab,kw MeSH descriptor: [Endometrial Neoplasms] explode all trees MeSH descriptor: [Uterine Neoplasms] this term only

10

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

1–3/or MeSH descriptor: [Uterus] this term only MeSH descriptor: [Endometrium] explode all trees Adenocarcinoma or Adenocarcinomas:ti,ab,kw MeSH descriptor: [Adenocarcinoma] this term only 7 or 8 MeSH descriptor: [Carcinoma, Endometrioid] explode all trees Endometrial OR Endometrioid OR Endometrium OR Uterus OR Uterine 11 or 5 or 6 12 and 9 13/trial

A total of 6,969 papers were searched using the aforementioned method until December 2014. Inclusion and exclusion criteria were applied to these papers as shown in Figure 1, and three papers were finally selected.

Figure 1. Flow chart of searching strategy for answering KQ3.

3-3.

Quality assessment

The three finally selected papers were all nonrandomized studies (NRSs), and, to assess the appropriateness of their design, the suggested risk of bias criteria for Effective Practice and Organization of Care (EPOC) reviews was examined. The results of the evaluation of the three papers are summarized in Table 2. Table 2. Study design characteristics study ID

Was the intervention independent of other changes?

Was the shape of the intervention effect prespecified?

Was the intervention unlikely to affect data collection?

11

Was knowledge of the allocated interventions adequately prevented during the study?

Were incomplete outcome data adequately addressed?

Was the study free from selective outcome reporting?

Was the study free from other risks of bias?

Wang, 2014

Low

Low

Low

Unclear

Unclear

Low

(-)

Park, 2013

Low

Low

Low

Unclear

Unclear

Low

(-)

Ushijima, 2007

Low

Low

Low

Unclear

Unclear

Low

(-)

12

3-4.


Table 3. Evidence table for progestin-based therapy Study ID

Number (age, year)

Inclusion criteria

Progestin-based therapy (no hysterectomy)

37 (-)

Grade 1 endometrioi d EC at presumed stage IA

Park, 2013 Retrospecti Korea ve cohort (KGOG)


Ushijima, 2007


Wang, 2014

Study design

Country

Retrospecti Taiwan ve cohort

Prospective cohort

Japan (Japan GCSG)

Population

Outcome

Type of treatment

Result CR rate

Recurence rate

CR rate, MA, 160 recurrence- mg/d free survival

81.1% (30/37), lasting > 6 months

50.0% (15/30) 51.0% median PFI: 20.0 months (11–154 months)

11 attempted pregnancies, 8 pregnancies (2 abortions, 2 ectopic, 1 preterm, 3 fullterm)

148 (