Supplementary Table 1. Search Strategy 1 exp esophagus

(1)

Supplementary Table 1. Search Strategy 1 exp esophagus/

2 oesophagus.mp.

3 esophageal.mp.

4 oesophageal.mp.

5 or/1-4

6 exp malignant neoplasm/ or exp neoplasm/

7 cancer.mp.

8 malignancy.mp.

9 tumor.mp.

10 carcinoma.mp.

11 adenocarcinoma.mp.

12 EAC.mp.

13 squamous cell carcinoma.mp.

14 SCC.mp.

15 ESCC.mp.

16 or/6-15

17 exp adjuvant chemotherapy/ or exp adjuvant therapy/ or exp cancer adjuvant therapy/

18 adjuvant treatment.mp.

19 chemotherapy.mp.

20 radiation therapy.mp.

21 chemoradiation therapy.mp.

22 chemoradiotherapy.mp.

23 external-beam radiation therapy.mp.

24 EBRT.mp.

25 internal radiation therapy.mp.

26 brachytherapy.mp.

27 exp neoadjuvant therapy/

28 or/17-26

29 5 and 16 and 27 and 28

30 remove duplicates from 29

(2)

Supplementary Table 2. Specific neoadjuvant and adjuvant therapy used by included studies

Study Type of Treatment

N Analyzed

# of NACT cycles

NACT Drugs

Day: name of drug (dose)

Neoadjuvant Radiotherapy (day: dose)

# of ACT cycles

ACT Drugs

Day: name of drug (dose)

Adjuvant Radiotherapy (day: dose) Ardalan,

2007

NACT + S

NACT + S + ACT

18

15

2

Day 1: Cisplatin (100 mg/m²)

Day 2: FUdR (80 mg/kg), leucovorin (500 mg/m²) Days 14 & 21: FUdR (150 mg/kg), leucovorin (500 mg/m²)

Day 28: paclitaxel (125 mg/m²)

Day 29: FUdR (80 mg/kg), leucovorin (500 mg/m²) Days 42 & 49: FUdR (150 mg/kg), leucovorin (500 mg/m²)

Day 28: paclitaxel (125 mg/m²)

-

2

-

Day 2: FUdR (80 mg/kg), leucovorin (500 mg/m²) Days 14 & 21: FUdR (150 mg/kg), leucovorin (500 mg/m²)

Day 28: paclitaxel (125 mg/m²) Day 29: FUdR (80 mg/kg), leucovorin (500 mg/m²) Days 42 & 49: FUdR (150 mg/kg), leucovorin (500 mg/m²)

-

Hsu, 2016

NACRT + S

NACRT + S + ACRT

32

1

Days 1-4 & 29-33: 5-fluorouracil (1000 mg/m^2 per day)

Days 8 & 29: Cisplatin

Days 1-4 & 29-33: 5-fluorouracil (1000 mg/m^2 per day)

Days 8-29: 30 Gy (administered as 200 cGy 5 days per week) Days 8-29: 30 Gy (administered as 200 cGy 5 days per week)

-

1 Days 1-4 & 29-33: 5-fluorouracil (1000 mg/m^2 per day)

-

23.4-30 Gy

Drake, 2019

NACRT + S

NACRT + S + ACT

295

-

Received but not specified

Median of 5000 rads Median of 4500 rads

-

- Huang,

2019

NACT + S

NACT + S + ACRT

81

2

paclitaxel + cisplatin or paclitaxel + nedaplatin or paclitaxel + carboplatin, irinotecan + cesplatin, etoposide + cisplatin, docetaxel + nedaplatin paclitaxel + cisplatin or paclitaxel + nedaplatin or paclitaxel + carboplatin, irinotecan + cesplatin, etoposide + cisplatin, docetaxel + nedaplatin

-

2-4

-

41.4-50.4 Gy

Ruhstall er, 2018

NACRT + S

NACRT + S + ACT

151

149

2 of induction chemo followed by chemoradiati on 2 of induction chemo

Days 1 & 22: cisplatin (75 mg/m^2) + docetaxel (75 mg/m^2); Concomitant chemotherapy: IV cisplatin (25 mg/m^2) + docetaxel 20 mg/m^2)

Days 1 & 22: cisplatin (75 mg/m^2) + docetaxel (75 mg/m^2); Concomitant chemotherapy: IV cisplatin (25 mg/m^2) + docetaxel 20 mg/m^2)

45 Gy over 5 weeks

46 Gy over 5 weeks

-

2

-

Cetuximab (500 mg/m^2 fortnightly for 3 months)

-

(3)

followed by chemoradiati on Huang,

2017

NACRT + S

NACRT + S + ART

41

29

-

Once weekly: Cisplatin (30 mg/m^2) + fluorouracil (425 mg/m^2); OR paclitaxel (35mg/m^2 on Days 1

& 4 of each week) + cisplatin (15 mg/m^2 on days 2 and 5 of each week); OR once weekly: docetaxel (20 mg/m^2) + cisplatin (20 mg/m^2)

Once weekly: Cisplatin (30 mg/m^2) + fluorouracil (425 mg/m^2); OR paclitaxel (35mg/m^2 on Days 1

& 4 of each week) + cisplatin (15 mg/m^2 on days 2 and 5 of each week); OR once weekly: docetaxel (20 mg/m^2) + cisplatin (20 mg/m^2)

5 days a week:

total dose of 36- 45 Gy

5 days a week:

total dose of 36- 45 Gy

-

20 Gy

Saeed, 2017

NACT + S

NACT + S + ACT

92

46

-

Platinum + 5- fluorouracil /capecitabine; OR platinum + taxane

-

Decetaxel; OR 5- fluorouracil + leucovorin; OR 5- fluorouracil + cisplatin; OR 5- fluorouracil;

OR carboplatin + paclitaxel; OR carboplatin -

-

Mokdad , 2017

NACRT + S

NACRT + S + ACT

3660

732

-

Received but not specified -

-

Luc, 2014

NACRT + S

NACT + S + ACT

55

61

2-7

3

Days 1-5: 5- fluorouracil (750 mg/m^2/day by continuous infusion)

Day 1: cisplatin (20 mg/m^2)

Days 1 & 22 & 43: docetaxel (75 mg/m^2) + cisplatin (75 mg/m^2)

Started on day 28: 45 Gy total dose Started on day 28: 45 Gy total dose

-

3

-

Days 1 & 22 & 43: docetaxel (75 mg/m^2) + cisplatin (75 mg/m^2)

-

Hoeppn er, 2014

NACRT + S

NACT + S + ACT

58

47

4

3 or 4

Days 1-5: 5-flurouracil (500 mg/m^2) + cisplatin (20 mg/m^2)

Day 1: bolus epirubicin (50 mg/m^2) + cisplatin (60 mg/m^2) + fluorouracil (200 mg/m^2); OR Day 1:

doxatel (50 mg/m^2) + folinic acid (200 mg/m^2) + fluorouracil (2600 mg/m^2) + oxaliplatin (85 mg/m^2)

Days 1-5: 1.8 Gy/day (total of 26-45 Gy) -

3

-

Days 1 & 8: cisplatin (30 mg/m^2) + irinotecan (65 mg/m^2)

-

Samson, 2018

NACRT + S

NACRT + S + ACT

2625

475

-

Received but not specified Received but not specified

-

Received, but not specified

-

- Semenk

ovich, 2019

NACRT + S NACRT + S + ACT

873 209

- -

12.6-70 Gy 12.6-70 Gy

- -

-

Received but not specified Burt,

2016

3257 335

- -

-

- -

(4)

Eng, 2018

4306 373

- -

-

- -

NACT=Neoadjuvant chemotherapy, NACRT=Neoadjuvant chemoradiotherapy, ACRT=Adjuvant chemoradiotherapy, ACT=Adjuvant chemotherapy, ART=Adjuvant radiotherapy, AT=Adjuvant therapy

(5)

Supplementary Table 3. Study Characteristics

Study Study type Histology Type of Treatment

N analyzed

% Female

Age (yr, SD/range)

Follow-up Time Interval (mo, range)

% negative margins after Surgery

T stage (0 or is/1/2/3/4)

N stage (N-/N+)

Overall stage (1/2/3/4)

CCI NCDB

data (Y/N);

Timeline Ardalan,

2007

Phase II Clinical Trial

Adenocarcinoma NACT + S NACT + S + ACT

18 15

12% 68 (48-80) 73 (45-89) 91% (30)

T0: 9%

T1: 21%

T2: 15%

T3: 55%

N+: 100% - -

- -

N; 1998- 2002

Hsu, 2016 Retrospective Cohort

SCC NACRT + S

NACRT + S + ACRT

32

32 0.3%

0.3%

57.53 ± 8.67

57.34 ± 8.64

- (6-60)

100% (32)

T0: 3%

T1: 9%

T2: 19%

T3: 69%

T0: 3%

T1: 3%

T2: 13%

T3: 81%

N-: 47%

N+: 53%

N-: 47%

N+: 53%

-

0: 69%

1: 22%

>1: 9%

0: 56%

1: 41%

>1: 3%

N; 2000- 2012

Drake, 2019

Retrospective Cohort

Adenocarcinoma NACRT + S

NACRT + S + ACT

295

295 5.40%

7.50%

57.9 ± 9.6

57.9 ± 9.1

22.92 (14.04- 36.72)

25.92 (16.32- 42.96)

100% (295)

T1: 16%

T2: 3%

T3: 78%

T4: 3%

T1: 18%

T2: 3%

T3: 74%

T4: 4%

N+: 100%

-

0: 76%

1: 20%

>1: 3%

0: 78%

1: 19%

>1: 3%

Y; 2006- 2012

Huang, 2019

Retrospective Cohort

SCC NACT + S

NACT + S + ACRT

81

81 15%

15%

-

59.6 (6-108)

100% (81)

T0-2: 40%

T3-4: 61%

T0-2: 42%

T3-4: 58%

N-: 48%

N+: 52%

N-: 47%

N+: 53%

-

N; 2007- 2016

Ruhstaller, 2018

RCT Adenocarcinoma

& SCC

NACRT + S

NACRT + S + ACT

151

149 12%

13%

61 (53-68)

61 (56-68)

48 (6-72)

97% (146)

95% (142)

T2: 15%

T3: 80%

T4: 5%

T2: 14%

T3: 84%

T4: 2%

N-: 9%

N+: 91%

N-: 12%

N+: 88%

-

N; 2010- 2013

Huang, 2017

Retrospective Cohort

Adenocarcinoma

& SCC

NACRT + S NACRT + S + ART

41 29

1.4%

57.1 ± - 54.9 ± -

- (12-120) - (12-120)

100% (41) 100% (29)

- -

N+: 100%

3: 95.7%

4: 4.3%

- -

N; 1996- 2009

Saeed, 2017

Retrospective Cohort

Adenocarcinoma

& SCC

NACT + S 92 16.3% 62.9 (30-

82.5)

84.8% (78) T0: 9%

T1: 17%

T2: 25%

T3: 45%

T4:4%

N-: 34%

N+: 66%

- - N; 1994-

2015

(6)

NACT + S +

ACT 46 19.6% 59.2 (38.1-

79.2)

28.8 (12-144)

84.8% (39) T0: 13%

T1: 9%

T2: 30%

T3: 46%

T4: 2%

N-: 22%

N+: 78%

- -

Mokdad, 2017

Retrospective Cohort

Adenocarcinoma NACRT + S

NACRT + S + ACT

3660

732 11%

11%

-

27 (17-44)

90% (3294)

95% (695)

T0: 10%

T1: 10%

T2: 19%

T3: 57%

T4: 3%

T0: 10%

T1: 10%

T2: 18%

T3: 58%

T4: 4%

N-: 31%

N+: 69%

N-: 30%

N+: 70%

-

0: 75%

1: 20%

≥2: 4%

0: 75%

1: 21%

≥2: 4%

Y; 2006- 2013

Luc, 2014 Retrospective Cohort

Adenocarcinoma NACRT + S

NACT + S + ACT

55

61 1.8 %

16.4%

Mean 64.7 (40-79)

Mean 64.5 (40-78)

21 (1-120)

94.6% (52)

75.4% (46) -

-

N-: 58.2%

N+: 41.8%

N-: 37.7%

N+: 62.3%

0: 20.0%

1: 29.1%

2: 20.0%

3: 30.9%

0: 3.3%

1: 14.7%

2: 29.5%

3: 52.5%

-

N; 2000- 2012

Hoeppner, 2014

Retrospective Cohort

Adenocarcinoma NACRT + S

NACT + S + ACT

58

47 9%

8%

58 (36-78)

62 (31-77)

21.6 (2.64-138)

95% (55)

96% (45)

T0: 21%

T1: 12%

T2: 33%

T3: 33%

T4: 2%

T0: 17%

T1: 15%

T2: 36%

T3: 32%

T4: 0%

N-: 60%

N+: 40%

N-: 49%

N+: 51%

-

N; 2000- 2012

Samson, 2018

Retrospective Cohort

Adenocarcinoma

& SCC

NACRT + S

NACRT + S + ACT

2625

475 13.7%

10.9%

62 ± 14

59 ± 13

21 (12-60)

88.5% (2323)

87.3% (415)

T0: 8.4%

T1: 11.8%

T2: 17.4%

T3: 59.6%

T4: 2.7%

T0: 6.4%

T1: 11.6%

T2: 18.2%

T3: 62.6%

T4: 1.1%

N+: 100%

-

Y; 2006- 2012

Semenkovi ch, 2019

Retrospective Cohort

Adenocarcinoma

& SCC

NACRT + S 873 13.6% 62 (54-68) 89.9% (785) T0: 11.7%

T1: 10.1%

N+: 100% 2: 31.5%

3: 68.5%

- N; 2000-

2014

(7)

NACRT + S + ACT

209 16.3% 58 (51-64)

- (12-180)

90.4% (189)

T2: 19.0%

T3: 57.2 T4: 1.7%

T0: 6.2%

T1: 12.4%

T2: 18.7%

T3: 60.8%

T4: 1.9%

N+: 100% 2: 20.6%

3:79.4%

-

Burt, 2017 Retrospective Cohort

Adenocarcinoma

& SCC

NACRT + S

NACRT + S + ACT

3257

335 14.2%

10.1%

60.8 ± 9.2

58.3 ± 8.7

25.5 (13.9-45.0)

92% (2996)

88.3% (296)

T0: 26.8%

T1: 14.7%

T2: 19.3%

T3: 37.1%

T4: 1.3%

T0: 15.5%

T1: 11.0%

T2: 20.9%

T3: 51.9%

T4: 0.3%

N-: 66.3%

N+: 33.7%

N-: 39.1%

N+: 60.9%

-

0: 75.9%

1: 19.7%

≥2: 4.4%

0: 77.6%

1: 20.0%

≥2: 2.4%

Y; 2006- 2012

Eng, 2018 Retrospective Cohort

Adenocarcinoma NACRT + S NACRT + S + ACT

4306 373

10% 62 (55-68) - (12-60) 92% (4326)

T0: 15%

T1: 18%

T2: 20%

T3: 40%

T4: 1%

N-: 59%

N+: 41%

- -

0: 74%

1: 21%

>1: 5%

Y; 2006- 2013

CCI = Charlson Comorbidities Index, SCC = squamous cell carcinoma, NACT=Neoadjuvant chemotherapy, NACRT=Neoadjuvant chemoradiotherapy, ACRT=Adjuvant chemoradiotherapy,

ACT=Adjuvant chemotherapy, ART=Adjuvant radiotherapy, AT=Adjuvant therapy

(8)

Supplementary Table 4. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) of meta-analyzed outcomes

Certainty assessment Summary of findings

№ of participants

Risk of bias

Inconsistency Indirectness Imprecision Publication bias

Overall certainty of

evidence

Pooled effect size (95% CI)

Anticipated effects

Overall Survival at 1-Year 6,458

(10 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.52, 95% CI 0.41 to 0.65, P<0.001, I

²

=7%

Adjuvant therapy decreases mortality by 48% more than

surgery-only at 1-year Adenocarcinoma

4,642 (4 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁⨁

HIGH

RR 0.44, 95% CI 0.33 to 0.59, P<0.001, I

²

=0%

Adjuvant therapy decreases mortality by 57% more than

surgery-only at 1-year in adenocarcinoma patients SCC

226 (2 Studies)

not serious

¹

not serious

⁴

not serious

⁵

somewhat serious

⁶

none ⨁⨁⨁◯

MODERATE

RR 0.43, 95% CI 0.22 to 0.83, P=0.01, I

²

=0%

Adjuvant therapy decreases mortality by 57% more than

surgery-only at 1-year in SCC patients ACT

6,162 (7 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.52, 95% CI 0.42 to 0.64, P<0.001, I

²

=0%

Adjuvant therapy decreases mortality by 48% more than

surgery-only at 1-year for patients receiving ACT Node Status +

3,606 (5 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.57, 95% CI 0.42 to 0.77, P<0.001, I

²

=26%

Adjuvant therapy decreases mortality by 43% more than

surgery-only at 1-year for patients with positive node

status T0-2

1,086 (3 Studies)

not serious

¹

not serious

⁴

not serious

⁵

somewhat serious

⁶

none ⨁⨁◯◯

LOW

RR 0.54, 95% CI 0.25 to 1.18, P=0.12, I

²

=30%

There is no significant

difference in 1-year

mortality in T0-2 patients

compared to surgery-only

T3-4

(9)

6,029 (6 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.51, 95% CI 0.41 to 0.63, P<0.001, I

²

=0%

Adjuvant therapy decreases mortality by 10% more than

surgery-only at 1-year for T3-4 patients Overall Survival at 5-Year

6,458 (10 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.91, 95% CI 0.87 to 0.96, P<0.001, I

²

=0%

Adjuvant therapy decreases mortality by 9% more than neoadjuvant and surgery

only at 5-year Adenocarcinoma

4,642 (4 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.88, 95% CI 0.77 to 1.00, P=0.04, I

²

=18%

Adjuvant therapy decreases mortality by 12% more than

neoadjuvant and surgery only at 5-year in adenocarcinoma patients SCC

226 (2 Studies)

not serious

¹

not serious

⁴

not serious

⁵

very serious

^6,7

none ⨁◯◯◯

VERY LOW

RR 0.89, 95% CI 0.67 to 1.18, P=0.42, I

²

=46%

There is no significant different in 5-year mortality

for SCC patients receiving adjuvant therapy compared to neoadjuvant therapy and

surgery only ACT

6,162 (7 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.91, 95% CI 0.86 to 0.96, P<0.001, I

²

=5%

Adjuvant therapy decreases mortality by 9% more than neoadjuvant and surgery only at 5-year for patients

receiving ACT Node Status +

3,606 (5 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.89, 95% CI 0.84 to 0.95, P<0.001, I

²

=0%

Adjuvant therapy decreases mortality by 11% more than

neoadjuvant therapy and surgery only at 5-year for patients with positive node

status T0-2

1,086 (3 Studies)

not serious

¹

not serious

⁴

not serious

⁵

somewhat serious

⁶

none ⨁◯◯◯

VERY LOW

RR 0.89, 95% CI 0.71 to 1.12, P=0.33, I

²

=22%

There is no significant

difference in 5-year

mortality in T0-2 patients

receiving adjuvant therapy

(10)

compared to neoadjuvant therapy and surgery only T3-4

6,029 (6 Studies)

not serious

¹

not serious

⁴

not serious

⁵

not serious none ⨁⨁⨁◯

MODERATE

RR 0.91, 95% CI 0.85 to 0.97, P=0.005, I

²

=11%

Adjuvant therapy decreases mortality by 10% more than

neoadjuvant and surgery only at 5-year for T3-4

patients Disease Free Survival at 1-Year

780 (5 Studies)

not serious

¹

not serious

⁴

not serious

⁵

very serious

^6,7

none ⨁◯◯◯

VERY LOW

RR 0.82, 95% CI 0.67 to 1.02 P=0.07, I

²

=0%

There is no significant difference in adjuvant therapy vs surgery-only in 1-

year disease free survival Disease Free Survival at 5-Year

780 (5 Studies)

not serious

¹

serious

²

not serious

⁵

somewhat serious

⁶

none ⨁◯◯◯

VERY LOW

RR 0.96, 95% CI 0.79 to 1.17, P=0.68, I

²

=66%

There is no significant difference in adjuvant therapy vs surgery-only in 5-

year disease free survival Locoregional Recurrence

550 (4 Studies)

not serious

¹

not serious

⁴

not serious

⁵

very serious

^6,7

none ⨁◯◯◯

VERY LOW

RR 0.81, 95% CI 0.53 to 1.24, P=0.31, I

²

=15%

There is no significant difference in adjuvant therapy vs neoadjuvant therapy and surgery only in

locoregional recurrence Distal Recurrence

134 (2 Studies)

not serious

¹

serious

²

not serious

⁵

very serious

^6,7

none ⨁◯◯◯

VERY LOW

RR 0.68, 95% CI 0.30 to 1.52, P=0.34, I

²

=72%

There is no significant difference in adjuvant therapy vs neoadjuvant therapy and surgery only in

distal recurrence

1. While the majority of studies were not RCTs, all included studies demonstrated a low risk of selection bias, reporting bias and confirmation bias.

2. Quality of evidence was downgraded because high heterogeneity (I2>50%) was present in these meta-analyzed outcomes.

3. While I2<50%, the quality of the evidence was downgraded because point estimates varied greatly across studies with little overlap of confidence intervals.

4. Low heterogeneity, I2<50% with similar point estimates and overlapping confidence intervals.

5. The majority of included studies directly compare adjuvant therapy use to no adjuvant therapy in relevant patients and report common outcomes of interest.

6. Downgraded one point because of large confidence intervals that overlaps no effect, as well as effects favoring both adjuvant therapy and no adjuvant therapy, suggesting that more studies with larger sample sizes are needed 7. Downgraded one point because the total number of events was less than 300 or the total number of sample size was less than 400.

(11)

Supplementary Table 5. Summary of survival outcomes

N Analyzed

Follow-up Time (mo, SD)

Hazard Ratio for Mortality

Overall Survival N(rate)

Median Overall Survival (mo, range)

Disease-free Survival N(rate)

Median Disease-free Survival (mo, range)

Locoregional Recurrence N(%)

Distant Recurrence N(%)

Hospital Length of Stay (days, SD)

Operative or Postoperative Complications N (%) Ardalan,

2007

NACT + S

NACT + S + ACT

14

15

6 12 18 24 48 60 6 12 18 24 48 60

- - - - - Reference - - - - - 0.37

- 9 (64%) 7 (50%) 7 (50%) 4 (28%) 3 (20%) - 14 (94%) 12 (80%) 12 (80%) 9 (60%) 7 (47%)

- - - - - - - - - - - -

- - - - - - - - - - - - Hsu, 2016 NACRT + S

NACRT + S + ACRT

32

6 12 18 24 30 36 42 48 54 60 72 84 96 10 12 6 12 18 24 30 36 42 48 54 60 72 84 96 108 120

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

29 (90%) 22 (67%) 12 (38%) 10 (32%) 8 (25%) 7 (21.6%) 7 (22%) 5 (17%) 5 (17%) 5 (17%) 5 (15%) 4 (12%) 4 (12%) 4 (12%) 4 (12%) 32 (100%) 29 (90%) 19 (60%) 12 (38%) 12 (38%) 12 (38%) 12 (38%) 11 (34%) 11 (34%) 11 (34%) 11 (34%) 9 (30%) 8 (24%) 8 (24%) 8 (24%)

- - - - - - - - - - - - - - 17.36 (-) - - - - - - - - - - - - - - 19.73 (-)

15 (45%) 11 (35%) 8 (25%) 8 (25%) 7 (22%) 7 (22.3%) 7 (22%) 7 (22%) 7 (22%) 7 (22%) 7 (22%) 7 (22%) 7 (22%) 7 (22%) 7 (22%) 27 (84%) 16 (49%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%) 14 (45%)

- - - - - - - - - - - - - - 5.1 (-) - - - - - - - - - - - - - - 11.76 (-)

- - - - - - - - - - - - - - 9 (28.1%) - - - - - - - - - - - - - - 11 (34.3%)

- - - - - - - - - - - - - - 14 (43.8%) - - - - - - - - - - - - - - 6 (18.8%)

- - - - - - - - - - - - - - 22.47 ± 6.56 - - - - - - - - - - - - - - 21.69 ± 6.93

- - - - - - - - - - - - - - 5 (15.6%) - - - - - - - - - - - - - - 5 (15.6%)

Drake, 2019 NACRT + S 295 12

24 36 48

- - - -

250 (85%) 160 (54%) 117 (40%) 96 (33%)

- - - -

(12)

NACRT + S + ACT

295

60 12 24 36 48 60

Reference - - - - 0.839 (95%

CI: 0.715- 0.984)

60 (20.2%) 269 (91%) 186 (63%) 136 (46%) 110 (37%) 82 (27.9%)

24 (-) - - - - 31.2 (-)

- - - - - -

Huang, 2019 NACT + S

NACT + S + ACRT

81

6 12 18 24 30 36 42 48 54 60 72 84 96 108 6 12 18 24 30 36 42 48 54 60 72 84 96 108

- - - - - - - - - - - - - - - - - - - - - - - - - - - -

71 (88%) 65 (81%) 55 (68%) 51 (63%) 47 (58%) 45 (55%) 43 (53%) 42 (52%) 42 (52%) 39 (48%) 39 (48%) 39 (48%) 39 (48%) 39 (48%) 81 (100%) 73 (91%) 67 (83%) 62 (76%) 58 (71%) 48 (60%) 43 (54%) 40 (50%) 38 (47%) 38 (47%) 38 (47%) 38 (47%) 38 (47%) 38 (47%)

- - - - - - - - - - - - - - - - - - - - - - - - - - - -

- 54 (67%) - 50 (62%) 49 (61%) 47 (58%) 44 (55%) 42 (52%) 42 (52%) 40 (49%) 40 (49%) 39 (48%) 39 (48%) 39 (48%) - 63 (77%) - 50 (62%) 48 (59%) 39 (48%) 31 (39%) 27 (34%) 26 (33%) 25 (30%) 25 (30%) 25 (30%) 25 (30%) 25 (30%)

- - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - - - - - - Ruhstaller,

2018

NACRT + S

NACRT + S + ACT

151

149

6 12 18 24 30 36 42 48 54 60 72 6 12 18 24 30 36 42

- - - - - - - - - - - - - - - - - -

135 (89%) 119 (79%) 104 (69%) 95 (63%) 86 (57%) 77 (52%) 71 (47%) 65 (43%) 63 (42 %) 63 (42 %) 63 (42 %) 137 (92%) 127 (85%) 134 (76%) 106 (71%) 98 (66%) 92 (62%) 89 (60%)

- - - - - - - - - - 36 (95% CI:

26.4-50.4) - - - - - - -

136 (90%) 110 (73%) 88 (58%) 76 (50%) 65 (43%) 62 (41%) 60 (40%) 56 (37%) 55 (36%) 54 (36%) 53 (35%) 135 (91%) 110 (74%) 94 (63%) 86 (58%) 82 (55%) 75 (50%) 73 (49%)

- - - - - - - - - - 24 (95% CI:

18-33.6) - - - - - - -

- - - - - - - - - - 37 (24.5%) - - - - - - -

- - - - - - - - - - - - - - - - - -

(13)

48 54 60 72

- - - -

83 (56%) 81 (54%) 79 (53%) 75 (47%)

- - - 61.2 (95%

CI: 44.4-not reached)

72 (48%) 69 (46%) 69 (46%) 69 (46%)

- - -

34.8 (95% CI:

24-not reached) - - - 21 (14.1%)

- - - -

Huang, 2017 NACRT + S

NACRT + S + ART

41

29

12 24 36 48 60 72 84 96 108 120 12 24 36 48 60 72 84 96 108 120

- - - - - - - - - - - - - - - - - - - -

41 (100%) 16 (40%) 10 (24%) 7 (18%) 7 (18%) 7 (16%) 6 (15%) 6 (15%) 6 (15%) 6 (15%) 26 (89%) 14 (49%) 9 (31%) 7 (24%) 6 (21%) 5 (17%) 5 (17%) 3 (11%) 3 (11%) 3 (11%)

- - - - - - - - - - - - - - - - - - - -

- - - - - - - - - 7 (17.1%) - - - - - - - - - 5 (17.2%)

- - - - - - - - - 31 (75.6%) - - - - - - - - - 20 (69.0%)

- - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - Saeed, 2017 NACT + S

NACT + S + ACT

92

46

12 24 36 48 60 72 84 96 108 120 132 144 12 24 36 48 60 72 84 96 108 120 132 144

- - - - - - - - - - - - - - - - - - - - - - - -

79 (86%) 60 (65%) 45 (49%) 39 (42%) 33 (36%) 31 (34%) 26 (28%) 24 (26%) 22 (24%) 19 (21%) 13 (14%) 13 (14%) 41 (89%) 30 (66%) 21 (45%) 19 (41%) 18 (40%) 17 (37%) 17 (37%) 17 (37%) 16 (34%) 16 (34%) 11 (25%) 11 (25%)

- - - - - - - - - - - 33.6 (95%

CI: 24-43.2) - - - - - - - - - - - 32.4 (95%

CI: 19.2- 44.4)

70 (76%) 50 (54%) 40 (43%) 34 (37%) 30 (33%) 29 (31%) 26 (28%) 21 (23%) 21 (23%) 18 (20%) 16 (17%) 12 (13%) 38 (82%) 26 (56%) 18 (39%) 18 (39%) 15 (33%) 14 (31%) 14 (31%) 14 (31%) 14 (31%) 14 (31%) 14 (31%) 10 (21%)

- - - - - - - - - - -

26.4 (95% CI:

21.6-34.8) - - - - - - - - - - -

26.4 (95% CI:

16.8-36) - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - -

Mokdad, 2017

NACRT + S 3660 12

24 36

- - -

3257 (89%) 2269 (62%) 1720 (47%)

- - -

(14)

NACRT + S + ACT

732

48 60 12 24 36 48 60

- Reference - - - - 0.80 (95%

CI: 0.70- 0.92)

*negative margins subgroup*

1427 (39%) 1244 (34%) 695 (95%) 512 (70%) 401 (55%) 329 (45%) 285 (39%)

- - - - - - -

Luc, 2014 NACRT + S

NACT + S + ACT

55

61

6 12 18 24 30 36 48 60 6 12 18 24 30 36 48 60

- - - - - - - - - - - - - - - -

47 (85%) 42 (76%) 36 (66%) 31 (57%) 30 (55%) 30 (55%) 25 (45%) 20 (36%) 57 (93%) 54 (89%) 66 (82%) 46 (76%) 44 (72%) 27 (60%) 28 (46%) 28 (48%)

- - - - - - - 41 (-) - - - - - - - 45 (-)

44 (80%) 34 (61%) 26 (47%) 26 (47%) 21 (39%) 20 (36%) 18 (33%) 17 (31%) 52 (86%) 40 (65%) 40 (65%) 35 (57%) 33 (54%) 21 (35%) 21 (35%) 21 (35%)

- - - - - - - 36 (-) - - - - - - - 21 (-)

- - - - - - - 3 (5.4%) - - - - - - - 4 (6.6%)

- - - - - - - - - - - - - - - -

- - - - - - - 22 ± - - - - - - - - 33 ± -

- - - - - - - - - - - - - - - - Hoeppner,

2014

NACRT + S

NACT + S + ACT

58

47

12 24 36 48 60 12 24 36 48 60

- - - - - - - - - -

45 (78%) 37 (63%) 30 (52%) 29 (50%) 26 (45%) 45 (96%) 38 (81%) 32 (68%) 30 (63%) 30 (63%)

- - - - - - - - - -

- - - - 44 (75.9%) - - - - 25 (53.2%) Samson, 2018 NACRT + S

NACRT + S + ACT

1789

336

12 24 36 48 60 12 24 36 48 60

- - - - - - - - - -

1431 (80%) 930 (52%) 662 (37%) 501 (28%) 411 (23%) 302 (90%) 215 (64%) 165 (49%) 124 (37%) 108 (34%)

- - - - 33,3 (17.0- 74.0) - - - - 24.0 (13.5- 49.8)

- - - - - - - - - -

- - - - - - - - - - Semenkovich,

2019

NACRT + S 873 12

24 36 48

- - - -

716 (82%) 524 (60%) 428 (49%) 358 (41%)

- - - -

(15)

NACRT + S + ACT

209

60 72 84 96 108 120 180 12 24 36 48 60 72 84 96 108 120 180

- - - - - - Reference - - - - - - - - - - 0.76 (95%

CI: 0.62- 0.92)

332 (38%) 306 (35%) 297 (34%) 279 (32%) 271 (31%) 262 (30%) 267 (26%) 186 (89%) 142 (68%) 111 (53%) 90 (43%) 86 (41%) 79 (38%) 75 (36%) 75 (36%) 75 (36%) 67 (32%) 67 (32%)

- - - - - - 27.6 (95%

CI: 24-30) - - - - - - - - - 31.2 (95%

CI: 27.6- 40.8)

- - - - - - - - - - - - - - - - - -

- - - - - - Median 9 (8-14) - - - - - - - - - Median 10 (8-13)

- - - - - -

918 (105.1%) -

- - - - - - - - - 186 (89.0%)

Burt, 2016 NACRT + S

NACRT + S + ACT

808

35

12 24 36 48 60 12 24 36 48 60

- - - - Reference - - - - 0.82 (95%

CI: 0.50- 1.35)

711 (88%) 590 (73%) 509 (63%) 444 (55%) 420 (52%) 32 (92%) 29 (83%) 23 (67%) 22 (63%) 18 (52%)

- - - - - - - - - -

- - - - Median 10 (8-14) - - - - Median 10 (8-13)

- - - - - - - - - -

Eng, 2018 NACRT + S NACRT + S + ACT

4306 373

60 ± - 60 ± -

Reference 0.87 (95%

CI: 0.63- 0.88)

- -

NACT=Neoadjuvant chemotherapy, NACRT=Neoadjuvant chemoradiotherapy, ACRT=Adjuvant chemoradiotherapy, ACT=Adjuvant chemotherapy, ART=Adjuvant radiotherapy, AT=Adjuvant therapy

(16)

Supplementary Table 6. Incidence of toxicity related to neoadjuvant and/or adjuvant therapy

N Analyzed

Fatigue N(%)

Nausea/

Vomiting N(%)

Diarrhea N(%)

Constipation N(%)

Somatitis/

Mucositis N(%)

Anorexia N(%)

Dermatitis N(%)

Alopecia N(%)

Anemia N(%)

Leukopenia N(%)

Neutropenia N(%)

Thromboc ytopenia N(%) Ardalan,

2007

NACT + S NACT + S + ACT

33 15

20 (60.6%) 3 (20.0%)

14 (42.4%) 0 (0%)

9 (27.2%) 2 (13.3%)

6 (18.2%) 1 (6.7%)

13 (39.4%) 2 (13.3%)

6 (18.2%) 2 (13.3%)

- -

6 (18.2%) 2 (13.3%)

- -

5 (15.2%) 0 (0%)

- -

- - Hsu,

2016

NACRT + S NACRT + S + ACRT

41 74

- 11 (14.86%)

- 28 (37.84%)

- -

- 14 (18.92%)

- 9 (12.16%)

- 2 (2.7%)

- -

- 1 (1.35%)

- 10 (13.51%)

- -

- - Drake,

2019

295 295

- -

- - Huang,

2019

NACT + S NACT + S + ACRT

81 81

- -

- - Ruhstall

er, 2018

151 149

- -

- - Huang,

2017

NACRT + S NACRT + S + ART

41 29

- -

- - Saeed,

2017

NACT + S NACT + S + ACT

92 46

- -

- - Mokdad

, 2017

3660 732

- -

- - Luc,

2014

NACRT + S NACT + S + ACT

55 61

- -

- - Hoeppn

er, 2014

NACRT + S NACT + S + ACT

58 47

- -

- - Samson,

2018

2625 475

- -

- - Semenk

ovich, 2019

873 209

- -

- - Burt,

2016

NACRT + S 3257

335

- -

(17)

NACRT + S + ACT Eng,

2018

4306 373

- -

NACT=Neoadjuvant chemotherapy, NACRT=Neoadjuvant chemoradiotherapy, ACRT=Adjuvant chemoradiotherapy, ACT=Adjuvant chemotherapy, ART=Adjuvant radiotherapy, AT=Adjuvant therapy

(18)