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Table 7 Selected trials evaluating total neoadjuvant therapy approaches

From: Recent advances in (chemo-)radiation therapy for rectal cancer: a comprehensive review

Author

Year

Phase

Stage

n

Ind. CHT

RT dose

Conc. CHT

Cons. CHT

Adj. CHT

pCR (%)

Downst

3y-DFS

3y-OS

Tox gr.3+

Pop. c

Chau [144]

2006

II

High risk1

105

4xCAPOX

54

Cap

None

4xCap

20

n.r

68%

83%

n.r

n.r

Chua [145]

2010

              

Koeberle [146]

2008

II

T3/4

60

1xXELOX

45

Cap/Ox

None

dis

23

n.r

n.r

n.r

n.r

n.r

Zampino [147]

2009

II

T3/4 or N+

51

None

50,4

Cap

2xCap

Cap or CAPOX 6

18

30%9

85%12

n.r

n.r

n.r

Fernandez [148]

2010

II

T3/4 or N+

108

None

50,4

Cap/Ox

None

4xCAPOX

13

53%10

64%12

78%12

CRT 29%/adj. 54%

7%21

Fernandez [149]

2015

   

4xCAPOX

50,4

Cap/Ox

None

None

14

35%10

62%12

75%12

CRT 23%/ind. 19%

8%21

Nogue [150]

2011

II

T3/4 or N+2

47

4xXELOX/Bev

50,4

Cap/Bev

None

rec

36

69%10

n.r

n.r

n.r

24%21

Chiorean [151]

2012

II

T3/4 or N+

22

2xCap/Iri

50,4

Cap

None

rec

33

n.r

76%

n.r

n.r

n.r

Di Petrillo [64]

2012

II

T3/4 or N+

26

2xmFOLFOX6/Bev

50,4

5-FU ci/Ox/Bev

None

6xmFOLFOX6/Bev

20

n.r

80%13

95%13

n.r

n.r

Marechal [152]

2012

II

T3/4

57

None

45

5-FU ci

None

dis

28

35%11

n.r

n.r

CRT 7%

n.r

   

Or T2N+

 

2xmFOLFOX6

45

5-FU ci

None

dis

25

32%11

n.r

n.r

CRT 7%/ind. 25%

n.r

Dewdney [88]

2012

II, r

High risk3

165

4xCAPOX

50,4

Cap

None

CAPOX

15

n.r

Not sig

Not sig

n.r

n.r

Expert-C

    

4xCAPOX/Cet

50,4

Cap/Cet

None

CAPOX/Cet

18

n.r

Diff

Diff

n.r

n.r

Zhu [153]

2013

II

T3/4 or N+

42

None

44 5

Cap/Ox

1xCap

6-8xXELOX

16

n.r

57%

66%

n.r

n.r

Gao [154]

2014

II

T3/4 or N+

51

1xXELOX

50

Cap/Ox

1xXELOX

4xXELOX

42

n.r

n.r

n.r

n.r

11%

Borg [155]

2014

II, r

T3

91

6xFOLFOX/Bev

45

5-FU ci/Bev

None

n.s

24

66%9

n.r

n.r

50%

22%

     

None

45

5-FU ci/Bev

None

n.s

11

55%9

n.r

n.r

20%

22%

  

II

T3/4 or N+ 

259

None

50

5-FU ci

None

8xmFOLFOX6

18

n.r

50%12

79%12

cons. n.a.15,16

9%

Garcia-A [24]

2015

      

2xmFOLFOX6

6xmFOLFOX6

25

n.r

81%12

92%12

cons. 4%15,16

6%

Marco [156]

2018

      

4xmFOLFOX6

4xmFOLFOX6

30

n.r

86%12

88%12

cons. 18%15,16

4%

        

6xmFOLFOX6

2xmFOLFOX6

38

n.r

76%12

84%12

cons. 35%15,16

9%

Bujko [157]

2016

III

fix. T3

515

None

5 × 5

None

3xFOLFOX

dis

16

n.r

43%26

49%26

24%

n.r

Cisel [20]

  

or T4

 

None

50.4

5-FU/LV/Ox

None

dis

12

n.r

41%26

49%26

24%

n.r

Perez [158]

2017

II

T3/4 or N+

39

8xmFOLFOX6

50.4

Cap

None

n.s

33

56%10

80%13

n.r

n.r

13%

Cercek [159]

2018

re

T3/4 or N+

308

5xCAPOX19

50–50,4

5-FU ci or Cap

None

None

187

n.r

n.r

n.r

n.r

n.r

    

320

None

50–50,4

5-FU ci or Cap

None

CAPOX20

178

n.r

n.r

n.r

n.r

n.r

Fokas [25]

2019

II, r

T3/4 or N+

306

3 × 5-FU/LV/Ox

50,4

5-FU ci/Ox

None

None

17

n.r

n.r

n.r

CRT 37%/CHT 22%

17%

ARO-2012

    

None

50.4

5-FU ci/Ox

3 × 5-FU/LV/Ox

None

25

n.r

n.r

n.r

CRT 27%/CHT 22%

16%

van der Valk [160]

2020

III

High risk4

911

None

50.4

Cap

None

Opt.22

14

n.r

30%14

89%

25%17,23

15%

Hospers [161] RAPIDO

    

None

5 × 5

None

6xCAPOX18

Opt.22

28

n.r

24%14

89%

48%17,23

14%

Conroy [162]

2020

III

T3/4

461

None

50,4

Cap

None

8xCap24

12

n.r

69%

88%

n.r

n.r

PRODIGE 23

    

6 × mFOLFIRINOX

50,4

Cap

None

4xCap25

28

n.r

76%

91%

n.r

n.r

  1. n = number of patients, ind.: induction CHT (prior to chemoradiation), RT dose: radiation dose in Gy, conc. CHT: chemotherapy concurrent to radiation, cons. CHT: consolidation chemotherapy (after chemoradiation prior to surgery), adj. CHT: adjuvant chemotherapy after surgery, pCR rate: percentage of patients with pathologic complete regression, downstaging: percentage of patients with major downstaging defined according to study protocol (only listed if combined T and N downstaging was reported), 3y-DFS: 3-year disease free survival, 3y-OS: 3-year overall survival, grade 3+ tox: acute grade 3+ toxicity during chemotherapy and/or chemoradiation (only listed if an overall percentage was reported), pop.c.: postoperative complications grade 3+ (only listed if an overall percentage was reported), r.: randomized, re.: retrospective, fix.: fixed tumors, CAPOX: combination regimen including capecitabine and oxaliplatin, XELOX: combination regimen including capecitabine and oxaliplatin, Bev: Bevacizumab, Cap: Capecitabine, Iri: irinotecan, mFOLFOX6: combination regimen including 5-FU, leucovorine and oxaliplatin, Cet: Cetuximab, 5-FU: 5-fluorouracil, LV: leucovorine, Ox: Oxaliplatin, ci: contineous infusion, b: bolus, FOLFOX: combination regimen including 5-FU, leucovorine and oxaliplatin, dis.: at the discretion of the treating physician, rec.: recommended, n.s.: not specified, opt.: optional, n.r.: not reported, no. sig. diff.: no significant difference between arms, CRT: chemoradiation, n.a.: not applicable, 1: T3c or T4 or MRF+ or N2 orT3 at levator level,: T3 only if distal located or < 2 mm from MRF, 3: T3c or T4 or MRF+ or EVSI or tumor at levator level, 4: T4 or N2 or EVSI or MRF+ or positive lateral nodes, 5: in 20 fractions, 6: if pCR none, if N0 Cap., if N+ CAPOX, 7: 24% of the patients chose non-oprative management due to clinical complete remission, 8: 8% of the patients chose non-oprative management due to clinical complete remission, 9: downstaging defined as lower p vs c stage, 10: downstaging defined as ypstage 0–1, 11: downstaging defined as ypT0-1N0, 12: 5-year rate, 13: estimated from curve, 14: disease-related treatment failure (DrTF), 15: CRT toxicity reported for all groups together (28%), did not significantly differ between the groups, 16: toxicities for adjuvant CHT not reported, significantly less patients received adjuvant chemotherapy in group 1, 17: toxicities reported only for preoperative part of treatment, 18: or 9 × FOLFOX, 19: or 8 × mFOLFOX6, 20 or mFOLFOX6, 21: re-operation rate, 22: predifined strategy by center, either none or 8 × CAPOX or 12 × FOLFOX, 23: 35% for adjuvant chemotherapy, 24: or 12 × mFOLFOX (predefined choice by center), 25: or 6xmFOLFOX6 (predefined choice by center), 26: 8-year rate