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Table 6 Prospective trials with neoadjuvant concurrent chemoradiation with radiation dose escalation or altered fractionation

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

Author

Year

Phase

Disease stage

n

RT dose

Conc. CHT

Adj. CHT

pCR rate

Downst

Tox gr.3+

Postop. C

late gr3+

Meade [110]

1995

po

T3/4

20

45–54 (25–30 Fx)

5-FU

dis

35%

70%31

10%

n.r

5%

Movsas [111]

1998

I

T3/441

27

54.6–61.8 (33–39 Fx)1

5-FU

5-FU/LV

17%

57%31

37%

13%

n.r

Mohiuddin [112]

2000

po

Fixed

15

45–50 (25 Fx)

5-FU b or ci

n.s

13%

n.r

33%37

n.r

9%

    

18

55–60 (30 Fx)

5-FU b or ci

 

44%

    

Pfeiffer [113]

2005

I/II

Irres. or rec

18

60 (30 Fx)2

UFT (esc)

n.s

11%

n.r

7%

n.r

n.r

Jakobsen [114]

2006

po

T3

50

60 (30 Fx)2 + Br. 1 × 5

UFT

n.s

27%

n.r

10%

8%40

n.r

Movsas [115]

2006

II

T3/441

22

61.8 (39 Fx) 3

5-FU

5-FU/LV

n.r

50%31

14%

14%

n.r

Freedman [116]

2007

I

T3/4 or N+

8

55 (25 Fx) 4

Cap

n.s

0%

50%31

38%

n.r

n.r

El-Sayed [117]

2008

II

T3/4

17

45 (25 Fx) + Br. 2 × 4

Cap + Ox

n.s

47%

n.r

n.r

n.r

0%

Jakobsen [99]

2008

II

T3/4

35

60 (30 Fx)2 + Br. 1 × 5

UFT + Cele

n.s

21%

n.r

6% (49%38)

n.r

n.r

Vestermark [118]

2008

II

Irres. or rec

52

60 (30 Fx)2

UFT + LV

n.s

13%

n.r

8%

n.r

n.r

Ballonoff [119]

2008

II

T3/4 or N+

8

55 (25 Fx)4

Cap

Cap or 5-FU/LV

38%

63%31

13%

n.r

n.r

Lindebjerg [120]

2009

II

T3/4

135

60 (30 Fx)2

5-FU/LV

n.s

19%

n.r

n.r

n.r

n.r

Marsh [121]

2010

II

T3/4 or N1

16

50.4–55.2 (42–46 Fx)5

Cap

Reco

18%

69%31

19%

n.r

n.r

Maluta [122]

2010

II

T3/4 or N+

70

60 (30 Fx)6

5-FU + Ox + HT

dis

24%

63%31

n.r

3%40

3%

Arbea [123]

2011

II

T3/4 or N+

100

47.5 (19–20 Fx)

Cap + Ox

CAPOX24

13%

n.r

n.r

5%40

n.r

Caravatta [124]

2011

II

T3/4 or N+ 

25

55 (25 Fx)8

Ral + Ox

Reco.25

32%29

76%31

8%

n.r

n.r

Barsukov [125]

2012

II

Fixed T4

64

40 (10 Fx)9

Cap + Ox + HT

n.s

11%

n.r

20%

n.r

n.r

Caravatta [126]

2012

I/II

T3/4 or N+

46

50.4 (28 Fx)

Ral

n.s

0%29

0%32

DLT 0%

n.r

n.r

     

55 (25 Fx)8

Ral

 

25%29

25%32

DLT 13%

  
     

50.4 (28 Fx)

Ral + Ox

 

25%29

31%32

DLT 18%

  
     

55 (25 Fx)8

Ral + Ox

 

25%29

31%32

DLT 25%

  

Li [127]

2012

II

T3N0 or N+

63

50.6 (22 Fx)10

Cap

dis

31%

79%31

n.r

7%40

n.r

Jakobsen [128]

2012

III

T3-4 or N+

248

50.4 (28 Fx)

UFT/LV

dis

18%

n.r

n.s. diff

8%40

n.r

     

50.4 (28 Fx) + Br. 2 × 5

UFT/LV

 

18%

  

5%40

 

Vestermark [129]

2012

I

Irres. or rec

18

60 (30 Fx)2

UFT/LV + Ox (esc)21

n.s

33%

Res. 83%

n.r

n.r

n.r

Mohiuddin [51, 52]

2013

II, rand

T3/4

106

55.2–60 (46–50 Fx)11

5-FU ci

Reco.26

28%

78%31

42%

n.r

4%

RTOG 0012

    

50.4–54 (28–30 Fx)

5-FU ci + Iri

 

28%

78%31

51%

n.r

8%

Zhu [130]

2014

II

T3/4 or N+

78

55 (25 Fx)12

Cap + Ox22

CAPOX

24%

n.r

n.r

n.r

n.r

Cubillo [131]

2014

po

T3 or N1

16

57.5 (23 Fx)13

Cap + Iri/Ox/Bev23

dis

50%

75%31

25%

n.r

n.r

Hernando [132]

2014

po

T3/4 or N+

74

57.5 (23 Fx)13

Cap

n.s

31%

n.r

18%

7% (gr. 4)

n.r

Appelt [133]

2015

po

T2/3 N0-1

55

60 (30 Fx)14 + Br. 1 × 5

UFT

Reco.27

78%30

n.r

12%

n.a

7%

Omidvari [134]

2015

II, mat

T3/4 or N+

34

45 (25 Fx) + Br. 3 × 515

Cap + Ox

n.s

29%

n.r

6%

n.r

n.r

    

102

45 (25 Fx)

Cap + Ox

n.s

12%

 

1%

  

But-Hadzic [135]

2016

II

T3/4 or N+

51

46.2–48.4 (22 Fx)16

Cap

n.s

26%

87%31

4%

9%

n.r

Picardi [136]

2016

II

T4 or rec

18

55 (25 Fx)8

Ral + Ox

n.s

28%

89%33

44%

n.r

11%

Hall [137]

2016

NODA

T3/4 or N+

3298

< 4516

5-FU or Cap

n.s

n.r

n.r.34

n.r

n.r

n.r

     

4516

  

11%

37%34

   
     

50.416

w/wo Ox

 

16%

44%34

   
     

5416

  

19%

49%34

   

Picardi [138]

2016

II

T3/4 or N+42

18

57.5 (25 Fx)18

Cap + Ox

n.s

25%

n.r

44%

n.r

n.r

Tey [139]

2017

II

T3/4 or N+

23

55 (25 Fx)4

Cap

Cap or CAPOX

35%

n.r

5%

0%

5%

Idasiak [140]

2017

II

T2N+ or T3/4

53

42 (28 Fx)17

5-FU b

reco.28

11%

n.r

8%

8%40

n.r

Alongi [141]

2017

po

Loc. adv

40

60 (30 Fx)19

Cap

n.s

18%

n.r

n.r

10%

3%

Gunther [142]

2017

II, mat

T3/4 or N+

76

52.5 (25 Fx)20

5-FU ci

5-FU

17%

n.r.36

n.s. diff

n.s. diff

n.r

    

76

45 (25 Fx)

5-FU ci

5-FU

16%

    
  1. n = number of patients, RT dose: radiation dose in Gy (Fx: number of fractions), conc. CHT: concurrent chemotherapy, adj. CHT: adjuvant chemotherapy, 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), tox gr.3+: acute grade 3+ toxicity during chemoradiation (only listed if an overall percentage was reported), postop. c.: postoperative complications (only listed if an overall percentage was reported), late gr.3+: grade 3+ late complications (only listed if an overall percentage was reported), NODA: National Oncology Data Alliance database TM, po: prospective observational, rand.: randomized, mat.: with matched pair arm, cm: centimeter, irres.: irresectable, rec.: recurrent, 5-FU: 5-fluorouracil, b: bolus, ci: contineous infusion, UFT: uracil tegafur, esc: dose escalated, Cap: capecitabine, Ox: oxaliplatin, Cele: celecoxib, LV: leucovorine, HT: hyperthermia, Rali: ralitrexed, Iri: irinotecan, Bev: bevacizumab, w/wo: with or without, dis.: at the discretion of the treating physician, n.s.: not specified, reco.: recommended, CAPOX: combination regimen including capecitabine and oxaliplatin, n.r.: not reported, DLT: dose limiting toxicity, n.s. diff.: not significantly different, n.a.: not applicable, seq.: sequential, bid: 2 fractions per day, conco: concomittant, SIB: simultaneous integrated boost, Br.: brachytherapy boost, 1: 45 Gy in 25 Fx to pelvis, seq. boost 9.6–16.8 Gy (1.2 Gy bid), 2: 48.6 Gy in 27 Fx to pelvis with conco. boost 5.4 Gy /27 Fx + seq. boost 6 Gy (3 Fx), 3: 45 Gy in 25 Fx to pelvis, seq. boost 16.8 Gy (1.2 Gy bid), 4: 45 Gy in 25 Fx to pelvis, SIB to 55 Gy, 5: 50.4 Gy (1.2 Gy bid) for T3, 54 Gy (1.2 Gy bid) for T4, 6: 50 Gy in 25 Frx to pelvis, seq. boost 10 Gy/5 Fx, 8: 45 Gy in 25 fx to pelvis, conco boost 10 Gy/25 Fx, 9: 3 fx per week, 10: 41.8 Gy in 22 Fx to pelvis, SIB to 50.6 Gy, 11: 55.2–60 Gy (1.2 Gy bid), 12: 50 Gy in 25 Fx to pelvis, conco. boost 5 Gy /5 Fx, 13: 46 Gy in 23 Fx to pelvis, SIB 57.5 Gy, 14: 50 Gy in 30 Fx to pelvis, SIB to 60 Gy, 15: Low-dose-rate Brachytherapy, 16: 41.8 Gy in 22 Fx to pelvis, SIB 46.2 for T3, 48.4 Gy for T4, 16: conventional fractionation (altered fractionation excluded from analysis), 17: 42 Gy (1.5 Gy bid), 18: 45 Gy in 25 Fx to pelvis, SIB to 57.5 Gy, 19: 54 Gy in 30 Fx to pelvis, SIB to 60 Gy, 20: 45 Gy in 25 Fx to pelvis, conco. boost last week 7.5 Gy/5Fx, 21: one additional cycle of chemotherapy prior to and after chemoradiation prior to surgery, 22: one cycle of chemotherapy after chemoradiation prior to surgery, 23: Cap. combined with Iri or Ox or Bev according to KRAS-, BRAF-, ERCC-1, Topo-1-Status, 24: in patients with cN+, pN+ or poor response, 25: if ypN+, 26: 6: adjuvant chemotherapy was recommended for all patients with residual disease, in patients without residual disease Chemotherapy was at the discretion of the treating physician, 27: chemotherapy was recommended after surgery in case of T4, R1, EVSI, Pn1, N+ or G3, 28: chemotherapy was recommended if N+, 29: pCR defined as ypT0, 30: clinical complete response, 31: downstaging defined as reduction of p stage compared to c stage, 32: downstaging defined as ypT0-mic, 33: downstaging defined as achieving secondary resectability, 34: downstaging defined as ypT0-2N0, 36: significantly increased rate of T downstaging by RT dose escalation, 37: both arms together, 38: treatment with celecoxib terminated due to rash although all grade 1–2, 39: 18% vs 4% for 19 fx vs 20 fx arm, 40: re-operation rate, 41: only T3 < 4 cm, 42: recurrent tumors eligible
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Radiation Oncology

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