Bevacizumab in the pre-operative treatment of locally advanced rectal cancer: A systematic review

Table 1 Bevacizumab with conventional chemo-radiotherapy: Overview of the discussed studies

Ref.	Phase	n	Treatment	Stage	Post-operative complications (n)	pCR
Willet et al[11], 2009	I-II	32	BV 5 or 10 mg/kg, 5-FU 225 mg/m2 daily, RT 50.4 Gy in 28 fr.	II-III	Anastomotic leak with presacral abscess (1)	16%
					Vaginal tear with presacral hematoma and abscess (1)
					Pelvic hematoma (1)
					Delayed healing of perineal incision (2)
					Ileus (2)
					Neurogenic bladder (1)
					Perforated ileostomy (1)
					Pulmonary embolus (1)
					Wound infection (3)
Crane et al[12], 2010	II	25	BV 5 mg/kg, CAPE 900 mg/m2bid, RT 50.4 Gy in 28 fr.	II-III	Wound complications requiring surgical intervention (3)	32%
					Minor complications (5)
Velenik et al[13], 2011	II	61	BV 5 mg/kg, CAPE 825 mg/m2bid, RT 50.4 Gy in 28 fr.	II-III	Delayed wound healing (18)	13.3%
					Infection/abscess (12)
					Anastomotic leakage (7)
					Pneumothorax (1)
Villacampa et al[15], 2012	IIb	90	Arm A: BV 5 mg/kg, CAPE 825 mg/m2bid, RT 45 Gy in 25 fr.	II-III	19 vs 18 patients (not specified)	16% vs 11%
			Arm B: CAPE 825 mg/m2bid, RT 45 Gy in 25 fr.
Gasparini et al[16], 2012	II	43	BV 5 mg/kg, CAPE 825 mg/m2bid, RT 50.4 Gy in 28 fr.	II-III	Bowel perforation (1)	14%
					Anastomosis failure (1)
					Abscess (1)
Marijnen et al[17], 2008	II	23	BV 5 mg /kg, CAPE 825 mg/m2bid, RT 50 Gy in 25 fr.	II-III	Perineal dehiscence (1)	9%
					Rectovaginal fistula (1)
					Peri-operative bleeding (1)
					Pulmonary embolism (1)

BV: Bevacizumab; RT: Radiotherapy; 5-FU: 5-fluorouracil; CAPE: Capecitabine; fr.: Fractions; pCR: Pathological complete response.

Table 2 Bevacizumab with oxaliplatin-based chemo-radiotherapy: Overview of the discussed studies

Ref.	Phase	n	Treatment	Stage	Post-operative complications (n)	pCR
Czito et al[18], 2007	I	11	BV 15 mg/kg and 10 mg/kg, CAPE 625 mg/m2bid, oxaliplatin 50 mg/m2 weekly, RT 50.4 Gy in 28 fr.	II-III	Abscess (1)	18%
Dellas et al[19], 2013	II	70	BV 5 mg/kg, CAPE 825 mg/m2bid, oxaliplatin 50 mg/m2 weekly, RT 50.4 Gy in 28 fr.	II-III-IV	Anal fistula (1)	17.4%
					Pelvic abscess (1)
					Delayed wound healing (1)
Kennecke et al[20], 2012	II	42	BV 5 mg/kg, CAPE 825 mg/m2bid, oxaliplatin 50 mg/m2 weekly, RT 50.4 Gy in 28 fr.	II-III-IV	Pelvic infection (11)	18.4%
					Delayed healing (7)
					Anastomotic leak (6)
					Fistula (3)
Landry et al[21], 2013	II	57	BV 5 mg/kg, CAPE 825 mg/m2bid, oxaliplatin 50 mg/m2 weekly, RT 50.4 Gy in 28 fr. (+ post-operative FOLFOX + BV)	II-III	Early complications:	17%
					Wound infection (8)
					Fascial dehiscence (5)
					Intra-abdominal abscess (1)
					Fistula (1)
					Bowel obstruction (1)
					Thromboembolism (1)
					Late complications:
					Wound infection (23)
					Wound/fascial dehiscence (12)
					Bowel obstruction/ileus (5)
					Intra-abdominal abscess (2)
					Anastomotic leak (1)

CT-RT: Chemo-radiotherapy; BV: Bevacizumab; RT: Radiotherapy; CAPE: Capecitabine; fr.: Fractions; FOLFOX: 5-fluorouracil and oxaliplatin; pCR: Pathological complete response.

Table 3 Bevacizumab with chemotherapy as induction therapy before chemo-radiotherapy: Overview of the discussed studies

Ref.	Phase	n	Treatment	Stage	Post-operative complications (n)	pCR
Dipetrillo et al[26], 2012	II	25	Induction FOLFOX + BV followed by BV 5 mg/kg, 5-FU 200 mg/m2 daily, oxaliplatin 50 mg/m2 weekly, RT 50.4 Gy in 28 fr.	II-III	Infection (4)	20%
					Delayed healing (3)
					Leak/abscess (2)
					Sterile fluid collection (2)
					Ischemic colonic reservoir (1)
					Fistula (1)
Nogué et al[27], 2011	II	47	Induction XELOX + BV followed by BV 5 mg/kg, CAPE 825 mg/m2bid, RT 50.4 Gy in 28 fr.	II-III	Wound infection (10)	36%
					Intra-abdominal infections (7)
					Anastomotic leak (5)
					Stoma complications (2)
					Other (not specified) (10)
Vivaldi et al[28], 2013	II	15	Induction FOLFOXIRI + BV followed by BV 5 mg/kg, CAPE 825 mg/m2bid or 5-FU 225 mg/m2 daily, RT 50.4 Gy in 28 fr.	II-III	Dehiscence of anastomosis (1)	38%

CT: Chemotherapy; CT-RT: Chemo-radiotherapy; BV: Bevacizumab; RT: Radiotherapy; 5-FU: 5-fluorouracil; CAPE: Capecitabine; fr.: Fractions; FOLFOX: 5-FU and oxaliplatin; XELOX: Capecitabine and oxaliplatin; pCR: Pathological complete response.

Table 4 Bevacizumab with chemotherapy without chemo-radiotherapy: Overview of the discussed studies

Ref.	Phase	n	Treatment	Stage	Post-operative complications (n)	pCR
Schrag et al[31], 2014	II	32	FOLFOX + BV for 4 cycles, then FOLFOX for 2 cycles, CT-RT in case of SD or PD (post-op. if R1-R2 resections, pT4 or pN2)	II-III (no T4)	Renal failure due to dehydration from high volume ileostomy output resulting in death (1)	25%
Hasegawa et al[32], 2013	II	25	XELOX + BV for 3 cycles, then XELOX for 1 cycle	II-III (T4 or N+)	Nine patients (not specified)	4%
Fernandez-Martos et al[33], 2012	II	46	XELOX + BV for 3 cycles, then XELOX for 1 cycle, CT-RT in case of PD	Intermediate-risk T3	Three patients (not specified)	15%

CT: Chemotherapy; CT-RT: Chemo-radiotherapy; BV: Bevacizumab; RT: Radiotherapy; post-op.: Post-operative; FOLFOX: 5-FU and oxaliplatin; XELOX: Capecitabine and oxaliplatin; SD: Stable disease; PD: Progressive disease; pCR: Pathological complete response.

Table 5 Main ongoing trials with bevacizumab in locally-advanced rectal cancer

Study	Design	n	Pre-operative treatment	RT	Primary endpoint	Status	Comments
AXE BEAM trial (NCT00828672)	Randomized	80	Concomitant XELOX +/- BV + RT	CT-RT	pCR	Recruiting
	Phase II			45 Gy
New Beat trial (NCT01554059)	Phase II	28	Concomitant FOLFOX + BV + RT	CT-RT	pCR	Recruiting
				40 Gy/20 fractions
NCT01818973	Phase II	45	XELOX + BV for 1 cycle followed by concomitant CT-RT with XELOX + BV for 2 cycles and RT	CT-RT	Tumor regression grade	Recruiting	Adjuvant CT with XELOX for 3 cycles followed by capecitabine for 2 cycles
				50 Gy/25 fractions
BACCHUS trial (NCT01650428)	RandomizedPhase II	60	FOLFOX + BV for 5 cycles followed by FOLFOX for 1 cycle vs FOLFOXIRI + BV for 5 cycles followed by FOLFOXIRI for 1 cycle	No	pCR	Recruiting	Magnetic resonance imaging-defined poor risk criteria
NCT01871571	Phase II	43	mFOLFOX7 + BV for 6 cycles	No	pCR	Recruiting
NCT00865189	Randomized Phase II	91	FOLFOX + BV for 6 cycles followed by CT-RT with BV and 5-FU vs CT-RT alone	CT-RT	pCR	Ongoing, not recruiting	Not specified RT dose and fractioning
NCT00462501	Phase II	36	FOLFOX + BV for 4 cycles followed by FOLFOX for 2 cycles with selective use of CT-RT with 5-FU in patients not candidate for R0 resection	CT-RT	R0 resection rate	Ongoing, not recruiting	Not specified RT dose and fractioning
TRUST trial (EUDRACT 2011-003340-45)	Phase II	43	FOLFOXIRI + BV for 6 cycles followed by CTRT with BV and capecitabine or 5-FU	CT-RT 50.4 Gy/28 fractions	DFS rate at 2 yr	Recruiting

LARC: Locally-advanced rectal cancer; BV: Bevacizumab; RT: Radiotherapy; CT: Chemotherapy; CT-RT: Chemo-radiotherapy; pCR: Pathological complete response; DFS: Disease-free survival; 5-FU: Fluorouracil; XELOX: Capecitabine and oxaliplatin; FOLFOX: 5-FU and oxaliplatin; FOLFOXIRI: 5-FU, oxaliplatin and irinotecan.