The ultimate local failure rate after the watch-and-wait strategy for rectal cancer: a systematic review of literature and meta-analysis

Figures & data

Figure 1. The pooled weighted rate of the ultimate local failure in the intention-to-treat analysis of all the patients starting radio(chemo)therapy (potential candidates for w&w).

Table 1. Ultimate local failure among all the patients starting radio(chemo)therapy as potential candidates for w&w.

	Patients’ and treatment characteristics	Median follow-up (months)	Rate of patients starting w&w N starting w&w/N starting radio(chemo)therapy	Regrowth rate N with regrowth/N starting w&w	Ultimate local failure rate N with local failure/N starting radio(chemo)therapy
OPRA, Garcia-Aguilar [2]	Stage II-III. Randomised study on planned w&w using TNT and comparing 4 months of induction vs consolidation FOLFOX or CAPOX combined with chemoradiation (50–56 Gy with FU continuous infusion or with cap.) W&w in cCR and all near-cCR.	36	225/312 (72%)	75/225 (33%)	45/312 (14%)^b
OPERA, Gerard [7]	Low or mid tumours, cT2-T3ab ≤5 cm in length and <50% circumferential involvement, cN0-N1 < 8mm. Randomised study comparing after chemoradiation (45 Gy with cap.) an EBRT boost of 9 Gy in 5 fractions, arm A (opportunistic strategy) vs RT dose escalation with a CXB boost of 90 Gy in 3 fractions, arm B (planned strategy). W&w in cCR and all near-cCR. 113 patients started w&w: 93 who achieved cCR/near-cCR and 20 after local excision.	38	Arm A 30/69 (43%) Arm B 63/72 (88%)	Arm A 10/30 (33%) Arm B 9/63 (14%)	Arm A 2/69 (3%) Arm B 3/72 (4%)^c
MORPHEUS, Garant [8]	Low or mid tumours, cT2-T3ab ≤5 cm in length and <50% circumferential involvement, cN0. Randomised study comparing after chemoradiation (45 Gy with cap.) an EBRT boost of 9 Gy in 5 fractions, arm A (opportunistic strategy) vs a BRT boost of 30 Gy in 3 fractions, arm B (planned strategy). W&w only in cCR.^a	39	Arm A 10/20 (50%) Arm B 18/20 (90%)	Arm A 4/10 (40%) Arm B 4/18 (22%)	Arm A 6/20 (30%) Arm B 3/20 (15%)^d
Habr-Gama [12]	Low and mid tumours, cT2-4 N1-2. Prospective study on planned w&w using TNT consisting of chemoradiation (54 Gy + 3 cycles of bolus FU and LV) and 2 months of consolidation bolus FU and LV. W&w group included cCR and near-cCR showing ypT0 after local excision.	23	43/70 (61%)	12/43 (28%)	3/70 (4%)^e
Appelt [13]	Low tumours, cT2-3 N0. Prospective study on planned w&w using RT dose escalation (60 Gy + BRT 5 Gy one fraction + tegafur-uracil). W&w only in cCR.^a	24	40/51 (78%)	9/40 (23%)	3/51 (6%)^f
Wang [14]	Low tumours, cT2-T3ab, MRF (−), EMVI (−), lateral nodes (−). Prospective study on planned w&w using TNT chemoradiation (50.6 Gy + cap.) + 3 months of consolidation CAPOX. W&w in cCR and all near-cCR.	40	40/64 (63%)	7/40 (18%)	2/64 (3%)^g
Asoglu [15,16]	Stage II-III. Retrospective study on planned w&w using TNT consisting of chemoradiation (50.4 Gy + cap.) + 3 months of consolidation FOLOX or 6 months of consolidation CAPOX. W&w only in cCR.^a	63	39/66 (59%)	10/39 (26%)	4/66 (6%)^h
PINTO [17]	Low tumours, stage I–III. Prospective study on opportunistic w&w after chemoradiation (50.4 Gy + cap.). W&w only in cCR.^a	12	16/93 (17%)	4/16 (25%)	8/93 (9%)^i

Intention-to-treat analysis.

N: numer of patients; w&w: watch-and-wait; FU: fluorouracil; FOLFOX: fluorouracil + leucovorin + oxaliplatin; CAPOX: capecitabine + oxaliplatin; cap.: capecitabine; LV: leucovorin; EBRT: external beam radiotherapy; CXB: contact X-ray brachytherapy; BRT: brachytherapy using Irydium; TME: total mesorectal excision; TNT: total neoadjuvant therapy; MRF(−): mesorectal fascia unphretened; EMVI(−): extramural vascular invasion absent.

^a“w&w only in cCR” confers that an analysis was performed in the subgroup of patients starting w&w formed after excluding those with near-cCR who did not achieved cCR and eventually required salvage surgery because of persistent or progressive near-cCR diagnosed during further observation.

^bRecurrence after TME for persistent tumour (n = 10), recurrence after salvage TME (n = 15), refused TME for persistent tumour (n = 4), refused salvage TME (n = 6), died during TNT (n = 6) and did not have salvage surgery because of distant metastases (n = 4).

^cArm A: refused salvage TME (n = 2), Arm B: no salvage surgery because of distant metastases (n = 1), refused salvage TME (n = 2).

^dArm A: died during chemoradiation (n = 1), unresectable persistent tumour (n = 1), refused salvage TME (n = 2), and recurrence after salvage TME (n = 2), Arm B: died from non-cancer reason before TME for persistent tumour (n = 1), refused salvage TME (n = 1) and recurrence after salvage TME (n = 1).

^eRecurrence after salvage TME (n = 1), no salvage TME because of frailty (n = 1), death during neoadjuvant CRT (n = 1).

^fRefused TME for persistent tumour (n = 3).

^gRefused TME for persistent tumour (n = 1), refused salvage TME (n = 1).

^hNo salvage TME because of distant metastases (n = 2), no TME for persistent tumour because of liver toxicity during TNT (n = 1), recurrence after TME for persistent tumour (n = 1).

ⁱRecurrences after TME for persistent tumour (n = 3), died before TME for persistent tumour (n = 1), patients who died or were severely disabled before re-evaluation (n = 4).

Figure 2. The pooled weighted rate of ultimate local failure among patients starting w&w.

Table 2. Ultimate local failure among the patients starting w&w strategy.

STUDY	Treatment characteristics	Median follow-up (months)	Rate of patients starting w&w N starting w&w/N starting radio(chemo)therapy	Regrowth rate N with regrowth/N starting w&w	Ultimate local failure rate N with local failure/N starting w&w	Local failure rate after salvage TMEN with local failure after salvage TME/N undergoing salvage TME	Rate of patients with local failure because of unresectable pelvic regrowth N with unresectable pelvic regrowth/N with regrowth	Rate of patients without salvage TME because of DM N without salvage TME because of DM/N with regrowth	Rate of pts refusing salvage TME N refusing salvage TME surgery/N with regrowth
OPRA, Garcia-Aguilar [2]	Stage II-III. Randomised study on planned w&w using TNT and comparing 4 months of induction vs consolidation FOLFOX or CAPOX combined with chemoradiation (50–56 Gy with FU continuous infusion or with cap.) W&w in cCR and all near-cCR.	36	225/312 (72%)	75/225 (33%)	23/225 (10%)^b	15/62 (24%)	0/75	2/75 (3%)	6/75 (8%)
OPERA Gerard [7]	Low or mid tumours, cT2-T3ab ≤5 cm in length and <50% circumferential involvement cN0-N1 < 8mm. Randomised study comparing after chemoradiation (45 Gy with cap.) an EBRT boost of 9 Gy in 5 fractions, arm A (opportunistic strategy) vs RT dose escalation with a CXB boost of 90 Gy in 3 fractions, arm B (planned strategy). w&w in cCR and all near-cCR. 113 patients started w&w: 93 who achieved cCR/near-cCR and 20 after local excision.	38	Arm A 30/69 (43%) Arm B 63/72 (88%)	Arm A 10/30 (33%) Arm B 9/63 (14%)	Arm A 2/30 (7%) Arm B 3/63 (5%)^c	Arm A 0/7 Arm B 0/6	Arm A 0/10 Arm B 0/9	Arm A 0/10 Arm B 1/9 (11%)	Arm A 2/10 (20%) Arm B 2/9 (22%)
MORPHEUS Garant [8]	Low or mid tumours, cT2-T3ab ≤5 cm in length and <50% circumferential involvement cN0. Randomised study comparing after chemoradiation (45 Gy with cap.) an EBRT boost of 9 Gy in 5 fractions, arm A (opportunistic strategy) vs a BRT boost of 30 Gy in 3 fractions, Arm B (planned strategy). W&w only in cCR.^a	39	Arm A 10/20 (50%) Arm B 18/20 (90%)	Arm A 4/10 (40%) Arm B 4/18 (22%)	Arm A 2/10 (20%) Arm B 2/18 (11%)^d	Arm A 2/3 (67%) Arm B 1/2 (50%)	Arm A 0/4 Arm B 0/4	Arm A 0/4 Arm B 0/4	Arm A 0/4 Arm B 1/4 (25%)
Habr-Gama [12]	Low and mid tumours, cT2-4 N1-2. Prospective study on planned l w&w using TNT consisting of chemoradiation (54 Gy + 3 cycles of bolus FU and LV) and 2 months of consolidation bolus FU and LV. w&w included cCR and near-cCR showing ypT0 after local excision.	23	43/70 (61%)	12/43 (28%)	2/43 (5%)^e	1/6 (17%)	0/12	0/12	0/12
Appelt [13]	Low tumours, cT2-3 N0. Prospective study on planned w&w using RT dose escalation (60 Gy + BRT 5 Gy one fraction + tegafur-uracil). W&w only in cCR.^a	24	40/51 (78%)	9/40 (23%)	0/40	0/9	0/9	0/9	0/9
Wang [14]	Low tumours, T2-T3ab, MRF (−), EMVI (−), lateral nodes (–). Prospective study on planned w&w using TNT consisting of chemoradiation (50.6 Gy + cap.) + 3 months of consolidation CAPOX. W&w in cCR and all near-cCR.	40	40/64 (63%)	7/40 (18%)	1/40 (3%)^f	0/4	0/7	0/7	1/7 (14%)
Asoglu [15,16]	Stage II–III. Retrospective study on planned w&w using TNT consisting of chemoradiation (50.4 Gy + cap.) + 3 months of consolidation FOLOX or 6 months of consolidation CAPOX. W&w only in cCR.^a	63	39/66 (59%)	10/39 (26%)	0/39	0/7	0/10	0/10	0/10
PINTO [17]	Low tumours, stage I–III. Prospective study on opportunistic w&w after chemoradiation (50.4 Gy + cap.). W&w only in cCR.^a	17	16/93 (17%)	4/16 (25%)	0/16	0/4	0/4	0/4	0/4
Van der Sande [18]	cT2-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation or 5 × 5 Gy. W&w in cCR and all near-cCR.	28	385/n. d.	89/385 (23%)	7/385 (2%)^g	2/65 (3%)	0/89	1/89 (1%)	1/89 (1%)
Habr-Gama [19]	cT2-4 N0-2. Prospective study on opportunistic w&w after chemoradiation (50.4–54 Gy with FU-based chemotherapy) W&w only in cCR.^a	60	90/183 (49%)	28/90 (31%)	6/90 (7%)^h	4/18 (22%)	0/28	1/28 (6%)	0/28
Martens [20]	cT1-4 N0-2. Prospective study on opportunistic w&w after chemoradiation (50.4 Gy with cap.) or 5 × 5 Gy. W&w only in cCR.^a	41	85/n. d.	12/85 (14%)	1/85 (1%)^i	0/11	0/12	1/12	0/12
Bitterman [21]	cT1-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with cap. or continuous FU). W&w only in cCR.^a	22	6/138 (4%)	0/6	0/6	0/0	0/0	0/0	0/0
Dalton [22]	cT2-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (45 Gy with cap.). W&w only in cCR.^a	mean 26	6/49 (12%)	0/6	0/6	0/0	0/0	0/0	0/0
Torres-Mesa [23]	cT2-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (40–55 Gy with FU). W&w only in cCR.^a	21	19/480 (4%)	8/19 (42%)	2/19 (10%)^j	0/6	2/8 (25%)	0/8	0/8
Gossedge [24]	cT2-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (50 Gy with cap.). W&w only in cCR.^a	48	15/28 (54%)	1/15 (7%)	1/15 (7%)^k	0/0	0/1	1/1 (100%)	0/1
Dickson-Lowe [25]	Stage not given. Retrospective study on opportunistic w&w after chemoradiation. W&w only in cCR.^a	Ng	14/n. d.	7/14 (50%)	0/14	0/3	0/7	0/7	0/7
Coraglio [26]	cT1-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (45–50.4 Gy with cap.). 3 months of induction XELOX was given for high risk tumours. W&w only in cCR.^a	47	23/256 (9%)	2/23 (9%)	0/23	0/2	0/2	0/2	0/2
Lee [27]	Low or mid tumours, cT2–3 N0–2. Retrospective study on opportunistic w&w after chemoradiation with cap. or FU. W&w only in cCR.^a	64.7	14/n. d.	3/14 (21%)	1/14 (7%)^l	0/2	0/3	0/3	1/3 (33%)
Yeom [28]	cT1-4 or N+. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with FU). W&w only in cCR.^a	20	169/1140 (15%)	4/15 (27%)	3/15 (20%)^m	0/1	0/4	1/4 (25%)	1/4 (25%)
Al-Najami [29]	cT1-4 or N0-2. Retrospective study on opportunistic w&w after chemoradiation (52 Gy with cap. or FU continuous infusion). W&w only in cCR.^a Some patients were included because of frailty.	45	42/231 (18%)	11/42 (26%)	8/42 (19%)^n	0/2	0/11	0/11	6/11 (55%)
Wang [30]	Stage II–III. Retrospective study on opportunistic w&w after chemoradiation (50 Gy wth cap. or FU ± oxaliplatin [28%]). 72% of the patients received consolidation or induction chemotherapy. W&w only in cCR.^a	38	94/n. d.	14/94 (15%)	2/94 (2%)^o	0/12	0/14	2/14 (14%)	0/14
Nilsson [31]	cT1-4 or N0-2. Prospective study on opportunistic w&w after 5 × 5 Gy, 5 × 5 Gy with 3 months of consolidation CAPOX or chemoradiation. W&w only in cCR.^a	33	87/n. d.	17/87 (20%)	2/87 (2%)^p	1/16 (6%)	0/17	1/17 (6%)	0/17
Cotti [32]	cT3-4 or N + or low cT2N0. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with FU continuous invusion). w&w only in cCR.^a	63	67/792 (8%)	20/67 (30%)	3/67 (4%)^q	3/20 (15%)	0/20	0/20	0/20
Lee [33]	cT3-4 or N + or low cT2N0. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with FU-based chemotherapy ± oxaliplatin). W&w only in cCR.^a	41	8/319 (3%)	2/8 (25%)	1/8^r	0/1	1/2 (50%)	0/2	0/2
Hsu [34]	Low or mid tumours cT1-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with FU ± oxaliplatin) or 5 × 5 Gy. W&w only in cCR.	78	36/680 (5%)	7/36 (19%)	4/36 (11%)^s	1/4 (25%)	1/7 (14%)	0/7 (6%)	1/7 (14%)
Nessar [35]	cT2-4 N+. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with bolus FU). W&w only in cCR.^a	56	7/61 (11%)	0/7	0/7	0/0	0/0	0/0	0/0
Sposato [36]	Stage II–III. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with cap. or infusional FU). W&w only in cCR.^a	38	32/185 (17%)	7/32 (22%)	1/32 (3%)^t	1/6 (17%)	0/7	0/7	0/7
d‘Amata [37]	cT1-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (55 Gy with cap.) W&w only in cCR.^a	24	8/n. d.	1/8 (13%)	0/8	0/1	0/1	0/1	0/1
Beard [38]	cT1-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (50.4 Gy with cap. or infusional FU). 15% of the patients received induction or consolidation FOLFOX or CAPOX.	35	53/465 (11%)	6/53 (11%)	2/53 (4%)^u	0/4	0/6	0/6	2/6 (33%)
Dai [39]	cT1-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (50 Gy with cap.). 93% of the patients received induction CAPOX.	34	25/100 (25%)	12/25 (48%)	3/25 (12%)^v	0/6	0/12	2/12 (17%)	1/12 (8%)
Engineer [40]	cT2-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (50–54 Gy with cap.). W&w in cCR and all near-cCR.	35	36/n. d.	6/36 (17%)	2/36 (6%)^w	0/4	0/6	0/6	2/6 (33%)
Simpson [41]	cT2-4 N0-2. Retrospective study on opportunistic w&w after chemoradiation (45 Gy with cap. or infusional FU). W&w only in cCR.^a	44	39/155 (25%)	6/39 (15%)	4/39 (10%)^x	0/1	0/6	0/6	3/6 (50%)
Rega [42]	cT2-4 N0-N+. Retrospective study on opportunistic w&w after chemoradiation (50 Gy with cap.) or 5 × 5 Gy. W-w only in cCR.^a	28	39/670 (6%)	6/39 (15%)	2/39 (5%)^y	0/4	0/6	0/6	2/6 (33%)
Chapman [43]	Stage II-III. Retrospective study on opportunistic w&w after TNT (4 months of induction CAPOX or FOLFOX, 50.4 Gy with cap. or infusional FU). W-w only in cCR.^a	23	18/102 (18%)	3/18 (17%)	0/18	0/2	0/3	0/3	0/3
Smith [44]	cT2-4 N0-1 Retrospective study on opportunistic w&w after 4 months of induction or consolidation FOLFOX with chemoradiation (45–54 Gy with cap. or infusional FU). W-w only in cCR.^a	33	113/1070 (11%)	22/113 (19%)	2/113 (2%)^z	2/20 (10%)	0/22	0/22	0/22
Smith RK [45]	cT1-4 N0-2 Retrospective study on opportunistic w&w after chemoradiation with cap. or FU. w-w only in cCR.^a	68	18/n. d.	1/18	1/18 (6%)^A	1/1	0/1	0/1	0/1

N: number of patients; w&w: watch-and-wait; FU: fluorouracil; FOLFOX: fluorouracil + leucovorin + oxaliplatin; CAPOX: capecitabine + oxaliplatin; cap.: capecitabine; LV: leucovorin; EBRT: external beam radiotherapy; CXB: contact X-ray brachytherapy; BRT: brachytherapy using Iridium; TME: total mesorectal excision; TNT: total neoadjuvant therapy; DM: distant metastases; n. d.: no data.

^a‘w&w only in cCR’ confers that an analysis was performed in the subgroup of patients starting w&w formed after excluding those with near-cCR who did not achieved cCR and eventually required salvage surgery because of persistent or progressive near-cCR diagnosed during further observation.

^bRecurrence after salvage TME (n = 15), refused salvage TME (n = 6), no salvage TME because of distant metastases (n = 2).

^cArm A: refused salvage TME (n = 2), Arm B: refused salvage TME (n = 2), no salvage TME because of distant metastases (n = 1).

^dArm A: recurrence after salvage TME (n = 2), Arm B: recurrence after salvage TME (n = 1), refused salvage TME (n = 1).

^eRecurrence after salvage TME (n = 1), no salvage TME because of frailty (n = 1).

^fRefused salvage TME (n = 1).

^gRecurrence after salvage TME (n = 2), recurrence after salvage brachytherapy (n = 2), refused salvage TME (n = 1), no salvage TME because of distant metastases (n = 1), no salvage TME because of frailty (n = 1).

^hRecurrence after salvage TME (n = 4), no salvage TME because of distant metastases (n = 1), no salvage TME because of frailty (n = 1).

ⁱNo salvage TME because of distant metastases (n = 1).

^jNo salvage TME because of unresectable pelvic disease (n = 2).

^kNo salvage TME because of distant metastases (n = 1).

^lrefused salvage TME (n = 1).

^mRefused salvage TME (n = 1), no salvage TME because of distant metastases (n = 1), regrowth treated with chemotherapy only - no reason given for the absence of TME (n = 1).

ⁿRefused salvage TME (n = 6), no TME because of frailty (n = 2).

^oNo salvage TME because of distant metastases (n = 2).

^pNo salvage TME because of distant metastases (n = 1), recurrence after salvage TME (n = 1).

^qRecurrence after salvage TME (n = 3).

^rNo salvage TME because of ‘inoperable stage’, details not given (n = 1).

^sRecurrence after salvage TME (n = 1), pelvic recurrence after salvage TME (n = 1), refused salvage TME (n = 1), lost from follow-up with regrowth without salvage TME (n = 1).

^tRecurrence after salvage TME (n = 1).

^uRefused salvage TME (n = 2).

^vNo salvage TME because of distant metastases (n = 2), refused salvage TME (n = 1).

^wRefused salvage TME (n = 2).

^xRefused salvage TME (n = 3), salvage TME not performed because of frailty (n = 1). All these 4 patients had salvage CXB.

^yRefused salvage TME (n = 2).

^zRecurrence after salvage TME (n = 2).

^ARecurrence after salvage TME (n = 1).

Figure 3. The pooled weighted rate of ultimate local failure among patients with regrowth.

Table 3. Measures potentially leading to a reduction of regrowth risk in the watch-and-wait (w&w) strategy.

Avoiding the use of the w&w strategy in patients with very advanced cancer where sustained complete clinical response (cCR) is unlikely, such as in patients with circular tumours or with a tumour length greater than 7 cm [49]. Moreover, in such advanced tumours, residual fibrosis and bowel narrowing make early detection of regrowth challenging. Avoiding the w&w strategy in patients with major tumour response, i.e., those with a small gross tumour that persists at evaluation. The implementation of w&w in such cases results in a high rate of regrowth [49,50]. Limiting the use of w&w in fit patients with cancer located beyond the reach of digital rectal examination. In such cases, digital rectal examination cannot be used as an accurate diagnostic toolfor tumour response evaluation and for the early detection of regrowth. Furthermore, the benefits of w&w, such as avoiding a permanent stoma, are less likely to be achieved in these patients compared with those with low-lying tumours. Applying brachytherapy boost. This technique has been shown to result in a reduction of the regrowth rate to about 15% [7,8,51]. Using consolidation instead of induction chemotherapy when adopting TNT. The OPRA trial demonstrated a lower regrowth rate after consolidation chemotherapy compared with induction chemotherapy [2]. This could be attributed to the higher risk of repopulation of surviving clonogens with induction chemotherapy. The risk of such repopulation is lower when radiotherapy is administered first, as the number of clonogens is more effectively reduced at the onset of treatment. Evaluating tumour response at the midpoint of consolidation chemotherapy. A reduction of tumour volume by more than 80% after chemoradiation predicts ypT0 [52]. Therefore, for patients with a smaller response at the midpoint of consolidation chemotherapy, immediate surgery might be considered.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.