Watch and wait in locally advanced rectal cancer: Evolution, current evidence, and future directions

Table 1 Phase III clinical trials using total neoadjuvant therapy in organ preserving therapy, %

Ref.	Patient included	Treatment1	Survival	P value	Survival free of disease	P value	Local recurrence	P value
Gastrointestinal Tumor Study Group[55], 1985	227	Surgery	36	0.20	45	0.85	55	< 0.009
		Surgery + RT	46	0.20	55	0.85	48	< 0.009
		Surgery + CT	46	0.20	60	0.85	46	< 0.009
		Surgery + CTRT	56	0.20	70	0.85	33	< 0.009
Fisher et al[56], 1988	555	Surgery, control	43		30		24.5	0.06
		Surgery + RT	45	0.7	33	0.4	16.3	0.06
		Surgery + CT	53	0.05	42	0.006	21.4	0.06
Krook et al[57], 1991	204	Surgery + RT	62	0.043			62	0.0025
		Surgery + CTRT	49	0.043			40	0.0025
Frykholm et al[61], 1993	471	RT + surgery	54	0.5			13	0.02
		Surgery + RT	52	0.5			22	0.02
Swedish Rectal Cancer Trial[58], 1997	1168, < 80 years	RT + surgery	74	0.002			11	< 0.001
		Surgery	65	0.002			27	< 0.001
Kapiteijn et al[59], 2001	1861	RT + surgery, TME	82	0.84			2.4	< 0.001
		Surgery, TME	81.2	0.84			8.2	< 0.001
Bosset et al[65], 2006	1011, T3-4	RT + surgery, TME	64.8	0.84	54.4	0.52	17.1	0.002
		CTRT + surgery, TME	65.8	0.84	56.1	0.52	8.7	0.002
		RT + surgery, TME + CT	64.8	0.84	54.4	0.52	9.6	0.002
		CTRT + surgery, TME + CT	65.8	0.84	56.1	0.52	7.6	0.002
van Gijn et al[60], 2011	1861	RT + surgery, TME, TNM III, circumferential margin negative	50	0.032			5	< 0.0001
		Surgery, TME, TNM III, circumferential margin negative	40	0.032			11	< 0.0001
Sauer et al[64], 2012	823	CTRT + surgery, TME + CT	59.6	0.85	68.1	0.65	7.1	0.048
		Surgery, TME + CTRT	59.9	0.85	67.8	0.65	10.1	0.048

¹No benefit in overall or disease-specific survival was observed when adding chemotherapy. Significant reduction in local recurrences. Radiotherapy as the standard treatment alongside total mesorectal excision for locally advanced rectal cancer.

CT: Chemotherapy; CTRT: Chemotherapy and radiotherapy; RT: Radiotherapy; TME: Total mesorectal excision; TNM: Tumor-node-metastasis.

Table 2 Clinical trials review in total neoadjuvant therapy in organ preserving therapy, %

Ref.	Clinical trials	Patients	Stage	Treatments1	pCR rates	Locorregional control	MFS	DFS
Bujko et al[118], 2016	POLISH II	261	T3-4	SCRT + CT	16	78	70	53
				RT + CT	12	79	73	52
Bahadoer et al[76], 2021	RAPIDO	462	T4, N2	SCRT + CT	28	92	80	76
				RT + CT	14	94	73	70
Conroy et al[78], 2021	UNICANCER-PRODIGE 23	231	T3-4, N1-2	CT + RT + CT	28	96	79	76
				RT + CT	13	94	72	69
Jin et al[120], 2022	STELLAR	298	T3-4, N1-2	SCRT + CT + CT	17	92	77	65
				RT + CT	12	89	75	62

¹Short course radiotherapy shows comparable disease-free survival to long-course radiotherapy but higher clinically complete response rates without differences in overall survival.

CT: Chemotherapy; DFS: Disease-free survival; MFS: Metastasis-free survival; pCR: Pathological complete response; RT: Radiotherapy; SCRT: Short course radiotherapy.