Implications of recent neoadjuvant clinical trials on the future practice of radiotherapy in locally advanced rectal cancer

Table 1 Recent randomized trials evaluating the total neoadjuvant treatment approach in locally advanced rectal cancer

Trials	Identifier	Patients	Primary endpoint	Treatment arms	Results (arm A vs B vs C)
POLISH II[11,21]	NCT00833131	cT4 or fixed cT3 (primary or locally recurrent)	R0 resection	A: CRT (5-FU+LV #2) → S (→ CT); B: SCRT → FOLFOX4 #3 → S (→ CT)	R0: 71% vs 77% (NS); pCR: 12% vs 16% (NS)
FOWARC[12]	NCT01211210	cT3-4 or cN+	3 yr DFS	A: CRT (de Gramont #5) → TME → de Gramont #7; B: CRT (mFOLFOX6 #5) → TME → mFOLFOX6 #7; C: mFOLFOX6 #4-6 → TME → mFOLFOX6 #6-8	pCR: 14.0% vs 27.5% vs 6.5%; 3 yr DFS: 72.9% vs 77.2% vs 73.5% (NS); 3 yr LF: 8.0% vs 7.0% vs 8.3% (NS); 3 yr OS: 91.3% vs 89.1% vs 90.7% (NS)
RAPIDO[13,109]	NCT01558921	cT4 or MRF+ or N2 or lateral LN+ or EMVI+	3 yr DRTF1	A: CRT (cape) → TME → CAPOX #9 or FOLFOX4 #12; B: SCRT → CAPOX #6 or FOLFOX4 #9 → TME	3 yr DRTF: 30.4% vs 23.7%2; 3 yr DM: 26.8% vs 20.0%2; pCR: 14% vs 28%2
PRODIGE23[14]	NCT01804790	cT3-4 Nany	3 yr DFS	A: CRT (cape) → TME → mFOLFOX6 #12; B: FOLFIRINOX #6 → CRT (cape) → TME → mFOLFOX6 #6	3 yr DFS: 69% vs 76%2; pCR: 12% vs 28%2
STELLAR[15]	NCT02533271	cT3-4 or cN+	3 yr DFS	A: CRT (cape) → TME → CAPOX #6; B: SCRT → CAPOX #4 → TME → CAPOX #6	3 yr DFS: 62.3% vs 64.5% (NS); 3 yr OS: 75.1% vs 86.5%2; pCR: 11.8% vs 16.6%2
CAO/ARO/AIO-12[22,23]	NCT02363374	cT3-4 or cN+	pCR	A: FOLFOX #3 → CRT (5-FU+oxaliplatin) → TME; B: CRT (5-FU+oxaliplatin) → FOLFOX #3→ TME	pCR: 17% vs 25%2
OPRA[24,110]	NCT02008656	cT3-4N0 or cTanyN1-2	3 yr DFS	A: mFOLFOX6 #8 or CAPOX #5→ CRT → WW or TME; B: CRT → mFOLFOX6 #8 or CAPOX #5 → WW or TME	3 yr DFS: 76% vs 76% (NS); 3 yr TME-free survival: 41% vs 53%2
Tang et al[68] ongoing	NCT04543695	Stage II-III with at least one high-risk factors: MRF+, T4, N2, lateral LN, EMVI+	Downstaging (yp0-II, cCR)	A: CRT → TME → CAPOX #6; B: CRT → CAPOX #6 → TME or WW; C: CAPOX #6 → CRT → TME or WW	(Preliminary) yp0-II: 77.1% vs 84.2% vs 57.1%; pCR + sustained cCR: 22.9% vs 42.1% vs 28.6%
CAO/ARO/AIO-18.1[76] ongoing	NCT04246684	MRI-defined intermediate and high-risk factors: cT3 low rectal (< 6 cm from AV), cT3c/d middle rectal (≥ 6-12 cm), cT4 tumors, Tany middle/low third of rectum with N+, CRM ≤ 1 mm, EMVI+	3 yr organ preservation	A: SCRT → CAPOX #6 or mFOLFOX6 #8 → WW or TME; B: CRT (5-FU+oxaliplatin) → CAPOX #4 or mFOLFOX6 #6 → WW or TME

¹Disease-related treatment failure was defined as the first occurrence of locoregional failure, distant metastasis, a new primary colorectal tumor, or treatment­related death.

²Denotes statistically significant differences.

5-FU: 5-fluorouracil; AV: Anal verge; cape: Capecitabine; cCR: Clinical complete response; CRM: Circumferential resection margin; CRT: Chemoradiotherapy; CT: Chemotherapy; DFS: Disease-free survival; DM: Distant metastasis; DRTF: Disease-related treatment failure; EMVI: Extramural vascular invasion; LF: Local failure; LN: Lymph node; MRF: Mesorectal fascia; MRI: Magnetic resonance image; NS: Not significant; OS: Overall survival; pCR: Pathologic complete response; S: Surgery; SCRT: Short-course radiotherapy; TME: Total mesorectal excision; WW: Watch-and-wait.

Table 2 Recent prospective clinical trials using immune checkpoint inhibitors as a component of neoadjuvant treatment for locally advanced rectal cancer

Trials	Identifier	Patients	Primary endpoint	Treatment	Results
VOLTAGE-A[16]	NCT02948348	cT3-4 Nany (regardless of MMR status)	pCR	CRT (cape) → Nivolumab #5 → TME (→ mFOLFOX6/CAPOX)	pCR: 30% for MSS, 60% for MSI-H
AVANA[17]	NCT03854799	cN+ or cT4 or high-risk cT3 (CRM ≤ 1 mm, ≤ 6 cm from AV, or T3c/d)	pCR	CRT (cape) + Avelumab #6 → TME	pCR: 23%
R-IMMUNE[18]	NCT03127007	Stage II or III	pCR, safety	CRT(5-FU) + Atezolizumab #4 → S	pCR: 24%
NRG-GI002[19]	NCT02921256	Stage II or III with at least 1 of the following criteria: cT3-4 ≤ 5 cm from AV, any cT4 or tumor within 3 mm of MRF, cN2, not candidates for sphincter-sparing surgery at presentation	Neoadjuvant rectal score	A: mFOLFOX6 #6 → CRT (cape) → TME; B: mFOLFOX6 #6 → CRT (cape) + Pembrolizumab #6 → TME	NAR score: 14.08 vs 11.53 (NS); pCR: 29.4% vs 31.9% (NS)
AVERECTAL[41,111,112]	NCT03503630	cT2N+ or cT3-4aNany	pCR	SCRT → mFOLFOX6 + Avelumab #6 → TME	pCR: 37.5%
Lin et al[42]	NCT04231552	Stage II or III	pCR	SCRT → CAPOX + Camrelizumab #2 →TME	pCR: 48.1% (13/27), 46.2% (12/26) for pMMR, 100% (1/1) for dMMR
TORCH[43,113] ongoing	NCT04518280	cT3-4 or cN+	cCR or pCR	A: SCRT → CAPOX + toripalimab #6 → TME or WW; B: CAPOX + toripalimab #2 → SCRT → CAPOX + toripalimab #4 → TME or WW	(Preliminary) cCR + pCR: 81.3% (13/16 MSS patients); group A (n = 7): cCR 1, pCR 4, near pCR 1; group B (n = 9): cCR 4, pCR 4
Cercek et al[20] ongoing	NCT04165772	cT3-4 or cN+ with dMMR or MSI-H	cCR, pCR, overall response	Dostarlimab #9 → if cCR → WW; if residual+ → CRT → WW (cCR) or TME (residual+)	cCR: 100%
PRIME-RT[45] ongoing	NCT04621370	cT3b+ or EMVI+ or CRM ≤ 2 mm or a low rectal tumor requiring abdomino-perineal excision	cCR or pCR	A: (SCRT → mFOLFOX6 #6) + durvalumab #4 → S or WW; B: (CRT → mFOLFOX6 #4) + durvalumab #4 → S or WW
EA2201[46] ongoing	NCT04751370	cT3-4 or cN+ with dMMR or MSI-H	pCR	Ipilimumab/Nivolumab #2 → SCRT → Ipilimumab/Nivolumab #2 → TME
Qiu[47] ongoing	NCT04636008	cT2 or higher with dMMR or MSI-H	Adverse reaction after neoadjuvant treatment and perioperative complications	SCRT + Sintilimab #3 → TME or WW

5-FU: 5-fluorouracil; AV: Anal verge; cape: Capecitabine; cCR: Clinical complete response; CRM: Circumferential resection margin; CRT: Chemoradiotherapy; dMMR: Deficient mismatch repair; EMVI: Extramural vascular invasion; MMR: Mismatch repair; MRF: Mesorectal fascia; MSI-H: High microsatellite instability; MSS: Microsatellite stable; NAR: Neoadjuvant rectal; NS: Not significant; pCR: Pathologic complete response; pMMR: Proficient mismatch repair; S: Surgery; SCRT: Short-course radiotherapy; TME: Total mesorectal excision; WW: Watch-and-wait.