European Journal of Cancer

Volume 218, 11 March 2025, 115261

Review

Total neoadjuvant treatment, non-operative

management and radiotherapy-free
strategies: New approaches for the
management of proficient mismatch
repair/microsatellite stable locally advanced
rectal cancer. A narrative review and
evidence-based algorithm
Roberto Moretto a, Chiara Boccaccio a b, Matteo Landi a b, Gianluca Masi a b,
Chiara Cremolini a b

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 Highlights

• New strategies have recently emerged for the treatment of

pMMR/MSS LARC.

• TNT including CTRT reduced distant recurrence with similar LR

respect to CTRT.

• NOM is a promising strategy to preserve rectum in patients

achieving cCR/ncCR.

• RT-free strategies improve QoL and reduce toxicity in low-risk LARC.

• An algorithm to integrate new approaches into clinical practice is

needed.

Abstract
In recent years, new therapeutic approaches have emerged in addition to classical
neoadjuvant (chemo)radiotherapy for the treatment of locally advanced rectal cancer
(LARC): total neoadjuvant treatment, non-operative management, and radiotherapy-free
strategy. While the introduction of these approaches in a relatively short timeframe has
quickly increased our therapeutic armamentarium, on the other hand it has complicated
the decision-making process regarding the choice of the most appropriate treatment
strategy for each patient with LARC. Therefore, a tool to interpret the evidence from
clinical trials and to translate them into daily practice is highly demanded. In the present
review, we address how these new developments are changing the multimodal
treatment of LARC and offer an algorithm to integrate them into clinical practice.

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Keywords
Locally advanced rectal cancer; Total neoadjuvant treatment; Non-operative
management; Radiotherapy-free approach

1. Introduction
Neoadjuvant long-course chemoradiotherapy (CTRT) or short-course radiotherapy (SCRT)
followed by total mesorectal excision (TME) and possibly by adjuvant chemotherapy has
been the standard of care for the treatment of locally advanced rectal cancer (LARC)
(cT3/4 and/or N + ) over the past 20 years [1]. However, although this multimodal
approach showed remarkable local disease control leading to a reduction of local relapse
from 11 % to 12 % with TME alone or followed by adjuvant CTRT to about 6–7 % and with a
pathological complete response (pCR) of about 15 %, the high distant relapse rate (25–
30 %) remains a crucial issue. A possible reason explaining the lack of distant relapse
reduction can be attributed to the poor compliance to adjuvant treatment. Indeed, only
about 75 % and 50 % of patients start and complete adjuvant chemotherapy, respectively,
after neoadjuvant treatment and surgery [2]. In addition, relevant long-lasting morbidity
related to surgery and radiotherapy like temporary or permanent stoma, bowel, urinary,
and sexual dysfunctions can permanently impair patients’ well-being [3], [4]. In
particular, a specific intestinal disorder named low anterior resection syndrome (LARS)
can affect up to 70–90 % of patients after sphincter-preserving surgery with major
symptoms in up to the 40 % of cases that can become permanent in about 25 % of
patients leading to a relevant detriment of long-term quality of life (QoL) [5], [6], [7].

Based on these considerations, several alternative strategies were investigated in the last
few years

including total neoadjuvant treatment (TNT), non-operative management (NOM) and

radiotherapy (RT)-free strategies in order to reduce distant relapse, avoid surgery in
patients achieving complete response and sparing RT in those with low risk of local
relapse, respectively. However, the simultaneous introduction into clinical practice of
these strategies complicated the choice of the most appropriate therapeutic approach for
each patient mainly in proficient mismatch repair (pMMR)/microsatellite stable (MSS)
tumours [8], [9], [10]. On the other hand, considering the excellent sensitivity to
immune-checkpoint inhibitors [11] and the poor sensitivity to chemotherapy [12] and
CTRT [13], [14] of the small subgroup of deficient mismatch repair (dMMR)/microsatellite
high (MSI-H) LARC (about 2–3 %) [15], patients bearing dMMR/MSI-H tumours should
receive immunotherapy, and in particular the anti-PD1 dostarlimab. Indeed, a recent
phase II single-arm study reported a 100 % of complete clinical response (cCR) among 42
dMMR/MSI-H LARC treated with 6 months of dostarlimab with no recurrence observed
at a median follow-up of about 18 months [16], [17]. Even if a longer follow-up and other
confirmatory studies are needed, this approach has become the new standard of care for
this subset of patients [18], [19].

In the present review, we therefore focus on TNT, NOM and RT-free strategies and their
possible implementation into the therapeutic algorithm for pMMR/MSS LARC with the
aim of helping clinicians in their decision-making process in the clinical practice.

2. Total neoadjuvant treatment

TNT strategies shift the adjuvant chemotherapy to the pre-operative phase of the
multimodal treatment with the aim of improving compliance to systemic chemotherapy,
treating micro-metastases earlier in order to reduce distance recurrence, increase
tumour response and thus enhance the chance of organ preservation, while allowing to
anticipate the closure of temporary ostomies. Two TNT approaches emerged from several
phase II and III studies: induction chemotherapy (INCT) followed by CTRT and CTRT or
SCRT followed by consolidation chemotherapy (CNCT) [8].

Study designs and main results of the most relevant phase III trials assessing the efficacy
of TNT strategies respect to neoadjuvant CTRT (PRODIGE23, RAPIDO, STELLAR and
TNTCRT) are listed in the Table 1 [20], [21], [22], [23], [24], [25], [26]. Overall, all studies
met their primary objectives consisting in prolonging disease-free survival (DFS) for
PRODIGE23 and TNTCRT, increasing time to disease-related treatment failure (DrTF) for
RAPIDO, and showing non-inferior DFS for STELLAR respect to standard neoadjuvant
CTRT. These favourable results, mainly due to the reduction of distant recurrence,
strengthen the adoption of TNT regimen in clinical practice. Indeed, among several
studies assessing the benefit of adjuvant oxaliplatin-based chemotherapy after
neoadjuvant CTRT and surgery, only two trials (CAO/ARO/AIO-03 and ADORE) showed a
DFS benefit compared with adjuvant fluoropyrimidines alone. However, CAO/ARO/AIO-
03 used low-doses of oxaliplatin in addition to 5-fluorouracil during neoadjuvant RT, and
this strategy was poorly adopted due to the lack of reduction of local recurrences and the
unconfirmed DFS benefit at the price of increased toxicity. ADORE randomised only
patients achieving a poor response to neoadjuvant CTRT and able to receive an
oxaliplatin-based chemotherapy, thus excluding patients not fit for adjuvant treatment
due to post-operative morbidities.

Table 1. Main phase III trials investigating the role of TNT strategies.

Primary CR
Study Study designEligibility Treatment strategy endpoint % LR %

PRODIGE−23 Randomized phase IIIcT3/T4 3-y DFS 3y 5y

and/or N+
Exp: FOLFIRINOX × 6 → CTRT 28a 4 ND
(50Gy/25f)→ S → FOLFOX *
× 6/Capecitabine × 4 (n = 231)

Ctr: CTRT (50 Gy/25f) → S → 12a 6 ND

FOLFOX × 12/Capecitabine × 8 *
(n = 230)

RAPIDO Randomizedphase Exp:SCRT (5Gy/5f) → CAPOX 3-y DrTF 28a 8 10 *

IIIcT4/N2MRF+ EMVI+Lateral × 6 orFOLFOX × 9 → *
nodes+ S (n = 462)

Ctr:CTRT (50Gy/25f) → S → 14 * 6 6*
a
optional CAPOX x 8/FOLFOX
× 12 (n = 450)
STELLAR Randomized phase IIINon- Exp:SCRT (5Gy/5f)→ CAPOX x 3-y DFS 11f 8 ND
inferiorityDistal or middle 4 → S→ CAPOX x 2 (n = 298) * 22
a
third cT3/T4 and/or N+ *

Ctr:CTRT (50Gy/25f)→ S → 4f 11 ND
FOLFOX × 12/Capecitabine * 12
a
× 8 (n = 293) *

TNTCRT Randomized phase IIIcT3c-d Exp:CAPOX x1 →CTRT (50– 3-y DFS 27a 3 ND
and EMVI+ /cT4a-b/cN2 50,4Gy/25-28f) with CAPOX *
and/or MRF+ x2 →CAPOX x3 → S (n = 232)

Ctr:CTRT (50–50,4Gy/25-28f) 10a 3 ND

with capecitabine → S → *
CAPOX/Capecitabine (n = 226)

Abbreviations: Adj: adjuvant; Ctr: control; CT: chemotherapy; CTRT: chemo-radiotherapy; DFS:
disease free survival; DrTF: disease-related treatment failure; DM: distant metastasis; Exp:
experimental; EMVI: extramural vascular invasion; LR: local recurrence; MRF: mesorectal fascia;
ND: not determined; OS: overall survival; RMST: restricted mean survival time; SCRT: short-
course radiotherapy; S: surgery; TNT: total neoadjuvant treatment.

*Statistically significant (p log-rank ≤ 0,05). If absent, it means not statistically significant.

Statistically significant (p RMST ≤ 0,05).

 a
pathological Complete Response (pCR)

b
Metastasis free survival (MFS)

c
During induction treatment

d
DrTF

e
during consolidation treatment

f
complete Clinical Response (cCR)

g
during TNT

Overall, important differences in secondary endpoints among TNT trials may drive the
choice of the most appropriate strategy. In the RAPIDO trial, the lack of OS benefit and
above all the higher locoregional failure for the experimental SCRT followed by CNCT
with FOLFOX (5-fluorouracil + oxaliplatin)/CAPOX (capecitabine + oxaliplatin) for 4
months and surgery respect to standard CTRT followed by surgery and optional adjuvant
chemotherapy stands as an important concern [24]. Indeed, local relapse can cause
severe pain, mucinous discharge and incontinence, negatively impacting on the QoL. In
addition, salvage surgery involves demolitive procedures, including abdominoperineal
resection and pelvic exenteration in more than 60 % of cases, with a significant surgical
morbidity in about 40 % of patients [27]. Even if no specific baseline characteristics (i.e.
location of rectal cancer and high-risk features) were associated to a higher risk of local
relapse in the experimental arm respect to the standard group, mesorectal breach,
occurring more frequently in the TNT arm probably due to the longer duration of the
preoperative treatment, was associated to a higher risk of local relapse. In addition, the
worse local recurrence in the experimental treatment was observed only among patients
receiving 3D-RT, but not among these treated with intensity modulated radiation therapy
(IMRT)/volumetric-modulated arc therapy (VMAT) [24]. However, this non-preplanned
subgroup analysis is only hypothesis generating and should be prospectively confirmed.

Conversely, the STELLAR study, assessing the efficacy of a “RAPIDO-like” strategy, did not
confirm the worse local relapse with SCRT followed by doublet CNCT respect to
neoadjuvant CTRT alone probably due to the lower percentage of patients with more
aggressive features enrolled in this trial (cT4: 14 % versus 31 %; cN2: 34 % versus 64 %).
Unexpectedly, the experimental treatment showed a benefit in terms of 3-year OS
without a consistent DFS benefit and without any significant reduction in the occurrence
of distant metastases [25]. However, these data should be confirmed at a longer follow-
up. Indeed, in a previous similar study named Polish II, the 3-year OS benefit of SCRT
followed by doublet CNCT compared with neoadjuvant CTRT alone, disappeared at the 8
years follow-up [28].

On the other hand, the recently updated PRODIGE23 trial showed both a longer DFS and
OS with three months of INCT with FOLFIRINOX (5-fluorouracil, irinotecan and
oxaliplatin) followed by TME and three months of adjuvant FOLFOX or capecitabine
respect to standard neoadjuvant CTRT followed by surgery and six months of adjuvant
FOLFOX or capecitabine, with similar local relapse rate [21]. However, the OS advantage
in favour of the experimental arm is debated. Indeed, at an updated follow-up, Conroy et
al. showed a higher 7-years restricted mean survival time (RMST) for the INCT arm
without reporting the results of the Cox and long-rank tests due to a non-proportionality
of hazards declared from the authors (Schoenfeld residuals method: p = 0.10). However,
the proportional hazard assumption was maintained for OS (Schoenfeld residuals
method: p > 0.05) and the OS advantage was not statistically significant compared to the
standard arm (HR: 0.73, 95 %CI: 0.48–1.09), although clinically relevant (7-year OS: 81.9 %
versus 76.1 %) [21], [29], [30], [31].

The more recent TNTCRT trial reported a longer DFS with similar local recurrence rate
and OS with neoadjuvant CAPOX as a “sandwich” TNT strategy with CTRT followed by
TME respect to CTRT followed by rectal resection and adjuvant CAPOX or capecitabine in
high-risk LARC [26]. In addition, the phase II CAO/ARO/AIO-12 trial showed similar DFS
results between doublet FOLFOX as induction or consolidation treatment both in
combination with CTRT with a higher pCR rate in favour of CNCT strategy [32].
Therefore, TNT with CTRT seems to guarantee better outcomes respect to SCRT-based
strategy. Although no formal comparison between triplet and doublet was available, INCT
with FOLFIRINOX showed an OS advantage, although questionable, [21], [30], [31] while
no OS benefit was observed with doublet both compared to neoadjuvant CTRT alone [26].
In addition, a recent pooled analysis of phase II and III trials reported a longer DFS and OS
in favour of triplet respect to doublet INCT both in combination with CTRT at the price of
higher toxicity [33]. Indeed, a careful selection of patients candidates to an intensified
chemotherapy regimen based on age and clinical conditions should be done.

3. Non-operative management
The high long-term morbidity burden including urinary and sexual dysfunction, bowel
disorder like low-anterior resection syndrome (LARS), temporary and permanent
ostomies and detrimental quality of life (QoL) associated with rectal resection in
particular when preceded by radiotherapy [34], [35], [36] led to development of organ
preservation strategies for patients achieving complete clinical response (cCR) or small
residual tumour after neoadjuvant treatments [37]. In addition, the higher response rate
with the introduction of TNT strategies induced a growing interest in these strategies
[38].

After promising and reassuring survival and safety results of NOM irrespectively of the
neoadjuvant treatment strategy reported by several retrospective and prospective studies
[39], [40], [41], [42], a phase II trial named OPRA was conducted [43], [44]. In this trial,
patients with LARC were randomized to 4 months of INCT with FOLFOX or CAPOX
followed by CTRT versus the reverse sequence both followed by Watch-and-Wait (WW)
in patients with cCR or near complete clinical response (ncCR) and TME in case of
incomplete response. Main results were listed in Table 2. The OPRA study did not meet
the primary endpoint of DFS superiority of at least one of the TNT approaches followed
by the selective NOM strategy over historical controls of neoadjuvant CTRT always
followed by surgery regardless of clinical response. However, it might be speculated that
the incorporation of NOM preceded by TNT in the overall management of LARC does not
harm survival, although at the price of possible overtreatment. Indeed, in case of tumour
regrowth after NOM, the possibility of performing a TME was not impaired with a similar
survival between patients resected after local regrowth respect to patients receiving TME
at restaging, underlying that the deferral of surgery does not increase the risk of distant
tumour spread. Although both arms showed similar DFS, OS, distant and local relapse,
the longer TME-free survival in favour of CNCT arm leads to identify consolidation
approach as the preferred strategy when a NOM is pursued.

Table 2. Main results of the OPRA trial.

Subsequent
Treatment after TME
the end of free
Study Treatment neoadj therapy Primary survival LRFS
Study designEligibility strategy % endpoint % % DFS % MFS %

Surgery* NOM* 3y 5y 3y 5y 3y 5y 3y

OPRA Randomized Exp1:FOLFOX 28 72 3y DFS 41 39 95 94 76 72 83

phase IIStage II × 8/Cape × 5 →
and III CTRT
(54 Gy,25 f) →
S/NOM(n = 158)

Exp2:CTRT 24 76 55 54 94 90 72 71 83
(54 Gy,25 f) →
FOLFOX
× 6/Cape × 5 →
S/NOM(n = 166)
 *for those who completed TNT and were restaged

statistically significant (p ≤ 0,05)

Abbreviations: CT: chemotherapy; CTRT: chemo-radiotherapy; DFS: disease free survival; DM:
distant metastasis; Exp: experimental; LRFS: local recurrence free survival; MRF: mesorectal
fascia; NOM: non operative management; OS: overall survival; S: surgery; TME: total mesorectal
excision; TNT: total neoadjuvant treatment.

Although results of the OPRA study are very appealing, some concerns need to be
emphasised. Despite a clear definition of clinical response in the OPRA protocol based on
digital rectal examination (DRE), magnetic resonance imaging (MRI) and endoscopy
exam [45], the high risk of local regrowth (44 % and 29 % with INCT and CNCT arms,
respectively) as well as the rate of pCR (almost 10 %) among patients resected due to
clinical incomplete response at restaging, highlight the intrinsic limit of post-treatment
radiological and endoscopic assessment in particular for the high risk of undetectable
persistence of local or nodal microscopic disease. Specifically, if most patients with a cCR
achieved organ preservation (about 80 %), a significant proportion of patients with a
ncCR developed tumour regrowth (about 60 %), while a smaller fraction (about 40 %)
would require more time to obtain a cCR justifying a longer observation period before
going to TME [46]. Some features of ncCR including ulcer, nodularity and irregular
mucosa on restaging endoscopy were associated to higher risk of residual tumour [47].
This raises the question of proposing a local resection when ncCR occurs, in particular in
the case of endoluminal signs of suspected residual disease, in order to exclude or
confirm a complete response and not to delay a surgical resection or jeopardise organ
preservation, respectively [48]. Although some baseline characteristics were associated
with lower chances of NOM, like nodal disease, extramural venous invasion, mesorectal
fascia involvement, and tumour length, these should not lead to exclude a priori the
possibility of pursuing an organ preservation [49]. Tumour regrowth, usually occurring
within 2–3 years from the end of the treatment [50], is associated with a higher risk of
distant recurrence compared to the absence of local regrowth lasting up to 5 years [51].
Therefore, a specific expertise and an intensified follow-up with a good adherence by
patients is required for the assessment of tumour response and regrowth. Of note, an
increased and rigorous follow-up is needed also for dMMR/MSI-H LARC patients
achieving a cCR after treatment with dostarlimab [16], [17].

A recent single-arm phase II trial named NO-CUT assessing the impact of the INCT with
CAPOX followed by CTRT and NOM in case of cCR or TME in case of incomplete response
including ncCR, confirmed data of the INCT arm of the OPRA trial [52].

Although these promising results have prompted international guidelines to introduce

organ preservation as an alternative to surgery in patients with cCR regardless of the
neoadjuvant treatment approach [18], [19], further confirmatory studies are needed in
order to better define the strategy with the highest chance of achieving organ
preservation (i.e. LCRT vs SCRT, triplet vs doublet CNCT, the addition of
immunotherapeutic agents), the criteria to recognize cCR/ncCR and local regrowth (i.e.
radiomic parameters), and those to select candidates to organ preservation (i. e.
immunoscore, ctDNA, transcriptomics).

The increasing evidence supporting organ preservation after neoadjuvant treatment in

LARC led to assess this approach also in earlier stages of rectal cancers (cT1–3 superficial
and N0), where the standard treatment is TME alone [1]. Several phase II and III trials
evaluated different strategies including (chemo)radiotherapy, intensification of
neoadjuvant radiotherapy with external beam radiotherapy (EBRT) or contact
brachytherapy (CBX) boost, and doublet oxaliplatin-based chemotherapy without
radiotherapy followed by watch-and-wait or local resection [48], [53], [54], [55], [56],
[57], [58], [59], [60], [61], [62], [63], [64], [65]. Preliminary data showed the feasibility
and acceptable tolerability of these strategies with an organ preservation rate at 2- or 3-
years exceeding 50 %. However, although the results of these trials are very promising,
the high risk of overtreatment especially for poorly responding patients, the lack of
survival data at a more mature follow-up and of long-term QoL and bowel function data
limit the use of NOM strategies for patients with cT1–3bN0 rectal cancer.

4. Radiotherapy-free approach
Preoperative radiotherapy may cause long-term adverse events including bowel, urinary
and sexual dysfunction with the consequent worsening of QoL [34], [35]. In addition, in
pre-menopausal female patients, pelvic radiotherapy is associated to gonadal toxicity
determining early menopause and a consequent increased risk of osteoporosis and
cardiovascular events other than a reduced fertility [66]. Considering the increased
incidence of early-onset rectal cancers in recent years [67], this toxicity is becoming
increasingly relevant and should be appropriately managed [68].

Drawing from these considerations, several studies addressed RT-free approaches for the
management of LARC at least for those with low-risk of local recurrence (Table 3).

Table 3. RT-free approaches.

Treatment Primary CR
Study Study designEligibility strategy endpoint % LR % DFS %

PROSPECT Randomized phase IIINon- DFS 3y 5y 10y 3y 5y 10y

inferioritycT2N1/T3N0/T3N1,
Exp:FOLFOX 22h ND 98 ND ND 81 * ND
MRF- candidates for i
x6 → [CTRT #
sphincter-sparing surgery
(50,4 Gy/28f)
only if < 20 %
shrinkage or
FOLFOX
intolerance]
→S → CTRT (if
 R1/2)/ adj
FOLFOX x6
(suggested)
(n = 585)

Ctr:CTRT (50,4 24h ND 98 ND ND 79 * ND

i
Gy/28f) → S → #
FOLFOX × 8
(suggested)
(n = 543)

FOWARC Randomized phase IIIcT3– FU-RT 3-y DFS 14h 8 11 11 73 65 52

4N0/cT1–4N1–2 < 12 cm group:5-FU #
from AV x5 + RT → S →
5-FU x7
(n = 165)

FOLFOX-RT 27,5 7 8 8 77 68 63
h
group:FOLFOX #
x5 + RT→S →
FOLFOX x7
(n = 165)

FOLFOX 6,5h 8 9 10 73 67 60
group:FOLFOX #
x4–6 → S→
FOLFOX x6–8
(n = 165)

CONVERT Randomized phase IIINon- Exp: CAPOX 3-y 11h 96 ND 89 ND

k
inferiority12 cm or less from x4 → [salvage LRRFS #
AVcT2N+ /cT3–4a any CTRT if local
cNMRF neg. PD or MRF+ at
MRI restaging]
→S → adj
CAPOX x4
(n = 300)
 Ctr:CTRT 14h 97 ND 88 ND
k
(50 Gy) → S → #
CAPOX x6
(n = 289)

OCUM Observational prospective16 High risk 5-y LR; ND 1# 2 ND 77# 67# ND

cm or less from AVcT2–4, (middle-lower 5-y OS #
Any cN,cM0 third
mrCRM+,
anyT4, cT3
lower
third):CTRT
(50,4 Gy/25f)
with 5-FU →S
(n = 174)

Low risk ND 1# 2 ND 85# 76# ND

(mrCRM-, #
upper
third):Sm
(n = 254)

Abbreviations: Adj: adjuvant; AV: anal verge; Ctr: control; CT: chemotherapy; CTRT: chemo-
radiotherapy; DFS: disease free survival; DM: distant metastasis; Exp: experimental; EMVI:
extramural vascular invasion; LR: local recurrence; LRRFS: local regional recurrence free survival;
MRF: mesorectal fascia; ND: not determined; OS: overall survival; SCRT: short-course
radiotherapy; S: surgery; TNT: total neoadjuvant treatment.

* Statistically significant (p ≤ 0,05). If absent, it means not statistically significant.

# p not available

h
pathological Complete Response (pCR)

i
LRFS
 j
patients who had surgery

k
LRRFS

l
peri-operative DM

m
except for cT4 tumours with urinary bladder infiltration

The phase III PROSPECT trial [69] showed the non-inferiority of six months of peri-
operative FOLFOX and TME respect to neoadjuvant CTRT followed by TME and four
months of adjuvant FOLFOX in terms of DFS with similar pathological response, local
relapse and OS. In the experimental arm, neoadjuvant CTRT was planned in the case of
poor response or intolerance to neoadjuvant chemotherapy treatment, and it was
actually administered to the 9 % of patients. As expected, a different toxicity profile was
reported between two arms, and a better QoL was observed in favour of RT-free approach
in terms of bowel function during neoadjuvant treatment and long-term sexual function
[70]. Although pre-operative pelvic MRI was not mandatory, it was performed in about
85 % of cases, and only patients with cT2N1/T3N0/T3N1, candidate to sphincter-sparing
surgery (about 85 % in medium-high rectum) and with no involvement of the mesorectal
fascia (MRF) were enrolled in the PROSPECT trial. Therefore, this strategy should be
reserved only to patients with low-risk of relapse based on study inclusion criteria [69].
No data about the impact of extramural venous invasion (EMVI) were available.

The high rates of 5-years DFS and OS together with the very low risk of local recurrence
shown by the PROSPECT trial, questioned the need for any neoadjuvant chemotherapy or
CTRT/SCRT treatment in a patients’ population with above mentioned characteristics,
suggesting that surgery alone could have been enough to achieve an adequate outcome
in this group of patients at low risk of recurrence [71]. Indeed, the prospective OCUM
trial showed that patients with low-risk LARC (medium-high ≤cT3, MRF-, any cN) treated
with upfront surgery followed by adjuvant chemotherapy or CTRT in case of pN+ or
CRM+ , respectively, achieved outcome similar to patients enrolled in the PROSPECT trial.
On the other hand, patients with high-risk LARC (low cT3, cT4, MRF+) obtained poor
outcome despite neoadjuvant CTRT treatment suggesting the adoption of a neoadjuvant
treatment intensification in this group [72]. These results were also confirmed by a
United Kingdom retrospective study including patients treated with upfront rectal
resection where high risk LARC (MRF+ or EMVI+ or tumour deposits (TDs) + ) showed
lower 5-years DFS (66 % versus 88 %; HR: 3.01 [95 %CI: 2.02–4.47]; p < 0.0001) and 5-years
OS (71 % versus 89 %; HR: 2.59 [95 %CI: 1.62–3.88]; p < 0.0001) respect to low-risk LARC
(MRF-, EMVI- and TDs -) patients [73].

Other two phase III trials, FOWARC [74] and CONVERT [75], assessed RT-free strategies
with perioperative fluoropyrimidine and oxaliplatin respect to standard neoadjuvant
CTRT both followed by TME and adjuvant chemotherapy. However, both studies did not
meet their primary endpoints. Specifically, FOWARC failed to show a superiority of
perioperative FOLFOX in terms of DFS and CONVERT did not demonstrate the non-
inferiority of perioperative CAPOX in terms of locoregional recurrence-free survival.
However, comparing to PROSPECT study, FOWARC and CONVERT trials included also
patients with high-risk features like cT4, N2, EMVI+ , low rectal tumours and, only for
FOWARC study, MRF+ . Overall, although both studies are negative for their primary
endpoints, comparable results were observed between experimental and standard arms
in terms of local relapse, DFS and OS. Therefore, in patients with tumours located in the
lower third of the rectum and with contraindications to radiotherapy (e.g. previous pelvic
radiotherapy or active autoimmune disease such as lupus or scleroderma) or wishing to
avoid radiotherapy, the perioperative strategy may be considered regardless of the
recurrence risk.

5. Proposed algorithm
The introduction of many different options for the treatment of LARC in a relatively short
timeframe has increased the therapeutic armamentarium, and clearly complicated the
decision-making process regarding the choice of the most appropriate treatment strategy
for each individual patient. In the space of a rapidly evolving and complex scenario, with
some still unanswered questions, a tool to interpret the evidence from clinical trials and
to translate them into daily practice might prove effective. Therefore, assuming that
dMMR/MSI-H patients are treated with immunotherapy, we propose a reasonable and
pragmatic algorithm incorporating TNT, NOM and RT-free strategies to classical
neoadjuvant (chemo)radiotherapy approach on the basis of the most up-to-date data
from clinical studies to orientate clinicians among treatment options for pMMR/MSS
LARC (Fig. 1).

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Fig. 1. Treatment algorithm. cCR: complete clinical response; ncCR: near complete
clinical response; Y: yes; N: no; NOM: non operative management; WW: Watch and
Wait; CTRT: chemo-radiotherapy; pMMR/MSS: proficient mismatch repair
system/microsatellite stable; FOLFOX: 5-fluorouracil and oxaliplatin; CAPOX:
capecitabine and oxaliplatin; CT: chemotherapy; SCRT: short-course radiotherapy;
FOLFIRINOX: 5-fluorouracil, irinotecan and oxaliplatin. *High-risk features: cT4, cN2,
enlarged later nodes, TDs, EMVI+ or MRF+ . The progressive numbers refer to the
preferred choice for each specific category. Dashed lines indicate a possible treatment
strategy although not defined ab-initio.

The crucial step is the treatment objective. In particular, if the goal is NOM, the strategy
that guarantees the higher chance of achieving organ preservation without compromise
survival or surgery in case of local recurrence is CTRT followed by CNCT with doublet and
a WW strategy in case of cCR and ncCR or TME in case of incomplete response [43], [44].
Local resection may be and option in case of ncCR in order to confirm or exclude a
complete response [48]. Organ preservation approach should be proposed to strongly
motivated patients and in specialised centres with enough experience in NOM for the
careful surveillance that is needed [76]. A major issue for the implementation of NOM is
the recognition of cCR or ncCR. Indeed, several criteria were reported in the literature to
define cCR and ncCR [1], [41], [77], [78], [79]. Although recent consensus statement has
definitively established criteria of cCR and ncCR identification [76], this remains a leading
concern requiring specific expertise. When organ preservation strategies are proposed, a
personalized follow-up schedule should be offered, specifically addressing the risk of
local relapse including DRE, endoscopy and MRI every 3–4 months in the first 2 years,
when the risk of local recurrence is higher [50], followed by the same exams every 6
months in the following three years [76].

When NOM is not the goal, the risk stratification and tumour location may guide the
choice of the most appropriate strategy in order to ensure the highest survival
probability and at the same time the lowest risk of overtreatment. Patients with high-
risk of recurrence (i.e. cT4, cN2, TDs, enlarged lateral pelvic lymph nodes, EMVI+, MRF+)
and clinically fit for combination chemotherapy may benefit of TNT strategy, that, for the
first time after the introduction of TME, reported a reduction of distant relapses [20],
[21], [22], [23], [26]. Most of patients included in TNT studies had tumours with
characteristics of high risk of recurrence. Among TNT strategies, triplet chemotherapy
induction followed by CTRT and surgery showed the best results for longer DFS, OS and
higher pCR compared to neoadjuvant CTRT [20], [21]. On the other hand, SCRT followed
by doublet chemotherapy and surgery, although reported a reduction of distant
recurrences, may increase the risk of local relapse compared to neoadjuvant CTRT and
therefore should be adopted with caution} [22], [23], [24]. In patients unfit for triplet
chemotherapy, FOLFOX/CAPOX may be administered as INCT or CNCT in combination
with CTRT [26], [32]. In patients unfit for combination chemotherapy or with a
contraindication to radiotherapy, neoadjuvant CTRT/SCRT [6], [7], [80] or perioperative
doublet [74], [75] are the most appropriate choices, respectively.

Conversely, for low-risk LARC defined as cT3N1, cT3N0 or cT2N1 without high-risk
features, a perioperative doublet chemotherapy with selected CTRT in case of poor
response or intolerance to chemotherapy may be an alternative to neoadjuvant CTRT
with reduced long-term sexual dysfunction as reported in the PROSPECT trial [69], [70].
Considering that low rectal tumours were poorly represented in this study [69], patients
with low-risk LARC located in the in the lower third of the rectum should receive
standard neoadjuvant CTRT [7], [80]. In this subgroup, perioperative doublet
chemotherapy or SCRT followed by delayed surgery may be an option in case of
contraindication to radiotherapy or unfit for CTRT, respectively [74], [75] [81].

Overall, low-risk tumours located in the meddle-high rectum have a low risk of both
local and distant recurrence and therefore surgery alone may be enough, especially if
cN0. Although randomised studies comparing upfront surgery and perioperative
treatment are not available, the prospective OCUM study showed excellent survival and
low risk of local relapse with upfront TME in this subgroup of patients [72]. Considering
that N1 patients receive perioperative and adjuvant chemotherapy in the PROSPECT [69]
and OCUM [72] studies, respectively, and that the feasibility of adjuvant treatment is
poor [2], perioperative chemotherapy should be preferable to upfront surgery in cN1
tumours. Neoadjuvant CTRT and SCRT remain alternative options [6], [7], [80].

In cases of cCR or ncCR, regardless of the neoadjuvant treatment strategy adopted, a WW

approach may still be proposed even if it was not the initial objective [18], [19], [42].

Also a recent update of the ASCO guideline [19] proposed an algorithm introducing TNT,
NOM and RT-free strategies for the management of LARC. However, some differences
were showed between the two tools. In particular, in pMMR/MSS tumours our algorithm
includes the treatment goal at the top. When the main objective is organ preservation,
CTRT followed by CNCT should be the preferred treatment regardless of the risk of
recurrence [43], [44]. Instead, the ASCO algorithm recommends perioperative
chemotherapy in patients with low-risk and medium-high rectal cancer and possible
NOM in case of cCR. Nevertheless, the chance of achieving a cCR with chemotherapy
alone is low [69]. In addition, our algorithm includes the option of surgery alone in
patients with low-risk and medium-high LARC although the level of evidence is not high
[72], NOM with possible local resection also in case of ncCR [48] in order to not preclude
organ preservation in about 40 % of these patients [46], and suggests more clearly the
most appropriate TNT strategy for each individual patient based on the goal, risk of
relapse and physical conditions.
Funding
None.

CRediT authorship contribution statement

Moretto Roberto: Writing – review & editing, Writing – original draft, Validation,
Supervision, Project administration, Methodology, Data curation, Conceptualization.
Boccaccio Chiara: Writing – review & editing, Writing – original draft, Methodology,
Data curation, Conceptualization. Landi Matteo: Writing – review & editing, Writing –
original draft, Methodology, Data curation, Conceptualization. Masi Gianluca: Writing –
review & editing, Validation, Supervision, Conceptualization. Cremolini Chiara: Writing
– review & editing, Validation, Supervision, Methodology, Data curation,
Conceptualization.

Declaration of Competing Interest

C.C. has received honoraria for speaker or advisory roles from Bayer, Roche, Merck
Serono, Amgen, Servier, Mirati, Pierre Fabre, MSD, Nordic Pharma and Takeda; and
research grants from Bayer, Servier, Merck and Amgen. G.M. has received payment or
honoraria for lectures, presentations, speakers bureaux, manuscript writing or
educational events from Roche, MSD, Eisai, Terumo, Amgen, Merck Serono; support for
attending meetings and or travel from Roche, MSD, Eisai, Terumo, Amgen, Merck Serono;
participation on a Data Safety Monitoring Board or Advisory Board from Roche,MSD,
Eisai. R.M., C.B., M.L. declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this
paper.

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