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2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 39
https://t.me/med1917
DFS (%) OS (%)
R0
resection
(%)
pCR
(%)
Chemotherapy
compliance
(%)
a
13 86 62(5y) 75 (5y)
14 87 64 (5y) 78 (5y)
a
NR NR NR
a
only)
NR NR NR
a
(pT0
only)
patients
cT3-4, N0-2 nCRT → TME → CAPOX (4) 52 57
Phase
II
CAPOX (4) → nCRT → TME 56 94
cT2-4, N+ LC-CRT → TME 29 NR 28 96 NR NR
Phase
II
FOLFOX (2) → nCRT → TME 28 95 25 86 NR NR
II–III UFT based nCRT → TME 62 NR 8(pT0
Phase
II
52 NR 29
FOLFOX (2) → UFT based
nCRT→ TME
Study (year) Design Clinical stage Treatment type (no. of cycles) N of
Tab le 2.1 (continued)
GCR-3 (2015)
[20, 72]
Marechal
(2012) [19]
Calvo (2006)
[18]
RCTs, randomized controlled trial; TNT, total neoadjuvant therapy; LARC, locally advanced rectal cancer; pCR, pathologic complete response; DFS, disease free
survival; OS, overall survival; nCRT, long-course neoadjuvant chemoradiotherapy; TME, total mesorectal excision; 5-FU, 5-fluorouracil; FOLFOX, oxaliplatin
+ leucovorin + 5-FU; CAPOX, oxaliplatin + capecitabine; y, years; FOLFIRINOX, oxaliplatin + irinotecan + leucovorin + 5-FU; HDRBT, high dose-rate
brachytherapy; RT, radiotherapy; R0, microscopically clear resection; UFT, tegafur/uracil; CRM, circumferential resection margin; DRM, distal resection margin;
Gy, grey; NR, not reported
Good responders (≥75% tumour volume reduction)
Indicates statistically significant outcome
a
b
Poor responders (≤75% tumour volume reduction or a predictive CRM ≤ 1 mm)
c
40 S. Bedrikovetski and T. Sammour
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over 90% for the intended chemotherapy regimen. The findings of the Spanish
GCR-3 study were corroborated by the KIR study, which shared a similar TNT
sequence but utilized high dose rate brachytherapy (HDRBT) as a foundation.
The KIR study met its primary endpoint (compliance at or above 85% of the
cumulative dose of planned FOLFOX) and demonstrated that the induction arm
exhibited a higher compliance rate in comparison to the adjuvant arm (80 vs. 53%,
P = 0.0002), without any significant differences in the rate of pCR or 3-year DFS
[23].
The French PRODIGE-23 trial was the first phase III trial on induction
chemotherapy that was powered to detect a difference in 3-year DFS. This trial
showed that, compared with nCRT and adjuvant chemotherapy (control arm),
induction FOLFIRINOX followed by nCRT and adjuvant chemotherapy (TNT
arm) significantly improves pCR rates (12 vs. 28%, P < 0.001), 3-year DFS (69
vs. 76%, P = 0.034) and 3-year metastatic free survival (72 vs. 79%, P < 0.02)
without any difference in R0 resection, postoperative morbidity, or reduction in RT
compliance. In addition, 92% of patients completed six cycles of FOLFIRINOX
with manageable toxicities (grade 3–4 adverse events: 46%) and serious adverse
events during the whole treatment period was similar between the two arms (27
vs. 22%, P = 0.167). The two arms also had similar rates of 3-year OS, cancerspecific survival and LR [24]. Currently long-term trial results are only available
in abstract form, but preliminary data indicate that 7-year DFS (68 vs. 63%, P =
0.048), 7-year OS (82 vs. 76%, P = 0.033), 7-year metastasis-free survival (74
vs. 65%, P = 0.011) will be significantly better in the TNT arm compared to the
control arm. There were similar in rates of 7-year LR (8 vs. 5%, P = 0.38) and
7-year cancer specific survival (85 vs. 80%, P = 0.051) [25].
The Chinese FOWARC phase III trial randomized 495 patients with LARC
into three arms including an induction FOLFOX only arm, induction FOLFOX
plus nCRT (TNT) arm, and nCRT arm. The pCR rate in the TNT arm was significantly higher compared to the nCRT arm (28 vs. 14%, P = 0.005). However, more
patients in the TNT arm experienced grade 3 and 4 adverse events compared with
the other two treatment arms. Despite this, chemotherapy and RT compliance rate
was over 90%. After a 3-year follow-up, no significant differences were detected
in DFS, OS and LR between the three treatment arms. These data suggest that
induction chemotherapy alone may be suitable in selected patients (namely those
where a cCR is not a primary treatment goal or where radiotherapy needs to be
avoided or not possible).
2.2.2 Consolidation Chemotherapy
Consolidation chemotherapy after nCRT or SC-RT prior to surgery is another
TNT sequencing option. Table 2.2 outlines the RCTs comparing TNT using
consolidation chemotherapy versus nCRT as the control arm.
The WAIT trial from Australia and the KCG CO 14–03 trial from Korea compared nCRT followed by moderate doses of consolidation chemotherapy during
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 41
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a
a
OS
(%)
DFS
(%)
R0 resection
(%)
pCR
(%)
compliance (%)
17 92 65 (3y) 87 (3y)
298 59 (98
a
a
neoadjuvant only)
89 (3y), 80
,66
90 70 (3y)
14
450 67 (adjuvant
(5y)
a,b
(5y)
only)
89 (3y), 82
,72
a
90 76 (3y)
a
462 85 28
a,b
(5y)
(5y)
a
96 69 (4y) 80 (4y)
97 74 (4y) 85 (4y)
a
180 92 34
(continued)
25 NR 25 92 76 (2y) 84 (2y)
Treatment type (no. of cycles) N Chemotherapy
stage
Phase III cT3-4, N+ nCRT→ TME → CAPOX (6) 293 58 12 88 62 (3y) 75 (3y)
Study (year) Design Clinical
Tab le 2.2 RCTs of consolidation TNT for LARC patients
STELLAR
SC-RT→ CAPOX
(8)/FOLFOX (12)
(4) → TME → CAPOX (2)
nCRT→ TME →±CAPOX
SC-RT→ FOLFOX (9)/
CAPOX (6) → TME
nCRT + Irinotecan→ CAPIRI
(1) → TME
nCRT→ CAPOX (2) → TME 53 NR 14 92 NR NR
nCRT→ 5FU + LV
(3) → TME
LARC
Phase III High-risk
(2022) [73]
RAPIDO
(2020) [30, 33]
Phase III cT3-4, N+ nCRT→ CAPOX (1) → TME 180 96 18
CinClare
(2020) [45, 47]
Phase II cT3-4, N+ nCRT → TME 55 NR 6 100 NR NR
KCSG CO
14–03 (2018)
[27]
Phase II cT3-4, N+ nCRT → TME 24 NR 16 92 79 (2y) 96 (2y)
WAIT (2017)
[16, 26]
42 S. Bedrikovetski and T. Sammour
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,
,
a
a
49 (8y)
(8y)
65 (3y)
49 (8y)
(8y)
OS
(%)
DFS
(%)
R0 resection
(%)
pCR
(%)
73 (3y)
compliance (%)
261 99 16 77 53 (3y), 43
Treatment type (no. of cycles) N Chemotherapy
stage
Phase II cT3-4 SC-RT→ FOLFOX
Study (year) Design Clinical
Tab le 2.2 (continued)
POLISH II
(3) → TME
(2016) [28, 29]
nCRT + FOLFOX (2) → TME 254 NR 12 71 52 (3y), 41
RCTs, randomized controlled trial; TNT, total neoadjuvant therapy; LARC, locally advanced rectal cancer; pCR, pathologic complete response; DFS, disease free
survival; OS, overall survival; nCRT, long-course neoadjuvant chemoradiotherapy; TME, total mesorectal excision; 5-FU, 5-fluorouracil; FOLFOX, oxaliplatin
+ leucovorin + 5-FU; CAPOX, oxaliplatin + capecitabine; y, years; CAPIRI, capecitabine + irinotecan; SC-RT, short-course radiotherapy; R0, microscopically
The inverse of disease-related treatment failure
Indicates statistically significant outcome
a
b
clear resection; NR, not reported
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 43
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the wait period versus nCRT [26, 27]. Both trials failed to meet their primary endpoints of pCR rate (16 vs. 25%, P = 0.49) and downstaging rate (36 vs. 21%, P =
0.07) respectively, most likely due to their small sample size. The POLISH II trial
was the first phase III trial of SC-RT followed by three cycles of FOLFOX (TNT
arm) compared with nCRT (control arm). The trial enrolled 515 patients with poor
prognosis (ei. clinical T3 and T4 tumours and approximately half were in the distal rectum). The TNT arm had better RT compliance (100 vs. 92%, P < 0.001)
and lower acute adverse events (any grade: 75 vs. 83%, P = 0.006). However,
the trial was negative regarding its primary endpoint of R0 resection rate (77 vs.
71%, P = 0.07) and found no significant difference in the pCR rate (16 vs. 12%,
P = 0.17), probably because of the low number of chemotherapy cycles and short
interval between SC-RT and surgery (median 12.4 weeks). In contrast, 3-year OS
was significantly better in the TNT arm compared to the control arm (73 vs. 65%,
P = 0.046), however the two arms were similar in regard to 3-year DFS (53 vs.
52%, P = 0.85) [28]. After a median follow-up of 7 years, the two arms had no
significant differences in 8-year rate of OS (49 vs. 49%, P = 0.38), DFS (43 vs.
41%, P = 0.85), LR (35 vs. 32%, P = 0.60) and DM (36 vs. 36%, P = 0.85)
[29]. It is important to note that this trial did not mandate the use of MRI which
is essential for the assessment of tumour progression in both treatment arms, thus
reducing the overall quality of the trial.
The Dutch RAPIDO phase III trial shared a similar design to the POLISH II
trial in which the TNT arm employed SC-RT, but used six cycles of CAPOX
or nine cycles of FOLFOX, while the control arm was nCRT [30]. Notably, the
RAPIDO trial shifted its primary study endpoint from OS to disease-related treatment failure (DRTF) and changed sample size calculations at less than 6 months
before completing enrolment [31, 32]. The study met the unconventional new primary endpoint of 3-year DRTF (24 vs. 30%, P = 0.0019). Although the TNT arm
had a higher pCR rate (28 vs. 14%, P < 0.001), there was no significant improvement in 3-year OS (89 vs. 89%, P = 0.59) or LR (8 vs. 6%, P = 0.12). The lower
probability of DRTF in the TNT arm could be attributed to the higher compliance
with chemotherapy compared to the control arm (85 vs. 67%). Long-term data for
the trial revealed a higher rate of LR was detected in the TNT arm compared to
the control arm (10 vs. 6%, P = 0.027), whereas the reduction in DRTF (28 vs.
34%, P = 0.048) and DM (23 vs. 30%, P = 0.011) along with similar OS (82
vs. 80%, P = 0.50) remained after 5 years [33
TNT significantly decreased the occurrence of metastasis, particularly in the liver
[34].
Another positive phase III RCT was the STELLAR trial from China. This trial
randomized 599 patients with LARC to receive SC-RT followed by four cycles of
CAPOX before TME then two cycles of adjuvant CAPOX versus nCRT. Unlike
the POLISH II and RAPIDO trials, STELLAR mandated adjuvant chemotherapy in the TNT arm which only 58% of the patients completed. The induction
chemotherapy arm was associated with higher rates of full-dose completion of
neoadjuvant treatment (93 vs. 75%, P < 0.001), complete response (23 vs. 13%,
P = 0.001) and 3-year OS (87 vs. 75%, P = 0.036) when compared to nCRT.
]. Interestingly, compared to nCRT,
44 S. Bedrikovetski and T. Sammour
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However, there was no statistical difference in 3-year DFS, pCR, metastasis-free
survival and LR between the arms. Compared with the RAPIDO trial, the STELLAR trial had fewer patients with cT4 and cN2 disease and used only four cycles
instead of six to nine cycles of consolidation chemotherapy, thus raising the question whether a shorter course of chemotherapy is sufficient in select patients with
fewer high-risk features of LR. On the other hand, early POLISH II data showed
similar 3-year OS results, which disappeared in long-term follow-up. Overall, the
results of the POLISH II, RAPIDO and STELLAR trials suggest that SC-RT followed by consolidation chemotherapy may represent a new therapeutic option for
LARC, but there remains concern about LR rates in RAPIDO which need to be
further studied before this is considered a standard option.
2.2.3 Induction Versus Consolidation Chemotherapy
Sequencing
Table 2.3 summarizes RCTs that have compared induction versus consolidation
sequences of TNT.
The German multicentre, phase II CAO/ARO/AIO-12 trial randomly assigned
311 patients with LARC to receive either three cycles of FOLFOX before nCRT
(induction arm) or after nCRT (consolidation arm). Consolidation arm had better
compliance with radiation (97 vs. 91%, P < 0.05) but worse compliance with
chemotherapy compared with the induction arm (85 vs. 92%), suggesting that
patients are more likely to complete whichever treatment started first. The former
arm also had a higher pCR rate (25 vs. 17%, P < 0.001) and fewer grade 3 and 4
adverse events (27 vs. 37%), however both arms had similar rates of R0 resection
and postoperative complications [35]. Long-term follow up found no difference in
3-year DFS, LR, DM, OS, and chronic toxicity between the two treatment arms
[36].
In North America, the OPRA trial was the first multicentred phase II study to
evaluate the feasibility and safety of TNT for nonoperative management among
patients with stage II-III distal rectal cancer. Like the CAO/ARO/AIO-12 trial,
OPRA trial also randomized patients to receive induction chemotherapy followed
by nCRT or nCRT followed by consolidation chemotherapy, except that the OPRA
trial administered more cycles of neoadjuvant chemotherapy (8 cycles of FOLFOX
or 6 cycles of CAPOX) and those achieving a cCR or near-cCR after TNT were
offered to nonoperative management. Compliance with chemotherapy was similar
in both arms (82 vs. 81%). After a median follow-up period of 3 years, the consolidation arm was associated with increased organ preservation rates (53 vs. 41%,
P = 0.01) with no significant difference in DFS (76 vs. 76%, P = 0.90), LR-free
survival (LRFS), DM-free survival (DMFS), or OS. Currently, long-term follow-up
results are available only in abstract form, but preliminary data demonstrate organ
preservation rates at 5-years remain significantly higher for the consolidation arm
compared with the induction arm (54 vs. 39%, P = 0.01). However, no statistical
differences were found in 5-year DFS, LRFS, DMFS and OS between the two
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 45
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94 (3y),
88 (5y)
95 (3y),
88 (5y)
DFS (%) OS (%)
(%)
pCR (%) R0 resection
compliance (%)
N Chemotherapy
NR 76 (3y),
155 81 Organ
71 (5y)
preservation: 55
a
a
, 54 (5y)
(3y)
NR 77 (3y),
152 82 Organ
72 (5y)
preservation: 41
a
, 39 (5y)
a
(3y)
156 85 25 91 73 (3y) 92 (3y)
150 92 17 92 73 (3y) 92 (3y)
Tab le 2.3 RCTs of induction versus consolidation TNT for LARC patients
(8)/CAPOX
(6) → TME
FOLFOX (8)/CAPOX
(6) → nCRT→ TME
nCRT→ FOLFOX
(3) → TME
FOLFOX
from AV, > cT3b
if 6–12 cm from
AIO-12
(2019) [35,
(3) → nCRT→ TME
AV, c T 4 o r N +
36]
RCTs, randomized controlled trial; TNT, total neoadjuvant therapy; LARC, locally advanced rectal cancer; pCR, pathologic complete response; DFS, disease free
survival; OS, overall survival; nCRT, long-course neoadjuvant chemoradiotherapy; TME, total mesorectal excision; 5-FU, 5-fluorouracil; FOLFOX, oxaliplatin
Indicates statistically significant outcome
+ leucovorin + 5-FU; CAPOX, oxaliplatin + capecitabine; y, years; R0, microscopically clear resection; AV, anal verge; NR, not reported
a
cycles)
Phase II II-III nCRT → FOLFOX
Study (year) Design Clinical stage Treatment type (no. of
OPRA
(2022) [37,
63]
Phase II cT3if<6cm
CAO/ARO/
46 S. Bedrikovetski and T. Sammour
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arms [37]. Overall, the results of the CAO/ARO/AIO-12 and OPRA trials indicate
that consolidation chemotherapy is better when aiming at a nonoperative management approach than induction chemotherapy, however induction chemotherapy
may have the advantage of reduced chemotherapy toxicity and improved compliance in patient where distant metastasis risk is a priority over complete response
in the primary [15].
2.2.4 Total Neoadjuvant Therapy Combined
with Immunotherapy or Biologics
The addition of immunotherapy or biologic agents to TNT to enhance tumour
response has also been studied. Table 2.4 summarizes RCTs that have combined
TNT with immunotherapy or biologics in patients with LARC.
The Spanish GEMCAD 1402 phase II trial randomly assigned patients with
high-risk LARC in a 2:1 ratio to induction chemotherapy with six cycles of FOLFOX with (arm A) or without aflibercept (arm B) followed by nCRT and TME.
Over 90% of patients completed the six cycles of induction chemotherapy with or
without dose reduction in both arms. Patients in arm A had a statistically higher
pCR rate than arm B (23 vs. 14%). However, during the induction chemotherapy
period, patients in arm A experienced a higher rate of grade 3 and 4 toxicity (51
vs. 23%), but these observations neither compromised subsequent nCRT or R0
resection rates nor resulted in additional postoperative morbidity [38]. Long-term
follow-up results revealed no significant difference in 3-year DFS and OS between
the two arms [39].
The EXPERT-C trial investigated the effect of adding cetuximab to induction
chemotherapy by CAPOX followed by nCRT and then adding cetuximab in adjuvant chemotherapy in patients with high-risk LARC. Compliance with neoadjuvant
chemotherapy and nCRT was over 90% in the CAPOX + C and CAPOX arms.
There was no statistical difference between the two arms with respect to complete
response rate (11 vs. 9%, P = 1.0), pCR rate (11 vs. 7%, P = 0.71), R0 resection
rate, sphincter preserving surgery rate or postoperative morbidity. Additionally,
there was no statistical difference in DFS between the two arms. However, the
CAPOX + C arm significantly improved radiologic response after chemotherapy
(71 vs. 51%, P = 0.038) and after nCRT (93 vs. 75%, P = 0.028) and OS (P =
0.034) [40].
The NRG-GI002 trial conducted in the US, is the only phase II RCT in which
patients with LARC were randomized (1:1) to eight cycles of induction FOLFOX
and then nCRT with or without pembrolizumab. The study endpoint was neoadjuvant rectal (NAR) score. The results showed that the median NAR score of the
control arm and the pembrolizumab arm were 14.08 and 11.53 respectively, however the difference was not statistically significant (p = 0.26). Moreover, the rates
of cCR (14 vs. 14%, P = 0.95) and pCR (32 vs. 29%, P = 0.79) were similar in
both arms. Although the tumour regression and complete response rates were similar in both arms, complete response was as high as 44%. Hence, approximately
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 47
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(3y)
(3y)
a
OS (%)
DFS
(%)
R0 resection
(%)
pCR
(%)
89 (3y)
(3y)
91 (3y)
(3y)
87
(3y)
a
95
92 (3y)
95 (3y)
(3y)
(3y)
(3y)
compliance (%)
Tab le 2.4 RCTs of TNT combined with immunotherapy or biologics for LARC patients
Treatment type (no. of cycles) N Chemotherapy
stage
Study (year) Design Clinical
115 92 26 98 75
Aflibercept + FOLFOX
FOLFOX (6) → nCRT → TME 65 97 15 97 82
(6) → nCRT→ TME
LARC
Phase II High-risk
GEMCAD
1402 (2019)
[38, 39]
83 95 18 96 NR NR
+ CAPOX (4)
(4) → nCRT→ TME → Cetuximab
Cetuximab + CAPOX
LARC
Phase II High-risk
EXPERT-C
(2012) [40]
81 93 15 92 NR NR
CAPOX
(4) → nCRT→ TME → CAPOX (4)
90 NR 32 94 64
FOLFOX (8) → nCRT → TME 95 NR 29 89 64
Pembrolizumab (6) → TME
FOLFOX (8) → nCRT +
LARC
Phase II High-risk
NRG-GI002
(2021) [41,
42]
FOLFOX (8) → nCRT → TME 88 NR NR NR 67
90 NR NR NR 60
FOLFOX (8) → nCRT +
Vel i p ar i b → TME
RCTs, randomized controlled trial; TNT, total neoadjuvant therapy; LARC, locally advanced rectal cancer; pCR, pathologic complete response; DFS, disease free
survival; OS, overall survival; nCRT, long-course neoadjuvant chemoradiotherapy; TME, total mesorectal excision; 5-FU, 5-fluorouracil; FOLFOX, oxaliplatin
Indicates statistically significant outcome
+ leucovorin + 5-FU; CAPOX, oxaliplatin + capecitabine; y, years; R0, microscopically clear resection; NR, not reported
a
48 S. Bedrikovetski and T. Sammour
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half of patients achieved a complete response, suggesting that the combination of
TNT and immunotherapy is beneficial in achieving a complete response. However,
this trial failed to meet its primary endpoint likely due to the low completion rate
of pembrolizumab (46%) and slightly higher grade 3 and 4 RT toxicity (48%)
[41]. After a 3-year follow-up period, the addition of pembrolizumab to TNT was
associated with a statistically significant improvement in OS (95 vs. 87%, P =
0.04), but not DFS (64 vs. 64%, P = 0.82) [42].
2.3 Where Next?
2.3.1 Personalized Total Neoadjuvant Therapy Sequencing
Based on the results of the aforementioned RCTs, the broad implementation of
TNT for all patients with LARC is highly appealing. Nonetheless, such aggressive
trimodal therapy carries demonstrable risk and the decision to use this approach
should carefully consider whether the potential benefits of chemotherapy and radiation outweighs the associated morbidity with each strategy. Therefore, intensive
initial evaluation consisting of digital rectal examination (DRE), complete highquality colonoscopy, computed tomography (CT) of the chest/abdomen/pelvis and
high-resolution rectal MRI can allow for appropriate risk stratification into lowand high-risk groups. A framework based on substantifying high-risk patients
according to systemic (eg, stage IV disease, positive mesorectal or lateral pelvic
lymph nodes, and EMVI) and local (bulky local disease, cT4 extension and distal
rectal tumours) risk of recurrence has been extensively discussed in the literature, however published data on the feasibility and efficacy of a personalized
TNT approach based on this framework has only been described some one local
Australian group [15, 16, 43].
Patients with a high-risk of LR can derive benefit from upfront nCRT followed
by consolidation chemotherapy. Moreover, because the QoL after TME is significantly reduced, the demand for organ preservation with nonoperative management
has substantially increased. A Canadian study showed that patients were willing to accept a 20% (ie. From 0 to 20%) absolute increase in LR and a 20%
decrease in OS (ie. From 80 to 60%) with nonoperative management relative to an
abdominoperineal resection [44]. Therefore, based on the CAO/ARO/AIO-12 trial
showing a 25% increase in pCR and the OPRA trial reporting organ presentation
rates of over 50%, the optimal chemotherapy sequence appears to be consolidation
TNT in patients seeking cCR. Earlier nCRT can also help alleviate symptoms for
patients with bleeding, tenesmus, proctitis or near obstruction. However, patients
with RT resistant cancers who continue treatment may experience unnecessary toxicity without any oncological benefit. These patients may face disadvantages such
as delayed switching to potentially more effective alternative treatment strategies
or undergo TME.
Additionally, it is crucial to integrate dose de-escalation strategies to prevent
overtreatment, particularly in TNT regimens that utilize highly toxic agents like
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