Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / @xirurgi_2025 / @xirurgi_2025 - 598 - файл
.pdf
280
https://t.me/medicina_free
42. Fernandez LM, São Julião GP, Renehan AG, Beets GL, Papoila AL, Vailati BB, etal. The risk
of distant metastases in patients with clinical complete response managed by watch & wait after
neoadjuvant therapy for rectal cancer: the inuence of local regrowth in the international watch
and wait database. Dis Colon Rectum. https://doi.org/10.1097/DCR.0000000000002494.
43. Appelt AL, Pløen J, Harling H, Jensen FS, Jensen LH, Jørgensen JCR, etal. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study.
Lancet Oncol. 2015;16:919–27.
44. Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS, etal. Watch-and-wait
approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the
OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol. 2016;17:174–83.
45. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, etal. PD-1 blockade in
mismatch repair-decient, locally advanced rectal cancer. N Engl J Med. 2022;386:2363–76.
F. F. Quezada-Diaz and J. J. Smith
Which Patients Are theRight Candidates
https://t.me/medicina_free
forTotal Neoadjuvant Therapy (TNT)?
MaxwellD.Mirande andScottR.Kelley
Introduction
Outcomes for locally advanced rectal cancer (LARC) have signicantly improved
over the past several decades with the introduction of total mesorectal excision
(TME) and the addition of 5-uorouracil (5-FU)-based neoadjuvant chemoradiotherapy (nCRT) [1–8] but have failed to improve overall survival (OS) due to distant
metastases (DM) [4–9]. Distant recurrences occur in up to 30% and remain a signicant cause of mortality for patients with LARC [9]. The addition of oxaliplatin
to 5-FU-based chemotherapy (CT) has signicantly improved disease-free survival
(DFS) and OS in patients with stage II or III colon cancer [10]; however, an OS
benet has not been demonstrated for adjuvant chemotherapy (AC) use in LARC
patients who have received nCRT [11, 12]. Delayed administration of AC and/or
poor compliance affect up to 50% of patients, and are factors thought to contribute
to this discrepancy. For these reasons, traditional trimodal therapy (nCRT, TME,
AC) has been called into question and the concept of total neoadjuvant therapy
(TNT) has emerged.
TNT is a novel approach which consists of the administration of multidrug systemic CT plus chemoradiotherapy (CRT) prior to surgery with the goal of reducing
DM and maintaining local control in patients with LARC.TNT strategies comprise
of either induction (prior to nCRT) or consolidation (after nCRT) CT.Proponents of
TNT suggest the approach allows for earlier systemic treatment of occult
24
M. D. Mirande (*)
Mayo Clinic, General Surgery, Rochester, MN, USA
e-mail: Mirande.Maxwell@mayo.edu
S. R. Kelley
Mayo Clinic, Colon and Rectal Surgery, Rochester, MN, USA
e-mail: kelley.scott@mayo.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
K. Umanskiy, N. Hyman (eds.), Difcult Decisions in Colorectal Surgery,
Difcult Decisions in Surgery: An Evidence-Based Approach,
https://doi.org/10.1007/978-3-031-42303-1_24
281
282
https://t.me/medicina_free
micrometastases leading to improved survival, better therapy compliance, better
tumor response, and the potential for organ preservation. However, several questions remain regarding TNT including the optimal timing and protocol used, induction versus consolidation, variable tumor response, and possible overtreatment.
Herein we review the literature and discuss which patients with LARC are the right
candidates for TNT.
M. D. Mirande and S. R. Kelley
Search Strategy
Utilizing Embase and Medline databases, a search of the English literature was
conducted using the terms rectal cancer, rectal neoplasms, total neoadjuvant therapy
(TNT), chemoradiotherapy, induction chemotherapy, and consolidation chemotherapy. The search was limited to human studies over the last 10years (2012–2022).
Original studies evaluating outcomes of patients with LARC treated with TNT were
included and manuscript reference lists were reviewed for additional articles (Tables
24.1). Studies from the same institution/author were excluded if previously reported.
A total of nine studies were chosen for review.
Results
The Spanish GCR-3 multicenter phase II trial randomized 108 patients with cT3T4, and/or N+ mid to distal rectal cancer into either a control (capecitabine plus
oxaliplatin [CAPOX]-based long course CRT (LCCRT) followed by surgery and
four cycles of CAPOX) or experimental arm (four cycles of induction CAPOX followed by the same LCCRT and surgery), with a primary endpoint of pathologic
complete response (pCR) [13]. The experimental arm included more T4 and grade
3 tumors whereas the control arm had more tumors with a threatened circumferential resection margin (CRM). On an intention-to-treat analysis, induction CAPOX
demonstrated a similar pCR, R0 resection, downstaging, and tumor regression rate.
There was signicantly higher compliance with induction CT as 94% received all
four cycles (p< 0.0001) compared to 57% in the control arm. Additionally, there
were no differences between the arms in grade 3 or 4 toxicities during CRT; however, there were signicantly more grade 3 or 4 toxicities during AC when compared to induction CT (54% v 19%; p=0.0004, respectively). With a median follow
up of 69.5months, no differences between the control and experimental arms were
observed in 5-year cumulative LR (2% v 5%; p=0.61), DM (21% v 23%; p=0.79),
DFS (64% v 62%; p=0.85), or OS (78% v 75%; p=0.64), respectively (Tables
24.2, 24.3, 24.4).
The Polish II study was one of the rst multicenter phase III randomized trials to
investigate short-course radiation (SCRT) plus consolidation CT [14]. A total of 515
patients with cT3-T4 rectal cancer were randomized to either the control arm
(LCCRT with concomitant leucovorin, 5-FU, and oxaliplatin [FOLFOX]) or the
experimental arm (SCRT plus three cycles of FOLFOX4), with a primary endpoint
24 Which Patients Are theRight Candidates forTotal Neoadjuvant Therapy (TNT)?
https://t.me/medicina_free
283
of R0 resection rate. The overall acute toxicity was lower in the experimental group
than in the control (75% v 83%; p=0.006), but similar grade 3 or 4 toxicities were
observed between both groups (23% v 21%). No differences were seen in post-op
complications (29% v 25%; p=0.18) between the two groups. The R0 resection
rate and pCR rates were also similar between both groups (77% v 71%; p=0.07)
and (16% v 12%; p=0.17), respectively. At 3-years, the OS for the experimental
arm was signicantly higher at 73% versus 65% in the control arm (HR=0.73, 95%
CI 0.53–1.01; p=0.046) but no differences were seen in 3-year LR, DM, or DFS. At
8-years, the difference in OS was no longer signicant (HR = 0.90, 95% CI
0.70–1.15; p=0.38) [15].
The phase II WAIT trial randomized 49 patients to either a control arm (LCCRT
followed by surgery) or experimental arm (LCCRT plus three cycles of bolus 5-FU/
leucovorin followed by surgery), with the primary endpoint of pCR [16]. Most
patients were cT3 (86%) and 96% were considered node positive on MRI.A wait
period of 10weeks after completion of CRT was used. There were similar postoperative complications and length of stay between the two groups. The pCR was
similar between both arms (16% v 25%; p= 0.49); however, this study was not
powered to detect small differences.
The Korean Cancer Study Group (KCSG) CO 14–03 phase II randomized trial
aimed to evaluate the efcacy of CAPOX consolidation CT [17]. A total of 108
patients with cT3-T4 rectal cancer were randomized into either the control arm
(LCCRT followed by surgery) or the experimental arm (LCCRT followed by two
cycles of CAPOX and surgery), with a primary endpoint of downstaging. The
experimental arm had marginal improvements in pCR (13.6% v 5.8%; p= 0.167)
and downstaging (36.4% v 21.2%; p=0.077) compared to the control arm, but neither were signicant. However, there was a high dropout rate of 13% with only 96
total patients undergoing surgery per protocol. Due to the dropout rate and safety
concerns, a phase III trial using this strategy was discouraged.
The Chinese FOWARC study was a multicenter phase III randomized trial that
compared LCCRT (control) versus ve cycles of mFOLFOX6 with long-course
radiation (exp. 1) versus ve cycles of mFOLFOX6 alone (exp. 2) [18]. A total of
495 patients with stage II or III tumors within 12cm of the anal verge were randomized with a primary endpoint of 3-year DFS. All groups underwent surgery
6–8 weeks following therapy and received postoperative AC. The pCR rate was
14.0%, 27.5%, and 6.6% for the control, exp. 1, and exp. 2 groups respectively (OR
0.428, 95% CI 0.237–0.776; p = 0.005). There was high treatment compliance
(>90% of full-dose neoadjuvant CT) amongst the control (88.4%), exp. 1 (94.9%),
and exp. 2 (94.5%) groups. At 3-years, there were no differences observed in DFS
between the control (72.9%), exp. 1 (73.5%), and exp. 2 (73.5%) groups (log rank
p=0.709). The 3-year LR was rate was 8%, 7%, and 8.3% (log rank p=0.873) and
the 3-year OS was of 91.3%, 89.1%, and 90.7% (log rank p=0.971), respectively.
Although the exp. 2 group had inferior pCR, there was similar downstaging rates
compared to the control group (35.5% v 37%) with less toxicity, complications, and
no differences in DFS, LR, or OS.The role of neoadjuvant CT alone remains unclear
284
https://t.me/medicina_free
M. D. Mirande and S. R. Kelley
but several ongoing studies, including the phase III randomized PROSPECT trial
will provide additional insight [19].
The Swedish RAPIDO multicenter phase III trial randomized 912 patients with
tumors less than 16cm from the anal verge and MRI high-risk criteria (cT4a or
cT4b, extramural vascular invasion, cN2, involved mesorectal fascia, or enlarged
lateral lymph nodes considered to be metastatic) into either a control (LCCRT followed by surgery and optional adjuvant CAPOX or FOLFOX4) or experimental
arm (SCRT followed by six cycles of CAPOX or nine cycles of FOLFOX4 followed
by surgery), with a primary endpoint of 3-year disease-related treatment failure
(DrTF) [20]. The experimental arm had a signicantly higher pCR rate (28% v 14%;
OR 2.37, 95% CI 1.67–3.37; p < 0.0001), fewer 3-year DrTF events (23.7% v
30.4%; HR=0.75, 95% CI 0.60–0.95; p=0.019), and a lower 3-year cumulative
probability of DM (20.0% v 26.8%; HR= 0.69, 95% CI 0.54–0.90; p =0.0048)
compared to the control. The 3-year cumulative probability of locoregional failure
(8.3% v 6.0%; p=0.12) and OS (89.1% v 88.8%; p=0.59) were similar between
both arms, respectively. The authors concluded that SCRT followed by 18weeks of
consolidation CT before surgery can be considered as a new standard of treatment
for patients with high-risk LARC and can potentially contribute to organ
preservation.
The PRODIGE 23 trial is a multicenter phase III randomized trial that compared
induction FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) to LCCRT
[21]. A total of 461 patients with tumors within 15cm of the anal verge and cT3 or
cT4 were included. Patients were randomly assigned to either the experimental
group (six cycles of FOLFIRINOX, followed by LCCRT, surgery, and adjuvant
mFOLFOX6 or capecitabine) or the control group (LCCRT, surgery, and adjuvant
mFOLFOX6 or capecitabine), with a primary endpoint of 3-year DFS. Like the
RAPIDO trial, the experimental group had a signicantly higher pCR rate (28% v
12%; p<0.001). With a median follow-up of 46.5months, the experimental group
had improved 3-year DFS (76% v 69%; HR 0.69, 95% CI 0.49–0.97; p=0.034) and
3-year metastasis-free survival (79% v 72%; HR 0.64, 95% CI 0.44–0.93; p=0.017),
with no differences in 3-year OS (91% v 88%, p=0.0773). The authors concluded
that induction FOLFIRINOX can be considered as one of the new standard-of-care
treatment approaches for eligible patients with LARC.
The German CAO/ARO/AIO-12 trial is the rst multicenter, phase II randomized trial to compare induction and consolidation CT [22]. Patients with cT3–4 and/
or node positive tumors within 12cm of the anal verge were included. A total of 306
were randomized into the induction CT group (three cycles of FOLFOX followed
by LCCRT and surgery) or the consolidation CT group (LCCRT followed by three
cycles of FOLFOX and surgery), with a primary endpoint of pCR.The trial demonstrated a higher pCR rate in the consolidation CT group (25% v 17%; OR 1.69, 95%
CI 0.96–2.99; p=0.071). It also showed that the treatment modality given rst as
part of TNT will likely always have higher compliance and lower toxicity. With a
median follow-up of 43months, the 3-year DFS was 73% in the induction group
and 73% in the consolidation group (p=0.82). The 3-year LR (6% v 5%; p=0.67),
3-year DM (18% v 16%; p=0.52), and 3-year OS (92% v 92%; p=0.81) were all
24 Which Patients Are theRight Candidates forTotal Neoadjuvant Therapy (TNT)?
https://t.me/medicina_free
285
similar between both groups, respectively. The authors concluded that the consolidation TNT strategy was able to achieve higher pCR without compromising longterm oncologic outcomes, toxicity, or quality of life (QOL) and may be the best
choice if organ preservation is a priority. The consolidation TNT regimen from this
trial will be compared against the TNT regimen from the RAPIDO trial in the ACO/
ARO/AIO-18.1 trial (NCT04246684), with 3-year DFS as the primary endpoint.
The OPRA trial is the rst multicenter, phase II randomized trial evaluating TNT
and a selective watch-and-wait (WW) strategy [23]. A total of 324 clinical stage II
or III rectal cancer patients were randomized into the induction or consolidation CT
groups, with a primary outcome of 3-year DFS. Patients were treated with either
eight cycles of mFOLFOX6 or ve cycles of CAPOX, and LCCRT.Tumor restaging was performed within 8 (+/−4) weeks after completion of TNT, and TME versus WW was offered based on tumor response. The trial demonstrated a 3-year DFS
of 76% (95% CI, 69–84) for the induction and 76% (95% CI, 69–83) for the consolidation group. No differences were in seen in LR-free survival, DM-free survival,
or OS between the two groups. Rectal preservation at 3years was 41% (95% CI,
33–50) for the induction and 53% (95% CI, 45–62; p=0.1) for the consolidation
group. DFS was similar between patients who underwent initial TME and patients
who underwent TME after tumor regrowth, thus demonstrating no apparent adverse
impact on oncologic outcomes with WW.
Table 24.1 PICO table
Patients
Locally advanced rectal
cancer (LARC)
Intervention Comparator
Totally neoadjuvant
therapy (TNT)
Trimodal
therapy
Outcomes
Pathologic complete
response (pCR)
Recurrence
Survival
286
https://t.me/medicina_free
Secondary End Points
downstaging, R0
resection, 30-day
complications, LR,
Primary End
Point
DM, DFS, OS
Toxicity, 30-day and
late complications,
pCR, LR, DM, DFS,
OS
rate
complications
pCR, LR, RFS, DFS,
OS, safety prole,
rate to yp
pCR, R0 resection,
QOL
stage 0–1
M. D. Mirande and S. R. Kelley
R0 resection, pCR,
30-day complications,
sphincter-saving
surgery, LR, OS, RFS,
QOL
LR, QOL, OS
Median
Follow-Up
(month)
Design Treatment Arms
69.5 pCR Toxicity, compliance,
Con: CRT (capecitabine/oxaliplatin)→surg →
CAPOX×4
Exp: CAPOX×4→CRT (capecitabine/
oxaliplatin)→surg
RCT
phase II
35 R0 resection
Con: CRT (FOLFOX)→surg
Exp: SCRT → FOLFOX4×3→surg
phase III
26 Downstaging
NR pCR LOS, 30-day
Con: CRT (capecitabine)→surg
Exp: CRT (5-FU)→5-FU/LV×3→surg
phase II
RCT
Exp: CRT (capecitabine)→CAPOX×2→surg
phase II
Con: CRT (5-FU)→surg
45.2 3-yr DFS Toxicity, response rate,
Con: 5-FU×5+RT→surg → 5FU×7
Exp 1: mFOLFOX6×5+RT→surg →
mFOLFOX6×7
Exp 2: mFOLFOX6×4–6→surg →
mFOLFOX6×6–8
phase III
55.2 3-yr DrTF Compliance, toxicity,
FOLFOX4×12 (optional)
Exp: SCRT → CAPOX×6/ FOLFOX4×9→surg
Con: CRT (capecitabine)→surg → CAPOX×8/
phase III
Author/Year/Study
Fernández-Martos/ 2015/
Table 24.2 Trial characteristics
GCR-3
Bujko/2016/ POLISH II RCT
Kim/2018/ KCSG CO
Moore/2017/ WAIT RCT
14–03
Deng/2019/ FOWARC RCT
Bahadoer/2020/ RAPIDO RCT
24 Which Patients Are theRight Candidates forTotal Neoadjuvant Therapy (TNT)?
https://t.me/medicina_free
adverse events, LR,
Secondary End Points
DM, pCR, R0
resection,
complications, safety,
Primary End
Point
QOL
toxicity, QOL
DM, OS, QOL
287
Median
Follow-Up
(month)
Design Treatment Arms
46.5 3-yr DFS OS, MFS, CSS, LR,
Con: CRT (capecitabine)→surg → mFOLFOX6×12/
capecitabine×8
RCT
phase III
43 pCR DFS, LR, DM, OS,
Exp: FOLFIRINOX×6→CRT (capecitabine)→surg
→ mFOLFOX6×6/capecitabine×4
Exp 1: FOLFOX×3→CRT (5-FU)→surg
Exp 2: CRT (5-FU)→FOLFOX×3→surg
RCT
phase II
36 3-yr DFS TME-free survival,
Exp 1: mFOLFOX6×8 or CAPOX×5→CRT (5-FU
or capecitabine)→WW or surg
Exp 2: CRT (5-FU or capecitabine)→mFOLFOX6×8
RCT
phase II
or CAPOX×5→WW or surg
RCT Randomized control trial, CRT Chemoradiotherapy, surg Surgery, CAPOX Capecitabine and oxaliplatin, pCR Pathologic complete response, LR Local
recurrence, DM Distant metastases, DFS Disease-free survival, OS Overall survival, FOLFOX Leucovorin calcium, 5-FU, and oxaliplatin, SCRT Short-course
radiation, QOL Quality of life, RFS Relapse-free survival, FOLFIRINOX Leucovorin, 5-FU, irinotecan, and oxaliplatin, MFS Metastasis-free survival, CSS
Cancer-specic survival, WW Watch-and-wait, TME Total mesorectal excision
288
https://t.me/medicina_free
Median Age
(range)
62 (42–75)
60 (38–76)
Gender (%)
M:F
65:35
70:30
Arms
(N)
Exp: (56)
60
60
67:33
70:30
Exp: (261)
61
60
75:25
72:28
Exp: (25)
55
56
84:16
68:32
Exp: (53)
545254
62:38
69:31
66:34
Exp 1: (162)
Exp 2: (163)
M. D. Mirande and S. R. Kelley
62 (23–84)
62 (31–83)
62 (26–75)
61 (34–77)
60
62
59
69:31
65:35
68:32
65:35
68:32
67:33
65:35
Exp: (462)
Exp: (231)
Exp 2: (150)
324 Exp 1: (158)
56
61:39
Exp 2: (166)
Inclusion Criteria N
Study
Table 24.3 Patient characteristics
GCR-3 Distal/middle third, cT3-T4 and or N+ 108 Con: (52)
POLISH II cT3-T4 515 Con: (254)
WAIT Non metastatic distal rectal LARC 49 Con: (24)
KCSG CO 14–03 cT3-T4, N+ 108 Con: (55)
FOWARC cT3-cT4, N+ 495 Con: (158)
RAPIDO High risk criteria on MRI (cT4a, CT4b, cN2) 912 Con: (450)
PRODIGE-23 cT3-T4 461 Con: (230)
CAO/ARO/AIO-12 cT3–4, N+ 306 Exp 1: (156)
N1–2)
OPRA Stage II (cT3–4, N0) or Stage III (any T,
LARC Locally advanced rectal cancer, MRI Magnetic resonance imaging, Con Control, Exp Experimental
24 Which Patients Are theRight Candidates forTotal Neoadjuvant Therapy (TNT)?
https://t.me/medicina_free
c
c
, 49
, 49
a
b
OS (%)
DFS
(%)
Distant
Recurrence
(%)
Local
Recurrence
(%)
pCR
(%)
78a75
a
64
21a23
2a5
13
b
65
73
–
–
–
c
c
, 43
, 41
a
b
b
62
52
53
–
–
–
c
c
, 36
, 34
b
b
a
25
29
–
–
–
a
–
–
–
–
–
12
16
25
16
14
6
–
–
–
–
14
b
91b89b91
b
73b77b74
–––
b
8b7b8
14287
b
89b89
–
–
b
27b20
b
6b8
14
28
b
88b91
b
69b76
25
17
4
6
12
28
b
92b92
b
73b73
b
18b16
b
6b5
17
25
–
76b76
b*
/17
b
17
b*
/10
b
7
12
–
b
b*
/21
b
24
b*
/15
b
11
16
289
Post-operative
Complications
No. (%)
Grade 3–4
Toxicity
(%)
Compliance
with CT (%)
Arms (N)
Table 24.4 Trial outcomes
Study
21 (45)
27 (51)
54
19
57
94
Exp: (56)
GCR-3 Con: (52)
49 (25)
62 (29)
23
– 21
Exp: (261)
POLISH II Con: (254)
10 (42)
13 (52)
–
–
–
–
Exp: (25)
WAIT Con: (24)
2
4
–
KCSG CO 14–03 Con: (55)
9
9
89
Exp: (53)
–––
–––
889594
Exp 1: (162)
Exp 2: (163)
FOWARC Con: (158)
189 (47)
215 (50)
–
25
48
74
90
84
79
Exp: (462)
RAPIDO Con: (450)
PRODIGE–23 Con: (230)
–
42
46
37
92
93/92
Exp: (231)
Exp 1: (156)
CAO/ARO/
34
–
27
71 (45)
90/85
83
Exp 2: (150)
AIO–12
OPRA Exp 1: (158)
–
63 (38)
81
Exp 2: (166)
Results at 5years
CT Chemotherapy, pCR Pathologic complete response, DFS Disease-free survival, OS Overall survival, Con Control, Exp Experimental
a
b
Results at 3years
Patients who underwent total mesorectal excision after local regrowth
Results at 8years
c
*
Соседние файлы в папке @xirurgi_2025