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1 Triage Optimisation in Patients with Symptoms Suspicious of Colorectal … 29
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Total Neoadjuvant Therapy (TNT)
https://t.me/med1917
in Rectal Cancer; Where Now, Where
Next?
S. Bedrikovetski and T. Sammour
Abstract
In this chapter, we summarize the key findings of pivotal RCTs on TNT for
patients with Locally Advanced Rectal Cancer (LARC) and discuss future directions of TNT including: personalization, optimization of chemotherapy regimen
and sequencing, selective omission of RT, nonoperative management, quality
of life implications, and options for patients with microsatellite instability and
low-risk LARC.
Keywords
Total neoadjuvant therapy (TNT)•Rectal cancer•Neoadjuvant therapy
Chemoradiotherapy•Preoperative treatment•Oncological outcomes•Surgical
•
management
Tumour downstaging•Local recurrence•Systemic therapy
2
•
Key Points
•
Neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision
(TME) and adjuvant chemotherapy has been the standard treatment for locally
advanced rectal cancer (LARC). Although effective in terms of locoregional
control, this strategy seemed to make little difference to distant metastasis.
•
Several randomized controlled trials (RCTs) have since shown the potential benefits of Total Neoadjuvant Therapy (TNT) which attempts to deliver both systemic
chemotherapy and nCRT prior to surgery.
•
TNT improves disease-free survival, treatment compliance, pathological complete response rate, and facilitates organ preservation in clinical complete
responders adopting a nonoperative management approach.
S. Bedrikovetski · T. Sammour (B)
Discipline of Surgery, Faculty of Health and Medical Sciences, School of Medicine, University of
Adelaide, Adelaide, South Australia, Australia
e-mail: tarik.sammour@gmail.com
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
M. Evans e t al. (eds.), Coloproctology, https://doi.org/10.1007/978-3-031-59630-8_2
35
36 S. Bedrikovetski and T. Sammour
https://t.me/med1917
•
However, TNT protocols are highly variable and may incorporate different
radiation dosages (short-course or long-course) and chemotherapy sequences
(induction or consolidation).
2.1 Introduction
During the latter part of the twentieth century, the standard of care for locally
advanced rectal cancer (LARC) was long-course neoadjuvant chemoradiation
(nCRT) or short-course radiation (SC-RT) followed by total mesorectal excision
(TME) and adjuvant chemotherapy [1–3]. This treatment strategy provided excellent locoregional control, reducing the 5-year local recurrence (LR) rate from 27%
to approximately 10%. The characteristics of these 10% were further clarified by
the UK MERCURY study which used magnetic resonance image (MRI) to demonstrate that an involved or threatened circumferential resection margin (CRM),
extramural vascular invasion (EMVI) and tumours located in the lower third of
the rectum are at high-risk of LR [4]. This finding was further corroborated by the
OCUM and QuickSilver studies reporting that patients with high-risk features are
not only at risk of LR but also of distant metastasis (DM) and poor overall survival
(OS) [5, 6]. In spite of nCRT improving LR rates, 5-year incidence of DM and
OS remained around 30 and 65%, respectively [1, 3, 7]. This is thought to be due
to poor tolerance of, and low compliance with, adjuvant chemotherapy, as a result
of treatment delays and postoperative complications [8]. Additionally, nCRT followed by TME surgery are associated with significant morbidity and long-lasting
problems such as sexual and urinary dysfunction, significant defecatory problems,
or a permanent stoma [9, 10]. As a result, many patients experience a significant
decline in quality of life (QoL) after TME.
To overcome such problems, a new treatment strategy referred to as Total
Neoadjuvant Therapy (TNT) attempts to deliver systemic chemotherapy before
(induction) or after (consolidation) nCRT prior to TME surgery. The potential
advantages of TNT include earlier treatment of subclinical micro-metastases,
improvement in treatment compliance, enhanced response in the primary tumour,
and reduction in the time to ileostomy closure. Importantly, patients who receive
TNT have a greater chance of achieving a pathologic complete response (pCR) or
clinical complete response (cCR), with the latter allowing for surgery to be avoided
all together in selected patients. The potential disadvantages of TNT include delaying definitive local treatment and potential over-treatment particularly in patients
with stage II and early stage III disease without risk factors for increased distant
recurrence.
According to the National Comprehensive Cancer Network (NCCN) guidelines
risk classification is crucial in neoadjuvant treatment decisions for patients with
LARC [11]. LARC can be stratified into low-risk (cT3, cN any with clear CRM)
and high-risk groups (cT3, cN any with involved or threatened CRM; cT4, cN any
or locally unresectable or medically inoperable). Differences in guidelines between
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 37
https://t.me/med1917
Fig. 2.1 Variation in approaches in TNT
the United States (US), Europe, China, and Australasia highlight the lack of consensus regarding the use of TNT in LARC [11–14]. The 2022 NCCN guidelines
have made TNT the standard of care for the high-risk LARC group. European and
Chinese guidelines recommend a more selective approach. European and Chinese
recommendations suggest TNT for high-risk, low rectal tumours or those with
positive lateral pelvic lymph nodes (LPLN). In Australian guidelines, TNT is not
listed as a treatment option for LARC. However, numerous Australian centres are
providing TNT either selectively or routinely as part of clinical studies [15–17].
TNT approaches differ substantially with regards to radiation dosages,
chemotherapy regimens and sequencing (Fig. 2.1).
Hence, it is crucial for surgeons to possess an in-depth comprehension of these
novel techniques to effectively identify the appropriate instances for advocating the
use of TNT, recognizing situations where it is unnecessary, and discerning when
it may be unsuitable. This chapter will review key randomised controlled trials
(RCTs) investigating the use of TNT in LARC and provide a brief discussion on
the future direction involving this treatment strategy.
2.2 Where Are We Now?
2.2.1 Induction Chemotherapy
One of the earliest TNT designs used for patients with LARC was give induction
chemotherapy upfront before nCRT and TME surgery. Table 2.1 summarizes some
of the key RCTs comparing TNT using induction chemotherapy and nCRT versus
nCRT alone or with adjuvant chemotherapy as a control arm.
The phase II RCTs observed no significant differences in rates of pCR, tumour
regression, or sphincter preserving surgery between induction TNT and control
arms [18–22]. However, induction chemotherapy demonstrated a lower occurrence
of grade 3 and 4 adverse events and better compliance compared to the control arm,
as indicated by the Spanish GCR-3 study. This trial reported a completion rate of
38 S. Bedrikovetski and T. Sammour
https://t.me/med1917
DFS (%) OS (%)
R0
resection
(%)
pCR
(%)
Chemotherapy
compliance
(%)
patients
88 (3y),
,
a
94 69 (3y)
a
a
80 (5y),
a
66 (5y),
76 (7y)
63 (7y)
91 (3y),
,
a
95 76 (3y)
a
28
231 78 (92
a
87 (5y)
a
73 (5y),
neoadjuvant
82 (7y)
68 (7y)
only)
a
28 NR 68 (5y) 82 (5y)
a
31 NR 72 (5y) 84 (5y)
120 80
16 73 10 100 80 (5y) 90 (5y)
b
14 68 58 100 90 (5y) 93 (5y)
113 73 14 83 73 (5y) 84 (5y)
51 86 20 88 73 (5y) 86 (5y)
a
90 77 (3y) 89 (3y)
165 NR 28
(continued)
91 73 (3y) 91 (3y)
a
165 NR 7 89 74 (3y) 91 (3y)
Study (year) Design Clinical stage Treatment type (no. of cycles) N of
Tab le 2.1 RCTs of induction TNT for LARC patients
cT3-4 nCRT→ TME → FOLFOX (8) 230 75 12
Phase
III
PRODIGE-23
(2021) [24, 25]
b
c
c
FOLFIRINOX
(6) → nCRT→ TME → FOLFOX
(6)
High-risk LARC HDRBT → TME → FOLFOX (12) 60 53
Phase
KIR study
(6)
FOLFOX
(6) → HDRBT → TME → FOLFOX
FOLFIRINOX (4) → TME
FOLFIRINOX (4) → nCRT
(50 Gy) → TME
FOLFIRINOX (4) → nCRT
(50 Gy) → TME
FOLFIRINOX (4) → intensive nCRT
(60 Gy) → TME
cT3cd-T4 or
CRM ≤ 1mmand
DRM ≥ 1cm
II
(2021) [23]
Phase
II
GRECCAR4
(2017) [21, 22]
nCRT→ TME → FOLFOX (7)
II–III FOLFOX +
Phase
III
FOWARC
(2016) [70, 71]
FOLFOX (4–6) → TME ± pre or
post op RT→ FOLFOX (6–8)
nCRT→ TME → 5FU (7) 165 NR 14
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