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2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 49
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irinotecan. The CinClare multicentred phase III trial from China is a good example
of this. Here the authors used UDP-glucuronosyltransferase (UGT1A1) genotyping for polymorphism at *1*1 or *1*28 to guide the dosing of irinotecan in
patients who were randomized to irinotecan-containing arm. The trial showed that
the irinotecan-containing arm had a higher pCR rate (34 vs. 18%, P = 0.001),
but had a higher incidence of grade 3 and 4 adverse events (38 vs. 6%, P <
0.001) than the control arm, despite irinotecan dose de-escalation for carriers of
the UGT1A1 ∗ 1 ∗ 28 polymorphisms [45]. An expanded analysis of the trial found
that complete response rate (combining sustained cCR and pCR) was significantly
higher in the group that completed four to five cycles of weekly irinotecan compared to the group that completed one to three cycles (22 vs. 34%, P = 0.02) [46].
Long-term data presented at the American Society of Clinical Oncology (ASCO)
Annual Meeting reported no significant differences in 4-year OS or DFS between
the two arms [47].
Among patients with a high-risk for systemic failure, induction chemotherapy
provides an opportunity to deliver more systemic treatment upfront, and to identify
patients with chemo-resistant tumours early. The results of the GRECCAR 4 phase
II RCT showed that tailoring nCRT based on response to induction FOLFIRINOX
is safe for poor responses and promising for good responders. Although dose escalation is a feasible strategy it did not appear to increase R0 resection rates or
provide advantages in terms of 5-year DFS or OS. It is important to note that the
GRECCAR 4 trial was prematurely stopped because of low accrual numbers in the
first two-arms of the study, thus making it difficult to draw definitive conclusions.
Future directions include correlative biomarkers analysis to potentially identify subgroups who may derive benefit from TNT. Some pre-treatment biomarkers
have already been identified including sarcopenia, cN2, tumours size and elevated CEA [48, 49]. It is also important to precisely evaluate the initial response,
irrespective of the TNT sequence employed, in order to avoid adverse outcomes [50]. New tools to assess local and distant treatment response such as
endoscopic biopsies, next generation sequencing liquid biopsy, local excision,
F18-fluorodeoxyglucose positron emission tomography are continuously being
investigated [51]. As research progresses, these advancements have the potential
to become integral components of personalized care in the future.
2.3.2 Optimising Chemotherapy Regimen
The optimal regimen remains unclear. While most TNT trials have employed
oxaliplatin-based therapies like FOLFOX/CAPOX, the promising outcomes
observed in PRODIGE-23, GRECCAR 4, and CinClare trials, which confirmed
the efficacy of CAPIRI and FOLFIRINOX in LARC, suggest that the utilization
of triplet therapy could be the subsequent rational progression for optimizing TNT.
In North America, the SWOG, NRG and Alliance groups have developed
the Janus Rectal Cancer trial (NCT05610163) which aims to randomize patients
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with high-risk LARC in mid/low rectum to receive nCRT followed by consolidation doublet (FOLFOX or CAPOX) or triplet chemotherapy (FOLFIRINOX)
for 4 months, with cCR as the primary endpoint [52]. In Europe, consolidation
TNT in currently being evaluated in a German organ preservation phase II trial
(CAO/ARO/AIO-16 [NCT03561142]) in addition to a phase III trial (CAO/ARO/
AIO-18 [NCT04246684]) comparing SC-RT (control arm according to RAPIDO
trial) versus nCRT followed by consolidation chemotherapy (investigational arm
according to CAO/ARO/AIO-12 and OPRA trials) with selective organ preservation for patients with intermediate and high-risk LARC. The authors hypothesize
that the 3-year organ preservation rate will improve from 30% in control arm to
40% in the investigational arm. Moreover, the German Rectal Cancer Study Group
has recently unravelled a critical role of ineterleukin-1α (IL-1α) signalling in activating inflammatory cancer-associated fibroblasts and mediating radiation-induced
senescence, extracellular matrix accumulation and ultimately therapy resistance.
Consequently, the phase I ACO/ARO/AIO-21 trial is currently testing the IL1 receptor antagonist anakinra in combination with nCRT for advanced rectal
cancer [53]. Similar to the GRECCAR 4 trial, the French GRECCAR 12 trial
(NCT02514278) has added induction chemotherapy to enhance tumour response
rate and increase organ preservation rates. The trial included patients with middle
and low rectal tumours classified as cT2-T3 N0-N1 < 4 cm who were randomized
to receive either induction FOLFIRINOX followed by nCRT or nCRT alone. Evaluation is done between 8 and 10 weeks after neoadjuvant treatment. Local excision
is proposed in good responders (tumour residue ≤ 2 cm), while poor responders
underwent TME surgery. The primary endpoint was organ preservation rate at
1 year.
2.3.3 Neoadjuvant Chemotherapy or Immunotherapy
with Selective Omission of Radiotherapy
Chemotherapy and surgery have each improved over the years, hence there has
been an increased interest in omission of RT in select patients. The recently published PROSPECT trial (FOLFOX alone compared to nCRT in treating patients
with LARC undergoing surgery) showed FOLFOX was non-inferior to nCRT for
5-year DFS. The groups were also similar with respect to 5-year OS and LR.
Hence, the results of the PROSPECT trial may affect the decision to use or
omit neoadjuvant RT in patients who respond to systemic chemotherapy and are
willing to undergo surgery [54]. Moreover, the CONVERT phase III trial comparing neoadjuvant chemotherapy with CAPOX alone versus nCRT in LARC with
clear CRM. The authors found that chemotherapy alone achieved similar pCR
and downstaging rates with significantly lower incidence of perioperative distant metastasis (0.5 vs. 3%, P = 0.03), significantly preventive ileostomy rate
(52 vs. 64%, P = 0.008) compared with nCRT [55]. Nevertheless the benefit
of neoadjuvant treatment in patients with early tumours remains unclear. Despite
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 51
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the relatively young (median age 60 years) and healthy cohort (ECOG performance status ≤ 1, adequate hematologic, liver, and renal function), 70% in the
chemotherapy alone arm and 65% in the nCRT arm experienced toxicities. The
rate of postoperative morbidity was 19 and 26%, respectively. Therefore, there is
an argument to be made that a comparison of two overtreatment options does not
necessarily make the treatment appropriate. The overall goal is to find a minimal therapy sufficient for success rather than maximal therapy applicable to every
patient [56]. The NORAD01-GRECCAR16 (NCT03875781) multicentre phase III
trial is a non-inferiority RCT comparing preoperative systemic chemotherapy using
six cycles of FOLFIRINOX alone to nCRT in patients with resectable LARC. The
main goal of this trial is to provide further insight into whether the use of neoadjuvant chemotherapy instead of nCRT could be associated with better functional
results and QoL [57].
High microsatellite instability (MSI-H) in the primary tumour could affect the
decision to begin treatment with immunotherapy rather than systemic therapy. A
phase II study of 12 patients with MSI-H stage II-III LARC found neoadjuvant
single-agent dostarlimab (PD-1 blockade) was associated with 100% cCR rate
after at least 6 months follow-up. No patients have undergone nCRT or TME
at last follow-up and there have been no cases of progression or recurrence [58].
These results may have revolutionized treatment of MSI-H LARC pending further
validation and long-term follow-up.
2.3.4 Pushing the Boundaries of Nonoperative Management
TNT strategies have been of particular interest for distal rectal tumours, in which
coloanal anastomosis or abdominoperineal resection may result in poor bowel
function or a permanent stoma. There is growing evidence that a nonoperative
management approach aimed at organ preservation with a cCR after neoadjuvant
treatment, is oncologically safe [59–61]. The primary methods utilized to assess
a cCR include MRI, DRE, and flexible endoscopy. While the interpretation of
images in MRI could be considered subjective, DRE and flexible endoscopy may
involve an even greater element of subjectivity.
The argument that a nonoperative management approach is suitable for patients
with cCR is uncontroversial. However, a significant portion of patients exhibit a
very good response to treatment during the first reassessment, albeit not a complete one. These patients, known as good responders, are often described as having
a near-cCR. Despite the absence of a precise definition for near-complete clinical
response (near-cCR), the term is widely employed by clinicians and in recent literature publications [62–64]. Typically, a near-cCR is assigned to patients who have
a high likelihood of achieving a cCR, despite not displaying the typical features on
endoscopy and/or MRI. Consequently, there is a growing trend towards extending
the observation period and conducting repeated reassessments for such patients.
The OPRA trial highlighted the fact that patients with LARC treated with TNT
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who achieved a cCR or near-cCR were good candidates for a nonoperative management. More recently a study comparing outcomes in patients which achieved
a cCR at later reassessment found that oncological outcomes are no worse than
those of patients with a cCR at first assessment [65].
There has been some informal discussion regarding the role of TNT and nonoperative management in patients with early, low risk rectal cancer, i.e. patients
who traditionally would have proceeded straight to surgery [66]. While this may
be feasible for patients with very low tumours who decline surgery or a stoma,
there are no comparative data to guide treatment currently. Therefore, this strategy
would not be considered standard care, and should really be undertaken within the
context of a clinical trial.
2.3.5 Quality of Life Implications
QoL is an important aspect when considering the TNT approach, and data on this
are emerging. The FORWARC trial found constipation to be significantly higher
in TNT arm compared to the nCRT arm (36 vs. 24%, P = 0.003). However,
no other significant differences were observed between the arms regarding other
QoL questionnaires or Low Anterior Resection Syndrome (LARS) scores [67]. The
GRECCAR 4 trial found late morbidity and QoL evaluations were not significantly
different between the four study arms. In the PRODIGE-23 trial the QoL was
assessed at baseline, during treatments and at 2-year follow-up. Results showed
that compared to baseline, QoL scores during neoadjuvant chemotherapy were better for tumour symptoms but worse for global health status, functional domains,
fatigue, nauseas/vomiting, and appetite loss. During follow-up, improved emotional functioning was observed, but deterioration of body image, increased urinary
incontinence, and lower male sexual function were observed. Further longitudinal
analysis using a linear mixed model revealed a treatment-by-time interaction effect
for nausea/vomiting and insomnia symptoms showing a greater deterioration in the
nCRT arm [68].
The authors of the PRODIGE-23 trial concluded that induction TNT improved
tumour-related symptoms and transitorily reduced most functional scores compared to nCRT. In the RAPIDO trial, 3-years after surgery patients received QoL
and LARS questionnaires. No statistically significant and clinically meaningful
differences regarding the QoL scores were observed between the two arms. Major
LARS occurred more frequently in the nCRT arm than in the TNT arm (76 vs
59%), but this was not statistically different. It is important to note that one third of
patients in the RAPIDO trial had tumours located in the upper third of the rectum
(>10 cm from the anal verge), some of whom would have had a partial mesorectal
excision and a colorectal anastomosis, which makes the overall incidence of major
LARS potentially concerning. Neuropathy symptoms (tingling fingers or hands,
numbness toes or feet, pain in toes or feet, trouble standing or walking) occurred
significantly more often in the TNT arm compared to the nCRT arm. Additionally, late toxicity over time was not significantly different between the two arms
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 53
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at any time point. The authors from the RAPIDO trial concluded that consolidation chemotherapy did not compromise QoL, bowel functional or any grade and
grade ≥ 3 toxicity compared to nCRT [69].
The EXPERT-C trial defined QoL and bowel function as study endpoints. The
authors found that QoL scores during neoadjuvant treatment were better for symptoms associated with the primary rectal tumour, whereas global health status, role
function, and symptoms related to the specific safety profile of each treatment
modality worsened. During neoadjuvant chemotherapy, the addition of cetuximab
led to a deterioration of global health status. During follow-up, emotional function,
anxiety, and insomnia ameliorated, whereas body image, urinary incontinence,
sexual interest in men, impotence and dyspareunia deteriorated. After neoadjuvant treatment and 3 years after sphincter preserving surgery, bowel continence
improved. Remarkably, an intense treatment regimen of nCRT, 2 cytotoxic agents,
surgery, and in the CAPOX-C arm, additional cetuximab had no excessive negative effect on bowel function and QoL. Lastly, the CAO/ARO/AIO-12 found at
3 years, chronic toxicity grade 3 and 4 occurred in 12% in the induction TNT arm
and 10% in the consolidation TNT arm. The QoL score decreased after TME but
returned to pre-treatment levels at 1 year after randomization with no difference
between the two arms. Stool incontinence was not different between the two arms
at any point. Notably, stool incontinence deteriorated 1 years after randomization
in both arms and only improved slightly at 3 years, but never reached baseline
levels [36].
To summarize, TNT does not negatively impact the QoL when compared to
nCRT in patients with LARC. It is important to note that although TNT leads
to favourable oncological outcomes, it does not result in an improvement in QoL
when surgery is also undertaken, but that most data are from studies that did not
include the option of organ preservation. Consequently, is essential for future RCTs
examining organ preservation after TNT in LARC to include QoL questionnaires
as part of their data collection as this may be where most of the QoL gains are
made. To this end, the Australasian RENO trial (ACTRN12619000207112) which
examines QoL after non-operative management, now includes TNT as an option
for treatment, and the North American OPERa study (NCT04893876) which was
developed with the goal to evaluate QoL after rectal cancer treatment includes
patients undergoing non-operative management in the analysis. Data from these
two trials are eagerly awaited.
2.4 Conclusion
Management of LARC requires careful navigation of the complex balance between
oncological outcomes and patient QoL goals. TNT has demonstrated superior
oncological outcomes compared to nCRT, including an improvement in DFS and
primary tumour response rates, affording a high rate of organ preserving nonoperative management approaches. Personalization of treatment sequencing, dosage,
54 S. Bedrikovetski and T. Sammour
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and targeted chemotherapy/immunotherapy have the potential to further revolutionise neoadjuvant treatment strategies. Nevertheless, further data are necessary
to optimise QoL outcomes, refine patient selection and prognostication to avoid
over treatment, and to more clearly define management of patients with a near
complete response.
References
1. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40.
https://doi.org/10.1056/NEJMoa040694.
2. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German
CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin
Oncol. 2012;30(16):1926–33. https://doi.org/10.1200/JCO.2011.40.1836.
3. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy
with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114–23. https://
doi.org/10.1056/NEJMoa060829.
4. Taylor FG, Quirke P, Heald RJ, Moran BJ, Blomqvist L, Swift IR, et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free
survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol.
2014;32(1):34–43. https://doi.org/10.1200/JCO.2012.45.3258.
5. Ruppert R, Junginger T, Ptok H, Strassburg J, Maurer CA, Brosi P, et al. Oncological outcome
after MRI-based selection for neoadjuvant chemoradiotherapy in the OCUM Rectal Cancer
Trial. Br J Surg. 2018;105(11):1519–29. https://doi.org/10.1002/bjs.10879.
6. Kennedy ED, Simunovic M, Jhaveri K, Kirsch R, Brierley J, Drolet S, et al. Safety and feasibility of using magnetic resonance imaging criteria to identify patients with “good prognosis”
rectal cancer eligible for primary surgery: the phase 2 nonrandomized quicksilver clinical trial.
JAMA Oncol. 2019;5(7):961–6. https://doi.org/10.1001/jamaoncol.2019.0186.
7. Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal
cancers: results of FFCD 9203. J Clin Oncol. 2006;24(28):4620–5. https://doi.org/10.1200/
JCO.2006.06.7629.
8. Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al.
Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after
neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin
(XELOX) versus control. Ann Oncol. 2014;25(7):1356–62. https://doi.org/10.1093/annonc/
mdu147.
9. Lange MM, van de Velde CJ. Urinary and sexual dysfunction after rectal cancer treatment. Nat
Rev Urol. 2011;8(1):51–7. https://doi.org/10.1038/nrurol.2010.206.
10. Floodeen H, Lindgren R, Hallbook O, Matthiessen P. Evaluation of long-term anorectal function after low anterior resection: a 5-year follow-up of a randomized multicenter trial. Dis
Colon Rectum. 2014;57(10):1162–8. https://doi.org/10.1097/DCR.0000000000000197.
11. Benson AB, Venook AP, Al-Hawary MM, Azad N, Chen YJ, Ciombor KK, et al. Rectal cancer, Version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw.
2022;20(10):1139–67. https://doi.org/10.6004/jnccn.2022.0051.
12. Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rodel C, Cervantes A, et al. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol.
2017;28(suppl_4):iv22–iv40. https://doi.org/10.1093/annonc/mdx224.
13. Kathryn Field DY, Les B, Kirsten G, Alexander H, George H, Ian J, Christos K, Elizabeth
M, Sam N. Cancer Council Australia colorectal cancer guidelines working party: neoadjuvant
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 55
https://t.me/med1917
chemotherapy regimen - cancer guidelines Wiki. https://wiki.cancer.org.au/australia/Guidel
ines:Colorectal_cancer/Neoadjuvant_chemotherapy_regimen (2017). Accessed 23/07/2023.
14. Yuan Z, Weng S, Ye C, Hu H, Zhang S, Yuan Y. CSCO guidelines for colorectal cancer version 2022: Updates and discussions. Chin J Cancer Res. 2022;34(2):67–70. https://doi.org/10.
21147/j.issn.1000-9604.2022.02.01.
15. Bedrikovetski S, Fitzsimmons T, Perry J, Vather R, Carruthers S, Selva-Nayagam S, et al. Personalized total neoadjuvant therapy (pTNT) for advanced rectal cancer with tailored treatment
sequencing based on clinical stage at presentation. ANZ J Surg. 2023;93(1–2):173–81. https://
doi.org/10.1111/ans.18021.
16. Bedrikovetski S, Traeger L, Fitzsimmons T, Perry J, Vather R, Moore JW, et al. Personalized total neoadjuvant therapy versus chemotherapy during the ‘wait period’ versus standard chemoradiotherapy for locally advanced rectal cancer. ANZ J Surg. 2023;93(5):1267–73.
https://doi.org/10.1111/ans.18229.
17. Khattak A, Ferguson T, Theophilus M, Tiong SS, Ali S, Khan Y. Total neoadjuvant therapy for
locally advanced rectal cancer: A western Australian experience. J Clinic Oncol. 2023;41(16_
suppl):e15582-e. https://doi.org/10.1200/JCO.2023.41.16_suppl.e15582.
18. Calvo FA, Serrano FJ, Diaz-Gonzalez JA, Gomez-Espi M, Lozano E, Garcia R, et al. Improved
incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC)
treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann
Oncol. 2006;17(7):1103–10. https://doi.org/10.1093/annonc/mdl085.
19. Marechal R, Vos B, Polus M, Delaunoit T, Peeters M, Demetter P, et al. Short course
chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced
rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2012;23(6):1525–30.
https://doi.org/10.1093/annonc/mdr473.
20. Fernandez-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, et al. Phase
II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant
capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally
advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol. 2010;28(5):859–65.
https://doi.org/10.1200/JCO.2009.25.8541.
21. Rouanet P, Rullier E, Lelong B, Maingon P, Tuech JJ, Pezet D, et al. Tailored treatment strategy
for locally advanced rectal carcinoma based on the tumor response to induction chemotherapy:
preliminary results of the French phase II Multicenter GRECCAR4 trial. Dis Colon Rectum.
2017;60(7):653–63. https://doi.org/10.1097/DCR.0000000000000849.
22. Rouanet P, Rullier E, Lelong B, Maingon P, Tuech JJ, Pezet D, et al. Tailored strategy for
locally advanced rectal carcinoma (GRECCAR 4): long-term results from a multicenter, randomized, open-label phase II trail. Dis Colon Rectum. 2022;65(8):986–95. https://doi.org/10.
1097/DCR.0000000000002153.
23. Garant A, Kavan P, Martin AG, Azoulay L, Vendrely V, Lavoie C, et al. Optimizing treatment
sequencing of chemotherapy for patients with rectal cancer: the KIR randomized phase II trial.
Radiother Oncol. 2021;155:237–45. https://doi.org/10.1016/j.radonc.2020.11.008.
24. Conroy T, Bosset JF, Etienne PL, Rio E, Francois E, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients
with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised,
open-label, phase 3 trial. Lancet Oncol. 2021;22(5):702–15. https://doi.org/10.1016/S1470-
2045(21)00079-6.
25. Conroy T, Etienne P-L, Rio E, Evesque L, Mesgouez-Nebout N, Vendrely V, et al. Total
neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients
with locally advanced rectal cancer: 7-year results of PRODIGE 23 phase III trial, a UNICANCER GI trial. J Clinic Oncol. 2023;41(17_suppl):LBA3504-LBA. https://doi.org/10.
1200/JCO.2023.41.17_suppl.LBA3504.
56 S. Bedrikovetski and T. Sammour
https://t.me/med1917
26. Moore J, Price T, Carruthers S, Selva-Nayagam S, Luck A, Thomas M, et al. Prospective randomized trial of neoadjuvant chemotherapy during the ‘wait period’ following preoperative chemoradiotherapy for rectal cancer: results of the WAIT trial. Colorectal Dis.
2017;19(11):973–9. https://doi.org/10.1111/codi.13724.
27. Kim SY, Joo J, Kim TW, Hong YS, Kim JE, Hwang IG, et al. A randomized phase 2 trial of
consolidation chemotherapy after preoperative chemoradiation therapy versus chemoradiation
therapy alone for locally advanced rectal cancer: KCSG CO 14–03. Int J Radiat Oncol Biol
Phys. 2018;101(4):889–99. https://doi.org/10.1016/j.ijrobp.2018.04.013.
28. Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Krynski J, et al. Long-course
oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol.
2016;27(5):834–42. https://doi.org/10.1093/annonc/mdw062.
29. Cisel B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E, et al. Long-course
preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for clinical T4
and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Ann
Oncol. 2019;30(8):1298–303. https://doi.org/10.1093/annonc/mdz186.
30. Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, et al.
Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME)
versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally
advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol.
2021;22(1):29–42. https://doi.org/10.1016/S1470-2045(20)30555-6.
31. Yuval JB, Patil S, Garcia-Aguilar J. Interpreting the RAPIDO trial: factors to consider. Lancet
Oncol. 2021;22(3):e87–8. https://doi.org/10.1016/S1470-2045(21)00061-9.
32. Pastorino A, Negru ME, Aschele C. Interpreting the RAPIDO trial: factors to consider. Lancet
Oncol. 2021;22(3): e89. https://doi.org/10.1016/S1470-2045(21)00072-3.
33. Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR, Meershoek-Klein Kranenbarg E, Roodvoets AGH, et al. Locoregional failure during and after short-course radiotherapy followed by
chemotherapy and surgery compared to long-course chemoradiotherapy and surgery—a fiveyear follow-up of the RAPIDO trial. Ann Surg. 2023. https://doi.org/10.1097/SLA.000000000
0005799.
34. Bahadoer RR, Hospers GAP, Marijnen CAM, Peeters K, Putter H, Dijkstra EA, et al. Risk and
location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial. Eur J Cancer. 2023;185:139–49.
https://doi.org/10.1016/j.ejca.2023.02.027.
35. Fokas E, Allgauer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Randomized
phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total
neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol.
2019;37(34):3212–22. https://doi.org/10.1200/JCO.19.00308.
36. Fokas E, Schlenska-Lange A, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for
patients with locally advanced rectal cancer: long-term results of the CAO/ARO/AIO-12 randomized clinical trial. JAMA Oncol. 2022;8(1): e215445. https://doi.org/10.1001/jamaoncol.
2021.5445.
37. Verheij FS, Omer DMR, Williams H, Buckley JT, Lin ST, Qin L-X, et al. Sustained organ
preservation in patients with rectal cancer treated with total neoadjuvant therapy: Long-term
results of the OPRA trial. J Clinic Oncol. 2023;41(16_suppl):3520. https://doi.org/10.1200/
JCO.2023.41.16_suppl.3520.
38. Fernandez-Martos C, Pericay C, Losa F, Garcia-Carbonero R, Layos L, Rodriguez-Salas N,
et al. Effect of aflibercept plus modified FOLFOX6 induction chemotherapy before standard
chemoradiotherapy and surgery in patients with high-risk rectal adenocarcinoma: the GEMCAD 1402 randomized clinical trial. JAMA Oncol. 2019;5(11):1566–73. https://doi.org/10.
1001/jamaoncol.2019.2294.
2 Total Neoadjuvant Therapy (TNT) in Rectal Cancer; Where Now, Where Next? 57
https://t.me/med1917
39. Pesantez D, Ten Hoorn S, Machado I, Garcia-Albeniz X, Rodriguez-Salas N, Heredia-Soto V,
et al. Total neoadjuvant therapy with or without aflibercept in rectal cancer: Three-year results
of GEMCAD-1402. J Natl Cancer Inst. 2023. https://doi.org/10.1093/jnci/djad120.
40. Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and
preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in
patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012;30(14):1620–7. https://
doi.org/10.1200/JCO.2011.39.6036.
41. Rahma OE, Yothers G, Hong TS, Russell MM, You YN, Parker W, et al. Use of total neoadjuvant therapy for locally advanced rectal cancer: initial results from the pembrolizumab arm of
a phase 2 randomized clinical trial. JAMA Oncol. 2021;7(8):1225–30. https://doi.org/10.1001/
jamaoncol.2021.1683.
42. George TJ, Yothers G, Rahma OE, Hong TS, Russell MM, You YN, et al. Long-term results
from NRG-GI002: a phase II clinical trial platform using total neoadjuvant therapy (TNT) in
locally advanced rectal cancer (LARC). J Clinic Oncol. 2023;41(4_suppl):7. https://doi.org/
10.1200/JCO.2023.41.4_suppl.7.
43. Bhutiani N, Peacock O, Chang GJ. A practical framework for the targeted use of total neoadjuvant therapy for rectal cancer. Cancer. 2022;128(11):2064–72. https://doi.org/10.1002/cncr.
34149.
44. Kennedy ED, Borowiec AM, Schmocker S, Cho C, Brierley J, Li S, et al. Patient and physician
preferences for nonoperative management for low rectal cancer: is it a reasonable treatment
option? Dis Colon Rectum. 2018;61(11):1281–9. https://doi.org/10.1097/DCR.000000000000
1166.
45. Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, et al. Multicenter, randomized, phase iii trial
of neoadjuvant chemoradiation with capecitabine and irinotecan guided by UGT1A1 status in
patients with locally advanced rectal cancer. J Clin Oncol. 2020;38(36):4231–9. https://doi.org/
10.1200/JCO.20.01932.
46. Wang J, Fan J, Li C, Yang L, Wan J, Zhang H, et al. The impact of chemotherapy completion on the efficacy of irinotecan in the preoperative chemoradiotherapy of locally advanced
rectal cancer: an expanded analysis of the cinclare phase iii trial. Clin Colorectal Cancer.
2020;19(2):e58–69. https://doi.org/10.1016/j.clcc.2020.01.004.
47. Zhu J, Sun X, Liu A, Zhu Y, Zhang T, Liu L, et al. Long-term outcome of a phase III trial on
neoadjuvant chemoradiation with capecitabine and irinotecan in patients with locally advanced
rectal cancer: updated results of the CinClare trial. J Clinic Oncol. 2021;39(15_suppl):3603.
https://doi.org/10.1200/JCO.2021.39.15_suppl.3603.
48. Zhang H, Cao K, Li G, Zhai Z, Wei G, Qu H, et al. Active surveillance in long period of total
neoadjuvant therapy in rectal cancer: early prediction of poor regression response. Front Oncol.
2022;12:1049228. https://doi.org/10.3389/fonc.2022.1049228.
49. Bedrikovetski S, Traeger L, Price TJ, Carruthers S, Selva-Nayagam S, Moore JW, et al. Can
sarcopenia predict complete response after total neoadjuvant therapy in advanced rectal cancer? a multicentre observational cohort study. J Surg Oncol. 2023;128(1):75–84. https://doi.
org/10.1002/jso.27251.
50. Deidda S, Elmore U, Rosati R, De Nardi P, Vignali A, Puccetti F, et al. Association of delayed
surgery with oncologic long-term outcomes in patients with locally advanced rectal cancer
not responding to preoperative chemoradiation. JAMA Surg. 2021;156(12):1141–9. https://
doi.org/10.1001/jamasurg.2021.4566.
51. Matsuda A, Yamada T, Sonoda H, Shinji S, Iwai T, Takeda K, et al. The prediction of pathological complete response after total neoadjuvant therapy for locally advanced rectal cancer
using versatile liquid biopsy. J Clinic Oncol. 2023;41(4_suppl):230. https://doi.org/10.1200/
JCO.2023.41.4_suppl.230.
52. Smith JJ, Dasari A, Shi Q, Garcia-Aguilar J, Sanoff HK, George TJ, et al. Alliance A022104/
NRG-GI010: A randomized phase II trial testing the efficacy of triplet versus doublet
58 S. Bedrikovetski and T. Sammour
https://t.me/med1917
chemotherapy to achieve clinical complete response in patients with locally advanced rectal cancer—the janus rectal cancer trial. J Clinic Oncol. 2023;41(16_suppl):TPS3640-TPS.
https://doi.org/10.1200/JCO.2023.41.16_suppl.TPS3640
53. Fleischmann M, Diefenhardt M, Nicolas AM, Rodel F, Ghadimi M, Hofheinz RD, et al. ACO/
ARO/AIO-21 - Capecitabine-based chemoradiotherapy in combination with the IL-1 receptor
antagonist Anakinra for rectal cancer patients: a phase i trial of the German rectal cancer study
group. Clin Transl Radiat Oncol. 2022;34:99–106. https://doi.org/10.1016/j.ctro.2022.04.003.
54. Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, et al. Preoperative treatment
of locally advanced rectal cancer. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa230
3269.
55. Mei WJ, Wang XZ, Li YF, Sun YM, Yang CK, Lin JZ, et al. Neoadjuvant chemotherapy With
CAPOX versus chemoradiation for locally advanced rectal cancer with uninvolved mesorectal
fascia (CONVERT): initial results of a phase iii trial. Ann Surg. 2023;277(4):557–64. https://
doi.org/10.1097/SLA.0000000000005780.
56. Mroczkowski P. Comment on “neoadjuvant chemotherapy with CAPOX versus chemoradiation for locally advanced rectal cancer with uninvolved mesorectal fascia (CONVERT): initial
results of a phase iii trial” by Mei et al.: Two Overtreatments Compared. Ann Surg Open.
2023;4(2):e295. https://doi.org/10.1097/as9.0000000000000295.
57. Brouquet A, Bachet JB, Huguet F, Karoui M, Artru P, Sabbagh C, et al. NORAD01GRECCAR16 multicenter phase III non-inferiority randomized trial comparing preoperative modified FOLFIRINOX without irradiation to radiochemotherapy for resectable locally
advanced rectal cancer (intergroup FRENCH-GRECCAR- PRODIGE trial). BMC Cancer.
2020;20(1):485. https://doi.org/10.1186/s12885-020-06968-1.
58. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 blockade in
mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363–
76. https://doi.org/10.1056/NEJMoa2201445.
59. van der Valk MJM, Hilling DE, Bastiaannet E, Meershoek-Klein Kranenbarg E, Beets GL,
Figueiredo NL, et al. Long-term outcomes of clinical complete responders after neoadjuvant
treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018;391(10139):2537–45. https://doi.org/10.1016/
S0140-6736(18)31078-X.
60. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U, Jr., Silva e Sousa AH, Jr., et al.
Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240(4):711–7; discussion 7–8. https://doi.org/
10.1097/01.sla.0000141194.27992.32.
61. Smith JD, Ruby JA, Goodman KA, Saltz LB, Guillem JG, Weiser MR, et al. Nonoperative
management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann
Surg. 2012;256(6):965–72. https://doi.org/10.1097/SLA.0b013e3182759f1c.
62. Nilsson PJ, Ahlberg M, Kordnejad S, Holm T, Martling A. Organ preservation following shortcourse radiotherapy for rectal cancer. BJS Open. 2021;5(5). https://doi.org/10.1093/bjsopen/
zrab093.
63. Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin
Oncol. 2022;40(23):2546–56. https://doi.org/10.1200/jco.22.00032.
64. Fokas E, Appelt A, Glynne-Jones R, Beets G, Perez R, Garcia-Aguilar J, et al. International consensus recommendations on key outcome measures for organ preservation after
(chemo)radiotherapy in patients with rectal cancer. Nat Rev Clin Oncol. 2021;18(12):805–16.
https://doi.org/10.1038/s41571-021-00538-5.
65. Temmink SJD, Peeters K, Bahadoer RR, Kranenbarg EM, Roodvoets AGH, Melenhorst J,
et al. Watch and wait after neoadjuvant treatment in rectal cancer: comparison of outcomes
in patients with and without a complete response at first reassessment in the International
Watch & Wait Database (IWWD). Br J Surg. 2023;110(6):676–84. https://doi.org/10.1093/bjs/
znad051.
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