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94
those who would otherwise require a permanent colostomy.
Some surgeons are still skeptical of WW if the tumor can be
treated with a restorative resection, although a small study has
indicated that WW was associated with better anorectal func-
tional results when compared to a matched group of patients
undergoing sphincter-sparing TME [4]. Future studies will need
to focus on optimized combination treatments, including the pos-
sible role of short-course radiotherapy, and simplied surveil-
lance approaches. However, in one form or another, I feel that
WW is here to stay.
References
1. Verheij FS, Omer DM, Williams H, Lin ST, Qin LX, Buckley
JT, Thompson HM, Yuval JB, Kim JK, Dunne RF, Marcet J,
Cataldo P, Polite B, Herzig DO, Liska D, Oommen S, Friel
CM, Ternent C, Coveler AL, Hunt S, Gregory A, Varma MG,
Bello BL, Carmichael JC, Krauss J, Gleisner A, Guillem JG,
Temple L, Goodman KA, Segal NH, Cercek A, Yaeger R,
Nash GM, Widmar M, Wei IH, Pappou EP, Weiser MR, Paty
PB, Smith JJ, Wu AJ, Gollub MJ, Saltz LB, Garcia-Aguilar
J.Long-term results of organ preservation in patients with rec-
tal adenocarcinoma treated with Total neoadjuvant therapy:
the randomized phase II OPRA trial. J Clin Oncol.
2024;42(5):500–506.
2.
Habr
-Gama A, Perez RO, Nadalin W, et al. Operative versus
nonoperative treatment for stage 0 distal rectal cancer follow-
ing chemoradiation therapy: long-term results. Ann Surg.
2004;240:711–718.
3.
Benson AB,
Venook AP, Al-Hawary MM, Azad N, Chen YJ,
Ciombor KK, Cohen S, Cooper HS, Deming D, Garrido-
Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J,
Hunt S, Jeck W, Johung KL, Kirilcuk N, Krishnamurthi S,
Maratt JK, Messersmith WA, Meyerhardt J, Miller ED,
Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H,
Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM,
Sofocleous CT, Stotsky-Himelfarb E, Tavakkoli A, Willett CG,
Gregory K, Gurski L.Rectal cancer, version 2.2022, NCCN
15 Total Neoadjuvant Treatment andOrgan Preservation…
95
clinical practice guidelines in oncology. J Natl Compr Canc
Netw. 2022;20(10):1139–1167.
4. Quezada-Diaz FF, Smith JJ, Jimenez-Rodriguez RM,
Wasserman I, Pappou EP, Patil S, Wei IH, Nash GM, Guillem
JG, Weiser MR, Paty PB, Garcia-Aguilar J.Patient-reported
bowel function in patients with rectal cancer managed by a
watch-and-wait strategy after neoadjuvant therapy: a case-
control study. Dis Colon Rectum. 2020;63(7):
897–902.
Discussion
AM
I think organ preservation and nonoperative management are the
future of rectal cancer treatment. When comparing this with
PROSPECT, it seems like we went through this shift of no radia-
tion to radiation plus chemotherapy, from trying to omit radiation
to now bringing everything upfront through every possible treat-
ment combination to achieve complete response and nonoperative
management. Obviously, this only reports disease-free survival.
But really the key factor is the outcome of those patients who
experience regrowth who then undergo TME, and then, is there an
impact on their survival? And what is their true change in sur-
vival? I think the long-term results of OPRA were just published
in February 2024, and the TME-free survival was still high, but
greater with consolidation chemotherapy, 54% vs. 39% with
induction chemotherapy, and that was statistically signicant. The
other interesting thing with the long-term results is when are they
going to regrow? And how do you then follow these people who
have achieved complete clinical response? 90–95% of those with
recurrence/regrowth had it within 2years, and then, like 99% or
100% had occurred within 3years. And so, I think those that fail,
you tend to know pretty early, and overall, they still have very
good long-term results with avoiding surgery. Again, to me, it all
boils down to patient selection and patient counseling in terms of
outcomes in the setting of regrowth and subsequent surgery, and
some of that is still unknown.
Discussion
96
LS
The long-term results do indicate that survival is similar between
patients who are treated with salvage TME following regrowth vs.
initial TME after treatment, right?
AM
Disease-free survival, but we do not know overall survival.
LS
Yes.
DC
From a skeptic’s perspective, the issue here is that we still have
160 patients or so in each arm, so there is not going to be a lot of
patients. So, we have to take these results with a grain of salt. And
then, not insignicant is the fact that the surveillance is absolutely
necessary and rather intense. Having an MRI every 6months for
the rst 2years is something that patients have to sign up for. So,
this is not necessarily for everybody. It would be something for a
motivated patient who can continue intense surveillance tests and
follow-up visits. So, I am happy that this trial was done, and I am
excited about the promise that it brings, but I just think that we
need to take it with a grain of salt and take it for what it is with the
shortcomings that the treatment potentially has.
MD
I think that the results of this trial are very exciting with regard to
the nonoperative management of rectal cancer. What was interest-
ing in this trial was the number of patients who were offered
15 Total Neoadjuvant Treatment andOrgan Preservation…
97
watch-and-wait, which was about 75% in both arms, which I think
is an extraordinarily high number, although they did include
patients with near-complete response. I think it would be interest-
ing to differentiate how those with near complete vs. complete
response did, and I did not get that from the study. The study also
indicated that consolidation chemotherapy is a better choice when
we are trying to achieve a complete response as opposed to induc-
tion chemotherapy, which is an important conversation to have
with patients prior to treatment initiation. For you folks, how
comfortable do you feel offering watch-and-wait to patients with
near complete response? And how do you dene endoscopically
what a near complete response is?
AM
To me, all of it is largely driven by the patient in most situations.
When it is near complete versus even in the setting of complete
response. All of this is driven by the patient so much, but at least
less so by us, I think, as providers, because I think we have a natu-
ral bias in favor of surgery. Most of us do, I think. And when I say
us, I mean the colorectal community at large is only now starting
to shift, I think, toward some more widespread acceptance of
watch-and-wait. For your second question, I think what constitutes
near complete response has yet to be really dened appropriately.
I mean, we are only now better understanding and seeing pub-
lished information on the standardization of the denition of com-
plete response. Flat white scar telangiectasia vs. maybe a near
complete response. I just read about near complete response
described as a single, solitary ulceration. I think that part of the
problem is that we have not dened standards in the description of
near-complete response. And also, I am thinking, what are the
standards of evaluation in the setting of near complete response,
how do you follow these patients? At what interval should you get
imaging, or should you not? It has already been accepted that you
should not really biopsy lesions because of the risk of sampling
error. And do you believe a negative biopsy? I think that is an area
where there is still a lot to be known or learned.
Discussion
98
LS
I would say nodules and ulcer for example, if the lining of the
mucosa has any bumps, that to me excludes the idea of complete
clinical response. As far as my comfort level in continuing watch-
and-wait, not as comfortable but because there are data I men-
tion this to patients and to echo Amit’s comments, the patient
largely drives this, so I just write in my note something to the
effect that this is still an uncharted territory. Now, we have clinical
guidelines on clinical complete response. We do not have clinical
guidelines on near-complete response. We have data, especially
from Memorial Sloan Kettering, indicating that near-complete
response could progress to complete response over time. I have
continued watching patients with near-complete response at three-
month intervals. That has been my practice so far, and hopefully,
in the future, we will have more denitive data as we have now on
clinical complete response. I avoid biopsies in this setting for the
reasons you outlined.
DC
Another comment about this, not on the study itself, but on the
consequences of continuing this trend of watch-and-wait. There is
some import to the trainees. We already have some training cen-
ters that do less rectal cancer surgeries than I think should-to suf-
ciently train the colorectal surgery fellows. This will make rectal
cancer surgery scarcer, and outside of tertiary centers, it will be
hard to train fellows. Not that we should avoid implementing a bet-
ter treatment because we need to train surgeons, but it is something
we will have to contend with within the next 5years, or earlier.
AM
I think what will be interesting to look at is also rates of sphincter
preservation. I mean, we see it in these papers specically looking
at watch-and-wait, but we published an NCDB study looking at
15 Total Neoadjuvant Treatment andOrgan Preservation…
99
rates of sphincter preservation. It was very similar to the rates
reported in Rocco Ricciardi’s earlier papers examining a variety
of other databases, and it has always hovered between 23 and 25%
abdomino-perineal resection rate for rectal cancers across all
stages. So, it will be interesting to revisit the NCDB (National
Cancer DataBase) data on the abdomino-perineal resection rate as
the watch-and-wait practice becomes more mature to see if that
will change. I think the paper we wrote was from 2017.
LS
I agree. As we said though, this trend is also largely patient-driven.
I mean, you have patients that come in, and they might not be
necessarily very sophisticated, but they already know about this,
and they ask if we can treat their disease without giving them a
bag. So, I think that there is a lot of pressure to apply watch-and-
wait, which will also help in understanding its limitations and
establishing it as a viable practice.
Discussion
101
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
D. Colibaseanu et al., Essential Articles in Colorectal Surgery,
https://doi.org/10.1007/978-3-031-77745-5_16
16
Short-Course Vs.
Long-Course Radiotherapy
Before Chemotherapy
andSurgery forRectal
Cancer
Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR,
Meershoek-Klein Kranenbarg E, Roodvoets AGH, Putter H,
Berglund Å, Cervantes A, Crolla RMPH, Hendriks MP,
Capdevila J, Edhemovic I, Marijnen CAM, van de Velde CJH,
Glimelius B, van Etten B; Collaborative Investigators.
Locoregional failure during and after short-course radiotherapy
followed by chemotherapy and surgery compared with long-
course chemoradiotherapy and surgery: a 5-year follow-up of
the RAPIDO trial. Ann Surg. 2023;278(4):e766–e772.
Abstract
Objective: To analyze risk and patterns of locoregional failure
(LRF) in patients of the RAPIDO trial at 5 years.
Background: Multimodality treatment improves local control
in rectal cancer. Total neoadjuvant treatment (TNT) aims to
improve systemic control while local control is maintained. At 3
years, LRF rate was comparable between TNT and chemoradio-
therapy in the RAPIDO trial.
Methods: A total of 920 patients were randomized between an
experimental (EXP, short-course radiotherapy, chemotherapy, and
surgery) and a standard-care group (STD, chemoradiotherapy,
surgery, and optional postoperative chemotherapy). LRFs, includ-
ing early LRF (no resection except for organ preservation/R2
102
resection) and locoregional recurrence (LRR) after an R0/R1
resection, were analyzed.
Results: Totally, 460 EXP and 446 STD patients were eligible.
At 5.6 years (median follow-up), LRF was detected in 54/460
(12%) and 36/446 (8%) patients in the EXP and STD groups,
respectively (P=0.07), in which EXP patients were more often
treated with three-dimensional-conformed radiotherapy
(P= 0.029). In the EXP group, LRR was detected more often
[44/431 (10%) vs. 26/428 (6%); P=0.027], with more often a
breached mesorectum (9/44 (21%) vs. 1/26 (4); P=0.048). The
EXP treatment, enlarged lateral lymph nodes, positive circumfer-
ential resection margin, tumor deposits, and node positivity at
pathology were the signicant predictors for developing
LRR.Location of the LRRs was similar between groups. Overall
survival after LRF was comparable [hazard ratio: 0.76 (95% CI,
0.46–1.26); P=0.29].
Conclusions: The EXP treatment was associated with an
increased risk of LRR, whereas the reduction in disease-related
treatment failure and distant metastases remained after 5 years.
Further renement of the TNT in rectal cancer is mandated.
LS
This could be viewed as a large trial which assessed total neoad-
juvant treatment (TNT) using short-course radiotherapy. The
experimental arm consisted of short-course radiotherapy and
chemotherapy before radical surgery, while the comparative
standard arm consisted of long-course chemoradiotherapy, sur-
gery, and optional postoperative chemotherapy. The trial was
successful in that its results at 5 years conrm the previously
reported signicant association between experimental treatment
and reduction in both disease-related treatment failure and dis-
tant metastasis rates. However, the trial has been criticized in its
design with respect to the radiotherapy technique, the interval
between TNT and surgery, and because its endpoints were
16 Short-Course Vs. Long-Course Radiotherapy Before…
103
changed over time. In particular, disease-free survival was aban-
doned as an outcome of interest in favor of disease-related treat-
ment failure [1]. In addition, overall survival was similar,
although this is not necessarily surprising as some oncologic out-
comes require longer follow-ups to result in statistically different
mortality rates. From a more strictly surgical perspective, local
recurrence was signicantly more common in the short-course
radiotherapy plus chemotherapy group, although the difference
barely achieved statistical signicance. Importantly, the cases of
local recurrences in the experimental arm were also more com-
monly associated with a mesorectal breach, which has raised
concerns on the deleterious effect on the operative eld deriving
from a longer interval between short-course radiotherapy and
surgery [2]. Given these results, surgeons accustomed to long-
course chemoradiotherapy may feel uncomfortable at the idea of
just switching to short-course radiotherapy for the same indica-
tions. This is particularly the case for high-risk locally advanced
rectal cancer patients such as some of those accrued into
RAPIDO. The integration of long-course chemoradiotherapy,
total neoadjuvant treatment, and possible nonoperative manage-
ment is now part of accepted guidelines, and we also have impor-
tant information on regrowth risk and regrowth rate over time as
well as expected results of salvage surgery. If we assume that
long-course and short-course radiotherapy are per se equivalent,
it would seem logical that surgeons who are more familiar with
short-course radiotherapy would be more interested in a total
neoadjuvant therapy approach retaining their radiotherapy
modality of choice. With all its limitations, RAPIDO remains at
least a conrmatory trial on the suitability and effectiveness of
total neoadjuvant treatment which was associated with a 28%
pathologic complete response rate [3]. At the time of its imple-
mentation, the experience with watch-and-wait was limited in
Europe, and therefore, this was not included as an option already
embedded into the trial design [4]. The experience accumulated
in RAPIDO can now inform the design of future trials also exam-
ining nonoperative management.
LS
104
References
1. Riou O, Gourgou S, Conroy T. Comment on “Locoregional
failure during and after short-course radiotherapy followed by
chemotherapy and surgery compared to long-course chemora-
diotherapy and surgery: a ve-year follow-up of the RAPIDO
trial”: the RAPIDO trial does not achieve its primary endpoint.
Ann Surg Open. 2023;4(2):e288.
2. Glynne-Jones R, Hollingshead J.TNT and local recurrence in
the RAPIDO trial—untangling the puzzle. Nat Rev Clin
Oncol. 2023;20(6):357–358.
3. Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM,
Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID,
Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ,
Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson
PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO
Collaborative Investigators. Short-course radiotherapy fol-
lowed 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.
4. Nilsson PJ, van Etten B, Hospers GAP, Marijnen CAM,
Meershoek-Klein Kranenberg E, Roodvoets AGH, van de
Velde CJH, Glimelius B. Comment on the RAPIDO trial
point-counterpoint debate. Dis Colon Rectum.
2024;67(2):e126.
Discussion
AM
I think the early results of RAPIDO from the original paper were
encouraging, but their conclusions I thought were rather bold in
that this whole paradigm and the experimental treatment could be
considered as a new standard, as they called it. I thought that was
16 Short-Course Vs. Long-Course Radiotherapy Before…