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74
Results: Four hundred twenty-one patients were randomly
assigned to receive preoperative chemoradiotherapy and 402
patients to receive postoperative chemoradiotherapy. The overall
5-year survival rates were 76% and 74%, respectively (P=0.80).
The 5-year cumulative incidence of local relapse was 6% for
patients assigned to preoperative chemoradiotherapy and 13% in
the postoperative-treatment group (P=0.006). Grade 3 or 4 acute
toxic effects occurred in 27% of the patients in the preoperative-
treatment group, as compared with 40% of the patients in the
postoperative-treatment group (P = 0.001); the corresponding
rates of long-term toxic effects were 14% and 24%, respectively
(P=0.01).
Conclusions: Preoperative chemoradiotherapy, as compared
with postoperative chemoradiotherapy, improved local control
and was associated with reduced toxicity but did not improve
overall survival.
LS
This trial determined a fundamental shift in practice at least in the
United States and solidied the role of preoperative chemoradio-
therapy in the treatment of stage II–III rectal cancer. Its results
indicated a signicant reduction in treatment-related toxicity in
favor of long-course preoperative chemoradiotherapy, and this is
perhaps the main reason this modality has been widely preferred
since. However, the result of the analysis also emphasized some
known limitations of preoperative treatments. Eighteen percent of
patients who were randomized to the postoperative chemoradio-
therapy arm were found to have stage I cancer on their surgical
specimen and were therefore overstaged. Because of their pathol-
ogy staging, they never received chemoradiotherapy and therefore
were never subject to its inherent risks. Given the randomization
design, we could reasonably estimate that a similar proportion of
patients in the preoperative chemoradiotherapy arm were actually
overtreated. Therefore, the reported reduction inlocal recurrence
rate associated with neoadjuvant chemoradiotherapy could be
caused at least in part by overstaging rather than a truly increased
12 Preoperative vs. Postoperative Chemoradiotherapy…
75
effectiveness of preoperative treatment on the patient’s native,
well-perfused tissues. Patients enrolled in the trial were staged
using endorectal ultrasound and Computed Tomography scan,
and it is possible that with modern Magnetic Resonance of the
pelvis, the risk of overstaging is reduced. However, I still feel that
the statement that preoperative chemoradiotherapy is associated
with a reduction inlocal recurrence rate should be made with cau-
tion. Another important principle associated with this work is that
39% of patients in the preoperative treatment arm for whom an
abdominoperineal resection was deemed necessary at the time of
their preoperative evaluation could have a sphincter-preserving
surgery after neoadjuvant chemoradiotherapy. This challenges the
clinical practice of several surgeons who decide on sphincter pres-
ervation before initiation of any neoadjuvant treatments. The idea
behind this tradition is the belief that some viable tumor cells
could still be left in place in areas where the tumor is no longer
visible after neoadjuvant treatment. This trial provides compel-
ling evidence against this assumption and informs current clinical
practice to this day. The results after a median follow-up of
11years following the original trial corroborate the idea of decid-
ing on sphincter preservation only after neoadjuvant treatment has
been completed. The updated trial results indicate once more a
reduced local recurrence rate associated with the preoperative arm
without any differences in overall survival, disease-free survival,
or cumulative incidence of distant metastasis [1]. In retrospect,
this trial and the widespread acceptance of preoperative chemora-
diotherapy ended up creating the foundations for the increasing
use of total neoadjuvant therapy (TNT) [2], and the very principle
of deciding on surgery based on the results of the initial treatment
received is what made organ preservation conceivable. The cur-
rent guidelines still recommend postoperative chemoradiotherapy
for patients who have stage II or III rectal cancer on pathology and
have not received preoperative treatments [3]. However, it has
become rare to discuss postoperative chemoradiotherapy for rec-
tal cancer at our tumor board, which is probably to the benet of
our patients.
LS
76
References
1. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W,
Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H,
Wittekind C, Beissbarth T, Rödel C.Preoperative versus post-
operative chemoradiotherapy for locally advanced rectal can-
cer: 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.
2. Liu J, Ladbury C, Glaser S, Fakih M, Kaiser AM, Chen YJ,
Williams TM, Amini A. Patterns of care for patients with
locally advanced rectal cancer treated with total neoadjuvant
therapy at predominately academic centers between
2016–2020: an NCDB analysis. Clin Colorectal Cancer.
2023;22(2):167–74.
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
Clinical Practice Guidelines in Oncology. J Natl Compr Canc
Netw. 2022;20(10):1139–67.
Discussion
MD
I think that this paper denitely revolutionized the way how we
treat rectal cancer. I agree with the nuance on overstaging which
is usually not emphasized as much. Most people do talk about
preoperative radiotherapy as associated with decreased local
recurrence rates because of this study besides decreased toxicity
rates compared to postoperative therapy.
12 Preoperative vs. Postoperative Chemoradiotherapy…
77
With respect to deciding on sphincter preservation, I remember
when I was training at Cleveland Clinic, certainly, the teaching
was that the need for an APR was determined by the pretreatment
MRI, despite the ndings of this study, which were published
many years prior to me being there. And I agree on that with
regard to watch-and-wait.
Now that it has become evident that this is an appropriate treat-
ment strategy, we have to accept that operative planning can be
made after neoadjuvant therapy. So, the principle of deciding
before initiation of treatment is hard for me to accept.
DC
At least for me, at the beginning of my career, the decision on the
operative approach was being made on pretreatment imaging and
clinical ndings. Interval imaging (between chemoradiation and
surgery) did not change the level of transection or the operation
performed. Though this trial’s intent was not to look at TNT (total
neoadjuvant therapy), I think that we would nd the seeds of that
idea here. And so, in many ways, it is a crucial trial.
There are a lot of theories with regard to tumor regression,
whether the tumor dies off or regresses in a mosaic pattern or
linear pattern, and so forth. There were a lot of theories regarding
whether the transection level should be affected by the regression
of tumor that oftentimes we see with chemoradiotherapy. I think
that those questions still linger today, many years after the trial.
The cat is out of the bag, so to speak, with regards to utilization
of chemoradiotherapy, and I think that has expanded; and now, I
anticipate we will do fewer surgeries on patients that have TNT,
for example, and though this is obviously not TNT, to me, it is the
seed that germinated into TNT.
AM
I think it is not really debated at all anymore whether we should
use neoadjuvant vs. adjuvant chemoradiotherapy, but I think even
Discussion
78
at the time when the German rectal cancer trial was published, as
you stated, this concept of shifting decision for surgery based on
response was still debated and even in the era of the training para-
digms that have been discussed, I think. There was still variability,
but at least I think it sounds like in our respective institutions
probably, surgeons tended more toward the pretreatment decision.
This was carried forward regardless of tumor response. But I do
not think that is really as strongly debated now, and it is far more
accepted that your treatment potentially changes based on results.
Maybe it is a little bit risky to say, but maybe, that is actually the
more interesting nding of the German trial. But I think there is
other evidence to support that despite data suggesting what you
were mentioning with respect to the mosaic distribution of
response, there are also other data, denitely other data to support
change in treatment decision based on tumor response.
LS
Do you feel that at Mayo, for example, in the years 2005–2010 or
so, this issue of deciding on sphincter preservation before treat-
ment was the existing culture? Or was it pretty much accepted that
after treatment, if the patient responded well, sphincters could be
preserved as a result of shrinking of the primary tumors? The vast
majority would make that decision based on preoperative imag-
ing, and it would not change. So that is I guess what we would call
the general practice at that time.
DC
Yes, and that is what I was saying earlier that the level of transec-
tion, at least for me, had always been made pretreatment based on
the imaging and clinical ndings of pre-chemoradiotherapy rather
than post-chemoradiotherapy. And even if the tumor regressed,
many still did not change the transection level.
12 Preoperative vs. Postoperative Chemoradiotherapy…
79
© 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_13
13
Synergy Between
Preoperative Radiotherapy
andSurgery inthe
Treatment ofRectal Cancer
Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH,
Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van Krieken
JH, Leer JW, van de Velde CJ; Dutch Colorectal Cancer
Group. Preoperative radiotherapy combined with total meso-
rectal excision for resectable rectal cancer. N Engl J Med.
2001;345(9):638–46.
Abstract
Background: Short-term preoperative radiotherapy followed by
total mesorectal excision has been shown to improve local control
of disease in patients with resectable rectal cancer. We conducted
a multicenter, randomized trial to determine whether the addition
of preoperative radiotherapy increases the benet of total meso-
rectal excision.
Methods: We randomly assigned 1861 patients with resectable
rectal cancer either to preoperative radiotherapy (5Gy on each of
5days) followed by total mesorectal excision (924 patients) or to
total mesorectal excision alone (937 patients). The trial was con-
ducted with the use of standardization and quality control mea-
sures to ensure the consistency of the radiotherapy, surgery, and
pathological techniques.
Results: Of the 1861 patients randomly assigned to one of the
two treatment groups, 1805 were eligible to participate. The over-
all rate of survival at 2 years among the eligible patients was
80
82.0% in the group assigned to both radiotherapy and surgery and
81.8% in the group assigned to surgery alone (P=0.84). Among
the 1748 patients who underwent a macroscopically complete
local resection, the rate of local recurrence at 2years was 5.3%.
The rate of local recurrence at 2years was 2.4% in the radiother-
apy-plus-surgery group and 8.2% in the surgery-only group
(P<0.001).
Conclusions: Short-term preoperative radiotherapy reduces
the risk of local recurrence in patients with rectal cancer who
undergo a standardized total mesorectal excision.
LS
The Dutch trial has contributed to establish the role of neoadjuvant
radiotherapy as complementary and not alternative to optimized
radical surgery for rectal cancer in minimizing the risk of local
recurrence rate. This was the rst large multicenter prospective ran-
domized trial where the use of radiotherapy was evaluated in a large
group of patients in whom surgery for rectal cancer was meticu-
lously standardized through workshops and other educational mate-
rials to perform an adequate total mesorectal excision. The successful
use of short-course preoperative radiotherapy in combination with
total mesorectal excision was also the base for subsequent trials.
After a median follow-up of 24.9months, patients receiving neoad-
juvant radiotherapy before surgery were associated with a signi-
cantly reduced local recurrence rate, 2.4% vs. 8.2% following
surgery alone. Overall survival was similar. Long-term results after
a median 11.6-year follow-up among surviving patients conrmed a
reduced 10-year cumulative incidence of local recurrence, which
was 5% in the radiotherapy group vs. 11% in the surgery-alone
group. Out of all individuals experiencing local recurrence, the pro-
portion presenting later than 5years after surgery was 11% in the
surgery-alone group and 9% in the irradiated group. There were
again no differences between groups in overall survival. The reduc-
tion in mortality for rectal cancer in the irradiated group was offset
by an increased death rate from other causes, which included sec-
ondary malignancy. On the other hand, in the subgroup of patients
13 Synergy Between Preoperative Radiotherapy andSurgery…
81
with stage III cancer and negative circumferential resection margin
on pathology, the use of preoperative short-course radiotherapy was
associated with a signicant 10-year survival advantage [1]. This
indicates that radiotherapy can be benecial but is also associated
with substantial long-term risks, and its use should be focused on
those disease presentations at elevated risk of local recurrence. The
debate on the exact boundaries of this patient subgroup remains
open. In this respect, patients enrolled in the Dutch trial did not have
their tumors staged using modern pelvic MR imaging, which can
lead today to a better patient selection. Individuals with all rectal
cancer stages were randomized, including those with stage I disease.
This resulted in overtreatment in a substantial proportion of patients.
The preparation and design of the Dutch trial were possible through
extraordinary and unprecedented efforts. The low local recurrence
rates, particularly in the study group, speak to the advancements in
the management of rectal cancer. Despite compelling evidence from
this and other well-designed trials, neoadjuvant short-course radio-
therapy remains rarely utilized in the United States. While this might
be based on individual preferences and strictly medical decision-
making, it also at least in part depends on reimbursement disadvan-
tages associated with short-course radiotherapy when compared to
the more frequently used long-course radiotherapy [2].
References
1. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM,
Putter H, Wiggers T, Rutten HJ, Påhlman L, Glimelius B, van
de Velde CJ; Dutch Colorectal Cancer Group. Preoperative
radiotherapy combined with total mesorectal excision for
resectable rectal cancer: 12-year follow-up of the multicentre,
randomised controlled TME trial. Lancet Oncol.
2011;12(6):575–82.
2.
Mo
wery YM, Salama JK, Zafar SY, Moore HG, Willett CG,
Czito BG, Hopkins MB, Palta M. Neoadjuvant long-course
chemoradiation remains strongly favored over short-course
radiotherapy by radiation oncologists in the United States.
Cancer. 2017;123(8):1434–1441.
References
82
Discussion
MD
One striking aspect of this study was that when looking at the
height of the tumor, the investigators found benet with regard to
local recurrence in tumors located at less than 10cm from the anal
verge. The use of radiotherapy for upper rectal tumors is more
controversial, and here, we generally do not radiate them, but this
clearly showed there was not any benet from radiation therapy in
the upper rectal tumors. Do you know why they decided to use
short course in this study instead of traditionally long course?
LS
I think it is more of their traditional practice. Apart from any dis-
cussion on indications, I have to recognize that short-course treat-
ment is at least more convenient. I mean, if I were a patient and
somebody tells me I can receive radiotherapy for a week and, the
following Monday or Tuesday, I can have surgery for rectal can-
cer, a condition which makes me upset and distraught, I would
prefer it in terms of practicality. And I think that it is also impor-
tant to point out that there is some data indicating that the decision
to give long course or short course, at least in part, is related to
reimbursement [2] with long-course treatment being associated
with better reimbursement. So, if you put this kind of decision-
making within a fragmented healthcare environment where the
majority of physicians are private practitioners, this does matter.
For example, if you are at Washington University in St. Louis
receiving a salary, you can promote short-course treatment which
they have historically investigated and used in the United States
with good science and good data. But if you are a private practi-
tioner, I think it is difcult to promote something when there is
some debate about the fractionation and risk of increased toxicity
associated with short course, and on top of that, you know that
you will be paid less. Unless you feel strongly from a scientic
standpoint, what would be the incentive to give short course ther-
13 Synergy Between Preoperative Radiotherapy andSurgery…
83
apy to your patients? I think that this is an important part of the
debate on why we do not use this more in the United States.
AM
I think you are denitely right. When you look at the penetrance
of short-course radiotherapy throughout Europe, it is to a far
greater degree than in the United States. I think those economic
factors denitely play a role.
DC
I nd this study very impressive. Here we are 23years later, and
we are still talking about the study and its results. It is very rare to
see a study like this where it is quoted even now, and we talk about
this study not infrequently in our tumor board. So, I think the
work that they did is outstanding. Having said that, I do not want
to say shortcomings, but there are limitations to what we can
interpret from the study. The authors could probably tell us a lot
more clearly on what their exact intent was, but I think that their
data indicate that using radiation in appropriate patients reduces
the local recurrence rate by half. That is an easy gure to remem-
ber and something I still talk to my patients about, so I think it is
a great study. I agree with the comments on short-course variabil-
ity with regard to its implementation. I think that the question of
whether short course versus long course has better or worse onco-
logic outcomes and better or worse side effects for patients is the
question that we might clearly identify and then choose, but I
think that the scale is probably tipped toward short-course radia-
tion, it is just a matter of implementation.
AM
I think the thing that goes hand in hand with deciding short course
vs. long course, which has been seen in more recent trials, has
Discussion