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126
laparoscopically than with open technique. When doing laparo-
scopic surgery, I did not feel that way. I felt like I could do it safely,
and the literature on colon cancer had indicated recovery advan-
tages associated with laparoscopic surgery; therefore, I embraced
the trial and I put patients in the trial, waiting for its results. But I
also realized in going to trial meetings that the majority of the
investigators were very experienced in laparoscopic surgery. My
impression was that as a group, we were not approaching the trial
with the equipoise that for example a medical oncology group
would have in approaching a study comparing 2 chemotherapy
regimens. As surgeons, we tend to be very invested in what we do,
which can include laparoscopic surgery. We learned it, we went
through the learning curve of it, and we tend to believe in it as an
advantage for our patients so that it is more difcult to have equi-
poise when reading the unexpected results of a trial and just change
practice. I came into the trial thinking that laparoscopic surgery
could provide patient advantages, but I felt that visualization
remained difcult. I do not mean to suggest that an open operation
is easy, but it did not seem like laparoscopy was making it much
easier. After the trial was published I came to the conclusion that if
the patient is an obese male with mid or low rectal cancer, I am not
going to do his operation laparoscopically anymore, so I started
doing more open surgery as a result of the trial. Given my disillu-
sionment with laparoscopic proctectomy, I also became interested
in robotic surgery. There was this known issue of higher costs to
face, but at the same time, I thought this could be the technique
which could make a rectal dissection in a difcult pelvis a little
easier. Not easy, but a little easier. I felt I could still do laparoscopic
surgery in some of the patients who were not included in the trial,
for example, recto-sigmoid cancers, high rectal cancer, earlier dis-
ease, leaner patients, women with wider pelvis, etc., and they can
do very well and have both an oncologically adequate operation
and the recovery advantages of laparoscopic surgery. With respect
to the oncologic outcomes, I was not very worried that laparo-
scopic proctectomy was inherently a worse oncologic operation, I
rather felt that setting up the composite pathologic outcome was an
ambitious target to achieve. I am pleased that subsequent follow-
up studies have not indicated oncologic differences between the 2
techniques.
18 Laparoscopic vs. Open Proctectomy forRectal Cancer
127
AM
I agree with much of what has been said regarding the confusion
and conicting opinions regarding laparoscopic surgery after the
publication of this study.
The follow-up report on oncologic outcomes, from this patient
cohort, published in Annals of Surgery in 2019 showed similar
rates of disease-free survival, locoregional recurrence, and distant
recurrence which many held up as evidence of laparoscopic sur-
gery being equivalent to open. However, this trial was not pow-
ered to detect these longer-term oncologic outcomes. Thus, at
least at the time of this study, the jury was still out on oncologic
outcomes of laparoscopy compared to open surgery.
My opinion about the modality used for rectal cancer surgery
is that it depends on the individual surgeon. With the technical
demands of TME, we must ensure as surgeons that the critical
outcome that we wish to optimize is oncologic control, and so the
surgeon should choose the modality (open, laparoscopic, or
robotic) that they feel can give them the greatest likelihood of
achieving an appropriate resection and a complete TME.
Discussion
129
© 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_19
19
Immunotherapy forLocally
Advanced Rectal Cancer
Cercek A, Lumish M, Sinopoli J, Weiss J, etal. PD-1 blockade in
mismatch repair-decient, locally advanced rectal cancer. N Engl
J Med. 2022;386(25):2363–76.
Abstract
Background: Neoadjuvant chemotherapy and radiation followed
by surgical resection of the rectum is a standard treatment for
locally advanced rectal cancer. A subset of rectal cancer is caused
by a deciency in mismatch repair. Because mismatch repair-
decient colorectal cancer is responsive to programmed death 1
(PD-1) blockade in the context of metastatic disease, it was hypoth-
esized that checkpoint blockade could be effective in patients with
mismatch repair-decient, locally advanced rectal cancer.
Methods: We initiated a prospective phase 2 study in which
single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was
administered every 3 weeks for 6 months in patients with mis-
match repair-decient stage II or III rectal adenocarcinoma. This
treatment was to be followed by standard chemoradiotherapy and
surgery. Patients who had a clinical complete response after com-
pletion of dostarlimab therapy would proceed without chemora-
diotherapy and surgery. The primary endpoints are sustained
clinical complete response 12 months after completion of dostar-
limab therapy or pathological complete response after completion
of dostarlimab therapy with or without chemoradiotherapy and
130
overall response to neoadjuvant dostarlimab therapy with or with-
out chemoradiotherapy.
Results: A total of 12 patients have completed treatment with
dostarlimab and have undergone at least 6 months of follow-up.
All 12 patients (100%; 95% condence interval, 74–100) had a
clinical complete response, with no evidence of tumor on mag-
netic resonance imaging, 18F-uorodeoxyglucose-positron-emis-
sion tomography, endoscopic evaluation, digital rectal
examination, or biopsy. At the time of this report, no patients had
received chemoradiotherapy or undergone surgery, and no cases
of progression or recurrence had been reported during follow-up
(range, 6–25 months). No adverse events of grade 3 or higher
have been reported.
Conclusions: Mismatch repair-decient, locally advanced rec-
tal cancer was highly sensitive to single-agent PD-1 blockade.
Longer follow-up is needed to assess the duration of response.
DC
This is another landmark study in the evolution of rectal cancer
treatment. Admittedly, this is only applicable to rectal cancers that
are mismatch repair-decient (MMR-D), somewhere between 2
and 10% of all rectal cancers [1, 2]. This includes the Lynch syn-
drome variants and the much more common, sporadic MMR-D
rectal cancers. It is clear that these cancers do behave differently,
as MMR-Ds are not sensitive to treatment with 5-uorouracil, and
lymphocytic inltration is more common and tends to be of lower
pathological stage [2].
Previous studies in metastatic, MMR-D rectal cancer have
shown survival benets with the use of pembrolizumab, a pro-
grammed death 1 (PD-1) inhibitor. This study intended to have an
arm that had pembrolizumab only and another that had pembroli-
zumab, chemoradiation, and then surgery. However, because all
12 included patients who received pembrolizumab had a sustained
clinical response (by digital rectal examination, endoscopy, and
MRI) 1year after the start of the trial, the other arm could not be
recruited. Though the study is reported to have recruited both
stage II and III patients, only one stage II patient was recruited,
19 Immunotherapy forLocally Advanced Rectal Cancer
131
the remainder stage III.There is one study that was able to enroll
5/44 patients with MMR-D locally advanced cancer (the rest 39
MMR-normal) which underwent chemoradiotherapy, then pem-
brolizumab, and then resection. All patients underwent the same
treatment, but only the MMR-D patients had 100% relapse-free
survival at 3years (compared to 80%) [3, 4]. There has been no
shortage of enthusiasm for using PDL-1 inhibitors in colorectal
cancer, and in a recent study, 68% of the colon cancer patients
treated with 2 PD-1 inhibitors had a complete pathological
response [5]. Though analyzing the rationale for dual PD-1 inhib-
itor in colon cancers is beyond the scope of this communication,
sufce it to say that PD-1 inhibitors will be universally used in all
MMR-D rectal cancers, with great expectations of disease-free
survival (though little data on 5-year disease-free survival exists
of yet). It is hard to believe that such a small study made such a
great impact, but the nearly 100% reproducibility of their ndings
is hard to ignore.
References
1. Alatise OI, Knapp GC, Sharma A, etal. Molecular and pheno-
typic proling of colorectal cancer patients in West Africa
reveals biological insights. Nat Commun. 2021;12:6821.
2.
F
archoukh LF, Celebrezze J, Medich D, etal. DNA mismatch
repair-decient rectal cancer is frequently associated with
Lynch syndrome and with poor response to neoadjuvant ther-
apy. Am J Surg Pathol. 2022;46:1260–8.
3.
V
ilar E, Gruber S.Microsatellite instability in colorectal can-
cer—the stable evidence. Nat Rev. Clin Oncol. 2010;7:153–62.
https://doi.org/10.1038/nrclinonc.2009.237
4.
Tsukada
Y, Bando H, Inamori K, etal. Three-year outcomes of
preoperative chemoradiotherapy plus nivolumab in microsat-
ellite stable and microsatellite instability-high locally advanced
rectal cancer. Br J Cancer. 2024;131(2):283–9.
5. Chalabi M, Verschoor YL, Batista Tan P, et al. Neoadjuvant
immunotherapy inlocally advanced mismatch repair–decient
colon cancer. N Engl J Med. 2024;390:1949–58.
References
132
Discussion
DC
This study inuenced greatly how we treat mismatch repair de-
cient rectal cancers. Using this PD-1 inhibitor (now multiple
drugs within this class) essentially melts cancers away, at least
these specic rectal cancers. It is hard to argue with their ndings,
especially since they have been reproduced. I do not know for
sure if we have solid 5-year outcomes, but that will be interesting
to see, and I am very optimistic.
LS
The update to this trial waspresented at the latest ASCO (Cercek,
J Clin Oncol 42, 2024 (suppl 17; abstr LBA3512)) and conrmed
sustained response after a median follow-up of 29months. I agree
that we need to wait for the 5-year outcomes. I feel that after such
a dramatic result, the question becomes to which extent we should
approach all MMR-D colorectal cancers with PD-1 blockade as
rst-line treatment and utilize surgery only as salvage treatment.
This would include, for example, colon cancers that are amenable
to resection, rather than metastatic disease of locally advanced
rectal cancers, which was the population of this particular study.
An important question is also the prevention of metachronous
cancers especially in Lynch syndrome, and there is a subpopula-
tion of patients with MMR-D cancer in the background of inam-
matory bowel disease in whom the role of PD-1 inhibitors would
make sense, but we do not have lots of data about it. A particular
nding which constitutes a challenge in MMR-D cancers after
PD-1 inhibitor treatment is a residual mass visible radiologically
associated with pathologic complete response after resection.
This is a known phenomenon after chemo(radio)therapy in MMR
procient tumors but seems to be more pronounced in the MMR-D
subpopulation. I feel future investigations should focus on meth-
ods to identify patients who have a complete treatment response
despite a residual radiological mass and still could be saved from
surgery.
19 Immunotherapy forLocally Advanced Rectal Cancer
133
MD
Yes, I was going to echo that. We looked at our own data, we
looked at about seven patients that we had treated with PD-1
inhibitors, and they seem to use pembrolizumab more frequently
than dostarlimab. In our series, none of them had radiographically
complete responses. And many of them, four of them, had under-
gone major surgical procedures including pelvic exenteration,
abdominoperineal resection, etc., and four of them had complete
pathologic responses despite large, bulky tumors being seen on
MRI.I feel that with these types of tumors, the disconnect between
radiographic ndings and pathologic ndings is more enhanced in
that the tumors look quite bulky on MRI but then end up having a
complete pathologic response, whereas in the MSI stable tumors,
generally, if there is a big, bulky tumor, there’s still disease in the
pathologic specimen. Therefore, I think that the study is exciting
with regard to this patient population in terms of avoiding radia-
tion and surgery, but we still have some ways to go with regard to
determining or being able to capture those patients who don’t
have a radiographic response, but still have a complete pathologic
response like you were saying. This could be better imaging or
perhaps blood testing looking for tumor markers, etc. I think that
will be the next step in these types of tumors.
DC
So, it is more that radiologic ndings indicate that there could be
a tumor, but when this is excised and examined pathologically, it
is not. Is that correct?
MD
Yes, and when I looked at the actual MRIs, it is not like subtle
ndings. Possibly, there is something like when we are talking
about a near-complete response, they look like big mucinous
tumors that are even invading other structures, but then all that
tumor is actually tissue without any disease. It is interesting they
Discussion
134
do not really note that in this study, but when we looked at our
data, a lot of the patients were in that situation. And a lot of other
retrospective reviews and other institutions also indicate that the
MRI technology does not have sufcient specicity to tell us
whether it is scar or tumor, not yet at least.
AM
Agree, this is clearly a signicant milestone in the treatment of
colorectal cancer. The issues you speak of with regard to knowing
which patients have truly achieved pathologic complete response
on PD-1 blockade are analogous to the problems we have in pre-
dicting this in complete clinical responders in general. Our test-
ing, whether MRI imaging, blood, or others, is not of sufcient
resolution yet to accurately determine this 100% of the time.
Furthermore, MRI technology and protocol techniques are very
variable, and at least in the United States, insufcient standards
exist which are not uniform wherever the patient goes.
Also, while this study demonstrated a 100% response rate, this
has not always been seen in practice, and so it is also necessary to
temper expectations of patients.
19 Immunotherapy forLocally Advanced Rectal Cancer
135
© 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_20
20
Surgery forLocally
Recurrent Rectal Cancer
van Kessel CS, Solomon MJ.Understanding the philosophy, anat-
omy, and surgery of the extra-TME plane of locally advanced and
locally recurrent rectal cancer; single institution experience with
international benchmarking. Cancers (Basel). 2022;14(20):5058.
Abstract
Objective: To assess the results of multimodality therapy for
patients with recurrent rectal cancer and to analyze factors predic-
tive of curative resection and prognostic for overall survival.
Summary of Background Data: Locally recurrent rectal can-
cer is a difcult clinical problem, and radical treatment options
with curative intent are not generally accepted.
Methods: A total of 394 patients underwent surgical explora-
tion for recurrent rectal cancer. Ninety were found to have unre-
sectable local or extrapelvic disease and 304 underwent resection
of the recurrence. The latter patients were prospectively followed
to determine long-term survival and factors inuencing survival.
Results: Overall 5-year survival was 25%. Curative, negative
resection margins were obtained in 45% of patients; in these
patients, a 5-year survival of 37% was achieved, compared to 16%
(P<0.001) in patients with either microscopic or gross residual
disease. In a logistic regression analysis, initial surgery with end-
colostomy and symptomatic pain (both univariate) and increasing
number of sites of the recurrent tumor xation in the pelvis (mul-
136
tivariate) were associated with palliative surgery. Overall survival
was signicantly decreased for symptomatic pain (P<0.001) and
more than one xation (P=0.029). Survival following extended
resection of adjacent organs was not different from limited resec-
tion (28% vs. 21%, P= 0.11). Patient demographics and factors
related to the initial rectal cancer did not affect outcome. Periop-
erative mortality was only 0.3%, but signicant morbidity
occurred in 26% of patients, with pelvic abscess being the most
common complication.
Conclusions: This study demonstrates that many patients with
locally recurrent rectal cancer can be resected with negative mar-
gins. Long-term survival can be achieved, especially for patients
with no symptoms and minimal xation of the recurrence in the
pelvis, provided no gross residual disease remains.
DC
This review comes from a well-respected group with a wealth of
experience in treating recurrent rectal cancers and a publication
track record to prove their well-deserved place as experts in the
eld. At the very heart of this paper lies the question of whether
we—as a specialty, or at least those of us who treat recurrent rec-
tal cancer—are veering away from extensive resections and
toward using more chemotherapy or radiotherapy. This was the
report’s underlying premise.
The data used to illustrate this dichotomy is obtained from
their own institutional experience at the Royal Prince Alfred
Hospital (RPA) and the PelvEx Collaborative. “The PelvEx
Collaborative is an international collaborative group involving
over 140units across ve continents, with the aim to examine out-
comes for patients who have had pelvic exenterative surgery.”—
from their own website [1].
There are three principal data-driven observations that support
this report’s underlying premise: (1) The PelvEx collaborative
uses perioperative radiation more frequently, (2) the R0 rate is
higher in the RPA group (compared to the PelvEx group), and 3.
the median overall survival (OS) rate is higher in the RPA group.
It is especially worth mentioning that the difference here is espe-
cially stark, with a mean OS of 95months (almost 8years) in the
20 Surgery forLocally Recurrent Rectal Cancer