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II and stage III patients [hazard ratio (HR), 0.47; 95% condence
interval (CI) 0.31–0.93]. The median OS for the patients with
LRCC was 13.1 months (95% CI 9.1–18.3 months). Curative-
intent treatment was given to 22.4% of the LRCC patients, and the
subsequent 3 years OS was 71% (95% CI 58–87%). The patients
treated with palliative treatment and best supportive care showed
3-year OS rates of 15% (95% CI 7.0–31%) and 3.7% (95% CI
1.0–14%), respectively.
Conclusions: The cumulative incidence of LRCC was low,
and adjuvant chemotherapy was associated with a decreased risk
for LRCC among targeted patients. Curative-intent treatment was
given to nearly 1 in 4 LRCC patients, and the OS for this group
was high.
DC
As with most population-based studies, this study comes from the
Netherlands. As of this writing, it is the most recent study and
probably one of the best written. The overarching story is the
same, but some of the details are interesting and bear further dis-
cussion.
Overall, the 3554 patients here are followed for just over
3.5years and all had stages I–III colon cancers. The patients have
excellent resections with a microscopically negative margin in
97.6% of the cases. Adjuvant chemotherapy was administered to
87.7% of stage III cancers and 11.7% of stage II cancers. The
locally recurrent (LR) rate was 3.8% at 3years. Of those, 37.3%
had isolated local recurrences, and 62.7% had synchronous dis-
tant metastases. LR was over 5 times higher in stage II disease
compared to stage I and 14 times higher in stage III.One interest-
ing fact was that contrary to other studies, the sidedness of cancer
did not have an effect on the rate of recurrence [1, 2].
The risk factors for LR were older age, T4 tumors, N+, posi-
tive margins, lymphovascular invasion, and poor tumor differen-
tiation. One staggering statistic is that of the patients that
recurred, only 22% received an intention to cure surgery. Patients
that recurred within one year of primary resection did the worst.
23 Surgery forLocally Recurrent Colon Cancer
159
Still, the overall recurrence rate in this study was only 3.8% at
3years which is less than half of what is usually reported in the
literature [3].
The second interesting point was that less than 1/3 of the
patients with a recurrence who went on to surgery received che-
motherapy. It is unclear why that is, but given that the majority of
the recurrences here had concurrent metastatic disease, additional
chemotherapy would probably be helpful, a practice more alike to
the US and Canada. In the study, chemotherapy is inversely asso-
ciated with the risk of a LR.This strengthens the point that che-
motherapy should be employed prior to resection in cases of LR.
Though it was impossible to record in this study, the location
of recurrence bears some importance to the success of subsequent
treatment. Anastomotic recurrences tend to be most favorable
with respect to the success of resection and overall survival, while
abdominal recurrences were the least favorable [4]. It may be use-
ful to especially consider initiation of systemic therapy in cases
where the recurrence is least favorable, as would be an abdominal
(non-anastomotic) recurrence within one year of primary resec-
tion of a high-risk tumor (positive neurovascular invasion).
In conclusion, LR colon cancer is not well studied, and there is
no uniform protocol on how to approach it. This study under-
scores that few of the recurrences are truly localized diseases, and
even in those cases, serious consideration should be given to initi-
ating systemic chemotherapy as the rst step in approaching treat-
ing this disease.
References
1. Yang CY, Yen MH, Kiu KT, etal. Outcomes of right-sided and
left-sided colon cancer after curative resection. Sci Rep.
2022;12:11323.
2. Sjövall A, Granath F, Cedermark B, Glimelius B, Holm
T.Loco-regional recurrence from colon cancer: a population-
based study. Ann Surg Oncol. 2007;14:432–40.
3. Storli PE, Dille-Amdam RG, Skjærseth GH, Gran MV,
Myklebust TÅ, Grønbech JE, Bringeland EA. Cumulative
References
160
incidence of rst recurrence after curative treatment of stage
I–III colorectal cancer. Competing risk analyses of temporal
and anatomic patterns. Acta Oncol. 2023;62(12):1822–30.
4. Jarrar A, Sheth R, Tiernan J, Sebikali-Potts A, Liska D, Vitello
D, Kalady M, Delaney CP, Valente M, Steele SR. Curative
intent resection for loco-regionally recurrent colon cancer:
Cleveland clinic experience. Am J Surg. 2020;219(3):419–23.
Discussion
LS
It is impressive to see an 87.7% adherence to postoperative che-
motherapy in a national population in a Western nation having a
presumably high proportion of elderly individuals, even consider-
ing the relatively small size of the Netherlands. Non-adherence
rates of 30% or above have been reported in large studies in the
US, and the data specic for disadvantaged subpopulations and
the elderly are even more sobering. I think the fragmentation of
the healthcare system in the US renders implementation of guide-
lines on a population basis more difcult. Considering the high
use of adjuvant chemotherapy following the index operations, I
view these recurrences as the expression of an inherently more
aggressive cancer rather than the result of a suboptimal surgical
technique.
The other aspect that is a sort of the elephant in the room to me
is the overall low rate of local recurrence after colon cancer. There
were no comments on the surgical techniques used which I imag-
ine were variable among the many participating hospitals. This
reminds me of the controversy associated with complete meso-
colic excision and whether a wide implementation of this tech-
nique would result in substantially improved outcomes. These
population-based data look quite different from the dismal onco-
logic outcomes of rectal cancer surgery before the widespread
implementation of total mesorectal excision. The article obvi-
ously does not focus on this, but for me, as a reader, it is impos-
sible not to think about it.
23 Surgery forLocally Recurrent Colon Cancer
161
A practical aspect of this work which connects with recent data
is that pT4 and incomplete resection margins after index surgery
were identied as independent risk factors for local recurrence.
Given the encouraging results of the FOxTROT trial if preopera-
tive imaging suggested an elevated risk of positive resection mar-
gin and/or multivisceral resection, I would favor neoadjuvant
chemotherapy. This could increase the possibility of an R0 resec-
tion which in turn could help reduce the risk of local recurrence.
MD
The data says it should be done, but the data is not denitive.
Although this is obviously not a frequent occurrence, I am
impressed by the absence of a clear pathway to treat these cases. I
am surprised at the low rate of chemotherapy to treat locally
recurrent colon cancer which is something that I would anticipate
would be the expected initial approach in our practice. The other
aspect that struck me is that there was no difference between right
and left colon cancer. I would have imagined more variability in
the management of left colon cancer than right.
AM
As has been proven again... Biology is King. I think this study
highlights that from a number of factors that have already been
discussed, those that have early recurrences and non-anastomotic
recurrences do worse. I agree with the other sentiments that have
been expressed and do feel that neoadjuvant chemotherapy in the
setting of a recurrence can only benet the patient—not just from
the completeness of resection perspective, but it also allows us to
test the biology of the tumor and to better understand the impact
of the chemotherapeutic regimen on an overall multimodal treat-
ment strategy. We operate far too frequently on recurrences that
are truly resectable, and I think that at least in the United States,
this is probably largely a function of the patients not being evalu-
ated as completely as they should be and seeing surgeons who can
Discussion
162
truly make that decision. And I think that we see that in our own
practice when probably 50% or more of patients who come here
with some element of recurrence are in fact resectable when they
have been told they are otherwise not resectable. And then I think,
other adjuncts such as advanced metastasectomy or ablation or
even now, liver transplant, increase the patient population, I think,
becoming eligible for resection in the setting of recurrent disease.
LS
While I recognize the potential role of intraoperative radiotherapy
in the appropriate setting, one aspect which I am not sure about is
the role of HIPEC (hyperthermic intraperitoneal chemotherapy)
for locally recurrent colon cancer. I am happy we work in an insti-
tution with HIPEC capabilities where we can openly discuss with
our surgical oncology colleagues its possible application and plan
a combined procedure as needed. I do not have a sort of ideologi-
cal view of HIPEC indications in this patient population, which
admittedly remains rare.
AM
There is now more emerging data on the use of HIPEC in those
who have just a T4 primary colon cancer at the time of index
surgery in an effort to reduce the potential likelihood of recur-
rence. Some of that data is relatively new so there is an element
of the unknown there. In terms of radiation therapy, I mean, to
me, I see a limited role in the abdomen just because more often
than not, I think you can just take the local recurrence out. There
are very few areas, I would imagine the vertebral bodies, which
you cannot just cut out, whereas, in the pelvis, you are limited by
its own bony connes. I do not think there’s denitive data. Just
going back to HIPEC, I do not think there’s denitive data for
these cases either. I mean, PRODIGE 7, which assessed primary
HIPEC, had its own problems and generated a lot of criticisms.
And that did change the landscape of HIPEC at least in the set-
23 Surgery forLocally Recurrent Colon Cancer
163
ting of primary disease, and perhaps, the pendulum swung too far
because of the weaknesses of that trial, which inevitably would
have then impacted the use of HIPEC in the locally recurrent
population.
LS
In abstract terms, I am struggling with the concept of considering
the peritoneum as a separate organ to be proactively addressed or
does it constitute overtreatment? For example, how often would
we consider prophylactic locoregional treatment of the liver with-
out liver metastases?
AM
I guess I would say the cases I have done involved the peritoneum,
so not just any locally recurrent colon cancer. If there is the
involvement of the peritoneum, then I would seek out the surgical
oncology colleagues’ insight and consider HIPEC, and denitely,
we have done that.
MD
You see these patients with multiple recurrent metastases within
the abdomen.
AM
Yes, we have treated cases not limited to loco-regional recurrence
of colon cancer, but also involving multiple metastases, and we
have cytoreduced them, resected those metastases, and then deliv-
ered HIPEC. Admittedly there is not a lot of great data for that but
adding the HIPEC probably imparts minimal additional morbidity
compared to what the resection itself does.
Discussion
165
© 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_24
24
Avoiding Surgery
inAsymptomatic Patients
withStage IV Colon Cancer
Poultsides GA, Servais EL, Saltz LB, Patil S, Kemeny NE,
Guillem JG, Weiser M, Temple LK, Wong WD, Paty PB.Outcome
of primary tumor in patients with synchronous stage IV colorectal
cancer receiving combination chemotherapy without surgery as
initial treatment. J Clin Oncol. 2009;27:3379–84.
Abstract
Purpose: The purpose of this study was to describe the frequency
of interventions necessary to palliate the intact primary tumor in
patients who present with synchronous, stage IV colorectal cancer
(CRC) and who receive up-front modern combination chemother-
apy without prophylactic surgery.
Patients and Methods: By using a prospective institutional
database, we identied 233 consecutive patients from 2000
through 2006 with synchronous metastatic CRC and an unre-
sected primary tumor who received oxaliplatin- or irinotecan-
based, triple-drug chemotherapy (infusional uorouracil,
leucovorin, and oxaliplatin; bolus uorouracil, leucovorin, and
irinotecan; or uorouracil, leucovorin, and irinotecan) with or
without bevacizumab as their initial treatment. The incidence of
subsequent use of surgery, radiotherapy, and/or endoluminal
stenting to manage primary tumor complications was recorded.
Results: Of 233 patients, 217 (93%) never required surgical
palliation of their primary tumor. Sixteen patients (7%) required
166
emergent surgery for primary tumor obstruction or perforation, 10
patients (4%) required nonoperative intervention (i.e., stent or
radiotherapy), and 213 (89%) never required any direct symptom-
atic management for their intact primary tumor. Of those 213
patients, 47 patients (20%) ultimately underwent elective colon
resection at the time of metastasectomy, and eight patients (3%)
underwent this resection during laparotomy for hepatic artery
infusion pump placement. Use of bevacizumab, location of the
primary tumor in the rectum, and metastatic disease burden were
not associated with increased intervention rate.
Conclusion: Most patients with synchronous, stage IV CRC
who receive up-front modern combination chemotherapy never
require palliative surgery for their intact primary tumor. These
data support the use of chemotherapy, without routine prophylac-
tic resection, as the appropriate standard practice for patients with
neither obstructed nor hemorrhaging primary colorectal tumors in
the setting of metastatic disease.
LS
This is the fundamental study which consolidated the role of
initial chemotherapy for stage IV colorectal cancer patients
instead of surgery. This has been a widely debated topic for a
long time, and the traditional teaching was that it was oftentimes
necessary to resect the primary disease even when the patient
was poorly symptomatic or asymptomatic because of the risk of
subsequent obstruction, perforation, or bleeding. The other
putative rationale for resection of the primary tumor would be
tumor debulking to allow prolonged survival. Although in a ret-
rospective fashion over the span of 7years, the authors indicated
that out of 233 consecutive patients with synchronous metastatic
colorectal cancer and unresected primary tumor, 93% never
required emergent surgery. The remaining 7% required emer-
gent surgery for primary tumor obstruction or perforation. This
is a particularly difcult group of patients to study given that in
retrospective studies, patients undergoing palliative surgery tend
to be tter than patients receiving initial chemotherapy. Stage IV
24 Avoiding Surgery in Asymptomatic Patients with Stage IV…
167
disease group is a heterogeneous group including for example
patients with widely metastatic disease who could not tolerate
either surgery or chemotherapy and are unfortunately toward the
end of their lives but also patients who experience substantial
tumor response after upfront chemotherapy and ultimately
undergo surgery with curative intent which was actually the case
for 20% of patients in this study. Most patients probably fall in
between these two subgroups. The other signicant variable in
this debate has been the evolution of available agents for chemo-
therapy beyond uoropyrimidines which has offered more effec-
tive treatment options to clinicians. Subsequent data from
randomized clinical trials have corroborated the approach pro-
posed in this article. The Japanese JCOG 1007 trial randomized
165 patients and indicated no survival benets associated with
primary tumor resection. Patient accrual was discontinued
because of futility after a median follow-up of 22months based
on the recommendation of the Data and Safety Monitoring
Committee [1]. The European CAIRO4 trial showed increased
60-day mortality among patients who underwent primary tumor
resection followed by chemotherapy when compared with
patients receiving upfront chemotherapy without surgery [2].
The more recent SYNCHRONOUS trial also conrmed the lack
of benets associated with primary tumor resection after ran-
domization of 393 patients treated in 100 different centers and
followed for a median follow-up of 36.7months [3].
References
1. Kanemitsu Y, Shitara K, Mizusawa J, Hamaguchi T, Shida D,
Komori K, Ikeda S, Ojima H, Ike H, Shiomi A, Watanabe J,
Takii Y, Yamaguchi T, Katsumata K, Ito M, Okuda J,
Hyakudomi R, Shimada Y, Katayama H, Fukuda H; JCOG
Colorectal Cancer Study Group. Primary tumor resection plus
chemotherapy versus chemotherapy alone for colorectal can-
cer patients with asymptomatic, synchronous unresectable
metastases (JCOG1007; iPACS): a randomized clinical trial. J
Clin Oncol. 2021;39(10):1098–1107.
References
168
2. van der Kruijssen DEW, Elias SG, Vink GR, van Rooijen KL,
‘t Lam-Boer J, Mol L, Punt CJA, de Wilt JHW, Koopman M;
CAIRO4 Working Group. Sixty-day mortality of patients with
metastatic colorectal cancer randomized to systemic treatment
vs primary tumor resection followed by systemic treatment:
the CAIRO4 phase 3 randomized clinical trial. JAMA Surg.
2021;156(12):1093–1101.
3. Rahbari NN, Biondo S, Feißt M, Bruckner T, Rossion I, Luntz
S, Bork U, Büchler MW, Folprecht G, Kieser M, et al.
Randomized clinical trial on resection of the primary tumor
versus no resection prior to systemic therapy in patients with
colon cancer and synchronous unresectable metastases. J Clin
Oncol. 2022;40(17_suppl). LBA3507.
Discussion
DC
This was a great paper—even though it has been more than
14 years since it was published, it is still valid today. It really
makes the point that the focus of treatment in metastatic colorec-
tal cancer should be the metastatic disease as opposed to the pri-
mary site with the exception of complications (bleeding or
obstruction). Distal rectal cancer deserves its own discussion, and
others have addressed this, and in cases of impending obstruc-
tion…radiation tends to help, and endoluminal stents are hard to
deploy in distal rectal cancer- and the patients tend to tolerate
those poorly. This paper is making a more general point which is
very valid and applicable.
MD
I found this study remarkably impactful. It offers solid evidence
for managing this patient population, allowing us to avoid surgery
for the majority of patients. This spares them from the potential
need for a stoma and perioperative morbidity that can be associ-
ated with the operation, which is particularly crucial for these
24 Avoiding Surgery in Asymptomatic Patients with Stage IV…