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While combination therapy with iniximab and thiopurine is associated with a
favorable outcome in Crohn’s disease, there is no RCT assessing the superiority of
combination therapy in postoperative Crohn’s disease [41]. A nationwide study
using propensity-matched analysis showed the superiority of combination therapy
to iniximab monotherapy with regard to postoperative endoscopic recurrence [42].
Considering the fact that patients with a preoperative history of multiple TNFi exposures were associated with postoperative recurrence, these refractory patients with
high-risk features may be considered as candidates for combination therapy [24].
On the other hand, adalimumab has also been used as prophylaxis after operation
in Crohn’s disease. The rst RCT compared adalimumab with thioprine and mesalamine group showed that the adalimumab group had a much lower endoscopic and
clinical recurrence 2years after surgery [43]. Each group was not stratied according to well-known recurrence risks in this study. Notably, only 6% of patients demonstrated endoscopic recurrence at the 2-year follow-up after surgery, though the
adalimumab group included more patients who were active smokers [44].
In addition, a sub-analysis of the POCER study which enrolled patients with
high-risk recurrence factors dened as smokers, penetrating disease, or history of at
least one resection, demonstrated that adalimumab was more likely to maintain
complete endoscopic remission than azathioprine combined with 3 months metronidazole [45]. Although this study was not designed to directly compare the efcacy
of adalimumab with that of azathioprine in that all patients who were intolerant to
thioprine were assigned to the adalimumab group, it may show feasible evidence of
the superiority of adalimumab to thiopurine in postoperative Crohn’s disease.
Meta-analysis of postoperative prophylaxis with TNFi which included six RCTs
with iniximab and two with adalimumab indicated that the relative risk of endoscopic and clinical recurrence was 0.34[95% CI 0.22–0.53] and 0.60[0.36–1.02],
respectively [1]. Furthermore, no difference between iniximab and adalimumab
was indicated by other meta-analyses [10, 46].
On the other hand, real-world data shows that the same TNFi was often used as
postoperative treatment partially due to a lack of alternative options as maintenance
therapy [47]. Is it effective to use the same drug following surgery even though it
failed before surgery? A retrospective study indicated that patients treated with the
same TNFi as a preoperative treatment showed similar efcacy as TNFi naïve
patients who used TNFi after surgery. In addition, the study also analyzed pharmacokinetics data of drug levels and antidrug antibodies of TNFi before and after
surgery, which showed that patients with preoperative primary failure or secondary
loss of response to TNFi despite therapeutic serum drug levels without antidrug
antibodies responded adequately to TNFi after surgery. This data may suggest that
removal of the disease burden of TNF-α in the tissue of severely inamed areas led
to improvement of TNFi pharmacokinetics [48].
Y. Miyatani and A. Sakuraba
Other Biologics
There is scarce evidence regarding the effect of other biologics for postoperative
Crohn’s disease.
11 Which Patients Benet from Biologic Agents to Prevent Disease Recurrence…
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The rst study which compared ustekinumab to azathioprine in postoperative
Crohn’s disease using propensity score analysis of data from RCT indicated that
ustekinumab treated patients were signicantly less likely to develop endoscopic
recurrence at 6months after resection than azathioprine treated patients. Notably,
ustekinumab was effective even though approximately 90% of patients had a history
of TNFi before surgery [49].
While vedolizumab improved the endoscopic inammation even detected at
postoperative follow-up endoscopy, [50] postoperative prophylaxis with vedolizumab demonstrated a signicantly higher rate of endoscopic recurrence within one
year compared to that with iniximab [47].
The latest retrospective multicenter study was conducted to compare the rate of
endoscopic recurrence with TNFi with those with vedolizumab and ustekinumab in
a real-world setting. Although patients treated with ustekinumab had the highest
rate of endoscopic recurrence at one year (ustekinumab 61% vs. TNFi 40.2% vs.
vedolizumab 33%), there was no statistical difference after adjusted by the numbers
of pre-biologics and surgical histories with inverse probability of treatment weighting. Past history of iniximab and adalimumab is associated with postoperative
endoscopic recurrence factor at one year adjusted by multivariable logistic regression analysis [51].
133
Conclusion
The emergence of novel therapies will provide us with more prophylaxis options in
postoperative Crohn’s disease. Further head-to-head RCTs between biologics are
warranted to assess postoperative prophylaxis. Based on available evidence, it is
proposed that patients with multiple risk factors of postoperative recurrence should
be treated with TNFi and followed up with a colonoscopy 6months after surgery for
step-up treatment for recurrence (Fig. 11.1). Fecal calprotectin may be used in
between colonoscopies for early detection of endoscopic recurrence [52].
Individualized risk stratication and approach with a multidisciplinary team are
indispensable to prevent disease recurrence after resection in Crohn’s disease.
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Continue same
treatment *
Rutgeerts score ≤1
Increase anti-TNF or
switch to different class of biologic *
Rutgeerts score ≥2
Y. Miyatani and A. Sakuraba
Colonoscopy at 6 months
postoperatively
thiopurine/methotrexate
Anti-TNF with/without
High risk
≥2 risk factors
Assess individual risk of
Crohn’s surgery
(ileocolectomy or stricturoplasty)
postsurgical recurrence
Fig. 11.1 Recommended strategy for postoperative Crohn’s disease with high-risk features. *Fecal calprotectin measurement in between colonoscopies may
be useful
11 Which Patients Benet from Biologic Agents to Prevent Disease Recurrence…
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135
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Part II
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Colon Cancer
Is Intensive Surveillance Necessary After
https://t.me/medicina_free
Curative Resection forColon Cancer?
TerrahJ.PaulOlson
Introduction
Colorectal cancer is consistently in the top three cancer diagnoses both in the United
States and worldwide. According to the American Cancer Society, estimated incidence of colorectal cancer in 2020 was 147,950, with 53,200 estimated deaths
attributable to colorectal cancer [1]. About 40% of new CRC diagnoses are stage I
or II (local disease), 36% are stage III (locoregional disease), and 20% at stage IV
(metastatic disease) [2]. Local and locoregional disease is often able to be treated
with curative surgery. Following treatment, patients embark on a period of surveillance as there is a denite risk of recurrence even after appropriate therapy. Risk of
recurrence ranges from 30% to 50%, with a yearly incidence of 9.9% at one year,
increasing to 26.2% by 3years, and 31.5% at 5years when grouping various stages
together [3]. There are different rates based on stage and clinicopathologic
characteristics.
While there is consensus that surveillance needs to be provided to patients after
denite treatment, the exact timing and nature of that surveillance has been a contentious topic, with more or less intensive strategies being adopted. More frequent
surveillance would hopefully nd recurrences sooner, thereby allowing salvage
treatment, but at the expense of increased interactions with the medical system,
potentially leading to mental, physical, and nancial costs to both patients and medical systems. This chapter will review the data for more versus less intensive surveillance following curative surgery for colorectal cancer. Surveillance modalities
include blood tests, imaging studies, and colonoscopy.
12
T. J. PaulOlson (*)
Division of Colorectal Surgery, Department of Surgery, Emory University, Atlanta, GA, USA
e-mail: tpaulol@emory.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
K. Umanskiy, N. Hyman (eds.), Difcult Decisions in Colorectal Surgery,
Difcult Decisions in Surgery: An Evidence-Based Approach,
https://doi.org/10.1007/978-3-031-42303-1_12
141
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Table 12.1 PICO table
Population
Patients with non-metastatic
colon cancer who underwent
curative resection, +/−
adjuvant therapy
Intervention Comparison
Intensive surveillance
with routine labs,
imaging, and endoscopy
Less intensive
surveillance
T. J. PaulOlson
Outcome
Overall survival
Cancer specic
survival
Recurrence
treated with
surgery
Search Strategy
Table 12.1 summarized the PICO question used to design this search strategy. A
comprehensive search of PubMed, EMBASE, and Cochrane Library was performed. Search strategies employed search engine-appropriate combinations of
terms including: “colon cancer surveillance”, “intensive surveillance”, “surveillance”, “overall survival”, “disease free survival”, and “colon cancer surgery”.
Articles from 2004–July 2022 were included. Search limits included human studies,
articles and/or conference reviews/abstracts, and English language. The references
of included articles were reviewed to identify additional relevant articles.
Results
A total of 4326 titles were retrieved with this search strategy. There were three
duplicate titles. After reviewing titles and abstracts, 48 articles underwent full text
review for data extraction and summary of recommendations. Four randomized
controlled trials and three meta-analyses were selected for detailed discussion. Of
note, most studies combined colon and rectal cancer outcomes, making it difcult
to tease out the exact role of different surveillance programs for these two
malignancies.
Tjandra etal. [4] performed a meta-analysis of randomized trials examining this
issue available up to 2007. This included a total of eight trials with a cumulative
patient population of 2923. These were patients who had undergone curative resection for colorectal cancer. They were randomized to intensive follow up (n=1474)
or less intensive/minimal follow up (n=1449). Criteria for follow up intensity were
variable between trials, but typically included serum carcinoembryonic antigen
(CEA) levels, chest radiographs (CXR), and colonoscopy or exible sigmoidoscopy, with variable liver imaging. Less intensive follow up ranged from only written
instructions to the same surveillance modalities but at less frequent intervals. Overall
mortality was reduced with intensive surveillance (21.8% vs 25.7%, OR 0.74,
p=0.01), with serum CEA levels (p=0.0002) and colonoscopy (p=0.04) contributing to this effect. Cancer-related mortality was not signicantly different between
groups (11.5% vs 12.5%; OR 0.91, p=0.52). Recurrences were found 5.91months
earlier (p<0.0001) and more frequently while asymptomatic with intensive surveillance (odds ration [OR] 3.42, p<0.0001). When recurrences happened, they were
12 Is Intensive Surveillance Necessary After Curative Resection forColon Cancer?
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143
more amenable to re-resection (10.7% vs 5.7%, p=0.0002) and had higher rates of
curative surgery in the intensive surveillance group (24.3% vs 9.9%, p=0.0001) [4].
The GILDA trial was an international randomized clinical trial based out of Italy
examining outcomes after curative treatment for Dukes B2 or C colorectal cancer
[5]. Subjects were randomized to high intensity surveillance with CEA, complete
blood count, Ca 19-9, colonoscopy, CXR, and liver ultrasound or low intensity with
CEA, colonoscopy, and liver ultrasonography at less frequent intervals. From 1998
until 2006, 1228 subjects were randomized from three countries, with median follow up of 62months in both arms, and 90% of subjects completing surveillance as
planned. By calculating the difference between the disease-free survival curves,
intensive surveillance was shown to detect recurrences 5.9 months earlier (95%
condence interval [CI] 2.71–9.11). However, this did not translate to a difference
in overall survival (hazard ratio [HR] 1.14, 95% CI 0.87–1.48, p=0.34) or disease
free survival (HR 1.22, 95% CI 0.95–1.57, p=0.11). Health related quality of life
was similar between groups [5].
The FACS (Follow-up After Colorectal Surgery) trial was a randomized clinical
trial with four arms evaluating different strategies using CEA and CT imaging for
surveillance after curative surgical treatment for stage I-III colorectal cancer [6].
This multisite trial in the UK enrolled 1202 subjects between 2003 and 2009 who
were randomized to minimal follow up with a single CT chest/abdomen/pelvis;
CEA surveillance; CT scan surveillance; or combined CEA and CT scan surveillance. Subjects were followed for a mean of 4.4years, and surveillance with either
CEA monitoring or CT scans had higher rates of surgical treatment of recurrence
with curative intent. Specically, rate of surgery with curative intent for recurrence
was 2.3% in the minimum follow up group, whereas rates were 6.7% in CEA group
(adjusted OR 3.00, 95% CI 1.23–7.33), 8% in CT group (adjusted OR 3.63, 95% CI
1.51–8.69), and 6.6% in CEA and CT group (adjusted OR 3.10, 95% CI 1.10–8.71).
The combination of CEA and CT scans did not signicantly increase the yield of
surveillance, and there were not differences in overall or cancer specic deaths
between the minimal follow up group and the intensive surveillance groups (15.9%
vs 18.2%, difference 2.3%, 95% CI −2.6% to 7.1%). While intensive surveillance
again had a higher rate of surgically treatable recurrences, no survival benet was
demonstrated [6].
The COLOFOL trial was an international randomized clinical trial of subjects
with stage II or III colorectal cancer after curative surgery [7]. This study randomized 2509 subjects looking specically at overall and colorectal cancer-specic
mortality rates, and time to colorectal cancer specic recurrence in subjects undergoing more frequent vs less frequent surveillance with CEA and CT scans of the
abdomen. Overall 5-year mortality rate was 13.0% in the high frequency group vs
14.1% in the low frequency group (risk difference 1.1%, 95% CI −1.6% to 3.8%,
p=0.43). Likewise, there was no signicant difference in 5-year colorectal cancer
specic mortality between groups– 10.6% vs 11.4% (risk difference 0.8%, 95% CI
−1.7 to 3.3%, p=0.52). Detection rates of colorectal cancer recurrence was also
similar between groups– 21.6% vs 19.4% (risk difference 2.2%, 95% CI −1.0% to
5.4%, p=0.15) [7].
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