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257
POSITRON EMISSION TOMOGRAPHY
CONCEPTS AND DEFINITIONS
PET is a diagnostic nuclear imaging study that measures uptake of
2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG), an analogue
of glucose, to detect metabolic abnormalities based on increased
glucose uptake and glycolysis in cells of the body. Cancer cells have
increased glucose metabolism compared with normal cells and thus
higher FDG uptake in viable cancer cells. Standardized uptake value
(SUV) evaluates the metabolic uptake of FDG in tumor cells. SUV
may be quantified as the standardized maximum (SUV
(SUV
) uptake. SUV
mean
is defined as the highest uptake value of
max
) or mean
max
the most intense pixel inside an ROI divided by the injected dose
(corrected for decay and normalized for the patient’s body weight or
body surface area). SUV
does not reflect overall tumor behavior
max
because several confounding factors might affect SUV measurement: tumor heterogeneity, body size, image acquisition time, and
partial volume effects. The SUV
uptake values within an ROI. Increased SUV
is the average of all the pixel
mean
values represent
mean
higher metabolic rates, which correlate with more aggressive tumor
histology and worse overall survival (OS). Volumetric parameters
of PET CT studies reflect the burden of the metabolically active
tumor. The metabolic tumor volume (MTV) is the volume of tumor
tissue with pathologic FDG uptake within a three-dimensional
ROI. Total lesion glycolysis (TLG) is calculated by multiplying the
SUV
by MTV.
mean
INITIAL DIAGNOSIS, WORKUP, AND
STAGING OF COLORECTAL CANCER
In the most current NCCN guidelines, initial staging of CRC
involves a CT of the chest, abdomen, and pelvis to evaluate for the
presence of distant metastasis. In rectal cancer, MRI is used for initial tumor and nodal staging. PET CT is not indicated in the initial
workup of a pedunculated or sessile polyp with invasive cancer or
resectable CRC (nonmetastatic) (stages I–III). Of note, mucinous
tumors have no FDG uptake and account for ∼17% of CRCs. PET
CT also has limited sensitivity in detecting metastatic tumors less
than 10 mm. Special consideration may be given to patients with
a significant allergy to iodinated or gadolinium contrast or renal
failure. In these circumstances, MRI without contrast or FDG-PET
CT is recommended. FDG-PET CT may also be considered in cases
where CT or MRI yields equivocal or nondiagnostic information
to assist in percutaneous or surgical biopsy for a tissue diagnosis.
There is no established consensus regarding criteria to differentiate between benign, premalignant, or malignant lesions based on
standard CT or MRI imaging. A small series evaluating 76 rectal
cancer patients with preoperative FDG-PET CT determined that
an MTV threshold of 2.5 predicted pathologic T3 and T4 staging
as opposed to T1 and T2 staging (odds ratio, 1.81; 95% confidence
interval, 1.26-2.60; P
Preoperative nodal staging (N-staging) with FDG-PET CT
requires accurate identification of pericolorectal and mesenteric
lymph nodes with metastatic disease. Studies have evaluated the
cut-off value of SUV
increasing the identification of malignant lymph nodes. FDG-PET
CT has been found to increase the accuracy of N-staging from
48% to 66% when compared to CT, with a potential change in
rectal cancer management by 26%. False-negative FDG-PET CT
results can be due to intense FDG uptake by the primary tumor,
which can obscure adjacent structures, as well as low FDG uptake
in microscopically positive nodes. For this reason, FDG-PET CT
has been found to have low sensitivity for regional lymph node
metastases. In two small, prospective studies comparing contrast
enhanced CT with FDG-PET CT in patients with rectal cancer,
PET CT altered the staging in nearly one-third of cases, and altered
staging (primarily due to revised nodal status). This changed the
management strategy and/or surgical plan in up to 14% of the
= 0.001).
of 1.5 or 2.0, both values significantly
max
cases. Despite a handful of positive studies, others have found that
the routine use of PET CT for preoperative staging in colon and
rectal cancers did not impact disease management in more than
96% of patients.
The major advantage of FDG-PET CT compared with contrast-enhanced CT is its superiority in identifying extrahepatic
metastatic lesions with a high accuracy of up to 97%. Regarding
lung metastases, some studies demonstrate high positive predictive value (PPV) and negative predictive value (NPV) for FDGPET CT (90% and 94%, respectively), whereas other studies show
similar low accuracy both for FDG-PET CT and CT. For liver
metastases, a meta-analysis reported the sensitivity and specificity of FDG-PET CT to be 74.1% and 93.9%, respectively. The
role of FDG-PET CT in the diagnosis, workup, and preoperative
management of liver metastases will be discussed further in this
chapter.
THE ROLE OF PREOPERATIVE FDG-PET
CT IN COLORECTAL MALIGNANCY
The panel for NCCN strongly discourages the routine use of
FDG-PET CT scanning for staging, baseline imaging, or routine
follow-up. However, the panel recommends consideration of a
preoperative FDG-PET CT at baseline if prior anatomic imaging
indicates the presence of potentially surgically curable metastatic
disease (M1). Two different meta-analyses studying more than
3000 study participants have demonstrated that FDG-PET CT may
identify unrecognized metastatic disease that would preclude the
possibility of surgical management, such as hepatic resection or
radiofrequency ablation.
POSTTREATMENT EVALUATION OF
COLORECTAL MALIGNANCY
In the past decade, overall survival has improved as a result of the
introduction of treatment options, such as new chemoradiation
therapy techniques (e.g., total neoadjuvant therapy [TNT]) and
immunotherapy. However, it remains a challenge to determine
which patients are optimal candidates for what type of therapy.
Currently, we rely on response evaluation after treatment. It is difficult to predict response to treatment at treatment outset and longterm outcomes. Imaging is routinely used during diagnosis and
follow-up and may aid in identifying noninvasive biomarkers that
could determine response and long-term outcomes and ultimately
tailor treatment regimens for CRC.
Standard assessment of the response to chemotherapy utilizes
Response Evaluation Criteria in Solid Tumor (RECIST) to measure
the change in size of the posttreatment tumor. However, these criteria
do not take into account information about intralesional features,
such as tumor necrosis.
In the posttreatment setting, a decrease in SUV on FDG-PET
CT following treatment correlates to a greater chance of a complete
response and improved long-term survival. A preliminary case series
evaluated response to neoadjuvant chemoradiation therapy (nCRT)
for rectal cancer 12 days after beginning nCRT identified a ≥52%
decrease in SUV
for responders, of whom responders had a 5-year
mean
recurrence-free survival that was significantly higher than that of
nonresponders.
On a cautionary note, PET CT may be transiently negative after
chemotherapy, despite the presence of residual microscopic cancer
cells that may not allow for sufficient FDG uptake. In addition,
false-positive PET CT results can occur in the presence of tissue
inflammation after surgery or infection.
COLORECTAL CANCER SURVEILLANCE
NCCN guidelines recommend that serial carcinoembryonic antigen (CEA) levels, colonoscopies, and CT scans are obtained for
258 PET SCANNING IN THE MANAGEMENT OF COLORECTAL CANCER
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CRC surveillance. FDG-PET CT is not indicated in standard CRC
surveillance.
As per NCCN guidelines, circumstances that may warrant
FDG-PET CT are reserved for select patients, in which distant
recurrence workup with metachronous metastases is documented
by CT, MRI, or biopsy. In this situation, FDG-PET CT determines
whether there are other distant metastases that would disqualify
the patient from surgery and thus make the patient a candidate for
systemic chemotherapy. FDG-PET CT plays an important role in
the detection of recurrence in patients who have an unexplained
rise in their CEA levels. Residual soft tissue abnormalities are
frequently seen in the tumor bed after treatment, which can complicate the interpretation of follow-up scans using conventional
imaging techniques; therefore, FDG-PET CT may be considered
as the next step in the workup of cancer recurrence. A soft tissue
lesion identified using FDG-PET CT 6 months after completion
of therapy likely represents recurrence, and the PPV of such a
finding increases if it has been more than 12 months since the
completion of therapy. The sensitivity and specificity of detection
varies by anatomic location, with the highest sensitivity, specificity, and accuracy for the detection of extraabdominal and hepatic
recurrence (sensitivity 95%, specificity 100%, and accuracy 99%).
For intraabdominal but extrahepatic recurrence, the sensitivity is
88%, specificity 94%, and accuracy 92%. After image-guided liver-directed therapies (i.e., ablation, radioembolization), FDG-PET
CT can be considered for assessment of treatment response and
liver recurrence.
FDG-PET CT may also be helpful in determining local recurrence of rectal cancer. In a meta-analysis, detection of local recurrence (i.e., recurrence at the anastomosis or in the presacral region
for rectal cancers) or distant metastasis, sensitivity of detection by
PET CT was 94%, with a specificity of 93%. Postchemoradiation
therapy and surgery yields presacral soft tissue findings on surveillance imaging in up to half of rectal cancer patients. FDGPET CT may be useful in determining whether this presacral or
anastomotic thickening represents fibrosis that is metabolically
inactive versus recurrent cancer. However, FDG avidity in the
pelvis may also be due to benign inflammatory changes from previous postoperative complications such as abscess or anastomotic
leak or fistula. Thus, FDG-PET CT false-positive results of local
recurrence may require further investigation via endoscopic, percutaneous, or image-guided biopsy.
THE ROLE OF PET CT IN COLORECTAL
LIVER METASTASES
There is evolving evidence in the literature to support the utilization of FDG-PET CT in the preoperative evaluation of colorectal
liver metastases (CRLM) and surveillance in a select population
of patients. A randomized controlled trial evaluating preoperative
CRLM, FDG-PET CT on surgical management for metastatic Colorectal Adenocarcinoma to liver Metastases (“PET-CAM”), was a
multicenter study that aimed to identify the effect of preoperative
PET CT vs. no PET CT on the surgical management of patients with
resectable CRC liver metastases as determined by CT scan and/or
MRI. Of the 263 participants who underwent FDG-PET CT in the
trial, 21 (8%) had a change in surgical management with 7 (2.7%)
avoiding futile laparotomy after the discovery of additional loci of
metastatic disease (i.e., within the bone, peritoneum/omentum,
and lymph nodes). In addition, 1.5% of patients underwent more
extensive hepatic resections and 3.4% underwent extrahepatic surgery for distant metastases. A meta-analysis of 18 studies including
1059 patients with hepatic colorectal metastases found that PET
or PET CT results changed management in 24% of patients. Controlling for similar baseline patient characteristics, the proportion
of major liver resection (defined as greater than two liver segments)
performed was higher in the PET-CT arm compared with the no
PET-CT arm (76% vs. 67%, respectively). Preoperative staging PET
CT improves survival in patients with resectable liver metastases
primarily by demonstrating the presence of extrahepatic metastases,
thereby identifying patients with inoperable disease who would not
benefit from undergoing surgical resection and may instead benefit
from neoadjuvant chemotherapy. Thus, these data support the use of
FDG-PET CT before hepatic surgery among patients with otherwise
resectable CRC liver metastases, as identified on CT scan or MRI.
FDG-PET CT is highly accurate for detection of liver metastases on a
per-patient basis but less accurate on a per-lesion basis. Notably, PET
CT is limited in its ability to demonstrate lesions smaller than 1 cm;
these lesions are best detected with MRI. PET CT may be especially
useful in guiding liver biopsies, ablations, or hepatic resections in
patients with indeterminate or suspicious findings on CT. PET CT is
also used to detect occult recurrence and liver metastases in patients
with a history of CRC, rising or abnormal CEA level, and otherwise
negative imaging studies.
The Ontario Clinical Oncology Group (OCOG) performed
a follow-up study evaluating long-term oncologic data (cancer
recurrence events and death) for 7 years after the last day of follow-up of the original PET-CAM trial. However, they found no
difference in median disease-free survival or OS between both trial
arms among those patients who underwent liver resection. Most
first recurrences were isolated to one organ site, primarily the lung
or the liver, and the majority of recurrences happened more than
1 year following liver resection. These results are similar to prior
published literature.
FDG-PET MRI
The use of FDG-PET combined with MRI has recently been introduced
as a diagnostic method of detecting CRC metastasis. One retrospective
study demonstrated the added value of PET MRI to CT to detect extrahepatic CRC metastasis, whereas another study reported that PET MRI
can improve the limited sensitivity of PET CT to detect small lesions. In
general, the combination of PET and MRI can improve the detection of
both intra- and extrahepatic lesions over PET CT alone.
CONCLUSION
The imaging modalities of CT and MRI remain mainstays of the
initial diagnosis, workup, and preoperative planning in management
of CRC. Hybrid imaging modalities combining PET and either CT or
MRI continue to evolve and has proven utility in a select population
of CRC patients. Although CT and MRI are the preferred modalities
in detecting extrahepatic and hepatic metastasis, the combination of
functional and anatomical imaging modalities such as FDG-PET CT
and/or FDG-PET MRI can improve the diagnostic detection of intrahepatic and extrahepatic CRC metastases and aid in the preoperative
evaluation of CRC.
Hazhirkarzar B, Khoshpouri P, Shaghaghi M, et al. Current state of the art
imaging approaches for colorectal liver metastasis. Hepatobiliary Surgery
and Nutrition. 2020;9(1):35.
Mainenti PP, Stanzione A, Guarino S, et al. Colorectal cancer: Parametric
evaluation of morphological, functional and molecular tomographic
imaging. World Journal of Gastroenterology. 2019;25(35):5233.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice
Guidelines in Oncology. Plymouth Meeting (PA): National Comprehensive
Cancer Network; 2021 Colon Cancer. Version 2.2021: colon.pdf (nccn.
org). Rectal Cancer. Version 1.2021: rectal.pdf (nccn.org).
LARGE BOWEL
Colon Carcinoma
% Relative Survival
Months
IIIA
IIIB
IIIC
Months
Rectal Carcinoma
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259
Neoadjuvant and
Adjuvant Therapy
forColorectal
Cancer
Yilin (Linda) Cao, MD, and Nilofer Azad, MD
olon and rectal cancer, or colorectal cancer (CRC), is a common
disease in the United States with an estimated 104,610 new cases
C
of colon cancer and 43,340 new cases of rectal cancer in 2020. The
lifetime risk of developing CRC is approximately 1 in 23 (4.4%) for
men and 1 in 25 (4.1%) for women. Although the mortality and
incidence rates have been declining over the last few decades, CRC
remains the second leading cause of cancer-related deaths in the
United States, expected to cause nearly 53,000 deaths during 2021.
Moreover, deaths from CRC among individuals under the age of 55
have actually increased 1% annually from 2008 to 2017.
For early-stage CRC (stages I–III), surgical resection remains the
basis of curative treatment. Distant recurrence, despite appropriate
surgical resection, increases based on stage and is thought to be due
to micrometastatic disease that is not readily detectable by current
methods. For this reason, neoadjuvant and adjuvant therapies are often
utilized to target micrometastases with the goal of complete eradication and prolonged survival. The challenge lies in determining which
patients will benefit from additional therapy beyond surgical resection.
The decision to add neoadjuvant or adjuvant therapy is based in large
part on evaluating risk factors, which take into consideration not only
clinical tumor stage but also patient-specific data like clinicopathologic
features, such as lymphovascular invasion, and molecular profiling,
such as microsatellite instability (MSI) status. Adjuvant and neoadjuvant therapeutic approaches to CRC are different for colon versus
rectal cancer and are discussed separately in this chapter.
STAGING
Formal CRC staging is essential to risk stratification for guiding clinician treatment decisions for individual patients. Guidelines from the
National Comprehensive Cancer Network (NCCN) for preoperative
workup of newly diagnosed CRC should include the following: colonoscopy (plus consideration of rigid proctoscopy for rectal cancer)
with biopsy and pathology review; complete blood counts, chemistry
profile, and carcinoembryonic antigen (CEA) serum level; and computed tomographic (CT) scan of chest, abdomen, and pelvis for colon
cancer versus CT chest with magnetic resonance imaging (MRI) of
the abdomen and pelvis with contrast for rectal cancer. Endorectal
ultrasound for rectal cancer is no longer indicated unless a patient
has contraindications to MRI, such as an incompatible pacemaker.
Preoperative staging is particularly important in rectal cancer because
it determines whether patients receive neoadjuvant radiation therapy
(RT), with the goal of both improved long-term local control as well as
down-staging, allowing for less morbidity from curative surgical resection. Per the 2021 NCCN Guidelines, positron emission tomography
is not recommended. CRC is staged based on the TNM staging system
(T, primary tumor; N, regional lymph nodes; M, distant metastasis)
adopted by the American Joint Committee on Cancer (AJCC). In the
most recent version of the AJCC Cancer Staging Manual (eighth edition, 2017), several modifications were made to assist clinicians with
prognostication, including the additional subdivision of M1c, which
qualifies peritoneal carcinomatosis as a poor prognostic factor; clarification as to how tumor deposits in lymph nodes are defined; reintroduction of the “L” and “V” elements to better identify lymphatic and
vessel invasion; and the identification of MSI status, KRAS, NRAS, and
BRAF mutations as additional prognostic and predictive factors. The
importance of accurate staging is reflected in Figure 1, which outlines
the predicted 2-year overall survival rates by stage.
Colon Cancer
Stage II Colon Cancer
Adjuvant chemotherapy in stage II disease remains controversial
due to a lack of demonstrated survival benefit in subset analyses of
large clinical trials encompassing stage II–III colon cancer patients.
However, stage II colon cancer is a highly heterogeneous group, and
accordingly, stratification into a low-risk and high-risk group has been
established. Based on NCCN 2021, high-risk factors for recurrence
include poorly differentiated/undifferentiated histology, lymphovascular invasion, perineural invasion, emergency presentation such as
bowel obstruction or perforation, inadequate lymph node sampling
(<12 nodes in the surgical specimen), tumor budding, and indeterminate/close/positive margins. Tumor budding is the presence of single
tumor cells or small clusters of tumor cells in the stroma at the invasive
front of the tumor (i.e., “buds” that have detached from the main mass)
and is thought to reflect epithelial-mesenchymal transition.
Unfortunately, there is currently no consensus for interpreting
the relative importance of these diverse factors and how each should
impact adjuvant chemotherapy selection in stage II disease. Studies
do suggest that pT4 staging may be one of the most prognostic of
these factors, with T4 accounting for a loss of 10% to 15% in 5-year
overall survival (OS) compared with T3. A particularly pertinent
risk factor within the surgeon’s purview is that of lymph node sample
size. The minimum number of 12 noted in NCCN stems from a 1989
publication reporting that this was an adequate number to determine
node positivity in 94% of specimens. Furthermore, the importance
FIG. 1 Survival by stage for colon and rectal cancer patients in the SEER database since 2010. (Data from AJCC Cancer Staging Manual. 8th ed. New York:
Springer; 2017.)
100
80
60
40
20
0
012
24 012
% Relative Survival
100
80
60
40
20
I
IIA
IIB
IIC
0
24
IV
260 NEOADJUVANT AND ADJUVANT THERAPY FORCOLORECTAL CANCER
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of adequate lymph node sampling was demonstrated clinically by the
Intergroup 0089 study, which found an absolute 5-year OS difference
of 14% in stage II patients who had <10 negative lymph nodes examined compared with those with >20. These data and similar patterns
demonstrated by other studies may be enough to warrant surgical reassessment in cases of particularly low-yielding lymph node dissection.
Generally, the presence of any of these high-risk features supports at least the consideration of adjuvant chemotherapy in stage
II patients. The most common regimens are 6 months of FOLFOX
(folinic acid, 5-FU, and oxaliplatin) or 3 months of XELOX (also
known as CAPOX, capecitabine and oxaliplatin). An analysis of
high-risk stage II patients from four of the six studies in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration published in 2021 found that, while noninferiority of 3 vs.
6 months of therapy could not be demonstrated, the decreased cost
and toxicity of 3 months of adjuvant therapy made it a reasonable
choice in this population given the small relative difference in outcomes. DNA mismatch repair status is another emerging prognostic
factor, where MSI-high (i.e., mismatch repair deficient or dMMR)
tumors portend a survival advantage, favoring observation over
adjuvant therapy due to high rates of resistance.
There are also molecular assays that predict recurrence of CRC in
the stage II setting. Five assays are commercially available, with the
most data available for Oncotype-DX colon, a 12-gene recurrence
score that has been validated to predict recurrence in mismatch repair
proficient stage II disease. However, the assay has not been validated to
show which patients benefit from adjuvant therapy. Multiple assays are
in development and will require prospective studies to show that they
have both a prognostic and predictive benefit, the latter of which could
help in clinical decision making regarding adjuvant therapy.
Stage III Colon Cancer
In stage III colon cancer, adjuvant chemotherapy has been the standard of care since 1990, with several large randomized clinical trials
showing benefits in both OS and disease-free survival (DFS). The
addition of adjuvant chemotherapy to surgical resection in patients
with stage III colon cancer leads to an approximately 40% to 50%
reduction in recurrence and 22% to 32% reduction in mortality.
The National Surgical Adjuvant Breast and Bowel Project (NSABP)
C-01, conducted from 1977 to 1983, was the first trial to demonstrate
5-year OS benefit for adjuvant therapy in colon cancer, specifically
with the regimen of semustine, vincristine, and 5-FU (MOF). The
NSABP C-03 trial, along with other similar studies, later demonstrated inferiority of MOF to intravenous 5-FU/LV regimens.
The benefit of the addition of oxaliplatin to 5-FU/LV (i.e., to
become modern-day FOLFOX) was demonstrated by the MOSAIC
trial. The primary endpoint of 5-year DFS was significantly higher
with FOLFOX (73% vs. 67%, hazard ratio [HR]: 0.8). However, this
came at the cost of increased rates of febrile neutropenia, peripheral
neuropathy, and grade 3 to 4 diarrhea. OS rates were significantly
higher for stage III disease (60% of the cohort) with FOLFOX but
not in stage II disease. Subsequently, when capecitabine was combined with oxaliplatin (i.e., XELOX or CAPOX) in the NO16968 trial
and compared with bolus 5-FU/LV, this demonstrated significantly
improved 7-year DFS (63% vs. 56%, HR: 0.8), which translated to a
7-year OS benefit.
The current recommendation for adjuvant therapy for stage III
colon cancer is 3 to 6 months of an oxaliplatin-containing regimen
such as FOLFOX or XELOX. The IDEA collaboration analyzed six
randomized trials of 3 versus 6 months of oxaliplatin-based adjuvant
therapy. Results suggested that 6 months of therapy remains the
standard of care for high-risk stage III colon cancer (T4N1-2; or
any N2 disease). However, in low-risk disease (T1-3N1), 3 months
of XELOX is considered noninferior to 6 months while conferring
significantly less neuropathy. For patients with significant comorbidities, peripheral neuropathy, or age greater than 70 years, 3 to 6
months of infusional 5-FU/LV or capecitabine without oxaliplatin
can be considered.
As new biomarkers and predictors of recurrence/prognosis are
discovered and more antineoplastic agents are developed, recommendations will continue to be updated. A promising tool in its infancy is
the use of cell-free DNA (cfDNA) for minimal residual disease detection after surgery to guide adjuvant therapy. One biomarker study by
Tie et al. in 100 stage III colon cancer patients found that detectable
cfDNA in postoperative plasma samples was significantly associated
with inferior recurrence-free survival (HR 3.8), which remained independently predictive after adjusting for known clinicopathologic risk
factors. Tools such as this will likely lead to more highly individualized
cancer therapy algorithms in the coming years, but a graphical summary of current clinical decision making can be found in Figure 2.
RECTAL CANCER
Although rectal cancer has similar pathogenesis and molecular
phenotypes to colon cancer, local recurrence rates in rectal cancer
are significantly higher than in colon cancer. This discrepancy may
be secondary to differences in both tumor factors, such as vasculature and lymphatic drainage patterns associated with the anatomic
location, and surgical factors, such as completeness of mesorectal
excision and extent of lymphadenectomy. As many as 10% of patients
with T1 or T2 rectal cancer, 15% to 35% of patients with T3N0 rectal
cancer, and 45% to 65% of patients with node positive T3 or T4 rectal cancer will experience local recurrence with standard resection,
which can be significantly decreased with total mesorectal excision
(TME) and neoadjuvant or adjuvant radiation.
In terms of the adjuvant/neoadjuvant therapy approach, two
significant factors distinguish the management of rectal cancer from
colon cancer. The first is that, in rectal cancer, there has been increasing emphasis of neoadjuvant as opposed to adjuvant therapy, termed
“total neoadjuvant therapy” or TNT. The second is that RT and
radiation therapy with concurrent chemotherapy (chemoRT) play a
significant role in rectal cancer, whereas it is not standardly indicated
in colon cancer. Concurrent chemotherapy refers to chemotherapy
that overlaps the RT course (altogether termed chemoRT), which is
delivered at lower than standard doses to help potentiate the ability
of RT to kill tumor cells, or “radiosensitization”.
Adjuvant Therapy for Rectal Cancer
Although neoadjuvant therapy is now the standard of care, historically, adjuvant therapy was intended to address the high rates of local
recurrence and low rates of survival in rectal cancer. In 1985, the
Gastrointestinal Tumor Study Group (GITSG) published a prospective
randomized control trial of 227 patients with T3-4 or node-positive
disease and negative margins on resection who were randomized to
(1) surgery alone, (2) post-op bolus 5-FU/lomustine, (3) post-op RT
alone, or (4) post-op chemoRT with 5-FU followed by 5-FU/lomustine. In this trial, recurrence rates were significantly reduced with combined chemoRT (33%) versus observation (55%), and OS was longer
for chemoRT as well, although it did not reach statistical significance.
It was not until the mid-2000s and the era of TME that the German Rectal Study established the role of neoadjuvant chemoRT in
cT3-4 or node-positive disease. It compared 50.4 Gy in 28 fractions
(∼5.5 weeks of RT) with concurrent infusional 5-FU preoperatively 6
weeks before TME to postoperatively 4 weeks after TME. All patients
had four cycles of IV bolus 5-FU after completion of trial arm therapy. Although the study did not show any benefit in the primary
endpoint of OS (∼60% at 10 years for both arms), several advantages of the neoadjuvant setting led to this becoming the prevailing
paradigm for chemoradiation therapy. Specifically, the study found
that the neoadjuvant arm had much higher compliance (90% vs.
50%), decreased nodal involvement rate (25% vs. 40%), significantly
improved acute and late grade ≥3 toxicity rates, 3% absolute reduction in 10-year local recurrence rate (7% vs. 10%), and improved
likelihood of sphincter-preservation surgery in those initially felt to
require abdominal perineal resection (39% vs. 19%).
Resected colon cancer
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LARGE BOWEL
261
Low-risk
No therapy
FOLFOX
CAPOX
or XELOX
FOLFIRI
Yes
Stage II
T4,
<12 LN,
perforation
No
dMMR,
MSI-H
No
Intermed.
risk
• Clinical
factors
• Molecular
markers
Stage III
Yes
High-risk
FOLFOX or
XELOX
5–FU/LV or
capecitabine
FOL = Folinic acid (Leucovorin)
F = Fluorouracil
OX = Oxaliplatin
CAP = Capecitabine
OX = Oxaliplatin
FOL = Folinic acid (Leucovorin)
F = Fluorouracil
IRI = Irinotecan
Age >70,
Borderline PS
5FU/LV
FIG. 2 Algorithm for use of adjuvant treatment for colon cancer. dMMR, Defective mismatch repair; LN, lymph nodes; MSI-H, microsatellite instability high;
PS, performance status.
Neoadjuvant Therapy for Rectal Cancer
Currently, the majority of United States cancer centers utilize a combined modality approach to neoadjuvant therapy with radiotherapy
(50.4 Gy total radiation dose over the course of ∼5.5 weeks) and
concurrent chemotherapy (5-FU/LV or capecitabine), followed by
surgical resection 4 to 6 weeks after completion of chemoRT. An
emerging alternative strategy that is quickly gaining increasing utilization is short-course (or hypofractionated) radiotherapy of 5 Gy × 5
fractions (25 Gy total dose), which is not delivered with concurrent
chemotherapy but is generally followed by a variable number of
cycles of neoadjuvant chemotherapy. The need for adjuvant chemotherapy after TNT is still being assessed, with recent trials described
in the following sections suggesting that it may not be necessary.
RT is most clearly indicated in stage II–III rectal cancers (i.e.,
T3-4 disease or node-positive disease). The goal of RT is two fold:
to shrink the primary disease and to sterilize the draining lymph
nodes. The typical radiation field will cover the perirectal, presacral,
and internal iliac lymph nodes to a dose of 45 Gy followed by a more
focused field on the primary tumor and mesorectum to 50.4 Gy
when using standard chemoRT. For the short-course RT approach,
the entire volume receives 25 Gy over 5 fractions (Fig. 3). If there
is tumor extension to the prostate or vagina, one would consider
adding the external iliac nodal region to the RT treatment volume
FU = Fluorouracil
LV = Leucovorin (Folinic acid)
as well. The Polish II trial established oncologic equivalence of neoadjuvant short-course RT and standard chemoRT in patients with
cT3-4 disease, with no difference in sphincter preservation, local
recurrence, and disease-free or overall survival. Short-course RT was
associated with significantly lower grade ≥3 acute toxicity, but both
regimens are considered to be acceptable and largely dependent on
institutional practice preferences.
Preoperative therapy offers the opportunity to achieve pathologic
complete response, with rates as high as 12% to 16% in the aforementioned Polish II trial. There has been increasing interest in modifying
perioperative therapy to optimize pathologic complete response
(pCR) rates and oncologic outcomes, potentially even opening a
window for patients who may qualify for nonoperative treatment
strategies aimed at organ preservation. The Timing of Rectal Cancer
Response to Chemoradiation Consortium designed a phase II trial to
investigate the effect of extending the interval between neoadjuvant
chemoRT and surgery while administering additional chemotherapy
(modified-FOLFOX) during the waiting period. Nearly 300 patients
with stage II–III locally advanced rectal cancer were assigned to four
treatment groups ranging from standard therapy (chemoRT followed
by TME in 6–8 weeks), to groups receiving two, four, or six cycles of
mFOLFOX6 following chemoRT. The pCR rate increased linearly
by number of chemotherapy cycles, ranging from 18% in standard
262 NEOADJUVANT AND ADJUVANT THERAPY FORCOLORECTAL CANCER
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FIG. 3 An example of a preoperative short-course radiation therapy field for rectal cancer, including the perirectal, presacral, and internal iliac nodes (blue
colorwash) and gross disease (red colorwash).
chemoRT alone to 38% in the group receiving six additional cycles
of neoadjuvant mFOLFOX. This promising data encouraged further
studies in TNT. The RADIPO trial enrolled 920 patients with highrisk, locally advanced rectal cancer based on pelvic MRI features.
Patients received 50 to 50.4 Gy of chemoRT with concurrent oral
capecitabine and postoperative chemotherapy (XELOX or FOLFOX)
vs. the experimental arm of short-course RT followed by preoperative chemotherapy. The 3-year treatment failure rate was significantly
lower in the experimental arm (23.7% vs. 30.4%). The PRODIGE
23 trial corroborated the improvement in oncologic results with
TNT, although it utilized a more rigorous chemotherapy regimen
The “watch and wait” strategy for organ preservation has also gained
increasing academic interest. A case series of 113 patients at Memorial Sloan Kettering who elected for a watchful waiting approach after
clinical complete response to neoadjuvant therapy demonstrated
excellent rectal preservation and pelvic tumor control rates (82% and
91%, respectively). However, when compared with a surgical group
that achieved pCR, the watchful waiting group had worse overall
survival (73% vs. 94%), potentially owing to a high rate of distant
metastasis in patients who had local recurrence (36%). These data
suggest that better tools for risk stratification are necessary to iden-
tify optimal candidates for organ preservation strategies.
(FOLFIRINOX), and chemoRT therapy in both arms and allowed
both low- and high-risk rectal cancer, with a 7% absolute benefit in
3-year DFS for the neoadjuvant group. These key trials for TNT are
summarized in Table 1.
Treatment deescalation is also being actively investigated. Currently, a large phase III randomized prospective trial (PROSPECT-N1048) is ongoing to assess R0 resection rate and DFS for
neoadjuvant chemotherapy alone vs. chemotherapy plus RT in
patients with locally advanced rectal cancer (T2N1, T3N0, T3N1).
SURVEILLANCE
Despite the ever-evolving therapies for CRC, distant and local recurrence rates can be as high as 40%, with the majority of recurrences
occurring in the first 2 years after completion of initial definitive
therapy. Early identification of recurrence or new primary tumors
may allow for potentially curative therapy (surgical resection or systemic therapy) and improved outcomes. For this reason, appropriate
TABLE 1 Key Trials Investigating Total Neoadjuvant Therapy in Rectal Cancer
Neoadjuvant Treatment
Trial Patient Population
RAPIDO 920 high-risk
patients*
Regimen
Short course RT CAPOX 6c or
FOLFOX 9c surgery
vs.
ChemoRT surgery optional
adjuvant chemo
TIMING 259 patients w/ T3-4,
N1-2 disease <12 cm
from anal verge
PRODIGE 23 461 patients w/ cT3-4
disease <15 cm
from anal verge
Concurrent chemoRT with
5-FU FOLFOX for 0c, 2c,
4c, or 6c surgery
FOLFIRINOX × 6c concur-
rent chemoRT with capecitabine surgery adjuvant
FOLFOX × 3c
vs.
Concurrent chemoRT sur-
gery adjuvant chemo × 6
months
*High risk was defined as at least one of the following MRI features: cT4, cN2, enlarged lateral lymph nodes, extramural vascular invasion, or mesorectal fascia
involvement.c, Cycles; CAPOX, capecitabine and oxaliplatin; FOLFOX, folinic acid, fluorouracil, oxaliplatin; FOLFIRINOX, folinic acid, fluorouracil, irinote-
can, oxaliplatin; pCR, pathologic complete response; TNT, total neoadjuvant therapy.
Time to
Surgery pCR Rate Result
4–6 weeks 28% vs. 14% No differences in complication
rates, TNT improved pCR
and 3-yr disease-related failure rates
6–8 weeks 0c = 18%
2c = 25%
4c = 30%
6c = 38%
No significant differences in
surgical complications when
bridging with FOLFOX during
increasing interval to surgery
6–8 weeks 28% vs. 12% Significant improvement in
3-yr disease-free survival and
increased pCR rate with neoadjuvant FOLFIRINOX
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263
aggressive surveillance is imperative. Although there are subtle differences among professional organizations, most guidelines are generally in line with those published by NCCN.
For patients with stage I–III colon or rectal cancer, recommended
surveillance is colonoscopy 1 year after resection, with subsequent
colonoscopy in 3 years, then followed by every 5 years assuming
no advanced adenomas are detected. For patients with rectal cancer
who underwent transanal local excision only, the addition of proctoscopy with endoscopic ultrasound scan or MRI with contrast is
recommended every 3 to 6 months for the first 2 years, then every 6
months through year 5.
For patients with stages II–III colon or rectal cancer, serum CEA
is recommended every 3 to 6 months for 2 years, then every 6 months
until year 5. CT chest, abdomen, and pelvis should be performed
Management of
Colorectal Polyps
Gifty Kwakye, MD, MPH, and Genevieve B. Melton-Meaux,
MD, PhD
OVERVIEW
Colorectal cancer (CRC) remains the second leading cause of cancer
deaths in the United States for men and women combined. Rates of
early-onset CRC have also increased steadily over the past several
decades, with 1 in 10 CRC patients diagnosed under the age of 50
years associated with a 58% greater risk of presenting with late-stage
disease than their older counterparts. Identifying and removing premalignant colorectal polyps forms the basis of CRC screening programs using a variety of approaches. Of those approved by governing
bodies, colonoscopy is the only one that allows for both detection
and simultaneous removal of polyps, facilitating CRC prevention.
A colorectal polyp is a macroscopically visible lesion or mass that
results from pathologic epithelial elevation of the colonic mucosa.
Several other lesions can present as luminal masses, such as lipomas,
carcinoid tumors, and leiomyomas. These lesions are covered by normal mucosa and, by definition, are not polyps. Most colonic polyps are
asymptomatic; however, they are of clinical concern because of their
malignant potential. The term polyp is nonspecific, and the importance of any one colorectal polyp is based on its histopathology, which
determines the patient’s risk of malignancy and, therefore, further
treatment and follow-up. Colorectal polyps can be classified as either
sporadic (approximately 60%) or hereditary, with the latter comprising
a variety of familial syndromes that are potentially malignant conditions. A variety of approaches are used to address polyps, as outlined.
HISTOPATHOLOGY OF POLYPS
Adenomas
Adenomas are the most common neoplastic polyp identified in
patients undergoing colonoscopy, representing 50% to 65% of all
colonic polyps. Of sporadic CRC, approximately 80% develop from
adenomas. The adenoma-carcinoma sequence, also known as the loss
of heterozygosity or chromosomal instability pathway, is a cascade of
sequentially accumulated genetic mutations (Fig. 1). Approximately
10% to 25% of asymptomatic patients at average risk and older
than 50 years of age have an adenomatous polyp. The histology of
these adenomas is most commonly tubular (65% to 85%), but they
every 6 to 12 months for 5 years. Positron emission tomography/CT
is not indicated for routine surveillance.
S u g g e S t e d R e a d i n g S
André T, Meyerhardt J, Iveson T, et al. Effect of duration of adjuvant che-
motherapy for patients with stage III colon cancer (IDEA collaboration):
final results from a prospective, pooled analysis of six randomised, phase
3 trials. Lancet Oncol. 2020;21(12):1620–1629.
Iveson TJ, Sobrero AF, Yoshino T, et al. Duration of Adjuvant Doublet
Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal
Cancer. 2021;39(6):631–641, https://doi.org/10.1200/JCO2001330.
Kong JC, Soucisse M, Michael M, etal. Total Neoadjuvant Therapy in Locally
Advanced Rectal Cancer: A Systematic Review and Metaanalysis of
Oncological and Operative Outcomes. Ann Surg Oncol. 2021;2021:1–11.
may also be tubulovillous (10%–25%) or villous (10%). Advanced
adenomas are those that are greater than 1 cm or having a villous
architecture, severe dysplasia, or carcinoma. The prevalence rate of
advanced adenomas ranges from 3.5% to 9.5%, depending on gender
and age. Identification of an adenoma should prompt a complete
colonoscopy because of the 20% to 40% risk of proximal neoplastic
lesions. Recommendations for follow-up colonoscopy are made
based on the number, size, and histopathology of the adenomas and
other clinical factors such as personal risk factors and family history.
Removal of adenomas reduces future CRC and the development of
advanced adenomas.
Serrated Polyps
In addition to the adenoma-carcinoma sequence, an increasingly
recognized CRC carcinogenesis process is the serrated pathway (see
Fig. 1). In fact, recent studies show that prevalence of serrated polyps
in average-risk individuals is as high as 20% to 40%, accounting for
almost 25% of sporadic CRCs. As outlined by the updated World
Health Organization (WHO) classification system, serrated polyps
include hyperplastic polyps (HPs), sessile serrated lesions (SSLs) and
traditional serrated adenomas (TSAs). HPs are small, diminutive
polyps, typically located in the left side of the colon and are identified
by the absence of SSL architectural features on pathology. They have
traditionally been thought of as benign but in special situations can
have an increased malignant potential. These include large size (>1
cm diameter), location in the right colon, mixed adenoma/hyperplastic histology, more than 20 hyperplastic colonic polyps, familial
hyperplastic polyposis, and a family history of CRC.
SSL is the recommended terminology for polyps previously called
sessile serrated adenoma, sessile serrated polyp, or sessile serrated
adenoma/polyp. Unlike HPs, SSLs have crypt distortion, presence
of mucosal prolapse, or stromal proliferations. TSAs have distinct
features that include ectopic crypts with narrow slits, prominent
eosinophilic cytoplasm, and penicillate nuclei. Serrated polyposis
syndrome can occur, characterized by the presence of either (1) ≥5
serrated lesions/polyps proximal to the rectum, all being ≥5 mm in
size, with ≥2 being ≥10 mm in size or (2) >20 serrated lesions/polyps
of any size distributed throughout the large bowel, with ≥5 being
proximal to the rectum.
Hamartomas
A hamartoma is an outgrowth composed of normal mature cells
that originate from below the mucosa. When sporadic, hamartomas
264 MANAGEMENT OF COLORECTAL POLYPS
Adenomatous pathway
Serrated pathway
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K-ras
activation
methylation
FIG. 1 Colorectal carcinogenesis pathways.
p16
Intermediate
adenoma
serrated lesions
inactivation
Normal
mucosa
APC
BRAF
mutation
Early
adenoma
Microvesicular
hyperplastic
polyps
are frequently called juvenile polyps because they are relatively
common in children. This second histologic category of colorectal
polyps is mostly associated with one of three autosomal-dominant
familial syndromes: Peutz-Jeghers syndrome, juvenile polyposis,
and Cowden’s syndrome. Although sporadic hamartomatous polyps
are not considered premalignant, the familial syndromes have a
significant rate of cancer development; therefore patients with these
syndromes should undergo regular colonoscopic surveillance.
The typical phenotype of patients with Peutz-Jeghers syndrome
includes perioral hyperpigmentation and multiple hamartomatous
polyps located in the small or large bowel. These polyps may cause
intussusception, bleeding, or obstruction at a young age. After
the third decade, patients with Peutz-Jeghers syndrome have a 2%
to 13% risk of gastrointestinal (GI) cancer and therefore should
undergo regular endoscopic surveillance.
Juvenile polyposis is diagnosed when a young patient has 10 or
more hamartomatous GI polyps. Lesions may occur anywhere within
the GI tract, although they are frequently in the colon. These polyps
may twist and auto-amputate, causing bleeding. Colon cancer affects
up to 50% of those afflicted with juvenile polyposis and may occur
in the fourth decade of life.
Cowden’s disease, also known as multiple hamartoma syndrome,
is characterized by hamartomatous neoplasms of the skin and
mucosa, GI tract, bones, central nervous system, eyes, and genitourinary tract. A significant risk exists for skin, thyroid, endometrial, and
breast cancer in Cowden’s syndrome. Emerging evidence suggests an
increased incidence of CRC as well.
TECHNIQUES FOR EXCISING POLYPS
Colonoscopic Approach
Polypectomy has proven to be an effective means of CRC prevention,
allowing for identification, removal, and histopathologic evaluation
of polyps. Most colorectal polyps are treated with endoscopic polypectomy, either with biopsy forceps or snare polypectomy, both of
which can be either hot with electrocautery or cold. Snare excision
typically provides a larger specimen, and the stalk (or base) can be
evaluated histopathologically to better define the level of superficial
malignancy if present. Large lesions may be removed with a piecemeal excisional technique, which allows for sequential excision of the
entire lesion or en bloc with more advanced endoscopic techniques
described in the next section.
Relative contraindications to colonoscopic polypectomy include
anticoagulation therapy, bleeding diathesis, acute colitis, and
Sessile
DCC
inactivation
CDKN2A
MLH1 methylation
TGFβ mutation
Advanced
adenoma
p53
inactivation
Carcinoma
Microsatellite stable (MSS)
Carcinoma
Microsatellite Instability
High (MSI-H) Carcinoma
evidence of invasive malignancy, such as central ulceration, a hard or
fixed lesion, necrosis, or inability to raise the lesion with submucosal
injection.
Complications related to colonoscopic polypectomy are
uncommon and typically minor. The risk of death is 1 in 14,000.
The most common serious complications are bleeding and
perforation. Bleeding occurs in 4.8 in 1000 patients after colonoscopic polypectomy and may occur immediately or days later
when clot dissolution occurs. Most post-polypectomy bleeds stop
spontaneously and, when persistent, can usually be controlled
with endoscopic clipping or cauterization. Rarely, interventional
angiography or colectomy is necessary. Bleeding risk should be
minimized by stopping warfarin and aspirin 5 days before polypectomy and clopidogrel 7 days before and possibly holding these
agents for several days after polypectomy, although stopping any
of these agents must be tailored to the patient’s risk profile (e.g.,
patient with a mechanical mitral valve with a high risk of stroke
off anticoagulation therapy).
Colonic perforation after conventional polypectomy occurs in
0.1% of patients, most of whom undergo successful treatment with
conservative therapy that includes inpatient observation, bowel rest,
and intravenous antibiotics. These patients must be followed closely
as inpatients for any sign of clinical deterioration warranting laparotomy. One alternative approach is early laparoscopic primary repair of
the defect, with colonoscopic assistance if the perforation is not easily
identified on laparoscopy. The patient should be in the lithotomy
position, and if colonoscopy is necessary, minimal insufflation with
carbon dioxide should be used. Contraindications to this approach
include peritonitis, malignancy, and the presence of significant fecal
soilage.
Post-polypectomy syndrome has been reported to occur in up to
0.3% of patients after polypectomy, most often when cauterization
has been used. The etiology is believed to be that the cautery causes a
microperforation in the colonic wall and results in bacterial translocation. Patients typically present anywhere from 0 to 3 days after the
polypectomy with abdominal pain and tenderness, fever, and leukocytosis. On computerized tomographic scan, fat stranding is typically
seen in the mesentery, and the colonic wall of the polypectomy site
is thickened; however, unlike with colonic perforation, pneumoperitoneum is not present. Patients should be treated with bowel
rest, intravenous antibiotics, and close observation until symptoms
resolve. Recognition of post-polypectomy syndrome is important to
avoid unnecessary laparotomy in these patients, who may present
with localized peritonitis.
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CBA
FIG. 2 Endoscopic mucosal resection (EMR) of a large multilobar colonic polyp. (A) Polyp. (B) Injection of a lifting agent. (C) Resection bed after polyp
removal. (Photographs courtesy Dr. Allison Schulman, Advanced Gastrointestinal Endoscopist, University of Michigan).
265
Endoscopic Mucosal Resection
Initially described in Japan, endoscopic mucosal resection (EMR)
is one of two advanced endoscopy techniques gaining traction
that allows for removal of large superficial polyps within the GI
tract. A solution is injected into the submucosa, right underneath
the polyp (Fig. 2). This raises the mucosal layer, facilitating better encirclement with the snare device. Solutions typically used
include saline (normal or hypertonic), glycerol, hyaluronic acid,
and diluted epinephrine. EMR improves the safety of polypectomy
by increasing the distance between the mucosa and the muscularis
propria. It is critical to tattoo the area with India ink when large or
suspicious polyps are removed because typically further endoscopic
evaluation or resection is indicated. For larger lesions, a piecemeal
polypectomy typically still occurs because of the limitations of the
procedure. This affects the ability to perform accurate pathologic
staging, resulting in the need for a segmental colectomy that could
potentially have been avoided.
Endoscopic Submucosal Dissection
Compared with EMR, endoscopic submucosal dissection (ESD)
better allows for en bloc resection of even large polyps. The border of the polyp is typically marked by injecting indigo carmine.
The polyp is then lifted with introduction of solution into the
submucosal layer, like in EMR. Using special endoscopic knives
and electrocautery, the lesion is excised in one piece. Because of
violation of the submucosal layer, bleeding is quite common and
can be easily controlled with electrocautery or placement of endoscopic hemoclips. Caution should however be used when applying
any heat device in the thin-walled colon because this could lead to
perforation. Although ESD allows for en bloc polyp excision consistent with oncologic principles, it has a higher perforation rate,
takes longer to complete, and has a steeper learning curve, which
have affected widespread adoption.
Combined Endo-Laparoscopic Surgery
Even with advanced endoscopic techniques described earlier,
removal of large colonic polyps is not always feasible. Traditionally, these cases have been referred for segmental colectomy,
which has an associated increased risk for morbidity and, in select
patients, even mortality. In combined endo-laparoscopic surgery
(CELS), endoscopic resection of the polyp is performed while
manipulating the bowel laparoscopically by either invaginating
the bowel wall to allow for easier polyp snaring or mobilizing the
bowel to improve reach endoscopically. One of its advantages is
immediate detection of full-thickness bowel injury, which can be
repaired laparoscopically in experienced hands. However, it is
limited by the challenges presented by combining two very different techniques. For instance, insufflation of the bowel lumen
endoscopically might limit the ability to visualize and maneuver
laparoscopic instruments, increasing the risk for injury to underlying intraabdominal structures. Clamping the terminal ileum
during endoscopic insufflation could limit distension of the small
bowel but fails to address colonic distension. At the end of the
case, an air leak test can be performed to identify any injury not
detected previously. With careful patient selection, CELS has been
shown to be successful in 70% to 97% of cases.
Surgical Approach
Large polyps or early rectal cancers not amendable to endoscopic
excision can be addressed using surgical techniques performed
transanally. These allow for complete en bloc excision of the lesion,
which is important for pathologic evaluation. This also potentially
avoids the morbidity and mortality of a more invasive low anterior
resection or abdominoperineal resection in patients with benign
disease or early cancers. The surgical approach used is determined
by location of the polyp relative to the anal verge. In addition to
routine history and physical examination, patients should have a
proctoscopy completed to assess the location of the polyp and its
size to assist with both patient positioning intraoperatively but also
choice of surgical technique to use. Placement of the patient in the
lithotomy position, prone with split legs or lateral decubitus should
be performed aiming to have the lesion located inferiorly in the 5
to 7 o’clock position. Orientation of the specimen once removed
needs to be always maintained in case additional margin(s) must be
resected after pathology review. An easy strategy to accomplish this
involves pinning the specimen to the white pad found in most surgical needle boxes and labeling the cardinal points with permanent
ink. Complications related to surgical polypectomy include urinary
retention, bleeding, infections, and bowel perforation. There is also
a chance for incomplete resection or need to convert to a different
more invasive approach. Both can be avoided with proper patient
selection following careful review of perioperative workup. The
surgery can be done as an outpatient or with a short period of inpatient observation depending on practice preferences.
Conventional Transanal Excision
For large polyps in the distal rectum, local excision has been shown
to be effective at complete removal, where lymph node sampling is
not required. Polyps amendable to standard conventional transanal
excision (TAE) must be located within 6 to 8 cm from the anal
verge, be <3 cm in size, and occupy less than 30% of the rectal
circumference. For known malignant polyps, recommendation is
to proceed with TAE in tumors with T1 depth of invasion only.
Because of the tendency for suboptimal visualization, higher rates
of positive margins and recurrence following conventional TAE
resections have been reported.
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Transanal Endoscopic Microsurgery
Transanal endoscopic microsurgery (TEM) allows for excision of
lesions higher up in the rectum than conventional TAE, including
up to the distal sigmoid colon per published reports. It requires a
reusable, rigid 4-cm-diameter proctoscope, which comes in either
a 12-cm or 20-cm length; a laparoscopic camera; and modified
angled laparoscopic instruments. The rigid platform has three
additional 5- to 9-mm ports through which instruments and a
suction device can be passed. CO
pneumorectum is established
2
through a port on the proctoscope to help maintain distension of
the bowel wall while operating. Electrocautery is used to demarcate a 5- to 10-mm margin around the lesion. Then, using an
instrument to grasp and adjust the distal edge, an energy device
is used to perform submucosal or full-thickness dissection of the
outlined area. For mainly posterior tumors, a partial resection of
the mesorectum can be performed en bloc with the polyp. Care
must be taken to avoid grasping the lesion directly because this
could result in tissue breakage. Also, it is important to remain
perpendicular to the lesion during dissection to avoid early
tunneling, which could compromise the deep margin. Once the
specimen is removed, hemostasis is achieved.
If a full-thickness excision was performed, it is recommended
that the defect be closed transversely using a running or interrupted
figure-of-8 absorbable suture. This tends to be a more time-consuming aspect of the procedure and requires some comfort with laparoscopic suturing to complete successfully. One could consider using
barbed suture (e.g., V-lock), a knot pusher, or laparoscopic suture
clips to eliminate the need to tie intracorporal knots, which can be
challenging. Studies show that lesions located anteriorly in the upper
or middle rectum tend to have a higher rate of intraperitoneal entry
during dissection. In experienced hands, this can be sutured closed
using the TEM platform with the patient placed in the steep Trendelenburg position to shift the bowel out from the pelvis. If unable, a
transabdominal approach might be required.
The main limitation of TEM is the cost of the equipment. In
addition, the rigid proctoscope can make it difficult to manipulate
instruments when operating, requiring a steep learning curve to
troubleshoot. Patients should complete a full bowel prep before the
procedure to avoid stool interfering with visualization during the
intraluminal portion of the case. This is also important if one anticipates a higher risk for intraperitoneal entry, with the potential need
for transabdominal surgery based on lesion location.
Transanal Minimally Invasive Surgery
Because of the limitations associated with TEM, transanal minimally
invasive surgery (TAMIS) was introduced as an alternative. It combines TEM principles with single-site laparoscopy, without the need
for expensive specialized equipment or complex learning curves. The
setup includes a flexible disposable single-site laparoscopic platform
along with standard laparoscopic cameras, insufflators, and instruments. The more commonly used GelPOINT Path access channel
comes in three lengths: 4 cm, 5.5 cm, and 9 cm. Channel length
selection again is based on lesion location from the anal verge. The
kit comes with self-retaining sleeves that are inserted into the gel
cap, which can accommodate 5- to 10-mm standard instruments,
in addition to frequently used needle sizes. Pneumorectum is established through a side port using standard insufflation equipment.
If available, the AirSeal device can be used instead with the added
advantage of providing stable bowel distension, even during suctioning activities. Dissection is performed in a similar fashion as in TEM.
Although the flexible platform allows easier maneuvering of instruments, the most challenging part of the procedure remains suturing
the defect close at the end of the case because of the confined intraluminal space. To navigate this issue, many have turned to using the
robotic platform with the TAMIS setup, capitalizing on the increased
degree of articulation at the wrist of the robotic instruments.
Even though most vendors offer a shorter channel length, lesions
in the distal rectum just above the dentate line might still be difficult
to resect completely because of the platform. A hybrid approach
using TAMIS for the proximal margin and then removing the platform to facilitate a conventional TAE can allow for complete excision
and closure of the defect.
APPROACH TO THE MALIGNANT POLYP
Up to 5% of polyps that appear benign contain invasive cancer. This
risk of cancer correlates with increasing polyp size such that polyps
greater than 2 cm have an approximately 30% risk of cancer. For this
reason, as mentioned previously, the colon should be tattooed at the
site of any large polyp or any suspicious polyp if further treatment
and evaluation are necessary.
Malignant polyps with deeper depth of invasion (i.e., >T1) have
increased risk for lymph node metastases and should proceed to
formal segmental resection. Even superficial or T1 early cancers can
have higher risk for lymph node involvement based on the location
within the polyp. To assist with risk prediction in this setting, the
Haggitt level and Kikuchi submucosal (Sm) classification systems
are used (Table 1). Haggitt levels 1 to 3 correspond with Sm1, but
Haggitt level 4 can be Sm1, Sm2, or Sm3. A malignant polyp with an
Sm3 classification is an indication for formal resection. Other factors
predictive of lymph node metastases or recurrence are high tumor
grade, extensive tumor budding, and lymphovascular invasion. In
the absence of any of these features, the risk of adverse outcome is
less than 1%; however, if a malignant polyp has one of these features,
the risk increases to 20%. If two or more of these adverse features
are present, the risk of adverse outcomes increases to 36%. Further
evaluation of these features may better define patients who can be
spared major surgery.
TABLE 1 Classification of Invasion Level
Haggitt Classification
(Pedunculated Polyps) Definition
1 Invades submucosa but lim-
2 Invades the neck of the polyp Sm2 Invades into the middle third of
3 Invades the stalk of the polyp Sm3 Invades into the lower third of
4 Invades the submucosa of the
Haggit 1-3 corresponds to Sm1. Haggit 4 corresponds to Sm1, Sm2, or Sm3 levels.
ited to the head of the polyp
bowel wall below the stalk
Kikuchi Classification
(Sessile Polyps) Definition
Sm1 Invades into the upper third of
the submucosa
the submucosa
the submucosa
Risk of Lymph
Node Metastasis
3%
8%
23%
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