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8 Cancer of the Small Intestine
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Yardenna Dolev, Yasmin Leshem, Nadir Arber & Ravit Geva
Oncology Unit, Tel Aviv Medical Center, Israel, Middle East
[See Chapters 23, 24 and 26 for GIST, Neuroendocrine and Lymphoma tumour management details].
Introduction
The prevalence of cancer in the small intestine is low, with an
incidence rate of 11 to 22 annual cases per one million people.
Altogether, this entity occupies approximately three percent
(Jemal 2008) of the working diagnoses in a general gastrointestinal (GI) oncology service (Bilimoria 2009). Yet, the incidence
has been rising in an average rate of 2.3% each year in the past
few years (Puccini et al. 2018). The low incidence is surprising,
considering that the small intestine epithelium makes up more
than 95% of the intestinal surface area. Moreover, unlike other
GI cancers that include mostly adenocarcinoma, the histology
of small intestine tumors is more diverse and comprises 45%
adenocarcinoma, 30% neuroendocrine cancers, 15% lymphoma, and 10% sarcoma; those are mostly gastrointestinal
stromal tumors (GIST). The prevalence of specific cancer types
is influenced by location. While adenocarcinoma is the leading
diagnosis in the duodenum, NET cancers are the leading diagnosis in the ileum. This chapter will focus mainly on adenocarcinoma of the small bowel while summarizing the current
knowledge in the field and will provide directions for diagnosis
and treatment.
Clinical Presentation and Diagnosis
The most frequent presenting symptom of small bowel tumors
is abdominal pain, which is present in 43 to 66 percent of cases
(Dabaja et al. 2004; Halfdanarson et al. 2010). Because of the
vagal innervation of the small bowel, the pain is often vague
and poorly localized. Other symptoms may include GI
bleeding, nausea, weight loss, bowel obstruction, and perforation. In most cases, symptoms are mild at first leading to a
protracted medical evaluation and diagnosis.
The evaluation of the small bowel is challenging because
of its length. Computerized tomography (CT) is a frequent
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
tool used to evaluate non-specific abdominal pain with a
sensitivity of 70–80 percent to small bowel tumors (Laurent
1991). CT enteroclysis is a more sensitive and hybrid technic
in which in addition to a CT scan, the small intestine is filled
with two types of contrast materials: Natural contrast media
such as water and positive contrast material such as barium.
Other means of direct visualization of the small intestine
are wireless video capsule endoscopy and double-balloon
enteroscopy.
Adenocarcinoma
Pathogenesis and Gene Analysis
Like colon cancer, it is believed that adenocarcinoma of the
small bowel is a result of adenoma to carcinoma transition
through a multistep accumulation of mutations. In support
of this assumption is the correlation between the size of
adenoma found in Small Bowel Adenocarcinoma (SBA) to
the risk of carcinoma in it. However, analysis of genome
alteration suggests that small bowel adenocarcinoma is a
unique entity. In a genomic analysis of GI adenocarcinoma
from 7559 patients including 6353 patients with ColoRectal Cancer (CRC), 889 patients with Gastric Carcinoma,
and 317 patients with small bowel tumors, it was demonstrated that the most frequent gene alteration in SBA were
P53 (58%), KRAS (53%), APC (26.8%), SMAD4 (17.4%),
PIK3CA (16.1%), CDKN2A (14.5%), ARID1A (12.3%). The
frequency of these genes was distinctively different from
both colonic and gastric adenocarcinoma. For example,
APC gene alteration in colonic adenocarcinoma was found
to be 75.9% in this analysis but a similar frequency of
KRAS gene alternation was found at around 50%. The frequency of KRAS in gastric adenocarcinoma was only 14.2%.
Microsatellite instability was found in 7.6% of SBA compared to 3.9% in CRC and 4% in GC. In addition, 9.5% of
this cohort had a high tumor mutational burden of more
than 20 mutations/Megabase. To note, 78% of the cohort
patients had metastatic disease (Schrock 2017).
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Predisposition
The development of SBA can be facilitated by exposure to
inflammation, carcinogen, or by germline gene alternation that
leads to hereditary cancer syndromes.
The hallmark of chronic inflammation is cell damage and
tissue repair resulting in accelerated accumulation of mutation
and cell growth. This explains why patients with conditions that
cause chronic inflammation are at high risk to develop SBA:
• Evidence (Frank and Shorey 1973) from the early 70s describes
a high prevalence of SBA in patients with longstanding Crohn’s
disease (Munkholm et al. 1993). When comparing (Hoffman
et al. 1977) Crohn’s-mediated SBA to non-enteritis-related
SBA, patients with Crohn’s are younger, have a less successful
cure, rise in a larger frequency in the ileum, and occur more
frequently. Although CRC prevalence has been reduced in the
last 30 years, small-bowel cancer in patients with Crohn’s has
not shown a significant reduction over the years and is still
with a high relative risk of 33 (Canavan et al. 2006).
• Celiac disease is another cause of inflammation with a higher
prevalence of SBA, (Rampertab et al. 2003) though these
patients might have better overall survival than patients with
non-celiac-associated SBA (Caio et al. 2019) adhering to a
gluten-free diet might be a protective manner regarding the
development of SBA in celiac patients (Green 2003).
Hereditary syndromes known to increase the risk for SBA
include Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
also known as Lynch syndrome, Familial Adenomatous
Polyposis (FAP), and Peutz-Jeghers. These three syndromes are
autosomal dominant, meaning a person is born with a mutation in one allele and the other is lost or silenced subsequently
in the tumor formed.
Of these, Lynch syndrome is the most common. In its hereditary form, a person is born with one allele of mismatch repair
(MMR) proteins missing and the other is lost in the tumor. This
results in a high level of microsatellite instability when a cell
divides, leading to an increased number of non-homologous
tumor mutations. The estimated lifetime risk to develop SBA
with Lynch syndrome is approximately 4% (Koornstra et al.
2008) However, most SBA lacking expression of MMR (defined
as dMMR) proteins do not have a genetic base (Suerink 2021).
In a cohort (Aparicio 2020) of 347 patients with small bowel
adenocarcinoma, approximately 20 percent had a predisposi-
tion condition including Crohn’s disease (8.7%), Lynch syndrome (6.9%), familial adenomatosis polyposis (1.7%), Celiac
disease (1.7%), and Peutz-Jeghers syndrome (0.6%). The high
incidence of predisposing conditions suggests that patients presenting with SMA should be screened for occult conditions.
Predisposing conditions occasionally correlate with specific
genetic alterations in SBA . For instance, patients with Lynch
syndrome are more prone to show ATM, FGFR3, and FGFR1
gene alterations, and patients with Crohn’s disease have more
IDH1 mutations (Aparicio 2021).
Guidelines for Treatment of Local Disease
According to the Surveillance, Epidemiology, and End Results
(SEER) Program, most patients are diagnosed with local disease including 10% stage I, 30% stage II, and 25% stage III.
Only 35% are diagnosed with stage IV disease (Khosla 2022).
According to the NCCN, initial workup should include
abdominal/pelvic/chest imaging (PET/FDG is not indicated),
blood work including tumor markers (CEA/CA19-9), consider studies for celiac, and esophagogastroduodenoscopy
(EGD) with Endoscopic Ultrasound (EUS) (if needed for better
imaging). Treatment then differs according to findings:
• Resectable disease requires resection with en-bloc removal
of local lymph nodes.
• Unresectable disease requires systemic treatment in
combination with surgical (if needed – diversion or stent in
case of obstruction).
Surgical Treatment
• Surgery is the most important component of treatment to
achieve cure in localized SBA and changes according to location. Periampullary and proximal duodenal cancer will often
require pancreatoduodenectomy. Distal ileal tumors might
require a right colectomy. Tumors in other locations will be
treated with wide local segmented resection and lymph node
dissection. However, the blood supply to the remaining
bowel might limit the extent of the surgery, thus compromising the number of lymph node available to resect. The
optimal number of lymph nodes to be extracted is a matter
of debate. According to the National Comprehensive Cancer
Network (NCCN) guidelines, the recommended minimum
is the resection of at least eight lymph nodes.
Systemic Treatment
• There are currently no randomized trials to guide the
treatment approach after complete tumor resection. The
global BALLAD phase III adjuvant trial is now recruiting
and is aimed to evaluate the role of adjuvant chemotherapy
(Journal of Clinical Oncology 2016 34:15_suppl, TPS4154TPS4154, NCT04257461). Retrospective data regarding
adjuvant therapy is inconsistent. Many of the retrospective
studies collected data from a single center, and do not
show any benefit for adjuvant chemotherapy. However,
this data is prone to major biases, as patients that received
chemotherapy might be selected for adjuvant treatment
due to bad prognostic factors (Dabaja et al. 2004,
Halfdanarson et al. 2010; Nakanoko 2015; Swartz 2007;
Young 2016). A single matched analysis of 4747 patients
from the national cancer database shows a significant
advantage of adjuvant chemotherapy is achieved in patients
with stage III disease (Ecker 2016).
• In the case of an irresectable disease, one small study
(Onkendi 2012) has shown that neoadjuvant therapy
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(chemotherapy with or without radiation) has converted
the locally unresectable disease to a resectable disease with
prolonged survival.
Adjuvant chemotherapy for 3-6 months is therefore indicated in
cases for patients post resection with a high pathologic al stage –
T3 with MSS (MicroSatellite Stable) or pMMR (hence – no deficiency in MMR proteins). Similar to colon cancer, the regimen of
choice is either 5FU or the combination of 5FU and oxaliplatin,
depending on the number of risk factors and age. Capecitabine is
also possible instead of 5FU. In cases with no involvement of
lymph nodes (N0), no presence of Perineural invasion (PNI) or
Lymphovascular invasion (LVI) – observation is also acceptable.
By extrapolation from CRC, patients with stage II MSI-H/dMMR
have improved prognosis and therefore may not need adjuvant
chemotherapy. Based on publications in CRC, it is reasonable
to consider incorporating Immune Checkpoint Inhibitors
(ICI) treatment for high-risk patients. (Alvi, 2016)
A recently published review (Khosla 2022) of acceptable treatments for SBA emphasizes the role of chemoradiation in the
setting of duodenal disease, since these tend to local recurrence,
although this treatment has not shown improvement in survival.
Surveillance includes physical examination and marker levels
every 3–6 months for the first 2 years and then every 6–12 months
until year 5. In addition, imaging every 6–12 months for the first
2 years followed by imaging every 12 months until year 5.
Metastatic Adenocarcinoma of the Small
Intestine
Common metastatic sites of SBA are the liver and peritoneum.
Peritoneal metastases are more common in jejunal and ileal
pr imar y.
Chemotherapy
• There are no randomized control trials that evaluated the effi-
cacy of chemotherapy in metastatic small bowel adenocarcinoma. Retrospective and prospective phase II studies show
that different types of chemotherapies can induce tumor
regression: The efficacy of 5FU and oxaliplatin combination
as first-line treatment was evaluated in two phase II trials.
Overman et al. (Overman 2009) explored the efficacy of
CAPOX regimen (Oxaliplatin and capecitabine) in 25 patients
and found a response rate of 52% and median overall survival
of 20.4 months. Xiang et al. (Xiang 2012) evaluated the efficacy of FOLFOX regimen (fluorouracil and oxaliplatin) in 33
patients and demonstrated a response rate of 48.5% with
median overall survival of 15.2 months.
• One phase II study (McWilliams 2017) has shown that the
addition of genotype-directed dosing UGT1A1 of Irinotecan
(gCAPIRINOX) was feasible with favorable rates of hematologic toxicity in previously untreated SBA patients. Few retrospective studies evaluated the efficacy of irinotecan-based
regimens in both first- and second-line showing a response
rate of 9 to 25 percent and median overall survival of 9 to 10
months (Tsushima 2012; Zaanan 2010, 2011).
• Historically, the treatment approach to metastatic SBA was
mainly influenced by the treatment paradigm of colon cancer.
However, insights from genomic analysis supporting a more
unique entity for SBA encouraged an effort to explore other
drugs less effective in colon cancer. A small phase II trial
(Overman 2018) evaluated the role of nab-paclitaxel in 10
patients showing an objective response in two patients supporting the ability of SBA to respond to agents that are not
active in colon cancer. Another retrospective study (Aldrich et
al. 2019) showed a response rate of 30% to second-line taxanebased therapy at various drug combinations including gemcitabine. These options are now included in the NCCN
guidelines as an option for second-line treatment.
According to the NCCN, chemotherapy treatment for metastatic
disease is based on 5FU/Capecitabine with or without oxaliplatin
(according to the intensity of the intended regimen).
Immunotherapy
• The KeyNote 158 study (Marabelle 2020) included 19 patients
with small bowel cancer, dMMR, and has shown response to
pembrolizumab in 42% including complete response in three
patient. In contrast, the ZEBRA trial (Pedersen 2021) a phase II
study including 40 patients with previously treated SBA, did not
achieve the expected endpoints with little response in the MSS
group and 50% of the MSI-H achieving PR (Partial Response).
• One prospective study (Aydin 2017) including 28 patients
with advanced SBA showed that second-line treatment with
the addition of Bevacizumab was more effective than chemo-
therapy alone, though results were not statistically significant.
And yet, in a meta-analysis (Vergara et al. 2019) combining
this trial and another phase 2 study (Gulhati 2017) they have
demonstrated an improvement in the overall survival for
patients with added Bevacizumab to chemotherapy.
• Panitumumab (an anti-EGFR protein) has shown no clinical
activity in a phase II trial (Gulhati 2018) although was well
tolerated.
The guidelines state that in addition to chemotherapy, patients
should receive either Bevacizumab (efficacy is yet to be proven,
although it has shown safety) in pMMR cases or Immune
Checkpoint Inhibitors (ICI) exclusively in dMMR patients, comprised of Nivolumab with Ipilimumab or pembrolizumab.
Although not part of the guidelines, treatment with pembrolizumab in metastatic SBA should remain an option even when
unknown MSI status, or If MSS, according to the ZEBRA trial
(Pedersen 2021). The rationale is led by the hypothesis that
metastatic SBA patients have a high programmed death-ligand
1 (PD-L1) expression.
Surgical Treatment
• Metastasectomy might be considered in patients with single
metastasis to visceral organs (Adam 2006).
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• Cytoreductive surgery plus hyperthermic intraperitoneal
chemotherapy for peritoneal metastases has also been shown
(Liu 2018) to achieve prolonged survival for selected patients,
as shown in a series of 152 patients.
Regarding biological treatment – according to the available
data, there seems to be no clear benefit for monotherapy with
panitumumab or cetuximab, in metastatic SBA. Albeit, the
addition of cetuximab to chemotherapy might be safe and welltolerated, with efficacy yet to be proven (Mazlom et al. 2021).
Prognosis
Small Bowel Adenocarcinoma is lethal in its advanced stages
(Locher 2018). Due to its rarity, little is known about effective
treatment. A nomogram (Zhu 2022) based on the SEER
program has evaluated the following characteristics as bad
prognostic features for three-year survival in metastatic SBA:
Advanced age (>76 years), primary duodenal disease,
large tumors with high tumor grade, primary tumor
resection, and chemotherapy treatment.
Other less common pathologies of the small bowel include
Neuroendocrine tumors, Lymphomas, Sarcomas, and metastasis to
the small intestine. Hereby is a short brief of these pathologies, a
more elaborate description will take place in the relevant chapters.
NET
Treatment for Metastatic Disease
Treatment should include resection, when possible, even
with liver metastasis, although surgery in patients with carcinoid syndrome might be hazardous. Systemic treatment with
somatostatin analogs might provide long-term relief of symptoms in addition to having an antiproliferative effect (Scott
and Howe 2020).
Lymphoma
Lymphomas to the GI tract are most commonly non-Hodgkin
and have better prognosis than lymphomas of lymph node
origin. Nonetheless, treatment is similar to standard extranodal lymphoma treatment, with the exclusion of surgery in
cases of small bowel obstruction (Beaton et al. 2012).
GIST
The most common sarcomas of the small bowel are gastrointestinal stromal tumors (GIST). Non-GIST sarcomas include leiomyosarcoma, fibrosarcoma, liposarcoma, Kaposi sarcoma, and
angiosarcoma. The molecular hallmark of GIST is a mutation
in either KIT or PDGFRA gene. While the mutations cause
resistance to chemotherapy, they can be targeted by Imatinib
leading to prolonged tumor control (Kang et al. 2015).
Surgical treatments include en-bloc resection. Mesenteric
lymphadenectomy is not obligatory.
Pathogenesis
Neuroendocrine tumors of the small intestine are most often
indolent tumors once called carcinoid, implying that they are
cancer-like but are not cancerous. However, though they are
slow-growing, they frequently do send metastasis and are lethal
in many cases. The ability of these tumors to produce hormones
can cause “carcinoid syndrome” which characteristics differ
according to the mediator, mostly including flushing and diarrhea (Kulke and Mayer 1999).
These tumors are less aggressive than other malignancies of
the GI tract. They originate from neuroendocrine cells and can
be divided into functional tumors, which are capable of producing hormones, and non-functional tumors. Tumors can
metastasize even if the primary tumor is small (Rorstad 2005).
Treatment for Local Disease
A wide en-bloc resection of local disease is recommended. This
includes the resection of the mesentery and lymph nodes (Loftus
and van Heerden 1995). Due to the high incidence of a second
GI malignancy in patients with SB-NET, patients should undergo
an entire GI and possibly GU evaluation prior to surgery and
have an intraoperative assessment (Prommegger 2014).
Metastasis to the Small Intestine
The small intestine is rarely involved in metastasis from other
origins. The most common sites of hematogenous spread
include melanoma, breast, and lung cancer (Kadakia et al.
1992) Treatment is mostly palliative.
Key Take Home Messages
• Small bowel cancer is rare, with a non-unique pattern of pre-
sentation – mostly vague abdominal pain. Diagnosis can be
complicated due to low visualization abilities of the small
bowel; therefore, early disease diagnosis is uncommon.
• Adenocarcinoma is the most common type of cancer in the
small bowel, though there are rising portions of NET in the
past few years. Other types are lymphoma and sarcoma.
Adenocarcinoma is believed to evolve from an adenoma,
similarly to CRC, though gene analysis suggests that small
bowel adenocarcinoma is a unique entity. Microsatellite
instability was found in a higher percentage of metastatic
SBA in comparison to metastatic CRC.
• Patients with inflammation (i.e. Crohn’s and celiac dis-
eases) are at a higher risk of developing SBA, suggesting
screening in these patients. Other common predispositions
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are hereditary syndromes such as Lynch, FAP, and PeutzJegher. One study showed almost 20% of patients with SBA
had a predisposition condition, raising the question
regarding the screening of patients presenting with SBA for
occult conditions.
• Treatment in stages I-III is primarily reliant on surgery, with
scarce studies showing benefits for adjuvant therapy, mostly
retrospective. The common practice is chemotherapy for stage
III disease, comprising of oxaliplatin-based combinations.
• Treatment for metastatic disease has very little evidence and is
mostly based on relevant treatment for CRC. Mostly oxaliplatin-based in combination with Immune Checkpoint Inhibitors.
Knowledge Gaps
• It is suggested that chronic inflammation is a strong risk
factor for the development of SBA, but it has not been proven
and screening guidelines are rather deficient. Further investigation regarding relevant populations and appropriate
screening methods should take place.
• There are many gaps in the evidence for the need for systemic
treatment for advanced disease. Prospective studies should
take place to fill these gaps.
• Patients with unresectable disease are and no doubt in need
of systemic treatment, yet there is little evidence regarding
the benefits of chemotherapy, and the addition of more
advanced treatments such as biological or immunological
regimens.
National Evidence-based Guideline
• NIH patient guide: https://www.cancer.gov/types/small-
intestine/patient/small-intestine-treatment-pdq
• NCCN: https://jnccn.org/view/journals/jnccn/17/9/article-
p1109.xml
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