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Colucci, G., Gebbia, V., Paoletti, G. etal. (2005). Phase III randomized trial of
FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer:
a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J
Clin Oncol 23: 4866–4875. https://doi.org/10.1200/JCO.2005.07.113.
Falcone, A., Ricci, S., Brunetti, I. etal. (2007). Phase III trial of infusional
fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)
compared with infusional fluorouracil, leucovorin, and irinotecan
(FOLFIRI) as first-line treatment for metastatic colorectal cancer: the
Gruppo Oncologico Nord Ovest. J Clin Oncol 25: 1670–1676. https://
doi.org/10.1200/JCO.2006.09.0928.
Fuchs, C.S., Marshall, J., Mitchell, E. etal. (2007). Randomized, controlled trial
of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line
treatment of metastatic colorectal cancer: results from the BICC-C Study. J
Clin Oncol 25: 4779–4786. https://doi.org/10.1200/JCO.2007.11.3357.
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fluorouracil-based adjuvant therapy for stage II and III colon cancer:
who benefits and by how much? J Clin Oncol 22: 1797–1806. https://doi.
org/10.1200/JCO.2004.09.059.
Hoff, P.M., Ansari, R., Batist, G. et al. (2001). Comparison of oral
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Khoo, E., O’Neill, S., Brown, E. etal. (2016). Systematic review of systemic
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Nordlinger, B., Sorbye, H., Glimelius, B. et al. (2013). Perioperative
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liver metastases from colorectal cancer (EORTC 40983): long-term
results of a randomised, controlled, phase 3 trial. Lancet Oncol 14: 1208–
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org/10.1200/JCO.1998.16.1.301.
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acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic
acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic
colorectal cancer (MCC): a multicentre randomised phase III trial from
the Hellenic Oncology Research Group (HORG). Br J Cancer 94: 798–
805. https://doi.org/10.1038/sj.bjc.6603011.
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Biologic and Immunotherapy for
Colorectal Cancer
Faiz Jabbar, (With help from David Church)
History of Biological Therapy for CRC
While the history of biologic (or molecularly targeted)
therapy and immunotherapy for colorectal cancer (CRC) is
somewhat shorter than that of cytotoxic chemotherapy and
radiotherapy, these agents have established themselves as an
essential part of the therapeutic armamentarium in this disease. With the exception of early, arguably disappointing,
vaccine studies, biologics and immunotherapeutics really
came of age in the 2000s following advances in molecular
biology and methods for production of monoclonal antibodies at therapeutic scale.
Biologics for CRC
The identification in 1978 of the epidermal growth factor
receptor (EGFR) as a critical regulator of intracellular signaling and cell growth, survival and migration (Gschwind
et al. 2004) stimulated research into its role in cancer.
Aberrant EGFR expression was found in multiple cancer
types including 25–77% of CRC (Xie etal. 2020). Cetuximab,
a chimeric monoclonal antibody against EGFR, was the first
targeted agent approved for CRC by the US Food and Drug
Administration (FDA) in 2004 (Xie et al. 2020), based on
prolongation of progression-free survival (PFS) in patients
with metastatic CRC (mCRC) refractory to irinotecan
(Cunningham etal. 2004). Subsequent studies demonstrated
that the addition of cetuximab or the alternative anti-EGFR
monoclonal panitumumab to first line chemotherapy improves
clinical outcome in mCRC (Jonker etal. 2007), although this
benefit is limited to patients with tumors lacking mutations
in KRAS, NRAS and to a lesser extent BRAF (Karapetis etal.
2008). Although the importance of angiogenesis in promoting
tumor growth, invasion and metastasis has long been recognized, the identification of the vascular endothelial growth
factor (VEGF) family as mediators of this provided a rational
therapeutic target. A landmark trial published in 2004 demonstrated that the addition of the anti-VEGF monoclonal bevacizumab to irinotecan-based chemotherapy improved PFS
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and overall survival (OS) in mCRC (Hurwitz etal. 2004) and
led to FDA approval for this indication. While a subsequent
study showed more modest benefit for bevacizumab in
combination with first-line oxaliplatin-based chemotherapy,
the chemo-bevacizumab doublet has established itself as a
standard of care for mCRC. From these data, one may reasonably ask how clinicians should decide between anti-EGFR
and anti-VEGF therapy for their patients with mCRC? Data
accumulated over the last decade, including a meta-analysis
have revealed that chemotherapy plus anti-EGFR therapy is
superior to chemotherapy plus anti-VEGF therapy in patients
with RAS/BRAF-wild-type tumors arising on the left-side
of the colon (i.e. distal to the transverse colon), while chemotherapy plus an anti-VEGF monoclonal is preferable for
patients with RAS/BRAF mutant tumors or those with rightsided primary tumor (Khattak etal. 2015). While it has been
postulated that the association of treatment (dis)benefit with
primary tumor location relates to the embryological derivation of the right and left side of the colon (Boeckx etal. 2018;
Yamashita etal. 2018), there are other plausible explanations,
including difference in the intestinal microbiome, and the
prevalence of other molecular alterations such as mutations
in PIK3CA, and amplification of HER2 and other possible
determinants of anti-EGFR sensitivity (Bertotti et al. 2015;
Mei etal. 2016; Seo etal. 2014). While BRAF mutation predicts resistance to anti-EGFR therapy alone or in combination
with cytotoxics, the development of specific inhibitors of the
most common BRAF mutation (V600E, present in ~10% of
mCRCs) permitted rational targeting in this patient subgroup. The BEACON study showed that a combination of
either a triplet of a BRAF inhibitor (encorafenib), cetuximab
and a MEK1/2 inhibitor (bimimetinib) or the encorafenib
and cetuximab doublet were highly active against BRAF
V600E-mutant mCRC as second line treatment, with significantly superior OS to chemotherapy (Kopetz etal. 2019). As
the doublet had near-identical efficacy to the triplet, but with
less toxicity, this has established itself as preferred therapy for
this patient subgroup; a trial in first line therapy is underway.
Importantly, the encorafenib and cetuximab doublet is the
first biologic-only regimen licensed in mCRC by the FDA.
Other biologics to have established roles in mCRC include
regorafenib, a tyrosine kinase inhibitor (TKI) with multiple targets for third line therapy (Grothey etal. 2013; Van
Cutsem etal. 2016) and agents targeting ERBB2/HER2 for
the 3% of CRCs with ERBB2/HER2 amplification (SartoreBianchi etal. 2019). Soberingly, despite their activity in metastatic disease, both anti-EGFR and anti-VEGF therapies have
failed to improve outcomes in early-stage CRC as adjuvant
therapy (Allegra etal. 2011; De Gramont etal., 2012; Kerr
etal. 2016). The reasons for this are not fully understood, but
these findings certainly advocate for caution when extrapolating activity in the metastatic setting to earlier in the disease
course.
Immunotherapy for CRC
As with biologics, the development of immune checkpoint
inhibitors (ICI) derives from painstaking preclinical studies
demonstrating the role of CTLA4 and PD1 in inhibiting the T
cell response in the setting of chronic antigen stimulation
(Robert 2020). Given that it was well recognized that the
density of lymphocytic infiltrate correlated with better outcome in CRC (Galon etal. 2006), the use of ICI in metastatic
CRC – where the immune response is self-evidently incapable
of preventing tumor growth – was a logical avenue to pursue.
However, in contrast to melanomas and lung cancer, for most
CRCs, these drugs failed to show meaningful activity as monotherapy or in combination with chemotherapy in most cases
(Brahmer etal. 2012). There was, however a stunning exception;
the subgroup of 4% of mCRCs with deficiency in DNA mismatch repair (dMMR) which showed profound, and in many
cases prolonged responses (Le etal. 2015; Overman etal. 2017).
Indeed, for this subgroup, ICIs also offer a more tolerable toxicity profile compared to chemotherapy. Consequently, antiPD1 therapy in the form of nivolumab or pembrolizumab
gained FDA approval for this indication in 2017, and is now
preferred over chemotherapy for first line therapy by many clinicians. The most plausible explanation for the responsiveness
of dMMR CRCs to ICI is that their elevated mutation rate
causes an abundance of non-self peptides which are recognized
by re-activated T cells. Understanding whether the failure of
ICI in CRCs with proficient MMR relates to their lower mutation burden or other factors is an area of active investigation, as
is the use of combination treatment, including immunotherapy-biologic and other immunomodulatory compounds (Lote
etal. 2022). In contrast to the seemingly reduced efficacy of
biologics in early-stage disease, emerging data indicate that
activity of ICI is significantly greater in early-stage dMMR
CRC. Exemplars include a prospective phase II study, in which
six months of Dostarlizumab (anti-PD-1) resulted in prolonged
clinical complete response (CR) for locally advanced dMMR
CRC in all patients (Cercek etal. 2022), the PICC trial in which
six months of Toripalimab (anti-PD-1) plus celecoxib (COX-2
inhibitor) in locally advanced dMMR CRC resulted in a
complete pathological response in 88% of patients (Hu etal.
2022), and the NICHE and NICHE-2 trials, where in the latter
6 weeks of neoadjuvant ICI resulted in pathological CR in 67%
of dMMR tumors (Chalabi etal. 2020). These studies pave the
way to organ-sparing approaches in dMMR CRC – something
which until recently was considered unfeasible.
Summary
In summary, during the last two decades’ biologics have
established themselves as standards of care in mCRC, while
immunotherapy has emerged as the treatment of choice for
dMMR mCRC and is near-certain to become the same in
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early-stage dMMR tumors. While the failure of anti-EGFR and
anti-VEGF therapies in early-stage disease militates caution, the
pace of advance in biological understanding and therapeutic
targeting means we can be sanguine about the improvements
biologics and immunotherapeutics will deliver for our patients
during the next twenty years. In addition to new targets and
drug combinations, future work should aim to rationalize the
use of these drugs to the patients most likely to benefit, as the
substantial costs of these agents poses a challenge for even the
best-funded healthcare systems (Weng etal. 2022).
Key Management Messages
• The addition of anti-EGFR or anti-VEGF biologics to chemotherapy improves survival in mCRC; the choice of which to
use depends on RAS/BRAF mutation status and primary tumor
location.
therapy.
• Immune checkpoint inhibition has unprecedented activity
in DNA mismatch repair deficient (dMMR) mCRC and offers
possibility of organ-sparing therapy in localized disease.
Areas for Further Research
• Development and application of novel molecularly-targeted
therapies in mCRC
• Combination strategies to sensitize resistant mismatch repair
proficient (pMMR) CRCs to immunotherapy
Trusted Links for Further Reading
• ESMO guidelines for metastatic colorectal cancer
• Review of biologics for colorectal cancer
References
Allegra, C.J., Yothers, G., O’connell, M.J. et al. (2011). Phase III trial
assessing bevacizumab in stages II and III carcinoma of the colon:
results of NSABP protocol C-08. J Clin Oncol 29: 11–16.
Bertotti, A., Papp, E., Jones, S. et al. (2015). The genomic landscape of
response to EGFR blockade in colorectal cancer. Nature 526: 263–267.
Boeckx, N., Janssens, K., Van Camp, G. etal. (2018). The predictive value
of primary tumor location in patients with metastatic colorectal cancer:
a systematic review. Crit Rev Oncol Hematol 121: 1–10.
Brahmer, J.R., Tykodi, S.S., Chow, L.Q.M. etal. (2012). Safety and activity
of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med
366: 2455–2465.
Cercek, A., Lumish, M., Sinopoli, J. et al. (2022). PD-1 blockade in
mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med
386: 2654–2666.
Chalabi, M., Fanchi, L.F., Dijkstra, K.K. et al. (2020). Neoadjuvant
immunotherapy leads to pathological responses in MMR-proficient and
MMR-deficient early-stage colon cancers. Nat Med 26: 566–576.
Cunningham, D., Humblet, Y., Siena, S. et al. (2004). Cetuximab
monotherapy and cetuximab plus irinotecan in irinotecan-refractory
metastatic colorectal cancer. N Engl J Med 351: 337–345.
De Gramont, A., Van Cutsem, E., Schmoll, H.J. etal. (2012). Bevacizumab
plus oxaliplatin-based chemotherapy as adjuvant treatment for colon
cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol
13: 1225–1233.
Galon, J., Costes, A., Sanchez-cabo, F. et al. (2006). Type, density, and
location of immune cells within human colorectal tumors predict
clinical outcome. Science 313: 1960–1964.
Grothey, A., Van Cutsem, E., Sobrero, A. etal. (2013). Regorafenib monotherapy
for previously treated metastatic colorectal cancer (CORRECT): an
international, multicentre, randomised, placebo-controlled, phase 3 trial.
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Gschwind, A., Fischer, O.M., and Ullrich, A. (2004). The discovery of
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361–370.
Hu, H., Kang, L., Zhang, J. etal. (2022). Neoadjuvant PD-1 blockade with
toripalimab, with or without celecoxib, in mismatch repair-deficient
or microsatellite instability-high, locally advanced, colorectal cancer
(PICC): a single-centre, parallel-group, non-comparative, randomised,
phase 2 trial. Lancet Gastroenterol Hepatol 7: 38–48.
Hurwitz, H., Fehrenbacher, L., Novotny, W. etal. (2004). Bevacizumab plus
irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
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Jonker, D.J., O’Callaghan, C.J., Karapetis, C.S. etal. (2007). Cetuximab for
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and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med
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Answers to Case Scenarios
Jeremy Meyer & Justin Davies
Case 1: Sporadic Localized Right
Colon Cancer
For the management of colon cancer, routine staging modalities include a complete colonoscopy, aimed at confirming the
nature of the tumor, tattooing the lesion distal to the tumor in
at least 2 separate places and ruling out any synchronous colorectal cancer (which can occur in 2–3% of patients, with a
higher incidence in cases of hereditary colorectal cancer).
Moreover, a CT of the chest, abdomen and pelvis should be
performed to clinically stage the tumor in terms of assessing for
distant metastases, and to allow assessment of local resectability with optimal planning of the surgical strategy. This
staging should be tailored to the patient, and more imaging
modalities (for example a PET-CT, a liver MRI) can be added in
case metastatic disease is suspected (Argiles etal. 2020).
In the case scenario, the lesion was staged as being cT3 N2 M0.
Ideally, the patient should be entered into an enhanced recovery
after surgery (ERAS) protocol (Gustafsson et al. 2019; Moran
et al. 2017). The surgical approach should be tailored to the
patient and the surgeon’s expertise, and can consist of open right
hemicolectomy, laparoscopic right hemicolectomy or robotic
right hemicolectomy. The Association of Coloproctology of
Great Britain and Ireland (ACPGBI) Guideline recommends
choosing the laparoscopic approach over the open approach
whenever possible (Moran etal. 2017), due to its similar operative specimen and oncological outcomes but short-term benefits in terms of post-operative pain, blood loss and length of stay
(Jayne etal. 2007; Kennedy etal. 2014). The minimally invasive
approach almost invariably includes the dissection of the right
colon along the anatomical planes, but sometimes bowel division, vessel division and anastomosis creation are performed
extra-corporeally through the incision made for the specimen
extraction due to technical challenges. Robotic surgery may
allow performing most of these procedures intra-corporeally,
and may potentially bring benefits in terms of length of specimen
extraction site. Finally, some surgeons advocate performing
complete mesocolic excision (CME) for right-sided colon cancer. CME was introduced by Hohenberger in 2009 to improve
oncological outcomes of right colectomy by transposing the
lessons learned from total mesorectal excision (TME) to colon
cancer (Hohenberger et al. 2009). CME aims at completely
removing the mesocolon and its lymph nodes (corresponding
to a Japanese D3 lymphadenectomy) and can be summarized in
three principles: 1. sharp dissection respecting the embryological planes (to remove D1, D2 and D3 lymph nodes), 2. central
vascular ligation (to remove D3 lymph nodes) and 3. sufficient
bowel resection (to remove pericolic lymph nodes). So far, the
potential benefits of the technique have not been demonstrated
by randomized controlled trials and vascular complications
have been reported (Xu etal. 2021). The ACPGBI recommends
additional evidence of the benefits of CME before its routine
adoption (Moran etal. 2017)
The case scenario depicts a patient with Union for
International Cancer Control (UICC) stage III colon cancer
who has been recommended consideration of adjuvant chemotherapy by the multidisciplinary team. The rationale for use of
adjuvant chemotherapy in colon cancer is to eradicate micrometastatic disease in draining lymph nodes that were not
removed by the surgical procedure and any other micrometastatic diases not detected on routine imaging. Current recommendations of the European Society for Medical Oncology
(ESMO) stipulate that patients with UICC stage III colon cancer (Node positive) should be offered adjuvant chemotherapy
to reduce the risk of recurrence and improve overall survival
(Argiles et al. 2020). Chemotherapy usually consists of a
combination of fluoropyrimidine and oxaliplatin, as the
addition of oxaliplatin to fluoropyrimidine brings a diseasefree survival benefit (Andre et al. 2004; Yothers et al. 2011).
Based on the IDEA study, both 6-month FOLFOX (a
combination of folinic acid, 5-FU and oxaliplatin) and 3 to
6-month CAPOX (a combination of capecitabin and oxaliplatin) constitute the current standard of care (Grothey et al.
2018), including recently updated National Institute for Health
and Care Excellence (NICE) Guidelines for Colorectal Cancer
in United Kingdom (NIfHaCE 2020). The benefit of chemotherapy in terms of survival in patients with UICC stage II (T3T4 N0) cancer is less clear, but chemotherapy can be proposed
to intermediate and high-risk patients (Argiles etal. 2020). The
level of risk is estimated based on the number of lymph nodes
harvested (<12 constitutes high risk), a pT4 stage including
perforation, the histological subtype and grading of the cancer,
the presence of lymphatic or vascular or perineural invasion,
lymphoid inflammatory response, involvement of resection
margins and serum pre-operative CEA (Argiles etal. 2020).
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After treatment for colon cancer with curative intent, follow-up should be performed for early detection of eventual
local recurrence and metachronous metastatic disease. Most
recurrences occur during the first 3 years of follow-up, and a
small proportion happen between years 3 and year 5. Therefore,
it is commonly agreed that follow-up should be performed during the first 3–5 years after curative treatment for colon cancer
(Argiles etal. 2020). However, as highlighted by the European
Society for Coloproctology (ESCP), national guidelines for follow-up are heterogeneous (Bastiaenen etal. 2019). Nevertheless,
the ESMO recommends performing physical examination and
CEA level every 3–6 months for the first 3 years, and every 6
months thereafter until year 5. Colonoscopy should be performed at year 1, and every 3–5 years thereafter. CT of the
abdomen and chest should be performed every 6–12 months
for the first three years for patients at higher risk (Argiles etal.
2020), who are usually defined as patients above UICC stage I.
NICE has similar recommendations for the first 3 years of
follow up, with colonoscopic surveillance recommended by
Guidelines from the British Society of Gastroenterology and
generally recommending a colonoscopy at 1 year after resection, and then at 3 years, with surveillance after that depending
on the colonoscopic findings (Rutter etal. 2020).
Case 2: Prophylactic Surgery for
Familial Adenomatous Polyposis
Familial adenomatous polyposis (FAP) is defined as the
presence of multiple adenomas (>100 in the classical phenotype and 10–100 in the attenuated phenotype) localized in the
colon and rectum of affected individuals. The syndrome has an
autosomal dominant transmission, a 100% penetrance and is
associated with a germline mutation of the APC gene. The APC
gene is a tumor suppressor gene which regulates epithelial
growth. FAP is associated with a wide range of cancers, but is
commonly associated with non-adenomatous gastric polyps,
adenomatous duodenal polyps and desmoid tumors, which
constitute an important cause of mortality in patients after
proctocolectomy. Considering the important risk of early colorectal cancer in patients suffering from FAP, yearly endoscopic
follow-up is started from age 12–15 years, and prophylactic
surgery is generally offered before the age of 25 (Stjepanovic
etal. 2019). Surgical options include initial subtotal colectomy
and end ileostomy (continent or not), subtotal colectomy and
ileo-rectal anastomosis, procto-colectomy and end ileostomy
(continent or not), or procto-colectomy with ileo-anal pouch
anastomosis. The extent of resection (subtotal colectomy or
procto-colectomy with/without mucosectomy; proctectomy
can also preserve the anal canal or not) depends on the estimated risk of metachronous cancer in the residual rectum (or
residual rectal mucosa), patient’s compliance with future follow-up and patient’s wishes regarding preservation of sexual
function. The risk can be estimated depending on the number
of polyps in the rectum (>20 polyps in the last 10 cm constitutes a higher risk) and depending on the mutated codon in the
APC gene. The decision to proceed to a restoration of continuity (ileo-rectal anastomosis or ileo-anal pouch) depends on
many factors, including the sphincter function, the risk of
anastomotic leak and patient’s expectations.
In the example provided, mutation in the codon 1309 exposes
the patient to a higher risk of rectal cancer (Ficari etal. 2000).
Therefore, the optimal surgical procedure was a proctocolectomy, with end ileostomy or creation of an ileo-anal pouch as a
quality of life decision for the patient. Ileo-anal pouch anastomosis is at risk for anastomotic leak. Therefore, it is a common
practice to divert the faecal stream with a temporary loop ilestomy. This could have been associated with a transanal mucosectomy to remove the residual at-risk rectal mucosa at the anal
transition zone, followed by a hand-sewn ileo-anal pouch anastomosis. However, some studies reported that, even with mucosectomy, some rectal mucosa is left behind. Therefore, a stapled
ileal-pouch anal anastomosis is now most commonly performed in this situation and is the recommended approach.
Close postoperative endoscopic follow-up is recommended in
all patients, whatever surgical procedure is performed. This follow-up usually consists of annual or biannual pouchoscopy
(after ileo-anal pouch) or flexible sigmoidoscopy (if the rectum
was preserved), and is associated with extra-intestinal surveillance (Ficari etal. 2000).
Recent evidence supports the use of chemoprophylaxis in
patients with FAP (Ricciardiello etal. 2016). Aspirin (Ishikawa
etal. 2021), sulindac with or without (Giardiello etal. 2002;
Samadder et al. 2018), celecoxib (Steinbach et al. 2000) and
Omega-3 polyunsaturated fatty acids (West etal. 2010) were
shown to reduce the polyp load and/or size in these patients.
However, none of these were demonstrated to reduce the incidence of colorectal cancer, and prophylactic surgery therefore
remains the gold standard in patients with FAP.
Case 3: Hereditary Non-polyposis
Colorectal Cancer
Hereditary non-polyposis colorectal cancer (HNPCC), also
named Lynch syndrome, is a hereditary cancer syndrome associated with germline mutations in the mismatch repair (MMR)
genes. Affected genes are mostly MLH1, MSH2, MSH6 or
PMS2. The syndrome causes an accumulation of errors during
DNA replication, ultimately leading to an increased risk of
colorectal cancer, endometrial cancer, ovarian cancer, gastric
cancer, small bowel cancer, urinary tract cancer, pancreatic
cancer and others (Samadder et al. 2017; Stjepanovic et al.
2019). Patients at risk should undergo regular surveillance and
be considered for prophylactic surgery, as both strategies lead
to a significant increase in survival.
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There are three methods to identify individuals who should
be screened for HNPCC: the Amsterdam II criteria, the revised
Bethesda criteria and the systematic screening of all colorectal
cancer specimens for defective MMR system. First, the
Amsterdam II criteria are clinical criteria which identifies individuals at risk for HNPCC (Vasen etal. 1999). The criteria are
the following:
• At least three relatives must have a cancer associated with
HNPCC
• All of the following criteria should be present:
One of the relative should be a first-degree relative of the
other two
• At least two successive generations must be affected
• At least one of the relative with cancer should be diag-
nosed before the age of 50
• FAP should be excluded
• Tumors should be verified whenever possible
In our example, the Amsterdam II criteria were therefore not
fulfilled.
Second, the revised Bethesda criteria are usually used by the
pathologist to identify operative specimen which should
undergo testing for defective MMR mechanism (either by
assessing microsatellite stability/instability (MSS/MSI) or by
assessing deficient MMR genes) (Umar etal. 2004). The criteria
are the following:
Tumors from individuals should be tested for MSI in the following situations:
• Colorectal cancer diagnosed in a patient who is younger
than 50 years of age
• Presence of synchronous or metachronous colorectal or
other HPNCC-related tumors, regardless of age
• Colorectal cancer with MSI-high histology diagnosed in a
patient who is younger than 60 years of age
• Colorectal cancer diagnosed in a patient with one or more
first-degree relatives with a HNPCC-related cancer, with one
of the cancers being diagnosed below age 50
• Colorectal cancer diagnosed in a patient with two or more
first- or second-degree relatives with HNPCC-related cancer
regardless of age
However, the Amsterdam II criteria and the revised
Bethesda criteria are not 100% sensitive and/or specific to
identify patients with HNPCC. In the United Kingdom,
these criteria have been replaced by the National Institute
for Health and Care Excellence (NICE) guidelines, which
recommends screening all preoperative cancer biopsy samples and operative specimens of colorectal cancer for defective MMR system (NIfHaCE 2017). If HNPCC is suspected,
tissue samples should be tested either for MSI using PCR and/
or for defective MMR-associated proteins using IHC (Li et al.
2020). Considering that approximately 10% of sporadic colorectal cancer cases also display MSI and loss of expression of
MLH1 due to hypermethylation of the promoter gene often
associated with BRAF V600E mutation, additional analysis
for MLH1 hypermethylation and/or BRAF V600E mutation
should also be performed in case of defective MLH1. The
diagnosis of HNPCC is then confirmed by germline analysis
(Stjepanovic et
The management of patients with HPNCC is as follows:
1) surveillance program screening for HPNCC-associated
cancers (colonoscopy 1x/1–2 years, transvaginal ultrasound
1x/year, CA-125 tumor marker blood test 1x/year, gastroscopy 1x/1–3 years (Stjepanovic et al. 2019)), 2) offering
prophylactic surgery after teenagehood and/or after completion of family (salpingo-oopharectomy, hysterectomy
and subtotal colectomy with ileorectal anastomosis versus
proctocolectomy and ileo-anal pouch). This strategy should
be discussed with the daughter of our patient. Moreover,
she should be encouraged to stop smoking and lose weight,
if indicated (Stjepanovic et al. 2019). Chemoprophylaxis
using Aspirin can also be proposed as it has been shown to
reduce the incidence of HNPCC-associated cancers (Burn
al. 2011).
et
In case of diagnosis of HNPCC after occurrence of cancer,
as it is the case in our patient, the ESCP recommendation is
to prefer subtotal colectomy with ileorectal anastomosis in
patients with mutations in either MLH1 and/or MSH2 considering the increased risk of metachronous colonic cancer.
However, this is not the case for rectal cancer, where the surgical resection should not be extended because of the MMR
status, except in case of synchronous cancers (Seppala et al.
2021). Moreover, in our example, the patient should have
benefited from endometrial cancer screening ideally before,
or at least after the surgical procedure. This would have
allowed to pick up her endometrial cancer earlier.
The ESMO guidelines recommend administering adjuvant
chemotherapy in HNPCC patients with high-risk stage II or
stage III colonic cancer. The estimation of the risk was detailed
in Question 1 above. Adjuvant chemotherapy does not bring
any survival benefit in HNPCC patients with intermediate risk
stage II cancer (Kim etal. 2015; Ribic etal. 2003), who generally have better oncological outcomes than their counterparts
with sporadic colorectal cancer.
al. 2019).
Case 4: Early Rectal Cancer
After endoscopic removal of a malignant polyp, the risk of
residual disease depends on several variables, such as the
depth of invasion into the submucosa (T1 substages as
defined by Kudo (1993), Kikuchi et al. (1995) and Haggitt
et al. for pedunculated lesions (Haggitt et al. 1985)), the
resection margin (a resection margin <1 mm is considered at
higher risk), poor differentiation of the tumor and the
presence of lymphovascular invasion (Williams etal. 2013).
Using the Kudo-Kikichu classification (Kikuchi etal. 1995;
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Kudo 1993), the risk of lymph node metastases was estimated
to be 3%, 8% and 23% for cancers involving the higher third
(T1sm1), the middle third (T1sm2) and the lower third
(T1sm3) of the submucosa (Nascimbeni et al. 2002). Exact
definitions of early rectal cancer vary according to variables
used to estimate the risk of recurrence (Morino etal. 2015),
but it is commonly admitted that rectal cancer at lowest risk
of recurrence (T1 sm1, no lymphovascular invasion, good
differenciation) can be considered as early rectal cancer. For
these cancers, local excision constitutes a valid treatment
option (Morino etal. 2015) and an alternative to the more
morbid anterior resection with total mesorectal excision,
which constitutes the standard of care for more locally
advanced rectal cancers. Moreover, a diameter criteria (4 cm,
<30% of circumferential rectal wall) is usually considered for
technical reasons (Morino etal. 2015).
In our example, the mid rectal polyp was initially staged as
being high-grade dysplasia, without any evidence of adenocarcinoma. However, the lesion was described as being flat (Paris
0-IIa) with a depressed centre, and therefore potential malignancy had to be considered. Therefore, a standard polypectomy was not performed. However, an endoscopic mucosal
resection (EMR) or endoscopic submucosal dissection (ESD)
could have been performed by an experienced gastroenterologist in the absence of a depressed centre.
In our scenario, a pelvic MRI was performed to better
characterize the lesion, which was then defined as mrT1/2
V0 N0 M0. Of note, the TREND study comparing EMR
versus transanal endoscopic microsurgery (TEM) for resection of non-cancerous polyps showed that 13% of lesions
preoperatively staged as benign tumors turned out to be
malignant (Barendse et al. 2018). There is also an ongoing
randomized controlled trial (TRIASSIC trial) comparing
transanal minimally invasive surgery (TAMIS) versus ESD,
with results are awaited (Dekkers et
ultrasound would have allowed to better define the T stage,
but was unfortunately not available. The patient underwent
transanal minimally invasive surgery (TAMIS) with fullthickness dissection. TAMIS can be either performed using
the TEM system or using more recent transanal plateforms,
such as the GelPoint (Rimonda et
gery performed without TAMIS should be reserved to very
distal tumors due to the suboptimal exposure increasing the
risk of R1/R2 resection (Morino et al. 2015). TAMIS dissection can be either simple mucosectomy or full-thickness
excision, which allows collection of a better specimen for
the pathologist and potentially reaching better surgical margins. In our example, pathology showed a pT1sm1 L0 V0 R0
adenocarcinoma, which is at low risk of local recurrence.
Therefore, the patient can enter a surveillance program and
does not need more extended resection or any adjuvant
therapy.
al. 2020). An endoanal
al. 2013). Transanal sur-
Case 5: Non-metastatic Rectal Cancer
Rectal cancer is most commonly defined as a cancer within 15
cm from the anal verge (Glynne-Jones etal. 2017). From an anatomical perspective, rectal cancer can be defined as a cancer
affecting “the portion of the large bowel below the sacral promon-
tory that is surrounded by a definable mesorectum posteriorly”
(Beyond TMEC 2013). Rectal cancer is usually subdivided into
high rectal cancer (10–15 cm from the anal verge), mid rectal
cancer (5–10 cm from the anal verge) and low rectal cancer (<5
cm from the anal verge) (Glynne-Jones etal. 2017). Other definitions, which are more useful in determining the best surgical
strategy can be used, such as the LOREC definition for low rectal
cancer (Moran etal. 2014). The localization of the cancer can be
accurately evaluated by rigid rectoscopy and/or pelvic MRI.
Historically, Heald etal. introduced in 1989 the concept of
total mesorectal excision (TME), which involves completely
removing an intact mesorectum en bloc with the rectum itself
(Heald and Ryall 1986). This concept led to an important
decrease in the incidence of local recurrence and in improved
survival. For a mid-rectal cancer, as is the case in our scenario,
the recommendation is to perform a complete TME down to the
pelvic floor, in order to remove para-rectal draining lymph
nodes, associated with a proximal ligation of the inferior mesenteric artery (Glynne-Jones etal. 2017; Moran etal. 2017). This
ligation can be “high tie” (1–2 cm distal to the aorta – which
corresponds to a D3 lymphadenectomy) or “low tie” (after the
division of the ascending left colic artery – which corresponds
to a D2 lymphadenectomy) (Hajibandeh etal. 2020). The recommended distal margin on the rectum itself (and not on the
TME) is usually considered to be at least 1 cm, but the true
requirement is the possibility to be able to apply a stapling
device or to divide the distal rectum without disrupting the
tumor (Karanjia etal. 1990; Williams etal. 1983). In case this is
not feasible, the tumor is considered as being a low rectal cancer.
The LOREC defines such cancer as “an adenocarcinoma with its
lower edge at, or below, the origin of the levators on the pelvic sidewall” (Moran etal. 2014), and in this case an abdomino-perineal
excision of the rectum (APER) may well be required.
Locally advanced primary rectal cancer is defined as a rectal
cancer extending beyond the TME plane and that requires an
extended surgical resection beyond the TME plane to achieve a
pathological R0 resection (Beyond TMEC 2013). In our sce-
nario, the mesorectal fascia was defined as being threatened on
the staging pelvic MRI (also indicated as threatened circumferential resection margin (CRM+)). This is defined as a tumor
and/or a lymph node located ≤1
fascia (Group MS 2006). Considering this threatened CRM, the
ESMO recommends pre-operative chemoradiotherapy (conventional scheme or, alternatively, short-course radiotherapy
combined with FOLFOX chemotherapy and long-wait) followed by TME (or beyond TME resection in this case).
mm from the mesorectal
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As for the surgical approach for colon cancer, the recommended surgical approach is via laparoscopy (Moran et al.
2017; NIfHaCE 2020). Two randomized controlled trials have
supported this strategy and established that laparoscopy has
better short-term outcomes than open surgery with similar
oncological outcomes (Bonjer etal. 2015; van der Pas et al.
2013). Two other randomized controlled trials have failed
to demonstrate non-inferiority of laparoscopic rectal surgery when compared to open rectal surgery in terms of cancer clearance/pathological outcomes (Fleshman et al. 2015;
Stevenson et al. 2015), but showed similar oncological outcomes (Fleshman etal. 2019; Stevenson etal. 2019). It should
be noted that the conversion rate from laparoscopy to open surgery was approximately 10% (Fleshman etal. 2015; Stevenson
etal. 2015). Indeed, laparoscopic TME is particularly challenging in male patients, who have a narrower pelvis, especially in
the presence of morbid obesity. Therefore, several alternative
minimally invasive approaches allowing TME in these patients
have been developed, such as transanal TME (taTME) and
robotic TME. However, the ROLARR trial did not show any
significant difference between laparoscopic TME and robotic
TME in terms of quality of surgical resection and conversion
to open in the treatment of rectal cancer (Jayne etal. 2017).
Moreover, a network meta-analysis of randomized controlled
trials did not show any important differences between the
techniques (Simillis etal. 2019). At present, whilst a minimally
invasive technique is generally preferable, it is important that
the mode of access is not the most important factor and that
appropriate rectal cancer surgery is performed irrespective of
access, to facilitate clear resection margins whilst aiming for
potential cure.
Finally, to conclude this scenario, if the patient had complete
clinical response (CCR) after neoadjuvant treatment, organ
preservation and entering a “watch and wait” surveillance
program could constitute an option. This approach was popularized by Habr-Gama in 2004 (Habr-Gama etal. 2004) and has
been supported by encouraging reports (Smith etal. 2019; van
der Valk etal. 2018). However, as CCR does not correspond to
compete pathological response, these patients are at risk of
local recurrence and should be closely followed-up with regular
digital rectal examination, MRI and flexible endoscopy.
Moreover, this approach should be reserved for the moment to
selected cases with good compliance, and with shared patient
decision making.
Case 6: Lateral Pelvic Lymph Nodes
This scenario depicts the case of a locally advanced rectal cancer
which will require beyond TME resection using an extralevator
abdominoperineal excision (ELAPE) in order to achieve an R0
resection (Beyond TMEC 2013; Moran etal. 2017). However,
this tumor did not only extend locally but also likely metastasized
into the lateral pelvic sidewall lymph nodes, which may expose
the patient to an important risk of recurrence (Kim etal. 2008).
These nodes include the internal iliac nodes, common iliac
nodes, obturator nodes, and external iliac nodes (Bell et al.
2009). The prevalence of lateral pelvic sidewall lymph node
metastasis in patients with mid/low rectal cancer is estimated to
be around 17.3% (Christou etal. 2021) and is inversely proportional to tumor height from the anal verge (Ueno etal. 2005).
In Western countries, suspected involvement of these lymph
nodes will constitute an indication for chemoradiotherapy with
or without a radiotherapy boost (Glynne-Jones etal. 2017). In
case of absence or partial response after neoadjuvant treatment,
the therapeutic strategy varies between observation or surgery
in the form of lateral lymph node dissection (Hazen etal. 2021).
Restaging MRI should be performed as it allows identification of
lymph nodes at higher risk of recurrence (those with no shrinkage of lymph node diameter and/or with post-treatment lymph
node ≥0.5 cm) (Malakorn etal. 2019; Ogura etal. 2019). In Asia,
lateral lymph node dissection is the preferred approach and can
be performed unilaterally or bilaterally (Kanemitsu etal. 2017).
Ongoing controversy exists regarding treatments for suspicious
lateral pelvic side wall lymph nodes and indications for lateral
lymph node dissection. Some authors recommend performing
a selective approach, with excision being performed either via
open or minimally invasive (laparoscopic or robotic) surgery
(Kim etal. 2020).
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