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4 Lynch Syndrome 131
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Neoadjuvant Therapy in Colon
https://t.me/med1917
Cancer
Geerard L. Beets
Abstract
Neoadjuvant therapy in colon cancer, traditionally reserved for rectal cancer, is
gaining traction as a promising treatment strategy. This chapter offers a concise
overview of neoadjuvant therapy in colon cancer, highlighting its evolving role,
benefits, and challenges. The synopsis underscores the potential for neoadjuvant
therapy to downstage tumours, improve surgical outcomes, and enhance overall
survival. Understanding the evolving landscape of neoadjuvant therapy is vital
for optimizing treatment strategies and improving outcomes in colon cancer
patients.
Keywords
Neoadjuvant therapy•Colon cancer•Preoperative treatment•Chemotherapy
Radiation therapy•Tumour downstaging•Surgical management•Oncological
•
outcomes
Response assessment•Multimodal therapy
5
•
Key Points
•
Because of the profound impact on the choices of systemic therapy, testing for
dMMR/MSI will become standard in the workup of colorectal cancer.
•
For pMMR/MSS colon tumours there is probably a small benefit for patients at a
higher risk for metastases from moving at least a part of the total of 3 months of
adjuvant chemotherapy to the neoadjuvant setting.
G. L. Beets (B)
Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
e-mail: g.beets@nki.nl
GROW Research Institute for Oncology and Reproduction, Maastricht University, Maastricht,
The Netherlands
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
M. Evans e t al. (eds.), Coloproctology, https://doi.org/10.1007/978-3-031-59630-8_5
133
134 G. L. Beets
https://t.me/med1917
•
For borderline resectable or unresectable pMMR/MSS colon tumours, neoadjuvant chemotherapy offers the additional advantage of increasing the chances of
resectability and tumour free margins.
•
The promising current developments in ctDNA could provide a tool that assesses
the actual presence of metastatic disease after the resection rather than the current
approach to estimate the risk. It therefore has the potential to change the current paradigm of overtreatment, and will renew the interest for adjuvant setting
chemotherapy in pMMR/MSS tumours.
•
Although the exact role and best regimen still has to be defined, the spectacular
response rates of immunotherapy in dMMR/MSI tumours in the neoadjuvant
setting will lead to incorporation of this approach in the standard guidelines.
5.1 Introduction
Adjuvant systemic therapy after the treatment of colorectal cancer was developed
in the 70’s and 80’s with the aim to eradicate subclinical micrometastatic disease.
The main active component was 5-fluorouracil, providing around 25–33% relative
risk reduction in death, correlating to an absolute improvement in survival of 7–
12% [1–4]. The relative risk reduction appeared the same across all subcategories,
translating into a meaningful clinical absolute survival benefit of 10–15% in stage
III disease, a smaller 3–5% benefit in high risk stage II disease (T4, tumour perforation, < 10 lymph nodes) and a benefit that is considered too small in low risk
stage II disease [5]. The addition of oxaliplatin to 5FU has been shown to add an
additional 4–5% absolute survival benefit in stage III disease [5]. Other improvements were the substitution of intravenous 5-FU by the oral prodrug capecitabine,
and the finding that in most patients a duration of 3 months is as effective as
6 months, hereby decreasing the chances of neurotoxicity from oxaliplatin [6, 7].
The results of these trials led to the current most commonly used adjuvant schedule of 3 months of capecitabine/oxaliplatin (CAPOX) [8]. The major downside of
the concept of adjuvant systemic therapy for subclinical metastatic disease is that it
is based on an inherently inaccurate risk assessment of the chance of micrometastases mainly based on the presence of nodal metastases. In older series without
adjuvant therapy the 5-yr overall survival in stage II disease is 68–83% and in
stage III 45–65%, with death mostly due to metastatic disease [5]. The value of
discriminating between presence of micrometastases is moderate, and basing the
decision on nodal status inherently leads therefore to both over and undertreatment.
An absolute survival advantage of 10% corresponds with a number needed to treat
of 10, meaning that only 1 out of 10 patients derives survival benefit, whereas with
an absolute survival advantage of 20% benefits 1 in five patients benefits. The current promising developments of ctDNA to detect minimal residual disease might
provide a much more accurate tool to select patients for adjuvant chemotherapy,
with less overtreatment, as discussed below.
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5.2 Rationale for Neoadjuvant Chemotherapy
Giving the adjuvant chemotherapy upfront rather than after the operation has
become common in subgroups of a variety of solid tumours types and is now
considered in colon cancer. There are a number of theoretical and practical advantages of this approach. If there is subclinical metastatic disease present, treatment
started as early as possible might be more effective, and furthermore has a higher
compliance because it avoids any interference from postoperative morbidity. In
addition, preclinical and clinical studies have shown that the stress of surgical
trauma can accelerate the growth of micrometastases, and theoretically neoadjuvant chemotherapy (NAC) could at least partially offset this effect [9]. Taken
together, chemotherapy in a neoadjuvant setting could therefore result in a higher
distant metastases-free and overall survival than when administered in the adjuvant
setting (Fig. 5.1).
The second potential advantage is that when the tumour responds well, there is
the potential for a higher percentage of R0 resections with a lower local recurrence
rate. Whereas in rectal cancer neoadjuvant therapy is a well-established approach
in large advanced tumours with a high risk for R1/2 resection, this is much less
established for colon cancer. Even with multivisceral resections the R0 resection
rate in large advanced colon tumours is lower and the local recurrence rate is
higher than in less advanced tumours [10] (Fig. 5.2).
Fig. 5.1 59-year-old man with anal blood loss was diagnosed with a sigmoid pMMR adenocarcinoma 20cm from the anal verge. A: baseline CT staging, with A1 showing the sigmoid tumor, A2 a
cluster of nodes along main vessels in mesosigmoid and/or EMVI, and A3 a large para-iliac node,
staged cT3N2Mx. Because of the estimated high risk of distant metastases the patient received 3
months of neoadjuvant CAPOX. B: Restaging CT showing little change in the primary tumour and
lymph nodes. Histology of the sigmoid resection specimen: little response, R0 resection of a T3
tumour with EMVI, 7 involved lymph nodes and 3 tumour deposits. No further chemotherapy was
given, and although the patient has an increased risk for distant metastases, he remains with no
evidence of disease at 12 months of follow up
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Fig. 5.2 48-year-old woman was diagnosed with a symptomatic pMMR adenocarcinoma of transverse colon. A: Baseline CT staging showing a circumferentially growing transverse tumour, growing into the mesentery and omentum and potentially anterior peritoneum, with several enlarged
mesenteric lymph nodes, staged cT4N2M0. To improve resectability the patient was treated with
3 months of neoadjuvant CAPOX. B: Restaging CT showing a very good response of the primary
tumour with normalization of the lymph nodes, but with signs of obstruction. Histology of the
extended right hemicolectomy specimen: R0 resection of a transverse colon tumor with ingrowth
into the omentum, and 3 involved nodes. No further chemotherapy was given, and patient remains
without evidence of disease at follow up
A third theoretical advantage is that the neoadjuvant setting provides an opportunity for in vivo testing of the effectiveness of the systemic treatment, which
could become useful when there is recurrent disease at a later stage.
There are also a number of disadvantages of neoadjuvant chemotherapy. In
unresponsive tumours there might be progression of disease, with obstruction or
complications, and the systemic therapy could have a detrimental effect on the
surgical complication rate. Whereas in adjuvant therapy the selection for systemic
therapy is traditionally based on histological features of the resection specimen,
mainly nodal status, in the neoadjuvant setting this selection is mainly based on
CT imaging, with only a moderate accuracy for predicting the T and N stage of the
tumour. This can potentially lead to even more overtreatment by selecting more
patients with a low risk for subclinical metastases.
5.3 Evidence on Neoadjuvant Chemotherapy
For the group of patients with large and locally advanced colon tumours that are
considered unresectable or borderline resectable with a higher risk of a R1/2 resection, both the options of upfront chemoradiation or chemotherapy to increase the
resectability and to improve R0 resection rate have been explored in small older
series, as described in the recent clinical practice guidelines of the American Society of Colon and Rectal Surgeons [11]. As the quality of the evidence is considered
only moderate, the recommendation to use these options to facilitate a margin free
resection is weak. The NCCN
cancer have mentioned the option of using FOLFOX or CAPOX for clinical T4b
®
Clinical Practice Guidelines in Oncology on colon
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since 2016, with the aim to improve resectability. When used in clinical practice
it is customary to start with 2–3 courses of chemotherapy, to evaluate with CT,
and to continue to a total of 4–8 courses when a good response is seen. With
a total of 4–8 neoadjuvant courses, there usually is no need to give any further
chemotherapy after the resection (Fig. 5.1 case).
There is more evidence on the much larger group of resectable T3/4 colon
cancer, with 4 recent reviews [12–15] describing a total of 6 reports on three small
and one large randomized controlled trial, 4 small prospective single arm studies, 2
small single arm retrospective studies, 5 large comparative registry studies, and one
medium-sized comparative retrospective/prospective study. The overall conclusion
is that there generally is no increase in surgical complication rate and that the R0
resection rate is higher. The effect of neoadjuvant chemotherapy on DFS and OS
is more difficult to interpret. Despite the propensity score matching methods used
in the retrospective comparative studies, there still is unknown bias, explaining
some of the conflicting results. The most reliable evidence comes from the RCT’s,
which will be discussed in the next paragraphs.
The FOxTROT study is the largest RCT and can be considered as a landmark
trial that provides most data and evidence on neoadjuvant chemotherapy in colon
cancer [16, 17]. The randomized trial had a 2× 2 factorial design and there were
some changes in both design and treatment arms throughout the trial period of
2008–2016 because of emerging new evidence. More than thousand patients with
T3–T4 Nany M0 were randomized basically between the standard arm of adjuvant 5FU/capecitabine with oxaliplatin for 24 weeks after the operation, or the
experimental arm where the same chemotherapy was given as a split regiment of
6 weeks before and 18 weeks after the operation. As expected, the compliance in
the neoadjuvant group was high, with 90% of patients completing the full 6-week
course of neoadjuvant therapy, with only 4.3% of patients developing obstructive
symptoms requiring an intervention. The surgical complication rate was not different between the two arms. This showed that the strategy of 6 weeks of neoadjuvant
chemotherapy is feasible and safe. Overall, the neoadjuvant group showed a significant downstaging and tumour regression, with a R0 rate of 94% versus 89% in
the standard group. The main endpoint was the 2-year recurrence rate, showing a
significantly lower recurrence rate of 16.9% in the NAC group versus 21.5% in the
standard group. The study was not powered for survival comparison, and showed a
non-significant relative reduction in mortality of 25% that, if sustained with longer
follow up, could correspond to a 4–6% absolute benefit at 5 years. Most likely
the benefit of the neoadjuvant strategy is due to a combination of earlier systemic
treatment, a higher R0 resection rate and a better compliance. A further comparison of the type of recurrences in the two groups could further point at the relative
importance of these mechanisms of action.
The Prodige 22 study is a small randomized trial that randomized 104 patients
with T3cd, T4 or N2 colon tumours between the standard arm of 6 months of adjuvant FOLFOX and the experimental arm of a split course of 2 months neoadjuvant
FOLFOX and 4 months adjuvant FOLFOX [18, 19]. The postoperative morbidity
or surgical complications were not different. There was some tumour regression
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and downstaging, although it was less than expected and not always significant.
The R0 resection rate was high in both arms, and not significantly different: 94%
in the NAC arm and 98% in the standard arm and. The study was not powered for
survival analyses, and revealed small non-significant differences in DFS and RFS
that are in line with the FOxTROT data.
The OPTICAL trial is a large randomized trial, that so far was only reported as
an abstract [20]. From 2016 to 2021 752 patients with colon tumours that on CT
were T4 or T3 with ≥ 5 mm invasion, were randomized between the experimental arm of 3 months mFOLFOX6 or CAPOX before surgery and then 3 months
of further adjuvant therapy versus standard adjuvant chemotherapy at the discretion of the treating physician based on the final histology after resection. The
3-year disease-free survival of 78.4% versus 76.6% was very modestly and nonsignificantly in favour of the neoadjuvant strategy with a HR of 0.83 (P = 0.138).
In a post-hoc analysis the effect was more pronounced in women with a HR of 0.54
(P = 0.025). The 3-year overall survival rate was interestingly enough reported to
be better in the neoadjuvant group, 94.9% versus 88.5% (HR 0.43 (P = 0.01). This
remains difficult to interpret given the small and non-significant 1.8% difference
in 3 yr DFS, and the full publication is eagerly awaited.
Two small trials in the Chinese literature trials are mentioned in the review
by Cheong et al. [12], comparing standard adjuvant CAPOX with a split course
of CAPOX. Again there is no difference reported in morbidity or surgical complications. Both trials suggest an improved overall survival, but they are severely
underpowered for this endpoint.
5.4 Current Status and Remaining Questions
on Neoadjuvant Chemotherapy
If 5% fewer recurrences at 2 years in stage II/III colon cancer can be achieved
by simply moving 6 weeks chemotherapy from adjuvant to neoadjuvant setting as
shown by the FOxTROT study, it is an option that is definitely worth considering.
There are however a number of remaining issues regarding the concept of neoadjuvant chemotherapy, like the duration and the best type of chemotherapy, whether
or not it is better to give everything upfront, how to treat the frail and elderly, and
the question of overtreatment and a better selection of patients who benefit the
most.
Regarding the duration of the course, it has now been established through a
pooled analysis of six randomized trials that in most patients 3 months rather than
6 months of adjuvant CAPOX is sufficient, and this has since become the standard
[6]. There is no reason to think that this would be otherwise in the neoadjuvant
setting. Whether or not the 3 months of chemotherapy should be given entirely
upfront or as a split course is another question that deserves attention. In the setting of very large tumours that require downsizing to improve resectability it seems
common sense to give the full course upfront, at least when the tumour is responding. This has become common practice in many referral centres who have a higher
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volume of these patients. Another question that is currently explored in the FoxTROT 3 trial is whether further intensification with the addition of irinotecan is
beneficial. Many more trials are ongoing [15].
In the FOxTROT trial as well as other trials there was a marked difference
in the response rates of neoadjuvant chemotherapy between pMMR and dMMR
tumours. There was no histological response effect in 23% of pMMR tumours
and in 70% of dMMR tumours, and the significant lower 2-year recurrence rate
was only observed in patients with pMMR tumours [17]. For patients with dMMR
tumours there is now strong emerging evidence of a pronounced effect of immune
checkpoint inhibition, as discussed below.
The main disadvantage of the concept of neoadjuvant treatment is the increased
risk of overtreatment. In the control arm of the FOxTROT study 24% of patients
had T3N0 tumours without additional risk factors, in whom the benefits of
chemotherapy are generally considered too low. This overtreatment is additional
to the overtreatment that is inherently already part of the concept of adjuvant treatment. An improved selection of patients at high risk of recurrence based on better
radiological and histological risk factors would evidently improve the benefit/harm
balance. There are ongoing further analyses of the FOxTROT data addressing this,
and all ongoing trials on neoadjuvant therapy have this question build into the
design. An example is the CONNECTION II trial, where the explicit aim is to test
the value of CMS subtypes as a predictive marker in pMMR colon cancer [21].
A competing strategy to avoid overtreatment is the highly promising technique to
select patients for adjuvant therapy with ctDNA, a technique aimed at detecting
minimal residual disease after the resection of the tumour.
5.5 Circulating Tumour DNA and Adjuvant Therapy
The current paradigm of (neo)adjuvant chemotherapy is to treat a large group
of patients in a ‘blind way’ to target undetected metastatic disease in a smaller
group of patients, eventually benefiting an even smaller group of patients. One of
the potential clinical applications of ctDNA is to assess minimal residual disease
after resection of the tumour and to guide the choices for adjuvant chemotherapy
more on actual presence of metastatic disease than on an estimated risk. Tie et al.
[22] reported on a randomized trial comparing adjuvant chemotherapy for stage II
colorectal cancer based on standard high-risk features versus postsurgical ctDNA
levels. The use of adjuvant chemotherapy declined from 28 to 15%, without compromising recurrence-free survival. Another large prospective observational cohort
study suggested that postsurgical ctDNA in stage II/III disease was able to identify patients who derived benefit from adjuvant chemotherapy with a hazard ratio
of 6.59 [23]. With a highly sensitive test, it is conceivable that a postsurgical
ctDNA negative patient with a stage III tumour will no longer require adjuvant
chemotherapy. There are currently a large number of ongoing studies designed to
use postsurgical MRD assessment with ctDNA to guide adjuvant treatment decisions [24]. Although the technical developments are still ongoing and many issues
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still need to be solved, it is clear that this technique will at some point have the
potential to change the current paradigm of overtreatment of many to benefit a
few.
5.6 Immunotherapy—Immune Checkpoint Inhibition
(ICI)
The idea of harnessing a patient’s own immune system to battle cancer cells
is old, with William Coley as an often-mentioned surgical pioneer who provided proof of concept as early as 1891, with injections of bacteria and bacterial
toxins leading to tumour regression in patients with sarcoma. The clinical usefulness of immunotherapy remained however very modest until the unravelling of
the immune checkpoint mechanism and the subsequent development of immune
checkpoint inhibitors (ICI). Ipilimumab, an antibody that blocks cytotoxic T
lymphocyte-associated protein 4, was approved for metastatic melanoma in 2011,
soon followed by inhibitors of programmed cell death protein (PD) 1 and PD-L1.
After establishing the role of ICI therapy in stage IV melanoma and lung cancer,
it was found to be beneficial in other tumours such as renal cancer, certain haematological cancers, and in the specific subset of microsatellite instable/mismatch
repair deficient (MSI/dMMR) metastasized colorectal cancers.
5.6.1 Deficient Mismatch Repair (dMMR) and Microsatellite
Instability (MSI)
Mismatch repair deficiency is characterized by the deficiency of a specific DNA
repair mechanism encoded by the genes MLH1, MSH2, PMS2 and MSH6. This
leads to the accumulation of mutations and a so-called high tumour mutational
burden. MSI is the molecular phenotype of dMMR cells, with accumulation of
repeated specific sequences of DNA. Tumour biopsies or resections specimens
can be tested either with immunohistochemistry for the loss of protein function
encoded by the four genes, labelling the tumour as pMMR or dMMR, or with
PCR based microsatellite testing, labelling the tumour as MSS or MSI. Initially
testing for dMMR/MSI on biopsies or resection specimens was only performed
selectively as a diagnostic screening tool to detect patients with the hereditary
autosomal-dominant Lynch syndrome. Of the 15% of colorectal tumours that are
dMMR/MSI, only 3% are Lynch associated tumours, generally caused by germline
mutations in one of the four mismatch repair genes. The other 12% of dMMR/MSI
tumours are sporadic, generally caused by somatic hypermethylation of MLH1
promotor region. Sporadic MSI tumours tend to be more right-sided, and occur
more frequently in women and at an older age than MSS tumours. In rectal cancer
the incidence of dMMR/MSI is only around 3%, and relatively more frequently
Lynch-associated.
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The impact on adjuvant therapy choice was low, with only some indication
that dMMR/MSI tumours were potentially less responsive to standard 5-FU based
chemotherapy [5]. The finding that these tumours were highly responsive to
immunotherapy sparked the current intensive interest. ICI was first approved for
st
dMMR/MSI metastatic colorectal cancer that progressed after 1
line standard
therapy in 2017, and is now also approved as first line treatment [25–27]. As
with melanoma, a striking result was the long and durable responses after discontinuation of the therapy in a number of patients, with a flattening of the survival
curve suggesting potential cure. As was common in the development in chemotherapy, the next step was to move ICI to the adjuvant setting to target undetected
micrometastatic disease. Again, this was first shown to be effective in melanoma
and lung cancer, with currently ongoing trials for other tumours. There is however
evidence from translational, preclinical, and early clinical studies to suggest that
ICI therapy for micrometastatic disease is more effective with the primary tumour
in situ. The main hypothesis is that there is a much more efficient priming of Tcells when there is much more tumour antigen present, with often T-cells already
present in the tumour, and with the locoregional immune components more intact
than after surgery, radiotherapy or chemotherapy.
5.6.2 Neoadjuvant Immunotherapy in Colorectal Cancer
There are two landmark papers on neoadjuvant ICI that are drastically changing
our treatment paradigms in dMMR/MSI colorectal cancer. The first paper is the
report of Cercek et al. on the ongoing single arm phase II study of 6 months of
anti-PD-1 in dMMR/MSI rectal cancer [28]. In the early results, all of the twelve
first patients had a clinical complete response, and did not require any further
surgery or chemoradiation. With a median follow up of 12 months there were no
re-growths, and a follow up report with a higher number of patients and especially
a longer follow up is eagerly awaited to confirm the durability of the response.
Given the long-term functional problems in standard rectal cancer treatment and
the current interest in organ preservation options, it is clear that ICI will most likely
become the preferred treatment option in the majority of patients with dMMR/MSI
rectal cancer.
The second paper is the report of Chalabi et al. on the NICHE-1 study and
the follow-up NICHE-2 study reported at ESMO 2022 [29, 30]. The NICHE-1
study was a small exploratory study testing a single dose of CTLA-4 blockade
and two doses of PD-1 blockade in 21 patients with dMMR and 20 patients with
pMMR colon cancer. The treatment was very well tolerated and the resection was
performed six weeks later, with dMMR tumours showing a highly promising major
pathological response with ≤ 10% residual viable tumour in 19/21 cases and a
complete response in 12/21. The dMMR cohort was expanded with the same ICI
regimen in the NICHE-2 study for patients with stage II/III disease to a total of
112 patients, with the main endpoints safety, response and DFS [30]. Toxicity
was very low with grade 3–4 immune reactions in only 3% of patients. A major
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