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Rectal Conditions: Stage IV Rectal Cancer
RussellC.Langan andMartinR.Weiser
40
Introduction
Colorectal cancer is the third most common
cause of cancer-related death in the United States,
with estimates of 147,950 new cases and 53,200
deaths for the year 2020. Approximately 20% of
patients present with synchronous disease, while
an additional 30% of patients experience metastases over the course of their disease. Recently,
the management of both locally advanced and
metastatic rectal cancer has undergone a paradigm shift. Our preference for treatment of
locally advanced disease is total neoadjuvant
therapy, with either induction or consolidation
chemotherapy, followed by chemoradiotherapy
and total mesorectal excision. However, the treatment algorithms for metastatic disease are less
well dened.
The treatment of locally advanced (T3/4 or
N1/2) rectal cancer includes chemotherapy, radiation, and surgery. Chemotherapy and radiation
are utilized to downsize a rectal tumor and facilitate margin-negative resection in the setting of
MRI documentation of a threatened mesorectal
margin. Total neoadjuvant therapy, with either
induction or consolidation chemotherapy in addition to chemoradiotherapy, followed by total
mesorectal excision is a popular treatment strat-
R. C. Langan · M. R. Weiser (*)
Department ofSurgery, Memorial Sloan Kettering
Cancer Center, NewYork, NY, USA
e-mail: Weiser1@mskcc.org
egy. However, such intensive preoperative treatment can delay denitive surgery by 4–6months.
Therefore, alternative approaches are required
for metastatic rectal cancer, generally based on
liver tumor resectability and the extent of pelvic
disease. The decision-making process described
below is diagrammed in Fig.40.1.
Refer to Algorithm in Fig. 40.1
A. Following the diagnosis of rectal cancer, a
thorough disease assessment must take place.
Laboratory investigations should include a
complete blood count, a complete metabolic
panel, and measurement of carcinoembryonic
antigen. Radiographic analysis should be
completed with high-quality contrastenhanced cross-sectional imaging (computed
tomography) of the chest, abdomen, and pelvis. Local staging generally requires proctoscopy with either endorectal ultrasound or
rectal MRI (preferred). If liver metastasis is
suspected, we favor liver MRI or triphasic
computed tomography of the liver.
B. If widespread metastasis is identied, sys-
temic therapy should be administered as outlined in NCCN guidelines. Per recent EORTC
(European Organisation for Research and
Treatment of Cancer) consensus guidelines,
in patients with unresectable metastatic
rectal cancer the primary treatment goal is
© Springer Nature Switzerland AG 2020
S. R. Steele etal. (eds.), Clinical Decision Making in Colorectal Surgery,
https://doi.org/10.1007/978-3-319-65942-8_40
315
316
R. C. Langan and M. R. Weiser
A. Thorough disease workup
Widespread metastasis
B. Systemic therapy
Resectable primary and
resectable metastasis
D. Simultaneous resection
Liver-only metastasis Rectal obstruction
C. Multidisciplinary consultation B. Colostomy, stenting
Unresectable or borderline
R0 resections
possible
H. Chemoradiotherapy
resectable metastasis
E. Systemic therapy, HAIP
Resectable metastasis but
threatened margin in primary
Locally advanced primary
F. Chemotherapy, SCR
G. Liver-first approach
Rectal resection
Fig. 40.1 Algorithm for treatment of stage IV rectal cancer. Following the diagnosis of rectal cancer, a thorough
disease workup must take place (A). Widely metastatic
disease should be treated with systemic therapy per
NCCN guidelines (B). If the metastasis is conned to the
liver, an early consultation with a hepatobiliary surgical
team is warranted (C). There are advantages to resecting
the primary tumor and the metastasis simultaneously (D).
If the liver disease is borderline resectable or unresectable, systemic therapy with or without hepatic arterial
infusion pump (HAIP) therapy should be implemented
(E). Short-course radiotherapy (SCR) can be considered
for very bulky and low lesions (F). Following therapy, if
the liver disease has become resectable and the rectal pri-
maintaining quality of life, alleviating
tumor- related symptoms, and minimizing
treatment-related side effects. Mortality after
resection of the primary tumor in patients
with incurable stage IV colorectal cancer is
I. Watch and wait
mary has also regressed to allow for a R0 resection, we
favor a simultaneous hepatectomy and rectal resection.
However, if the liver disease has become resectable but
the rectal primary tumor remains advanced with a threatened mesorectal margin, treatment options vary. One
approach is liver surgery rst (G), followed by chemoradiation. In the absence of a complete clinical response,
pelvic chemoradiotherapy (H) should be administered followed by total mesorectal excision. Alternatively, longcourse chemoradiotherapy or short-course radiotherapy
with delay for tumor regression can be utilized (if not previously used). If a complete clinical response is achieved
in the primary tumor, a nonoperative approach should be
considered (I)
signicantly higher than mortality after resection for colorectal cancer in general. For this
reason, a conservative approach to the primary tumor, especially in asymptomatic
patients, is warranted. Moreover, in patients
40 Rectal Conditions: Stage IV Rectal Cancer
317
with an asymptomatic rectal tumor and
synchronous liver metastases, if there is no
plan to resect the primary tumor, the EORTC
consensus panel recommends against immediate initiation of pelvic radiotherapy.
If there is colonic obstruction, a diverting
loop colostomy should be considered.
Additionally, endoscopic stenting should be
discussed. However, endoscopic stenting
options for distal low rectal tumors are limited, as difculties are present with stent
migration, inadequate length for stent xation, and unrelenting tenesmus. In a randomized study conducted by Fiori et al., 22
patients with stage IV unresectable rectosigmoid cancer and symptoms of subacute
obstruction underwent either endoscopic
placement of an expandable stent or diverting
proximal colostomy and were followed until
death. The two groups did not differ in treatment-related morbidity or mortality; however, patients who underwent stenting
experienced some benets in length of stay
and restoration of oral feeding and bowel
function. Palliative pelvic radiotherapy also
has a role, with an overall symptom response
rate of 75% according to a systematic review
by Cameron etal.
A study conducted at Memorial Sloan
Kettering Cancer Center (MSK) examined
primary-tumor outcomes in patients with
stage IV colorectal cancer treated with
upfront systemic therapy. The study found
that only 7% of the patients required emergent surgery for primary tumor obstruction or
perforation and 4% required nonoperative
intervention such as stenting or radiotherapy.
Thus, 89% of patients with metastatic
colorectal cancer did not need any direct
symptomatic management for their intact primary tumor during systemic therapy.
C. If the metastatic disease is conned to the liver,
a multidisciplinary discussion and early consultation with a hepatobiliary surgeon are warranted. Optimal treatment for synchronous
hepatic metastases, which occur in 15–25% of
patients with rectal cancer, is a matter of some
disagreement. The principal treatment goal is
complete resection of all primary and meta-
static lesions with a curative intent, but the
choice and sequence of the available treatment
modalities depend on the clinical situation.
Traditionally, rectal resection is preceded by
hepatectomy, with or without perioperative
systemic therapy. However, simultaneous
resections and liver-rst approaches are
becoming more common.
D. If the liver metastasis is resectable and the
rectal primary tumor is either T1 or T2 with
no evidence of nodal disease (N0) or threatened mesorectal fascial margin, we recommend a simultaneous surgical approach. No
improvement in progression-free or overall
survival has been reproducibly documented
for neoadjuvant systemic therapy. In a randomized trial evaluating perioperative
FOLFOX versus surgery alone for resectable
liver metastases, Nordlinger and colleagues
found no difference between chemotherapy
plus surgery and surgery alone in median
overall survival (61.3 and 54.3 months,
respectively; P = 0.34) or median progression-free survival (20.0 and 12.5 months,
respectively; P = 0.068). Our group, therefore, recommends upfront surgical resection
for all patients with resectable disease and
consideration of postoperative
chemotherapy.
Simultaneous resections of both the rectal
primary and hepatic disease have been found
to be safe and efcacious. Due to improvements in operative and perioperative management, simultaneous liver and colon
resections are an accepted approach at specialized centers for selected patients. A
recent study conducted at MSK compared
survival in 320 patients who underwent
simultaneous resections with survival in 109
patients who underwent staged resection.
The two groups did not differ in 1- or 5-year
overall survival or disease- free survival.
Current evidence supports the feasibility,
safety, and equivalent oncologic outcomes of
simultaneous curative resection in a well
selected patient population. Theoretically,
simultaneous resection reduces the need for
subsequent major surgery and therefore allows
earlier initiation of adjuvant systemic therapy
318
R. C. Langan and M. R. Weiser
without possible interruption. More importantly, an upfront simultaneous resection
offers the advantage of avoiding injury to the
liver from systemic therapy (e.g., oxaliplatin),
thus decreasing the risk of postoperative liver
failure. All four meta-analyses of simultaneous resections published to date (in 2010–
2014) demonstrated lower overall
complication rates for simultaneous resections than for staged resections.
E. If borderline resectable or unresectable
hepatic disease is identied, systemic therapy
is warranted, as is assessment for hepatic
arterial infusion pump (HAIP) therapy with
oxuridine. In a single-arm trial investigating
hepatic arterial infusion pump therapy with
oxuridine in 49 colorectal cancer patients
with unresectable hepatic metastases,
D’Angelica et al. found an overall response
rate of 76% and a conversion-to-resection
rate of 47%. Median overall survival was
38months, with progression-free survival of
13months. It should be noted that the median
number of hepatic metastases in this patient
population was 14, and 65% of the patients
had shown no response to conventional systemic therapy.
F. For locally advanced primary tumors (T3/4,
N1/2, with a threatened mesorectal margin),
treatment algorithms are less well dened,
as tumor down-staging is often necessary to
ensure a margin-negative resection. Options
include total neoadjuvant therapy (induction
or consolidation chemotherapy with chemoradiotherapy) and chemotherapy alone. One
possible sequence is neoadjuvant chemotherapy, liver resection, chemoradiotherapy
and nally rectal resection. Another strategy
recently developed by international consensus is the sequence of neoadjuvant chemotherapy, radiotherapy, hepatic resection, and
delayed rectal resection. The theory behind
this liver-rst strategy is that a delay of at
least 8weeks between radiotherapy and rectal surgery promotes tumor down-staging
and increases the chance of a complete
response, without increasing surgical complications. Thus, the delay is thought to not
disadvantage the patient. The timing of
hepatic resection does remain a matter of
debate.
Short-course radiotherapy (SCR) offers
additional options. This modality involves a
exible schedule of delivering accelerated
and hypofractionated intensive radiotherapy
in ve 25-Gy fractions over 5 days (5 × 5
model). Literature suggests that compliance
is high, with side effects such as nausea, diarrhea, proctitis, tenesmus, urinary frequency,
dysuria, and erythema/desquamation of the
perineum usually experienced only after
treatment is completed. Also, the overall
treatment time is shortened, since surgery
should be performed either within 7days or
after 21 days, avoiding the period of maximum inammatory response. Another advantage is the potential for lower costs.
A recent systematic review and metaanalysis examined the ndings of eight randomized controlled trials for a total of 6894
patients who had undergone SCR.Three trials (n= 3682) compared SCR and selective
postoperative radiation alone or combined
with chemotherapy. The rates of local recurrence were signicantly lower in patients
who received SCR (hazard ratio 0.44, 95%
condence interval 0.35–0.56). However, no
benet in overall survival was observed. Two
other trials (n = 638) found no statistically
signicant differences in the rates of local
recurrence or overall survival between SCR
and long-course chemoradiotherapy. Patients
who received SCR had lower rates of grade 3
or 4 acute treatment-related toxicities (relative risk 0.11, 95% condence interval 0.05–
0.22), but no difference in late toxicity was
observed. Overall, the data indicate that SCR
is a reasonable treatment strategy for resectable locally advanced rectal cancer.
G. Since survival in patients with metastatic
rectal cancer is often limited by hepatic disease, a liver-rst approach offers the advantage of avoiding delays associated with
treatments directed at the primary tumor.
Recent data suggest that patients treated with
the liver- rst approach are more likely to
40 Rectal Conditions: Stage IV Rectal Cancer
319
complete the full treatment protocol and may
avoid delays due to complications of rectal
surgery. Another advantage is that in a
chemo-naïve liver the risk of postoperative
hepatic failure is lower. The recent EORTC
consensus stated that standard chemoradiotherapy with a uoropyrimidine- alone chemotherapy backbone likely results in
undertreatment of the metastatic disease for a
substantial period, which may be further prolonged by postoperative complications if the
rectal tumor is removed rst. Therefore, the
panel recommends against starting the treatment of metastatic (resectable) rectal cancer
with radiotherapy.
H. The oncologic benet of administering pelvic
radiotherapy to rectal cancer patients with
simultaneous resectable liver metastases has
recently been challenged by the ndings of an
MSK analysis of 185 patients who underwent
complete resection of the rectal primary
tumor and liver metastases. In that cohort,
97% of patients received chemotherapy during their treatment course and 49% received
pelvic radiotherapy either before or after the
rectal resection. The 5-year rate of diseasespecic survival was 51% for the entire
cohort, with a median follow-up of 44months
for survivors. About 70% of patients had a
recurrence. However, only 10% of all patients
had a pelvic recurrence in combination with
other sites, and only 4% of patients had an
isolated pelvic recurrence. A competing risk
analysis found that the likelihood of a pelvic
recurrence was signicantly lower than that
of an extrapelvic recurrence (P<0.001). The
authors concluded that selective exclusion of
radiotherapy is appropriate in rectal cancer
patients with liver metastases.
Additional support for the use of chemotherapy and selective pelvic radiotherapy
comes from an MSK retrospective review
demonstrating that FOLFOX chemotherapy
can serve as a substitute for pelvic radiotherapy. The patients received preoperative
FOLFOX without chemoradiotherapy as initial management of locally advanced rectal
cancer (because of suspected metastatic dis-
ease, relative contraindications to radiotherapy, or patient refusal of radiotherapy). Six
patients with stage II or III rectal cancer
received preoperative FOLFOX, and 14
patients with synchronous metastatic colon or
rectal cancer received preoperative FOLFOX
alone or in combination with bevacizumab,
followed by resection of the primary tumor.
Overall, in 35% of patients the primary tumor
had a pathologic complete response.
Moreover, of the six patients who received
only FOLFOX, two had a pathologic complete response and three had treatment effects
of 99%, 95%, and 90%, respectively. These
ndings highlight the value of chemotherapy
for locally advanced rectal cancer and call
into question the necessity of reexive
chemoradiotherapy for locally advanced or
metastatic rectal cancer.
The ongoing PROSPECT trial (Preoperative
Radiation or Selective Preoperative Radiation
and Evaluation before Chemotherapy and
TME) challenges the current treatment paradigm and attempts to individualize treatment
by using radiotherapy selectively rather than
reexively. In this phase II/III multicenter trial,
neoadjuvant FOLFOX with selective use of
uorouracil and pelvic radiation is being tested
against the current standard of upfront uorouracil and pelvic radiation for rectal cancer
patients undergoing low anterior resection
with total mesorectal excision. By randomizing patients to the two arms, the PROSPECT
trial provides an opportunity to reduce the use
of pelvic radiation in patients who might not
benet from it.
I. Another argument to choose a liver-rst strat-
egy is the possibility of rectum preservation
with a watch-and-wait strategy in patients
whose primary tumor has a clinical complete
response to chemotherapy and chemoradiation. In an MSK analysis of 145 patients with
stage I to III rectal cancer, 73 patients had a
clinical complete response (no detectable
tumor by clinical exam, endoscopy, or imaging) after neoadjuvant chemoradiotherapy
and were treated nonoperatively. This cohort
was then compared to 72 matched patients
320
R. C. Langan and M. R. Weiser
treated conventionally who achieved a pathologic complete response and underwent total
mesorectal excision. (Of note, neoadjuvant
therapy administered to the nonoperative
patients was not standardized in this retrospective series.) Although all patients received
pelvic radiation (45–55Gy) plus a uoropyrimidine, beginning in 2011 most received
induction FOLFOX followed by chemoradiotherapy and then assessment for surgery.
Patients with clinical complete response were
offered the nonoperative, watch-and-wait
approach, which included frequent monitoring with clinical and endoscopic exams every
3 months and cross-sectional imaging every
6months.
After a median follow-up of 3.5years, 74%
of the 73 watch-and-wait patients achieved a
durable and sustained clinical complete
response. The 19 patients (26%) who had local
recurrence underwent salvage surgery. One
patient had a recurrence after salvage surgery.
Thus, the local control rate was 98%. Overall,
77% of patients were able to complete treatment with rectum preservation, and this conservative approach did not compromise outcomes.
A phase II multicenter randomized trial is currently investigating the use of neoadjuvant
treatment for locally advanced rectal cancer
and the use of nonoperative management in
patients with clinical complete response.
More recently, International Watch and
Wait Database data from 775 patients from 11
countries and 35 participating institutes was
presented at the 2017 annual meeting of the
American Society of Clinical Oncology.
Induction treatment (chemoradiotherapy in
90% of cases) produced a clinical complete
response in 90% of the patients, and those
patients were included in the analysis. With a
median follow-up of 2.6years, local regrowth
occurred in 25% (n = 167) of patients. Of
note, 84% of the occurrences of local regrowth
occurred within the rst 2years of follow-up.
The 3-year overall survival rate was 91% for
the full cohort and 87% for patients with local
regrowth.
Although the patients in this cohort did not
have metastases, we believe the watch-andwait treatment strategy can be extrapolated to
stage IV rectal cancer with resectable hepatic
metastases.
Acknowledgment The authors gratefully acknowledge
the editorial assistance of Arthur Gelmis.
Suggested Reading
Adam R, et al. Managing synchronous liver metastases
from colorectal cancer: a multidisciplinary international consensus. Cancer Treat Rev. 2015;41:729–41.
Butte JM, etal. Patterns of failure in patients with early
onset (synchronous) resectable liver metastases from
rectal cancer. Cancer. 2012;118:5414–23.
Cameron MG, et al. Palliative pelvic radiotherapy for
symptomatic rectal cancer- a prospective multicenter
study. Acta Oncol. 2016;55:1400–7.
D’Angelica MI, etal. Phase II trial of hepatic artery infu-
sional and systemic chemotherapy for patients with
unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes.
Ann Surg. 2015;261:353–60.
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tosigmoidal obstruction. Colostomy vs. endoscopic
stenting. A randomized prospective trial. Anticancer
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for Research and Treatment of Cancer Gastrointestinal
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cancer. Eur J Cancer. 2016;63:11–24.
Nordlinger B, et al. Perioperative FOLFOX4 chemo-
therapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC
40983): long-term results of a randomised, controlled,
phase 3 trial. Lancet Oncol. 2013;14:1208–15.
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patients with synchronous stage IV colorectal cancer
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Rectal Cancer: Watch andWait
AngelitaHabr-Gama, GuilhermePaginSãoJulião,
BrunaBorbaVailati, andRodrigoOlivaPerez
41
Refer to Algorithm in Fig. 41.1
A. In up to 42% of patients undergoing neoadju-
vant chemoradiotherapy (nCRT) for advanced
rectal cancer, complete tumor regression may
develop depending on variables including
baseline features and specic treatment
regimens.
B. Patients with complete clinical response
(cCR) based on clinical (including digital
rectal examination), endoscopic and radiological ndings have been offered no immediate radical surgery. Instead, it has been
suggested that strict surveillance, also known
as the “Watch and Wait” (WW) strategy, with
frequent reassessment of tumor response by
an experienced colorectal surgeon and radiological imaging could provide safe and
acceptable oncological outcomes.
C. Clinical assessment of tumor response can
accurately detect pathological response when
stringent criteria are used. These ndings
include the absence of any residual ulcer,
mass or stenosis and only clinically detectable whitening of the mucosa, telangiectasias
and/or slight induration of the rectal wall.
A. Habr-Gama · G. P. SãoJulião · B. B. Vailati
R. O. Perez (*)
Angelita andJoaquim Gama Institute,
São Paulo, Brazil
D. On the other hand, the low overall sensitivity
of these features in identifying a pCR will
inevitably lead to a signicant proportion of
patients that still undergo radical surgery in
the presence of incomplete clinical response,
but complete pathological response.
E. In addition, clinical/endoscopic ndings
should be further supported by radiological
imaging preferably by high-resolution
Magnetic Resonance or alternatively, PET-CT
showing no evidence of residual disease.
F. Digital rectal examination (DRE) is perhaps
one of the most relevant tools in tumor
response assessment. In terms of DRE, a
cCR is the absence of any irregularity of the
rectal wall. There is currently no single diagnostic tool that can possibly replace the
information given by DRE.Very frequently,
irregularities of the rectal wall are better felt
than seen, and should be considered as
highly suspicious for residual cancer. In the
presence of rectal wall irregularities, mass
ulceration or stenosis, patients are recommended standard radical resection. The area
can be thickened and rm, but to be considered a cCR, the surface has to be regular and
smooth.
G. Endoscopic assessment is also very impor-
tant. Whitening of the mucosa and telangiectasia are usually seen in patients with a cCR
(Fig.41.2). The presence of any ulceration or
mucosal irregularity missed on DRE should
© Springer Nature Switzerland AG 2020
S. R. Steele etal. (eds.), Clinical Decision Making in Colorectal Surgery,
https://doi.org/10.1007/978-3-319-65942-8_41
321
322
Fig. 41.1 Algorithm for Watch and Wait
A. Habr-Gama et al.
Fig. 41.2 Endoscopic view of rectal cancer that developed complete clinical response after neoadjuvant chemoradiation, showing whitening of the mucosa and
telangiectasia
prompt additional investigations and usually
rule out a cCR.
H. Magnetic Resonance (MR) imaging should
be routinely used for the assessment of
response in patients after CRT. Currently,
we would only consider a true complete
responder in a patient showing low signal
intensity area replacing the area of the previous tumor and no evidence of disease on
clinical and endoscopic examination
(Fig.41.3). The presence of mixed signal
intensity within the area of the previous
cancer should raise a suspicion of an
incomplete clinical response. In addition to
the assessment of the rectal wall, the mesorectum is also at risk for the presence of
residual cancer despite complete primary
regression (ypT0N1). Therefore, MR
imaging should also provide the colorectal
surgeon with information regarding possible mesorectal (or even lateral node)
involvement regardless of primary tumor
response.
I. PET/CT has been used for the assessment of
tumor response to neoadjuvant chemoradiation therapy. It offers information on tumor
metabolism in addition to standard radiological anatomical features. Recently, it has been
suggested that combination of tumor volume
and metabolism reduction provided by
sequential PET-CT imaging (before and after
CRT) may be a useful predictor of complete
tumor response to treatment.
J. Timing of assessment after CRT completion
may also be relevant. Longer intervals were
originally thought to be associated with
higher pCR rates. However there are conicting data suggesting that longer intervals may
41 Rectal Cancer: Watch andWait
Fig. 41.3 MR imaging of rectal cancer after neoadjuvant treatment showing complete radiological response, as low
signal intensity
323
or may not increase tumor response.
Accordingly, there are data to support that
longer intervals may increase or not postoperative morbidity. It has been our practice to
assess tumor response after at least
8–10weeks after CRT completion.
K. Endoscopic forceps biopsies may be mislead-
ing. It has been our practice to AVOID endoscopic biopsies in the presence of a complete
clinical response. In the presence of incomplete clinical response, positive biopsies (of
residual adenocarcinoma) may provide conrmation of residual cancer at that particular
time period after CRT completion. However,
negative biopsies (for residual adenocarcinoma) rarely correlate to the presence of complete pathological response. Therefore,
patients should not be considered a cCR based
on ndings of negative endoscopic biopsies.
L. Transanal local excision or full excisional
biopsy of the residual lesion is a powerful diagnostic tool. It provides adequate and complete
pathological information regarding the ypT
status, tumor regression grade, differentiation,
and other pathological features. However, it
may also have signicant disadvantages
including frequent wound dehiscences and
considerable associated rectal pain.
M. Therefore, when deciding between local exci-
sion and observation alone for the management
of patients with cCR following neoadjuvant
CRT, one has to balance the benets of pathological conrmation of a complete pathological
primary tumor response to the disadvantages of
postoperative morbidity and worse anorectal
functional outcomes, when compared to observation alone. It has been our practice to only
consider local excision among selected patients
with incomplete clinical response as a denitive treatment strategy.
N. A considerable number of patients with com-
plete regression of the primary cancer after
CRT may still harbor residual adenomas at
the site of the primary rectal cancer. These
lesions usually harbor high grade dysplasia
adenomatous tissue and may be more resistant to CRT than we expected. Full-thickness
excision of these lesions provides appropriate management of the adenoma in addition
to accurate assessment of primary cancer
response within the rectal wall to CRT of
these patients and should be the preferred initial treatment alternative.
O. When a non-operative strategy for cCR in
rectal cancer is considered, a relatively intensive follow-up is required. Patients should be
encouraged to adhere to this strict follow-up
program in order to allow early recognition
of any local or systemic recurrence and therefore, increasing the chance of a successful
324
A. Habr-Gama et al.
salvage treatment. After initial assessment of
response conrming a cCR, visits should be
performed every 1–2months during the rst
year, every 3months during the second year
and every 6months thereafter. Digital rectal
examination (DRE), proctoscopy and CEA
level determination are recommended for all
visits. Timing for radiological assessment
during follow-up has not yet been standardized. Routine MR for the assessment of the
rectal wall, mesorectum and pelvic nodes
every 6months for the rst 2years and yearly
thereafter has been our practice.
P. Patients managed non-operatively under the
WW strategy were originally reported to have
similar long-term oncological outcomes to
patients with complete pathological response
after radical surgery. These ndings further
support the idea that patients with a cCR may
be spared from the surgical morbidity and
mortality of radical surgery with no oncological compromise and improved colostomy-free
survival. In addition, functional outcomes of
patients managed non- operatively not only
appear to be better than radical surgery but
also to other organ- preserving strategies
(transanal local excision).
Q. Local recurrences after this treatment strat-
egy are still a concern and may develop at
any time during follow-up. The majority of
local recurrences seems to develop within the
rst 12months of follow-up and may represent limitations in accurate identication of
microscopic residual disease among “apparent” complete clinical responders. For these
reasons, these “early recurrences” developing within the initial 12months of follow-up
have been called “early regrowths” instead.
Still, close and strict follow-up may allow
early detection of regrowths leading to identical oncological outcomes to patients with
incomplete clinical response immediately
after 8–12 weeks from CRT completion.
However, patients with local regrowths
appear to be at higher risk for the development of systemic recurrences when compared to patients with no local regrowth.
R. Local recurrences (late and early regrowths)
are usually amenable to salvage therapies,
often allowing sphincter preservation and are
associated with excellent long-term local disease control.
S. Considering that the rate of complete clinical
or pathological response was historically
<30% of patients across most of the studies,
one could assume that this treatment strategy
could benet a rather limited proportion of
patients with rectal cancer. However, the
observation of increased rates of complete
response (clinical or pathological) using regimens with consolidation chemotherapy,
increased primary RT boost doses and with
the inclusion of earlier stages of disease
(cT2N0 otherwise candidates for ultra-low
resections or APRs) may result in over 50%
that may ultimately avoid surgical resection.
T. Patients with a complete clinical or pathologi-
cal response to CRT are still at risk for developing systemic recurrences. There is insufcient
data to support the routine use for adjuvant chemotherapy among these patients. However,
with the increased use of regimens with consolidation chemotherapy in association with
RT, patients may ultimately have received
almost a complete course of adjuvant chemotherapy by the time neoadjuvant therapy has
been completed and prior to any denitive surgical or non-surgical management.
U. Several studies have focused on the search
for predictive features on pre-treatment biopsies that could possibly identify complete
responders to neoadjuvant CRT prior to neoadjuvant treatment initiation. However, gene
expression signatures have failed to provide
clinically useful and reproducible information to accurately identify patients that ultimately will develop complete tumor
regression and/or will avoid denitive surgical management. The presence of signicant
intratumoral heterogeneity may have contributed to these ndings, as small biopsy samples may ultimately not be representative of
the entirety of the primary rectal cancer, and
therefore insufcient to provide accurate prediction of response.
Figure 41.1 illustrates treatment protocol for
rectal cancer.