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G. J. Chang and T. P. Nickerson
after transanal endoscopic microsurgery (TEM) for T1
rectal cancer. Dis Colon Rectum. 2010;53(9):1234–9.
67. Jeong JU, Nam TK, Kim HR, Shim HJ, Kim YH,
Yoon MS, et al. Adjuvant chemoradiotherapy
instead of revision radical resection after local excision for high-risk early rectal cancer. Radiat Oncol.
2016;11(1):114.
68. Rockwood TH, Church JM, Fleshman JW, Kane
RL, Mavrantonis C, Thorson AG, et al. Patient
and surgeon ranking of the severity of symptoms associated with fecal incontinence: the fecal
incontinence severity index. Dis Colon Rectum.
1999;42(12):1525–32.
Complete Clinical Response
inRectal Cancer After
Neoadjuvant Therapy: Organ
Preservation Strategies
andtheRole ofSurgery
LauraMelinaFernandez,
GuilhermePaginSãoJulião, BrunaBorbaVailati,
AngelitaHabr-Gama, andRodrigoO.Perez
4
Introduction
Surgical management of low rectal cancer is
associated with a signicant rate of postoperative
complications. Even mortality may be quite signicant, depending on patients’ age and comorbidities [1]. In addition, even after an uneventful
recovery, patients may still have to deal with signicantly negative functional consequences. A
major proportion of patients will develop fecal
incontinence and considerable rates of low anterior resection syndrome [2, 3]. These symptoms
may be so signicant that a proportion of these
patients will require antegrade enemas performed
L. M. Fernandez · G. P. SãoJulião · B. B. Vailati
Angelita & Joaquim Gama Institute,
Sao Paulo, Brazil
A. Habr-Gama
Angelita & Joaquim Gama Institute,
Sao Paulo, Brazil
Colorectal Surgery Division, University of São Paulo
School of Medicine, Sao Paulo, Brazil
R. O. Perez (*)
Angelita & Joaquim Gama Institute,
Sao Paulo, Brazil
Colorectal Surgery Division, University of São Paulo
School of Medicine, Sao Paulo, Brazil
Ludwig Institute for Cancer Research São Paulo
Branch, Sao Paulo, Brazil
through an endoscopically placed cecostomy as
the last resource to avoid a denitive stoma [3].
Even though denitive colostomy rates have been
reported to be ≤10% in dedicated centers for the
management of rectal cancer, long-term colostomy rates may increase to ≥22% due to anastomotic failures related to poor function, leaks, or
even local recurrence [4]. Finally, patients who
underwent a radical surgery for rectal cancer
have more than twofold increased risk for being
out of work, despite being recurrence-free. The
risk increased according to the type of operation
performed (higher for APR compared to AR) and
to the presence of surgical/postoperative complications [5].
Neoadjuvant CRT may lead to signicant
tumor regression of rectal cancers that can be
observed not only in the primary tumor but also
in perirectal nodes, setting the “perfect” scenario
for organ preservation strategies such as transanal excision (TAMIS) of small and supercial
residual tumors [6, 7]. In addition, the observation that this effect may be so intense leading to
complete tumor regression in up to 30% of
patients [pathological complete response (pCR)]
prompted surgeons to an attempt in the identication of these patients before surgical resection,
known as complete clinical response (cCR) [7].
These patients with complete tumor regression to
© Springer Nature Switzerland AG 2019
S. Atallah (ed.), Transanal Minimally Invasive Surgery (TAMIS) and Transanal Total Mesorectal
Excision (taTME), https://doi.org/10.1007/978-3-030-11572-2_4
31
32
L. M. Fernandez et al.
nCRT would also constitute the ideal candidates
to consider organ preservation strategies such as
no immediate surgery and strict surveillance
(also known as the “watch and wait” strategy
(WW)) [8]. In order to even consider these
approaches, colorectal surgeons have to address
several aspects of the assessment of the disease,
patients, and treatment modalities that may be
quite relevant during their clinical decisionmaking process.
Neoadjuvant Chemoradiation
(nCRT): Indications andOptions
Following the results of the German trial, nCRT
was considered the preferred initial strategy for
most cT3–4 or cN+ rectal cancer patients due to
the potential benets in terms of local disease
control after radical surgery [9, 10]. However, the
MERCURY study suggested that nCRT could
preferably be restricted only to patients at highest
risk for local recurrence after TME.This would
include patients with radiological evidence of a
threatened or positive circumferential margin
(cCRM+), presence of extramural venous invasion (cEMVI+), and ≥3 positive lymph nodes
(cN2) [11]. In addition, preoperative radiation
following radical surgery was shown to result in
inferior functional outcomes and higher surgical
morbidity when compared to surgery alone [12,
13]. Altogether, these ndings suggested that the
sole benet of nCRT would be to improve local
disease control only in high-risk rectal cancer
patients (dened by high-resolution MR).
Considering that baseline staging may affect
rates of response to nCRT, one could expect that
very few patients with considerably advanced
disease would ever develop a complete clinical
response and benet from avoiding radical surgical resection.
Instead, the idea of offering nCRT to intentionally achieve a cCR and avoid radical surgery
with its related comorbidities led colorectal surgeons to consider nCRT to more early-stage disease, particularly in most distal tumors otherwise
candidates for abdominal perineal resections or
ultralow intersphincteric anastomosis (and worse
expected anorectal function). Patients with
cT2 N0 or early cT3N0 are potentially more
likely to develop a complete clinical response
following nCRT and could benet the most from
nCRT if organ preservation is considered
[14–16].
Therefore, nCRT should be considered for
local disease control purposes in patients with
high-risk features (threatened cCRM, cN2, or
cEMVI+) if total mesorectal excision (TME) is to
be performed regardless of response. However, it
could be offered to most rectal cancer patients if
organ preservation is an option (including stage I
disease—mrT2N0M0) [17].
Different regimens of neoadjuvant chemoradiation may inuence response rates and should
be considered if an organ preservation approach
is an option. Long-course CRT was the rst regimen associated with signicant rates of complete response. However, with the idea of
prolonged interval period for the assessment of
response, short-course RT may result in similar
rates of response to long-course regimens [18].
In addition to the effect of time interval, the
nal dose of radiation therapy and the method of
delivered may also inuence the odds of developing a cCR. Dose escalation studies have demonstrated a direct relationship between CR rates
with doses of RT delivered to the primary tumor
[19]. In this mathematical model, depending on
tumor size (as an estimate of tumor volume),
progressive increases in RT dose (dose escalation) would lead to predictive rates of major and
complete response [19]. Dose escalation may be
facilitated with the combination of external
beam or intensity- modulated RT (EBRT or
IMRT) with endorectal brachytherapy (HBRT)
or even with contact RT.The idea of adding signicant doses of RT with these approaches may
ultimately maximize the chances of developing
complete clinical response and still avoid major
treatment-related toxicity [20–22]. Recently,
one study has investigated the role of CXB in
patients with an initial incomplete clinical
response (residual tumor ≤3cm) in successfully
achieving a complete clinical response and
improving the chances of organ preservation
[23].
4 Complete Clinical Response inRectal Cancer After Neoadjuvant Therapy: Organ Preservation…
33
Finally, another way of increasing the rates of
cCR and organ preservation is optimization of
concomitant or even exclusive chemotherapy
regimens.
The incorporation of additional chemotherapy
cycles in standard nCRT has been suggested. The
incorporation of additional chemotherapy during
the interval between RT completion and assessment of response using 5FU-based chemotherapy
(consolidation CRT regimens) demonstrated an
increase of CR rates to more than half of consecutive patients with T2/T3 rectal cancer [24,
25]. Although the observation that chemotherapy
may have an important role in tumor regression,
the incorporation of additional drugs to 5FU has
been disappointing. The addition of oxaliplatin
did not improve pCR rates in most studies.
Instead, it resulted in signicantly higher toxicity
rates [26].
Alternative neoadjuvant strategies that could
spare patients from the potential detrimental
effects of radiation (with the same benets) are
an attractive alternative. Patients may develop
worse functional outcomes after TME in the setting of previous exposure to RT [13]. Even
patients that develop a cCR and avoid radical surgery may not have perfect function [27, 28]. In
this setting, the use of chemotherapy alone is an
attractive option and has been used to restrict
standard CRT to patients showing poor response
to chemotherapy alone and therefore decreasing
the number of patients receiving RT [29]. Also,
the incorporation of biological agents including
anti-EGFR or anti-VEGF has been tested in the
neoadjuvant setting of patients with rectal cancer.
Even though these agents have demonstrated
good safety proles, their real benets in terms of
tumor regression have been even more disappointing with pCR rates even lower than usually
observed with standard CRT regimens [30–32].
A recent study reported the results with the
use of total neoadjuvant treatment (TNT, induction of uorouracil- and oxaliplatin-based chemotherapy followed by CRT) for patients with
rectal cancer. The authors compared patients
treated with standard long-course neoadjuvant
regimen followed by postoperative adjuvant chemotherapy with patients receiving TNT. TNT
consisted of systemic chemotherapy rst
(FOLFOX) followed by nCRT and nally radical
surgery. The comparison of TNT to standard
nCRT-surgery-adjuvant suggested higher rates of
complete planned treatment among patients with
TNT regimen. Although very promising and
attractive, the implementation of TNT in clinical
practice should be done with caution. The inclusion of systemic chemotherapy, including oxaliplatin in this regimen, may lead to overtreatment
of a signicant proportion of patients that may
have ultimately never have required oxaliplatin in
the adjuvant setting. Also, TNT will need to be
compared to standard nCRT with consolidation
chemotherapy (without oxaliplatin) already with
considerably high cCR and organ preservation
rates.
Assessing Tumor Response tonCRT
Assessment of tumor response to nCRT becomes
crucial when considering patients for organ preservation management. During this process two
important issues remain as challenges: the optimal timing for assessment and clinical/radiological tools for this purpose.
Assessment of tumor response should be routinely performed independently of the decision
for an organ-preserving strategy. Even if the plan
is radical surgery, it is important to consider that
CRT may lead to signicant modications in the
primary tumor dimension and architecture and its
relationship with surrounding tissues. Knowing
these potential anatomical changes between preand posttreatment status ahead of time may help
in optimization of intraoperative surgical strategies and anticipate surgical challenges during the
procedure [33].
Intervals After nCRT
Tumor regression after nCRT appears to be timedependent. The rst association between different time intervals (from CRT completion and
surgery) and tumor response was reported by the
French randomized trial comparing 2 versus
34
L. M. Fernandez et al.
6weeks from nCRT.The study showed that those
patients with longer interval to surgery (6weeks)
were more likely to present tumor regression
after nCRT [34]. Six-week intervals from nCRT
completion to assessment of tumor response
shortly became the standard of care for many
years. However, retrospective data suggested that
patients operated on after longer intervals from
CRT completion, as long as 12weeks, were more
likely to develop pCR [35]. After the observation
that these considerably longer intervals could
increase response to CRT, a hypothesis was made
suggesting that waiting more time to surgery
could lead to tissue brosis and increased technical difculties and postoperative morbidity after
radical surgery. In order to address this concern,
a prospective, non-randomized study evaluated
patients in nCRT regimens with progressively
longer interval periods prior to surgical resection
[36]. Patients after a 6-week interval showed similar postoperative complications than patients
after a 12-week interval. In addition, after progressively longer intervals (6, 12, 18, and
24weeks), the study showed that longer intervals
were associated with signicantly higher rates of
pCR with no negative impact on postoperative
morbidity, even with additional chemotherapy
cycles during the longer intervals (consolidation
mFOLFOX) [37]. However, another recently
published prospective randomized study failed to
demonstrate increased rates of pCR when comparing 7- and 11-week intervals from standard
nCRT. Moreover, the trial observed that more
postoperative complications and worse quality of
the mesorectum were associated with the
11-week interval group, suggesting the potentially negative effects of prolonged time intervals
after nCRT associated with brotic changes in
the surgical and previously irradiated elds [38].
The optimal interval after nCRT remains
undetermined, and additional ongoing trials will
provide more data to allow us to understand the
benets and risks of waiting extended intervals
after treatment. One recently published study
suggested that patients with an excellent radiological response and minor irregularities during
the clinical exam, referred as “near”-complete
responses, may benet from additional waiting
period. In this study, patients with a “near” clinical complete response and mrTRG1 or 2 were
deferred from immediate radical surgery and
underwent further reassessment in a 6–8-week
interval. Outcomes revealed that 90% of these
patients went on to achieve a cCR and were successfully managed by organ preservation [39].
Altogether, it is possible that individual tumors
respond differently to nCRT as a function of
time. In this setting, responsive tumors may
require and benet from extended intervals,
whereas unresponsive tumors may not [40].
Studies fortheAssessment
ofResponse
Clinical andEndoscopic Findings
Clinical assessment remains as one of the most
important tools in the evaluation of tumor
response to treatment. Digital rectal examination
(DRE) may be able to detect subtle residual irregularities within the rectal wall, residual masses,
ulceration, or stenosis, even in the absence of
clinical symptoms after nCRT.During DRE, the
surgeon has to be able to feel a regular and
smooth surface with only mild induration and
subtle loss in the pliability of the rectal wall.
These are acceptable ndings consistent with a
cCR [7].
Suspicious ndings of incomplete clinical
response (irregularity or supercial ulcer missed
during DRE) are easily detected during endoscopic evaluation. Instead, a at white scar and
telangiectasia are normal ndings encountered
during endoscopic assessment of patients with a
cCR (Fig.4.1).
In the context of a cCR (during clinical and
endoscopic assessment), routine endoscopic
biopsies are not recommended. In other words, in
the presence of a regular and smooth mucosa,
there is no need for a negative biopsy to conrm
a complete clinical response. Even in the presence of an incomplete clinical response, endoscopic biopsies should be interpreted with
caution. A negative biopsy in the context of residual ulcers, mass, or stenosis (incomplete clinical
4 Complete Clinical Response inRectal Cancer After Neoadjuvant Therapy: Organ Preservation…
Radiological Assessment
Radiological studies are also essential for the
assessment of response not only to conrm clinical and endoscopic ndings of a cCR but also
provide additional information of the mesorectum compartment unavailable to the nger or the
endoscope. High-resolution magnetic resonance
(MR) is routinely used for the assessment of
tumor response. The ability to discriminate
between brotic changes and residual disease has
improved with advances in technology, placing
Fig. 4.1 Typical endoscopic ndings of a cCR with whitening of the mucosa and the presence of telangiectasias.
No ulceration or evident mass is present. cCR complete
clinical response
MR as an integral part in the assessment of
response to nCRT [43]. Typical ndings of complete tumor regression include the presence of
low-signal intensity areas in the area previously
harboring the rectal cancer with multiple patterns
[43] (Figs. 4.3 and 4.4). MR may estimate the
pathological tumor regression grade (TRG) by
providing a similar radiological scoring system
(mrTRG) and therefore able to identify patients
with poor or good response prior to surgical treatment and with a signicant correlation between
response and survival [33, 44].
Diffusion-weighted magnetic resonance imaging (DWI-MR) may provide additional information to standard MR imaging. The properties of
35
Fig. 4.2 Endoscopic ndings consistent with incomplete
clinical response including the presence of an obvious
ulcer and signicant amount of brin covering it (yellow
arrows)
response) is rarely associated with no residual
cancer. Most of these patients will have residual
viable cancer in nearly 80% of the cases despite a
negative endoscopic biopsies [41] (Fig.4.2). An
interesting study has revealed that after nCRT,
the mucosa is the layer of the rectal wall less
likely to harbor residual cancer cells [42].
Therefore, the presence of a negative biopsy
should not be interpreted as a complete clinical
response or as an accurate marker of a complete
pathological response.
Fig. 4.3 Radiological assessment of tumor response with
high-resolution magnetic resonance showing ndings of
complete response with the presence of low-signal intensity
signal in the area harboring the original tumor (yellow arrow)
36
Fig. 4.4 Radiological ndings consistent with incomplete response in magnetic resonance indicated by the
presence of a mixed signal intensity area (yellow arrow)
water molecule diffusion may vary within areas of
tissue necrosis, high cellularity (commonly
observed within residual tumor) or brotic scarring. This could be used to improve the identication of responders and represent an additional tool
during assessment of tumor response [45, 46].
Finally, the addition of PET/CT by providing
an estimate of tumor metabolism could be used to
help assess tumor response to nCRT.The variation in mean standard uptake values (SUV) and
metabolic tumor volume reduction between preand posttreatment scans was found to be one of
the best predictors of response to nCRT among
patients with rectal cancer [47].
In fact, it has been suggested that the combination of all these studies (including clinical,
endoscopic, and radiological) may increase the
accuracy in the detection of complete tumor
response to nCRT [48].
Transanal Full-Thickness Local Excisions (FTLEs)
Denitive information on pathological response
including nal ypT status, TRG, lymphovascular/
perineural invasion placed excisional biopsies as
an attractive tool for the assessment of primary
L. M. Fernandez et al.
tumor response to nCRT [49]. Performance of
transanal local excision with the use of transanal
endoscopic platforms (TEMs or TAMIS) will
provide an ideal specimen with lower risk of positive margins (in the case of residual cancer) and
specimen fragmentation when compared to standard transanal surgical techniques, often associated with poor illumination and exposure of the
surgical eld [50]. In addition, appropriate pathological information and resection margins of the
tumor may aid in the decision regarding the need
for additional TME.Otherwise, in the case of a
complete pathological response, it could be used
as an objective conrmation of pCR (ypT0) and
obviate the need for additional TME.
However, these attractive advantages should
be balanced against by several potential disadvantages. First, healing of the rectal defects created by local resection after nCRT may be quite
challenging. In the setting of a dehiscence, pain is
frequently quite signicant, and it could take as
long as 8 weeks to completely heal. Although,
Grade III or IV postoperative complications are
not usually observed, pain is a common cause for
readmission to the hospital [51]. As a result of
difcult healing, scarring with signicant distortion and irregularities may occur within areas of
the rectal wall previously resected. This may ultimately also contribute to difculties in differentiating postoperative brosis or local recurrences
during follow-up of these patients by clinical,
endoscopic, and radiological surveillance studies
[52]. Secondly, sphincter preservation may be
signicantly compromised after a FTLE. When
patients with cCR and non-operative management were compared to patients with “nearcomplete” response and FTLE following nCRT,
functional outcomes were signicantly better
among patients under WW [53]. In this setting,
even though organ preservation has been achieved
with FTLE, anorectal function may be far from
normal in these patients.
Even if patients are found to have incomplete
pathological response, FTLE may signicant disadvantages. Patients that required additional TME
after FTLE (due to the presence of unfavorable
pathological features) frequently ended up with an
APR, despite the fact that they originally were candidates for a sphincter-preserving strategy [54, 55].
4 Complete Clinical Response inRectal Cancer After Neoadjuvant Therapy: Organ Preservation…
37
In addition, completion of TME in this setting has
been associated with a risk factor for poor quality
of the mesorectal specimen. A recent review of
patients undergoing completion TME indicated
that previous TEM was a risk factor for poor quality of the TME specimen [56]. Finally, in the prospective GRECCAR 2 study, patients with baseline
small cT2/T3 tumors (≤4 cm) underwent
nCRT. Those with “good” clinical response
(≤2cm) were randomized to TME or local excision (LE). In an “intention to treat” analysis (using
a composite primary endpoint including mortality,
morbidity, function, and recurrence), patients who
underwent LE had similar oncological and functional outcomes to those after TME. On a rst
glance, this could suggest that local excision after
nCRT is a valid alternative in this highly selected
patient population (small baseline tumors and
excellent clinical response). However, in a subgroup analysis of patients that needed completion
TME due to the presence of high-risk/unfavorable
pathological features in the LE specimen, outcomes were not as good. These patients had signicantly more postoperative complications, need for
APR, and worse functional outcomes. In conclusion, patients that underwent LE alone (with favorable pathological features) did the best when
compared to TME or LE + TME. Patients who
underwent LE and required TME (unfavorable
pathological features) did the worse when compared to LE alone or TME alone [38].
Special Situation: Salvage
forLocal Recurrence After aTransanal
Local Excision
Several series reported on the outcomes of local
excision with or without the use of preoperative
CRT. A few signicant issues may represent
challenges in the setting of a local recurrence following local excision with signicant consequences in terms of optimal salvage. First, local
recurrences after a previous local excision usually present as more advanced disease when compared to initially resected. One interesting series
looking at pT1 managed by transanal endoscopic
microsurgery revealed that local recurrences
were frequently salvaged in the setting of pT3 or
even pT4 disease [57]. Also, the risk of a pCRM+
specimen may be quite signicant here [58].
Second, after undergoing previous transanal
endoscopic microsurgery, patients requiring salvage resection often require abdominal perineal
resections (APRs) [55]. Finally, these patients
requiring salvage or completion total mesorectal
excision frequently present suboptimal TME
specimens at the time of resection [56]. In this
setting, salvage resection after a local recurrence
following transanal local excision should be considered at high risk for unfavorable outcomes,
and surgical management should be optimized to
provide a R0 resection. One recent case-matched
study has compared the short-term outcomes of
patients undergoing completion TME after previous local excision with transanal TME or standard TME.The study suggests superior quality of
the specimen and decreased risk of rectal perforation with the transanal approach [59]. Still, further studies comparing taTME to standard TME
in the setting of local recurrences after previous
local excision are warranted. The reason is that
completion TME and salvage TME may have
distinct surgical outcomes. Still, transanal TME
seems to be an attractive approach for the management of these patients requiring salvage TME
in an attempt to provide optimal oncological and
functional outcomes.
Complete Clinical Response: Watch
andWait Strategy
Non-operative management of patients with a
complete clinical response has to be coupled to a
relative intensive follow-up strategy. The importance to adhere to this strict follow-up program is
to allow early recognition of any local or systemic recurrence and, therefore, increase the
chances of successful salvage. Visits have been
recommended with 1–2-month intervals in the
rst year, 3-month intervals for the second year,
and 6-month for the remaining years of follow up. Complete clinical and endoscopic assessments are recommended in all visits. Even though
not yet standardized, radiological assessment of
response has been performed at least every
6months for the rst 2years and yearly thereafter
38
L. M. Fernandez et al.
in our practice [60]. PET/CT imaging has been
reserved for equivocal cases.
Outcomes
Even though there are very few series looking at
oncological outcomes after local excision after
ypT0, the available data is excellent [61]. Longterm oncological outcomes appear to be similar
between patients undergoing watch and wait
strategy after a cCR following nCRT and patients
managed by TME in the presence of a pCR [8].
Additional retrospective studies further supported this similar oncological outcomes between
these subgroups of patients [62, 63].
Local recurrences after WW are still a concern
and have been considered a signicant limitation
in widespread implementation of such strategy.
However, considering that the majority of local
recurrences appears to develop within the rst
24 months of follow-up and nearly all of them
(90%) have an endoluminal component, a strict
follow-up and simple clinical assessment may
allow early detection of regrowths without compromising oncological outcomes [64, 65].
Patients with more advanced cT stage at baseline
staging appear to be at greater risk for local recurrence after initial cCR and should be carefully
monitored [16]. Ultimately, the pooled local
recurrence rate including all published series
analyzed in a systematic review suggested to be
around 16–22% [62, 63].
Systemic recurrences may also develop after
non-operative management of patients that achieve
a cCR. A recent meta-analysis reported similar
incidences of systemic recurrence among patients
managed non-operatively with a cCR and patients
with pCR after radical surgery [63]. Curiously,
overall survival among these patients with cCR
was 93% without the use of adjuvant chemotherapy. These rates compare favorably with the 90%
overall survival after radical surgery in patients
with pCR with nearly 40% of patients undergoing
adjuvant systemic chemotherapy [66]. Finally, the
largest series of patients with cCR managed nonoperatively has been recently reported from a multinational registry including nearly 1000 patients.
Similar outcomes of successful salvage after local
recurrence and excellent survival long-term results
further support this organ preservation strategy as
an attractive alternative for the management of
selected patients with rectal cancer and complete
clinical response to nCRT [67].
Future Perspectives inOrgan
Preservation
With the increasing interest of organ preservation
strategies and the use of nCRT regimens to intentionally develop complete clinical response,
accurate prediction of tumor response with
molecular biology studies will become increasingly relevant. Identication of ideal candidates
for non-operative management would allow better selection of patients who would benet the
most from nCRT and avoidance of potentially
unnecessary treatment to poor responders [17,
68]. However, the presence of signicant inter-
and intratumoral heterogeneity observed in rectal
cancer may have contributed for the lack of clinically useful gene expression signatures in predicting tumor response [68–70]. Considering this
intratumoral heterogeneity within a single rectal
cancer, the coexistence of subpopulations of cancer cells resistant and sensitive to treatment may
render that gene signatures derived from single
biopsy specimens may not work simply because
these fragments are not representative of the
entirety of the tumors. Instead of prediction of
tumor response, introduction of liquid biopsies
for the assessment and monitoring of tumor
response may also represent a clinically useful
tool for the management and surveillance of
patients during this approach [71].
Conicts of Interest The authors have no conicts of
interest to declare.
References
1. Smith FM, Rao C, Oliva Perez R, et al. Avoiding
radical surgery improves early survival in elderly
patients with rectal cancer, demonstrating complete
clinical response after neoadjuvant therapy: results
of a decision-analytic model. Dis Colon Rectum.
2015;58:159–71.
4 Complete Clinical Response inRectal Cancer After Neoadjuvant Therapy: Organ Preservation…
39
2. Denost Q, Laurent C, Capdepont M, etal. Risk factors
for fecal incontinence after intersphincteric resection
for rectal cancer. Dis Colon Rectum. 2011;54:963–8.
3. Didailler R, Denost Q, Loughlin P, et al. Antegrade
Enema after total mesorectal excision for rectal cancer: the last chance to avoid denitive colostomy for
refractory low anterior resection syndrome and fecal
incontinence. Dis Colon Rectum. 2018;61:667–72.
4. Celerier B, Denost Q, Van Geluwe B, et al. The risk
of denitive stoma formation at 10 years after low and
ultralow anterior resection for rectal cancer. Color
Dis. 2016;18:59–66.
5. Chen L, Glimelius I, Neovius M, etal. Risk of disability pension in patients following rectal cancer treatment and surgery. Br J Surg. 2015;102:1426–32.
6. Smith FM, Waldron D, Winter DC. Rectumconserving surgery in the era of chemoradiotherapy.
Br J Surg. 2010;97:1752–64.
7. Habr-Gama A, Perez RO, Wynn G, et al. Complete
clinical response after neoadjuvant chemoradiation
therapy for distal rectal cancer: characterization of
clinical and endoscopic ndings for standardization.
Dis Colon Rectum. 2010;53:1692–8.
8. Habr-Gama A, Perez RO, Nadalin W, etal. Operative
versus nonoperative treatment for stage 0 distal rectal
cancer following chemoradiation therapy: long-term
results. Ann Surg. 2004;240:711–7. discussion 7-8.
9. Sauer R, Becker H, Hohenberger W, etal. Preoperative
versus postoperative chemoradiotherapy for rectal
cancer. N Engl J Med. 2004;351:1731–40.
10. Sauer R, Liersch T, Merkel S, etal. Preoperative versus
postoperative chemoradiotherapy for locally advanced
rectal cancer: results of the German CAO/ARO/AIO94 randomized phase III trial after a median follow-up
of 11 years. J Clin Oncol. 2012;30:1926–33.
11. Taylor FG, Quirke P, Heald RJ, etal. Preoperative
high-resolution magnetic resonance imaging can
identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg.
2011;253:711–9.
12. Peeters KC, van de Velde CJ, Leer JW, etal. Late side
effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer:
increased bowel dysfunction in irradiated patients--a
Dutch colorectal cancer group study. J Clin Oncol.
2005;23:6199–206.
13. Loos M, Quentmeier P, Schuster T, etal. Effect of
preoperative radio(chemo)therapy on long-term
functional outcome in rectal cancer patients: a systematic review and meta-analysis. Ann Surg Oncol.
2013;20:1816–28.
14. Perez RO, Habr-Gama A, Sao Juliao GP, et al.
Predicting complete response to neoadjuvant CRT for
distal rectal cancer using sequential PET/CT imaging.
Tech Coloproctol. 2014;18:699–708.
15. Garcia-Aguilar J, Shi Q, Thomas CR Jr, et al. A
phase II trial of neoadjuvant chemoradiation and
local excision for T2N0 rectal cancer: preliminary
results of the ACOSOG Z6041 trial. Ann Surg Oncol.
2012;19:384–91.
16. Habr-Gama A, Sao Juliao GP, Gama-Rodrigues J,
et al. Baseline T classication predicts early tumor
regrowth after nonoperative management in distal
rectal cancer after extended neoadjuvant chemoradiation and initial complete clinical response. Dis Colon
Rectum. 2017;60:586–94.
17. Habr-Gama A, Gama-Rodrigues J, Perez RO. Is tailoring treatment of rectal cancer the only true benet of long-course neoadjuvant chemoradiation? Dis
Colon Rectum. 2013;56:264–6.
18. Radu C, Berglund A, Pahlman L, etal. Short-course
preoperative radiotherapy with delayed surgery in
rectal cancer- a retrospective study. Radiother Oncol.
2008;87:343–9.
19. Appelt AL, Ploen J, Vogelius IR, et al. Radiation
dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy. Int J
Radiat Oncol Biol Phys. 2013;85:74–80.
20. Appelt AL, Ploen J, Harling H, et al. High-dose
chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study.
Lancet Oncol. 2015;16:919–27.
21. Vuong T, Devic S. High-dose-rate pre-operative
endorectal brachytherapy for patients with rectal cancer. J Contemp Brachytherapy. 2015;7:183–8.
22. Gerard JP, Benezery K, Doyen J, etal. Aims of combined modality therapy in rectal cancer (M0). Recent
results. Cancer Res. 2014;203:153–69.
23. Sun Myint A, Smith FM, Gollins S, et al. Dose
escalation using contact x-ray brachytherapy after
external beam radiotherapy as nonsurgical treatment
option for rectal cancer: outcomes from a singlecenter experience. Int J Radiat Oncol Biol Phys.
2018;100(3):565–73.
24. Habr-Gama A, Perez RO, Sabbaga J, etal. Increasing
the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the
resting period. Dis Colon Rectum. 2009;52:1927–34.
25. Habr-Gama A, Sabbaga J, Gama-Rodrigues J, et al.
Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we
getting closer to anal cancer management? Dis Colon
Rectum. 2013;56:1109–17.
26. Fu XL, Fang Z, Shu LH, et al. Meta-analysis of
oxaliplatin-based versus uorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy for locally advanced rectal cancer. Oncotarget.
2017;8(21):34340–51.
27. Hupkens BJP, Martens MH, Stoot JH, et al. Quality
of life in rectal cancer patients after chemoradiation: watch-and-wait policy versus standard resection- a matched-controlled study. Dis Colon Rectum.
2017;60:1032–40.
28. Vailati BB, Habr-Gama A, Mattacheo AE, et al.
Quality of life in patients with rectal cancer after
chemoradiation: watch-and-wait policy versus standard resection-are we comparing apples to oranges?
Dis Colon Rectum. 2018;61:e21.
29. Schrag D, Weiser MR, Goodman KA, et al.
Neoadjuvant chemotherapy without routine use