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ANNSURG-D-19-00291

META-ANALYSIS

Total Neoadjuvant Therapy in Rectal Cancer

A Systematic Review and Meta-analysis of Treatment Outcomes
Fausto Petrelli, MD,  Y Francesca Trevisan, MD,y Mary Cabiddu, MD,  Giovanni Sgroi, MD,z
Lorenza Bruschieri, MD,y Emanuele Rausa, MD,z Michele Ghidini, MD,§ and Luca Turati, MDz

increased the complete pathologic response (pCR) rate and

Background: The addition of induction chemotherapy to concomitant neo-
prolonged disease-free survival (DFS).1 In particular, in the German
adjuvant chemoradiation in locally advanced rectal cancer could increase
study CAO/ARO/AIO-04, the addition of oxaliplatin to standard
pathological downstaging and act on occult micrometastatic disease, leading
5-Fluorouracil (5FU)-based chemoradiotherapy, while reducing the
ultimately to a better outcome. A systematic review was carried out of the
risk of relapse by 20%, showed that about 70% of failures were at
existing literature on the treatment outcomes of total neoadjuvant therapy
distant sites.
(TNT) on locally advanced rectal cancer. TNT was defined as chemotherapy
A substantial body of evidence on the use of adjuvant
using cycles of induction and/or consolidation in conjunction with standard
chemotherapy after chemoradiotherapy and surgery does not
chemoradiotherapy prior to surgery.
exist, and intensification of neoadjuvant treatment with stan-
Methods: A systematic search of PubMed, Embase, and the Cochrane
dard-dose polychemotherapy added before chemoradiotherapy
Library was performed according to the PRISMA statement up until
may help to decrease distant failure, increase conservative sur-
January 2019. The primary endpoints were complete pathologic response
geries and resectability for initially unresectable disease, and
(pCR), disease-free survival, and overall survival rates.
permit greater adherence than adjuvant chemotherapy. Given
Results: A total of 28 studies (3 retrospective and 25 prospective for a total of
these facts, some small Phase II studies were implemented in
3579 patients) were included in the final analysis (n ¼ 2688 treated with TNT
order to explore total neoadjuvant therapy (TNT) for LARC.2 – 5
and n ¼ 891 with neoadjuvant chemoradiotherapy therapy). The pooled pCR
In these studies, the authors discovered a high rate of treatment
rate was 22.4% (95% CI 19.4%–25.7%) in all patients treated with TNT (n ¼
completion with a pCR rate of approximately 20%. Other studies
27 studies with data available). In n ¼ 10 comparative studies with data
delivered a full dose of systemic chemotherapy (eg, mFOLFOX6
available, TNT was found to increase the odds of pCR by 39% (1.40, 95% CI
immediately after chemoradiotherapy), obtaining a pCR rate of
1.08–1.81, P ¼ 0.01).
about 30% and sphincter-saving surgeries and radical (R0)
Conclusions: The addition of induction or consolidation chemotherapy to
resections in 75 and near 100% of cases.6
standard neoadjuvant chemoradiotherapy results in a higher pCR rate. Given
TNT includes different strategies, some comprising full doses
that the comparative analysis was derived from few randomized publications,
of chemotherapy for 3 to 4 months followed by standard chemo-
large confirmatory trials should be carried out before a strong recommenda-
radiotherapy and surgery as well as other courses of treatment,
tion is made in favor of TNT.
including short-course RT after chemotherapy. Alternatively, some
Keywords: induction chemotherapy, meta-analysis, neoadjuvant researchers have delivered chemotherapy immediately before sur-
chemoradiotherapy, rectal cancer gery and after RT. Additionally, the promoters of TNT suggest there
is an advantage of greater compliance with neoadjuvant chemother-
(Ann Surg 2019;xx:xxx–xxx) apy compared with its adjuvant counterpart. In fact, in the largest
adjuvant trial for LARC (EORTC 22921 study), only 73% of patients
T he treatment of locally advanced rectal cancer (LARC) primarily
aims to allow local control, increase the likelihood of sphincter
preservation, and increase the rate of relapse-free survival by acting
assigned to adjuvant chemotherapy initiated postoperative therapy,
and only 43% received 95% of the planned 5FU dose.7 Furthermore,
in patients with clinical complete response after TNT, a wait-and-see
on gross tumor volume and the micrometastatic disease. Long-course option could be considered prior to proceeding with surgery.
preoperative radiotherapy (RT) associated with fluoropyrimidine- Here, we performed a systematic review and pooled analysis
based chemotherapy and followed by surgery after a period of at least of all those published studies adopting the TNT strategy for LARC
6 to 8 weeks is the standard treatment for LARC, even if a prolonged with the primary aims being pCR, safety, and outcome compared
interval of at least 10 to 12 weeks seems to guarantee a better with standard neoadjuvant chemoradiotherapy.
outcome for what concerns local recurrence. Intensification of the
treatment by adding a second cytotoxic agent (traditionally oxali-
platin), thereby increasing the care standards of the chemotherapy, METHODS
did not lead to a significant improvement in the outcomes of A systematic review was performed according to the Preferred
randomized studies. Conversely, dose intensification moderately Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines.
From the Oncology Unit, ASST Bergamo Ovest, Treviglio (BG), Italy;
yRadiotherapy Unit, ASST Bergamo Ovest, Treviglio (BG), Italy; zSurgical
Search Strategy and Inclusion Criteria
Oncology Unit, ASST Bergamo Ovest, Treviglio (BG), Italy; and §Oncology A bibliographical search was performed of PubMed, Embase,
Unit, ASST Cremona, Cremona, Italy. and the Cochrane Library up to January 13, 2019. The following
Y faupe@libero.it. Medical Subject Headings (MeSH) terms were used in combination
The authors report no conflicts of interest.
Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved.
with Boolean operators (AND, OR, NOT): (induction[All Fields] OR
ISSN: 0003-4932/16/XXXX-0001 (total[All Fields] AND (‘‘neoadjuvant therapy’’[MeSH Terms] OR
DOI: 10.1097/SLA.0000000000003471 (‘‘neoadjuvant’’ [All Fields] AND ‘‘therapy’’ [All Fields]) OR

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ANNSURG-D-19-00291
Petrelli et al
‘‘neoadjuvant therapy’’ [All Fields] OR ‘‘neoadjuvant’’ [All Fields]))
OR (‘‘neoadjuvant therapy’’ [MeSH Terms] OR (‘‘neoadjuvant’’ [All
Fields] AND ‘‘therapy’’ [All Fields]) OR ‘‘neoadjuvant therapy’’ [All
Fields] OR ‘‘neoadjuvant’’ [All Fields])) AND (‘‘drug therapy’’
[Subheading] OR (‘‘drug’’ [All Fields] AND ‘‘therapy’’ [All Fields])
OR ‘‘drug therapy’’ [All Fields] OR ‘‘chemotherapy’’ [All Fields] OR
‘‘drug therapy’’ [MeSH Terms] OR (‘‘drug’’ [All Fields] AND
‘‘therapy’’ [All Fields]) OR ‘‘chemotherapy’’ [All Fields]) AND
((‘‘chemoradiotherapy’’ [MeSH Terms] OR ‘‘chemoradiotherapy’’
[All Fields]) OR (‘‘chemoradiotherapy’’ [MeSH Terms] OR ‘‘chemo-
radiotherapy’’ [All Fields] OR ‘‘chemoradiation’’ [All Fields])) AND
‘‘rectal cancer’’ [All Fields]. Two independent authors (F.P., L.T.)
searched for potentially eligible articles retrieved by the initial
search, and prospective disagreements were resolved by consensus
with a third reviewer (F.T.). References for the included studies and
for previously published systematic reviews were manually
assessed in order to detect any missing studies. Studies were
considered eligible if all of the following criteria were met: 1)
data were reported on the outcomes (OS or DFS) or the pCR rate of
patients with LARC who had undergone neoadjuvant (or consoli-
dation) chemotherapy plus neoadjuvant chemoradiotherapy; 2) the
study included at least 20 patients; and 3) the study was reported in
English. Exclusion criteria included the following: 1) patients
treated with biological agents (eg, anti-EGFR or anti-VEGF drugs)
in addition to chemotherapy; 2) patients treated with observation
alone after neoadjuvant therapy (the wait-and-see strategy); 3) case
reports; 4) reviews and meta-analyses; 5) editorials, commentaries,
and letters; and 6) overlapping studies. In the case of duplicate
publications, only the most recent or most informative study for a
single center was included in the analyses. Articles that fulfilled the
inclusion criteria were retrieved for full-text evaluation.
Data Extraction
After reviewing the full texts of eligible studies, two indepen-
dent authors (F.P., F.T.) performed the data extraction and cross-
checked all the results. Potential discrepancies in the selection of
articles and the extraction of the data were resolved following
consensus with a third reviewer (L.T.). Extracted variables included
general study characteristics (eg, author, year of publication, study
design, number of patients, median follow-up), clinical character-
istics (eg, median age, stage), treatment characteristics (eg, type and
number of induction/consolidation chemotherapy cycles, RT dosage,
concomitant chemotherapy), short- and long-term outcomes (eg,
pCR, pNO, and R0 percentages; median DFS and OS; HR for
DFS and OS [if available]; rate of OS, DFS, distant and locoregional
DFS at 1, 2, 3, and 5 years; cumulative rates of distant and locore-
gional failures and deaths), and toxicities (eg, surgical complications,
toxicities of chemoradiotherapy, and chemoradiotherapy completion
percentages). Quality of studies was evaluated with the Jadad score
for randomized studies and the Nottingham–Ottawa Scale for
nonrandomized studies.
Statistical Analysis
The primary endpoint was the pCR percentage in the TNT
arm. Secondary endpoints were nodal downstaging, R0-resection
percentage, compliance to treatment, OS, DFS, and toxicity. HRs and
95% CIs for OS and DFS were pooled into formal meta-analyses.
Additionally, the proportions of pCR among patients treated with
TNT were compared with those treated with standard NT to obtain
ORs and 95% CIs. Due to the retrospective nature of most studies,
statistical pooling of effect measures was based on random-effect
models according to the DerSimonian and Laird method. Subgroup
analysis was performed according to the type of induction/consoli-
dation chemotherapy (multiagent vs monotherapy), the type of study
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Annals of Surgery  Volume XX, Number XX, Month 2019
(retrospective vs prospective), and RT fractionation (short vs long
course).
Subsequently, funnel plots were created to assess small-study
effects and publication bias. Statistical analyses were performed
using RevMan 5.3 (The Cochrane Centre) and a 2-sided P value of <
0.05 was considered significant.
RESULTS
After screening 3808 records, a total of 43 studies were
considered potentially eligible for inclusion in the systematic review.
Ultimately, 7 studies were excluded as older series with existing
updated publications, and a further 8 studies were excluded because
they incorporated targeted therapies in addition to standard chemo-
radiotherapy. A total of 28 studies (n ¼ 3579 patients) were included
in the final analysis (n ¼ 2688 treated with TNT and n ¼ 891 with
standard neoadjuvant chemoradiotherapy therapy).2 –4,8 –32 The flow
of the selection process is shown in Figure 1, while the characteristics
of the eligible studies and main outcomes are summarized in Tables 1
and 2. The publication years ranged from 2003 to 2019, with 3
retrospective series; the remaining were prospective studies. Ran-
domized studies were n ¼ 5 (1 Phase III and 4 randomized Phase II
studies3,12,17,22,27). All studies were included for descriptive analysis,
and 10 for quantitative meta-analysis (n ¼ 10 in pCR and n ¼ 7 in
both DFS and OS meta-analyses).
In all studies (except n ¼ 5), induction or consolidation
(neoadjuvant) chemotherapy was multiagent oxaliplatin-based. In
the remaining, 5FU plus folinic acid, capecitabine alone, 5FU plus
mitomycin C, or –ecitabine/irinotecan were used. In n ¼ 25 studies,
patients were treated with standard, long-course, neoadjuvant che-
moradiotherapy (approximately 50 Gy). In n ¼ 3 series, short-course
RT (25 Gy in 5 fractions) was the selected regimen. Median follow-
up was available in n ¼ 23 studies and ranged from 15 to 72.6 months
(median 43). The mean Jadad score of the 5 randomized studies was
3.4 (range 3–4), and the median NOS scale of nonrandomized
studies was 6.47 (range 5–8) (Table 1).
Meta-analysis of pCR Rates
The pooled rate of pCR was 22.4% (95% CI 19.4%–25.7%, I2
¼ 59%, P < 0.001, random effect model) in all patients treated with
TNT (n ¼ 27 studies with data available). In n ¼ 10 with data
available for comparison, TNT increased the odds of pCR by 39%
(1.39, 95% CI 1.08–1.81, P ¼ 0.01; random-effect model; Fig. 2).
Meta-analysis of OS and DFS
Seven studies were available for comparative analysis of DFS
and OS. In comparative series, patients who received TNT and
surgery had a better DFS (HR ¼ 0.75, 95% CI 0.52–1.07, P ¼
0.1; I2 ¼ 74%, random effect model; Fig. 3) and OS (HR ¼ 0.73, 95%
CI 0.59–0.9, P ¼ 0.004; random-effect model; Fig. 4) than those who
received chemoradiotherapy only.
Nodal Downstaging and R0 Surgeries
Nodal downstaging to pN0 disease was available in n ¼ 21
papers and ranged from 30% to 91.6% (median 63.5%). Radical
surgeries (R0; n ¼ 26 studies) ranged from 71% to 100% (median
95%).
Compliance and Safety
Compliance was excellent (a chemoradiotherapy completion
rate of 81.9%–100%; median 100%). The toxicity profile of TNT
regimens was comparable to that of standard chemoradiotherapy.
Radiation dermatitis, diarrhea, proctitis, and hematological toxicities
were the most frequent G3–4 toxicities (Table 2).
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Annals of Surgery  Volume XX, Number XX, Month 2019
FIGURE 1. Flow diagram of
included studies.
Long-term Outcome
The mean pooled 1-, 2-, 3-, and 5-year DFS rates were 86%,
78%, 67%, and 65%, respectively, while the corresponding values for
OS were 93%, 78%, 78.9%, and 74%. The cumulative mean rates of
distant metastases and locoregional recurrence were 21.5% and 6%.
Pooled locoregional failures and distant metastases were reduced by
about 30% OR ¼ 0.68 (95% CI 0.16–2.8, P ¼ 0.6) and OR ¼ 0.72
(95% CI 0.55–0.95, P ¼ 0.02), respectively, in n ¼ 3 and n ¼ 5
studies with data available).
Subgroup Analysis
The pCR comparisons were similar in prospective (OR ¼ 1.39,
95% CI 0.96–2.01, P ¼ 0.08) and retrospective series (OR ¼ 1.41,
95% CI 0.99–2.01, P ¼ 0.06). In addition, in studies with long-course
chemoradiotherapy (OR ¼ 1.35, 95% CI 1.02–1.8, P ¼ 0.04) and
short-course RT (OR ¼ 1.59, 95% CI 0.91–2.8, P ¼ 0.11) there were
no differences between TNT and chemoradiotherapy arms. After
exclusion of the n ¼ 1 study (Moore et al) using monotherapy with
5FU and folinic acid after chemoradiotherapy, OR for pCR was
significantly better for the TNT arm (OR ¼ 1.44, 95% CI 1.11–
1.88, P ¼ 0.006). Pathologic complete response rate was increased
more in nonrandomized than in randomized studies (OR ¼ 1.51, 95%
CI 1.11–2.04 and OR 1.15, 95% 0.7–1.87; P for difference ¼ 0.35).
Similarly, in DFS and OS analyses, even if a larger benefit was
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Total Neoadjuvant Therapy for Rectal Cancer
calculated in retrospective and/or nonrandomized studies, the differ-
ence among subgroups was not significant (P for difference 0.26 and
0.66; data not shown).
Publication Bias
For the pCR meta-analysis, there was no evidence of publica-
tion bias, and neither Begg nor Egger test was significant (P ¼ 0.3
and 0.49).
DISCUSSION
Although neoadjuvant long-course chemoradiotherapy with
systemic fluoropyrimidines followed by surgery is the preferred
approach for LARC, it provided no better outcome in terms of
OS and DFS rates compared with surgery and adjuvant chemo-
radiotherapy. The rationale of the neoadjuvant approach centers
around the possibility of downstaging unresectable tumors and
obtaining an R0 resection. The preoperative approach, however,
has no proven role in reducing distant and local recurrences, as a
10-year update of CAO/ARO/AIO-94 showed, and the long-term OS
rate is about 60%.33 Meanwhile, an addition of oxaliplatin to radio-
sensitizing regimens showed no benefit in terms of OS rates, with
only a reduction in preoperative metastases, and long-term local
failure.1 So-called TNT, in which preoperative treatment includes not
only the chemoradiotherapy element but also several months of
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Petrelli et al
TABLE 1. Characteristics of Included Studies
Median R0 NOS or
Follow- Clinical Stage (%) Resections Jadad
Author/Year No Pts Study Design up (mo) Exp Arm Type of Neoadjuvant Tx pCR (%) pN0 (%) (%) Score
Aboelnaga/2015 27 Phase 1–2 20 cT3–4: 81.5 FOLFOX x2 ! HFRT (45 Gy) 25.9 59.3 88.8 6
cNþ: 70.4 þ 5FU bolus
Aghili/2018 33 Phase 2 NR cT3-4: 100 CAPOX þ SRT (25 Gy) ! CAPOX x1 30.8 (n ¼ 26) – 100 (n ¼ 26) 6
cNþ: 72.6
Bhatti/2015 154 (93/61) Retrospective 45 cT3-4: 88; cNþ: 90% CAPOX x4 ! CAP þ RT (50.4 Gy) 31.2 vs 21.3 64.5 vs 50.8 91.4 vs 72.1 7
Bujko/2016 515 (261/254) Phase 3 35 Fixed cT3 or cT4: 100 SRT (25 Gy) ! FOLFOX x3 (n¼261) 16 (n ¼ 244) vs 12 69 vs 68 77 vs 71 4 (Jadad)
vs CT (5FU bolus þ AF þ OXA) þ (n ¼ 235)
RT (50.4 Gy) (n ¼ 254)
Calvo/2014 335 Prospective cohort 72.6 cT2-4: 100 FOLFOX x2 (n ¼ 207) ! 5FU ci þ RT – 60 vs 43 96 vs 97 8
study cNþ: 69 (50.4 Gy) vs 5FU ci þ RT (50.4 Gy)
(n ¼ 128)
Cercek/2018 628 (308/320) Retrospective 23–40y cT3-4: 93.2 FOLFOX/CAPOX/FLOX x4 months ! 18 (n ¼ 235) vs 17 – – 7

ANNSURG-D-19-00291
cNþ: 86 5FU ci/CAP þ RT (50.4 Gy) vs 5FU (n ¼ 296)
ci/CAP þ RT (50.4 Gy)
Chau/2003 36 Prospective cohort 15 cT3–4: 93 5FU ci þ MMC x2 ! 5FU ci þ RT 2.7 55.5 82 (n ¼ 32) 5
study cNþ: 58.4 (50.4–54 Gy)
Chiorean/2012 22 Phase 2 29.5 cT3–4: 95 CAPIRI x2 ! CAP þ RT (50.4 Gy) 33 (n ¼ 18) – 81.8 6
cNþ: 91
Dueland/2016 97 Prospective cohort 74 cT3–4: 95 FLOX x2 ! CAPOX þ RT (50.4 Gy) 17 (n ¼ 92) 67 90 (n ¼ 92) 6
study cNþ: 87
Fekete/2014 88 Prospective cohort 16.7 cT3–4: 92 FOLFOX/CAPOX x2–4 ! CAP þ RT 10 – 79 5
study cNþ: 86 (50.4 Gy)
Fernandez-Martos/2015 108 Randomized phase 2 69 cT4: 9; lower cT3: 27; CAPOX þ RT (50.4 Gy) vs CAPOX x4 14 (n ¼ 56) 87 86 4 (Jadad)
cNþ: 57 ! CAPOX þ RT (50.4 Gy)
Gao/2014 51 Phase 2 NR cT3–4: 88 CAPOX x1 ! CAPOX x2 þ RT (50 42.2 (n ¼ 45) 86.7 100 5
cNþ: 69.4 Gy) ! CAPOX x1
Gao/2014 (2) 42 Prospective cohort NR Low T/bulky, cT4 or CAPOX x1 ! CAPOX þ RT (50 Gy) 15 (n ¼ 40) 82.5 97.5 5

Annals of Surgery  Volume XX, Number XX, Month 2019

study cNþ or " CEA CAPOX x2
(100)
Liang/2019 156 (76/80) Retrospective 31 cT4: 76.3; cNþ: 78 CAP/CAPOX/FOLFOX þ RT ! CAP/ 21.1 vs 11.25 55 vs 35 96 vs 90 6
ß

CAPOX/FOLFOX vs CAP/CAPOX/
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FOLFOX þ RT (50.4 Gy)

Marco/2018 259 Phase 2 59 cT3–4: 69; cNþ: 83 5FU ci þ RT (50.4 Gy) vs 5FU ci þ RT 29.2 (n ¼ 171) vs – 98 7
(50.4 Gy) ! FOLFOX x2–4–6 25 (n ¼ 40)
Golo/2018 43 Phase 2 55 cT3-: 86.4; cNþ: 86.4 CAPOX x1 ! CAPOX x2 þ RT (50.4– 17.5 (n ¼ 63) 51 98.4 7
54 Gy) ! CAPOX x2
Hess/2016 51 Phase 2 70.2 cT3–4: 100; cNþ:79 CAPOX x1 ! CAPOX x2 þ RT (50.4– 22 – 98 8
54 Gy)
Kim/2018 110 (56/54) Randomized phase 2 26 cT3–4: 100; cNþ:92 CAP þ RT (50.4 Gy) vs CAP þ RT 5.8 (n ¼ 52) vs 13.6 51.9 vs 63.6 90.4 vs 84.1 3 (Jadad)
(50.4 Gy) þ CAPOX x2 (n ¼ 44)
Markovina/2017 138 (69/69) Prospective cohort 49 cT3–4: 100; cNþ:75% SRT (25 Gy) ! mFOLFOX6 x4 vs with 28 vs 16 74 vs 58 71 vs 62 7
study 5FU/CAP þ RT (50.4 Gy)
Marechal/2011 57 (29/28) Randomized phase 2 NR cT3–4: 96; cNþ: 93 5FU ci þ RT (50.4 Gy) vs mFOLFOX6 28 (n ¼ 29) vs 25 55 vs 46 86 vs 96 3 (Jadad)
x2 ! 5FU ci þ RT (50.4 Gy) (n ¼ 28)
Moore/2017 49 (24/25) Randomized phase 2 NR cT3–4: 98; cNþ: 56 5FU ci þ RT (50.4 Gy) vs 5FU ci þ RT 25 vs 16 91.6 vs 92 92 vs 92 3 (Jadad)
(50.4 Gy) þ 5FU þ FA x3
Perez/2017 39 Prospective cohort 23.5 cT3–4 or cNþ:100 mFOLFOX6 x8 ! CAP þ RT (50.4 Gy) 33 (n ¼ 38) 90.9 – 6
study
Schou/2012 84 Prospective cohort 56.5 cT3-T4: 100 T3-T4Nþ: CAPOX x2!CAPþRT (48.7–54 Gy) 25% (n ¼ 77) – 94 (n ¼ 72) 8
study 28
Sclafani/2016 269 Pooled analysis of n 71.9 cT3c-d-4: 82.2 CAPOX x4  CETUX ! CAP þ RT 20 (n ¼ 244) 46.7 (n ¼ 244) 89.2 8
¼ 2 phase 2 cNþ: 69.9 (50.4 Gy) ! surgery ! CAP x4
studies

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Annals of Surgery  Volume XX, Number XX, Month 2019 Total Neoadjuvant Therapy for Rectal Cancer

continuous infusion þ oxaliplatin þ folinic acid; HR, hazard ratio; MMC, mitomicyn C; NOS, Nottingham–Ottawa Scale; OS, overall survival; pCR, pathologic complete response; pN0, pathological node negative; pts, patients; R0,
CAP indicates capecitabine; CAPOX, capecitabine þ oxaliplatin; exp ctr, experimental and control arms; FFS, failuire-free survival; FLOX, 5Fluorouracil þ oxaliplatin þ folinic acid bolus; FOLFOX, 5Fluorouracil bolus/
NOS or

systemic chemotherapy (eg, FOLFOX/CAPOX), is a possible alter-

Jadad
Score

native to long-course chemoradiotherapy for patients with wide-

8

6
spread LARC who are at high risk of requiring a margin-positive
resection, for those with node-positive disease, and for those with a
Resections

low rectal tumor. In these cases, in fact, the expected greater

(%)
R0

opportunity for delivering full-dose chemotherapy in the preopera-

z

92.1
100

100

100

tive setting could theoretically improve local and systemic control of

the disease, and thus increase the resectability of the cancer. Even
though adjuvant chemotherapy, after neoadjuvant chemoradiother-
pN0 (%)

apy and surgery, has not demonstrated significant benefit in random-

ized studies, an immediate short course of induction chemotherapy
may prevent or eradicate earlier (occult) micrometastatic disease,
63.8

57.9
82

30

and may be better tolerated than postoperative therapy.

In this systematic review, we observed that the overall pCR
percentage may be increased with TNT compared with when chemo-
pCR (%)

radiotherapy is administered alone. Furthermore, local and distant

15.8 (n ¼ 38)
30 (n ¼ 47)

18 (n ¼ 50)

metastases are potentially fewer, and this may reduce the risk of
relapse and mortality, as observed in comparative series. Treatment
seems feasible, and almost all patients completed TNT with moderate
37.8

toxicity consistent with the treatment received (diarrhea, proctitis,

dermatitis, and hematological toxicities). Mean nodal downstaging
CAPOX x3 ! CAPOX x 2 þ RT (50.4

(pN0) was 63.5%, and the median rate of R0 surgeries was 95%.
CAPOX x2 þ RT (50 Gy) ! CAPOX

CAPOX þ IMRT (44 Gy) ! CAP x1

Even though pCR is not a valid surrogate for OS,34 the present meta-
Type of Neoadjuvant Tx

CAP þRT (50.4 Gy) ! CAP x2

analysis calculated an average pCR rate of 22% (39% higher than the
standard chemoradiotherapy regimens used here), greater than the
9% rate described in the CAO/ARO/AIO-94 study and than the 17%
Gy)! CAPOX x3

rate obtained in CAO/ARO/AIO-04 with the addition of concurrent

oxaliplatin.35 Patients with pCR have fewer metastases and a better
outcome compared with non-pCR patients.36 In a review of 16
studies totaling 3363 patients (approximately 37% with pCR after
neoadjuvant chemoradiotherapy and surgery), those who experi-
x1

enced pCR had a 75% reduced risk of distant (8.7%) and local
(0.7%) relapse compared with those without.36 Long-term OS and
DFS rates were approximately 90%.
A further potential advantage of delivering both polychemo-
Clinical Stage (%)

cT3: 40.4, cT4: 59.6,

cT3-T3 or cNþ: 100

Low T/bulky, cT4 or

cT3: 66.7 cT4: 33.3,

cNþ or " CEA

therapy and chemoradiotherapy together is that it avoids or delays

Exp Arm

surgery when a complete clinical response is observed and/or a

cNþ: 88.1
cNþ: 100

patient refuses surgery. In a pooled analysis of 22 studies adopting a

(100)

wait-and-see strategy, salvage therapy was possible in 95% of

patients with tumor regrowth (15% of the total), and no difference
in the OS rate (despite a poorer DFS rate compared to those who
received surgery after a pCR) was observed.37 Despite being gener-
up (mo)
Median
Follow-

ally safe, a recent case series showed that the high rate of rectal
7.3
52

43

26

preservation associated with the wait-and-see approach may come at

the cost of reduced OS rates and an increased risk of distant
radical resection; RT, radiotherapy; SRT, short course radiotherapy.

metastases in those who experience local recurrence.38 Moreover,

Prospective cohort

Prospective cohort
Study Design

though information about treatment at relapse or the type/site and

number of distant metastases were not provided in the included
Including 60 patients in CTRT only patients group.

studies, the reduced risk of distant metastases (or their burden) and
study

study
Phase 2

Phase 2

the improvements in available systemic and locoregional treatments

are possible explanations for the general improvement in TNT
outcomes, with a pooled 5-year OS rate of 74%. In the near future,
yTNT and standard arm respectively.

early-metastatic cancers should be selected earlier during the course

of disease and may be offered the TNT option.39
No Pts

The current research had several limitations. First, the major-

TABLE 1. (Continued)

ity of the studies were of the prospective observational type and, of

45

50

51

42

these, most were nonrandomized comparative studies. In quantitative

zAmong 47 evaluable.

meta-analysis, the benefit observed in nonrandomized studies was

not significantly larger, as expected, than in the 5 randomized trials.
Second, TNT constituted a relatively younger treatment strategy with
Zampino/2008
Author/Year

a median follow-up of 43 months, which is a reasonably short time in

Wang/2018
Tang/2018

Zhu/2013

which to capture late relapses or more mature data on survival. Third,

even though a 22% pCR rate in the whole population of TNT studies


was calculated, in studies in which direct comparison was possible,

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Petrelli et al Annals of Surgery  Volume XX, Number XX, Month 2019

FIGURE 2. Pathologic complete response with total neoadjuvant therapy versus standard chemoradiation.

FIGURE 3. Comparison of disease-free survival between total neoadjuvant therapy and standard chemoradiotherapy studies.

FIGURE 4. Comparison of overall survival between total neoadjuvant therapy and standard chemoradiotherapy studies.

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Annals of Surgery  Volume XX, Number XX, Month 2019

TABLE 2. Main Long-term Outcomes and Toxicities
2019 Wolters Kluwer Health, Inc. All rights reserved.
DFS (Median) OS (Median) CTRT Post-surgical Acute Complica- Main G3–4 Toxicities of CTRT
Author/Year Months Months 1–2–3–5 Yr DFS 1–2–3–5 Yr OS LRF/Mþ/Deaths % Completion % tions % (5%) % (10% of Patients)
Aboelnaga/2015 21.3 (19.3–23.3) 25.7 (23.8–27.5) –/70.2/–/– –/87.5/–/– 7/11/7 93 Leakage 7.4, wound healing Diarrhea (11.1), neuropathy
18.5, wound infection 11.1, (11.1)
ileus 7.4
Aghili/2018 – – –/–/52/– –/–/60/– 100 Proctitis G2–3 23 Proctitis (21.2)
Bhatti/2015 HR ¼ 1.07 (0.7– HR ¼ 0.53 (0.33– –/–/–/39 vs –/–/–/43 –/–/–/70 vs –/–/–/ 18.4/24.6/– vs 23.4/ 100 vs 93.4 – Overall 13.9
1.63) 0.93) 47 25.5/–

Bujko/2016 HR ¼ 0,96 (0,75– HR ¼ 0,73 (0,53– –/–/53/– vs –/–/52/– –/–/73/– vs –/–/ 13/29/25 vs 7/25/33 99.6 vs 100 8 vs 6 23 vs 19
1,24) 1,01) 65/–
Calvo/2013 HR ¼ 0.83 (0.45– HR ¼ 0.7 (0.33– – – – – 25 vs 22 29 vs 33 (G2–4)
1.73) 1.14) CSS
Cercek/2018 – – – – – 100 – –
Chau/2003 18.6 FFS Not reached 72.1/–/–/– FFS 93.5/70.3/–/– 6/26/16.7 100 14.7 Skin (27.8)

ANNSURG-D-19-00291
Chiorean/2012 Not reached – 100/86.3/75.5/– – 0/22/– 81.8 – 0
Dueland/2016 Not reached Not reached –/–/–/61 –/–/–/83 –/–/16.4 90 NR Diarrhea (12.6)
Fekete/2014 – – – – – 92 – Neuropathy (10.8)
Fernandez-Martos/ HR ¼ 0.87 (0.47– HR ¼ 1.11 (0.51– –/–/–/64 vs –/–/–/62 –/–/–/78 vs –/–/–/ 2/21/22 vs 5/23/25 91 Infection wound healing (27), 23
2015 1.61) 2.42) 75 stoma (8), reoperation (8)
Gao/2014 – – – – – 99 11.1 PLT (10.2); diarrhea (8.2)
Gao/2014 (2) – – – – – 100 Infection (5) Proctitis (7), diarrhea (7), skin
(7)
Liang/2019 HR ¼ 1.063 (0.58– HR ¼ 1.28 (0.63– –/–/70.9/– vs –/–/71.9/– –/–/73.9/– vs –/–/ –/29.3/– vs –/ 100 Infection (6.5), intestinal Leukopenia (11.8), PLT (10.5),
1.95) 2.66) 83.4/– 25.4/– obstruction (6.5) diarrhea (19.7)
Marco/2018 HR ¼ 0.31 (0.19– HR ¼ 0.52 (0.21– –/–/–/81 vs –/–/–/50 –/–/–/88 vs –/–/–/ –/–/12 vs –/–/21 – G3–4: 6.5 Diarrhea (6), lymphopenia (6)
0.49) 1.29) 79
Golo/2018 – Not reached –/–/–/64 –/–/–/69.5 1.6/21.2/30.3 98.5 G3–4: 0 Skin (7.5)
Hess/2016 Not reached Not reached –/–/–/61 –/–/–/78 8/24/8 100 – Diarrhea þ lymphopenia (55)
Kim/2018 – – – – – 98 vs 98 0 0 (any G3–4: 9)
Markovina/2007 HR ¼ 0.51 (0.27– HR ¼ 0.82 (0.37– –/–/85/– vs –/–/68/– –/–/96/– vs –/–/ 8/12/4 vs 4/30/12 100 – G3–4 hematological (22)
0.95) 1.81) 88/–
Marechal/2011 – – – – – 97 vs 96 Pelvic/perineal infections (21) 0 (any G3–4: 36)
Moore/2017 – – – – – 100 vs 100 G3–4: 16 vs 24 –
Perez/2014 Not reached – – – – 89.7 Ileus (5), wound healing (5), Neutropenia (32); PLT (10),
rectal pouch leak (5) anorexia/fatigue (10)
Schou/2012 – – –/–/–/63 –/–/–/52.2 1/25/6 100 NR Diarrhea (5), cardiac/

Total Neoadjuvant Therapy for Rectal Cancer

tromboembolic toxicity (4)
Sclafani/2016 – – –/–/68/66.4 PFS –/–/83/73.3 5.5/20.6/26.3z 90 12.6 Skin (15), diarrhea (7), rash (4)
Tang/2018 Not reached Not reached –/–/–/75.5/– –/–/88.6/– 2.2/22.2/13.3 100 Infection (5.5), chylous ascites 0
(5.6)
§
Wang/2018 – – – – – 98 Pelvic abscesses/infection (4.3), Leucopenia (10.6), radiation
www.annalsofsurgery.com | 7

anastomotic leakage (2.2) dermatitis (6.4)

and hemorrhage (2.2)
Zampino/2008 – Not reached –/–/–/85.4 – 8/12/4 100 NR Radiation dermatitis (8)
Zhu/2013 81.6 vs 16.8 (p ¼ 83.9 vs 40.7 (p ¼ –/–/57.4/– –/–/66/– 7.1/23.8/21.4 100 Incisional infection (13) Diarrhea (11.9) radiation
0.000)§ 0.007) dermatitis (21.43), fatigue
(7.14)

In 244 and 235 resected patients.
yTotal neoadjuvant and standard therapy arms.
zAmong 95 resected patients.
§Good and poor responders respectively.
CTRT indicates chemoradiotherapy; G, grade; LRF, locoregional failure; Mþ, metastases; OS, overall survival; PLT, platelets.

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CE: D.C.; ANNSURG-D-19-00291; Total nos of Pages: 9;
ANNSURG-D-19-00291
Petrelli et al
this rate was 19%. Control arms are also associated with a pCR of
13%, which is in line with, or even lower than, that which is currently
obtained in clinical practice. A greater pathological downstaging can
probably be influenced by delaying the interval from RT and surgery
that various authors adopted. Finally, the optimal sequence, type, and
duration of induction chemotherapy and the ideal timings and
dosages of RT (before vs after induction chemotherapy and short
vs long course) are yet to be defined and should derive from ongoing
studies. Data from this systematic review and meta-analysis sug-
gested that TNT was feasible and can be associated with a >20%
pCR percentage and an excellent outcome for patients with LARC.
Nevertheless, the quality of the sources was low, and strong evi-
denced-based recommendations cannot be made based on these
retrospective data, which were largely procured from single-institu-
tion case series and small randomized trials.
Numerous trials are ongoing, however, and these will eluci-
date the matter as to whether the addition of systemic therapy to
neoadjuvant chemoradiotherapy will improve the outcome in this
setting. The TNTCRT Chinese study is evaluating if induction and
consolidation chemotherapy (capecitabine with oxaliplatin) with
chemoradiotherapy and surgery will improve DFS compared with
neoadjuvant chemoradiotherapy and surgery (NCT03177382). In
another similar trial design, OS was the primary endpoint
(NCT02031939). In the RAPIDO trial, patients will be randomized
between a short-course 5  5 Gy radiation scheme followed by 6
cycles of combination chemotherapy (capecitabine/5FU and oxali-
platin) and surgery, and a control group with long-course chemo-
radiotherapy followed by surgery (NCT01558921).
Even though the efficacy on short-term outcomes such as pCR,
nodal downstaging, and rate of R0 resection is impressive, long-term
outcome data following TNT are still limited. Until confirmatory
prospective randomized controlled trial data are available, the deci-
sion to perform TNT in the context of rectal cancer that is locally
advanced or at high risk for distant metastases/margin positive (low
rectal cancers and/or node positive disease, cT4 or involving mes-
orectal fascia) should be made on an individualized basis as part of a
multidisciplinary evaluation. In these cases, but not in cT3N0 rectal
cancers, TNT may be proposed to improve local control and resect-
ability. Future randomized controlled trials, including molecular
biomarkers, will be critical in determining the optimal treatment
strategies for patients with this type of cancer.
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