Neck Dissection Timing in Transoral Robotic or Laser Microsurgery in Oropharyngeal Cancer: A Systematic Review

Abstract

Objective:
This review assesses the effect on intra- and postoperative patient outcomes of the timing of neck dissection in relation to transoral surgery. Outcome measures include postoperative bleeding, intra- and postoperative fistula formation, and disease-specific and overall survival.

Data sources:
A search was conducted across the MEDLINE, Embase, US National Library of Medicine, and Cochrane databases with search terms in July 2021.

Review methods:
Articles that conformed with specified inclusion criteria were included. Included articles were scanned for bias with the ROBINS-I tool.

Results:
Nineteen articles were selected for qualitative analysis, including 546 patients who had neck dissection in conjunction with transoral robotic surgery/transoral laser microsurgery (TORS/TLM). Seventy-one (18%) patients had neck dissection prior to TORS/TLM, 39 (10%) had neck dissection performed after TORS/TLM, and 281 (72%) had concurrent procedures. In patients with neck dissection before TORS/TLM, 3% experienced major postoperative bleeding, and fistula rates were 0%. In the cohort with neck dissection after TORS/TLM, 3% experienced minor postoperative hemorrhage, and 8% had intraoperative fistulae. In the concurrent cohort of patients, 1% had major postoperative bleeds and 0.3% had minor bleeds, while 4% developed intraoperative fistulas and 0.3% developed postoperative fistulas.

Conclusion:
Current evidence indicated that there appears to be no correlation between timing of neck dissection and complications. This systematic review found insufficient data to comment on whether the timing of neck dissection in relation to TORS/TLM affects the outcomes of patients.

Full text

Systematic Review/Meta-analysis
Neck Dissection Timing in Transoral
Robotic or Laser Microsurgery
in Oropharyngeal Cancer:
A Systematic Review
OTO Open
2022, Vol. 6(4) 1–11
ÓThe Authors 2022
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/2473974X221131513
http://oto-open.org
Jai Parkash Ramchandani, BSc
1
, Aina Brunet, FEBEORL-HNS, PhD
2
,
Nikoleta Skalidi, FRCS
2
, Jack Faulkner, MBBS
2
, Aleix Rovira, MD, PhD, FEBORL-HNS
2
,
Ricard Simo, LMS, FRCS
2
, Jean-Pierre Jeannon, MBChB, FRCS
2
,
and Asit Arora, MBChB, PhD, FRCS
2
Abstract
Objective. This review assesses the effect on intra- and post-
operative patient outcomes of the timing of neck dissection
in relation to transoral surgery. Outcome measures include
postoperative bleeding, intra- and postoperative fistula for-
mation, and disease-specific and overall survival.
Data Sources. A search was conducted across the MEDLINE,
Embase, US National Library of Medicine, and Cochrane
databases with search terms in July 2021.
Review Methods. Articles that conformed with specified inclu-
sion criteria were included. Included articles were scanned
for bias with the ROBINS-I tool.
Results. Nineteen articles were selected for qualitative
analysis, including 546 patients who had neck dissection in
conjunction with transoral robotic surgery/transoral laser
microsurgery (TORS/TLM). Seventy-one (18%) patients had
neck dissection prior to TORS/TLM, 39 (10%) had neck
dissection performed after TORS/TLM, and 281 (72%) had
concurrent procedures. In patients with neck dissection
before TORS/TLM, 3% experienced major postoperative
bleeding, and fistula rates were 0%. In the cohort with
neck dissection after TORS/TLM, 3% experienced minor
postoperative hemorrhage, and 8% had intraoperative fis-
tulae. In the concurrent cohort of patients, 1% had major
postoperative bleeds and 0.3% had minor bleeds, while 4%
developed intraoperative fistulas and 0.3% developed post-
operative fistulas.
Conclusion. Current evidence indicated that there appears
to be no correlation between timing of neck dissection
and complications. This systematic review found insuffi-
cient data to comment on whether the timing of neck dis-
section in relation to TORS/TLM affects the outcomes of
patients.
Keywords
transoral robotic surgery, transoral laser microsurgery, neck
dissection, fistula, hemorrhage, oropharyngeal cancer
Received June 16, 2022; accepted September 4, 2022.
Since the 1990s, the incidence of head and neck cancer
has increased by 33% in the United Kingdom.
1
Oropharyngeal squamous cell carcinoma (OPSCC) is a
significant contributor to this dramatic rise,
2
and it is thought
that the increasing prevalence of OPSCC is driven by human
papilloma virus.
3
In addition, cervical lymph node metastasis
is a common clinical finding at presentation. Current evidence
indicates that between 50% and 70% of patients presenting
with OPSCC will have lymph node metastasis in the neck.
4
In the last few decades, there has been a shift of treatment
paradigm from nonsurgical treatment to transoral surgical
resection in patients with human papilloma virus–associated
OPSCC. Improved outcomes of transoral robotic surgery
(TORS)/transoral laser microsurgery (TLM) procedures and
achieving primary resection with minimal morbidity are fac-
tors driving the increased popularity of these procedures.
5
However, the timing of neck dissection (ND) in conjunction
with these primary resection modalities remains controver-
sial. Currently, there are no universally accepted guidelines or
1
King’s College London, London, England
2
Department of Otorhinolaryngology and Head and Neck Surgery, Guy’s
and St Thomas NHS Foundation Trust, London, England
Corresponding Author:
Jai Parkash Ramchandani, King’s College London, Shivalaya, 23 Beaucroft Lane,
Wimborne, Dorset, BH21 2PF, England.
Email: jairamchan@icloud.com
Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License
(http://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without
further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/
open-access-at-sage).

consensus for ND timing in patients undergoing TORS for
OPSCC.
6
ND has been performed concurrently, before, or after the
primary tumor resection. Each technique is thought to have its
own advantages and drawbacks (Ta b l e 1). Performing con-
current TORS/TLM and ND allows for single-session treat-
ment. This will reduce the patient’s anaesthetic risk, overall
hospital stay, and associated costs and may reduce the risk of
delay of adjuvant therapy.
7
Performing ND before primary
resection allows vessel ligation before the TORS/TLM proce-
dure, which may reduce hemorrhage intra- and postopera-
tively.
8
It has been hypothesized that performing ND after
TORS/TLM resection reduces fistula formation.
9
Moreover,
it provides an opportunity to address any close or positive
resected margins in the histopathology report.
8
The purpose of this review is to assess the impact of the
timing of ND in relation to oropharyngeal cancer TORS/TLM
on intra- and postoperative complications. These complica-
tions include postoperative bleeding, intra- and postoperative
fistula formation, disease-specific survival (DSS), overall sur-
vival (OS), and recurrence rates.
Methods
The systematic review is reported in accordance with
the PRISMA guidelines (Preferred Reporting Items for
Systematic Reviews and Meta-analyses) via methodology
described in the Cochrane Handbook for Systematic Reviews
of Interventions. A protocol was developed and peer reviewed
locally before being registered on the PROSPERO database
(CRD42021233780).
Search Strategy
A search was conducted across the MEDLINE, Embase, US
National Library of Medicine, and Cochrane databases with
the search terms indicated (Figure 1), from their inception to
July 2021 when the search was performed. The references of
included articles were also searched.
Study Selection
The articles filtered by the search strategy were considered in
conformance with the following inclusion criteria:
Primary studies
Written in the English language (or provided English
translations)
Patients treated for a primary oropharyngeal cancer
Patients undergoing TORS/TLM for primary resec-
tion in conjunction with an ND
ND performed conventionally and not as robot-
assisted procedures
Timing of the ND specified as concurrent, before, or
after TORS/TLM
Results include surgical complications and functional
patient-related outcomes
Studies describing TORS/TLM and ND in the salvage setting
were excluded, and case reports were included. The main out-
come measures were rates of postoperative hemorrhage, intra-
and postoperative fistula formation, DSS, OS, and recurrence.
Study Evaluation
Two reviewers (J.P.R. and A.B.-G.) were involved in the
study selection process to ensure that no articles were missed.
Any disagreement was resolved by discussion. Data from all
the included articles were scanned independently by J.P.R.
and A.B.-G. for bias per the ROBINS-I tool,
10
and disagree-
ment was resolved by discussion. ROBINS-I tool assesses
bias within articles according to 7 domains:
Bias due to confounding
Bias in selection of participants into the study
Bias in classification of intervention
Bias due to deviations from intended interventions
Bias due to missing data
Bias in measurement of outcomes
Table 1. Advantages of Performing Neck Dissection Before, Concurrently, or After Transoral Surgery.
Before Concurrent After
Ligation of vessels to reduce
hemorrhage during resection
Single theater session Address close/positive margins
following initial resection
Reduced patient anesthetic risk
Reduced costs of surgery
No delay to adjuvant therapy
Figure 1. A list of search terms used for this review.
2OTO Open

Bias in selection of results
This was in accordance with guidance from the Cochrane
Handbook.
11
Categorization of ND
Timing of ND in relation to TORS/TLM was divided into 5
categories: before, concurrent before, concurrent, concurrent
after, and after (Figure 2). In articles with patients who had
concurrent procedures, it was not indicated whether the ND
was performed before or after the TORS/TLM procedure, and
so patients were grouped into a unified ‘‘concurrent’’ cate-
gory. The Clavien-Dindo classification was used to assess
complications among patients in the different cohorts.
Results
The initial literature search identified 703 articles. After
removal of duplicates, 502 studies remained. These under-
went a 2-stage screening process performed independently by
2 reviewers. Primary screening involved reading titles and
abstracts of the 502 articles, excluding 407 articles and leav-
ing 95 for secondary screening. The full texts of the remaining
articles were analyzed, and 19 studies
6,12-25
were identified
that fulfilled the criteria for inclusion in the qualitative analy-
sis for the review (Figure 3). Of these articles, 5 were pro-
spective studies,
13,16,21,22
and 14 were retrospective studies
(Tables 2 and 3).
6,12,14,15,17-20,23,25-29
There was significant
heterogeneity among study designs and recorded outcomes,
meaning that a formal meta-analysis was not possible.
Figure 2. Definitions of categories in which patients were assigned. ND, neck dissection.
Figure 3. Search results.
Ramchandani et al 3

Table 2. Study Demographics.
a
Patients Classification ND
Study
Type of
study
Years of
collection Overall
With
ND Intervention
Primary
tumor site T N Stage Level UNI/BIL
Ghanem
12
RET 4 4 (100) TORS Tonsil: 2 (50)
BOT: 1 (25)
Tonsil 1BOT: (25)
T1: 1 (25)
T2: 1 (25)
T4: 2 (50)
N1: 2 (50)
N2a: 1 (25)
N2b: 1 (25)
Rubek
13
PRO 2014-2016 30 30 (100) TORS Tonsil: 21 (70)
BOT: 7 (23)
PPW: 2 (7)
T1: 14 (47)
T2: 16 (53)
N0: 12 (40)
N1: 10 (33)
N2a: 1 (3)
N2b: 7 (23)
II-IV: 30 (100) UNI: 21 (70)
BIL: 9 (30)
Cannon
14
RET 2010-2016 88 88 (100) TORS Tonsil: 39 (44)
BOT: 49 (56)
T1: 45 (51)
T2: 34 (39)
T3: 9 (10)
N0: 6 (7)
N1: 13 (14)
N2a: 15 (17)
N2b: 48 (55)
N2c: 3 (3)
N3: 3 (3)
I: 2 (2)
II: 4 (5)
III: 13 (15)
IVa: 66 (75)
IVb: 3 (3)
II-IV: 88 (100) UNI: 85 (97)
BIL: 3 (3)
Kucur
15
RET 2008-2013 113 113 (100) TORS T1: 43 (38)
T2: 59 (52)
T3: 8 (7)
T4: 3 (3)
N0: 18 (16)
N1: 11 (10)
N2a: 33 (29)
N2b: 38 (34)
N2c: 8 (7)
N3: 5 (4)
I: 7 (6)
II: 4 (4)
III: 12 (11)
IVa: 81 (72)
IVb: 9 (8)
I-V: 56 (50)
I-IV: 25 (22)
II-V: 8 (7)
II-IV: 24 (21)
UNI: 97 (86)
BIL: 16 (14)
van Loon
16
PRO 2007-2012 18 9 (50) TORS Tonsil: 5 (56)
BOT: 3 (33)
Soft palate: 1 (11)
T1: 4 (44)
T2: 5 (56)
N0: 9 (100) I-IV: 9 (100) UNI: 9 (100)
BIL: 0 (0)
Granell
17
RET 1 1 (100) TORS Tonsil: 1 (100) T2: 1 (100) N2b: 1 (100)
Noel
18
RET 1 1 (100) TORS Tonsil: 1 (100) T2: 1 (100) N1: 1 (100) III: 1 (100) II-IV: 1 (100)
Olsen
19
RET 2007-2009 18 18 (100) TORS Tonsil: 12 (67)
BOT: 6 (33)
T1: 11 (61)
T2: 6 (33)
T3: 1 (6)
N0: 13 (72)
N1: 2 (11)
N2a: 1 (6)
N2b: 2 (11)
I: 8 (44)
II: 5 (28)
III: 2 (11)
IVa: 3 (17)
UNI: 17 (94)
BIL: 1 (6)
Tsukahara
20
RET 1 1 (100) TORS BOT: 1 (100) T1: 1 (100) N1: 1 (100) I: (100)
Genden
21
PRO April-Nov2007 20 11 (55) TORS Tonsil: 7 (64)
BOT: 2 (18)
Soft palate: 2 (18)
T1: 7 (64)
T2: 4 (36)
N0: 6 (55)
N1: 4 (36)
N2: 1 (9)
UNI: 10 (91)
BIL: 1 (9)
(continued)
4

Table 2. (continued)
Patients Classification ND
Study
Type of
study
Years of
collection Overall
With
ND Intervention
Primary
tumor site T N Stage Level UNI/BIL
Krishnan
6
RET 2008-2015 33 33 (100) TORS T1: 7 (21)
T2: 19 (58)
T3 3 (9)
T4: 4 (12)
N0: 7 (21)
N1: 1 (3)
N2: 3 (9)
N2a: 5 (15)
N2b: 16 (48)
N3: 1 (3)
II: 2 (6)
III: 4 (12)
IV: 27 (24)
I-V: 33 (100)
Tsang
22
PRO 1 1 (100) TORS Tonsil: 1 (100) T1: 1 (100) N1: 1 (100) I-IV: 1 (100) UNI: 1 (100)
Byeon
23
RET 2011-2012 5 4 (80) TORS Tonsil: 4 (100) T2: 3 (75)
T3: 1 (25)
N2b: 4 (100) II-V: 4 (100) UNI: 2 (50)
BIL: 2 (50)
Dabas
24
PRO 2013-2015 57 57 (100) TORS Tonsil: 22 (39)
BOT: 31 (54)
Soft palate: 3 (5)
PPW: 1 (2)
T1: 24 (42)
T2: 33 (58)
N0: 49 (86)
N1: 8 (14)
I: 19 (33)
II: 30 (53)
III: 8 (14)
UNI: 45 (79)
BIL: 12 (21)
Parhar
25
RET 2015-2019 20 20 (100) TORS Tonsil: 19 (95)
BOT: 1 (5)
T1: 3 (15)
T2: 6 (30)
T3: 1 (5)
T4: 10 (50)
N0: 9 (45)
N1: 10 (50)
N2: 1 (5)
Jackel
26
RET 2001-2005 6 5 (83) TLM T3: 4 (80)
T4a: 1 (20)
N0: 2 (40)
N2a: 2 (40)
N3: 1 (20)
Veit
27
RET 1 1 (100) TLM T2: 1 (100) N2c: 1 (100) I-V: 1 (100) UNI: 0 (0)
BIL: 1 (100)
Leong
28
RET 1 1 (100) TLM BOT: 1 (100) N0: 1 (100) UNI: 1 (100)
BIL: 0 (0)
Moore
29
RET 2007-2010 148 148 (100) TORS
Abbreviations: BIL, bilateral; BOT, base of tongue; ND, neck dissection; PRO, prospective; PPW, posterior pharyngeal wall; RET, retrospective; UNI, unilateral.
a
Values are presented as No. (%). Blank cells indicate not specified.
5

Table 3. Primary Outcomes.
a
Study Patients with ND Timing of ND
b
Hemorrhage Fistula formation
DDS/OS, %;
mean follow-up Recurrence rate
Ghanem
12
4 Concurrent after Major: 0 (0)
Minor: 0 (0)
Intra: 0 (0)
Post: 0 (0)
Rubek
13
30 Concurrent Major: 1 (3)
Minor: 2 (7)
Intra: 0 (0)
Post: 0 (0)
Cannon
14
88 Concurrent Intra: 2 (2)
Post: 0 (0)
DSS: 95
OS: 100
2y
2 (2)
Kucur
15
113 Concurrent Intra: 6 (5)
Post: 0 (0)
van Loon
16
9 After (4 wk) Major: 0 (0)
Minor: 0 (0)
Intra: 1 (11)
Post: 0 (0)
DSS: 89
OS: 100
2y
1 (11)
Granell
17
1 Before (2 wk) Intra: 0 (0)
Post: 0 (0)
Noel
18
1 Concurrent Major: 0 (0)
Minor: 0 (0)
Intra: 0 (0)
Post: 0 (0)
DSS: 100
OS: 100
6mo
0 (0)
Olsen
19
18 Concurrent Major: 0 (0)
Minor: 0 0)
Intra: 0 (0)
Post: 0 (0)
DSS: 78
OS: 94
2y
4 (22)
Tsukahara
20
1 Before (1 mo) Major: 1 (100)
Minor: 0 (0)
Intra: 0 (0)
Post: 0 (0)
DSS: 100
OS: 100
1y
0 (0)
Genden
21
11 Concurrent Major: 0 (0)
Minor: 0 (0)
Intra: 1 (9)
Post: 0 (0)
DSS: 100
OS: 100
4mo
0 (0)
Krishnan
6
33 Before: 8 (8 d)
Concurrent: 19
After: 6 (10 d)
Before
Major: 0 (0)
Minor: 0 (0)
Concurrent
Major: 1 (3)
Minor: 0 (0)
After
Major: 0 (0)
Minor: 1 (3)
Before
Intra: 0 (0)
Post: 0 (0)
Concurrent
Intra: 3 (16)
Post: 1 (5)
After
Intra: 2 (33)
Post: 0 (0)
Tsang
22
1 Concurrent Major: 0 ()
Minor: 0 (0)
Intra: 0 (0)
Post: 0 (0)
Byeon
23
4 Concurrent before Major: 0 (0)
Minor: 0 (0)
Intra: 0 (0)
Post: 0 (0)
Dabas
24
57 Concurrent before Major: 1 (2)
c
Minor: 0 (0)
c
DSS: 88
c
OS: 92
c
29 mo
2 (4)
c
Parhar
25
20 Concurrent after Major: 0 (0)
Minor: 0 (0)
Jackel
26
5 Concurrent before Major: 0 (0)
Minor: 1 (20)
Intra: 0 (0)
Post: 0 (0)
DSS: 80
OS: 80
24.8 mo
1 (20)
Veit
27
1 Concurrent DSS: 100
OS: 100
12 mo
0 (0)
(continued)
6OTO Open

Articles in this review were published between 2001 and
2020. The total number of patients who had TORS/TLM for
primary tumor resection was 566. Of these, 546 also had an
ND. The primary oropharyngeal sites were 54% tonsils, 42%
base of tongue, 2% soft palate, 1% posterior pharyngeal wall,
and 0.4% tonsil and base of tongue (n = 246). Five articles did
not specify the primary cancer site.
6,15,26,27,29
Stage of Disease
The stage of disease was reported according to the seventh
edition of the American Joint Committee on Cancer’s TNM
classification. Tumor size (T) was cited in all but 2 stud-
ies,
28,29
while nodal staging (N) was noted in all but 1 study.
29
Across all studies, 41% of patients had T1 disease, 48% had
T2 disease, 7% had T3 disease, and 5% had T4 disease (n =
397). Nodal disease was 33%, 16%, 48%, and 3% for N0, N1,
N2, and N3 staged disease, respectively (n = 298). Overall
cancer staging was reported in 7 studies and also showed
large heterogeneity.
6,14,15,18-20,24
The most common stage of
disease was IV with 61% of patients being treated with this
staging. A further 12% of patients were treated for stage I dis-
ease, while 14% were treated for stage II and 13% for stage III
(n = 311).
Neck Dissection
Two articles described ND as a separate procedure before
TORS/TLM
17,20
; 3 as concurrent before procedures
23,24,26
;10
as concurrent procedures
13-15,18,19,21,22,27-29
; 2 as concurrent
after procedures
12,25
; 1 as a separate procedure after TORS/
TLM
16
; and 1 as before, after, and concurrently to TORS/
TLM.
6
Of the 19 studies, 8 cited the level of ND.
6,13-16,18,22,23
This accounted for 279 patients, of which 13% had I to IV,
32% had I to V, 51% had II to IV, and 4% had II to V. The
ND was described in 11 studies as being unilateral or bilat-
eral.
13-16,19,21-24,27,28
Within these studies, 86% of patients
had unilateral ND and 14% had bilateral ND (n = 333).
Complications
Postoperative hemorrhage was divided broadly into major
and minor bleeding. Major hemorrhage required surgical
intervention (including arterial embolization) while minor
bleeds recovered with conservative management. Of the 13
studies that recorded postoperative hemorrhage as an out-
come, 4 cited major episodes of postoperative hemor-
rhage.
6,13,20,24
In 2020, Tsukahara et al
20
reported a patient
having 2 episodes of severe pharyngeal bleeding, both requir-
ing readmission. The second bleed led to hemorrhagic shock.
There were 3 episodes of minor hemorrhagic bleeding across
2 studies.
13,26
Altogether 15 studies with a total of 468 patients recorded
fistula formation as a patient outcome.
6,12-23,26,29
Of these,
12% had intraoperative fistulae, and 1% sustained postopera-
tive fistulae. All intraoperative fistulae were managed in thea-
ter, with local flap reconstructions. However, in the study by
Moore et al, 6 patients with intraoperative fistulae went on to
develop postoperative fistulae.
29
Clavien-Dindo Classification Analysis
Of the 431 patients undergoing concurrent ND, 2 (0.5%) had
grade III complications, 66 (15%) were classified as grade II,
and 6 (1%) patients had grade V complications. Of the 39
patients with ND performed after transoral surgery (including
the concurrent after and after cohorts), 3 (8%) had grade II
complications and 1 (3%) had grade V. Seventy-six patients
had ND prior to transoral surgery (including the before and
concurrent before cohorts). Of these, 1 patient (1%) had
grade IV complications, 2 (3%) were grade II, and 6 (8%) had
grade V.
Disease-Specific Survival and Overall Survival
Ten studies described DSS and OS, with varying follow-up
times. Five studies cited DSS and OS as 100% for 13
patients at follow-up times ranging from 2 months to 1
year.
18,20,21,27,28
Three studies with a 2-year follow-up period
found DSS to be 95%, 89%, and 78% while OS was at 100%,
100%, and 94%.
14,16,19
Dabas et al
24
cited a DSS of 88% and
OS of 92% at a mean follow-up time of 29 months, and
Jackel
26
reported DSS and OS at 80% with a mean follow-up
of 24.8 months. Ten studies (192 patients) recorded a recur-
rence rate, which was 5% on average.
14,16,18-21,24,26-28
Five
studies described no recurrence.
18,20,21,27,28
Table 3. (continued)
Study Patients with ND Timing of ND
b
Hemorrhage Fistula formation
DDS/OS, %;
mean follow-up Recurrence rate
Leong
28
1 Concurrent DSS: 100
OS: 100
12 mo
0 (0)
Moore
29
148 Concurrent Intra: 42 (28)
Post: 6 (4)
Abbreviations: DDS, disease-specific survival; Intra, intraoperative; ND, neckdissection;OS, overall survival; Post, postoperative; TORS, transoral robotic surgery.
a
Values are presented as No. (%) unless noted otherwise. Blank cells indicate not specified.
b
Mean time between ND and TORS in parentheses.
c
Eight patients with pathologically upstaged disease were excluded from these statistics.
Ramchandani et al 7

Effect of ND Timing
Across the studies, 12% had concurrent before procedures;
4% had concurrent after procedures; 2% had ND as a separate
procedure before (minimum 8 days and maximum 1 month
before TORS/TLM); 3% had ND as a separate procedure after
(minimum 10 days and maximum 8 weeks after TORS/TLM);
and 79% patients had a concurrent procedure. The timing of
ND was not mentioned in this cohort (n = 546).
In patients with ND before TORS/TLM (including concur-
rent before and before cohorts), 3% experienced major bleed-
ing and 1% experienced minor bleeding, while fistula rates
were at 0% (n = 76). Of patients with ND after TORS/TLM
(including concurrent after and after cohorts), 3% experienced
minor hemorrhage, and 8% had intraoperative fistulae (n =
39). In the concurrent cohort of patients, 1% experienced
major bleeds and 0.3% had minor bleeds. A further 13%
developed intraoperative fistulae and 2% developed post-
operative fistulae (n = 431). Recurrence rates were 4% in
patients who had ND before TORS/TLM and 11% in patients
who had ND after TORS/TLM. In the cohort of concurrent
ND and TORS/TLM, the recurrence rate was 1%.
Bias Assessment
The articles in this review were predominantly nonrando-
mized studies and were reviewed for bias with the ROBINS-I
tool (Table 4),
10
with case reports classified as ‘‘severe’’
bias.
17,18,20,22,27,28
Selection bias in disease severity and
stage, different inclusion and exclusion criteria, lack of
common outcome measures and varying lengths of follow-up
were identified as some of the factors increasing the bias
levels in the articles.
Discussion
When considering management of patients presenting with
oropharyngeal cancer, there is a divergence in approaches;
some have been identified in this review. Generally, ND
timing lacks standardization and varies among centers. This
review focuses on transoral surgery in conjunction with ND
and aims to shed light on whether the timing of ND has any
effect on patient outcomes.
Repanos et al in 2017 published a similar systematic
review looking at the timing of ND in relation to transoral sur-
gery, including TORS and TLM.
30
The review included arti-
cles that failed to mention ND timing, as well as articles in
which not all patients had ND. Case reports were also
excluded from the review. The modalities analyzed were
transoral laser surgery and TORS for resection of head and
neck squamous cell carcinoma. The results indicated that
timing of ND did not affect OS and highlighted the lack of
robust evidence in the literature regarding patient complica-
tions and oncologic outcomes with respect to timing of ND in
conjunction with primary surgery.
To date there have been no randomized controlled trials
(RCTs) assessing timing of ND in conjunction with transoral
surgery, although prospective and retrospective studies on
this topic have been performed.
8,31
Frenkel et al
31
Table 4. Bias Assessment of Studies With the ROBINS-I Tool.
a
Study D1 D2 D3 D4 D5 D6 D7 Overall bias
Ghanem
12
Low Low Low Low Low Low Low Low
Rubek
13
Low Low Low Moderate Low Low Low Moderate
Cannon
14
Low Low Low Moderate Low Low Low Moderate
Kucur
15
Low Low Low Low Low Low Low Low
van Loon
16
Low Moderate Low Moderate Low Low Low Moderate
Granell
17
Low Serious Serious Low No information Moderate Low Serious
Noel
18
Low Serious Serious Moderate Low No information No information Serious
Olsen
19
Low Low Low Low Low Low Low Low
Tsukahara
20
Low Serious No information Low Low Low Low Serious
Genden
21
Low Low Low Low Low Low Low Low
Krishnan
6
Low Low Low Low Low Low Low Low
Tsang
22
Low Serious Serious Low Low Moderate Low Serious
Byeon
23
Low Low Low Low Low Low Low Low
Dabas
24
Low Low Low Moderate Moderate Low Low Moderate
Parhar
25
Low Low Low Moderate Low Low Low Moderate
Jackel
26
Moderate Low Low Moderate Low Low Low Moderate
Veit
27
Low Serious Serious Low Moderate Low Low Serious
Leong
28
Low Serious Serious Low Low Low Low Serious
Moore
29
Low Low Low Low Low Low Low Low
a
D1, bias due to confounding; D2, bias in selection of participants into the study; D3, bias in classification of intervention; D4, bias due to deviations from
intended interventions; D5, bias due to missing data; D6, bias in measurement of outcomes; D7, bias in selection of reported result.
8OTO Open

retrospectively analyzed 386 procedures in New York State.
Patients had ND, performed concurrently, before, and after
TORS. Patient outcomes were not recorded in this study as it
predominantly focused on the economic implications of ND
timing. The study gathered objective data, showing that con-
current ND with TORS is cost-effective as it maximizes usage
of expensive medical equipment and reduces patients’ length
of stay. It was found that the difference in mean prices for
staged procedures as compared with concurrent procedures
was .$30,000.
Hemorrhage and Fistula Rates
There were insufficient data from the studies in this review to
draw meaningful conclusions about whether the timing of
ND affects postoperative hemorrhage rates. Six studies
(352 patients) did not identify hemorrhage as an out-
come.
14,15,17,27-29
Of the remaining patients who had concur-
rent ND, 3% had major bleeds and 3% had minor bleeds
recorded,
6,13
with an overall bleeding rate of 5% (n = 80). In
both instances of major bleeding, vessel ligation was not per-
formed during the initial procedure. In patients with ND per-
formed after TORS/TLM, 3% experienced minor bleeding (n
= 39).
6
In patients with ND performed before TORS/TLM,
3% had a major bleed,
20,24
and 1% had a minor bleed (n =
75).
26
In the case report by Tsukahara et al,
20
external carotid
artery ligation did not occur until the patient was readmitted
for the second episode of pharyngeal bleeding. In the majority
of patients with major bleeding, vessel ligation did not occur
regardless of ND timing. In all 4 episodes of major hemor-
rhage, bleeding was stopped with readmission and vessel
ligation.
6,13,20,24
Four studies (79 patients) did not include fistula rates as
outcome measures.
24,25,27,28
Of the concurrent cohort of
patients, 13% had intraoperative fistulae, and 2% had post-
operative fistulae (n = 429). There were no recorded fistulas
in patients with ND before TORS/TLM (n = 19). In patients
with ND after TORS/TLM (including concurrent after), 16%
reported intraoperative fistulae
6,16
and no postoperative fistu-
lae were noted (n = 19). Due to the variability in the sample
size of each cohort, definitive conclusions cannot be made
about fistula formation. However, the trends identified in this
study (increased fistula rate in patients with concurrent ND)
are in keeping with published literature.
Moore et al
29
found that 29% of patients developed intrao-
perative communications and that 4% resulted in delayed fis-
tula formation in patients undergoing concurrent transoral
surgery and ND (n = 148). Their results showed that fistulae
occur regardless of T stage but generally correlate with
advanced-stage neck disease, suggesting that there is an
increased probability of fistulae formation when treating
stage III and IV oropharyngeal disease.
Overall Survival and Disease-Specific Survival
Long-term patient outcomes such as DSS and OS were not
mentioned in 9 studies.
6,12,13,15,17,22,23,25,29
In studies report-
ing DSS and OS for concurrent ND, the mean DSS was
calculated to be 96% and mean OS was 99%, with a follow-up
period ranging from 2 to 29 months.
15,18,19,21,27,28
One study
cited DSS and OS rates of 89% and 100% at 2 years, respec-
tively, for patients undergoing ND after TORS/TLM.
16
Three
studies described mean DSS and OS rates of 89% and 91% at
a follow-up ranging from 1 year to 29 months in 58 patients
undergoing ND before (including concurrent before) TORS/
TLM.
20,24,26
It is important to note that while we have
reported DSS and OS, interpretation of these data should be
cautious due to the lack of TNM-stratified survival rates
within the studies in this review. The number of studies
reporting DSS and OS as outcomes for each category of ND
(before, concurrent, and after) was too small to draw defini-
tive conclusions.
Level of ND
Besides ND timing, one variation identified among studies in
this review is the level of ND performed. Most authors recom-
mended a selective ND of levels II to IV for OPSCC treat-
ment.
18
Performing level I ND in patients with OPSCC
carries added risk of creating PCF intra- or postoperatively.
Moreover, the rate of occult level I metastases based on preo-
perative evaluation is estimated to be 3%,
32
which is below
the threshold to indicate standard inclusion of this level
according to standard UK practice. The current guideline for
surgical management of these patients in the United Kingdom
is that ND should include levels II to IV and possibly level I.
33
This is reflected in the results of our study, with 100% of
patients having ND of levels II to IV and 64% having ND of
level I, while 36% had level V. In 2003, Doweck et al
34
per-
formed a study of 76 patients, looking at the extent of ND
required in oropharyngeal cancer. They concluded that surgi-
cal management of oropharyngeal cancer should include a
selective ND of levels II to IV and that without radiologic and
clinical evidence of positive nodes in level I and V, these
levels could be spared.
Limitations
A major issue encountered when performing this review was
interpreting the findings of the studies. The literature search
did not identify any RCTs, which limited analysis. In addition
to the 19 articles in the review, only 5 were prospective stud-
ies. Therefore, the articles reviewed showed variation in
design and outcome measures, and the lack of control arms in
the studies added to the heterogeneity among the articles. This
limited statistical analysis as a meta-analysis could not be per-
formed. Individual patient-level analysis was not possible to
extract from many of the studies.
Potential for Bias
We declare no biases in the construction of this review. A
thorough search was conducted by 2 independent reviewers;
the search was limited to the English language. Articles study-
ing cancers outside the oropharynx (including the oral cavity),
modalities other than TORS/TLM, and those failing to distin-
guish ND timing as a feature in the results were excluded.
Ramchandani et al 9

Future Implications
The evidence presented in this review is insufficient to draw
definitive conclusions surrounding ND timing and patient out-
comes. As such, practice should continue to reflect the
decision-making process of the multidisciplinary team. More
research should be conducted, including RCTs, to allow for a
more thorough review to be completed before any conclusive
decisions arise regarding ND timing. In addition, other factors
should be considered when looking at ND timing, including
cost-effectiveness of performing staged ND, the level of ND,
anaesthetic risk to the patient with having 2 procedures, and
the effects of potentially having delayed adjuvant treatment.
Conclusion
In conclusion, transoral surgery, TORS in particular, has
become a well-established modality for treating oropharyn-
geal carcinoma. Given the increasing rates of these cancers,
the role of TORS/TLM is becoming more relevant.
This review demonstrates the lack of robust literature
when analyzing ND timing in relation to TORS/TLM for oro-
pharyngeal carcinoma. There should be a focus on producing
more evidence for patient outcomes surrounding TORS/TLM
with concurrent or staged ND. Wherever possible, this evi-
dence should be in the form of RCTs or prospective studies,
although it is acknowledged that these would raise ethical
concerns regarding patient allocation to particular treatment
arms prospectively.
Due to the heterogeneity of existing studies and the lack of
comparator arms, meta-analysis could not be performed.
Pooled analysis was conducted for certain outcomes, where
this was possible. There are insufficient data to comment on
whether the timing of ND in relation to TORS affects the out-
comes of patients. However, within the limitations of the cur-
rent evidence base, there seems to be no correlation between
timing of ND and complications.
Finally, heterogeneity was identified in the extent of ND
routinely performed for oropharyngeal carcinoma. Therefore,
a dedicated systematic review on this topic would likely be
beneficial in providing the best possible quality evidence for
clinicians in assessing the necessity of level I ND in patients
with oropharyngeal cancer.
Author Contributions
Jai Parkash Ramchandani, wrote manuscript, involved in study
design, data acquisition and analysis, drafting, final review of the
manuscript prior to submission, study supervision; Aina Brunet-
Garcia, wrote manuscript, involved in study design, data acquisi-
tion and analysis, drafting, final review of the manuscript prior to
submission; Nikoleta Skalidi, involved in study design, data acqui-
sition and analysis, critical review of manuscript and final review
prior to submission; Jack Faulkner, involved in critical review of
manuscript and final review prior to submission; Aleix Rovira,
involved in critical review of manuscript and final review prior to
submission; Ricard Simo, involved in critical review of manu-
script and final review prior to submission; Jean-Pierre Jeannon,
involved in critical review of manuscript and final review prior to
submission; Asit Arora, involved in critical review of manuscript
and final review prior to submission.
Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: None.
ORCID iD
Jai Parkash Ramchandani https://orcid.org/0000-0003-1480-8783
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