Oral Oncology 102 (2020) 104563

Contents lists available at ScienceDirect

Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

The role of adjuvant (chemo-)radiotherapy in oral cancers in the T

contemporary era
Shao Hui Huanga, Ezra Hahna, Simion I. Chioseab, Zhi-Yuan Xuc, Ji-Shi Lic, Lin Shenc,
⁎
Brian O'Sullivana,c,
a
Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, ON, Canada
b
Department of Pathology, University of Pittsburgh Medical Center, PA, USA
c
Department of Clinical Oncology, The University of Hong Kong – Shenzhen Hospital, Shenzhen, PR China

A R T I C LE I N FO A B S T R A C T

Keywords: Squamous cell carcinoma of oral cavity (OSCC) is predominantly managed with surgery. Post-operative radio-
Oral cavity therapy (PORT) and chemoradiotherapy (POCRT) enhance disease control in OSCC patients with adverse ana-
Squamous cell carcinoma tomic and pathologic primary and nodal features. Knowledge about disease behavior, surgery and radiotherapy
Margins of excision advances, and the emergence of new systemic agents prompt refinement of PORT volumes and POCRT regimens.
IMRT
Traditional and emerging prognostic models that include adverse histopathological features underpin such ap-
Adjuvant radiotherapy
proaches. This review summarizes research over recent decades with emphasis on the 2015 to Feb 2019 period
Adjuvant chemoradiotherapy
Outcomes describing: (1) Indications for PORT and/or POCRT, addressing surgical “margin status” including the definition
of a “clear” margin to permit withholding PORT/POCRT; these concepts include characterizing the specimen
yielding these measurements, the optimal time point to assess these findings, and the putative value of a “revised
margin” performed during the same operative procedure, (2) Emerging prognostic factors including nodal
burden (total number of involved lymph nodes) and perineural invasion, (3) PORT volume design, dose/frac-
tionation and optimal surgery-to-PORT interval, (4) Chemotherapy dose, schedule, and agents, and (5) On-going
clinical trials involving systemic agents and combinations of chemotherapy with immunotherapy.

Introduction
The preferred primary treatment for resectable oral squamous cell
carcinoma (OSCC) is surgery due to tumor accessibility and visibility.
This paradigm is also linked to the desirable and frequently achievable
goal of avoiding external beam radiotherapy to important adjacent
structures including mandible and salivary tissues, although bra-
chytherapy could be deployed in favorable presentations. Unfortunately
surgery-alone is inadequate for cases with unfavourable clinico-patho-
logical features since postoperative radiotherapy (PORT) or post-
operative concurrent chemo-radiotherapy (POCRT) have shown im-
proved locoregional control (LRC) and overall survival (OS) in this
setting in several clinical trials [1–3].
There has been an increasing recognition of the prognostic im-
portance of several histopathological features, with the goal of refining
and optimizing treatment for OSCC. Depth of invasion (DOI) and ex-
tranodal extension (ENE) are recognized as strong prognostic factors
and now augment the T- and N- categories for OSCC in the 8th edition
TNM (TNM-8) [4,5] (Fig. 1). It is expected that the new staging criteria
will reclassify many historical “early-stage” OSCC into more advanced
subsets. In turn this prompts a reappraisal of indications and char-
acteristics of delivery of PORT/POCRT.
This comprehensive review summarizes landmark research with
special emphasis on reports from the 2015 to Feb 2019 period relating
to the indications for, treatment specifics, and outcomes of PORT/
POCRT in OSCC.
Adverse features and indication for PORT/POCRT
Adjuvant radiotherapy (RT) following surgery began in the
1940–1950 era with appreciation of increased risk of recurrence fol-
lowing surgery-alone. However the benefit of PORT was not truly de-
monstrated until the publication of a small randomized clinical trial
(RCT) from India involving 140 buccal mucosal OSCC patients [3] with
a 30% improvement in disease-free survival at 3-years compared to
surgery-alone. While a 10% OS difference was also evident, the trial

⁎
Corresponding author at: Department of Radiation Oncology, University of Toronto, Department of Otolaryngology/Head and Neck Surgery, University of
Toronto, The Princess Margaret Cancer Centre/University of Toronto, Toronto, ON M5G 2M9, Canada.
E-mail address: Brian.OSullivan@rmp.uhn.ca (B. O'Sullivan).

https://doi.org/10.1016/j.oraloncology.2019.104563
Received 26 March 2019; Received in revised form 23 December 2019; Accepted 31 December 2019
1368-8375/ © 2020 Elsevier Ltd. All rights reserved.
S.H. Huang, et al. Oral Oncology 102 (2020) 104563

Category 7th Edition T Classification 8th Edition T Classification

T1

T2 10 mm
– 4 cm -4 cm, and
DOI > 10 mm

10 mm
T3 Size > 4 cm -4 cm AND
Size >4 cm,
DOI > 10 mm

Size >4 cm AND DOI

Other adverse primary tumor
T4a Other adverse primary tumor features
features
*(removed term “extrinsic muscle
involvement”)
T4b Very advanced local disease Very advanced local disease

Category 7th Edition cN 8th Edition cN 7th Edition pN 8th Edition pN

No LN
cN0 N0 pN0
N0
Single ipsilateral LN, No cENE
No cENE cN1
N1 N1 pN1
pENE
cENE
Single ipsilateral LNs, No cENE
N2a cN2a N2a No cENE pN2a
3-6 cm cENE pENE
Multiple ipsilateral No cENE No cENE
N2b cN2b N2b pN2b
cENE pENE

Bilateral/contralateral No cENE
N2c No cENE cN2c N2c pN2c
cENE pENE

Any LN >6 cm No cENE No cENE

N3 cN3a N3 pN3a
pENE
cENE
c N3b pN3b

Figure 1. The 8th Edition TNM Staging Grid for Squamous Cell Carcinoma of Oral Cavity. (Adapted with permission from UICC including errata for the first printing
of the TNM8. Both traditional axial tumor size and depth of invasion are independent prognostic factors.). Abbreviation: LN = lymph node, DOI: depth of invasion;
cENE: clinical extranodal extension; pENE: pathological extranodal extension.

was underpowered to show significance for this end-point. A retro-
spective review [6] also indirectly demonstrated the benefit of adjuvant
RT in the initial management of locally-advanced OSCC where upfront
adjuvant RT provided better oncologic outcomes compared to early-
stage OSCC following initial surgery alone but requiring salvage
therapy (surgery and RT) for disease recurrence. A RCT (“The MD An-
derson Trial”) published in 1993 [7] was an important trial that showed
a dose response for PORT with reduction of locoregional failure (LRF)
in 240 head and neck cancer (HNC) patients (32% were OSCC) with
ENE and other adverse histological features. The principles derived
from this trial still guide risk-stratified approaches to post-operative RT
dose and volume design today. Subsequently, the RTOG-9501 [2]
(OSCC 27%) and EORTC-22931 [1] (OSCC 26%) trials simultaneously
demonstrated the benefit of chemotherapy in addition to PORT in lo-
cally advanced HNC with ‘high-risk’ features, although the inclusion
criteria were slightly different between the trials. A combined analysis
[8] of both [1,2] demonstrated that the benefit of POCRT was pre-
dominant in either positive resection margins and/or pENE, thereby
establishing POCRT as a standard of care for such populations. Re-
cognizing the prognostic value of DOI, the AREST Trial (Adjuvant
Radiotherapy in Early Stage Oral Cavity Cancers) (NCT03853655) is
currently open for recruitment in India to assess the benefit of post-
operative IMRT (60 Gy/30f/6w) in patients with a ≤4 cm OSCC
primary with DOI ≥ 0.5 cm (i.e. approximating T2 lesions in TNM8).
In 2011, the American College of Radiology (ACR) Expert Panel [9]
recommended the following adverse anatomic-pathological features as
indications for PORT or POCRT: T3 or T4 tumors, compromised surgical
resection margins, presence of lympho-vascular invasion (LVI) and/or
peri-neural invasion (PNI), and adverse nodal features including pa-
thological involvement of 2 or more lymph nodes (LNs) in the neck
dissection (ND) specimen, low neck LNs, or any evidence of ENE.
Among these features, positive (i.e. pathologically involved) resection
margins and/or ENE are considered high-risk features for which POCRT
is definitely indicated [8]. Practice variation exists in offering adjuvant
RT to a small primary (pT1) with a single LN metastasis (pN1) without
other adverse features. From a toxicity perspective, some reservation is
understandable. However, while the data are sparse and non-
randomized, evidence suggests that pT1N1 OSCC may still benefit from
adjuvant RT [10,11]. In clinical practice, PORT is also appropriate
when concerns are expressed by the surgical team (e.g. ‘difficult’ re-
sections, ‘peeling off’ tumor during resection, etc.). Controversies exist in
defining ‘margin status’ for withholding PORT/POCRT. Prognostic im-
portance has also recently been emphasized for several emerging his-
topathologic factors.

2
S.H. Huang, et al. Oral Oncology 102 (2020) 104563

Resection margin: Source, time of assessment, revision, and width/clearance
Achieving clear (R0) resection margins is the goal of successful
surgical treatment of OSCC. However, variations exist among surgeons
and across institutions regarding what constitutes an R0 resection,
specifically related to margin dimensions, the nature of the specimen
(main specimen vs patient/tumor bed margin) yielding these mea-
surements, the time-point used to assess these findings (intraoperative
frozen specimen vs final formalin-fixed-paraffin-embedded [FFPE]
specimen), and the putative value of a “revised margin” [12–16].
Withholding PORT/POCRT is traditionally governed by a “ > 5 mm”
resection margin “from the ink” in the FFPE specimen [17], although
several small retrospective studies used a “ > 2 mm” cutoff [18,19].
Recently, the World Health Organization (WHO) [20], College of
American Pathologists (CAP) [21], and American Joint Committee on
Cancer (AJCC) [4] acknowledged these issues and developed reporting
guidelines: (1) intra-operative assessment of margins is only relevant
for the actual resection specimen (specimen-driven approach) [4,20]; (2)
intraoperatively, the resection specimen is optimally assessed grossly,
followed by any microscopic (i.e., frozen) evaluation; (3) radial (rather
than shave) sampling is recommended, to allow for measurement of the
distance to the closest margin; (4) margin revisions are generally in-
adequate since it does not improve local control or survival [15,22–27];
pitfalls and limitations of margin revision are discussed elsewhere[15]
and illustrated in Fig. 2; (5) margin revision could also lead to confusion
in multi-part pathology reports (Fig. 2) obscuring the true margin status
and could lead to a false impression of negative and adequately revised
margins; and (6) the final disposition of the margin status will rely on
the examination and report of the final/permanent FFPE specimen [21].
Prognostic value of perineural invasion
Apart from the margin status, the adverse nature of LVI has con-
sistently been demonstrated and represents a relative indication for
PORT [28–35]. However, the prognostic value of PNI and the capacity
for PORT to offset risk from PNI alone is inconsistent [35,36]. Yang
[35] conducted a RCT of 221 cT1-T2N0 patients assigned to elective ND
(END) vs no END and showed that PNI is prognostically independent for
loco-regional relapse after controlling for pT and tumor grade, but the
role of PORT was not addressed in these early stage cases. Moreover, an
END did not improve neck control among patients with PNI. A meta-
analysis of 7 studies [37] failed to demonstrate a benefit from PORT in
mitigating the influence of PNI; however, a caveat highlighted by these
authors concerned the insufficient quality of the included original stu-
dies. Therefore variations in localization (intra-tumoral vs extratumoral
[38]) and multi-focality of PNI may influence its prognostic value.
Differences in PNI foci density [39] or PNI focus number [40] may
reflect more aggressive tumor biology. Cracchiol [39] found that PNI
was not predictive of LRF but associated with higher risk of distant
metastasis (DM), especially when PNI foci density (defined as the total
number of foci of PNI divided by the number of reviewed tumor sec-
tions) was > 1. However, the reliability of PNI foci density quantifi-
cation, density or site remains to be standardized.

Fig. 2. Spatial Relationship between Tumor at the

Resection Specimen Margin, Additional Revision
Margin, and the Structure of the Pathology Report.
(adapted with permission from Surgical Pathology
Clinics[15]). To illustrate the relationship between
the actual glossectomy margins and potential ad-
ditional resected tissue to augment the security of
the resection, the initial positive margin resected
specimen and the revised “new” margin resection
Initial resection with positive margin are superimposed (4th row). Due to the challenges
of re-locating the exact position of residual tumor,
margin in the tumor bed, size discrepancy, and
uncertain orientation of the additional tissue, it is
conceivable that in some cases the revised margin
may not actually cover the entire residual tumor at
the anterior glossectomy margin.

Re-excision The initial positive margin

resected specimen and the
revised “new” margin
Initial resection are superimposed.
residual In some cases, the revised
tumor margin may not actually cover
the entire residual tumor.

Additional
tissue removed
during revision

3
S.H. Huang, et al. Oral Oncology 102 (2020) 104563

Table 1
Investigational strategies to optimize adjuvant treatment in oral cavity cancer.
Trial Eligibility Intervention

RTOG 0920 cT1, N1-2 or T2-4a, N0-2 SCC of the oral cavity, • Intensity modulated radiotherapy (IMRT), vs
(NCT00956007) oropharynx, or larynx.Undergone surgery with
pathology showing > =1 “intermediate” risk factor
• IMRT + cetuximab
• Phase III
• Targeted/actual
accrual: 700/703
• Active, not recruiting
• Est.
2021
completion: Aug

RTOG 1216 SCC of the oral cavity, oropharynx (p16 neg), larynx, • IMRT + weekly cisplatin, vs
(NCT01810913) or hypopharynx, pathologic stage 3–4, M0. • IMRT + docetaxel, vs
Pathologic ENE or positive margin (tumor on ink) • IMRT + docetaxel + cetuximab
• Phase II/III
• Targeted/actual
accrual: 675/675
• Active, not recruiting
• Est.
2020
completion: May

HN003 (NCT02775812) SCC of the oral cavity, oropharynx (p16 neg), larynx,
or hypopharynx, pathologic stage 3–4,
• IMRT + weekly cisplatin → pembrolizumab
• Phase I M0.Pathologic ENE or positive margin (tumor on
• Targeted/actual
accrual: 56/37
ink)

• Active, not recruiting

• Est.
2018
completion: May

EORTC DUTRELASCO Resectable locally advanced oral cavity SCC stage IV IMRT 66 Gy (with q3 week cisplatin if ENE or positive margin), and:
(NCT03784066)
• Durvalumab, vs
• Phase I/II • Durvalumab and tremelimumab
• Targeted accrual: 20
• Recruiting
• Est. completion:
March 2020

NeoNivo (NCT03843515) Oral cavity SCC, stage 3–4, planned for curative
intent surgical resection
• Neoadjuvant nivolumab prior to surgery
• Targeted accrual: 15
• Recruiting
• Est. completion:
March 2021

NICO (NCT03721757) Oral cavity SCC, cT1-4, N1-2 or cT3-4, N0 (TNM8).

Planned surgical resection.
• risk)
Nivolumab → surgery → nivolumab → radiation ± chemo (low vs high
→ nivolumab
• Phase I
• Targeted accrual: 120
• Not yet recruiting
• Est.
2021
completion: May

EA3132 (NCT02734537) Oral cavity, oropharynx, larynx, or hypopharynx • IMRT over 6 weeks, vs
SCC. Surgical resection, pT3-4a, N0-3 or pT1-2, N1-3 • IMRT over 6 weeks + weekly cisplatin
• Phase II (TNM8).ENE and positive margins are excluded
• Targeted accrual: 345
• Recruiting
• Est.
2022
completion: May

SNOW-001
(NCT03575598)
Oral cavity SCC, surgically resectable, T2-4a, N0-2,
or T1 - > 1 cm - N2, M0
• Sitravatinib + nivolumab → surgery → radiation ± chemotherapy as indicated
• Phase I
• Targeted accrual: 15
• Recruiting
• Est.
2020
completion: Aug

CDSCAN (NCT02290145) Oral cavity SCC with high CD1 expression, stage 3–4, • Radical surgery → radiation, vs
surgically resectable. • Induction TPF → radical surgery → radiation
• Phase II
• Targeted accrual: 48
• Recruiting
• Est.
2018
completion: Dec

(continued on next page)

4
S.H. Huang, et al. Oral Oncology 102 (2020) 104563

Table 1 (continued)

Trial Eligibility Intervention

LCCC 1725
(NCT03529422)
Oral cavity, oropharynx, larynx, or hypopharynx
SCC. Surgical resection with > =1 “intermediate”
• Surgery → IMRT 60 Gy in 30 fractions + durvalumab q3 weeks x6
cycles + tremelimumab q3 week x4 cycles
risk factor.
• Phase I
• Targeted accrual: 24
• Recruiting
• Est.
2021
completion: Feb

17P.513 (NCT03342911) SCC of the oral cavity, oropharynx (p16 neg), larynx,
or hypopharynx, pathologic stage 3–4, M0 (TNM8).
• Induction nivolumab + carboplatin + paclitaxel → surgery
• Phase II Surgically resectable.
• Targeted accrual: 37
• Recruiting
• Est.
2020
completion: June

LCCC 1621 Surgically resectable SCC of the head and neck, stage Induction carboplatin + nab-paclitaxel + durvalumab → surgery→:
(NCT03174275) 3–4 (HPV positive or negative, M0). SCCHN of
unknown primary is excluded. • Low risk: durvalumab
• Phase II • Med risk: “involved field” radiation + weekly cisplatin → durvalumab
• Targeted accrual: 39 • High risk: IMRT + weekly cisplatin → durvalumab
• Recruiting
• Est.
2021
completion: Sept

103-0621A3
(NCT03121313)
Oral cavity SCC. Undergone surgical resection with
pathologic ENE.
• Surgery → radiation + chemotherapy → maintenance tegafur-uracil for one year.
• Phase II
• Targeted accrual: 68
• Recruiting
• Est.
2020
completion: May

NCI-2016-00639
(NCT02827838)
Oral cavity or oropharynx SCC. Planned for surgical
resection.
• Neoadjuvant durvalumab q2 weeks x2 cycles → surgery
• Phase II
• Targeted accrual: 20
• Recruiting
• Est.
2019
completion: July

INSPIRE (NCT02609386) Oral cavity SCC, stage 2, 3, or 4a (TNM7). Surgically

resectable.
• cyclophosphamide
therapy, vs
+ indomethacin + zinc + omeprazole as neoadjuvant and adjuvant

• Phase II • IRX-2 + cyclophosphamide + indomethacin + zinc + omeprazole as neoadjuvant and

• Targeted accrual: 200 adjuvant therapy.
• Actual accrual: 105
• Est.
2019
completion: Feb

Abbreviation: Est.: estimated; SCC: squamous cell carcinoma; ENE: extra-nodal extension; IMRT: intensity modulated radiotherapy; TNM7/8: TNM-7th/8th edition

High risk nodal features beyond ENE: Number of positive lymph nodes
ENE, defined as tumor invading beyond the LN capsule, is a well-
recognized adverse feature for OSCC [41–44]. Besides ENE and positive
resection margins, other nodal features have been suggested as con-
ferring a sufficiently high risk of relapse to consider the use of POCRT.
Zumsteg [45] analyzed 7144 HNC patients from the NCDB database
from 2004 to 2014 (68.4% were OSCC), and found that increasing
metastatic nodal burden (number of positive LNs) was associated with
increased survival impact from POCRT vs PORT. While no benefit from
POCRT vs PORT existed for 0–2 positive LNs, increased benefit was seen
with 3–5 LNs (HR 0.84, 95% CI 0.70–1.00, p = 0.05) and ≥6 LNs (HR
0.65, 95% CI 0.51–0.82, p < 0.001). Similarly, Hosni[46] and several
RTOG trials also consider ≥2 positive LNs as a high-risk feature for
POCRT trials [2,47]. Fan [48] reported that for patients with ≥3 minor
risk factors, POCRT increased OS [48]. Unfortunately, these studies
suffer from their retrospective nature.
Post-surgery ‘Early Recurrence’ and importance of imaging prior to PORT/
POCRT
Another high-risk feature is unanticipated ‘early recurrence’, de-
fined as recurrence manifested by the presence of grossly overt disease
(usually demonstrated by imaging) shortly after intended complete
surgery, prior to initiation of planned PORT/POCRT [49]. “Early re-
currence” may reflect aggressive biology in addition to other factors,
and was present in 15% of PORT/POCRT patients in one series [49],
where “oral tongue” subsite, positive resection margins, pT3-4, and
pN2-3 (by 7th edition TNM) were predictors [49]. Postoperative ima-
ging should be performed prior to PORT planning to identify these high
risk “early recurrences” since customized treatment appears capable of
salvage in approximately one-third of cases; appropriate RT volumes
and dose fractionation prescriptions are needed to achieve optimal
outcome. Moreover, the timing of the post-operative imaging scan is
important, balancing between waiting until postoperative changes have
resolved (4–6 weeks) while implementing PORT in a reasonable time
frame.

5
S.H. Huang, et al.
Oral Cavity Squamous Cell
Carcinoma
Low-Risk (all features): Intermediate-Risk (any feature):
T3-T4 (7th edition)
T1-T2 (7th edition)
Clear resection margin (>5 mm) Close resection margin (1-5
No LVI mm)
No microscopic muscle invasion LVI
PNI
Treatment Treatment:
Surgery alone PORT
Expected Outcome Expected Outcome
5-year LRC: >90% 5-year LRC: 78%
Only retrospective data available Effect size (PORT vs Surgery alone)
30% in DFS; 10% in OS (but NS)
(General literature) (Mishra EJSO 19962)
Post-operative radiotherapy: Volume and schedule
RT volume design and rationale
In the IMRT era, target delineation and quality RT delivery are
paramount to achieve high disease control. Contrast-enhanced plan-
ning/simulation CTs of diagnostic quality with 2 mm slices is desired.
Primary tumor volumes must be meticulously delineated in the CT
planning dataset. Typical RT volumes for primary tumor include the
location of the original pre-surgical gross primary tumor volume (GTV)
with an additional 5 mm margin to designate a clinical target volume
(CTV) that includes the highest risk region harboring potential micro-
scopic extensions of tumor to receive the therapeutic dose (CTV1); this
represents the region immediately adjacent to the original overt tumor
location. Another 5 mm expansion beyond CTV1 is then used to des-
ignate regions at risk of harboring lower degrees of subclinical micro-
scopic disease that should receive an elective or intermediate dose
(CTV2). CTVs should also be modified for natural barriers to tumor
spread such as uninvolved bone or unperturbed fascial planes, or ana-
tomic boundaries at the interface with air cavities beyond which tumor
will not be present [50]. The choice of the 5 mm CTV margin is em-
pirical, but justified by a study of 10 oral tongue cancer specimens [51]
where the majority (95%) of microscopic disease resided within
3.95 mm of the GTV; the primary CTV1 may require additional en-
largement in the post-operative setting to address altered adjacent
anatomy contaminated by potential undetectable microscopic disease.
A 5 mm CTV margin for nodal disease is supported by a further study
[52] which examined 48 neck dissection specimens that showed that
the majority of LNs (96%) had ENE < 5 mm from the capsule and no
ENE extent > 10 mm from the capsule. The authors recommended a
5 mm CTV margin for no ENE and 1 cm CTV margin for pENE+.
However, others [53] have argued that, since very few (< 5%) pENE
would extend beyond 5 mm, a pre-surgical GTV + 5 mm construct
seems sufficient in the majority of pENE+ cases. In the post-operative
setting pENE with invasion into structures, e.g. adjacent muscle, may
similarly warrant enlargement of the nodal CTV1 due to high risk of
contamination.
Accurate target delineation relies not only on post-operative ima-
ging, but also on pre-surgical clinical examination and imaging in order
to anticipate potential high-risk areas. In addition, communication with
Oral Oncology 102 (2020) 104563
Fig. 3. Risk-tailored Approach and
Treatment Effect Size by Adjuvant Chemo-
Radiotherapy in Management of Oral Cavity
Cancer. Abbreviation: LVI: lymphvascular in-
vasion; PNI: perineural invation; ENE: extra-
nodal extension; LRC: locoregional control;
High-Risk* (any feature):
OS: overall survival; LN: lymph node; PORT:
Positive resection margin
postoperative radiotherapy; POCRT: post-op-
(presence of tumor at inked
erative chemoradiotherapy; DM: distant me-
margin)
tastasis; NS: non-significant.
ENE
Treatment
POCRT
Expected Outcome
5-year LRC: ~80%
* DM is a major challenge
Effect size (POCRT vs PORT)
28% in OS; 42% in LRC
(Bernier Head Neck 20051)
the surgical team and pathologist to identify high risk regions (e.g. close
margins, PNI, levels of positive LN, especially the LN level containing
ENE) is extremely beneficial in practice. Identifying radiologically-
based ENE on the pre-operative scans (termed rENE) may provide ad-
ditional value [42]. Attention should also be paid to include adulterated
areas, such as surgical scars, the normal tissue-flap interface, and con-
sideration to tracheostomy inclusion in certain cases. A musculocuta-
neous flap should be delineated on the RT-planning CT, or on a fusion
dataset linked to the CT planning dataset. In such cases, the CTV should
include the entire flap plus a margin (5–10 mm) as well as any surgical
clips to permit the entirety of the surgical bed to be identified and in-
cluded in at least the elective dose volume region. While the flap itself is
not typically at risk of recurrence, the high-risk region comprises the
native tissues adjacent to the flap-normal tissue interface. For an
anterior oral tongue tumor, a bite block may stabilize oral tongue po-
sition or permit jaw separation to protect specific regions of the oral
cavity and tissue equivalent bolus may ensure sufficient dose to surgical
scars, which is warranted if adjacent to regions of positive margins or
tumor with subcutaneous involvement.
Postoperative neck volume
Another controversy concerns managing the dissected neck in a
lateralized primary tumor. Routine irradiation of bilateral neck levels I-
IV due to concern about potential “skip” nodal metastases or risk of
occult contralateral neck disease is frequently advocated. “Skip” nodal
metastases usually refers to the manifestation of erratic cervical me-
tastases distribution of bypassing the upper neck levels (I–II) with direct
involvement of levels III and IV. “Skip” nodal metastasis has been re-
ported in OSCC and occurs in approximately 1.5% of cases with an N0
neck and 5% of cases with an N+ neck [54,55], and is more frequent in
thick or large tumors[54]. Several studies have reported very low rates
of contralateral neck recurrence in lateralized OSCC thereby ques-
tioning the necessity of irradiating a pN0 neck with attendant potential
irreversible sequelae, including xerostomia. Habib [56] reported that
only 14/481 (2.9%) cN0 OSCC had isolated contralateral neck recur-
rence and suggested sparing elective contralateral neck treatment
(dissection or irradiation). Metcalfe [57] reported 0/21 and 0/9 con-
tralateral neck failures in pN0 and pN1 OSCC patients without con-
tralateral neck irradiation; this contrasts with 7/21 (33%) contralateral
6
S.H. Huang, et al.
regional recurrences in patients with pN2a/b disease without con-
tralateral irradiation. Long-term outcome in a phase II study [58] of 73
pN0 patients (20% were OSCC) with PORT omission showed no isolated
nodal failures in the un-irradiated pN0 neck. Only two regional failures
occurred, and both were preceded by local failure.
Postoperative radiotherapy schedule: Dose/fractionation and surgery-to-
PORT interval
Schedules for PORT have evolved over the past decades addressing
total doses, dose per fraction, and overall treatment time and tailored to
the risk of disease presence and burden in the post-operative tissues. An
RCT conducted by Ang et al. [59] revealed that a prolonged surgery-RT
interval and overall treatment time were detrimental for LRC and sur-
vival. Current NCCN guidelines recommend 2.0 Gy per fraction to a
total dose of 60–66 Gy in the adjuvant setting, and the preferred sur-
gery-to-PORT interval is ≤6 weeks. Commencing PORT as soon as
possible seems desirable [60] but may not always be achievable when
surgical complications are present. Careful planning and multi-
disciplinary collaboration is required. In addition, whenever unplanned
treatment interruption is identified, effort should be taken to make up
the dose without course prolongation.
Regarding dose/fractionation for PORT, the initial report of the MD
Anderson Trial [7] used daily fractions of 1.8 Gy and demonstrated that
a minimum dose of 57.6 Gy delivered to the entire surgical bed was
required, but higher doses were only beneficial in patients with ENE.
The updated long-term outcome of the trial [61] also found no sig-
nificant benefit from doses higher than 57.6 Gy, and the only significant
treatment variable was the total treatment package time. RTOG-9501
[2] and EORTC-00931 [1] both used 2 Gy/fraction to a total dose of
60–66 Gy/30–33 fractions. Currently, daily fractions in the adjuvant
setting vary between 2.0 Gy and 2.2 Gy across institutions. Daily
fraction size is particularly relevant in the adjuvant setting where the
disruption of lymphovascular supply and relative depopulation of epi-
thelial stem cells from the periphery of the surgical bed increase the
susceptibility of normal tissues to additional sequelae as a result of the
larger daily fraction size [62].
Chemotherapy: agents, indication, and dosage
Tri-weekly vs weekly cisplatin
Tri-weekly (Q3W) high dose cisplatin 100 mg/m2 is the current
standard [8] and the cumulative adjuvant cisplatin dose appears im-
portant as shown in a small single arm phase II trial [63]. However,
treatment tolerance and toxicity with tri-weekly cisplatin are significant
concerns. Potentially a weekly cisplatin schedule might be better tol-
erated. A retrospective review [64] showed that OSCC patients treated
with PORT with weekly 50 mg/m2 cisplatin received a higher cumu-
lative cisplatin dose with comparable toxicity compared to Q3W
100 mg/m2 cisplatin. A meta-analysis of published literature [65]
suggested that there was superior adherence to a weekly cisplatin re-
gimen with significantly less toxicity compared to Q3W schedules;
however, compliance did not differ in the adjuvant setting. Reasons for
the choice of lower cisplatin dose include intolerance of high dose
cisplatin in certain geographic regions (e.g. hotter climates with limited
supportive resources) which may influence their clinical design. A
single institution phase III RCT from India [66] (n = 300) comparing
weekly (30 mg/m2) vs Q3W (100 mg/m2) cisplatin (93% in adjuvant
setting) showed a lower cumulative cisplatin dose (median 210 vs
300 mg/m2) and inferior LRC (2-year: 58.5% vs 73.1%, p = 0.014)
with the weekly vs Q3W schedule, although acute toxicity was also
lower (71.6% vs 84.6%, p = 0.006). As noted, the weekly cisplatin arm
in the trial was 30 mg/m2 which is generally considered lower than
current practice (typically ≥ 40 mg/m2). Another small phase II ran-
domized trial from Taiwan (n = 55) [67] compared the efficacy of
7
Oral Oncology 102 (2020) 104563
weekly cisplatin 40 mg/m2 vs standard Q3W 100 mg/m2 cisplatin in
the adjuvant setting with concurrent RT (66 Gy in 33 fraction over
6.5 weeks) for OSCC and showed that more patients on the Q3W arm
received ≥200 mg/m2 total dose of cisplatin. However overall toxicity
was greater with weekly cisplatin. In the absence of high level evidence
for a benefit from weekly cisplatin, Q3W high dose cisplatin (100 mg/
m2) remains the current standard.
Systemic agents beyond cisplatin
Earlier, we noted that the benefit of adding high-dose cisplatin
chemotherapy concurrently with adjuvant radiotherapy for HNC pa-
tients with positive resection margins or pENE was demonstrated in the
combined analysis of the EORTC-22931 (NCT00002555) and RTOG-
9501 (NCT00002670) trials [8]. However, the long-term outcomes of
the RTOG-9501 trial [68] showed that the main influence of adding
chemotherapy appeared to be in reduction of LRF. DM is the main mode
of failure for both the PORT and POCRT cohorts, with rates of 21.2%
and 19.3%, respectively. Cetuximab, an epithelial growth factor in-
hibitor (EGFRI), in addition to definitive radiotherapy showed en-
hanced LRC and survival, but not distant control compared to radio-
therapy-alone in a phase III RCT [69]. Its efficacy has recently been
evaluated in the adjuvant setting in the RTOG-0920 trial
(NCT00956007) for intermediate risk patients who would ordinarily
receive PORT alone, and results are awaited. Whether other systemic
agents could have better outcomes, particularly for DM reduction, is an
area of active research. Docetaxel has emerged as a promising cytotoxic
agent and was evaluated in the RTOG-0234 Phase II RCT [47]
(NCT00084318) that compared the treatment efficacy of combined
cetuximab delivered once per week and PORT (60 Gy in 30 fractions)
with a randomization between either weekly lower dose cisplatin
30 mg/m2 or docetaxel 15 mg/m2 in stage III-IV HNC (47% OSCC). A
standard POCRT arm (RT with cisplatin alone) was not used in this
phase II study which sought to choose a new regimen for subsequent
testing. The authors reported that the docetaxel-cetuximab arm had
more favorable DM reduction and improved DFS and OS compared to
the cisplatin-cetuximab arm.
RTOG-1216 has subsequently emerged as a derivative phase II/III
trial following RTOG-0234 to determine the optimal adjuvant RT
(60–66 Gy/30f/6weeks) and chemotherapy regimen and included a
standard POCRT control arm (PORT with sufficient dose of concurrent
cisplatin). This three arm RCT was designed to commence with a phase
II design and randomization of the “winning” arm of RTOG-0234
(PORT with Docetaxel and Cetuximab) against the same combination
but omitting Cetuximab, versus a standard POCRT arm (PORT com-
bined with concurrent higher dose [40 mg/m2] weekly cisplatin). The
design also included a planned 1–2 year pause for events to mature to
choose the winning docetaxel arm and then continue in a two arm
Phase III RCT against the higher dose (40 mg/m2) weekly cisplatin arm.
The declaration of the result of the initial component of the trial is
awaited, and will govern the design for reactivation into the phase III
component. In the meantime, immunotherapy in the adjuvant setting is
gaining attraction and several trials are currently ongoing (e.g. HN003,
NCT027758120; EORTC DUTRELASCO, NCT03784066) and this pro-
mises to be an expanding field. For the present, practice changing trials
will continue to require comparison of PORT with higher dose cisplatin,
but protocol designs are likely to include experimental arms containing
PORT with immunotherapy alone or combinations of immunotherapy
with chemotherapy. Current ongoing trials on PORT/POCRT for OSCC
are listed in Table 1.
Conclusions
Risk-tailored approaches are needed in the management of OSCC.
PORT for intermediate–risk and POCRT for the high-risk subsets are
effective in enhancing disease control and survival in selected OSCC
S.H. Huang, et al.
patients with expected treatment effect sizes of 10% and 28% survival
benefit, respectively (Fig. 3). Prognostically relevant margins should be
derived from the actual resection specimen. The adequacy of margin
revision should be questioned and objectively assessed using CAP
protocol for OSCC. Reporting margins requires standardization (radial
margin sampling from resection specimens) and should be expressed as
the distance to closest margin. A ‘safe’ or ‘clear’ margin for withholding
PORT/POCRT remains as > 5 mm until further evidence available.
Attention is required to designing PORT volumes, total doses to targets,
fraction size, and the addition of systemic treatment (agents and
schedule) to optimize the therapeutic ratio for OSCC patients. Finally,
translational research is needed to understand biological mechanisms of
a subset of OSCC with aggressive clinical course without apparent
clinico-pathological adverse features.
Declaration of Competing Interest
The authors declared that there is no conflict of interest.
Acknowledgement
We acknowledge the O. Harold Warwick Prize of the Canadian
Cancer Society for supporting the author’s (BOS) academic activities.
We also acknowledge the Sanming Project of Medicine in Shenzhen
Fund (SZSM201612024) for supporting BOS, SHH, ZYX, JL, and LS.
Finally, we acknowledge the Bartley-Smith/Wharton, the Gordon
Tozer, the Wharton Head and Neck Translational, the Dr. Mariano Elia,
and the Petersen-Turofsky Funds, and the “Joe & Cara Finley Center for
Head & Neck Cancer Research”, and the “Discovery Fund” at the
Princess Margaret Cancer Foundation for supporting research by BOS,
SHH, and EH.
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