Review Article

Management and outcome of locally advanced oral

squamous cell carcinoma
ABSTRACT
Management of locally advanced OSCC is multimodal. No single therapy has been proved to be efficacious. However there is a trend towards
surgical intervention in operable disease. In this review we appraise the various therapies used for the management of locally advanced OSCC.
We review the literature with regards to the various treatment options for locally advanced OSCC. We categorically divided the manuscript into
resectable, unresectable and technically unresectable disease. Surgery is the ideal treatment modality for resectable disease. For unresectable
disease concurrent chemoradiation appears to improve survival compared to radiotherapy alone. Induction therapy might downstage tumors in
the unresectable category. Targeted and Immunotherapy is reserved for recurrent, metastatic or platinum refractory OSCC. Management of locally
advanced OSCC is multimodal with surgery playing the primary role. In the event where the tumor is in operable concurrent chemoradiotherapy
is regarded as the best treatment modality. Induction chemotherapy currently cannot be recommended for resectable or even unresectable oral
squamous cell carcinomas. However for technically unresectable disease it might play a role in improving respectability but it depends on the
response of the tumor. Targeted therapy and immunotherapy is currently used for recurrent, metastatic and/or platinum refractory Head and
Neck cancers. Currently it is not recommended for initial management of locally advanced disease.

Keywords: Chemoradiation, chemotherapy, concurrent chemoradiation, induction chemotherapy, locally advanced,

oral cancer

INTRODUCTION Rathindra N. Bera, Sapna Tandon1,

Oral cavity squamous cell carcinoma (OSCC) is one of the most
common malignancies worldwide with the highest prevalence
in South East Asia where it is the second most common. In
India, it is the most common cancer in males. Most of the
patients present with advanced‑stage disease with 30% of
patients having regional metastasis at the time of presentation;
in India 64% of patients present with stage IV disease.[1] The
management of locally advanced oral cancers is multimodal
with surgery being the most preferred treatment. Adjuvant
therapy including radiotherapy and chemotherapy is added
Akhilesh K. Singh2, Fargol M. A. Boojar3,
Gaurav Jaiswal1, Shraddha Borse1, Uma S. Pal4,
Naresh K. Sharma2
Department of Oral and Maxillofacial Surgery, Dental Institute
Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India,
1
Department of Oral and Maxillofacial Surgery, Career Post
Graduate Institute of Dental Sciences and Hospital, Lucknow,
Uttar Pradesh, India, 2Department of Oral and Maxillofacial
Surgery, Faculty of Dental Sciences Institute of Medical Sciences
Banaras Hindu University, Varanasi, Uttar Pradesh, India, 3Golestan
University of Medical Sciences, Gorgan, Iran, 4Department of Oral
and Maxillofacial Surgery, Faculty of Dental Sciences Kings George

according to the presentation and final histological analysis Medical University, Lucknow, Uttar Pradesh, India

of the tumors.[1,2] The treatment decision whether surgery
or non‑surgical therapy largely depends on the resectability
of the tumor.[1,2] The 5‑year survival rates of locally advanced
OSCC ranges from 11‑64% according to the available literature.
Relapse is seen in one‑third of patients and locoregional
recurrence is the most common pattern of failure.[3]
Address for correspondence: Dr. Sapna Tandon,
Department of Oral and Maxillofacial Surgery,
Career Post Graduate Institute of Dental Sciences and Hospital,
Lucknow, Uttar Pradesh, India.
E‑mail: drsapnatandon29@gmail.com
Received: 15 July 2022, Revised: 30 October 2022,
Accepted: 13 April 2023, Published: 13 July 2023

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DOI:
How to cite this article: Bera RN, Tandon S, Singh AK, Boojar FM,
10.4103/njms.njms_125_22 Jaiswal G, Borse S, et al. Management and outcome of locally advanced
oral squamous cell carcinoma. Natl J Maxillofac Surg 2023;14:185-9.

© 2023 National Journal of Maxillofacial Surgery | Published by Wolters Kluwer - Medknow 185
 Bera, et al.: Locally advanced oral cancer
WHAT IS LOCALLY ADVANCED OSCC?
Locally advanced oral cancer includes stage III and stage
IV cancers without distant metastasis.[2] The 8th edition
of AJCC classifies T4a as a moderately advanced local
disease (tumors involving the cortical bone of maxilla or
mandible, inferior alveolar nerve, the floor of the mouth,
facial skin, and maxillary sinus) and T4b as a very advanced
local disease (involvement of masticator space, pterygoid
involvement, skull base involvement and encasement of
internal carotid artery). In addition Depth of Invasion (DOI)
>1 cm irrespective of surface dimensions constitutes
T3 and beyond and is categorized as a locally advanced
disease.[4,5]
CONTEMPORARY MANAGEMENT
Since the last 4 decades, there has been a constant
improvement in the survival of locally advanced oral cancers
with overall survival ranging from 51.9% in 1973‑1980 to
70.3% in 2011‑2014. This is owing to improvements in the
diagnosis, management, and rehabilitation of these patients.[6]
Although the survival has improved the treatment archetype
largely remains the same with surgery being the mainstay
of treatment with adjuvant therapy as required. However,
in the event that surgery is not feasible, the treatment
decision largely remains unknown. One of the prime factors
in decision‑making is the resectability of the tumor. According
to the NCCN guidelines, the goal of surgical resection is to
achieve a clear margin, which is a distance greater than or
equal to 5 mm of normal margin from the resected margin.[7]
CRITERIA FOR RESECTABILITY
Oral cavity squamous cell carcinomas might be categorized
as resectable, unresectable, and technically unresectable
diseases.
Categorically unresectable disease includes[8,9]:
1. Tumors with prevertebral fascia adherence
2. Tumors with mediastinal extension.
3. Skull base involvement and/or erosion.
4. Encasement of the internal carotid artery >2700
The category of technically unresectable disease was
elaborated by Patil et al.[10] and includes
1. Buccal mucosa primary with diffuse margins and
peritumoral edema extending to or above the level of
the zygomatic arch and without any satellite nodules.
2. Primary oral tongue tumors extending up to or below
the level of the hyoid bone.
186 National Journal of Maxillofacial Surgery / Volume 14 / Issue 2 / May-August 2023
3. Extension of oral tongue tumors in the vallecula, tumor
extension into infratemporal fossa (supra notch tumors).
4. Extensive skin infiltration.
In our review, we would discuss the management of each of
these categories separately.
TECHNICALLY UNRESECTABLE OSCC
Patil et al. in 2013[11] hypothesized that there was a subset of
patients with locally advanced oral cancers and borderline
unresectable who could be made resectable with the use of
induction chemotherapy (IC). In their study patients either
received a platinum doublet or triplet regimen as neoadjuvant
therapy. The overall response rate ranged from 27.37‑32%.
Respectability was achieved in 68% of patients who received
platinum triplet and 37.89% in platinum doublet. The
use of a triplet regimen was significantly associated with
resectability. The study by Rudresha et al.[12] used platinum
doublet as induction chemotherapy. Stable disease was
achieved in 61.3% of patients, partial response in 21.3%, and
progressive disease in 17.4% of patients. Respectability was
achieved in 23.8% of patients who received IC. The median
Overall survival in patients who received surgery followed by
adjuvant therapy was 16.9 months compared to 8.8 months in
patients who received nonsurgical therapy. A following study
by Patil et al.[10] reviewed the usefulness of IC in 721 patients of
OSCC. In their study, 43% of patients had a sufficient reduction
in tumor size. The locoregional control rate was 32% in
patients undergoing surgery and 15% in patients undergoing
non‑surgical therapy (p = 0.0001). The median overall
survival was 19.6 months in the surgical group compared to
8.16 months in the non‑surgical group (p = 0.0001).
RESECTABLE OSCC
Surgery still remains the mainstay of treatment for patients
with locally advanced operable OSCC. A 2017 National Cancer
Database study comparing surgery followed by adjuvant
therapy compared to concurrent chemoradiation showed
better overall survival with the former treatment.[13] A 2014
study by Chinn et al.[14] compared IC followed by concurrent
chemoradiation with surgery followed by adjuvant therapy.
Improved overall survival, disease‑specific survival, and
locoregional control were associated with the latter. The
study by Soo et al.[15] compared concurrent chemoradiation
with surgery and radiotherapy in stage III/IV non‑metastatic
head‑neck squamous cell carcinoma. With a median follow‑up
of 6 years the organ preservation rate was 45% more so with
laryngeal/hypopharyngeal disease (68% vs 30%). There was
no difference in disease‑free survival rates between the two.
 Bera, et al.: Locally advanced oral cancer
Two other studies also showed superior results with surgery
followed by radiotherapy compared to chemoradiation in
resectable disease.[16,17] Tangthongkum et al.[18] on the other
hand, showed comparable outcomes in patients treated
either with primary surgery or nonsurgical methods.
The role of IC in resectable OSCC is less substantiated. Studies
by Zhong et al. and Licitra et al.[19‑21] showed no benefit in
survival with the use of IC in resectable OSCC. However, IC
might lead to organ preservation and increased response rate
with improved survival. The updated MACH‑NC analysis did
not show any significant benefit with IC in head and neck
cancers. There was no significant difference in event‑free
survival, 120 days mortality, and death. Overall survival was
also not improved with IC.[22]
UNRESECTABLE OSCC
The 2000 MACH‑NC (Meta‑Analysis of Chemotherapy on
Head and Neck Cancer) by Pignon et al.[23] showed the
absolute benefit of 4% at 2 years and 5 years in favor of the
addition of chemotherapy to radiotherapy. The updated 2009
meta‑analysis showed the absolute benefit of 6.5% at 5 years
with concomitant chemoradiation.[24] The 2021 updated
review also showed the absolute benefit of 6.5% at 5 years
in favor of concomitant chemoradiotherapy.[22]
The intergroup trial by Adelstein et al. evaluated the role
[25]
of concomitant chemoradiation in stage III/IV unresectable
head and neck squamous cell carcinoma (13% oral cancers).
The study concluded 3 years improved overall survival,
improved 3 years disease‑specific survival, and increased
the incidence of grade 3 toxicities in the concurrent
chemoradiotherapy arm. The 2006 meta‑analysis by
Budach et al.[26] evaluated the role of adding chemotherapy
to conventional radiotherapy (CFRT), hyper fractionated
radiotherapy (HFRT), and accelerated radiotherapy (AFRT).
An overall survival benefit of 12 months was observed with
the addition of chemotherapy. The recent meta‑analysis
by MACH‑NC and MARCH (meta‑analysis of radiotherapy
in carcinomas of the head and neck) showed HFRT with
concomitant chemotherapy as the best treatment for overall
survival. The study also showed an insignificant hazard ratio
for induction therapy in improving overall survival.[27] Also,
AFRT with chemotherapy did not improve overall survival.
A 2021 retrospective study showed no added advantage in
terms of overall survival and locoregional control of AFRT
with chemotherapy over CFRT with chemotherapy. However,
toxicities were increased in the AFRT + chemo group.[28]
The role of induction therapy followed by concurrent
chemoradiation for the unresectable disease is also not
National Journal of Maxillofacial Surgery / Volume 14 / Issue 2 / May-August 2023
properly confirmatory. Paccagnella et al.[29] compared the
effects of combing cisplatin with 5 Fluorouracil prior to
locoregional therapy versus locoregional therapy alone in
advanced head and neck squamous cell carcinomas. The
study failed to show any improvements in overall survival
with IC. However, in a subgroup analysis of inoperable
patients, IC showed a modest survival advantage. Later
two landmark trials evaluated the role of adding Taxanes to
the previous platinum doublet (TAX 323 and TAX 324).[30,31]
The TAX 323 trial had patients with unresectable head and
neck cancers. There was a higher objective radiographic
response rate, and improved overall, and progression‑free
survival with no significant increase in toxicities. The TAX
324 study conducted on advanced head and neck cancers
showed similar results. Three other trials on advanced head
and neck cancers failed to show any survival advantage of
IC prior to locoregional treatment.[32‑34] The 2021 MACH‑NC
analysis did not show any improvement in survival with the
addition of IC in locally advanced head and neck cancers.[22]
A 2016 meta‑analysis exclusively on OSCC showed no benefit
of IC in improving survival or reducing distant metastasis.
However, there was a decrease in loco‑regional recurrence.[35]
TARGETED THERAPY AND IMMUNOTHERAPY FOR
PREVIOUSLY UNTREATED OSCC
Cetuximab was the first biologic agent to be used in
the treatment of Head and Neck cancers. The Epidermal
Growth Factor Receptor (EGFR) is expressed in a variety of
tumors. Cetuximab is a recombinant human/mouse chimeric
monoclonal antibody binding with the extracellular domain
of EGFR and blocking its activity.[36] The ARTSCAN III trial[37]
compared cetuximab versus cisplatin with radiotherapy for
the treatment of locally advanced head and neck cancers.
There was no difference in overall survival at 3 years.
However locoregional failure was statistically significant
with cetuximab compared with cisplatin and there was no
difference in distant failure. Most of the studies pertaining
to cetuximab and immunotherapy are for recurrent and
metastatic head and neck cancer which is beyond the topic
of review. Phase III data is lacking considering the beneficial
effects of cetuximab in head and neck cancers.
CONCLUSION
Management of locally advanced OSCC is multimodal with
surgery playing the primary role. In the event that the tumor
is ‑operable concurrent chemoradiotherapy is regarded as the
best treatment modality. Induction chemotherapy currently
cannot be recommended for resectable or even unresectable
oral squamous cell carcinomas. However, for the technically
unresectable disease, it might play a role in improving
187
 Bera, et al.: Locally advanced oral cancer
resectability but it depends on the response of the tumor.
Targeted therapy and immunotherapy is currently used for
recurrent, metastatic, and/or platinum‑refractory Head and
Neck cancers. Currently, it is not recommended for the initial
management of the locally advanced disease.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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