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. 2023 Jul 13;14(2):185–189. doi: 10.4103/njms.njms_125_22

Management and outcome of locally advanced oral squamous cell carcinoma

Rathindra N Bera 1, Sapna Tandon 1,✉, Akhilesh K Singh 2, Fargol M A Boojar 3, Gaurav Jaiswal 1, Shraddha Borse 1, Uma S Pal 4, Naresh K Sharma 2
PMCID: PMC10474551  PMID: 37661995

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

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 according to the presentation and final histological analysis 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]

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.

  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. 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.[25] evaluated the role 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 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 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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