*3.5.2 For postop radiation therapy*

HRCTV encompasses the area of the tumour bed [if features such as margin positivity, node positivity with extracapsular extension, peri-neural invasion and soft tissue extension is present]. IRCTV [Intermediate Risk Clinical Target Volume] would include the involved nodes without ECE & uninvolved adjacent nodal levels.

#### **Figure 5.**

*Contouring of target volumes & organs at risk(OAR) for a case of carcinoma Oral tongue post surgery [pT3N1M0]; Orange – clinical target volume; Red – planning target volume; Cyan – mandible; brown – right parotid; green – spinal cord; pink - constrictor.*

LRCTV would include rest of the nodal levels based on the risk stratification and bilateral neck is treated if risk is higher. PTV would be 5 mm around the CTV trimmed from skin, but based on institutional protocol, it could range from 3 mm to 10 mm (**Figure 5**).

As far as dose and dose per fraction is concerned there are multiple regimens and multiple doses available with their pros and cons. The following table depicts the usual practice with some insight on hypothesis (**Tables 3** and **4**).

## **3.6 Radiation related toxicity in oral cancer management**

Radiotherapy is an essential part of multi-modality treatment for oral cancers. However, several uninvolved organs in the vicinity of these cancers like the skin, salivary glands, oral mucosa, masticatory apparatus, dentition and jaws receive significant doses of radiation during treatment. This could result in moderate to severe adverse effects during and after completion of treatment and also affect the patient's quality of life. The effects may be acute such as dermatitis, mucositis and hyposalivation or chronic and long-term such as xerostomia, radiation caries, trismus and osteoradionecrosis [38].

As many of these effects are dose-limiting, introduction of newer radiation techniques and schedules have minimised late effects to a large extent. Nutting et al. were able to demonstrate 50% reduction in subjective xerostomia rates with IMRT by keeping mean dose to contralateral parotid gland at 26Gy [39]. Parotid sparing IMRT was achieved by avoiding the contralateral parotid, upper parapharyngeal space as well as giving a tight constraint for the anterior oral cavity [36, 40].

A more problematic late effect is osteoradionecrosis, which is the process of bone and soft tissue necrosis, arising as a result of radiation induced hypocellularity, hypoxia and hypovascularity, resulting in a non-healing region [41]. As spontaneous ORN is dose dependent (>60Gy), IMRT is able to reduce the maximum

## *Radiotherapy in Oral Cancers: Current Perspective and Future Directions DOI: http://dx.doi.org/10.5772/intechopen.99557*


#### **Table 3.**

*Dose & volume consideration for post-op adjuvant radiotherapy.*

#### **Table 4.** *Dose & volume consideration for definitive radiotherapy.*

dose received by the mandible as well as volume of mandible covered by 50-55Gy isodoses. The reported ORN rates in IMRT series is 5–6%.

Chen et al. found that IMRT also helped reduce dysphagia related complications in oral cancer patients undergoing radiotherapy [42]. Those receiving IMRT had significantly lesser moderate (grade 2) and severe(grade 3) dysphagia when compared to those receiving conventional radiotherapy (21% vs. 59%; p = 0.02) [42].

## **3.7 Targeted therapy, current bio-markers and future perspectives for oral cancers**

Epidermal growth factor receptor (EGFR) regulates many cellular functions crucial for tumorigenesis. Huang et al. studied 160 oral cancer patients using immunohistochemistry for EGFR protein over-expression and fluorescence in situ hybridization for copy number [43]. EGFR overexpression was noted in 46.88% and 31.25% had increased gene copy numbers. They also found 100% concordance rate between EGFR gene amplification and protein overexpression. EGFR overexpression was associated with poor prognosis, both in terms of DFS and OS.

Cetuximab, an EGFR antibody has shown good results in head and neck cancers, in combination with definitive radiation [44]. The RTOG 0920 trial (Ongoing) is trying to address outcomes with addition of cetuximab to PORT in intermediaterisk oral cancers.

The development of PD-1/PD-L1 inhibitors (pembrolizumab & nivolumab) & other immune checkpoint inhibitors (ICI) has changed the systemic management of HNSCC [45, 46]. PD-L1 expression in pre-treatment biopsies have been associated with good prognosis. Preclinical data suggests synergy between anti-PD1 inhibitors and radiation, making it a potential therapeutic option for high-risk oral cancers in the future [47]. Several phase II studies addressing these agents in combination with standard therapy or as a neoadjuvant/adjuvant option are in the works [48].

Tumour mutational burden (TMB) as a biomarker of ICI response has shown mixed response in HNSCC, with KEYNOTE-012 trial showing a positive correlation while using a cut-off of ≥102 mutations per exome [49].

Other aspects being studied are tumour immune microenvironment and oral/gut microbiome as regulating mechanisms having implications for response of HNSCC to immune therapies. Oral microbiome has also shown an effect on toxicity profile of patients undergoing concurrent chemoradiation [50]. Cell therapy-based options such as the use of activated cytotoxic T-Lymphocytes (CTL's) to result in tumour cell death has also been attempted in HNSCC [51]. Chimeric antigen Receptor T cells are one such example being used in advanced oral cancers.
