Radiotherapy for Oral Cancer- an Overview as a Boon and a Bane

Oral cancer is the 11th most common cancer in the world, accounting for an estimated 300,000 new cases and 145,000 deaths in 2012 and 702,000 prevalent cases over a period of five years (old and new cases).¹ Two-thirds of the global incidence of oral cancer occurs in low- and middle-income countries (LMICs); half of those cases are in South Asia. India alone accounts for one-fifth of all oral cancer cases and one-fourth of all oral cancer deaths. (Ferlay et al)¹

Management options have expanded dramatically over the past century, resulting in improved control and survival rates from the disease while enhancing the patient’s quality of life.² The main approach to treating malignancies is still surgical but often in combination with other modalities such as radiotherapy and chemotherapy, especially in advanced cases of disease.

In cases where complete resection of neoplasm is non viable, irradiation is the treatment of choice given that most primary oral malignancies are radiosensitive squamous cell carcinomas.⁴ The aim of radiotherapy is to eradicate the tumour by doses of ionising radiation that, ideally, will be well tolerated by the surrounding structures.⁵

RADIOTHERAPY AS A SOLE TREATMENT

Radiotherapy as a sole treatment modality is not commonly used for oral cancers (usually only if the tumour site is inoperable or the patient chooses not to have surgery).[6-8] It can also be given as a palliative treatment option for more advanced/terminal cases. Radiation therapy is primarily used in combination with surgery and/or chemotherapy with the aim to kill rapidly dividing cancer cells by disrupting their DNA structure at the cost of healthy cells, which are also affected during the process.^4,9 However, with the evolution of radiation techniques, it is now frequently used as a sole treatment modality for oropharyngeal and laryngeal carcinomas (e.g. faucial tonsils or base of the tongue carcinomas).¹⁰ Altered fractionation techniques have produced significantly better results when compared with conventional radiotherapy in 5-year local control rates of tonsillar, base of tongue and laryngeal SCCs of all stages. More recently, IMRT has achieved encouraging results when used alone to treat early and intermediate stage nasopharyngeal and oropharyngeal carcinomas with 3- and 5-year locoregional control rates of above 85% and 95% respectively.^11,12 This technique is still relatively new with minimal clinical evidence but may form the basis for future management of these types of cancers. In terms of survival rate, radiation therapy alone has been found to achieve similar survival rates (up to 5 years) to surgery for early stage oral cancers and can be used for the management of tumours at certain sites (e.g. buccal mucosa or lip).^13-17 However, Schwartz et al.¹⁸ found 37% of all patients with recurrences received radiotherapy alone with the majority being diagnosed as stage 1/2 cancers (26%). It should be noted that all recurrences in this group occurred locally or locoregionally without any cases of distant/regional recurrence, whereas those treated with surgery or surgery and radiotherapy had incidences of regional recurrence. The main advantages of radiotherapy alone over surgery are milder complications following treatment and improved quality of life, while surgery of advanced tumours could lead to a 1%–2% chance of postoperative death as well as extensive permanent loss of function of oral structures.^19-23 For these reasons, radiotherapy alone is the treatment of choice for those cancers which have similar recurrence and survival rates as surgery alone or with radiotherapy in conjunction (e.g. oropharyngeal SCC).²⁴

POSTOPERATIVE RADIOTHERAPY COMBINED WITH SURGERY

Surgery combined with the use of postoperative radiotherapy is a common treatment modality for oral cancers and cancers of the head and neck region. Radiotherapy is typically applied after surgery due to the difficulty of surgically removing irradiated tissue as tissues become fibrosed and tend to heal slower.²⁵ Factors such as large primary tumours, positive or close surgical margins, and signs of perineural/lymph/vascular invasion dictate the use of radiation at the primary site but the neck is also commonly treated, especially if there are positive lymph nodes with or without extracapsular spread, to prevent potential metastasis and recurrence.^26,27 Radiation doses can vary but typically total doses of approximately 60 Gray(Gy) are divided into 30 daily fractions of 2 Gy each for a period of 6 weeks.³¹ More favourable local and locoregional reported primary recurrence rates of 39% in those with negative resection margins and 73% in positive margins in patients with stage 3/4 disease treated by surgery alone compared with only 2% and 10.5% respectively in those treated by surgery and postoperative radiotherapy. Dixit et al.²⁸ found 3-year locoregional control rates of 48% for 61 patients with stage 3/4 SCCs of the buccal mucosa while only 11% for 115 patients with the same condition treated by surgery alone (p = 0.001). However, no significant difference was found between the different modalities for stage 1/2 disease, indicating that surgery alone is sufficient in disease control. Fang et al.³⁰ also found similar results of 39% locoregional recurrence within a 3-year period in 57 patients with the same disease, and overall and disease-specific survival rates of 55% and 62% respectively to reinforce its effectiveness. Despite the lower local and locoregional recurrence rates, distant metastases were found to be higher by O’ Brien et al. although this was not a common finding amongst other studies. Survival rates have also been reported to improve as the relative risk of cancer-related deaths and deaths from any cause in those treated by surgery alone are 2.21 and 1.67 times greater than that receiving adjuvant radiotherapy for head and neck SCCs.37 Despite this, disease-free survival rates were not significantly improved with the use of adjuvant radiotherapy but determined by crucial factors such as positive surgical margins and presence of lymph node metastasis which indicate a high risk of locoregional recurrence and/or systemic metastasis.³¹

Over the past few decades varying techniques have been developed to improve the effectiveness of postoperative radiotherapy and produce more favourable local control rates, disease-specific survival rates and quality of life. These techniques included altered fractionation by either accelerated or hyperfractionated, radiotherapy combined with chemotherapy or targeted therapy, three-dimensional conformal radiation therapy (3D–CRT) and most recently intensity-modulated radiotherapy (IMRT).^6,7,9 Initially, issues such as acute side effects (e.g. mucositis) worsened following altered fractionation techniques, but modern 3D–CRT and IMRT techniques have reduced toxicities/side effects significantly while improving quality of life compared with traditional two-dimensional radiotherapy.⁸ Three-dimensional conformal radiation therapy allows for three-dimensional tailoring of radiation to the morphology of the tumour and IMRT further allows a conformal dose distribution to preserve vital organs at risk, e.g. parotid glands, optic nerve, brainstem and spinal cord.⁸ In terms of local control rates and survival rates, 3D-CRT and IMRT are comparable when used postoperatively after surgery and have both shown promising results with substantially less toxicity but still remain unsatisfactory for advance disease.^6-10 These techniques have now replaced conventional radiotherapy regimes in routine clinical practice but long-term studies proving their effectiveness are only just starting to emerge.

ORAL COMPLICATIONS OF CANCER RADIOTHERAPY

The oral complications of cancer radiotherapy stem from radiation injury to the salivary glands, oral mucosa, oral musculature, and alveolar bone. These injuries directly or indirectly create a cluster of clinical consequences, including xerostomia, rampant dental decay, mucositis, taste loss, osteoradionecrosis, infection, trismus, and nutritional stomatitis.²³ The manifestations vary in pattern, duration, and intensity and do not all affect every patient.

Xerostomia

The secretion of saliva declines drastically when the major salivary glands are included in the radiation fields. The reduction is related to the dose and the duration of therapy and reflects the progression of radiation-induced inflammatory and degenerative changes in the acinar and ductal cells. The normal cellular arrangement is replaced in the irradiated gland by ductal remnants and loose fibrous connective tissue moderately infiltrated with lymphocytes and plasma cells. Radiation-induced xerostomia is rapid in onset, pronounced, persistent, and irreversible.^27-28

Oral Mucositis

The oral mucosa responds to irradiation by a series of changes th at are related to the dose and the duration of therapy. lnitially, the mucosa in the path of radiation appears reddened and swollen due to irritative hyperemia and edema. As treatment continues, the mucosa becomes denuded, ulcerated, and covered with a fibrinous exudate. Pain, buming, and discomfort are commonly present at rest and are greatly intensified by contact with coarse or highly seasoned foods. Involvement of the pharyngeal mucosa produces difficulties in swallowing and speaking.⁵

Taste Loss

Patients undergoing radiotherapy for oral cancer quickly lose their sense of taste. Conger¹⁰ found that the rate of loss is smoothly exponential up to an accumulated dose of about 3,000 rads and then slows as acuity approaches zero. Patients who have had a dose of more than 3,000 rads can barely detect a sucrose solution equivalent to 25 teaspoonfuls of sugar per eup as sweet, a solution one half as concentrated as household-strength vinegar as acid, and a solution 1,500 times as strong as carbonated quinine water as bitter and cannot identify a highly concentrated sodium chloride solution as salty. Damage to the microvilli and outer surface of the taste cells has been proposed as the principal mechanism for loss of the sense of taste.^18-21

Osteoradionecrosis

Radiotherapy impairs the viability of the oral mucosa at the primary site of irradiation by inducing fibrosis and a decrease in blood supply. Necrotic ulcers may develop in these areas two to three months after completion of radiotherapy and anytime thereafter. The ulcers are usually precipitated by trauma, are extremely painful, are slow to heal, and enlarge rapidly unless treated quickly and energetically. Early, superficial necrotic ulcers are best managed with sprays or irrigations of warm, mild solutions of salt or, soda. The spread of necrosis can be controlled and healing can be promoted by application of a paste containing zinc peroxide, carboxymethylcellulose, and hydrogen peroxide or a spray of 0.5% prednisolone sodium phosphate with neomycin sulfate (NeoHydeltrasol).¹²

Trismus

Trismus, in which tonie spasms of the masticatory muscles limit opening of the mouth, may develop during or after radiotherapy if these muscles are included in the treatment fields. This disorder has been attributed to muscle fibrosis in response to radiation in jury. Patients whose masticatory muscles are to be heavily irradiated should be instructed to exercise them by opening the mouth as wide as possible 20 times at least three times daily. The purpose is to prevent excessive muscle fibrosis and loss of the interarch space. Patients in whom trismus has developed should be given an intensified exercise program to regain the lost space. Individually tailored prosthetic appliances containing springs and elastic bands designed to stretch the muscles and break the contracture have been helpful in sorne of these patients.¹⁴

CONCLUSION

The stomatologic complications of radiotherapy for oral cancer are physical and physiologic in nature, transient or lasting duration, and reversible or irreversible in type. But these complications can be considered as collateral damage in achieving a rather important goal in treating oral cancers. Some linger as permanent mementos long after the cancer has been destroyed. To maximize the quality of survival of these patients, each oral complication must be thoroughly evaluated, knowledgeably treated, and carefully controlled.

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