**2. Head and neck cancer**

The term oral cancer is used as a synonym for oral squamous cell carcinoma (OSCC), which accounts for 90% of all head and neck cancers and 3-4% of malignancies [1, 2]. The incidence of head and neck cancer has increased significantly over the past 20 years. Over 575,000 new oral cancer cases are annually diagnosed in the world [3]. According to data published in 1998 by Spanish National Epidemiology Centre, in our country, the number of deaths by oral, pharyngeal and labial cancer amounted to 1,891 of men and 374 of women. In Spain, incidence accounts for 12 to 15 cases per 100,000 men/year and two to four cases per 100,000 women/ year [4]. However, the figures are now matching up. This is because some women are adopting harmful habits, which were traditionally attributable to men. The disease mainly affects men over 40 years of age, with a peak of maximum incidence in their 60s [5, 6].

The etiology of cancer has multiple factors. The main risk factors are smoking and alcohol. Despite showing synergistic effects, these are independent risk factors, as shown in a study by Castellsagué et al. [6, 7]. In some cases of solar ultraviolet radiation in lip cancer, infections, diets low in fruit and vegetables, immunodepression, bad oral hygiene and the presence of genetic factors can have a relevant effect.

Patients diagnosed with this cancer are treated by surgery, radiotherapy (RTP), chemotherapy (QTP) or a combined treatment. The choice of a unique or combined treatment depends on the location of the tumour, its extension, histological subtype, tumour stage and the patient's general condition. Surgery and RTP are used in isolation to treat cases of non-metastatic disease (stages I and II). However, advanced stages (III and IV) require concomitant RTP and QTP. In the early stages, the treatment of choice is surgery. With this, the tumour is eliminated with safety margins. This is achieved with or without cervical emptying, depending on the location, size or suspicion of regional metastasis. Once the cervical emptying is completed and analysed, if the structures are affected, subsequent treatment with RTP is evaluated. Advanced stages can be treated with surgery followed by RTP but this combination only cures a minority of patients and fewer than 30% will be alive at five years. With these treatments, tumour control and survival rates are unsatisfactory. Only 30% of patients will be alive after three years, while 60-70% of patients will have a loco-regional recurrence and/or will develop distant metastasis, which, ultimately, is the main cause of death in these patients [8].

QTP, in addition to RTP and surgery, is associated with a better general survival rate in patients with oral or oropharyngeal cancer. Induction QTP can extend survival from 8% to 20% and concomitant adjuvant chemo-radiotherapy can prolong survival up to 16%.

QTP consists of the administration of cytotoxic drugs that are capable of destroying and inhibiting the growth and reproduction of malignant cells [9]. In head and neck cancers, the most extensively used drugs are bleomycin, cisplatin, methotrexate, 5-fluorouracil, vinblastine and cyclophosphamide [10]. QTP can be developed by administering one or more chemother‐ apeutic drugs. The use of isolated drugs (mono-chemotherapy) has proven useless in the induction of significant complete or partial responses. Thus, the current trend is polychemo‐ therapy, which affects the cellular populations in different cell-cycle phases. This is achieved by using the synergistic action of the drugs, decreasing the development of resistance to them and promoting a higher response per administered dose [10]. The most used combinations include cisplatin and 5-fluorouracil; cisplatin, 5-fluorouracil and taxol or cisplatin, bleomycin and methotrexate. Cytostatic drugs offer better results in tumours with a significant growth fraction and/or early distant or frequent dissemination such as lymphomas (90% growth fraction). This is not the case for squamous cell carcinoma, which is the most common head and neck malignancy (25% growth fraction). Therefore, QTP is usually associated with another therapeutic modality [11].

RTP can be applied locally (brachytherapy) or externally (teletherapy). The external radio‐ therapy is the classic way to administer radiotherapy with a remote radiation source of the organism. Sources of external irradiation are low voltage (X-ray), supervoltage (cobalt 60), megavoltage (linear accelerator) and electron beam (power source). Of these, the most widely used treatments for head and neck therapy are cobalt-60 and the linear particle accelerator [12]. External radiotherapy requires a division of the dose and a longer period to carry it out, consisting of a weekly dose of 10 Gy, 2 Gy daily for five days and two days of rest, usually spread out over a period of 5-7 weeks. Fractioned RTP allows a full high dose in the tumour, respecting the normal adjacent tissue and decreasing toxicity. It also conditions the response in healthy and tumour tissues by repairing injuries. This is because, compared to tumour tissue, normal tissue repairs damaged DNA better, especially at low doses. It also promotes the reoxygenation of tumour cells, increasing their radiosensitivity and the repopulation of the tissue between fractions. This is particularly the case during weekends when the area is not irradiated, thereby reducing the early effects [13]. The radiation dose depends on the location and type of tumour and whether the RTP is used alone or combined with other treatment modalities. When the RTP is exclusive, the dose is usually between 60 Gy and 80 Gy, whereas the dose administered post-surgically is 50-60 Gy [1].

On the other hand, brachytherapy is a method that uses ionizing radiation. It places radioactive material in the proximity of or within the tumour. There are different modalities of brachy‐ therapy, of which interstitial RTP is the most frequently used for head and neck tumours. In this modality, Iridium 192 (Ir192) and Iodine 125 (I125) are the most frequent radioactive sources.

RTP and QTP are combined to improve therapeutic results, increasing loco-regional tumour control and distant metastasis [14].

There are different ways to classify the effects produced by RTP on head and neck regions, as are shown in Table 1,2, 3 [10, 15-17].

**Table 1.** Acute and late effects of RTP.

**2. Head and neck cancer**

166 Updates on Cancer Treatment

genetic factors can have a relevant effect.

The term oral cancer is used as a synonym for oral squamous cell carcinoma (OSCC), which accounts for 90% of all head and neck cancers and 3-4% of malignancies [1, 2]. The incidence of head and neck cancer has increased significantly over the past 20 years. Over 575,000 new oral cancer cases are annually diagnosed in the world [3]. According to data published in 1998 by Spanish National Epidemiology Centre, in our country, the number of deaths by oral, pharyngeal and labial cancer amounted to 1,891 of men and 374 of women. In Spain, incidence accounts for 12 to 15 cases per 100,000 men/year and two to four cases per 100,000 women/ year [4]. However, the figures are now matching up. This is because some women are adopting harmful habits, which were traditionally attributable to men. The disease mainly affects men

The etiology of cancer has multiple factors. The main risk factors are smoking and alcohol. Despite showing synergistic effects, these are independent risk factors, as shown in a study by Castellsagué et al. [6, 7]. In some cases of solar ultraviolet radiation in lip cancer, infections, diets low in fruit and vegetables, immunodepression, bad oral hygiene and the presence of

Patients diagnosed with this cancer are treated by surgery, radiotherapy (RTP), chemotherapy (QTP) or a combined treatment. The choice of a unique or combined treatment depends on the location of the tumour, its extension, histological subtype, tumour stage and the patient's general condition. Surgery and RTP are used in isolation to treat cases of non-metastatic disease (stages I and II). However, advanced stages (III and IV) require concomitant RTP and QTP. In the early stages, the treatment of choice is surgery. With this, the tumour is eliminated with safety margins. This is achieved with or without cervical emptying, depending on the location, size or suspicion of regional metastasis. Once the cervical emptying is completed and analysed, if the structures are affected, subsequent treatment with RTP is evaluated. Advanced stages can be treated with surgery followed by RTP but this combination only cures a minority of patients and fewer than 30% will be alive at five years. With these treatments, tumour control and survival rates are unsatisfactory. Only 30% of patients will be alive after three years, while 60-70% of patients will have a loco-regional recurrence and/or will develop distant metastasis,

QTP, in addition to RTP and surgery, is associated with a better general survival rate in patients with oral or oropharyngeal cancer. Induction QTP can extend survival from 8% to 20% and

QTP consists of the administration of cytotoxic drugs that are capable of destroying and inhibiting the growth and reproduction of malignant cells [9]. In head and neck cancers, the most extensively used drugs are bleomycin, cisplatin, methotrexate, 5-fluorouracil, vinblastine and cyclophosphamide [10]. QTP can be developed by administering one or more chemother‐ apeutic drugs. The use of isolated drugs (mono-chemotherapy) has proven useless in the induction of significant complete or partial responses. Thus, the current trend is polychemo‐ therapy, which affects the cellular populations in different cell-cycle phases. This is achieved by using the synergistic action of the drugs, decreasing the development of resistance to them and promoting a higher response per administered dose [10]. The most used combinations

over 40 years of age, with a peak of maximum incidence in their 60s [5, 6].

which, ultimately, is the main cause of death in these patients [8].

concomitant adjuvant chemo-radiotherapy can prolong survival up to 16%.

**Table 2.** Chronology of RTP: immediate, medium term and long term effects.

**Table 3.** Evolution of RTP: reversible and irreversible effects.

#### **2.1. Acute complications of radiotherapy**

**a.** Mucositis is the inflammation of the oral-oropharynx as a result of the cytotoxic effects of RTP. It is the most common complication that appears among patients who have been irradiated with neck and head cancer, with an incidence of 80 %. Mucositis is dosedependent and therefore, it disappears with the end of the aggression [18]. The risk and its gravity depend on the characteristics of the treatment such as doses, size of the irradiated zone and its division.

The first sign is erythema, which appears when a dose of 10 Gy is accumulated (first week) and persists up to 15 days after the end of the RTP treatment. The point of maximum symp‐ tomatology is when there are accumulated doses of 60-70 Gy [19, 20]. Clinically, the mucosa is erythematous and edematous so it can become ulcerated and infected by fungi [19, 21]. The pain that accompanies mucositis can be so intense that it alters the patient's quality of life, limiting their basic oral functions such as speaking, swallowing saliva or eating [21].

Mucositis can be classified in four degrees, according to the intensity of the mucosa [16, 22]:

Grade 0: None (Figure 1).

Grade 1: Erythaema (Figure 2 and 3).

Grade 2: Erythaema, ulcers but capable of ingesting solids (Figure 4).

Radiotherapy and Chemotherapy Treatments in Head and Neck Cancer Patients — Protocol for Management… http://dx.doi.org/10.5772/60397 169

Grade 3: Ulcers, requiring liquid diet (Figure 5).

Grade 4: Oral feeding is impossible (Figure 6).

**Figure 1.** Grade 0.

**CHRONOLOGY IMMEDIATE MEDIUM TERM LONG TERM**

Xerostomia Necrosis of soft tissue

Mucositis Xerostomia

Radiodermatitis Alteration in taste Xerostomia Post-radiation caries Alteration in taste Osteoradionecrosis Opportunist infections Tooth disorder

**a.** Mucositis is the inflammation of the oral-oropharynx as a result of the cytotoxic effects of RTP. It is the most common complication that appears among patients who have been irradiated with neck and head cancer, with an incidence of 80 %. Mucositis is dosedependent and therefore, it disappears with the end of the aggression [18]. The risk and its gravity depend on the characteristics of the treatment such as doses, size of the

The first sign is erythema, which appears when a dose of 10 Gy is accumulated (first week) and persists up to 15 days after the end of the RTP treatment. The point of maximum symp‐ tomatology is when there are accumulated doses of 60-70 Gy [19, 20]. Clinically, the mucosa is erythematous and edematous so it can become ulcerated and infected by fungi [19, 21]. The pain that accompanies mucositis can be so intense that it alters the patient's quality of life,

Mucositis can be classified in four degrees, according to the intensity of the mucosa [16, 22]:

limiting their basic oral functions such as speaking, swallowing saliva or eating [21].

Grade 2: Erythaema, ulcers but capable of ingesting solids (Figure 4).

Radiodermatitis Trismus

**EVOLUTION REVERSIBLE IRREVERSIBLE**

**Table 2.** Chronology of RTP: immediate, medium term and long term effects.

168 Updates on Cancer Treatment

Necrosis of soft tissue

Trismus

**Table 3.** Evolution of RTP: reversible and irreversible effects.

**2.1. Acute complications of radiotherapy**

irradiated zone and its division.

Grade 0: None (Figure 1).

Grade 1: Erythaema (Figure 2 and 3).

Mucositis Post-radiation caries Osteoradionecrosis Alteration in taste Opportunist infections Tooth disorder

**Figure 2.** Grade 1.

**Figure 3.** Grade 1.

**Figure 4.** Grade 2.

**Figure 5.** Grade 3.

**Figure 6.** Grade 4.

**b.** RTP facilitates the surge of opportunist infections, mainly Candida (Figure 7 and 8) as a result of the reduction of saliva, the use of dentures, deficient oral hygiene and the persistence of habits such as smoking or drinking [23]. These types of infections tend to disappear with topical anti-fungal drugs. However, irradiated patients frequently have to use more effective systemic drugs [24].

**Figure 7.** Candidiasis during RTP.

**Figure 8.** Candidiasis during RTP.

**c.** Radiodermatitis is considered as skin and subcutaneous tissue toxicity. Depending on its severity, it is classified in three different levels. Transitory erythaema is produced by the congestion of dermal papillae within the first 24 hours. A dose of 3 Gy is enough to trigger it (Figure 9 and 10). A dose of 25 Gy will produce an acceleration of the skin flaking process, which is manifested as a significant decrease of thickness. This will then become dark, atrophic and flaky, which is called dry radiodermatitis (Figure 11). A 50-70 Gy dose will cause a delayed erythaema, followed by a superficial necrobiosis and the formation of skin scabs. If these lesions progress, bleeding vesicula easily appears, which is called wet radiodermatitis (Figure 12). These lesions are cured when the RTP treatment has ended, leaving scars on the skin. These can be white and esclerotic telangiectastic. Follicles are destroyed and, on occasions, pigmentations can appear [10].

**Figure 9.** Radiodermatitis: Grade 0, 5 sessions of RTP.

**Figure 5.** Grade 3.

170 Updates on Cancer Treatment

**Figure 6.** Grade 4.

**Figure 7.** Candidiasis during RTP.

**Figure 8.** Candidiasis during RTP.

to use more effective systemic drugs [24].

**b.** RTP facilitates the surge of opportunist infections, mainly Candida (Figure 7 and 8) as a result of the reduction of saliva, the use of dentures, deficient oral hygiene and the persistence of habits such as smoking or drinking [23]. These types of infections tend to disappear with topical anti-fungal drugs. However, irradiated patients frequently have

**Figure 10.** Radiodermatitis Grade I, 10 sessions of RTP.

**Figure 11.** Radiodermatitis: Grade II, 17 sessions of RTP.

**Figure 12.** Radiodermatitis Grade III, 24 sessions of RTP.

**d.** Most patients suffer xerostomia or salivary hypofunction due to RTP in head and neck cancers. This usually appears within the first weeks of radiation. In low doses (under 30 Gy), it is believed that the damage can be reversible. However, higher doses (over 60-70 Gy) result in an irreversible and permanent xerostomia. With the latter, there is a signif‐ icant degeneration of the acini, which is reflected by concomitant inflammation and fibrosis of the interstitium (Figure 13).

**Figure 13.** Rough tongue due to salivary hypofunction.

patients can experience a residual reduction of taste (hypogeusia), permanent damage to the sense (disgeusia) and the loss of taste (ageusia) [34, 35].

#### **2.2. Late complications of radiotherapy**

**Figure 12.** Radiodermatitis Grade III, 24 sessions of RTP.

172 Updates on Cancer Treatment

fibrosis of the interstitium (Figure 13).

**Figure 13.** Rough tongue due to salivary hypofunction.

**d.** Most patients suffer xerostomia or salivary hypofunction due to RTP in head and neck cancers. This usually appears within the first weeks of radiation. In low doses (under 30 Gy), it is believed that the damage can be reversible. However, higher doses (over 60-70 Gy) result in an irreversible and permanent xerostomia. With the latter, there is a signif‐ icant degeneration of the acini, which is reflected by concomitant inflammation and

**e.** Salivary hypofunction (a resting saliva flow of less than 0.2 ml per minute or a stimulated flow of less than 0.7 ml per minute) is caused by the damage of direct ionizing radiation of the salivary glands' cells [25]. This is the most persistent effect in patients submitted to RTP for head and neck tumours. It is characterized by changes in the amount and quality of saliva (more viscous and scarce). It produces oral discomfort and pain, a higher risk of dental caries, oral infection, difficulty of speech and disfagia. This has a damaging effect on the patient's quality of life [26-28]. The reduction of salivary flow can also increase the susceptibility of the dental caries and takes into account the integrity of the mucosa [29].

**f.** The alteration in taste is a result of direct radiation of the taste buds and receptors of taste, as well as changes in the saliva [30-32]. It contributes to loss of appetite, which results in the patient's weight loss. It appears 15 days after the treatment starts from the 4 Gy and it reaches its maximum once the RTP is finished. In most cases, the sense of taste gradually returns to normal or almost normal levels one year after radiotherapy [33]. However, some

**a.** There is a necrosis of soft tissue characterized by an ulcer located in the irradiated tissue, without the presence of residual malignancy (Figure 14 and 15). It is usually a painful condition and the tissues present a pale colour and lack of flexibility [36].

**Figure 14.** Necrosis of soft tissue two months after finishing RTP.

**Figure 15.** Necrosis of soft tissue two months after finishing RTP.

**b.** Trismus is characterized by a reduction in the opening due to the contraction and even fibrosis of the masticating muscles and the ATM (Figure 16). It appears between three and six months after radiation [23]. It can result in eating and communication problems. It also impacts oral hygiene and the use of prosthesis, as well as the development of dental treatments.

**Figure 16.** Still suffering from trismus one and a half years after finishing the RTP.

**c.** Osteoradionecrosis could be the most severe RTP complication [38]. It is defined as an area of bone exposure in a previously irradiated area, of at least six weeks of evolution and in absence of tumour recurrence [37]. ORN is the result of reduced vascularity of periodontal bone, the periosteum. It causes hypovascular, hypocellular and hypoxic tissue, where the capacity of bone repair and regeneration is severely compromised [38-40]. It can be asymptomatic or it can produce pain, dysaesthesia or anesthesia, depending on its relation with the dental nerve. Patients report halitosis, trismus and dysgeusia. Patients find that ORN impacts food in the lesion and they have difficulties in chewing and swallowing, as well as exhibiting phonation [36]. In most cases, the condition is chronic, developing gradually and becoming wider and painful [38, 41].

There are risk factors that can bring about ORN. These can be related to the tumour, with the patient and with the treatment. With regard to factors that depend on the patient, we funda‐ mentally focus on the realization of post radiotherapy extractions. In fact, the development of ORN with no previous surgery has proved to be extremely strange (incidence of 2.7% after five years). Some other determinant factors are poor oral hygienic, previous irradiations of the zone and the presence of periodontitis. Further factors include bad habits such as tobacco and alcohol. Depending on the treatment, the risk factors are the administrated dose, its division, the RTP type and the irradiated zone. Ultimately, the risk factors, depending on the tumour, include the anatomical localization, the proximity of other bone structures and the size of the tumour. These factors must be taken into account because they increase the risk of ORN and if we are aware of them, we can prevent it.

Most ORN cases take place in the jaw. Here, vascularization is deficient and there is high bone density (Figure 17, 18 and 19). Clinical manifestations of ORN may include pain, orofacial fistulas, exposure of the necrotic bone, pathological fractures and suppuration [42].

**Figure 17.** ORN in the jaw after extraction post-RTP.

**Figure 18.** ORN in the jaw after extraction post-RTP.

**Figure 19.** ORN after four months of finishing the RTP. Extraction had been carried out pre-RTP.

One third of ORN cases are spontaneous, although most cases occur due to teeth removal during radiotherapy or during an insufficient healing time after pre-RTP extractions. Accord‐ ing to Starcke, Shannon, Murray and Makkonen, when the pre-RTP tooth removal is performed correctly and a certain period passes, a significant increase of osteorradionecrosis is not observed [43-45].

**Figure 20.** Spontaneous ORN in the jaw after RTP.

**c.** Osteoradionecrosis could be the most severe RTP complication [38]. It is defined as an area of bone exposure in a previously irradiated area, of at least six weeks of evolution and in absence of tumour recurrence [37]. ORN is the result of reduced vascularity of periodontal bone, the periosteum. It causes hypovascular, hypocellular and hypoxic tissue, where the capacity of bone repair and regeneration is severely compromised [38-40]. It can be asymptomatic or it can produce pain, dysaesthesia or anesthesia, depending on its relation with the dental nerve. Patients report halitosis, trismus and dysgeusia. Patients find that ORN impacts food in the lesion and they have difficulties in chewing and swallowing, as well as exhibiting phonation [36]. In most cases, the condition

is chronic, developing gradually and becoming wider and painful [38, 41].

if we are aware of them, we can prevent it.

174 Updates on Cancer Treatment

**Figure 17.** ORN in the jaw after extraction post-RTP.

**Figure 18.** ORN in the jaw after extraction post-RTP.

There are risk factors that can bring about ORN. These can be related to the tumour, with the patient and with the treatment. With regard to factors that depend on the patient, we funda‐ mentally focus on the realization of post radiotherapy extractions. In fact, the development of ORN with no previous surgery has proved to be extremely strange (incidence of 2.7% after five years). Some other determinant factors are poor oral hygienic, previous irradiations of the zone and the presence of periodontitis. Further factors include bad habits such as tobacco and alcohol. Depending on the treatment, the risk factors are the administrated dose, its division, the RTP type and the irradiated zone. Ultimately, the risk factors, depending on the tumour, include the anatomical localization, the proximity of other bone structures and the size of the tumour. These factors must be taken into account because they increase the risk of ORN and

Most ORN cases take place in the jaw. Here, vascularization is deficient and there is high bone density (Figure 17, 18 and 19). Clinical manifestations of ORN may include pain, orofacial

fistulas, exposure of the necrotic bone, pathological fractures and suppuration [42].

**Figure 21.** ORN after extraction post-RTP.

Incidence of ORN is two times higher in patients with teeth, although poor dental hygiene and continued drinking and smoking can also contribute to its quick appearance [46]. A higher incidence of osteoradionecrosis has been observed after receiving doses of over 65 Gy. This depends on the fractioning of radiation and the treatment with QTP or surgery in the irradiated area [47] (Figure 22 and 23 - case report of ORN that, after seven months of treatment, positively developed chlorhexidine.).

**Figure 22.** ORN two months after finishing the RTP, without previous extractions.

**Figure 23.** After seven months of good oral hygiene and rinses with chlorhexidine and chlorhexidine gel, it has pro‐ gressed favourably.

**d.** Dental caries are very frequent in post-radiation starting three months after RTP has ended. There is a collapse and detachment of the enamel prisms that mainly affect the incisal edges, cuspids and cervical region of the teeth [10] (Figure 24). This is the result of a quantitative and qualitative alteration in the saliva, with a decrease of its stopping capacity. This favours the development of an acidogenic-cariogenic bacterial flora. A change towards a soft carbohydrate-rich diet, poor dental hygiene and the deterioration of motivation also influences this (Figure 25).

For irradiated patients, dietary changes - a softer or liquid diet with a higher concentration of carbohydrates - combined with a decrease in saliva, results in a change in the microbiota. This becomes increasingly cariogenic. This, in addition to poor dental hygiene, results in a demin‐ eralization of the enamel and the destruction of crowns and the cervical area. Here, the cement and dentin is exposed to the oral environment, producing increased dental sensitivity [48].

**Figure 24.** Dental wear during RTP.

**Figure 25.** Accumulation of plaque due to poor hygiene during RTP.