Mucosal atrophy after conventionally fractionated doses of 60–70 Gy over a period of 6–7 weeks is common, but necrosis, chronic ulceration, and bone exposure rarely occur unless large daily doses are delivered or the total dose exceeds 70 Gy in 7 weeks [10]. Thrombosis of small blood vessels in the submucosa results in ischemia and the consequent appearance of ulcers and telangiectasias. This condition may become apparent as soon as 6 months after irradiation or as late as 1–5 years and is irreversible. Scarring and fibrosis of the nasal mucosa can alter sinus drainage and predispose patients to persistent rhinosinusitis. Children may complain of symptoms of chronic sinusitis, which include chronic nasal discharge, postnasal drip, headache, and facial pain. Smell acuity is significantly affected by radiation treatment of the olfactory mucosa, and, although this is not usually voiced as a specific complaint, it can contribute to decreased appetite and poor nutrition.

Severe skin reactions, including permanent hyperpigmentation, telangiectasias, and skin ulcerations, are rarely seen with the use of modern-day megavoltage RT, unless the skin is intentionally treated with a high dose. A recent study showed that increasing RT dose and skin volume receiving >40 Gy were associated with the severity of radiation dermatitis in children receiving RT for sarcoma [49]. Another study compared children with nasopharyngeal carcinoma treated with conventional and intensity-modulated RT (IMRT). Both grade 3 skin (47.1 % vs. 5.3 %) and mucous membrane (52.9 % vs. 15.8 %) were found to be higher in the conventional RT compared to IMRT-treated patients [51]. Doxorubicin and actinomycin can interact with radiation to produce severe skin reactions and may contribute to late skin effects. When these drugs are given early in the course of radiation, such reactions may be seen after low doses of 20–30 Gy. These and other chemotherapeutics (i.e., capecitabine, gemcitabine, melphalan, docetaxel), if delivered after radiation, can be associated with either “radiation sensitivity” or “radiation recall,” in which skin reactions appear in the treated field [8, 19, 35]. Typically radiation sensitivity is defined by a time interval of <7 days between the end of radiation and the start of chemotherapy, and recall is reserved for intervals greater than 1 week apart [8]. The skin often remains chronically dry due to damage to the sebaceous and eccrine glands. The sebaceous glands are as radiosensitive as the basal epithelial cells of hair follicles; eccrine glands are less sensitive [36].

Epilation within the treatment field usually occurs 2–3 weeks into the course of radiation treatment. The permanency of the hair loss depends on the total dose of radiation delivered to the hair follicles, and this, in turn, depends on the treatment technique and beam energy. Single fraction doses of 7–8 Gy or more and total doses (after fractionated therapy) of greater than 45 Gy can result in permanent hair loss [53]. Hair loss is common with chemotherapy. After chemotherapy treatments have been concluded, hair begins to regrow within 1–2 months. It may be lighter in color and have a finer texture [26]. Microscopic analysis of hair samples of patients receiving chemotherapy has shown fracture and splitting of the hair cortex and decrease in diameter and depigmentation of the hair shaft, all of which may account for the changes in color and texture [65].

Clinical manifestations of radiation include hypoplasia, deformities, fracture, and necrosis [39, 73]. The age at which RT is given is the most important factor determining orbital growth retardation in tumors like retinoblastoma. As the orbit has three growth spurts, the first between 0 and 2 months, the second between 6 and 8 months, and the third during adolescence, radiation in children younger than 6 months of age is more damaging to orbital growth than if administered at an older age [43].

The craniofacial development of children is affected, resulting in reduced temporomandibular joint mobility, growth retardation, and osteoradionecrosis [13]. Impaired growth of the mandible and facial bones can contribute to malocclusion. Eventual fibrosis of the temporomandibular joint results in muscle pain and headaches [14]. Tumor invasion of the temporomandibular joint, surgery, and the use of large daily fractions further increase the risk of radiation-induced trismus. Combined modality therapy has a greater impact on facial structures when radiation doses are high as children receiving doses of 24 Gy or less to the temporomandibular joint have not demonstrated clinical signs of trismus [56]. Maxillary and mandibular hypoplasias are also common dento-maxillofacial defects after chemoradiation. Linear cephalometric values suggest that the growth of the mandible may be more affected than that of the maxilla [60].

Overall, the facial skeleton appears to be the most susceptible to high radiation doses before age 6 and at puberty, which are critical times of skeletal development. In a study of 26 children receiving a mean dose of 54 Gy for either nasopharyngeal cancer or rhabdomyosarcoma, cephalometric measurements utilizing CT showed deviations in the cranial vault, anterior and mid-interorbital distances, and lateral orbital wall length, compared with normal skulls [17]. Figure 7.2 shows an example of bony and muscular hypoplasia after surgery and two radiotherapy courses for rhabdomyosarcoma.

Chemotherapy may also affect the growing skeleton. A recent review of the alterations in height for long-term survivors of acute lymphoblastic leukemia noted that chemotherapy administration was associated with a decrease in height during treatment; that the use of intensive chemotherapy leads to a long-term decrease in height that can be worsened if patients also received radiotherapy; and that young children are more at risk for severe height loss [88].

Rhabdomyosarcoma of the head and neck is a condition in which the long-term side effects of combined modality therapy have been extensively studied. Late side effects in children treated with combined modality therapy for head and neck rhabdomyosarcoma are usually seen within the first 10 years after treatment [68], given that the most will have experienced their pubertal growth by that time. Clinical or radiographic dentofacial abnormalities have been observed in 80 % of long-term survivors [24]. Abnormalities including enamel defects, bony hypoplasia/facial asymmetry, trismus, velopharyngeal incompetence, tooth/root agenesis, and disturbance in root formation were the most common findings. The largest report on the late effects in pediatric head and neck rhabdomyosarcoma comes from IRS II and IRS III, in which 213 patients were followed for a median length of 7 years. Seventy-seven percent had one or more late sequelae, including poor statural growth, facial and nuchal asymmetry, dental abnormalities, and vision/hearing dysfunction [74].

Cosmetic effects become more apparent as normal growth proceeds in adjacent unirradiated areas. In 1983, Guyuron et al. reported on 41 patients who had been treated as children with RT to the head and face. They noted that hypoplastic development of the soft tissue and bone was a common finding [37]. Irradiation of the cranial base was often correlated with soft tissue deficits in the upper face and midface. Soft tissue was more vulnerable to RT than growing facial bones, with a threshold dose as low as 4 Gy (in contrast to 30 Gy for facial bones). In 1984, Jaffe reported on the maxillofacial abnormalities seen in 45 patients who had been treated as children with megavoltage RT for lymphoma, leukemia, rhabdomyosarcoma, and miscellaneous tumors [44]. Forty-three of the 45 patients also received chemotherapy (including vincristine, actinomycin D, cyclophosphamide, methotrexate, 6-mercaptopurine, prednisone, procarbazine, or nitrogen mustard in various combinations). In 82 % of the radiated patients, dental and maxillofacial abnormalities were detected, including trismus, abnormal occlusal relationships, and facial deformities. The most severe radiation deformities were seen in younger patients who received higher radiation doses.

Paulino found that 11 of 15 children treated for head and neck rhabdomyosarcoma with RT and chemotherapy developed facial asymmetry in the RT field at doses between 44 and 60 Gy [68]. Sonis studied 97 patients with acute lymphoblastic leukemia (ALL) who received either chemotherapy alone or with 18–24 Gy cranial RT [80]. The treatment fields routinely included the temporomandibular joints, posterior tooth buds, and the ramus of the mandible. A significant dose-effect relationship was seen between 18 and 24 Gy (2 Gy/fraction). Children under the age of 5 who received 24 Gy of cranial RT and chemotherapy had a 90 % incidence of craniofacial abnormalities, but no craniofacial abnormalities were seen in children over the age of 5 or in those receiving only 18 Gy of cranial RT and chemotherapy. No craniofacial abnormalities were noted after chemotherapy alone. It is unlikely that chemotherapy alone contributes to bony or soft tissue abnormalities, although it clearly does affect dental development in relation to age at treatment [59, 63]. Although amifostine, a radioprotective agent, has been demonstrated to reduce craniofacial growth inhibition in immature rabbits, evidence for its applicability in humans is lacking [29].

Radiation therapy also has an effect on wound healing that may be critical for those who require a surgical procedure in the irradiated region [18]. RT may also affect the connective tissues and bone, leading to fibrosis and osteoradionecrosis. In the Fromm series, two patients developed temporomandibular joint fibrosis with limitation of jaw motion [30]. While many studies have documented the appearance of bone hypoplasia in the dose range of 18–24 Gy, limited information is available regarding RT dose to the mandibular muscles (pterygoid and masseter) and its effect on jaw dysfunction including trismus. Krasin and colleagues found that for each 10 % of mandibular muscle volume treated above 40 Gy, a 2 mm reduction in jaw depression was seen [50]. Osteoradionecrosis has been well described in the adult head and neck literature; however, little has been written on its incidence in the pediatric population. Osteoradionecrosis usually develops in the mandible, and its risk is directly correlated with total radiation dose, fractionation dose, tumor size, and bony involvement by the tumor. In the adult literature, osteoradionecrosis is uncommon at mandibular doses <60 Gy. The incidence of osteoradionecrosis for adult head and neck cancer patients ranges from 5 % to 10 % in most series [54]. In one study, the incidence was 1.2 % for all head and neck and 5.5 % for oral cavity sites using IMRT. Maximum mandibular dose >70 Gy and mean mandibular dose >40 Gy correlated with dental extractions after IMRT [34]. In a small single-center review of the long-term effects of IMRT and platinum-based chemotherapy in pediatric patients with nasopharyngeal carcinoma (NPC), Louis et al. noted that while all patients experienced toxicity in at least three body systems, two of the five patients developed osteoradionecrosis of the mandible [55]. Historically, this risk is increased in patients who received postirradiation dental extraction, compared with pre-irradiation extraction. It is believed that radiation is associated with decreased blood flow and oxygen levels, consequently compromising tissue repair. An example of osteoradionecrosis in a nasopharyngeal patient treated with radiotherapy is shown in Fig. 7.3.

Bisphosphonate-related osteonecrosis of the jaw has also been reported. The median onset of bisphosphonate-related osteonecrosis of the jaw was 21 months with zoledronic acid, 30 with pamidronate, and 36 with zoledronic acid and pamidronate [93].

Salivary gland dysfunction may occur when one or more of the major salivary glands are irradiated. Permanent damage can lead to xerostomia, predisposing to dental caries, decay, and osteoradionecrosis. Studies of salivary function in children after RT are limited [52]. Fromm found that 8 of 11 parotid glands that received >45 Gy to more than 50 % of the gland volume failed to secrete saliva, whereas all parotid glands receiving 40 Gy retained the ability to secrete [30]. More recent studies in adult patients have shown a lower dose-response effect. In 2010, Deasy summarized the data from published manuscripts evaluating salivary function as related to radiation dose-volume parameters and noted that a minimal reduction of function is seen with doses to the parotid glands of <10–15 Gy, a gradual decrease in function with doses between 20 and 40 Gy, and severe (>75 %) reduction with doses >40 Gy [16]. The use of amifostine, as a radioprotector for xerostomia, is gaining popularity in the pediatric oncology community despite limited experience in children. Currently, patients on Children’s Oncology Group Protocol ARAR0331, treatment of nasopharyngeal cancer with neoadjuvant chemotherapy followed by concomitant chemoradiotherapy, are given amifostine prior to their daily RT dose. This practice is an extrapolation of results from randomized trials in adult oncology which shows the efficacy of amifostine in reducing acute and late xerostomia without compromising locoregional disease control [79, 92].

Chemotherapy for children with acute leukemia alters salivary function [58]. Mansson-Rahemtulla and colleagues showed decreased thiocyanate concentration in saliva following cytotoxic chemotherapy, which can lead to alteration in function of the salivary peroxidase system, as well as increased oral complications. Patients who undergo bone marrow transplantation are also at risk. Xerostomia, as has been noted in patients with chronic graft-versus-host disease, can persist for as long as a year and results in a high risk for developing dental caries [4]. Although only one of five children with NPC reported in the Louis et al. cohort reported xerostomia immediately after chemotherapy, four of five had symptoms noted during their long-term follow-up [55].

Late effects on dentition in children can be attributed directly to the cytotoxic effects on the growing tooth buds and indirectly to salivary gland damage. Salivary gland damage results in a pronounced shift toward highly acidogenic and cariogenic oral microflora, which promotes dental caries [10]. The severity and frequency of long-term dental complications due to RT are related to the type of RT given, the total dose, the size and location of RT fields, and the age of the patient. Growing tooth buds may be arrested with <10 Gy, while doses >10 Gy can completely destroy buds [57]. Root shortening, abnormal curvature, dwarfism, and hypocalcification are noted with doses of 20–40 Gy [44, 80].