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The ipsilateral neck is treated after a neck dissection has been performed for positive nodes; level IV should be included (100). There is no indication for bilateral elective neck treatment (94). The recommended postoperative dose for positive nodes is at least 60 Gy (30 fractions) (100). Elective irradiation of the neck should be considered for advanced T-stage, certain histologic subtypes (Table 40.1), facial nerve dysfunction at presentation, and recurrent disease. At least level Ib, II, and III should be included (5,30,100). A dose of around 46 to 50 Gy is recommended (3,37,100).
Three basic radiation therapy approaches are used, depending on available equipment: Conventional, three-dimensional conformal radiation therapy (3DCRT) planning procedure, and intensity-modulated radiation therapy (IMRT) planning. The first involves unilateral anterior and posterior wedged pair fields using 60Co or 4- to 6-MV photons (Fig. 40.9A). A slight inferior angulation of the beams avoids an exit dose through the contralateral eye. A simpler technique uses homolateral fields with 12- to 16-MeV electrons in combination with photons (37,41,113). Usually, 80% of the dose is delivered with electrons and 20% with 60Co or 4- to 6-MV photons to spare the opposite salivary gland, reduce mucositis, and decrease the skin reaction produced by electrons (Fig. 40.9B). Yaparpalvi et al. (113) compared nine conventional treatment techniques. Ipsilateral wedge pair technique with 6-MV photons, wedged anteroposterior and posteroanterior and lateral technique with 6-MV photons, and mixed beam using 6-MV photons and 16-MeV electrons (1:4 weighted) were most optimal, considering dose homogeneity within the target and dose to normal tissues. Electron beam (9 to 12 MeV) and tangential photon fields are effective conventional techniques for sparing the underlying spinal cord (from doses more than 45 Gy) and the opposite parotid gland in elective neck irradiation. Conventional techniques do not allow for tissue heterogeneity (air cavity, dense bones, and tissues); underdose and overdose may be seen.
After outlining of the target volumes and critical normal tissues on the planning CT scan, a more conformal 3DCRT plan by the use of geometrically shaped beams of uniform intensity may be reached (71). More normal tissue may be spared with this technique (71). Probably the most conformal radiation technique is IMRT. It can produce convex dose distributions and steep dose gradients. Five- to seven-field inverse IMRT allows excellent coverage of the tumor with sparing of mandible,


cochlea, spinal cord, brain, and oropharynx (12,71), compared with conformal 3DCRT. Figure 40.10 shows a comparison of 3DCRT and IMRT planning for a postoperative radiotherapy plan for a parotid cancer treated with a dose of 66 Gy. The mean dose to the mastoid, meatus acusticus externus, and contralateral parotid gland was 53 and 43 Gy, 57 and 51 Gy, 1 and 9 Gy, for 3DCRT and IMRT, respectively. The maximum dose to the cochlea was 39 and 32 Gy, respectively.

Submandibular Gland
Except for small acinic cell and adenoid cystic cancer (Table 40.1), the neck nodes level I-IV (5) should be irradiated electively, following the indications outlined for parotid tumors; technical considerations are similar. Bilateral fields may be required for tumor extension toward the midline. If there is no gross residual tumor or perineural invasion, 50 Gy in 5 weeks should be adequate for microscopic disease. If there is named perineural invasion of a major nerve, a tumor dose of 60 to 66 Gy in 6 to 6.5 weeks is recommended, and the nerve path to the base of skull should be treated, preferably by 3DCRT or IMRT. For an adenoid cystic carcinoma of the submandibular gland with only focal perineural invasion, an attempt to encompass the base of the skull would require a significant change in the treatment volume and may not be warranted because of potential morbidity and the low rate of relapse at that site (38). An example of 3DCRT for a T2 adenoid cystic carcinoma of the submandibular gland is shown in Figure 40.11.
Minor Salivary Glands
The radiation therapy technique for treating minor salivary gland tumors depends on the area involved and is similar to the treatment for squamous cell carcinomas in these areas, with two significant exceptions. First, when a named branch of a cranial nerve is involved by adenoid cystic carcinoma, the nerve pathways to the base of the skull should be electively treated. When only focal perineural invasion of small unnamed nerves is present, treatment of the base of the skull depends on the site. Second, for tumors of the palate or paranasal sinuses, the base of the skull is included because of its proximity to the tumor bed. In case of an adenoid cystic carcinoma with perineural invasion, IMRT may reduce the high-dose volume, compared to conventional bilateral opposed fields; Figure 40.12 shows an example for a patient with a minor salivary gland cancer of the palate. IMRT is a useful strategy for irradiating minor salivary gland sites such as the ethmoid sinuses while sparing the optic pathways (19).
Also, because the incidence of lymph node metastases is usually lower than that for squamous cell carcinomas of similar size, the radiation therapy fields are rarely extended to cover such areas if there are no palpable lymph node metastases. Indications for treating the neck are a primary tumor that arose in the tongue, floor of the mouth, pharynx, or larynx (74), and the neck was not dissected, or after resection of metastatic neck lymphadenopathy.
For patients receiving postoperative irradiation after surgical resection, a dose of 60 Gy is given for negative margins and 66 Gy for microscopically positive margins. For gross residual disease after surgery or for lesions treated with irradiation


alone, a total dose of 70 Gy is recommended at 2 Gy per fraction.

Results of Therapy
Surgery Plus or Minus Postoperative Radiotherapy
Tables 40.6, 40.7 and 40.8 list local control rates and 5- and 10-year survival rates for several series reporting the surgical, irradiation, and combination treatment of carcinomas of the major and minor salivary glands. Little adverse effect of delay between surgery and radiotherapy may be predicted for what are, in general, slow-growing salivary gland cancers. In only two studies, one concerning submandibular cancer (96) and another for minor salivary gland (38), impaired locoregional control rates were seen for a delay of more than 6 weeks, which was not confirmed in the Dutch study (100). The prognosis for children with a malignant salivary gland cancer (mostly mucoepidermoid cancer of the parotid gland) is excellent, with a 10 year overall survival of more than 90% (88). Most are treated with surgery alone because of the possible risk on radiation-induced malignancies.
Long-term follow-up is recommended because failures may appear after 5 years, especially for minor salivary gland tumors (17,29,57,101). Recurrent tumors in general are more difficult to control than are primary ones, so high initial locoregional control rates should be the goal (101). Because of high rates of local failure of approximately 40% for parotid, 60% for submandibular, and 65% for minor salivary glandswith surgery alone in the past (93), many institutions have advocated postoperative irradiation especially to reduce the incidence of local failure. Local tumor control appears to be improved by the combination of surgery and irradiation, although randomized, controlled trials have not been performed. Evidence of a positive role of postoperative radiotherapy is based on retrospective studies and a matched-pair analysis. In the study by Armstrong et al. (4), postoperative radiotherapy significantly improved locoregional control (from 17% to 51% for stage III-IV), not for stage I and II major salivary gland cancer. Locoregional control for patients with positive nodes increased from 40% to


69%. In most studies, an imbalance in prognostic factors is seen comparing surgery alone with combined therapy, favoring surgery alone. Despite this imbalance, locoregional control with combined surgery and postoperative radiotherapy is superior to surgery alone for patients with negative prognostic factors, irrespective of site (33,66,100,101,102). In the nationwide Dutch study, the relative risk for surgery alone, compared with combined treatment, was 9.7 for local recurrence and 2.3 for regional recurrence (100). In a study from Denmark, the relative risk of no radiotherapyversus radiotherapy was 4.7 for locoregional control (102). Postoperative radiotherapy is particularly effective if there are close and microscopic positive resection margins, enhancing local control from around 50% to 80% to 95% (33,41,77,100,102). Comparable results are noted for T3-T4 tumors and pathologically confirmed bone and perineural invasion (66,100). However, for a T1 or T2 tumor that was completely resected with no bone or perineural invasion, surgery alone will result in more than 90% 10-year local control rate, and radiotherapy is not indicated (100).

Treatment results also may depend on histopathologic status. However, after review, histologic type may change, even among experienced pathologists. In general, the best prognosis is shown for acinic cell and mucoepidemoid cancer, with a 15% risk of distant metastases after 10 years and a 10-year locoregional control rate of around 85%. Ten-year overall survival is around 80% and 65%, respectively (11,45,93,101). In one of three patients, postoperative radiotherapy is indicated (45,101). Squamous cell and undifferentiated tumors have been associatedwith a 10-year overall survival of 35% or less, caused by a high risk of distant metastases (35% and 50%, respectively) and locoregional recurrence (77,93,101). Postoperative radiotherapy is indicated in all cases to improve locoregional control. The intermediate-risk group consists of adenoid cystic cancer and cancer ex pleomorphic adenoma. Distant failure after 10 years is around 35% (39,92,101). Although the risk of nodal recurrence is low (5% to 10%), local recurrence is diagnosed more often (20% to 30%). A precipitous decrease in relapse-free survival is noted among 5 (around 70%), 10 (around 50%),
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and 15 years (around 45%) for patients with adenoid cystic carcinomas, which are well known for late recurrences (39,101). Significant improvement was reported in local control for adenoid cystic cancer with combined surgery and irradiation in several studies (33,39,81,89,96), regardless of site. Local tumor control rates with combined modality therapy for these tumors approach 85% to 90% at 10 years. Postoperative radiotherapy is also able to improve locoregional control rates with about 20% for high-grade tumors (62,81,96).

In the World Health Organization classification of 1991, among others, two new subtypes were described that are diagnosed relatively frequently. PLGA is situated solely in the palate.


Treatment consists of wide local excision. In a report by Castle et al. (17), treatment results of 164 tumors were analyzed, with 90% treated with surgery alone. Local control was 90%, with only few patients dying from PLGA. However, local failures may be seen even after long follow-up. In a series from Evans and Luna (29) of 40 patients with PLGA, local recurrence was seen in 43% of patients treated with surgery alone, mainly because of close and microscopic positive resection margins. No recurrence was seen in the nine patients treated with postoperative radiotherapy.

Salivary duct carcinoma is a very aggressive disease, and postoperative locoregional radiotherapy is indicated in all cases. Most patients die of disease, despite often successful locoregional combined therapy. Because of a high percentage of distant metastases, 5-year survival is only around 10% to 15% (42,52). The prognosis correlates with HER-2/neu receptor status; 3-year survival is 56% and 17% for (+)HER-2/neu and (+++)HER-2/neu, respectively (52).
Minor salivary gland tumors of the oral cavity have a more favorable prognosis than paranasal sinus tumors (maxillary and ethmoid sinus and nasal cavity) (38). Patients with hard palate lesions tend to be diagnosed when they have small asymptomatic lumps, which are easily detected on physical examination. On the other hand, paranasal sinus tumors usually do not cause symptoms until they are locally advanced. The surgical approach for these tumors is more difficult, with a greater chance for leaving behind residual disease, leading to high recurrence rates. A combined approach with surgery and postoperative irradiation is recommended.

Primary Radiotherapy
The poor results for salivary gland cancer with irradiation alone in several series have been attributed to the use of primary radiotherapy for patients with locally advanced lesions or distant metastases at presentation, who were essentially treated for palliation. Locoregional control rates after conventional photon or electron therapy are around 25% (49,60,66). For treatment with photons with curative intent, a clear dose-response relationship has been described (100). A dose of 66 to 70 Gy may result in 50% 5-year local control. Wang and Goodman (109) reported local control as high as 85% with accelerated hyperfractionated photon therapy. The follow-up was rather short, and the results have not been updated (109). The generally slow rate of regression of advanced salivary gland tumors have made them a logical target for alternative radiation therapy approaches, such as fast neutrons.
Neutron Therapy
Patients with inoperable primary or recurrent major or minor salivary glands were included in the RTOG-MRC randomized phase III clinical trial. Patients were randomized between 70 Gy for 7.5 weeks or 55 Gy for 4 weeks photon therapy and neutron


terapia. The study had to be stopped because of a statistically significant difference in 2-year locoregional control, after inclusion of only 32 patients. The 10-year locoregional control probability was 17% after photon therapy, and 56% after neutron therapy (60). However, survival was identical. Late morbidity was somewhat higher for neutron therapy. Douglas et al. (24) of the University of Washington have published results of 279 patients treated with neutrons. Almost all patients had evidence of gross residual disease. Major and minor salivary gland sites were equally distributed. Total dose, administered with neutrons, varied from 17.4 to 20.7 Gy. The 6-year locoregional control and cause-specific survival were 59% and 49%, respectively, conforming to the results of most studies. Locoregional control was only 19% for base of skull involvement and 67% for no involvement. Locoregional control was 72% for minor sites and 61% for major sites. The 6-year actuarial grade 3 and 4 toxicity was 10%. Less severe late morbidity may occur if neutron therapy is combined with photons. A study from Heidelberg for advanced, inoperable, recurrent, or incompletely resected adenoid cystic carcinoma compared results of treatment with neutrons, photons, or mixed beam (49). Severe late grade 3 and 4 toxicity was 19% with neutrons, compared to 10% with mixed beam and 4% with photon therapy. The 5-year local control was 75% for neutrons and 32% for mixed beams and photons; survival was identical.
In an effort to improve poor results for tumors invading the base of skull, several new techniques have been developed. A combination of neutron therapy with, after a 4-week split, a Gamma Knife stereotactic radiosurgical boost has been used for tumors invading the base of skull (26). Local control of eight patients treated with this technique looks promising; however, follow-up was only 2 years. Another option is a combination of photons (54 Gy) and carbon ions (18 Gy) radiotherapy (86). In a series of 16 patients with adenoid cystic cancer invading the base of skull, the 3-year local control was 65%, without late effects exceeding grade 2. Longer follow-up results of these new techniques are awaited.
In conclusion, neutron beam therapy seems to be the treatment of choice for unresectable, residual, or recurrent salivary gland tumors. Despite high locoregional control, survival is not improved and late toxicity is of concern.
Systemic Therapy
The rarity of these neoplasms and their localized nature provide limited opportunities for trials with chemotherapy. In a review by Lalami et al. (59), they stated that chemotherapy has to be considered as palliative treatment and should only be given for disease-related symptoms and rapidly progressive disease. Cisplatin as monotherapy shows a 20% response rate for locoregional disease and only 7% for distant failures, with a duration of 6 to 9 months. A combination of 5-fluorouacil, cyclophosphamide, cisplatin, and doxorubicin gives a response rate of 50% (59).
Carcinoma ex pleomorphic adenomas and salivary duct carcinomas express androgen receptors in a high frequency (69). There may be a possible role for antiandrogen therapy, combined with other treatment modalities. However, the efficacy of this treatment option for some salivary gland cancers still has to be proven.
Expression of vascular endothelial growth factor is seen frequently in salivary gland cancer and is related with poor prognosis. Overexpression of HER-2/neu also correlates with poor prognosis, and a great variety between histologic types has been demonstrated (59). In the future, the role of molecular-targeted therapy for these salivary gland cancers has to be established.
Esiti di trattamento
The most notable complication of treatment of parotid malignancies is facial nerve paralysis, which is often caused by the initial or a repeated surgical procedure. However, various series have shown that facial nerve sacrifice is rarely necessary, unless the nerve is directly involved by tumor, particularly when postoperative irradiation is given (33,77,91). When facial nerve sacrifice is required, facial nerve grafting and postoperative radiation therapy achieve comparable facial nerve function compared with unirradiated graft despite more negative prognostic factors (14). Other postoperative sequelae, such as salivary fistulae and neuromas of the greater auricular nerve, are sometimes seen. Frey's syndrome (ie, gustatory sweating) may occur in a few patients after parotid surgery, but it is rarely bothersome (58).
Partial xerostomia after irradiation of the parotid gland is frequently observed and may be permanent. Trismus may result from radiation-induced fibrosis of the temporomandibular joint or the masseter muscles. It usually occurs when there is extensive tumor infiltration of the masseter muscle and high doses are given. Data on dose-response relationship for radiation-induced hearing impairments are sparse. In a study by Chen et al. (18), with 21 patients treated for malignant parotid tumors, a significant hearing loss was noted after a cochlear dose of ≥60 Gy in 60%, and in no patient after a dose <60 Gy. Conductive hearing loss was caused by serous effusion in the middle ear and/or obstruction of the tuba Eustachius. In general, a dose as low as possible (<30 Gy) should be attempted (53).
Garden et al. (38) reported complications of irradiation in 51 of 160 patients receiving postoperative irradiation for minor salivary gland tumors. The most common complication was decreased hearing in 26 patients, 20 of whom had myringotomies or myringotomy tubes placed for serous otitis media. Bone necrosis or exposure was observed in several patients; however, this complication has been seen infrequently during the past decade with improved radiation therapy techniques and treatment of multiple, as opposed to single, fields per day. Complications to the eyes or optic pathways were most common in patients with paranasal sinus primary tumors. At least six cases of contralateral optic atrophy occurred. Other eye complications included dry eye syndrome, nasolacrimal duct obstruction, cataract, retinopathy, and perforated globe. To reduce the incidence of bilateral blindness, the dose to the optic chiasm and contralateral optic nerve is limited to 54 Gy. In patients with extensive tumor involvement of the orbit, it may be preferable to remove the eye surgically rather than to subject the entire orbit to high doses. Radiation-induced injury to the visual pathway is dose-dependent. None of the patients receiving a dose of less than 50 Gy develop optic neuropathy or chiasm injury, whereas the 10-year actuarial incidences of optic nerve chiasm injury is 5% and 30% for patients receiving 50 to 60 Gy and 61 to 78 Gy, respectively (54).
Radiotherapy of tumors of the pharynx, and less frequently the oral cavity, may result in permanent complaints of xerostomia. The mean dose to the parotid glands that relates to 1-year xerostomia may range from 26 Gy (27) to 39 Gy (82). This serious late complication may be significantly reduced by the use of IMRT (51,99). For those patients with a dose to both parotid glands that exceeds at least 39 Gy, amifostine administration during head and neck radiotherapy will reduce the severity and duration of xerostomia 2 years after radiotherapy (110), without compromising locoregional control.
Treatment of Recurrence
Retreatment usually involves additional surgery, if feasible, and postoperative irradiation in previously unirradiated patients (Fig. 40.13). In the retreatment of parotid neoplasms,


preserving facial nerve function and obtaining local control are more difficult than for the initial tumor. Therapy consisting of surgery with postoperative irradiation has demonstrated enhanced local control, and facial nerve sacrifice may be necessary less often if this combination is used. In certain histologic subtypes (eg, adenoid cystic carcinoma), retreatment of locally recurrent disease yields prolonged survival (89). Aggressive local therapy for recurrent disease is indicated if the probability of long-term survival is high.

Chemotherapy also has been used for recurrent disease. Polychemotherapy for recurrent high-grade disease may result in around 45% response rate, with a median duration of 7.5 months (1). However, in view of its significant toxicity and modest response rates in a population that may have recurrent yet indolent progressive disease, trials of aggressive cytotoxic therapy are recommended only on carefully drafted protocols. In the future, molecular target agents may be tested in selected recurrent salivary gland cancers.