Introduction
Primary cancers arising from the parotid gland represent a diverse biologic spectrum. Surgery remains the primary local curative modality with high rates of local regional control (LRC) for the majority of early stage parotid contained neoplasms. For more advanced, aggressive neoplasms, or in the setting of resectable recurrent cancers, adjuvant radiotherapy (RT) reduces the risk of local regional failure. Radiation sterilizes areas of residual microscopic disease, areas of tumor spillage, and areas of peripheral nerve involvement (named or unnamed) while sparing the patient the additional morbidity and disfigurement of a more comprehensive surgical resection. This chapter reviews the indications for adjuvant and primary RT, clinical outcomes, the role of particle therapy, dosing regimens, and current clinical trials.
Indications for Radiotherapy in the Treatment of Salivary Gland Tumors
Radiotherapy in the Adjuvant Setting
Given the rarity of these tumors, there are few prospective randomized trials that have been conducted for primary salivary gland cancers. The use of adjuvant RT is based on available single institutional retrospective studies. These retrospective studies collectively show that in the setting of identified high-risk (HR) factors, significant improvement in 10-year local control (LC) can be achieved. Adjuvant RT is typically offered in the setting of locally advanced tumors (T3–T4 primaries), incomplete resection, high-grade histology, nodal extracapsular extension, perineural invasion, lymphovascular space invasion, and adenoid cystic histology. Patients harboring one or more of these HR pathologic features treated with surgery alone can expect 10-year LC rates ranging from 17–78%, whereas those that underwent RT could expect control rates of 51–95%. Treatment is usually initiated within 6 weeks of resection to allow for adequate postoperative wound healing. Table 52.1 illustrates the improvement in LC with the addition of adjuvant RT in selected retrospective studies. Adenoid cystic carcinomas are more locally aggressive and may have a lower rate of LC when treated with surgery alone ( Table 52.2 ).
| Author | Year | Cases ( n ) | Surgery (Local Control Rate) | Surgery + RT (Local Control Rate) |
|---|---|---|---|---|
| Noh et al. | 2010 | 94 | 78.2% – 5-year LC | 94.7% – 5-year LC |
| Chen et a1. | 2007 | 63 | 49% – 5-year LC | 75% – 5-year LC |
| Terhaard et al. | 2005 | 538 | 76% – 10-year LC | 91% – 10-year LC |
| Armstrong et al. | 1990 | 46 | 16.8% – 5-year LC | 51.3% – 5-year LC |
| Author | Year | Cases ( n ) | Surgery (Local Control Rate) | Surgery + RT (Local Control Rate) |
|---|---|---|---|---|
| Chen et al. | 2006 | 140 | 61% – 10-year LC | 84% – 10-year LC |
| Mendenhall et al. | 2005 | 101 | N/A | 91% – 10-year LC |
| Silverman et al. | 2004 | 129 | 79% – 10-year LRC | 71.6% – 10-year LRC |
| Garden et al. | 1995 | 198 | N/A | 79% – 10-year LC |
Radiotherapy in the Definitive Setting
Definitive RT is utilized in cases where patients are medically unable to tolerate resection or are surgically inoperable. Single institution experiences with definitive RT for a variety of malignant salivary gland tumors suggest the 5- and 10-year LC rates to be 70% and 57%, respectively. There may be a dose–response relationship for these tumors with doses ≤66 Gy yielding inferior LC. Patients diagnosed with adenoid cystic carcinomas treated with definitive RT had 5- and 10-year LC rates of 56% and 43%, respectively.
Radiotherapy in the Neoadjuvant Setting
Unfortunately, there is lack of evidence for the use of RT in the neoadjuvant setting for malignant salivary gland tumors and it is not usually recommended outside of a clinical trial.
Radiotherapy in the Recurrent Setting for Malignant and Benign Tumors
The overall prognosis of recurrent salivary gland cancer is poor due to the fact that salvage options may be limited because of the infiltrative pattern of disease and the proximity to critical structures. While re-resection has remained the mainstay of salvage treatment, RT to improve LC has been incorporated in several forms. Intraoperative radiation therapy (IORT) has been used with typical doses ranging from 12–16 Gy with a median of 15 Gy. Five-year LC rates in one series were 60% for patients treated with surgery alone and 82% with IORT. The majority of these patients had received prior RT. Reirradiation with concurrent chemotherapy has also been investigated using various fractionation schedules (1.5 Gy BID or 2 Gy QID) to a median dose of 66 Gy (range 30–72 Gy) with a variety of systemic agents. The 3-year LC rate was 51.6%, and the majority of patients experienced Grade ≥3 mucositis. Stereotactic ablative radiotherapy (SABR) has proven useful in head and neck reirradiation. The advantage of SABR lies in its highly conformal dosimetry that reduces the risk of severe complications associated with reirradiation. Roh et al. reported 2-year local recurrence-free survival of 52% and 2-year overall survival of 31%. The median dose was 30 Gy delivered in five fractions. Long-term toxicities were uncommon, and included soft tissue necrosis, which seemed correlated with cumulative dose. RT in the recurrent setting becomes particularly challenging for the clinician when the patient has been previously irradiated. While reirradiation can offer LC benefits to selected patients, the risk of several late toxicities is likely higher and must be given appropriate consideration.
Recurrence among benign salivary gland tumors such as pleomorphic adenomas have declined significantly with the introduction of facial sparing parotidectomy with recurrence rates of 1–5%. However, recurrences can be particularly challenging, as these benign tumors can undergo malignant transformation or recur multifocally. In addition, patients who develop local recurrences even after salvage surgery are at a significantly higher risk of experiencing additional recurrences. Of course, these patients may have the option of undergoing additional surgical resection, but this may not be sufficient to control disease. One of the largest retrospective series of 114 patients with recurrent pleomorphic adenomas and a median follow-up time of 14 years demonstrated a clear LC advantage with the use of postoperative RT. At 15 years, the recurrence rate was 24% in patients treated with surgery alone and 8% in those treated with postoperative RT. A subset analysis revealed that this LC benefit was largely confined to multinodular recurrences.
Chemotherapy and Chemoradiation
The efficacy of chemotherapy either alone or with radiation is not well understood. Chemotherapy alone may be employed in the treatment of unresectable, recurrent, or metastatic disease. A number of small retrospective studies have examined the use of chemotherapy. Platinum drugs, taxanes, anthracyclines, and DNA antimetabolites are just a few agents that have been investigated along with various combinations. Overall, the response rates have been poor. In cases where an objective response is observed, it is typically short-lived. Despite the lack of response, chemotherapy alone has demonstrated improvement of tumor-associated symptoms and may have a role in palliation. In one large retrospective series from Taiwan of 156 patients treated with surgery and adjuvant RT or chemoradiotherapy (CRT), cisplatin added to adjuvant radiation failed to offer any improvement in LC except in selected cases with ACC or lymphoepitheliomas.
The use of CRT is the subject of an ongoing cooperative group clinical trial. Currently, RTOG 10-08, a phase II/III clinical trial opened in 2011, is investigating the potential efficacy with the addition of adjuvant concurrent cisplatin to RT for “high-risk” salivary tumors. Trial eligibility includes patients presenting with the following histologies: intermediate/high-grade adenocarcinoma; high-grade acinic cell or adenoid cystic carcinoma; undifferentiated or poorly differentiated carcinoma; or carcinoma ex-pleomorphic adenoma. Postoperative pathologic HR features required for consideration include: pT3-T4, N0 with close margins ≤1 mm, or R1 resection. Patients are randomized to 66 Gy of RT alone or in combination with 40 mg/m 2 of cisplatin. At present, the study is closed to accrual and the anticipated primary completion is 2023. There are also several clinical trials incorporating RT in the definitive, recurrent, and unresectable setting with some directly investigating salivary gland tumors or as part of a wider range of head and neck tumor primaries ( Table 52.3 ).
| Title | Clinical Trials ID | Phase | Anticipated Completion |
|---|---|---|---|
| Radiation therapy with or without chemotherapy in treating patients with high-risk malignant salivary gland tumors that have been removed by surgery | NCT01220583 | Phase II/III | 2023 |
| Proton beam or photon-based intensity-modulated radiation therapy in treating patients with salivary gland cancer, skin cancer, or melanoma | NCT02923570 | Phase II | 2021 |
| Stereotactic or hypofractionated radiation therapy in treating patients with recurrent or metastatic head and neck cancer | NCT02474368 | Phase I | 2021 |
| Stereotactic body radiation therapy and cisplatin in treating patients with recurrent head and neck cancer that cannot be removed by surgery | NCT02158234 | Phase I | 2020 |
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