RECURRENT PLEOMORPHIC ADENOMA OF THE PAROTID GLAND: LONG-TERM OUTCOME OF PATIENTS TREATED WITH RADIATION THERAPY

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 4, pp , 2006 Copyright 2006 Elsevier Inc. Printed in the USA. All rights reserved /06/$ see front matter CLINICAL INVESTIGATION Head and Neck RECURRENT PLEOMORPHIC ADENOMA OF THE PAROTID GLAND: LONG-TERM OUTCOME OF PATIENTS TREATED WITH RADIATION THERAPY ALLEN M. CHEN, M.D.,* JOAQUIN GARCIA, M.D., M. KARA BUCCI, M.D.,* JEANNE M. QUIVEY, M.D.,* AND DAVID W. EISELE, M.D. Departments of *Radiation Oncology, Pathology, and Otolaryngology Head and Neck Surgery, University of California, San Francisco (UCSF) Comprehensive Cancer Center, San Francisco, CA Purpose: To evaluate the role of radiation therapy in the management of recurrent pleomorphic adenoma of the parotid gland. Methods and Materials: Between 1960 and 2004, 34 patients were treated with postoperative radiation therapy for recurrent pleomorphic adenoma of the parotid gland to a median dose of 5000 cgy (range, 4,500 6,000 cgy). Median age was 48 years (range, years). Gross total resection at the time of surgery before radiation was achieved in 30 patients (88%), and histologic analysis demonstrated multifocal disease in 16 patients (47%). Radiation was delivered for a first, second, third, fourth, fifth, and sixth local recurrence in 24%, 21%, 24%, 24%, 6%, and 3% of patients, respectively. Results: With a median follow-up of 17.4 years (range, years), 2 patients had local recurrences at a median of 3.4 years after completion of radiation. The 20-year actuarial local control rate was 94%. One patient developed a second malignancy at approximately 14 years after completion of therapy. Conclusion: The use of postoperative radiation therapy leads to excellent long-term local control for the treatment of recurrent pleomorphic adenoma with acceptable late toxicity. Although the incidence of second malignancy was low in this population, continued follow-up is warranted Elsevier Inc. Pleomorphic adenoma, Parotid gland, Recurrence, Radiation therapy. INTRODUCTION Pleomorphic adenoma, also known as benign mixed tumor, is the most common neoplasm of the parotid gland and is generally treated by surgical excision. Although classified as a benign tumor, the incidence of local recurrence after initial operative treatment is not insignificant and varies largely because of differences in surgical technique. Historically, local excision procedures, particularly enucleation, were associated with the highest rates of failure, with local recurrence rates ranging from 20% to 45% (1 3). However, with the introduction of parotidectomy with facial nerve preservation, these rates have decreased substantially, with more contemporary series reporting local recurrences in 1% to 5% of patients (4 6). Regardless of its actual incidence, recurrent pleomorphic adenoma represents a distinct therapeutic challenge for clinicians. Although a local recurrence can almost always be treated with further surgery, the rate of developing an additional recurrence has been reported to vary between 30% and 50% (7 9). Moreover, it has been established that the probability of subsequent recurrence Reprint requests to: Allen M. Chen, M.D., Department of Radiation Oncology, UCSF Comprehensive Cancer Center, 1600 Divisadero Street, San Francisco, CA Tel: (415) ; Fax (415) ; achen@radonc17. increases with each recurrent episode, thus making local control increasingly difficult and damage to the facial nerve more likely (10 12). Last, the potential for malignant transformation must be considered, with some series reporting an incidence of carcinoma ex-pleomorphic adenoma as high as 9% with each local recurrence (12 14). Despite these concerns, the role of postoperative radiation therapy in the management of recurrent pleomorphic adenoma is controversial. Whereas some studies have reported enhanced local control with postoperative radiation therapy compared with historic controls treated with surgery alone, others have shown no significant improvement in outcome (15 17). There is also reluctance to administer postoperative radiation therapy because of concerns regarding the possibility of developing radiation-induced malignancies in patients who often present at a fairly young age for a benign process (18). Although the use of routine postoperative radiation therapy for recurrent pleomorphic adenoma has never been definitively recommended at the University of California San Francisco (UCSF), we have ucsf.edu Received May 22, 2006, and in revised form June 15, Accepted for publication June 16,

2 1032 I. J. Radiation Oncology Biology Physics Volume 66, Number 4, 2006 been offering postoperative radiation therapy to select cases based largely on individual patient characteristics and physician preference. The purpose of this study is to review the long-term clinical outcome of patients treated with surgery and postoperative radiation therapy for recurrent pleomorphic adenoma focusing on local control and the incidence of late toxicity, including the development of second malignancies. METHODS AND MATERIALS Retrospective review of all patient medical records and formal approval from the appropriate Institutional Review Boards was obtained before the collection. Between January 1960 and December 2002, 42 consecutive patients were referred to the Department of Radiation Oncology at UCSF for histologically proven recurrent pleomorphic adenoma of the parotid gland. Six patients who had recurrences in association with carcinoma ex-pleomorphic adenoma and 2 patients with inadequate follow-up were excluded from this analysis. The remaining 34 patients, all of whom were treated with postoperative radiation therapy for recurrent pleomorphic adenoma, comprised the primary study population. The median age at the time of radiation treatment was 48 years (range, years). Twenty-one patients (62%) were female. Postoperative radiation therapy was administered for a first local recurrence in 8 patients (24%), second local recurrence in 7 patients (21%), third local recurrence in 8 patients (24%), fourth local recurrence in 8 patients (24%), fifth local recurrence in 2 patients (6%), and sixth local recurrence in 1 patient (3%). The primary surgical procedure at the time of initial diagnosis varied depending on both the time period of treatment and the preference of the treating surgeon and consisted of total parotidectomy in 8 patients (24%), subtotal parotidectomy in 13 patients (38%), local excision or enucleation in 5 patients (15%), and was unknown in 8 patients (24%). The median time interval between the time of initial diagnosis and the commencement of postoperative radiation therapy was 9.4 years (range, years). The operative procedure for recurrent disease was performed at UCSF in 20 patients (59%) and at an outside facility for the remaining 14 patients (41%). The type of salvage surgery was determined at the discretion of the surgeon and varied based on the extent and location of the recurrence, as well as the type of surgical procedure performed initially. In general, recurrences after enucleation and local excision were more likely treated by parotidectomy, and recurrences after parotidectomy were treated by local excision. The surgery consisted of total parotidectomy with preservation of the facial nerve in 14 patients (41%), total parotidectomy with sacrifice of the facial nerve in 5 patients (15%), superficial parotidectomy in 4 patients (12%), and local excision in 11 patients (32%). Intraoperative identification of the facial nerve as it exited the stylomastoid foramen was accomplished whenever possible in all cases. Facial nerve sacrifice was required if direct infiltration of the nerve by tumor was evident and accompanied by immediate reconstruction with nerve grafting. Computed tomography was performed in 19 patients (56%) and magnetic resonance imaging was performed in 4 patients (12%) before surgery. Gross total resection at the time of salvage surgery before radiation therapy was achieved in 30 of 34 patients (88%), with intraoperative tumor spill reported in an additional 2 patients (6%). Final pathologic analysis demonstrated positive microscopic margins in 12 patients (35%). Median pathologic tumor size was 2.6 cm (range, cm). Tumor recurrence was lateral to the facial nerve in 23 patients, medial to the nerve in 6, and unspecified in 5. Multifocal recurrence was observed on histologic analysis in 16 patients (47%), with the largest nodule in these patients ranging from 0.2 cm to 5.0 cm (median 1.5 cm). The decision to offer postoperative radiation therapy was typically made by the treating radiation oncologist in conjunction with the head-and-neck surgeon. Postoperative radiation therapy was delivered to the ipsilateral parotid bed with megavoltage equipment using photons or mixed photons and electrons. The technique varied largely depending on the time of treatment, extent of disease, and discretion of the radiation oncologist. The treatment volume was designed to cover the entire parotid bed with 2- to 3-cm margins. In general, this was defined as the area bounded superiorly by the zygomatic arch; anteriorly by the masseter muscle, lateral pterygoid muscle, and mandibular ramus; posteriorly by the mastoid process; and inferiorly by the posterior belly of the digastric muscle. A wedged-pair technique incorporating ipsilateral anterior and posterior oblique beams was used in 19 patients (56%), and a mixed-beam technique using a combination of photons and electrons was used in the remaining 15 patients (44%). For patients treated with wedged-pair fields, beams were obliqued slightly to avoid anterior divergence into the oral cavity and contralateral orbits. For patients treated with a mixed-beam technique, relative weighting and electron energy was selected based on individual patient anatomy. The prescription point was determined by evaluating the depth to the pharyngeal wall. Wedges or tissue compensators were used to maintain dose homogeneity within 10% of the prescribed dose. Bolus was routinely placed over the surgical scar. No patient was treated with intensity-modulated radiation therapy (IMRT) or interstitial radiation. Treatment was by continuous-course radiation with once-a-day treatment. The median radiation dose was 5000 cgy (range, ) and was chosen at the discretion of the treating radiation oncologist. All patients were treated with conventional fractionation, and fraction size was 180 cgy in 13 patients (38%) and 200 cgy in 21 patients (62%). No patient had regional lymph node treatment. The median time interval from date of most recent surgery to the start of postoperative radiation therapy was 30 days (range, days). All patients completed the planned course of treatment. The median elapsed time of radiation therapy was 40 days (range, days). The primary endpoint measured was local control. All events were measured from the last day of radiation therapy. The median follow-up duration was 17.4 years (range, years). Follow-up consisted of routine physical examination and appropriate imaging studies of the parotid bed. Patients were typically seen at three-month intervals for 1 year and then annually thereafter. Patient follow-up was reported to the date last seen in clinic. In some cases, referring physicians were contacted to obtain information regarding patient health status. Toxicity was assessed retrospectively using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer normal tissue toxicity criteria (19). No attempt was made to retrospectively assess facial nerve function because it was felt that this could only be assessed prospectively. The actuarial rates of local control were calculated by the Kaplan-Meier method (20). RESULTS Local control Two patients had a subsequent local recurrence after completion of postoperative radiation therapy. These 2 pa-

3 Recurrent pleomorphic adenoma of the parotid gland A. M. CHEN et al tients were treated with postoperative radiation therapy (5000 cgy) for their third and fourth local recurrence, respectively, and both later recurred in the parotid bed deep to the facial nerve. The primary indications for postoperative radiation were multinodular disease and positive microscopic margins, respectively. Neither patient received radiation therapy for gross residual disease. The 2 local recurrences were detected clinically at 1.2 and 5.3 years, respectively, after completing radiation therapy. Both were subsequently treated with further local excision and were disease free at last follow-up. Pathology was consistent with locally recurrent disease without evidence of malignant transformation. Notably, 1 patient required sacrifice of the facial nerve at that time secondary to tumor infiltration and fibrosis. Figure 1 illustrates local control for the patients treated with postoperative radiation therapy for recurrent pleomorphic adenoma. The 20-year actuarial local control rate was 94%. Table 1 demonstrates local control according to tumor size at the time of presentation for treatment of recurrent disease. Table 1. Local control according to tumor size at presentation for recurrent disease Size of recurrence (cm) Recurrence # MN UK Total First 0/0 1/1 2/2 5/5 0/0 8/8 Second 0/0 1/1 1/1 4/4 1/1 7/7 Third 1/1 2/2 1/1 2/3 1/1 7/8 Fourth 2/2 2/2 0/1 3/3 0/0 7/8 Fifth 0/0 1/1 0/0 1/1 0/0 2/2 Sixth 1/1 0/0 0/0 0/0 0/0 1/1 Abbreviations: cm centimeter; MN multinodular; UK unknown. Toxicity The most common acute reaction was related to skin toxicity with 34 of 34 (100%) patients experiencing erythema with or without desquamation. Dermal changes were managed successfully with conservative wound care and generally resolved after completion of radiation therapy in all cases. No patients had Grade 3 or higher skin toxicity. Although 21 of 31 patients (67%) complained of varying degrees of xerostomia during the course of radiation therapy, all patients had complete recovery of subjective salivary function after completion of treatment. One patient (3%) had transient trismus immediately after completion of radiation therapy, which was at the time believed to be related more to surgical fibrosis than to radiation effect. With respect to late toxicity, no patients developed clinically evident hearing loss, chronic otitis media, vestibular dysfunction, or bone necrosis. At last follow-up, 11 of the 34 patients (32%) were reportedly on thyroid replacement for chemical or clinical evidence of hypothyroidism. Second malignancies One patient developed a second malignancy after completion of radiation therapy. This patient was diagnosed with pleomorphic adenoma at the age of 31 and treated initially with local excision alone. Approximately 3 years later, she experienced a local recurrence, which was treated with subtotal parotidectomy with facial nerve preservation. She was referred for postoperative radiation because of multiple positive margins and received a total dose of 5000 cgy. Approximately 14 years after completion of radiation therapy, she presented with an enlarging mass in the treated parotid region, which was proved to be lowgrade mucoepidermoid carcinoma on biopsy. She was treated with surgical resection consisting of a total parotidectomy with facial nerve preservation and remained clinically without evidence of disease 3 years later. There were no reported cases of radiation-induced sarcomas among the patients treated. Fig. 1. Local control of all patients treated with postoperative radiation therapy for recurrent pleomorphic adenoma. DISCUSSION Pleomorphic adenoma, the most common type of salivary gland tumor, has historically been of interest because of its propensity for local recurrence and its potential for malignant transformation, especially after inadequate surgery. Although the primary treatment of pleomorphic adenoma typically consists of surgical resection alone, the management of recurrent disease is less clearly defined, and the role of postoperative radiation therapy in this setting remains controversial not only because of concerns regarding efficacy, but also because of questions related to treatmentrelated morbidity. The 94% local control rate observed in the present study with a median follow-up in excess of 17 years is particularly encouraging in light of the fact that most of the patients included in this series were believed to be at relatively high risk for further recurrences. For example, more than three-

4 1034 I. J. Radiation Oncology Biology Physics Volume 66, Number 4, 2006 quarters of our patients were treated for their second or greater recurrence. In comparison, Fee et al. reported local control rates of 65% for first recurrences and only 29% for second recurrences among patients treated by surgery alone (21). Similarly, Glas et al. reported local control rates of 85% for first recurrences and 50% for second recurrences among patients treated by surgery alone (1). Indeed, the high rate of re-recurrence after surgery alone for recurrent pleomorphic adenoma is what has prompted some authors to recommend adjuvant radiation therapy in this setting to select patients (22 24). Although the literature reporting on the management of recurrent pleomorphic adenoma is limited to small, singleinstitutional series, it is possible to draw some generalized conclusions based on the retrospective data available. Table 2 summarizes reported outcomes in the literature. Although some of the observed discrepancies in outcome can be attributed to selection bias as well as differences in surgical approach and follow-up duration, it is noteworthy that studies in which patients received postoperative radiation therapy generally demonstrated the highest rates of local control. Similar to our results, Gleave et al. reported a local control rate of 95% among 42 patients treated with surgery followed by postoperative radiation therapy for recurrent pleomorphic adenoma (8). Douglas et al. also reported a 15-year actuarial local control rate of 85% among 16 patients, 10 with evidence of gross residual disease after surgery, treated with fast neutron radiation therapy at the University of Washington for recurrent pleomorphic adenoma (25). Renehan et al. analyzed 170 patients treated for recurrent pleomorphic adenoma at the Christie Hospital and reported a local control rate of 92% for those who received postoperative radiation compared with 76% for those who were treated by surgery alone (26). More recently, Carew Table 2. Selected studies: treatment of recurrent pleomorphic adenoma Study (reference) n Modality LC (%) TTF (y) FU (y) Carew et al. (27) 31 S/SR * Phillips and Olsen (12) 126 S Yugueros et al. (23) 39 S/SR Douglas et al. (25) 16 SR * Glas et al. (1) 52 S 85 NA 9.0* Renehan et al. (26) 114 S/SR * Fee et al. (21) 26 S NA Gleave et al. (8) 42 SR 95 NA NA Niparko et al. (22) 48 S Dawson (16) 28 SR 79 NA 8.5 Leonetti et al. (24) 42 S Zbaren et al. (13) 33 S Chen et al. (UCSF) 34 SR * Abbreviations: n number of patients; S surgery alone; SR surgery with postoperative radiation; LC local control; TTF time to failure; FU follow-up; yrs years. * Median. Mean. et al. analyzed 31 patients, and reported 10-year local control rates of 100% and 71%, respectively, among patients treated with and without postoperative radiation therapy at Memorial Sloan-Kettering Cancer Center (27). Notably, the importance of adequate follow-up cannot be overstated. While Zbaren et al. reported a local control rate of 82% among 33 patients treated with surgery alone for recurrent pleomorphic adenoma, this number decreased to 55% when the analysis was limited to patients with minimum follow-up of 10 years (13). Despite these studies that strongly suggest that postoperative radiation improves local control compared with surgery alone in the management of recurrent pleomorphic adenoma, there is reluctance to recommend adjuvant treatment largely because of concerns regarding complications, particularly the induction of second malignancies. To our knowledge, the data examining this issue exists only in the form of isolated case reports and anecdotal evidence (28 30). Armour et al. reported 2 patients who developed temporal bone necrosis and another who developed brainstem necrosis after completion of parotid radiation for benign disease (28). With respect to second malignancies, Dawson and Orr reported 1 patient who developed a radiation-induced sarcoma 14 years after treatment for primary pleomorphic adenoma (31). Gleave et al. also reported a fibrosarcoma occurring within the irradiated field 15 years after treatment of a recurrent pleomorphic adenoma (8). Although the present study is admittedly limited by small patient size, the results are nonetheless reassuring for patients who are treated with radiation therapy for recurrent pleomorphic adenoma. Others have similarly demonstrated that the xerostomia that occurs after unilateral irradiation is temporary with serial salivary flow measurements showing full recovery in the vast majority of patients 1 and 2 years after treatment (32). A limitation of this study was that we were unable to formally analyze how radiation therapy may have affected auditory function. Although none of the patients in our study developed clinical symptoms associated with hearing loss, reports by others using audiometry indicate that sensorineural hearing deficits can occur after parotid irradiation (33). Notably, studies have shown that IMRT has the potential to reduce the dose to radiosensitive organs, including the cochlea, semicircular canals, and vestibulo-cochlea nerve (34). Similarly, we were unable to retrospectively analyze how radiation therapy may have affected facial nerve function. Prior studies assessing this issue, however, have shown that the incidence of radiationinduced facial nerve palsy is extremely low (35). In contrast, facial nerve injury rates after re-operations for recurrent pleomorphic adenoma have been reported to range from 15% to 30% as a result of the presence of scar tissue, with distortion of anatomy from previous surgical manipulation (12). The results of the present series demonstrate that surgery followed by postoperative radiation therapy leads to excellent long-term local control for the treatment of recurrent

5 Recurrent pleomorphic adenoma of the parotid gland A. M. CHEN et al pleomorphic adenoma of the parotid gland. As importantly, the observed incidence of late toxicity, particularly the development of second malignancies, was acceptably low. Despite our encouraging results, these findings must be interpreted with caution largely because this histology is remarkably slow growing, and recurrences have been reported to occur as late as 30 years after diagnosis (13). Furthermore, data analyzing radiation-induced head and neck cancers have suggested that the latency period for the development of second malignancies is believed to be in excess of 30 years (36). Therefore, long-term follow-up and continued surveillance among this group of patients is imperative. Based on our experience, we conclude that it is reasonable to consider the judicious use of postoperative radiation therapy for essentially all patients with recurrent pleomorphic adenoma of the parotid gland. REFERENCES 1. 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