SALIVARY GLAND TUMORS TREATED WITH ADJUVANT INTENSITY-MODULATED RADIOTHERAPY WITH OR WITHOUT CONCURRENT CHEMOTHERAPY

doi:10.1016/j.ijrobp.2010.09.042 Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 1, pp. 308 314, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter CLINICAL INVESTIGATION Head and Neck Cancer SALIVARY GLAND TUMORS TREATED WITH ADJUVANT INTENSITY-MODULATED RADIOTHERAPY WITH OR WITHOUT CONCURRENT CHEMOTHERAPY JONATHAN D. SCHOENFELD, M.D.,* DAVID J. SHER, M.D., M.P.H., y CHARLES M. NORRIS, JR., M.D., z ROBERT I. HADDAD, M.D., x{ MARSHALL R. POSNER, M.D., x{ TRACY A. BALBONI, M.D., M.P.H., y AND ROY B. TISHLER, M.D., PH.D. y *Department of Radiation Oncology, Harvard Radiation Oncology Program, Boston, MA; y Department of Radiation Oncology, Dana- Farber Cancer Institute and Brigham and Women s Hospital, Boston, MA; z Department of Surgery, Division of Otolaryngology, Brigham and Women s Hospital, Boston, MA; x Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and { Department of Medicine, Brigham and Women s Hospital, Boston, MA Purpose: To analyze the recent single-institution experience of patients with salivary gland tumors who had undergone adjuvant intensity-modulated radiotherapy (IMRT), with or without concurrent chemotherapy. Patients and Methods: We performed a retrospective analysis of 35 salivary gland carcinoma patients treated primarily at the Dana-Farber Cancer Institute between 2005 and 2010 with surgery and adjuvant IMRT. The primary endpoints were local control, progression-free survival, and overall survival. The secondary endpoints were acute and chronic toxicity. The median follow-up was 2.3 years (interquartile range, 1.2 2.8) among the surviving patients. Results: The histologic types included adenoid cystic carcinoma in 15 (43%), mucoepidermoid carcinoma in 6 (17%), adenocarcinoma in 3 (9%), acinic cell carcinoma in 3 (9%), and other in 8 (23%). The primary sites were the parotid gland in 17 (49%), submandibular glands in 6 (17%), tongue in 4 (11%), palate in 4 (11%), and other in 4 (11%). The median radiation dose was 66 Gy, and 22 patients (63%) received CRT. The most common chemotherapy regimen was carboplatin and paclitaxel (n = 14, 64%). A trend was seen for patients undergoing CRT to have more adverse prognostic factors, including Stage T3-T4 disease (CRT, n = 12, 55% vs. n = 4, 31%, p =.29), nodal positivity (CRT, n = 8, 36% vs. n = 1, 8%, p =.10), and positive margins (n = 13, 59% vs. n = 5, 38%, p =.30). One patient who had undergone CRT developed an in-field recurrence, resulting in an overall actuarial 3- year local control rate of 92%. Five patients (14%) developed distant metastases (1 who had undergone IMRT only and 4 who had undergone CRT). Acute Grade 3 mucositis, esophagitis, and dermatitis occurred in 8%, 8%, and 8% (1 each) of IMRT patients and in 18%, 5%, and 14% (4, 1, and 3 patients) of the CRT group, respectively. No acute Grade 4 toxicity occurred. The most common late toxicity was Grade 1 xerostomia (n = 8, 23%). Conclusions: Treatment of salivary gland malignancies with postoperative IMRT was well tolerated with a high rate of local control. Chemoradiotherapy resulted in excellent local control in a subgroup of patients with adverse prognostic factors and might be warranted in select patients. Ó 2012 Elsevier Inc. Chemoradiotherapy, Salivary gland cancers, Intensity-modulated radiotherapy, Adenoid cystic carcinoma, Mucoepidermoid carcinoma. INTRODUCTION Salivary gland cancers are uncommon malignancies, occurring in approximately 1 in 100,000 people (1). When feasible, the standard initial therapy is surgical resection. Adjuvant radiotherapy (RT) is often delivered in the presence of adverse pathologic features (2 5). However, despite bimodality therapy for aggressive disease, local failure rates have still approached 20% and distant metastases have been frequent for certain histologic types and prognostic features (5, 6). During the past 15 years, the two most significant advances in nonoperative head-and-neck cancer treatment have been concurrent chemotherapy and intensity-modulated RT (IMRT). The former treatment paradigm has significantly increased the local control and overall survival rates for squamous cell cancers of the head and neck, and the latter technology has improved the late complication rates after RT (7 12). Nevertheless, the prospective data supporting these approaches have not included studies of salivary gland malignancies, and data suggesting these approaches improve the treatment outcomes are sparse (13, 14). Reprint requests to: Jonathan D. Schoenfeld, M.D., Department of Radiation Oncology, Harvard Radiation Oncology Program, 75 Francis St., Boston, MA 02114. Tel: (617) 632-3591; Fax: (617) 632-4247; E-mail: jdschoenfeld@partners.org 308 Conflict of interest: none. Received Aug 14, 2010, and in revised form Sept 15, 2010. Accepted for publication Sept 20, 2010.

Adjuvant IMRT for salivary gland cancers d J. D. SCHOENFELD et al. 309 Given the known local control benefit of chemoradiotherapy for squamous cell malignancies, we have been treating high-risk salivary gland cancer patients with adjuvant chemoradiotherapy. Furthermore, since 2004, patients receiving radical dose head-and-neck RT have routinely undergone IMRT to reduce the dose to the neighboring normal tissue structures. We report our results for patients treated at Dana-Farber Cancer Institute with adjuvant IMRT, with and without concurrent chemotherapy (CRT). PATIENTS AND METHODS Patients The eligible patients had been diagnosed with malignant salivary gland tumors and had undergone primary surgical resection, followed by IMRT at the Dana-Farber Cancer Institute between August 2004 and October 2009. All patients had undergone adjuvant RT at the Dana-Farber Cancer Institute; however, some surgical procedures had been performed outside of our institution. A formal pathology review was performed for all patients. The data were reviewed under an institutional review board-approved retrospective protocol. Evaluation All patients were initially evaluated by a multimodality treatment team consisting of an otolaryngologist, a medical oncologist, and a radiation oncologist. A detailed physical examination was performed for all patients. Histologic confirmation of malignancy was required before beginning treatment. All patients were evaluated before treatment with computed tomography, and most had also undergone either positron emission tomography or magnetic resonance imaging. Treatment All patients underwent initial primary surgical management. Adjuvant RT was delivered in all cases using IMRT, with or without CRT. During RT simulation and treatment, the patients were immobilized using an S-frame, which secures the shoulders, in addition to securing the head and neck. The patients were first imaged under fluoroscopy to ensure accurate isocenter placement and mask construction and then underwent simulation in the mask using highresolution (2.5-mm slices) computed tomography. Eclipse IMRT software (Varian Medical Systems, Palo Alto, CA) was used for treatment planning for all patients. Toxicity Acute and late toxicity was defined according to the National Cancer Center Institute Common Terminology Criteria for Adverse Events, version 4.0, and determined by retrospective chart review. Acute toxicity was defined as occurring within 90 days of treatment completion. A complication that occurred during treatment that persisted after 90 days was also considered late toxicity. Follow-up The patients were typically followed every 4 6 weeks in the first year and every 2 3 months in the second year by the multimodality treatment team at our institution. Occasionally, some follow-up was done locally near the patient s home. Lesions suspicious for recurrence were biopsied. Statistical analysis Overall survival and progression-free survival were calculated according to the Kaplan-Meier method from the date of the histologic diagnosis. Progression-free survival was defined as disease progression or death from any cause. Fisher s exact test was used to compare the baseline characteristics and toxicities between patients treated with and without CRT. Statistical Analysis Systems software (SAS Institute, Cary, NC) was used for all analyses. RESULTS Patient characteristics and disease presentation A total of 35 patients were identified who met the entry criteria. The initial patient and disease characteristics for this cohort are listed in Table 1. The median age at diagnosis was 59 years (interquartile range [IQR] 49 66). Of the 35 patients, 16 (46%) were men. The most common histologic types were adenoid cystic carcinoma in 15 (43%) and mucoepidermoid carcinoma in 6 patients (17%). A trend was seen for patients who underwent CRT to have more adverse prognostic pathologic features. Patients undergoing CRT were more likely to have Stage T3-T4 disease (CRT, n = 12, 55% vs. n = 4, 31%, p =.29), nodal positivity (CRT, n =8, 36% vs. n = 1, 8%, p =.10), positive margins (CRT, n = 13, 59% vs. n = 5, 38%, p =.30), and lymphovascular invasion (n = 7, 32% vs. n = 2, 15%, p =.43). Treatment characteristics The adjuvant treatment details are listed in Table 2. Of the 35 patients, 13 (37%) underwent adjuvant RT alone and 22 (63%) adjuvant CRT. The median interval between surgery and the initiation of adjuvant therapy was 45 days (IQR, 39 58). The most common chemotherapy regimen used was carboplatin and paclitaxel (n = 14, 64%), a regimen for which we had significant previous institutional experience owing to its previous use as a radiosensitizer in definitive cases. Some patients whose tumor stained positive for Her2/Neu on immunohistochemistry and/or fluorescence in situ hybridization (15) were treated with trastuzumab combined with chemotherapy. All patients underwent IMRT to a median dose of 66 Gy (IQR, 60 66). Figure 1 highlights a representative IMRT plan for a 46-year-old patient who underwent RT alone for a Stage T2N0 mucoepidermoid carcinoma. Patients undergoing RT alone were treated to a median dose of 60 Gy, and those undergoing CRT were treated to a median dose of 66 Gy. Only 2 patients received <60 Gy (46 and 59 Gy), 1 of whom stopped treatment early because of poor compliance. Neither patient had developed local or distant failure at >3 years of follow-up. The skull base was treated in 69% of patients (n = 24). The neck was irradiated in 20 patients (57%), 3 (23%) in the RT alone group and 17 (77%) in the CRT group. Three patients in the CRT group received bilateral neck treatment; all other neck treatments were unilateral. Two patients received adjuvant chemotherapy after CRT, one with trastuzumab, carboplatin, and paclitaxel and one with trastuzumab alone.

310 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 Table 1. Patient and disease characteristics Table 2. Treatment details Characteristic Overall (n = 35) RT (n = 13) CRT (n = 22) p Variable Overall (n = 35) RT (n = 13) CRT (n = 22) Age at diagnosis (y).24 Median 59 67 59 IQR 49 66 53 78 48 62 Gender.08 Male 16 3 13 Female 19 10 9 Performance status.71 0 31 (89) 11 (85) 20 (91) 1 3 (9) 1 (8) 2 (9) 2 0 0 0 3 1 (3) 1 (8) 0 Histologic type.68 Adenoid cystic 15 (43) 6 (46) 9 (41) Mucoepidermoid 6 (17) 3 (23) 3 (14) Adenocarcinoma 3 (9) 2 (15) 1 (5) Acinic cell 3 (9) 2 (15) 1 (5) Other 8 (23) 0 8 (37) Subsite.50 Parotid 17 (49) 7 (54) 10 (45) Submandibular 6 (17) 2 (15) 4 (18) Tongue 4 (11) 1 (8) 3 (14) Palate 4 (11) 3 (23) 1 (5) Other 4 (11) 0 4 (18) T stage.14 0 1 (3) 0 1 (5) 1 8 (23) 4 (31) 4 (18) 2 7 (20) 3 (23) 4 (18) 3 10 (29) 1 (8) 9 (41) 4 6 (17) 3 (23) 3 (14) Recurrent 2 (6) 2 (15) 0 Unknown 1 (3) 0 1 (5) N stage.17 0 25 (71) 11 (85) 14 (64) 1 3 (9) 0 3 (14) 2 6 (17) 1 (8) 5 (23) Unknown 1 (3) 1 (8) 0 Margin.30 Grossly positive 3 (9) 1 (8) 2 (9) Microscopically positive 15 (43) 4 (31) 11 (50) Negative 17 (49) 8 (62) 9 (41) Bone involvement 3 (9) 1 (8) 2 (9) 1.00 Perineural invasion 23 (66) 8 (62) 15 (68).73 Lymphovascular invasion 9 (26) 2 (15) 7 (32).52 Major nerve involvement 6 (17) 3 (23) 3 (14).78 Extracapsular extension 5 (14) 2 (15) 3 (14) 1.00 Abbreviations: RT = radiotherapy; CRT = chemoradiotherapy; IQR = interquartile. Data presented as numbers, with percentages in parentheses, unless otherwise noted. Recurrence and survival The crude survival outcomes are listed in Table 3. The median follow-up for the surviving patients after diagnosis was 2.3 years (IQR, 1.2 2.8). One patient in the CRT group with a Stage T3 adenoid cystic carcinoma of the paranasal sinus with extensive maxillary bone invasion, lymphovascular and perineural invasion, and positive margins after surgery developed local failure 2.5 years after diagnosis and was salvaged with surgical resection. No other patients developed local failure after adjuvant RT or CRT, for an overall 3-year locoregional progression-free survival rate of 92% for all patients. Chemotherapy Carboplatin/Taxol 14 (64) Carboplatin 6 (27) Carboplatin/Taxol/trastuzumab 2 (9) Cisplatin 4 (18) Chemotherapy duration (wk) <6 4 (18) 6 10 (45) 7 6 (27) Unknown 2 (9) Interval from surgery to RT (d) Median 45 42 46 IQR 39 58 36 51 40 60 Radiation dose (Gy) Median 66 60 66 IQR 60 66 60 66 64 66 Skull base RT 24 (69) 9 (69) 15 (68) Neck RT 20 (57) 3 (23) 17 (77) Unilateral 17 3 14 Bilateral 3 0 3 Data presented as numbers, with percentages in parentheses, unless otherwise noted. Five patients (14%) developed distant metastases, 1 after adjuvant RT and 4 after CRT. In retrospect, 1 of these patients likely had had metastatic disease at the initial presentation. In the remaining patients, distant failure occurred 0.8, 1.1, 2.5, and 3.1 years after the initial diagnosis. The 3-year distant metastasis-free survival rate was 83% for all patients. The cumulative incidence curves of locoregional recurrence and distant metastasis are shown in Fig. 2. No patient died of disease during follow-up, although 1 patient died of a cardiac event. The 3-year actuarial overall and progression-free survival rate was 97% and 73%, respectively. Acute and late toxicity The acute locoregional toxicities resulting from treatment are listed in Table 4. There was no acute Grade 4 or 5 toxicity. Mucositis, dermatitis, and esophagitis of any grade were the most common toxicities, occurring in most patients (34 [97%], 33 [94%], and 26 [74%] patients, respectively). Grade 3 mucositis, dermatitis, and esophagitis occurred in 5 (14%), 4 (11%), and 2 (6%) patients, respectively. Grade 1-2 toxicity of the ear occurred in 8 patients (23%). Patients who received adjuvant CRT had more severe acute mucositis, with 19 (86%) experiencing Grade 2-3 toxicity compared with 4 (30%) of those in the RT-alone group (p =.006). Also, a trend was seen for patients receiving CRT to experience more severe acute dermatitis, with 16 (73%) experiencing Grade 2-3 toxicity compared with 5 (38%) of those who had undergone adjuvant RT alone (p =.059). The late toxicities are listed in Table 5. The most common late toxicity was Grade 1 xerostomia, occurring in 8 patients (23%). One Grade 4 late toxicity (osteonecrosis) developed

Adjuvant IMRT for salivary gland cancers d J. D. SCHOENFELD et al. 311 Fig. 1. Example of intensity-modulated radiotherapy plan for 46-year-old woman diagnosed with Stage T2N0, left, parotid, low-grade mucoepidermoid carcinoma. No perineural invasion was found, but the tumor was within 1 mm of the surgical margin, and two major divisions of the facial nerve were splayed by the mass, requiring dissection of all its major branches. Given these pathologic and intraoperative findings, the patient was treated with adjuvant radiotherapy to the parotid bed. Contours were developed using preoperative imaging findings and in situ contralateral parotid as a guide to contour a dummy structure representing the removed parotid gland and tumor. This structure was expanded by 1 1.5 cm into the surrounding soft tissue to create the clinical target volume (CTV). The expansion was reduced at the natural barriers to tumor extension (e.g., bone) and expanded in areas at greater risk of residual disease (e.g., medially, near deep lobe). Planning target volume (PTV) was created by uniformly expanding the CTV by 5 mm. The PTV was prescribed to 60 Gy in 30 fractions. Avoidance structures included the oral cavity (mean dose, 26.8 Gy), contralateral parotid and submandibular glands (mean doses, 6.4 and 3.6 Gy, respectively), cochlea (mean and maximal dose, 20.6 and 30.5 Gy, respectively), and spinal cord (maximal dose, 14 Gy). The maximal hot spot was 105.3%, which was within the PTV. (A) Example axial slice representing method for contouring target and avoidance structures. Representative (B) axial, (C) coronal, and (D) sagittal slices with dose distributions. in 1 patient who had undergone adjuvant RT for a recurrent parotid tumor. This patient had previously undergone RT in 2000. No patients died of late treatment-related effects. No differences were seen in the rates or severity of late toxicity between the two groups. DISCUSSION The present study described our recent experience in treating salivary gland cancer patients with IMRT in the adjuvant setting, many of whom received CRT. The patients who underwent combined modality treatment tended to have more adverse prognostic features, including a greater T stage, nodal positivity, positive margins, and lymphovascular invasion, all factors that have been identified in retrospective series as portending a worse outcome (4, 16, 17). Combined modality treatment was well tolerated, although a modest expected increase in acute toxicity rates occurred, most notably in Grade 2 and 3 mucositis and dermatitis. No acute Grade 4 or 5 toxicity developed, and no discernable increase was seen in the rate of late toxicity.

312 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 Outcome Table 3. Crude survival outcomes Overall (n = 35) RT (n = 13) CRT (n = 22) Local failure 1 (3) 0 1 (5) Distant failure 5 (14) 1 (7) 4 (18) Any progression 5 (14) 1 (7) 4 (18) Cancer-specific mortality 0 0 0 Overall mortality 1 (3) 1 (7) 0 Follow-up (y) Median 2.3 1.7 2.4 IQR 1.1 2.8 1.1 2.4 1.3 2.9 With a selective approach using adjuvant CRT for poorer prognostic disease, we were able to achieve excellent rates of local control for patients with multiple unfavorable disease characteristics, with only 1 patient (with positive margins, bone invasion, lymphovascular invasion, and perineural invasion) developing local failure. Also, no patient had developed regional failure at a median follow-up of >2 years. Although this duration of follow-up was somewhat limited, given that local recurrence after adjuvant RT has been observed years after the initial therapy (3, 16, 17, 25), recurrences often develop earlier and more frequently in patients with adverse pathologic features. Furthermore, in contrast to the minimal rate of local failure, 14% of the patients developed metastatic disease. Distant failures were more frequent in the patients who had undergone CRT, as would be expected from the relatively worse prognostic features of their disease. However, even in the setting of metastatic disease, the importance of maintaining local control was underscored by the lack of disease-specific mortality in any of our patients. The data that guide the adjuvant treatment of patients with salivary gland malignancies are limited, in large part because of the rarity of these tumors. RT has been evaluated in several retrospective analyses of patients with adverse prognostic features with promising results (2, 5, 17). Specifically, Armstrong et al. (2) at Memorial Sloan- Kettering Cancer Center performed a matched-pair analysis Fig. 2. Cumulative incidence of locoregional failure and distant metastasis. Table 4. Acute toxicity during treatment Toxicity Overall (n = 35) RT (n = 13) CRT (n = 22) p Mucositis.006 Grade 1 11 (31) 8 (62) 3 (14) Grade 2 18 (51) 3 (23) 15 (68) Grade 3 5 (14) 1 (8) 4 (18) Dermatitis.059 Grade 1 12 (34) 8 (62) 4 (18) Grade 2 17 (49) 4 (31) 13 (59) Grade 3 4 (11) 1 (8) 3 (14) Esophagitis.594 Grade 1 11 (31) 5 (38) 6 (27) Grade 2 13 (37) 3 (23) 10 (45) Grade 3 2 (6) 1 (8) 1 (5) Ear.349 Grade 1 6 (17) 1 (8) 5 (23) Grade 2 2 (6) 0 2 (9) Other 1.0 Grade 1 1 (3) 0 1 (5) Grade 2 2 (3) 0 2 (9) Data presented as numbers, with percentages in parentheses. of 92 patients treated for salivary gland cancer and reported that adjuvant RT improved the 5-year disease-specific survival for those with Stage T3 and T4 disease from 10% without RT to 51% with RT. Adjuvant RT also improved the 5- year local control rate from 17% to 51% and improved the local control rates for patients with nodal disease (40% without RT to 69% with RT). Similarly, Terhaard et al. (5) demonstrated an increased 10-year local control rate in patients with Stage T3-T4 tumors, close or positive margins, bone invasion, or perineural invasion with adjuvant RT. The difference in local control (84% vs. 18%) after adjuvant RT was particularly striking in patients with Stage T3-T4 tumors. Both of these studies suggested a significant benefit to adjuvant treatment in patients at the greatest risk of relapse, although neither evaluated the use of adjuvant CRT. Table 5. Late toxicity after treatment Toxicity Overall (n = 35) RT (n = 13) CRT (n = 22) p Xerostomia.680 Grade 1 8 (23) 2 (15) 6 (27) Dysphagia 1.0 Grade 1 2 (6) 1 (7) 1 (5) Grade 2 1 (3) 0 1 (5) Dermatitis.347 Grade 1 6 (17) 3 (23) 3 (14) Grade 2 1 (3) 1 (7) 0 Ear.886 Grade 1 5 (14) 2 (15) 3 (14) Grade 2 2 (6) 0 2 (9) Grade 3 1 (3) 0 1 (5) Other.824 Grade 1 3 (9) 1 (7) 2 (9) Grade 2 1 (3) 0 1 (5) Grade 3 0 0 0 Grade 4 1 (3) 1 (7) 0 Data presented as numbers, with percentages in parentheses.

Adjuvant IMRT for salivary gland cancers d J. D. SCHOENFELD et al. 313 The benefit of CRT in head-and-neck squamous cell carcinoma has been established by multiple randomized controlled studies. The European Organization for the Research and Treatment of Cancer study 22931 demonstrated an increase in local control and progression-free and overall survival with the addition of bolus cisplatin to adjuvant external beam RT (7). Similarly, the Radiation Therapy Oncology Group 95-01/Intergroup study demonstrated a similar benefit in locoregional and disease-free survival with the addition of concurrent chemotherapy to adjuvant RT, although an overall survival benefit was not demonstrated (8). One small retrospective review evaluated the potential use of adjuvant CRT in 12 patients with major salivary gland carcinoma and suggested a potential benefit in 3-year overall survival compared with matched controls, although no difference was found in locoregional control (14). Also, the CRT group was more likely to have received IMRT (14). A retrospective review of 5 patients with adenoid cystic carcinoma treated with definitive CRT with carboplatin and paclitaxel without surgical resection reported no local failures at a median follow-up of 36 months (18). The retrospective nature of our analysis, the heterogeneity of tumor histologic types and subsites, and relatively shortterm follow-up have limited the conclusions that can be drawn from these data. However, the relatively low incidence of salivary gland cancers has precluded large randomized analyses or prospective trials of homogenous patient populations. Previously published experiences have often included patients treated during a span of decades, including wide variations in surgical and RT techniques. In contrast, the present study examined patients treated within a relatively short period of approximately 5 years, all of whom had undergone IMRT. An increased incidence of acute toxicity can be expected with CRT; however, the use of IMRT might have helped to improve the tolerability of the combined modality adjuvant treatment. Although the results from the present study have suggested a potential role for CRT for salivary gland malignancies, the most efficacious regimen and criteria for selecting which patients would derive the most benefit from combined modality treatment remain to be elucidated. A number of different chemotherapeutic agents have demonstrated activity against salivary gland malignancies, including cisplatin, 5-fluorouracil, Adriamycin, cyclophosphamide, herceptin, carboplatin, paclitaxel, and vinorelbine (19 24). Surgery remains the mainstay in the treatment of salivary gland cancer. 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