ORIGINAL ARTICLE RECURRENT SALIVARY GLAND CARCINOMAS TREATED BY SURGERY WITH OR WITHOUT INTRAOPERATIVE RADIATION THERAPY

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1 ORIGINAL ARTICLE RECURRENT SALIVARY GLAND CARCINOMAS TREATED BY SURGERY WITH OR WITHOUT INTRAOPERATIVE RADIATION THERAPY Allen M. Chen, MD, 1 Joaquin Garcia, MD, 2 M. Kara Bucci, MD, 3 Albert S. Chan, RTT, CMD, 1 Michael J. Kaplan, MD, 4 Mark I. Singer, MD, 5 Theodore L. Phillips, MD 1 * 1 Department of Radiation Oncology, Head and Neck Surgery, University of California, San Francisco (UCSF) Comprehensive Cancer Center, San Francisco, California allenmchen@yahoo.com 2 Department of Pathology, Head and Neck Surgery, University of California, San Francisco (UCSF) Comprehensive Cancer Center, San Francisco, California 3 Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 4 Department of Otolaryngology, Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 5 Department of Otolaryngology, Head and Neck Surgery, University of California, San Francisco (UCSF) Comprehensive Cancer Center, San Francisco, California Accepted 19 February 2007 Published online 7 September 2007 in Wiley InterScience ( DOI: /hed Abstract: Background. The optimal treatment for patients with locally recurrent carcinomas of the salivary glands is unclear. Methods. Ninety-nine patients underwent salvage surgery for locally recurrent salivary gland carcinomas. Eighty-one (82%) had previously received radiation. Thirty-seven patients (37%) received intraoperative radiation therapy (IORT) to a median dose of 15 Gy (range, Gy) at the time of salvage. Results. The 1-, 3-, and 5-year estimates of local control after salvage surgery were 88%, 75%, and 69%, respectively. A Cox proportional hazard model identified positive margins (0.01) and the omission of IORT (p ¼.001) as independent predictors of local failure. The 5-year overall survival was 34%. Distant metastasis was the most common site of subsequent failure, occurring in 42% of patients. Correspondence to: A. M. Chen * Theodore L. Phillips, M.D. is a member of the board of directors for Intraop Corporation, Santa Clara, California. VC 2007 Wiley Periodicals, Inc. Conclusions. IORT significantly improves disease control for patients with locally recurrent carcinomas of the salivary glands. The high rate of distant metastasis emphasizes the need for effective systemic therapies. VC 2007 Wiley Periodicals, Inc. Head Neck 30: 2 9, 2008 Keywords: carcinoma; recurrent; salivary gland; surgery; intraoperative radiation Although relatively uncommon, carcinomas of the salivary glands represent a diverse spectrum of tumors with biologic behavior dependent on such factors as histology, disease site, and stage. Following definitive treatment consisting typically of surgical resection with or without postoperative radiation therapy, local recurrences occur in approximately 10% to 25% of patients. 1 3 However, the prognosis of patients with recurrent salivary gland cancer is poor, largely because 2 Recurrent Salivary Gland Carcinomas HEAD & NECK DOI /hed January 2008

2 effective salvage treatment is often limited by the infiltrative pattern of local growth as well as the proximity of the recurrent tumor to critical structures in the head and neck. Since a large proportion of these patients have previously received radiation therapy, the potential for severe complications often deters the delivery of additional radiation using standard external beam techniques. 4 While surgery has historically formed the mainstay of salvage therapy at our institution, intraoperative radiation therapy (IORT) was instituted beginning in 1991 in an effort to improve disease control after local recurrence. The purpose of this study was to review our experience with the management of recurrent salivary gland carcinomas by surgery with or without IORT, in an attempt to analyze clinical and disease characteristics correlative of outcome. MATERIALS AND METHODS Patient Population. This study was approved by the Institutional Review Board at the University of California, San Francisco (UCSF) School of Medicine prior to the retrospective review of patient information. Between January 1960 and December 2004, 125 patients were treated at UCSF for locally recurrent salivary gland carcinoma. The following patients were excluded from the analysis: 9 patients treated with radiation therapy alone; 6 patients with gross residual disease after subtotal resection; 4 patients treated for a second or third local recurrence; 4 patients who received interstitial brachytherapy; and 3 patients with metastatic disease at the time of local recurrence. The remaining 99 patients who had gross total resection at the time of salvage surgery for histologically proven recurrent salivary gland carcinoma made up the primary population of this study. Median age was 59 years (range, years). Preoperative evaluation prior to salvage therapy included patient history, physical examination, and basic bloodwork. Axial imaging with CT of the head and neck has routinely been performed, since it was first available at UCSF in Thirty-one patients (31%) had additional imaging with MRI. All patients had been previously treated with definitive surgery for their initial disease, with 81 patients (82%) receiving postoperative radiation at that time. No definite policy existed regarding the use of postoperative radiation therapy in the initial management of salivary gland cancers, but in general, patients were referred for radiation therapy at the clinical judgment of the treating surgeon when there was uncertainty about the completeness or adequacy of the excision based on intraoperative and pathologic findings. Radiation technique varied, depending largely on the site of disease, the time period of treatment, and the discretion of the radiation oncologist. All patients were treated with megavoltage equipment using photons or mixed photons and electrons. The treatment volume was designed to cover the primary site with 2- to 3-cm margins. None of the patients received interstitial or IORT. Median dose was 60 Gy (range, Gy). Treatment was by continuous-course radiation, with once-a-day treatment with conventional fractionation at either 2 Gy (51 patients) or 1.8 Gy (30 patients) per fraction. Treatment. The median time interval from the date of initial surgery to local recurrence was 3.1 years (range, years). All patients were treated with salvage surgery. The type of procedure was dependent on the disease site, tumor extent, cosmetic considerations, and the discretion of the surgeon. Thirty-seven patients (37%) received IORT at the time of salvage surgery. Details of our experience with IORT have previously been described. 5 In brief, the IORT treatment cone was chosen, so that it included the operative bed with 1 to 2 cm of margin of normal tissue. Median dose was 15 Gy (range, Gy) and was prescribed to the 90% isodose line to encompass the area at risk for microscopic disease. Electron energy was chosen on the basis of the thickness of the tumor bed, taking into consideration underlying critical structures. Fourteen patients (14%), 5 of whom received IORT, underwent postsalvage external-beam radiation therapy to a median dose of 54 Gy (range, Gy). Nine patients (9%) received adjuvant chemotherapy. Treatment of the neck was dependent on multiple factors. Eight patients (8%) seen with palpable cervical lymphadenopathy at the time of local recurrence underwent neck dissection, with pathology confirming lymph node metastasis. Two of these patients, neither of whom had previously received radiation, were treated with postsalvage radiation. Elective node dissection of the clinically negative neck was performed in 12 patients (12%). Three of these patients had evidence of occult nodal disease on pathologic examination. None of these patients were treated with postsalvage radiation. Recurrent Salivary Gland Carcinomas HEAD & NECK DOI /hed January

3 Follow-up consisted of routine physical examination and imaging studies of the head and neck. Patients were typically seen at 3-month intervals for 1 year and then annually thereafter. Patient follow-up was reported to the date last seen in clinic. Survival status was obtained from information provided by the UCSF Tumor Registry and from publicly accessible databases using patient social security numbers. In some cases, referring physicians were contacted to obtain information regarding patient health status. Endpoints and Statistical Analysis. The endpoints analyzed were local control, overall survival, and disease-free survival. All events were measured from the date of salvage surgery. Median follow-up was 3.7 years (range, years). One-, 3-, and 5-year estimates of the probability of local control, overall survival, and disease-free survival were calculated using the Kaplan Meier method, with comparisons among groups performed with 2-sided log-rank tests. 6 A Cox proportional hazards model was used to identify independent predictors of disease recurrence. 7 Selection of variables to consider as predictors was based upon univariate analysis. A stepwise forward method was carried out, and the likelihood ratio test was used to identify significant independent predictors of outcome. Hazard ratio parameters were determined using the Wald test. All tests were 2-tailed, with a probability value of less than 0.05 considered statistically significant. Table 1. Patient characteristics. Characteristic No. of patients (%) Sex Male 63 (64) Female 36 (36) Ethnicity White 71 (72) Black 9 (9) Hispanic 8 (8) Asian 8 (8) Other 3 (3) Primary site Parotid glands 34 (34) Oral cavity 20 (20) Paranasal sinuses 12 (12) Submandibular glands 11 (11) Oropharynx 8 (8) Other 14 (14) Recurrent tumor size, cm (28) (41) >4 30 (30) Decade of treatment 1960s 10 (10) 1970s 18 (18) 1980s 17 (17) 1990s 34 (34) 2000s 20 (20) Abbreviations: IORT, intraoperative radiation therapy; EBRT, externalbeam radiation therapy. Disease Characteristics. Table 1 illustrates clinical and treatment characteristics for the patients at the time of salvage surgery. In all patients, histology was consistent with the known primary cancer. Histological subtypes included mucoepidermoid carcinoma (28 patients), adenocarcinoma (23 patients), adenoid cystic carcinoma (23 patients), malignant mixed tumor (9 patients), squamous cell carcinoma (5 patients), undifferentiated carcinoma (4 patients), acinic cell carcinoma (3 patients), salivary duct carcinoma (2 patients), and myoepithelial carcinoma (2 patients). The median size of the recurrent tumor at the time of pathologic analysis was 3.9 cm (range, cm). Final surgical margins were microscopically positive in 69 patients (70%) and negative in 30 patients (30%). Perineural invasion was present in the pathology specimen at salvage surgery for 81 patients (82%). Sixty-one patients (62%) and 42 patients (42%) had pathologic evidence of muscle and bony involvement, respectively. RESULTS Local Control. Thirty-two patients experienced a subsequent recurrence at the operative site after completion of salvage surgery, 15 of which were isolated first events that occurred in the absence of disease development elsewhere. The median time to second local recurrence was 1.3 years (range, years), with 6 patients having a recurrence more than 5 years after the time of salvage treatment. For the entire patient population, the 1-, 3- and 5-year estimates of local control were 88%, 75%, and 69%, respectively. Table 2 summarizes local control after salvage surgery according to patient and disease characteristics at the time of salvage surgery. On univariate analysis, parameters predictive of local recurrence were positive microscopic margins, pathologic tumor size greater than 4 cm, and the omission of IORT (p <.05, for all). A Cox proportional hazard model identified positive micro- 4 Recurrent Salivary Gland Carcinomas HEAD & NECK DOI /hed January 2008

4 Table 2. Local control after salvage by clinical and disease characteristics. Factor No. of failures 5-y local control, % p value Recurrent tumor size, cm of of >4 13 of Margin status 0.01 Negative 5 of Positive 27 of Perineural invasion 0.19 No 4 of Yes 28 of Muscle invasion 0.22 No 10 of Yes 22 of Bone invasion 0.11 No 16 of Yes 16 of Primary site 0.37 Major salivary gland 13 of Minor salivary gland 19 of IORT at salvage surgery No 26 of Yes 6 of Initial surgery to LR, years 0.40 <3 years 19 of >3 years 13 of Initial treatment modality 0.51 Surgery alone 6 of Surgery and EBRT 26 of EBRT after salvage surgery 0.34 No 28 of Yes 4 of Abbreviations: IORT, intraoperative radiation therapy; LR, local recurrence; EBRT, external-beam radiation therapy. scopic margins and the omission of IORT as significant independent predictors of local recurrence (LRR test: p ¼.01 and p ¼.001, respectively). Hazard ratios for local recurrence among those treated with positive margins and without IORT were 2.70 (95% confidence interval [CI], ) and 3.89 (95% CI, ), respectively. Twenty-seven of 69 patients with positive margins experienced a local recurrence compared with 5 of 30 with negative margins. As illustrated in Figure 1, the corresponding 5-year estimates of local control were 63% and 77%, respectively. Figure 2 demonstrates local control according to the use of IORT. Six of 37 patients treated with IORT experienced a local recurrence compared with 26 of 32 treated without IORT. The corresponding 5-year estimates of local control were 82% and 60%, respectively. The schematic in Figure 3 illustrates the crude rates of local recurrence after salvage therapy FIGURE 1. Local control for entire patient population according to surgical margins status. [Color figure can be viewed in the online issue, which is available at according to both initial treatment modality (surgery alone vs surgery and postoperative radiation therapy) and subsequent salvage therapy (surgery with or without either IORT or externalbeam radiation therapy). Overall Survival. Forty-six patients were alive at the time of this analysis. As illustrated in Figure 4, overall survival for the entire patient population at 1, 3, and 5 years was 83%,54%, and 34%, respectively. None of the patient or disease characteristics analyzed predicted for overall survival, with the exception of histology. Patients with locally recurrent adenoid cystic carcinoma FIGURE 2. Local control for entire patient population according to the use or omission of intraoperative radiation therapy (IORT). [Color figure can be viewed in the online issue, which is available at Recurrent Salivary Gland Carcinomas HEAD & NECK DOI /hed January

5 FIGURE 3. Crude rates of local recurrence according to initial and salvage treatment modalities. [Color figure can be viewed in the online issue, which is available at had a 5-year overall survival of 67% compared with 24% for those with other histological subtypes (p ¼.01). Disease-Free Survival. The most common pattern of disease relapse was distant metastasis, which developed at a median of 2.0 years (range, years) from the time of salvage therapy for locally recurrent disease. Forty-two patients developed distant disease after salvage surgery for locally recurrent salivary carcinomas. Distant metastasis was the first site of relapse in 34 of these patients. The remaining 8 patients developed distant disease subsequent to disease failure at the primary site after salvage surgery. Initial sites of distant metastasis included: lung (32 patients), bone (7 patients), liver (2 patients), and brain (1 patient). Ten patients developed regional failures, 2 of which were isolated first events. The remaining 8 occurred simultaneously or subsequent to the development of distant metastasis. Disease-free survival at 1, 3, and 5 years was 69%, 57%, and 46%, respectively. The only parameter predictive of disease-free survival was the use of IORT. The 5-year estimates of diseasefree survival for patients treated with and without IORT were 61% and 44%, respectively (p ¼.02). Complications. The incidence and severity of complications were assessed for patients treated with salvage surgery and IORT. There were no perioperative fatalities. Two patients had superficial wound infections without tissue breakdown, requiring intravenous antibiotics during the immediate postoperative period. An additional patient, treated with an IORT dose of 15 Gy for recurrent mucoepidermoid carcinoma of the parotid gland initially managed with surgery alone, developed trismus 4 months after completion of IORT that resolved over the course of 1 year with occupational therapy. Last, 1 patient, treated with an IORT dose of 15 Gy for adenoid cystic carcinoma of the submandibular gland, initially FIGURE 4. Overall survival for the entire patient population. [Color figure can be viewed in the online issue, which is available at 6 Recurrent Salivary Gland Carcinomas HEAD & NECK DOI /hed January 2008

6 managed with surgery and postoperative radiation to a dose of 64 Gy, developed sudden-onset facial pain secondary to neuropathy at approximately 1 month after salvage treatment. This patient s symptom was managed medically with narcotics and gradually resolved over the course of 2 years. No patients developed clinical evidence of osteoradionecrosis, bone fracture, orocutaneous fistula, brain necrosis, or carotid artery hemorrhage. DISCUSSION Despite advances in surgical techniques and reconstructive techniques, as well as the increasing use of adjuvant radiation therapy, a significant proportion of patients experience local recurrence after definitive therapy for salivary gland carcinomas. Although these patients are at high risk for the subsequent development of distant metastasis, local disease progression is also a considerable cause of morbidity and mortality. Honk et al 8 demonstrated that up to 60% of patients with locally recurrent head and neck cancer will die as a direct consequence of uncontrolled tumor growth at the primary site. The results of the present study, representing the largest series to date reporting on clinical outcome after salvage surgery for locally recurrent salivary gland carcinomas, demonstrate that the addition of IORT results in significantly improved local control and disease-free survival compared with resection alone. These findings are encouraging because, as expected, a large proportion of our patient population was seen with features that have traditionally been considered adverse. Despite the fact that 70% of patients had positive microscopic margins, 82% had perineural invasion, and 62% had muscle involvement at the time of salvage treatment in the present series, acceptable rates of local control were ultimately obtained, particularly with the integration of IORT. In comparison, Armstrong et al 9 reported a local control rate of 49% among 40 patients treated by surgery without IORT at Memorial Sloan-Kettering Cancer Center for locally recurrent salivary gland carcinomas with high risk features such as positive/close margins, high-grade histology, and lymph node metastasis. While the literature reporting on the management of recurrent salivary gland carcinomas is limited to small, single-institutional series, it is possible to draw some generalized conclusions based on the retrospective data available However, the specific surgical criteria for salvage of recurrent head and neck cancer differs widely both between and among institutions, with the proportion of patients eligible for salvage surgery ranging from 34% to 75% Although some of the observed discrepancies can be largely attributed to selection bias, it is noteworthy that studies that included IORT generally demonstrated better outcomes with respect to disease control. Freeman et al 16 observed an 88% local control rate among 24 patients treated with surgery and IORT at Indiana University for locally recurrent salivary gland carcinomas, with a median follow-up time of 21 months. Pinheiro et al 17 reported a 2- year local control rate of 52% for 10 patients with locally advanced or recurrent nonsquamous cell carcinomas treated by surgery with IORT at the Mayo Clinic. In comparison, Guillamondegui et al 18 reported a local regional control rate of 42% among 12 patients treated without IORT for recurrent salivary gland cancer at The University of Texas M. D. Anderson Cancer Center. Raux- Rakotomalala et al 19 similarly showed that surgery alone resulted in local control in only 1 of 6 patients treated for recurrent adenoid cystic carcinomas in France. While Armstrong et al 9 reported a 5-year local control of 69% among 38 patients treated by surgery without IORT for local recurrences of low or intermediate histological grade, the presence of high-risk features reduced the local control rate to 49%. It appears that overall survival for patients with locally recurrent salivary gland carcinomas is limited by the high competing risk of developing distant metastasis, which occurred in 42% of patients in the present series. The observed difference in survival between patients with adenoid cystic carcinomas and those with nonadenoid cystic subtypes likely reflects the characteristically slow-growing nature of the former and discrepancies in the natural history of salivary gland histological subtypes rather than a greater sensitivity to treatment. Indeed, the possibility of survival in excess of 10 years after the development of metastatic disease from adenoid cystic carcinoma has been well established Although it is currently not possible to delineate which specific patients will have long-term survival after developing distant metastasis from salivary gland cancer, the use of molecular markers holds promise in potentially improving prognostic stratification, thus clarifying who may derive the most benefit from aggressive local control. 23 At present, the unpredictable natural history of patients with salivary gland carcinomas, even among those with Recurrent Salivary Gland Carcinomas HEAD & NECK DOI /hed January

7 existing distant metastasis, underscores the paramount importance of maximizing local control while minimizing disease- and treatment-related toxicity. The use of brachytherapy as a component of salvage therapy for recurrent head and neck cancers has also yielded promising results. Puthawala et al 24 reported a local control of 77% among 220 patients treated with low-dose-rate iridium- 192 at the Long Beach Memorial Hospital. Hepel et al 25 reported a local control rate of 69% among 30 patients treated for locally recurrent disease at the same institution using a high-dose-rate technique with iodine-125. Notably, moderate-tosevere complications including necrosis, orocutaneous fistula, and carotid hemorrhage developed in 27% and 16% of the patients in these 2 series, respectively. Furthermore, since the overwhelming majority of the patients treated in these studies had head and neck recurrences of squamous cell histology, it remains uncertain whether these results can be similarly applied for recurrences of salivary gland histology. Similarly, salvage therapy using re-irradiation with external beam techniques is currently controversial. In a large study of 169 patients, De Crevoisier et al 4 demonstrated that full-dose reirradiation of head and neck sites resulted in unacceptably high rates of late toxicity, including mucosal necrosis in 21%, osteoradionecrosis in 8%, and 5 deaths due to carotid hemorrhage. While more sophisticated radiation techniques incorporating intensity-modulated radiation therapy (IMRT) has the theoretical potential to reduce treatment-related complications, some authors have expressed concerns regarding the large volume of normal tissue receiving low amounts of radiation as a result of the multiple beam angles and greater monitor units typically delivered with this technique The increased inhomogeneity associated with IMRT also could have adverse clinical consequences in the setting of re-irradiation. Although recently published preliminary data reporting on outcomes after re-irradiation using altered fractionation appears promising, it should be further recognized that the number of patients included with salivary gland cancers have generally been limited For instance, the recently completed phase II prospective trial (99-11) conducted by the Radiation Therapy Oncology Group analyzing split-course hyperfractionated re-irradiation with concurrent paclitaxel and cisplatin in the treatment of patients with locally recurrent head and neck cancers specifically excluded those with salivary gland histologies. The primary advantage of IORT is that normal tissue surrounding the tumor bed can be manually retracted and directly shielded. This visualization allows treatment with radiation even after prior delivery of full courses of radiation therapy. Although we did not analyze the incidence of treatment-related complications in the present series, others have demonstrated that IORT is well tolerated for the treatment of head and neck cancers and does not increase perioperative morbidity or mortality In conclusion, our results demonstrate that salvage surgery with IORT is a feasible strategy for the management of recurrent carcinomas of the salivary glands and results in effective disease control. With coordinated multidisciplinary care, IORT can be integrated in a combined-modality setting without undue toxicity. Based on this experience, our current policy is to recommend IORT for essentially all patients with locally recurrent salivary gland carcinomas treated by surgical resection. 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