Abstract
Background/Aim: This study aimed to assess the effect of adjuvant radiotherapy on locoregional control, disease-free survival, and overall survival rates in patients with major salivary gland malignancies. The study also aimed to provide findings to guide clinicians in selecting appropriate candidates for adjuvant radiotherapy and optimizing treatment strategies for this challenging disease. Patients and Methods: A retrospective single-center analysis was conducted, reviewing the medical records of patients diagnosed with major salivary gland malignancies between November 2008 and May 2023. Inclusion criteria were histologically confirmed malignancy, surgical resection of the primary tumor, adjuvant radiotherapy, and availability of clinical and follow-up data. Survival analyses were performed using the Kaplan-Meier method, and Cox proportional hazards regression models were used to assess survival outcomes. Results: The study included 37 patients with major salivary gland malignancies. The most common site was the parotid gland, and the predominant histopathological diagnosis was salivary duct carcinoma. Adjuvant radiotherapy was generally well-tolerated, with the most common acute toxicities being grade 1-2 mucositis and dermatitis. The 5-year overall survival and progression-free survival rates were 93.8% and 62.9%, respectively. Locoregional control rate at five years was 89.1%. Recurrence occurred in 12 patients, with most cases observed within two years from the start of adjuvant radiotherapy. Distant metastasis was observed in nine patients. Conclusion: This retrospective analysis highlights the positive impact of adjuvant radiotherapy on locoregional control and survival outcomes in major salivary gland malignancies. The findings contribute to the existing body of evidence, aiding clinicians in treatment decision-making and potentially informing future prospective studies and treatment guidelines for this challenging disease.
- Adjuvant radiotherapy
- salivary gland malignancies
- locoregional control
- disease-free survival
- overall survival
Major salivary gland malignancies are rare neoplasms, accounting for approximately 3-5% of all head and neck cancers (1). These malignancies pose significant diagnostic and therapeutic challenges owing to their diverse histological subtypes and anatomical complexities (2). While surgery is the key modality of treatment, adjuvant radiotherapy following surgical resection has been widely employed in the management of major salivary gland malignancies to improve local control and survival rates (3). However, the optimal use and effectiveness of adjuvant radiotherapy in this setting remains a subject of debate. The decision to administer adjuvant radiotherapy is multifactorial and is often influenced by various clinicopathological factors such as tumor size, histological subtype, margin status, and the presence of perineural invasion (4).
In this study, we assessed the effect of adjuvant radiotherapy on locoregional control, disease-free survival, and overall survival rates in patients with major salivary gland malignancies. The findings of this retrospective analysis may help guide clinicians in selecting appropriate candidates for adjuvant radiotherapy and optimizing treatment strategies for patients with major salivary gland malignancies. Additionally, it may contribute to the existing body of evidence, potentially informing future prospective studies and refining treatment guidelines for this challenging disease.
Patients and Methods
This retrospective single-center analysis was conducted to evaluate the efficacy of adjuvant radiotherapy for major salivary gland malignancies. Institutional Review Board approval was obtained prior to data collection. Medical records of patients diagnosed with major salivary gland malignancies and treated at the center between November 2008 and May 2023 were reviewed. Patients who met the following criteria were included in the study: (i) histologically confirmed major salivary gland malignancy, (ii) surgical resection of the primary tumor, (iii) adjuvant radiotherapy, and (iv) available clinical and follow-up data. Patients with incomplete medical records or those who had previously received radiotherapy were excluded.
All patients included in the study underwent surgical resection of the primary tumor. The surgical approach, extent of resection, and neck dissection were determined by the treating surgeon based on the individual patient characteristics. Adjuvant radiotherapy was administered to patients based on multidisciplinary tumor board recommendations and standard treatment protocols. Data on patient demographics, tumor characteristics, treatment details, and clinical outcomes were collected from medical records. Demographic variables included age, sex, and tumor characteristics such as histopathological diagnosis, tumor stage, and tumor site. Radiotherapy techniques included intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT). The dose and fractionation schedules were determined based on tumor characteristics, surgical margins, and individual patient factors. The target volume of radiotherapy covered the surgical bed and lymph node metastases, if existed. Prophylactic lymph node irradiation was adapted for locally advanced, high-grade histological, or positive lymph node metastases cases.
The main outcome measures were overall survival (OS) and progression-free survival (PFS). OS was defined as the time from the initial date of radiotherapy to death from any cause, and PFS was defined as the time from the initial date of radiotherapy to disease progression or death. Secondary outcome measures included locoregional control (LRC) and treatment-related toxicities. Survival analyses were performed using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Cox proportional hazards regression models were used to assess the association between various factors and survival outcomes after adjusting for potential confounders. Statistical significance was set at p<0.05.
Results
Overall, 37 patients with major salivary gland malignancies were included in this retrospective analysis. The patient cohort consisted of 25 men and 12 women, with a median age of 56 years (range:15-89 years) (Table I). The most common site of malignancy was the parotid gland (25 cases), followed by the submandibular (11 cases) and sublingual (1 case) glands. The most common pathological type of major salivary gland malignancy was salivary duct carcinoma (27%).
Patient background characteristics in the present study.
All adjuvant radiotherapy was performed at a standard fractionation of 2.0 Gy delivered once daily 5 days per week; most of the radiation treatment schemes were 60 Gy in 30 fractions (74%). Only one patient, classified as clinical stage IV, received concurrent chemotherapy with adjuvant radiotherapy, which is a triweekly regimen of cisplatin 100 mg/m2. The median interval between the initiation of surgery and adjuvant radiotherapy was 43 days (range:13-77 days). Prophylactic lymph node irradiation was undergone in 15 patients, consisting of 14 stage IV patients and one stage III patient.
The median follow-up period was 38.8 months. The 5-year OS and PFS in the entire cohort were 93.8% [95% confidence intervals (CI):77.3-98.4%] and 62.9% (95%CI:43.4-77.3%), respectively (Figure 1 and Figure 2). The locoregional control rate at 5 years was 89.1% (95%CI:69.0-96.5%), which indicates that patients who received adjuvant radiotherapy had a low risk of locoregional recurrence. Adjuvant radiotherapy was generally well-tolerated by the patients. The most common acute toxicities were grade 1-2 mucositis in 35 patients, followed by dermatitis in 34 patients. Late toxicities of grade 1-2 xerostomia were confirmed in 9 patients. Grade 3 adverse events were only observed in one patient, who experienced a grade 3 tasting disorder as an acute-phase toxicity.
Kaplan-Meier curves for overall survival in patients who underwent adjuvant radiotherapy.
Kaplan-Meier curves for progression-free survival in patients who underwent adjuvant radiotherapy.
Twelve patients were diagnosed with recurrence after postoperative adjuvant radiotherapy. The median time to first recurrence was 7.7 months (range:0.7-28.8 months). Eleven patients (91.6%) experienced recurrence within 2 years from the date of initiation of adjuvant radiotherapy. Three patients exhibited locoregional relapse; two of these were salvaged by surgery, and the remaining one chose best supportive care (BSC). Overall, 9 patients experienced distant metastasis (4 in the lung, 2 in the bone, 1 in the liver, 1 in the brain, and 1 in the orbit). Of these, 6 patients received systemic therapy, 2 were treated by stereotactic radiotherapy, and 1 chose BSC.
Discussion
In this retrospective analysis of major salivary gland malignancies, the addition of adjuvant radiotherapy following surgical resection significantly improved local control rates and overall survival. The role of adjuvant radiotherapy in the management of major salivary gland malignancies has been extensively investigated. A national cancer database analysis off 8,243 patients conducted by Bakst et al. reported that the use of adjuvant radiation therapy for salivary gland cancer patients with high-risk features improved overall survival (hazard ratio:0.76, 95%CI:0.64-0.91, p=0.002) (5). However, the definition of “high-risk” is controversial. Hong et al. reported that adjuvant radiation therapy was not associated with improved locoregional recurrence or disease-free survival rates in patients with early-stage salivary gland carcinoma (SGC), even those with malignant histological features (6). In contrast, Park et al. recommended adjuvant radiation therapy for patients having node-negative parotid gland cancer with high-grade histology to improve local disease control and survival rates (7).
However, the use of concurrent chemotherapy with adjuvant radiotherapy postoperatively in patients with SGC remains controversial. Kang et al. reported that concurrent chemotherapy provided limited survival benefits for patients with advanced major SGCs after surgical resection according to results of the Taiwan Cancer Registry database analysis (8). Gebhardt et al. also reported that concurrent chemoradiotherapy as an adjuvant treatment for high-risk salivary gland malignancies did not improve survival (9). Tanvetyanon et al. reported that the overall survival in the chemoradiation group was significantly better than that in the radiation alone group for locally advanced or high-grade SGCs (10). The clinical significance of concurrent chemotherapy with adjuvant radiotherapy for high-risk SGCs is currently under investigation (NCT01272037) (11).
In terms of specific histological subtypes, adenoid cystic carcinoma is well known for its aggressive behavior and high risk of perineural invasion and distant metastasis (12). Lee et al. conducted a study focusing on major salivary adenoid cystic carcinoma and reported improved outcomes after adjuvant radiotherapy (13). The study included 1784 patients who underwent surgery for salivary gland malignancies, and the addition of adjuvant radiation therapy was associated with improved 5-year survival rates (82.4 % vs. 72.5%, p<0.001) compared to surgery alone. Secretory carcinoma is a recently described malignant histological subtype characterized by the ETV6-NTRK3 gene rearrangement (14). We identified one case of secretory carcinoma in our cohort who was screened by immunohistochemistry to be positive for pan-TRK (15) and had an ETV6-NTRK3 gene fusion confirmed by reverse transcription-polymerase chain reaction.
It is important to consider the appropriate radiation dose for adjuvant radiotherapy. According to recently published practical guidelines for the management of salivary gland malignancy by the American Society of Clinical Oncology, at least 60 Gy should be delivered to high-risk targets with conventional fractionations (16). In the present study, 33 of 37 patients (89%) received radiotherapy of ≥60 Gy. Four patients who received <60 Gy of radiation therapy showed a trend toward poor 5-year PFS compared to those who received ≥60 Gy (37.5% vs. 65.6%, p=0.447).
This study has several limitations. First, its retrospective design may have introduced selection bias and confounding factors. Second, the study was conducted at a single center, which limits the generalizability of its findings. Third, the sample size may not have been large enough to detect rare complications or perform certain subgroup analyses.
In conclusion, our analysis revealed favorable clinical outcomes for locoregional control, disease-free survival, and overall survival in patients receiving adjuvant radiotherapy for major salivary gland malignancies. Adjuvant radiotherapy should be considered as an integral component of multidisciplinary treatment approaches. However, careful consideration of radiation techniques and potential toxicities is necessary to optimize treatment outcomes and patient quality of life. Further research is needed to address the limitations of the existing studies and establish standardized protocols regarding adjuvant radiotherapy for major salivary gland malignancies.
Footnotes
Authors’ Contributions
AK and HY equally contributed to the collection and analysis of data, drafting, and revising the manuscript, and read and approved the final article.
Conflicts of Interest
The Authors declare that they have no competing interests.
- Received July 6, 2023.
- Revision received August 2, 2023.
- Accepted August 3, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).