Comparison of postoperative radiotherapy and definitive radiotherapy for non-metastatic adenoid cystic carcinoma of the head and neck, a propensity score matching based on the SEER database

Introduction

Head and neck adenoid cystic carcinoma (HNACC) occurs predominantly in the salivary glands. It accounts for fewer than 1% of head and neck cancers and around 25% of all salivary gland cancers (1). The term adenoid cystic carcinoma (ACC) is derived from the tumor’s unique cystic form and adenoidal differentiation, which tends to be highly invasive and locally infiltrative (2).

The treatment for ACC is typically customized based on the tumor’s location and stage, with surgical intervention being the primary approach. However, the 10-year survival rate for systematically treated HNACC patients is only 50% (3), owing to treatment failure caused by local recurrence and, more commonly, metastasis (4).

The complex anatomical position of head and neck tumors often leads to suboptimal surgical outcomes when head and neck malignancies are treated locally. For instance, ACC at the base of the skull is typically detected in advanced stages, making effective resection challenging. Currently, the local therapeutic approach for HNACC involves a combination of surgical treatment and radiation therapy (5). However, some patients may not be suitable candidates for surgery or may refuse it. In such cases, radiation is the only local treatment option, and its therapeutic effectiveness warrants additional exploration.

Swain et al. conducted a retrospective review of 23 patients with locally advanced HNACC who received definitive concurrent chemoradiotherapy from 2011 to 2018. The study revealed 3- and 5-year overall survival (OS) rates of 78% and 79.7%, respectively, along with locoregional recurrence-free survival (LRRFS) rates of 67.4% and 63% (6). In another study, the outcomes of definitive radiation for 20 HNACC patients were compared with postoperative radiotherapy for 24 patients with HNACC. The findings showed comparable rates of local control (LC) and 5-year OS between the two groups, at 85.3% vs. 79.7% and 82.5% vs. 83.1%, respectively (7). However, it is essential to emphasize that the comparison’s validity is questionable due to the small sample sizes of these trials and the poor data matching between definitive radiation and postoperative radiotherapy groups.

Due to a lack of large patient cohorts for retrospective or prospective studies, and in order to objectively determine the benefits and risks of definitive radiotherapy, we used the Surveillance, Epidemiology, and End Results (SEER) project to evaluate the effect of definitive radiotherapy on the survival of patients with HNACC. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1221/rc).

Methods

Patient search

To identify eligible patients, we conducted a search using the SEER database (version 8.4.1.2), which is accessible online at http://www.seer.cancer.gov/seerstat. We extracted all cases of radiation therapy administered to patients diagnosed with HNACC between 2000 and 2023 from a total of 17 registries. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It is worth noting that the local ethics committee disregarded the need for informed consent and ethical clearance in this study because the SEER data is publicly available and anonymised.

Inclusion criteria for the study comprised the following: (I) confirmed cases of ACC as determined by histology. (II) Patients who had received radiation therapy as part of their treatment. The following cases were excluded from the study: (I) cases with incomplete staging information. (II) Cases with primary carcinoma in situ (TIS) or no tumor (T0). (III) Cases with T stage TX (unassessable primary tumor). (IV) Patients with undetermined M stage (M stage NA), unassessable distant metastasis (M stage MX), or confirmed distant metastasis (M stage M1). (V) Cases with uncertain racial information. (VI) Patients that were not head and neck cancers. Two treatment groups were identified for analysis: (I) postoperative radiotherapy group. (II) Definitive radiation group.

Statistical analysis

We used Fisher’s exact probability tests and Chi-squared test to investigate connections between qualitative data. To achieve the study’s objectives of identifying risk factors impacting disease-specific survival (DSS) and OS, we conducted univariate and multivariate Cox regression analyses. OS was defined as the duration between the diagnosis and death from any cause, while DSS was defined as the duration between the diagnosis and death due to ACC. Both OS and DSS were considered as primary outcomes. To address significant differences in baseline variables and reduce inherent selection bias between patients in the postoperative radiotherapy and definitive radiotherapy groups, we conducted a propensity score matching (PSM) analysis. The analysis was performed using the psmatch2 program in STATA 17.0. In this study, the definitive radiotherapy group served as the control group. Postoperative radiotherapy patients were matched to control group patients based on their closest propensity scores. Nearest neighbor matching was applied, focusing on variables expected to influence outcomes, including age, gender, year of diagnosis, tumor site, race, T stage, N stage, tumor grade, tumor size, and chemotherapy. Survival rates were calculated using the Kaplan-Meier method, and the log-rank test was employed to compare the survival curves. All data analyses were carried out using the SPSS software package (version 25.0, IBM Corporation, Armonk, NY, USA), and P values less than 0.05 were considered statistically significant.

Results

Patient characteristics

After conducting a search in the SEER database, we collected data on 1,889 patients with HNACC who underwent postoperative radiotherapy and 183 patients who received definitive radiotherapy. Prior to performing PSM, there were notable disparities between the two groups concerning age, marital status, T stage, N stage, tumor stage, tumor site, and chemotherapy. Subsequently, we executed PSM, resulting in a one-to-one match between the two groups. In the matched samples, the significant differences in median age, marital status, N stage, and tumor size between the two groups were no longer evident. In addition, improvements were observed in other factors influencing tumor survival, including T stage, tumor stage, tumor site, and chemotherapy. Although these variables did not reach statistical significance, the distribution of patients between the two groups became more similar after matching. Detailed data are presented in Table 1.

The effects of radiotherapy on the survival of HNACC patients

The comparison of the 3- and 5-year cumulative OS and DSS rates between the postoperative radiotherapy and definitive radiotherapy groups yielded the following results: before performing the PSM, the 3- and 5-year cumulative OS rates were 83% and 75%, respectively, in the postoperative radiotherapy group, and 58% and 37%, respectively, in the definitive radiotherapy group. As for DSS, the 3- and 5-year cumulative DSS rates in the postoperative radiotherapy group were 87% and 82%, respectively, while in the definitive radiotherapy group, they were 65% and 46%, respectively. Statistical analysis indicated significant differences in both OS and DSS between the two groups [P<0.001, hazard ratio (HR) =2.895 and P<0.001, HR =4.083], with lower survival rates observed in the definitive radiotherapy group (Figure 1). After conducting PSM, the 3- and 5-year cumulative OS rates in the postoperative radiotherapy group were 63% and 55%, respectively, while in the definitive radiotherapy group, they were 71% and 65%, respectively. Although the difference between the two groups decreased after matching, there were still significant differences (P=0.001, HR =1.531 and P<0.001, HR =1.821). Nevertheless, the trend improved after matching (Figure 1). Additionally, univariate analysis revealed significant differences in both OS and DSS [P<0.001; HR =0.266; 95% confidence interval (CI): 0.218–0.326] and (P<0.001; HR =0.236; 95% CI: 0.188–0.298). We proceeded to compare all matched cases of locally advanced T4. The results indicated a significant difference in OS (P=0.007; HR =1.517; 95% CI: 1.105–2.084). However, the previously observed difference in DSS between the two groups no longer remained significant (P=0.42; HR =0.8659; 95% CI: 0.6028–1.244) (Figure 2).

Figure 1 Overview of Kaplan-Meier survival curves for OS and DSS, comparing postoperative radiotherapy and definitive radiotherapy for head and neck adenoid cystic carcinoma. (A) Kaplan-Meier survival curve for OS before PSM. (B) Kaplan-Meier survival curve for DSS before PSM. (C) Kaplan-Meier survival curve for OS after PSM. (D) Kaplan-Meier survival curve for DSS after PSM. OS, overall survival; HR, hazard ratio; CI, confidence interval; DSS, disease-specific survival; PSM, propensity score matching.

Figure 2 Overview of Kaplan-Meier survival curves for OS and DSS in T4 head and neck adenoid cystic carcinoma subgroup comparing postoperative radiotherapy and definitive radiotherapy. (A) Kaplan-Meier survival curve for OS (B) Kaplan-Meier survival curve for DSS. OS, overall survival; HR, hazard ratio; CI, confidence interval; DSS, disease-specific survival.

Risk factors for OS and DSS

In terms of the OS, the univariate analysis revealed that the T stage (P<0.001, HR =1.424), N stage (P<0.001, HR =1.211), tumor stage (P<0.001, HR =1.404), and chemotherapy (P<0.001, HR =1.983) were significantly associated with a higher risk of patient survival. Out of all tumor sites, only primary HNACC in the larynx showed a significant negative prognostic correlation with both OS (P=0.01, HR =40.49) and DSS (P=0.007, HR =51.565). Furthermore, in the multivariate analysis, along with T stage, N stage, tumor stage, and chemotherapy, tumor size (P<0.001, HR =1.311) also exhibited a significant risk in predicting patient survival (Table 2). Moreover, tumor size emerged as an important predictor in predicting patient survival. Regarding DSS, both the univariate and multivariate analyses yielded similar results as for OS. T stage, N stage, tumor stage, and chemotherapy continued to be significantly associated with a higher risk of survival. Notably, in the multivariate analysis, chemotherapy displayed a more pronounced risk (P<0.001, HR =1.163) (Table 3). These outcomes emphasize the close relationship between DSS and disease stage and chemotherapy, with chemotherapy being particularly impactful on patient survival.

Discussion

Our findings underscore significant distinctions between definitive radiotherapy and postoperative radiotherapy for the treatment of HNACC, both in terms of OS and DSS. An investigation comparing outcomes between surgical and non-surgical treatments for patients with HNACC T4b revealed that, despite a high positive margin rate of 78.7%, the 3-year OS rate was significantly higher in the surgically treated group (84% vs. 70%; P=0.05). Furthermore, surgical treatment demonstrated an association with superior survival (P=0.005, HR =0.47) (8). Another recent study on HNACC and distant metastases exhibited that primary tumor surgery outperformed non-surgical approaches, yielding significantly improved OS (43.0 vs. 16.0 months, P<0.001) and DSS (64.0 vs. 22.0 months, P=0.001) (9). This suggests that primary tumor surgery maintains its potential to enhance OS even in cases of distant metastases. Moreover, the condition of surgical margins significantly impacts patient survival outcomes. Several studies have supported this finding. One study examined the correlation between margin status and survival in HNACC patients. Multivariate analyses involving 507 patients found that positive margins were associated with worse OS and DSS (10). Another analysis of 192 HNACC patients found that multivariate analysis identified pN2 status and favorable surgical margins as independent prognostic factors for both OS and DFS (11). However, due to the lack of detailed information on the extent of surgical resection and margin status, our conclusions remain based on more general data. Nonetheless, the available studies and our results suggest that surgery can offer significant benefits regardless of tumor location, stage, or the completeness of resection. This information may be particularly helpful for patients who are reluctant or hesitant to undergo surgery. Additionally, positive postoperative margins can be addressed with postoperative radiotherapy. Research indicates that postoperative radiotherapy improves survival in patients with positive margins. For example, a trial involving HNACC at the skull base showed promising results, with 5- and 10-year LC rates of 88.2%, despite a high prevalence of positive margins (81.3%) after surgery (12). Similarly, in patients with tracheal and main bronchial ACC, postoperative radiotherapy significantly reduced local recurrence rates, especially in cases with positive margins (13). Therefore, surgery combined with postoperative radiotherapy appears to be a complementary and effective treatment option for high-risk postoperative HNACC.

In our study, there was no statistically significant difference in DSS outcomes between definitive radiotherapy and postoperative radiotherapy in the matched subgroup of patients with locally advanced T4 disease. This finding suggests that the impact of definitive radiotherapy may be comparable to the combined effect of surgery and postoperative radiotherapy, particularly in terms of LC for patients with locally advanced HNACC. Moreover, not all patients are fortunate enough to undergo complete surgical removal. For those individuals, radiotherapy remains the only effective local treatment option available. Intensity-modulated radiotherapy (IMRT) is currently the primary technique used in radiotherapy. Our study spans from 2000 to 2023, a period during which IMRT became increasingly popular and mainstream. Therefore, the radiation treatments in this study likely predominantly utilized IMRT techniques. With technological advancements and the standardization of dosimetry, radiotherapy protocols have become more uniform across treatment centers. In recent years, there has been a progressive increase in studies focused on postoperative IMRT therapy. Chen et al.’s retrospectively study encompassed 227 non-metastatic HNACC patients who underwent postoperative radiotherapy between 2000 and 2017. Among them, 213 received IMRT, exhibiting 5- and 10-year rates of distant metastasis-free survival (DMFS) at 79% and 63%, LRRFS at 89% and 68%, and OS at 88% and 71%, respectively (14). Another study by Xu et al. also yielded promising outcomes. Analyzing 55 postoperative IMRT cases for HNACC between 2007 and 2016, they reported 5-year rates of DMFS at 75.3%, LRRFS at 93.9%, and OS at 82.5% (15). Choi et al.’s retrospectively study encompassed 126 cases of non-metastatic HNACC patients who received postoperative radiotherapy between 2005 and 2019, with 100 of them undergoing IMRT. This study revealed 5-year rates of LRRFS at 69.6%, progression-free survival (PFS) at 46.6%, and OS at 81.1% (16). Considering that our study mainly involved cases diagnosed between 2010 and 2020, a period dominated by IMRT usage for radiotherapy, the 5-year OS within our postoperative group stood at 75%. This is consistent with the findings of other studies in the subject.

Particle radiation therapy has gained popularity in recent years, particularly for treating tumors like HNACC that conventionally exhibits resistance to photon radiation. This shift is attributed to the “Bragg peak” phenomenon in particle radiotherapy, which facilitates precise radiation dose delivery to the tumor with steep dose peaks, thereby minimizing damage to surrounding critical structures (17). With the advancement of more powerful radiotherapy techniques, significant improvements in treatment outcomes are becoming increasingly likely. The effectiveness of proton and carbon ion therapy in managing unresectable or incompletely resected refractory tumors has long been established (18). Recent evidence further supports that particle radiotherapy notably enhances the prognosis for patients with positive surgical margins. For instance, a study on sacral chordoma found that carbon ion radiotherapy improves OS compared to margin-positive surgery without adjuvant radiotherapy or primary photon radiotherapy alone (19). Given that HNACC is also challenging to resect completely through surgery, particle therapy presents a promising new option. To explore its potential, several relevant studies have been published. Morimoto et al. conducted a research on patients with unresectable, locally advanced primary head and neck cancers, including 25 cases of ACC. The study revealed a 3-year OS of 83%, and a 3-year LC rate of 63%, though 13 patients experienced distant metastases (20). Heavy ion radiotherapy, especially represented by carbon ions possessing a superior relative biological effect (RBE), appears to be a promising option for definitive radiotherapy. Akbaba et al. investigated the outcomes of 227 patients with sinus [90 of whom received definitive radiotherapy (40%)] and 207 patients with ACC in the region of the greater salivary glands [31 of whom received definitive radiotherapy (15%)]. The treatment regimen consisted of 48–56 Gy of IMRT followed by 18–24 Gy (RBE) of carbon ion boost until a median total dose of 80 Gy was reached [equivalent dose in 2-Gy fractions (EQD2)]. The results demonstrated a 3-year LC of 79%, a 3-year PFS of 67%, and a 3-year OS of 64% for sinus patients. Predictive ratios for 5-year LC, PFS, and OS were 61%, 35%, and 73%, respectively, in patients with macro salivary glands (21,22). These outcomes surpassed the 3- and 5-year cumulative OS of 58% and 37%, respectively, in our definitive radiotherapy group. This shows that the use of heavy ion-based definitive radiation might become a revolutionary treatment technique. Additionally, our team conducted a meta-analysis to evaluate the effectiveness of particle therapy—specifically proton beam therapy and carbon-ion radiation therapy—in treating HNACC. We analyzed 14 studies involving a total of 1,297 patients. The pooled 5-year OS rate was 78%, and the PFS rate was 62% for primary HNACC. However, 22% of patients experienced grade 3 or higher acute toxicity (23). In summary, while particle therapy offers dosimetric advantages over conventional radiotherapy and demonstrates potential for enhanced survival and LC, its high cost and limited availability necessitate further investigation to assess its feasibility in clinical work.

Our investigation found substantial relationships between chemotherapy and both OS and DSS. This highlights the need of systemic therapies, such as chemotherapy, in the entire treatment of HNACC patients with a high risk of distant metastasis. Despite the abundance of relevant chemotherapeutic agents and research, chemotherapy for ACC has, unfortunately, yielded unsatisfactory results. When examining single-agent chemotherapy, cytotoxic agents like 5-FU, gemcitabine, cisplatin, vincristine, and paclitaxel have demonstrated an objective efficacy rate of approximately 10% (24). Among combination therapies, the cisplatin, adriamycin, and cyclophosphamide (CAP) regimen was widely employed for ACC treatment even before 2000 (25). However, due to limited case numbers, complete remission rates were only 27% and 33%. In recent times, the vincristine + cisplatin regimen has exhibited objective efficacy rates of 20–31%, which still fall short of expectations (26,27). Targeted therapies have proven less effective in treating ACC. While immunohistological investigations have indicated epidermal growth factor receptor (EGFR) over expression in ACC (28), studies targeting cetuximab, lapatinib, and gefitinib have failed to significantly improve objective remission rates (ORRs) (29-31). A recent systematic review of recurrent/metastatic adenoid cystic carcinoma (R/M ACC) found that apatinib achieved an ORR of 47.1%, outperforming other treatments. However, immunotherapy has been largely ineffective, with ORRs ranging from 0% to 18%, possibly due to the immune cold nature of ACC (32). This was further evidenced by a phase II trial of nivolumab and ipilimumab in metastatic salivary gland carcinomas, which showed only a 6% ORR in ACC patients, highlighting its limited efficacy (33). Additionally, targeted agents against the vascular endothelial growth factor receptor (VEGFR), such as sorafenib and lenvatinib, reported ORRs of less than 16% (34,35). A recent systematic review and meta-analysis of 10 VEGFR inhibitors in R/M ACC found that, although these inhibitors were associated with higher rates of disease stabilization, the ORR was only 6%, with a disease control rate of 82% and a 6-month disease control rate of 54%. Among these agents, lenvatinib and axitinib showed the best performance in terms of efficacy, safety, and tolerability, while rivoeranib, despite having the highest ORR (24%), demonstrated significant study heterogeneity (36). For registered clinical trials of advanced R/M ACC, small molecule inhibitors (e.g., apatinib and axitinib) have shown better efficacy under strict enrollment criteria, although PFS remains short (37). In addition to recent mainstream drugs, research is ongoing into niche targets, such as NOTCH gene mutations, which are found in about 20% of ACC patients and are associated with poor prognosis. Crenigacestat (LY3039478), a selective NOTCH inhibitor, demonstrated effectiveness in 22 patients with advanced or metastatic ACC, with a median PFS of 5.3 months and a disease control rate of 73%, though its overall efficacy remains limited (38). Another study using PRT543, which downregulates NOTCH1 and MYB signaling pathways by inhibiting protein arginine methyltransferase 5, found that 23% of 56 ACC patients experienced grade 3 treatment-related adverse events, with a median PFS of 5.9 months and a clinical benefit rate of 57%. Despite better tolerability, the overall efficacy of PRT543 remains limited (39). Most of these studies have focused on new drugs and recurrent metastatic patients, highlighting the ineffectiveness of current treatments. Future systemic therapy research with larger sample sizes, including treatment-naive patients, and continued exploration of new genes and pathways may be necessary to achieve a breakthrough in ACC.

Several limitations are inherent to this study. Firstly, due to the limitations imposed by the SEER database, which lacks detailed information on surgical margins and specific subdivided pathology, we are regrettably unable to delve further into specific surgical details. Additionally, it is unfortunate that comprehensive treatment data, including specific radiotherapy and chemotherapy details, cannot be fully presented due to policy constraints. Secondly, given the extended 20-year study duration, variations in tumor staging and discrepancies in combined staging might exist, potentially affecting the consistency and comparability of the data. Furthermore, the relatively modest number of HNACC patients who underwent definitive radiotherapy could impact the comprehensiveness of the sample, potentially leading to limitations in generalizability. Additionally, the study’s retrospective nature introduces the possibility of selection bias, as certain variables and factors might not have been accounted for adequately. It is critical to recognize these limitations in order to assess the findings of this study with a thorough grasp of its scope and consequences.

Conclusions

In summary, this is a study of definitive radiotherapy vs. postoperative radiotherapy for HNACC with the largest sample size available and with matched samples. This study draws the following key conclusions: surgical intervention remains a fundamental component of comprehensive therapy for patients with operable HNACC. Definitive radiotherapy presents a viable treatment avenue, particularly for individuals with inoperable or locally advanced HNACC. Progress in radiotherapy techniques, including proton radiotherapy and heavy ion radiotherapy, holds the potential to yield therapeutic outcomes akin to surgery and postoperative radiotherapy for HNACC in the future. Systemic therapy stands as an indispensable treatment option, especially for HNACC patients facing a heightened risk of distant metastases. These findings collectively shed light on the dynamic landscape of HNACC treatment, emphasizing the role of multiple therapeutic approaches in enhancing patient outcomes.

Acknowledgments

M.T. expresses heartfelt gratitude to parents and his wife’s family for their unwavering support and care throughout his life and career.

Funding: The study was supported by the Central Guidance Local Science and Technology Development Program (No. 24ZYQA029), the National Key Research and Development Program of China (No. 2022YFC2401500), Science and Technology Project of Lanzhou City (No. 2023-1-9), Gansu Province Project of Science and Technologies (Nos. 20JR10RA680 and 22CX8JA149), and the Lanzhou Heavy Ion Accelerator High-end User Project (No. HIR20GY007).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1221/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1221/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1221/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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