Role of radiotherapy in the multidisciplinary treatment of lacrimal gland adenoid cystic carcinoma

Abstract

Background:

The optimal treatment approach for lacrimal gland adenoid cystic carcinoma (LGACC) remains controversial.

Objectives:

We aim to demonstrate the value of radiotherapy (RT) in the multidisciplinary treatment of LGACC.

Design:

This was a retrospective cohort study.

Methods:

This study was conducted on 90 patients with LGACC treated from 2002 to 2023. We compared the overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) between those treated with surgery alone versus surgery plus postoperative radiotherapy (PORT). In addition, the ipsilateral visual outcome and ocular complications were evaluated.

Results:

The addition of radiotherapy significantly improved the 5-year RFS (63.4% vs 31.1%, p = 0.014) and PFS (56.8% vs 31.1%, p = 0.036) while showing no improvement in OS (79.7% vs 85.6%, p = 0.98) and DMFS (67.3% vs 70.1%, p = 0.70) compared to surgery alone. Further analysis indicated that, compared to the photon-RT group, the proton/carbon-ion group showed no significant differences in 5-year OS (p = 0.7), RFS (p = 0.37), PFS (p = 0.45), and DMFS (p = 0.57). Univariate (odds ratio (OR) = 0.14, 95% confidence interval (CI): 0.04–0.49, p = 0.002) and multivariate (OR = 0.16, 95% CI: 0.04–0.62, p = 0.008) logistic regression indicated that radiotherapy was a protective factor for local recurrence. Furthermore, among the long follow-up of 35 patients accepting eye-sparing surgery plus PORT, 13 patients (37.1%) had best-corrected visual acuity (⩾20/40) and 14 (40.0%) had severe vision loss (<20/200); furthermore, dry eye disease (100%, 35/35) and cataract progression (45.7%,16/35) are the most common ocular complications.

Conclusion:

Surgery plus radiotherapy is a safe and effective multidisciplinary treatment in improving local control with tolerable long-term ocular toxicity, but of limited impact on OS for LGACC.

Introduction

In spite of the rarity, lacrimal gland adenoid cystic carcinoma (LGACC) is still the most common malignant epithelial tumor of the lacrimal gland, accounting for 51%–76% of the lacrimal gland carcinomas ¹ and 1.6%–7% of all orbital tumors. ² The prognosis is poor, with high risks of blindness and orbital disfigurement (e.g., exenteration, eyelid loss); moreover, the survival rates are reported to be dismal, with less than 50% at 5 years and 20% at 10 years. ³ The optimal treatment approach for LGACC remains controversial, due to the rarity of the disease, the complexity of pathological subtypes, and the extent of local invasion (bone/perineural involvement). ⁴ Surgical resection (eye-sparing surgery or exenteration) followed by postoperative radiation therapy (PORT) is adopted by most institutions for individuals with LGACC, according to the previous retrospective studies.^5–7

Optimizing patient outcomes and minimizing blindness risks are critical to the treatment of LGACC. Surgery combined with adjuvant chemoradiotherapy seems to improve the therapeutic effect for patients with LGACC. ⁸ External beam radiotherapy (RT), ⁹ plaque brachytherapy, ¹⁰ proton therapy, ¹¹ carbon-ion therapy, ¹² and neutron therapy ¹³ have all been reported as radiotherapy approaches for LGACC patients. However, few investigations have discussed whether PORT could improve the efficacy of treatment and long-term survival. ¹⁴ The main dilemma of the studies might be the lack of enough cases for further analysis in any institution.

Fortunately, there have been quite a few cases in the authors’ institution over the past 20 years. The authors compared the long-term survival rates between surgery alone and surgery plus PORT, as well as the treatment effectiveness of photon therapy versus proton/carbon-ion therapy. This study aimed to demonstrate the value of PORT in the treatment of multidisciplinary modes. In addition, the authors still assessed the ipsilateral visual outcome and ocular complications in cases with eye-sparing surgery plus adjuvant radiation therapy.

Materials and methods

Patient selection

The authors evaluated all patients with LGACC diagnosed at the Eye & ENT Hospital of Fudan University from April 2022 to October 2023. Two experienced pathologists histologically confirmed all the biopsy specimens. The authors reviewed the patients’ demographic information, pathological characteristics, surgical records, radiation therapy planning, visual acuity, and follow-up data. Exclusion criteria included patients with recurrent LGACC subsequent to prior surgical intervention and/or RT, as well as patients diagnosed with metastatic disease at initial presentation. They defined good visual acuity, poor visual acuity, and non-function as ⩾20/40, between ⩾20/200 and <20/40, and <20/200. The staging was based on the American Joint Committee on Cancer 8th edition for the tumor. The study and data accumulation were conducted with the approval of the Research Ethics Committee of Eye & ENT Hospital of Fudan University (No. 2023131). Informed consent was waived because of its retrospective nature. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for cohort studies ¹⁵ (see Supplemental Material—Table S2 for a completed checklist).

All patients were examined weekly during radiation therapy. Acute radiation-related toxicity was evaluated and recorded weekly, and the late toxicity was evaluated in 35 patients, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE—Version 5.0). Post-treatment assessments were followed approximately 3–6 months after the completion of treatment during the first 2 years and then every 6–12 months afterward. In addition, several patients were contacted and followed up through telephone interviews and email communications. Contrasted orbital MRI/CT scan, chest CT scan, and abdominal ultrasound were performed every 6–12 months. Patients with evidence of metastatic lesions underwent whole-body PET/CT scans. All the patients were recommended to visit the ophthalmologist routinely. A comprehensive ophthalmologic examination, including best-corrected visual acuity, slit lamp biomicroscopy, intraocular pressure examination, and indirect ophthalmoscopic fundus examination, was performed for those accepting eye-sparing treatment.

Therapeutic strategy

Eye-sparing surgery was performed if the tumor was evaluated to be grossly resectable without sacrificing the eye or extraocular muscles by senior ophthalmologists, and the patient refused exenteration as the first choice.

Eventually, 41 patients underwent enucleation, with 33 having it done directly, and 8 due to local recurrence, residual tumor, or severe complications; therefore, all these 41 patients became blind.

PORT was recommended for LGACC patients regardless of T-stage due to the higher incidence of perineural invasion (PNI) and positive margin. The photon radiation therapy was managed at the Eye & ENT Hospital of Fudan University. Radiation techniques included three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), or volume arc-modulated radiotherapy (VMAT). Proton and carbon ion radiation therapies were administered at the Shanghai Proton and Heavy Ion Center, with follow-up visits conducted at the Eye & ENT Hospital. The radiation therapy field included the tumor bed, the residual gross tumor volume, and the supraorbital fissure to the cavernous sinus. Regarding the radiation techniques, 3D-CRT was used in 25 cases, IMRT in 29 cases, and VMAT in 7 cases for patients who accepted photon radiation. For photon therapy, with a mean dose of 65.3 Gy (range: 50–72.6) given at 1.9–2.2 Gy/fraction, the radiation dose was adjusted according to resection margins. Fourteen (18.7%, 14/75) individuals received carbon-ion radiation therapy, with a mean relative biological effectiveness (RBE) dose of 70 Gy (range: 60–72) given at 3.3–4.0 Gy/fraction. Two patients received proton beam therapy with 63 and 70 Gy (RBE) in 30 fractions, and one received 70.5 Gy (RBE) of carbon-ion and proton combination therapy. Supplemental Material—Table E1 shows the characteristics of the patients who underwent different radiation techniques.

Nine patients were administered cisplatin-based chemotherapy, with five patients receiving intra-arterial chemotherapy and four patients receiving intravenous chemotherapy.

Statistical analysis

The time to recurrence is defined as the time interval between the date of diagnosis and the date of local recurrence. The time to distant metastasis is defined as the time interval between the date of diagnosis and the date of distant metastasis. The long-term survival outcomes, including overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS), were evaluated.

Comparison between different groups was calculated using the Student’s t test for continuous data and the Pearson chi-square test or Fisher’s exact test for categorical data. Survival outcomes were calculated using the Kaplan–Meier method with prognostic factors determined by the log-rank test. Logistic regression was performed to select the risk factors for local recurrence and metastasis, and the odds ratio (OR) was mainly compared. Multivariate Cox regression was performed to determine the prognostic factors for RFS and DMFS, and hazard ratios (HRs) were used to evaluate the meaningful factors. Statistical analyses were conducted in R (version 4.2.0, http://www.R-project.org). Two-tailed p < 0.05 was considered statistically significant.

Results

Patients and clinical characteristics

The patient, tumor, and treatment characteristics are presented in Table 1. The median age at diagnosis was 58.4 years (range, 14–81), with 43 (47.8%) males and 47 (52.2%) females. A total of 59 (65.6%) individuals were classified as early T stage (T1/2), whereas 31 (34.4%) were advanced T stage (T3/4). PNI was identified by pathological examination in 83.3% (75/90) of patients. Nearly half (48.9%, 44/90) of the patients had evidence of bone invasion.

Table 1.

Patient characteristics by treatment modes.

Characteristic	S	S + RT	p
	N = 15 (16.7%)	N = 75 (83.3%)
Sex
Male	8 (53.3)	35 (46.7)	0.850
Female	7 (46.7)	40 (53.3)
Age
<60	11 (73.3)	65 (86.7)	0.363
⩾60	4 (26.7)	10 (13.3)
T stage
T1/2	9 (60.0)	50 (66.7)	0.246
T3	3 (20.0)	5 (6.7)
T4	3 (20.0)	20 (26.7)
Bone erosion
Yes	8 (53.3)	36 (48.0)	0.925
No	7 (46.7)	39 (52.0)
Surgical margin
R0	2 (13.3)	19 (25.3)	0.504
R1/R2	13 (86.7)	56 (74.7)
Eye sparing
Yes	13 (86.7)	43 (57.3)	0.032
No	2 (13.3)	32 (42.7)
Chemotherapy
Yes	2 (13.3)	7 (9.3)	1.000
No	13 (86.7)	68 (90.7)

RT, radiotherapy; S, surgery.

All of the patients had their surgical margins evaluated: 21 (23.3%) had R0 resection, 49 (54.4%) had R1 resection, and 20 (22.2%) had R2 resection. Fifteen (16.7%) patients underwent surgery alone for the initial disease, including 2 eye-sparing tumor resections and 13 enucleations; 75 (83.3%) patients received surgery plus PORT.

Predictors of local recurrence and distant metastasis

The median follow-up time was 50.5 months (range, 7.7–226.5). Eighteen (20%, 18/90) patients died from the disease. A total of 32 (35.5%) patients ultimately developed local recurrence; the median time from diagnosis to recurrence was 22.2 months (range, 3.9–200.9). Univariate logistic regression analysis showed that patients older than 60 years (OR = 2.98, 95% confidence interval (CI): 1.16–7.66, p = 0.023), those with R1/2 surgical margins (OR = 4.35, 95% CI: 1.17–16.16, p = 0.028), and patients not receiving radiotherapy (OR = 0.14, 95% CI: 0.04–0.49, p = 0.002) had a significantly higher risk of local recurrence. Multivariate logistic regression analysis proved that R1/2 surgical margin (OR = 3.98, 95% CI: 1.01–15.64, p = 0.048) and without radiotherapy (OR = 0.16, 95% CI: 0.04–0.62, p = 0.008) were the independent risk factors for local recurrence (Figure 1(a)). Interestingly, the initial eye-sparing treatment showed no impact on local failure (χ² = 4.35, p = 0.738).

Figure 1.

The forest plot displays the risk factors for local recurrence (a) and distant metastasis (b).

A total of 17 (17/90, 18.9%) patients experienced distant metastases. The most common site of distant metastasis was the lung (13.3%, 12/90), followed by bone (7.8%, 7/90), and liver (2.2%, 2/90). The median time from diagnosis to distant metastasis was 40.1 months (range, 8.4–80.0). Patients with orbital bone invasion were more prone to develop distant metastasis (χ² = 3.95, p = 0.047). Univariate and multivariate logistic regression analyses indicated that orbital bone invasion was a risk factor for distant metastasis (OR = 3.07, 95% CI: 0.98–9.63, p = 0.054; Figure 1(b)).

Long-term survival

The 5-year OS, RFS, DMFS, and PFS rates were 80.7%, 72.6%, 67.5%, and 52.3%, respectively (Figure 2). In univariate analysis, patients who received surgery alone had 5-year rates of 85.6%, 31.1%, 70.0%, and 31.1% for OS, RFS, DMFS, and PFS, respectively. Those who received PORT had rates of 79.7%, 63.4%, 67.3%, and 56.8%, respectively. The addition of radiation therapy significantly improved the 5-year RFS (p = 0.014) and PFS (p = 0.036) but did not provide a benefit for OS (p = 0.98) or DMFS (p = 0.70; Figure 3(a)–(d)). We also compared the long-term outcomes between photon irradiation and proton/carbon-ion irradiation. The proton/carbon-ion group showed a slight improvement, but there were no significant differences in 5-year OS (80.0% vs 78.6%, p = 0.7), RFS (60.3% vs 77.4%, p = 0.37), DMFS (65.3% vs 73.0%, p = 0.57), and PFS (53.7% vs 69.6%, p = 0.45; Figure 3(e)–(h)).

Figure 2.

Overall survival rate (a), recurrence-free survival rate (b), distant metastasis-free survival rate (c), and progression-free survival rate (d) were evaluated in the entire cohort.

Figure 3.

A Kaplan–Meier curve compares the survival outcomes of patients who received radiotherapy to those who did not. The addition of radiotherapy improved the RFS rate (b) and PFS rate (d). Still, it did not impact the OS rate (a) and DMFS rate (c). A Kaplan–Meier curve compares the survival outcomes between photon and proton/C-ion. Photon achieves a similar OS rate (e), RFS rate (f), DMFS rate (g), and PFS rate (h) to proton/C-ion.

DMFS, distant metastasis-free survival; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival.

Multivariate Cox analysis indicated that patients aged ⩾60 years (HR = 2.28, 95% CI: 1.06–5.0, p = 0.038) and R1/2 resection (HR = 5.20, 95% CI: 1.45–18.7, p = 0.012) were independent factors predicting poor RFS. However, multivariate Cox analysis demonstrated that orbit bone erosion (HR = 2.86, 95% CI: 1.06–7.7, p = 0.037) was the unique prognostic factor for poor DMFS (Table 2).

Table 2.

Multivariate Cox regression analysis for RFS and DMFS in patients (N = 90).

Variables	RFS		DMFS
	HR (95% CI)	p Value	HR (95% CI)	p Value
Sex
Female	Reference		Reference
Male	1.91 (0.90–0.41)	0.091	1.19 (0.51–2.80)	0.685
Age
<60 years	Reference		Reference
⩾60 years	2.28 (1.05–5.00)	0.038	1.57 (0.61–4.00)	0.349
T stage
T3/4	Reference		Reference
T1/2	0.99 (0.45–2.20)	0.984	0.92 (0.39–2.20)	0.857
Bone erosion
No	Reference	0.789	Reference
Yes	1.12 (0.49–2.60)		2.86 (1.06–7.70)	0.037
Radiotherapy
No	Reference		Reference
Yes	1.91 (0.90–0.41)	0.226	1.18 (0.40–3.50)	0.767
Eye sparing
No	Reference		Reference
Yes	0.91 (0.40–2.10)	0.817	0.71 (0.30–1.70)	0.447
Surgical margin
R0	Reference		Reference
R1/2	5.20 (1.45–18.70)	0.012	2.41 (0.67–8.70)	0.176

CI, confidence interval; DMFS, distant metastasis-free survival; HR, hazard ratio; RFS, recurrence-free survival.

Patients who received photon irradiation had 29.5% (18/61) of local recurrence, while those who received proton/Carbon-ion had 18.2% (3/14). There was no significant difference (χ² = 0.08, p = 0.782). 19.7% (12/61) of distant metastasis occurred in patients accepting photon irradiation, and 21.4% (3/14) occurred in patients accepting proton/carbon-ion; there was also no significant difference (χ² = 0, p = 1.0).

Visual outcome and RT-related ocular complications

Visual acuity outcomes varied. Not all patients had pretreatment visual examinations at the authors’ institute, as outside practitioners referred them. In total, 35 patients who accepted eye-sparing surgery combined with radiotherapy had complete visual acuity data. In the proton/carbon-ion radiation group, there was 75.0% (9/12) vision loss, and in the photon radiation group, there was 56.5% (13/23) vision loss during the follow-up. No statistical difference was observed between the different radiation types (p = 0.481; Table 3).

Table 3.

Vision acuity evaluation after eye-sparing treatment (n = 35).

RT technique	Total	Good (⩾20/40)	Poor (between ⩾20/200 and <20/40)	Non-function (<20/200)
All patients	35	13 (37.1%)	8 (22.9%)	14 (40.0%)
Proton/C-ion	12	3 (25.0%)	3 (25.0%)	6 (50.0%)
Photon	23	10 (43.5%)	5 (21.7%)	8 (34.8%)

RT, radiation therapy.

Of the 35 patients who underwent eye-sparing surgery plus PORT, all patients (100%, 35/35) developed post-radiation dry eye requiring artificial tears after the eyeball-sparing treatment; 45.7% (16/35) patients developed cataracts; 11.4% (4/35) patients developed frontal lobe radio-necrosis or edema; 5.7% (2/35) patients developed glaucoma; and 5.7% (2/35) had lesions in the fundus (Table 4).

Table 4.

Treatment-related ocular toxicity in 35 cases receiving PORT.

Adverse event type	No. of patients	%
Dry eye (requiring artificial tears)	35	100
Cataracts	16	45.7
Frontal lobe radio-necrosis/edema	4	11.4
Glaucoma	2	5.7
Lesions in fundus	2	5.7

PORT, postoperative radiotherapy.

Discussion

LGACC is an extremely rare malignancy that originates from lacrimal gland epithelium. Due to the complex regional anatomy and the aggressive behavior of the tumor, achieving both eyeball preservation and long-term disease-free survival is challenging. Multidisciplinary cooperation showed an enhancement in local control, organ preservation, and long-term survival.^8,16,17 Previous literature recommended surgery with PORT as the optimal treatment strategy. ¹⁸ Especially a combination of radiation therapy and eye-sparing surgery could achieve satisfactory local control and good tolerance in patients with early-stage lacrimal gland carcinoma.^19,20 However, there was also an opinion that surgery, rather than radiotherapy, was found to improve OS significantly. ²¹ In this study, the authors discuss the value of radiation therapy in LGACC. On univariate analysis, the addition of radiotherapy could not improve the 5-year OS (p = 0.98) and DMFS (p = 0.70), but indeed significantly improved the 5-year RFS (p = 0.014) and PFS (p = 0.036), indicating that PORT primarily contributes to local control rather than long-term survival. The authors further analyzed the potential factors that might have an impact on local recurrence. Old age (⩾60 years), positive margin, and lack of radiation therapy were identified as risk factors for local recurrence in univariate logistic regression analysis, and positive margin and lack of radiation therapy were observed in multivariate logistic regression analysis. The goal of achieving local control must be weighed against the toxicity and long-term effects of treatment, which may result in significant morbidity, such as blindness and orbital disfigurement.

LGACC is also known to infiltrate nerves, and PNI is traditionally associated with a warning sign of local failure and serves as a prognostic indicator. PNI was present in up to 72% (38/53) of patients with LGACC. ²² Liu et al. ²³ reported 37.3% (19/51) of PNI positivity, and PNI was linked to a high rate of local recurrence (73.7% vs 37.5%, p = 0.01). Goldberg et al. ²⁴ reported that PNI was present in 90% (45/50) of ACCs, and they suggested that the higher risk of local recurrence in ACCs compared to adenocarcinomas might be a higher incidence of PNI. In this study, the authors observed 83.3% of PNI through histopathological examination. It is noteworthy that ACC has the typical characteristics of neurotropic lesions and dissemination with perinerve. ²⁵ Therefore, from this perspective, the R0 resection not only reduced the risk of local recurrence but also could impede lesion dissemination along the perinerve. Cranial nerves II, III, IV, V, VI dominate the structures in the orbital and peri-orbit skin and pass through the supraorbital fissure to the cavernous sinus and orbital neural canal. Theoretically, the clinical target volume covering these fields could reduce the risk of recurrence due to perinerve invasion, especially for those accepted eye-sparing treatments. In accordance with Woo et al. ²⁶ ’s study, radiotherapy improved the 5-year RFS rate in lacrimal gland carcinoma patients with eye-preserving surgery. Similarly, this study demonstrated that radiation therapy significantly decreased the risk of local recurrence (OR = 0.16, 95% CI: 0.04–0.62, p = 0.008). A dose of 60 Gy for postoperative and 66 Gy for radical radiotherapy is generally recommended. ²⁷ In this study, the authors delivered a higher median dose of 65.3 Gy (range: 50–72.6) because of 76.7% R1/2 resection margins. An interesting report showed that no statistically significant differences in survival rates between complete surgery combined with RT and non-radical surgery plus RT. ²⁸ In combination with radiation therapy, accumulating evidence has supported the eye-sparing surgery in LGACC.

Particle radiotherapy, especially Carbon-ion radiotherapy (CIRT), known for its stronger biological effects and superior dose distribution, is increasingly utilized in cancer treatments. Besides the photon radiation, proton therapy or CIRT applied to lacrimal gland cancer is considered promising. ¹² Wolkow et al. ¹¹ demonstrated that globe-preserving surgery with proton had a favorable long-term survival compared to other modern modalities. Lesueur et al. ²⁹ treated 15 patients by surgery plus proton radiation, and local recurrence was observed in 40% of patients, with a median follow-up time of 67.4 months. However, it remains uncertain whether particle radiotherapy offers a greater advantage over photon therapy in adjuvant PORT. This comparison aimed to preliminarily reveal the effects of photon and particle radiotherapy in LGACC port cases. The results indicated that although particle radiotherapy showed slightly better outcomes, the difference was not statistically significant with 5-year OS (79.3% vs 100%, p = 0.43), RFS (60.9% vs 80.0%, p = 0.32), PFS (54.7% vs 70.0%, p = 0.44), and DMFS (66.3% vs 75.0%, p = 0.43), compared with the photon radiation group. Furthermore, there is no statistical difference in the rate of vision loss between the different radiation types (p = 0.43). The insignificance of the p-value may be due to the limited impact of the type of radiation beamlines in adjuvant radiotherapy or could be attributed to the insufficient follow-up time and substantial difference in the number of participants between the two groups (11 vs 64). In the future, multicenter prospective studies will be essential to gain a clearer understanding of how to choose suitable beamline for different LGACC subgroups.

Bone invasion has been previously reported as a poor prognostic factor in LGACC. ³⁰ In the present study, only bone erosion was observed as a risk factor for distant metastasis, not the positive resection margins or the absence of radiation therapy. Bone invasion was identified in nearly half of the patients. Therefore, more research is needed to determine whether early aggressive treatment for patients with bone erosion could reduce the risk of distant metastasis in LGACC. Even if such treatment is not feasible, patients with bone involvement should be aware of the possibility of distant metastasis, which most commonly occurs in the lung, liver, and bone.

Despite improving the RFS with surgery and radiotherapy, long-term outcomes for LGACC remain dismal, with many patients developing recurrent or metastatic (R/M) disease. In this study, 35.5% and 18.9% of patients progressed locally and distantly, respectively, and these risks might continue for decades after diagnosis. In addition to the local therapy, chemotherapy or targeted therapy was also administered to improve the local control and reduce the distant metastasis. Neoadjuvant intra-arterial cytoreductive chemotherapy seems promising for reducing the size of the lacrimal gland lesion and improving OS. ¹⁷ Several prospective studies have shown promising results with multikinase inhibitors targeting VEGFR in R/M disease.^31–33 In the future, high-quality prospective clinical trials are crucial to decrease the local recurrence and distant metastasis, with the goal of ultimately achieving long-term disease-free survival.

This study has several limitations. First, it is a retrospective design with a small cohort size, and a potential intercorrelation between variables might limit the results in multivariate analyses. Second, most patients who chose surgery alone as their initial treatment were in the early stages, which makes the treatment less appropriate. Third, the number of cases in the surgery-alone only group and the surgery plus radiotherapy group was not well matched, nor were the cases in the photon therapy and particle therapy groups. Fourthly, as only 35 patients had complete ophthalmologic follow-up, this limits the generalizability of visual outcomes and adverse events. In addition, the follow-up period is not long enough, especially for patients receiving proton/carbon-ion radiation therapy. Multicenter clinical trials may be necessary to improve better management of this rare tumor.

Conclusion

In summary, although the addition of radiation therapy did not confer benefits in the OS or DMFS, it did significantly improve the RFS for LGACC patients. In addition, radiation therapy served as a protective factor against local recurrence. These findings suggest that surgery combined with RT is effective in improving local control and could be a viable treatment option for LGACC with tolerable long-term ocular toxicity.