Long-term Outcomes and Prognostic Factors of Eye-preserving Treatment with Particle Beam Radiotherapy for Orbital Malignancies

Long-term Outcomes and Prognostic Factors of Eye-preserving Treatment with Particle Beam Radiotherapy for Orbital Malignancies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Long-term Outcomes and Prognostic Factors of Eye-preserving Treatment with Particle Beam Radiotherapy for Orbital Malignancies Weixu Hu, Qiong Cai, Jing Gao, Jiyi Hu, Qingting Huang, Haojiong Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5262260/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background This retrospective study report the clinical experience of eye-preserving treatment follow by particle beam radiotherapy (IMPT or CIRT) for orbital malignancies. And to evaluate prognostic factors for orbital and lacrimal gland tumors. Methods Sixty-two patients with orbital malignancies were identified in the records of a single center between 2015 and 2021. Sixty-one patients met inclusion criteria. All of the patients received eye-preserving treatment before PBRT. Majority of the patients (91.8%) were treatment with CIRT. Clinical data, treatment modality, local control, metastases and survivals and visual outcomes, as well as associated prognostic indicators were were assessed. Results Sixty-one patients were followed with a median of 40.7 months (44.3 months for surviving patients). The 3- and 5-year DSS and LC rates were 88.1% and 69.9%, and the 3- and 5-year DMC rates were 77.5% and 74.2% for entire orbital malignancies. For lacrimal gland carcinoma, the 5-year DSS, LC, DMC, and PFS rates were 83.3%, 64.8%, 66.8%, and 53.4%. Tumor size, T stage, extraorbital invasion, and bone invasion influenced survivals. No grade 3 or higher acute toxicities were observed. A total of 8 patients experienced grade 3–4 visual impairment. Conclusions Particle radiotherapy following eye-preserving treatment provided a favorable local control and survivals with moderate acute and late toxicities, even in patients with unresectable disease. Particle radiotherapy was a promising strategy for management of orbital tumors. Orbital tumors lacrimal gland tumors proton beam radiation carbon ion beam radiation eye-preserving survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Primary malignant orbital tumors are rare and histologically diverse due to the orbit's complex anatomy, which include the globe, muscles, adipose tissue, blood vessels, lymphatics, and nerves. Lymphoma is the most common type. Lacrimal gland malignancies account for approximately 20% of orbital tumors, with adenoid cystic carcinoma (ACC) being the most prevalent subtype[ 1 ]. The management is challenging due to the critical structures and the limited space within the orbit, which complicates achieving both tumor control and vision preservation. Eye-sparing surgery (ESS) combined with adjuvant radiotherapy has become as the standard treatment approach, offering survival outcomes comparable to orbital exenteration (OE)[ 2 – 4 ]. Proton and heavy ion radiotherapy, leveraging the Bragg peak effect, allow precise tumor targeting while minimizing damage to normal tissues[ 5 , 6 ]. Furthermore, carbon ions, as high-linear energy transfer (LET) radiation, possess greater biological efficacy compared to photons or protons[ 7 – 10 ], making them particularly effective in treating radioresistant tumors such as adenoid cystic carcinoma, malignant melanoma, and sarcomas. Particle radiotherapy (PBRT) has been increasingly used in head and neck malignancies[ 11 ]. This study reports updated results on the long-term efficacy and safety of proton beam (PBT) and carbon ion radiotherapy (CIRT) for malignant orbital tumors, analyzing prognostic factors for local control (LC), distant metastasis control (DMC), and disease-specific survival (DSS). Methods From November 2015 to November 2021, data from 62 consecutive patients with non-metastatic orbital malignancies were retrospectively reviewed. Excluding one patient whose pathological diagnosis changed mid-treatment. The study received approval from the Institutional Review Board (IRB) of our center. Prior to PBRT, all patients underwent a comprehensive assessment and imaging (MRI or CT) of the orbital region, with staging according to the AJCC 8th edition. Patients were immobilized in a supine position using a dual-component polyurethane foam and thermoplastic mask. Planning CT scan without contrast. MRI-CT fusion imaging guided target contouring. The gross tumor volume (GTV-p) was defined from imaging, with a 1–3 mm margin (dependent on OARs) added to create the high-risk clinical target volume (CTV-HR). The intermediate-risk CTV (CTV-IR) encompassed the tumor bed with a 1–3 mm margin and operative bed for cases with R1 or close surgical margins. The low-risk CTV (CTV-LR) included the orbital wall region within 1-1.5 cm of the primary tumor or its resection bed, and the periosteum. Orbital apex, superior and inferior orbital fissures, and foramen rotundum also included in CTV-LR in ACC, SCC, adenocarcinoma cases. Unless the cavernous sinus is involved, it is not routinely irradiated. An extra 3–6 mm margin created the planning target volume (PTV), accounting for setup errors and dose distribution uncertainties. The PBRT dose was expressed in Gy-equivalents (GyE). Both intensity-modulated proton therapy (IMPT) and CIRT were delivered using pencil beam scanning (PBS) technology. DSS was defined as the time from diagnosis to death from disease or the last follow-up. LC and DMC were calculated from the date of diagnosis to recurrence or metastasis. Acute toxicities occurred within 90 days of PBRT initiation and late toxicities arose after 3 months. Survival curves were generated using the Kaplan-Meier method, and differences assessed with log-rank tests. Prognostic factors were evaluated through univariate and multivariate Cox regression analyses. All statistical analyses were performed using SPSS (Version 26.0) and R (Version 3.4.2). RESULTS Characteristics of Patients Between 11/2015 and 11/2021, 61 eligible patients were treated at SPHIC. All patients underwent ESS or biopsy before PBRT. The median follow-up of all cohort was 40.7 months (range 7.7–91.8), and 44.3 months (range 11.6–91.8) for surviving patients. Of the entire cohort, 36 patients (59%) had lacrimal malignancies. The median tumor diameter was 3 cm, and 82% had primary disease. Visible lesions (gross lesions) were detected in 39 patients (63.9%) before PBRT ACC was the most common histology (28 patients, 45.9%) in lacrimal tumors, with 72.2% presenting with T2-stage disease. Gross lesions were detected in 23 patients (63.9%). In 7 patients (19.4%), the lesions extended beyond the orbit. Bone involvement in 44.4% of patients. Perineural invasion (PNI) occurred in 26 patients (72.2%). Detailed characteristics are summarized in Table 1 . Table 1 Characteristics of patients characteristic No. of patients (%) Median age (orbital tumor, range) 35 (14–74) Median age (lacrimal tumor, range) 35 (16–74) Sex (orbital tumor, n = 61) Male 33 (54.1) Female 28 (45.9) Sex (lacrimal tumor, n = 36) Male 20 (55.6) Female 16 (44.4) Tumor site Lacrimal gland 36 (59) Lacrimal sac 10 (16.4) Inside orbit 15 (24.6) Tumor histology (orbital tumor, n = 61) Adenoid cystic carcinoma 28 (45.9) Adenocarcinoma 8 (13.1) Sarcoma 8 (13.1) Chondrosarcoma 6 (9.8) Squamous cells carcinoma 3 (4.9) Myoepithelial carcinoma 4 (6.6) Undifferentiated carcinoma 2 (3.3) Melanoma 1 (1.6) Mucoepidermoid carcinoma 1 (1.6) Tumor histology (lacrimal tumor, n = 36) Adenoid cystic carcinoma 26 (72.2) Adenocarcinoma 7 (19.4) Myoepithelial carcinoma 3 (8.3) T category (lacrimal tumor, n = 36) T1 3 (8.3) T2 26 (72.2) T3 2 (5.6) T4 5 (13.9) Median Tumor diameter (orbital tumor range, cm) 3 (1.1–7.5) Median Tumor diameter (lacrimal tumor range, cm) 3 (1.2–4.3) Extension beyond orbit (orbital tumor, n = 61) Yes 13 (21,3) No 48 (78.7) Extension beyond orbit (lacrimal tumor, n = 36) Yes 7 (19.4) No 29 (80.6) Bone involvement (lacrimal tumor, n = 36) No 18 (50.0) Yes 16 (44.4) Unknow 2 (5.6) Perineural invasion (lacrimal tumor, n = 36) Yes 26 (72.2) No 4 (11.1) Unknow 6 (16.7) Tumor status (orbital tumor, n = 61) Primary 50 (82.0) Recurrence 11 (18.0) Tumor status (lacrimal tumor, n = 36) Primary 30 (83.3) Recurrence 6 (16.7) Radiation course (orbital tumor, n = 61) First course 58 (95.1) Re-irradiation 3 (4.9) Radiation course (lacrimal tumor, n = 36) First course 35 (97.2) Re-irradiation 1 (2.8) Margin status (orbital tumor, n = 61) R0 5 (8.2) R1/close margin 17 (27.9) R2/biopsy 39 (63.9) Margin status (lacrimal tumor, n = 36) R0 3 (8.3) R1/close margin 10 (27.8) R2/biopsy 23 (63.9) Radiotherapy technique (orbital tumor, n = 61) Proton 1 (1.6) Carbon Ion 56 (91.8) Proton & Carbon 4 (6.6) Concurrent chemotherapy (orbital tumor) Yes 5 (8.2) No 56 (91.8) Particle Radiotherapy Modalities In patients receiving PBRT, 91.8% were received CIRT alone, using 63-73.5 GyE in 18–22 fractions for primary or residual tumors and 54–60 GyE in 18–20 fractions for low-risk regions. Four patients received both IMPT and CIRT, with IMPT 56 GyE in 28 fractions to low-risk regions followed by a 15 GyE CIRT boost in 3 fractions for gross lesions. One patient who achieved R0 resection received IMPT alone (56 GyE in 28 fractions). Elective nodal irradiation was not performed. Figure 1 illustrates the target delineation for ACC. Survival Outcomes and Prognostic Factors For the entire group, the 3- and 5-year DSS rates were 88.1%, LC rates were 69.9%, DMC rates were 77.5%, and 74.2%, and PFS rates were 58.1% and 55.2%, respectively (Fig. 2 ). The tumor size was a critical prognostic factor. Tumors ≥ 4 cm was associated with poorer DSS, DMC rates, but not LC rate (Fig. 3AB, Table 2 ). Extraorbital extension significantly associated with worse DSS in univariate analysis and a higher risk of DM in multivariate analysis (Fig. 3 C, Table 2 ). Patients with recurrent disease and those undergoing re-irradiation had lower 5-year DSS (Fig. 3 D). Multivariate analysis (Table 2 ) identified melanoma patients, elderly, and females had a higher DM risk, while intraorbital malignancies had a lower PFS rate. Table 2 Prognostic factors of orbital malignancies (multivariate analysis) Factors Disease specific survival Local control Distance metastasis control Progression-free survival N p OR p OR p OR p OR Age ≤35 30 Reference Reference Reference Reference >35 31 0.942 15.26 0.639 0.77 0.056 4.936 0.339 1.552 Gender Male 33 Reference Reference Reference Reference Female 28 0.94 23.56 0.274 1.875 0.008 21.064 0.092 2.356 Tumor site Lacrimal gland 36 Reference Reference Reference Reference Lacrimal sac 10 0.987 0 0.438 0.526 0.06 0.1 0.282 0.509 Inside orbit 15 0.839 1.546 0.088 0.149 0.97 0 0.029 0.153 Tumor histology Epithelial 46 Reference Reference Reference Reference Sarcoma 14 0.969 0 0.139 4.0 0.973 0 0.547 1.58 Melanoma 1 0.999 30.51 0.989 0 0.021 83.51 0.2222 5.01 Tumor status Primary 50 Reference Reference Reference Reference Recurrence 11 0.283 9.542 0.832 0.795 0.489 0.445 0.6647 0.694 Radiation course First course 58 Reference Reference Reference Reference Re-irradiation 3 0.712 0.476 0.531 2.543 0.878 0.783 0.343 2.946 Margin status R0 + R1/close margin 22 Reference Reference Reference Reference R2/biopsy 39 0.86 0.737 0.141 2.861 0.734 0.776 0.585 11.342 Median Tumor diameter* <4cm 49 Reference Reference Reference Reference ≥ 4cm 11 0.048 28.01 0.161 2.768 0.001 25.4406 0.041 3.532 Extension beyond orbit No 48 Reference Reference Reference Reference Yes 13 0.946 61.91 0.56 1.598 0.046 9.744 0.187 2.319 * One patient primary tumor diameter was unknow A subgroup analysis of patients with lacrimal tumors showed 5-year DSS, LC, DMC, and PFS rates of 83.3%, 64.8%, 66.8%, and 53.4%, respectively (Fig. 4 ). ACC, the most common type (72.2%), with 5-year DSS, LC, DMC, PFS rates were 89.3%, 60.1%, 66.3%, 52.9%. Univariate analysis indicated worse DSS in adenocarcinoma patients, but this requires further validation due to the small sample size. Patients with T1/T2 disease had significantly better outcomes. However, LC rates between early and advanced stages were not significantly different (5-year LC rates: 67% vs. 56.3%) (Fig. 5 A-D). Tumors > 3 cm had a higher risk of metastasis and progression. When tumors ≥ 4 cm not only showed worse DSS and DMC, but also a lower LC rate(Fig. 5 E-H). Multivariate analysis confirmed that larger tumors were associated with a higher rate of disease progression (Table 3 ). Bone involvement was also a negative prognostic factor associated with lower LC, DMC, and PFS rates in both univariate and multivariate analyses, although DSS was not significantly affected (Fig. 5 I-L, Table 3 ). Extraorbital extension was correlated to worse DSS, DMC, and PFS, though LC rate was unaffected (Fig. 5 M-P). PNI was observed in 72.2% of patients, with those without PNI showing worse DSS, although LC, DMC and PFS rates was unaffected. Given that the 4 patients without PNI had other poor prognostic factors (2 had bone invasion and 2 had T4-stage disease), this finding may be subject to bias. Additionally, Recurrent disease was associated with lower 5-year DSS and DMC rates. Table 3 Prognostic factors of lacrimal gland tumor (multivariate analysis) Factors Disease specific survival Local control Distance metastasis control Progression-free survival N p OR p OR p OR p OR Age ≤35 17 Reference Reference Reference Reference >35 19 0.291 297.65 0.902 0.884 0.539 3.687 0.26 2.58 Gender Male 20 Reference Reference Reference Reference Female 16 0.35 126.92 0.915 0.899 0.106 117.23 0.881 1.15 Tumor histology Adenoid cystic carcinoma 26 Reference Reference Reference Reference Adenocarcinoma 7 0.165 157.03 0.82 0.712 0.103 81.63 0.633 1.652 Myoepithelial carcinoma 3 0.855 0.282 0.979 0 0.976 0 0.985 0 T category T1-2 29 Reference Reference Reference Reference T3-4 7 0.955 0.001 0.949 0 0.922 0 0.19 0.041 Tumor status Primary 30 Reference Reference Reference Reference Recurrence 6 0.893 0.311 0.193 30.183 0.953 158.1 0.317 7.044 Margin status R0 + R1/close margin 13 Reference Reference Reference Reference R2/biopsy 23 0.974 0.875 0.968 0.957 0.776 1.804 0.426 0.506 Median Tumor diameter <4cm 18 Reference Reference Reference Reference ≥ 4cm 18 0.168 51.98 0.944 111.38 0.909 157.66 0.016 120.55 Bone involvement* No 18 Reference Reference Reference Reference Yes 16 0.555 3.515 0.025 8.465 0.909 147.76 0.003 20.485 Extension beyond orbit No 29 Reference Reference Reference Reference Yes 7 0.914 832.06 0.582 0.238 0.095 55.26 0.809 1.654 * Two patients bone involvement status were unknow Patterns of failure Sisteen patients (26.2%) experienced local recurrence, with 6 also presenting DM, and 10 were single relapse. Seven recurrences occurred within the CTV-HR, three at the margin of the GTV or tumor bed or within the CTV-IR. Of the 6 local recurrence outside the CTV, most involved inferior or medial orbital wall, or the orbital parietal bone, with none in the cavernous sinus. A total of 13 patients experienced DM, the most common site was lung (4 patients), followed by skeletal (3 patients), brain (2 patients), parotid gland (2 patients), liver (1 patient), cerebral falx (1 patient), Frontal meninges (1 patient). No patients experienced regional lymph node recurrence. Toxicity Acute and late toxicities were detailed in Table 4 . Normal function of the contralateral eye was preserved in all patients. No grade 3 or higher acute toxicities were observed, with most patients developing grade 1 toxicities. Two patients experienced grade 2 conjunctival congestion, which fully resolved within a month post-treatment. Late toxicities were observed in 24 patients including two cases of cataracts (1 grade 1, 1 grade 2), two cases of grade 3 glaucoma, and three cases of retinopathy (2 grade 2, 1 grade 3). Three patients developed brain injury one year post-treatment. Table 4 Characteristics of toxicities Acute Toxicities Late Toxicities Grade 1 Grade 2 Grade 1 Grade 2 Grade 3 Grade 4 Adverse reaction N % N % N % N % N % N % Epiphora 4 6.6 0 3 4.9 0 0 0 Dry eyes 2 3.3 0 6 9.8 0 0 0 Conjunctival congestion 4 6.6 2 3.3 0 0 0 0 Periorbital edema 13 21.3 0 0 0 0 0 Decreased vision 3 4.9 0 3 4.9 2 3.3 3 4.9 5 8.2 Cataract 0 0 1 1.6 1 1.6 0 0 Glaucoma 0 0 0 0 2 3.3 0 Retinopathy 0 0 0 2 3.3 1 1.6 0 Brain injury 0 0 3 4.9 0 0 0 Regarding visual status. Three patients developed grade 1 visual impairment during acute phase. Two of these patients received CIRT (63GyE/18Fx and 70GyE/20Fx). One maintained grade 1 decreased vision at last follow-up of 6 years, while the other progressed to grade 3 two years post-treatment. The third patient, re-irradiation with CIRT (70GyE/20Fx) experienced worsening vision and eventually vision loss 4 months post-treatment. In the late phase, 13 patients experienced vision decline. Five patients had grade 1–2 deceased vision, while 8 had grade 3 or 4 (CIRT dose of 60-70GyE/18-20Fx). The median time to serve decreased vision (grade 3/4) was 11.5 months (4–24 months). Discussion Our retrospective study analyzed 61 patients with malignant orbital tumors treated with ESS or biopsy followed by PBRT. With a median follow-up of 40.7 months (44.3 months for surviving patients), the 3- and 5-year DSS and LC rates were 88.1% and 69.9%, respectively, and the 3- and 5-year DMC rates were 77.5% and 74.2%. For lacrimal gland carcinoma, the 5-year DSS, LC, DMC, and PFS rates were 83.3%, 64.8%, 66.8%, and 53.4%. Tumor size, T stage, extraorbital invasion, and bone invasion influenced survival, as detailed in the following sections. A multidisciplinary approach involving ESS and postoperative radiotherapy is gaining favor for malignant orbital tumors[ 2 – 4 , 12 – 15 ]. In 2019, studies by Jie Yang et al.[ 16 ] and Hung JY et al.[ 17 ] on lacrimal ACC treated with photon radiotherapy after ESS reported a 5-year LC rate of 20%, with 50–70% local recurrence. PBRT, with its superior dose distribution and biological effectiveness, has since been increasingly adopted. For patients with biopsy or residual disease, higher doses can enhance local control. Paul Lesueur et al. [ 18 ] reported 5-year OS and LC rates of 78% and 60% for PBT, exceeding photon therapy outcomes. Carbon ion radiation (CIRT) offers superior dose distribution and higher biological efficacy, though reports on its use for malignant orbital tumors are limited. In 2019, we reported early outcomes, and this study extends the follow-up to a median of 40.7 months[ 19 ]. The 3- and 5-year DSS rates were 88.1%, while the LC rates were 69.9%. DMC rates were 77.5% and 74.2%, with PFS rates of 58.1% and 55.2%, respectively. For patients without radiologically detectable gross lesions (36.1%), the 5-year LC and DSS rates were 82.9% and 86.1%. Patients with gross lesions (63.9%) received high-dose radiotherapy (CIRT of 70–72 GyE/18–20 fractions or IMPT 56 GyE/28 fractions combined with CIRT 15 GyE/5 fractions), with 5-year LC and DSS rates of 64.1% and 71.8%. However, both univariate and multivariate analyses showed the presence of gross lesions did not a significant prognostic factor for survivals. Therefore, high-dose PBRT may contribute to disease control. Tumor size ≥ 4 cm increased DM incidence and reduced DSS rates, however there was no significant impact on LC rates. These findings may underscore adequate dosing to the gross tumor is critical for local control. In univariate analysis, extraorbital invasion decreased 5-year DSS rates (61.9% vs. 97.7%), but no significant differences in LC or DM rates, and multivariate analysis also showed a significantly increased risk of DM, which may partially explain the lower DSS rate. In a retrospective study, Randa Tao et al.[ 20 ] included multiple types such as ACC, SCC, and adenocarcinoma and found that the pathological type did not affect OS. In our study, we categorized all patients into three groups: epithelial tumors, sarcomas, and melanoma. Multivariate analysis indicated a higher risk of DM in melanoma. Given the limited sample size, this conclusion may be biased. Generally, the efficacy of treatment for recurrent or re-irradiated diseases is unsatisfactory. In our cohort, recurrence or re-irradiation was associated with lower DSS in univariate analysis. Intraorbital tumors showed a tendency for disease progression in multivariate analysis, but pathological type may influence outcomes (93.3% of these patients had sarcomas or chondrosarcomas), this conclusion requiring further validation. Lacrimal tumors made up 59% of the cohort. The 5-year DSS, LC, DMC, and PFS rates were 83.3%, 64.8%, 66.8%, and 53.4%, respectively. Previous studies reported 5-year OS rate of photon radiotherapy after ESS ranging from 37–65% [ 3 , 4 ]. While a study by Ford JR et al. [ 2 ], with 49% of patients received PBT showed 5-year DSS and LC rates of 81% and 71%. Sati Akbaba et al. [ 21 ] reported outcomes of combination of photon and CIRT, with 5-year OS and LC rates of 68% and 44%. Japanese researchers use CIRT alone for locally advanced lacrimal tumors, with 5-year OS, LC, and DFS rates of 65%, 62%, and 34% [ 22 ]. In our cohort, 36.1% had R0-R1 margins with 5-year DSS, LC and DMC rates of 72.7%, 80.8% and 76.9%. For patients with gross lesions (63.9%), the 5-year DSS, LC, DMC, and PFS rates were 87%, 58.2%, 63%, and 48.4%. Although no significant differences in survivals between patients with or without gross lesions, we advocate high-dose treatment for those with gross lesions. ACC was the most common histological type in lacrimal tumor, accounting for 72.2%, consistent with data from MD Anderson[ 2 ], Moorfields Eye Hospital[ 4 ], Samsung Medical Center[ 23 ], and Heidelberg Ion-Beam Therapy Center[ 21 ]. Due to its radioresistance, local recurrence of photon radiotherapy is around 50%[ 16 , 17 ]. Studies by Natalie Wolkow et al.[ 24 ] and Paul Lesueur et al.[ 18 ] on lacrimal ACC treated with photon and PBT or PBT alone reported lower local recurrence rates of 22% and 20%, with 5-year LC and OS rates of 60% and 78%. Sati Akbaba et al.[ 21 ] reported 5-year LC and OS rate of 21% and 71% for lacrimal ACC treated with photon and CIRT or CIRT alone. Among our patients with lacrimal ACC, 65.4% had gross lesions, and 5-year DSS, LC, DMC, and PFS rates of 89.3%, 60.1%, 66.3%, and 52.9%, respectively. These outcomes suggest PBRT may offer a survival advantage over photon radiotherapy for ACC, supporting its prioritization in treatment. Our univariate analysis showed a worse DSS rate for adenocarcinoma compared to ACC, but with only 7 cases of adenocarcinoma, this requires validation with a larger sample. Multiple studies have shown that advanced T-stage is linked to poorer OS[ 17 , 25 – 27 ] and higher DM rates[ 2 , 16 , 25 , 27 ]. In our univariate analysis, T3/4 disease correlated with increased DM and reduced DSS, though LC rates were unaffected. Since T-stage is associated with tumor size, bone invasion, and extraconal extension, we analyzed these factors individually. Tumor size ≥ 3 cm was associated with a higher risk of DM, although LC rate remained unaffected. When the tumors ≥ 4 cm, not only an increased risk of DM and reduced DSS, but also reduced LC rates. Multivariate analysis confirmed larger tumors were more prone to disease progression. Skinner HD et al.[ 27 ] also reported the incidence of DM was higher when tumors ≥ 3.5 cm. The lacrimal gland is firmly anchored to the orbital periosteum and lacrimal tumors may directly invade the orbital bone. Bone invasion was reported common in tumors > 2 cm[ 28 ] and significantly reduced DSS rates[ 2 ]. Our analysis also showed bone invasion not only reduced LC rate but also increased metastasis risk. Therefore, High-dose irradiation is recommended for bone-involved areas. The study by Noh JM et al.[ 26 ] found that the 5-year survivals were poor in lacrimal ACC with extraorbital extension. Similarly in our study, extraorbital invasion linked to reduced DSS and higher DM rates, though LC was unaffected. Although some reported PNI as a negative factor for survivals[ 2 , 27 ], others suggested it has no significant impact[ 16 , 21 , 23 ]. Our analysis showed better DSS rate in patients with PNI, likely due to bias. Since all 4 PNI-negative patients had adverse factors like bone invasion, T4 stage, or re-irradiation. Thus, we excluded PNI from our multivariate analysis. Despite advancements in ocular preservation through ESS and adjuvant radiotherapy, managing radiation-induced toxicities remains challenging. In a study by Holliday EB et al.[ 29 ], after a median dose of 60 GyE, 35% of patients experienced Grade 3 acute dermatitis, and 30% developed chronic Grade 3 toxicities. Paul Lesueur et al.[ 18 ] reported no Grade 3 or higher acute toxicities with 73.8 GyE of PBT, but chronic toxicities included brain injury (27%), hyperprolactinemia (40%), and rare cases of cataracts, keratitis, and osteitis. Japanese study[ 22 ] on high-dose CIRT did not result in Grade 3 or higher acute toxicities, however significant late toxicities were observed such as Grade 4 optic nerve injury (36.4%), brain injury (6%), and Grade 3 keratitis (9%). In our center, most toxicities were mild, such as Grade 1 edema, epiphora, dry eye, or conjunctivitis. Among late toxicities, aside from vision deterioration, the common symptom was Grade 1 dry eye (9.8%) and brain injury (4.9%). Regarding visual outcomes, three patients (4.9%) experienced Grade 1 vision impairment during the acute phase. Vision decline occurred in 10 patients during the late phase. Four patients experienced vision deterioration 4 to 7 months post-treatment, two patients around 1 year, and two patients at 2 years. Grade 3–4 vision loss emerging at a median of 11.5 months post-treatment. Our study has several limitations. The low incidence of orbital tumors and varying biological behaviors of different pathological types introduce bias. Future studies should aim to increase the number of patients and analyze specific pathological types for greater accuracy. Additionally, no cases of cavernous sinus recurrence were observed. Therefore, for patients with lesions confined to the orbit, the cavernous sinus was excluded form irradiation field, though this warrants further study and longer follow-up. Lastly, currently studies are single-institution and focus on either proton or CIRT. In the future, prospective randomized studies are needed to optimize treatment strategies. Conclusion Despite the retrospective nature and modest number of patients, we can still come to the conclusion that proton and carbon ion beam radiation provided a favorable local control and survivals after eye-preserving treatment, and even in patients with unresectable disease. No severe acute PBRT induced toxicity was observed, and severe late toxicity was observed in < 15% of cases. Particle radiotherapy was a promising strategy for management of orbital tumors. Abbreviations IMPT: Intensity-modulated proton therapy PBT: Proton beam therapy CIRT: Carbon-ion radiotherapy PBRT: Particle radiotherapy PBS: Pencil beam scanning ACC: Adenoid cystic carcinoma SCC: Squamous cells carcinoma ESS: Eye-sparing surgery PNI: Perineural invasion OE: Orbital exenteration LET: High-linear energy transfer LC: Local control DMC: Distant metastasis control DSS: Disease-specific survival PFS: Progression free survival DFS: Disease free survival GTV: Gross tumor volume CTV: clinical target volume PTV: Planning target volume Declarations Ethical approval This study has been granted an exemption form the requirement of written informed consent and human participants in this study were reviewed and approved by institutional review board (IRB) of Shanghai Proton and Heavy Ion Center. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing of interest The authors declare there is no conflict of interest. Funding: This work was supported by the Shanghai Municipal Commission of Health (Grants No. 202040280); Pudong New Area Science and Technology Development Fund (Grants No. PKJ2022-Y52); Key Research and Development Program of the Ministry of Science and Technology (Grants No. 2022YFC2401505) Author contributions Weixu Hu and Qiong Cai contributed equally as co-first authors. Weixu Hu: design the study, collect data and analysis, interpretation, drafting, revising the article and final approval. Qiong Cai: collect data and analysis, drafting, revising the article and final approval. Jiyi Hu: data collection, data analysis, revision and final approval. Qingting Huang: collect data, drafting, revision and approve of the version. Jing Gao: collect data, revision and approve of the version. Haojiong Zhang: collect patient’s data, and approve of the version. Lin Kong: Conceptualization and design study, supervision, data analysis and results interpretation, revising the article, funding acquisition, final approval. References Kim JS, Al-Lozi A, Leyngold IM: Malignant Orbital Tumors: Current Approach to Diagnosis and Management . Current Ophthalmology Reports 2021, 9 (1):16-24. Ford JR, Rubin ML, Frank SJ, Ning J, Debnam JM, Bell D, El-Naggar A, Ferrarotto R, Esmaeli B: Prognostic factors for local recurrence and survival and impact of local treatments on survival in lacrimal gland carcinoma . Br J Ophthalmol 2021, 105 (6):768-774. Bonavolonta P, Esmaeli B, Donna P, Tranfa F, Iuliano A, Abbate V, Fossataro F, Attanasi F, Bonavolonta G: Outcomes after eye-sparing surgery vs orbital exenteration in patients with lacrimal gland carcinoma . Head Neck 2020, 42 (5):988-993. Rose GE, Gore SK, Plowman NP: Cranio-orbital Resection Does Not Appear to Improve Survival of Patients With Lacrimal Gland Carcinoma . Ophthalmic Plast Reconstr Surg 2019, 35 (1):77-84. van de Water TA, Bijl HP, Schilstra C, Pijls-Johannesma M, Langendijk JA: The potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: a systematic review of literature . Oncologist 2011, 16 (3):366-377. Khan FM: The Physics of Radiation Therapy : Lippincott Williams & Wilkins; 2009. Hirohiko Tsujii TK, Masayuki Baba, Hiroshi Tsuji, Hirotoshi Kato, Shingo Kato, Shigeru Yamada, Shigeo Yasuda, Takeshi Yanagi, Hiroyuki Kato, Ryusuke Hara, Naotaka Yamamoto, Junetsu Mizoe: Clinical advantages of carbon-ion radiotherapy . New Journal of Physics 2008, 10 . Kanai T, Endo M, Minohara S, Miyahara N, Koyama-ito H, Tomura H, Matsufuji N, Futami Y, Fukumura A, Hiraoka T et al : Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy . Int J Radiat Oncol Biol Phys 1999, 44 (1):201-210. Elsasser T, Kramer M, Scholz M: Accuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo . Int J Radiat Oncol Biol Phys 2008, 71 (3):866-872. Jones B: A Simpler Energy Transfer Efficiency Model to Predict Relative Biological Effect for Protons and Heavier Ions . Front Oncol 2015, 5 :184. Karcioglu ZA, Hadjistilianou D, Rozans M, DeFrancesco S: Orbital rhabdomyosarcoma . Cancer Control 2004, 11 (5):328-333. Woo KI, Kim YD, Sa HS, Esmaeli B: Current treatment of lacrimal gland carcinoma . Curr Opin Ophthalmol 2016, 27 (5):449-456. Han J, Kim YD, Woo KI, Sobti D: Long-Term Outcomes of Eye-Sparing Surgery for Adenoid Cystic Carcinoma of Lacrimal Gland . Ophthalmic Plast Reconstr Surg 2018, 34 (1):74-78. Esmaeli B, Yin VT, Hanna EY, Kies MS, William WN, Jr., Bell D, Frank SJ: Eye-sparing multidisciplinary approach for the management of lacrimal gland carcinoma . Head Neck 2016, 38 (8):1258-1262. Woo KI, Yeom A, Esmaeli B: Management of Lacrimal Gland Carcinoma: Lessons From the Literature in the Past 40 Years . Ophthalmic Plast Reconstr Surg 2016, 32 (1):1-10. Yang J, Zhou C, Wang Y, Fan X, Jia R: Multimodal therapy in the management of lacrimal gland adenoid cystic carcinoma . BMC Ophthalmol 2019, 19 (1):125. Hung JY, Wei YH, Huang CH, Chen LW, Fuh CS, Liao SL: Survival outcomes of eye-sparing surgery for adenoid cystic carcinoma of lacrimal gland . Jpn J Ophthalmol 2019, 63 (4):344-351. Lesueur P, Rapeaud E, De Marzi L, Goudjil F, Levy C, Galatoire O, Jacomet PV, Dendale R, Calugaru V: Adenoid Cystic Carcinoma of the Lacrimal Gland: High Dose Adjuvant Proton Therapy to Improve Patients Outcomes . Front Oncol 2020, 10 :135. Hu W, Hu J, Gao J, Yang J, Qiu X, Kong L, Lu JJ: Outcomes of orbital malignancies treated with eye-sparing surgery and adjuvant particle radiotherapy: a retrospective study . BMC Cancer 2019, 19 (1):776. Tao R, Ma D, Takiar V, Frank SJ, Fuller CD, Gunn GB, Beadle BM, Morrison WH, Rosenthal DI, Edson MA et al : Orbital carcinomas treated with adjuvant intensity-modulated radiation therapy . Head Neck 2016, 38 Suppl 1 :E580-587. Akbaba S, Lang K, Held T, Herfarth K, Rieber J, Plinkert P, Auffarth GU, Rieken S, Debus J, Adeberg S: Carbon-ion radiotherapy in accelerated hypofractionated active raster-scanning technique for malignant lacrimal gland tumors: feasibility and safety . Cancer Manag Res 2019, 11 :1155-1166. Hayashi K, Koto M, Ikawa H, Ogawa K, Kamada T: Efficacy and safety of carbon-ion radiotherapy for lacrimal gland carcinomas with extraorbital extension: a retrospective cohort study . Oncotarget 2018, 9 (16):12932-12940. Woo KI, Sagiv O, Han J, Frank SJ, Kim YD, Esmaeli B: Eye-Preserving Surgery Followed by Adjuvant Radiotherapy for Lacrimal Gland Carcinoma: Outcomes in 37 Patients . Ophthalmic Plast Reconstr Surg 2018, 34 (6):570-574. Wolkow N, Jakobiec FA, Lee H, Sutula FC: Long-term Outcomes of Globe-Preserving Surgery With Proton Beam Radiation for Adenoid Cystic Carcinoma of the Lacrimal Gland . Am J Ophthalmol 2018, 195 :43-62. Lin YH, Huang SM, Yap WK, Yang JW, Yeung L, Tsan DL, Chang JT, Chen LC: Outcomes in patients with lacrimal gland carcinoma treated with definitive radiotherapy or eye-sparing surgery followed by adjuvant radiotherapy . Radiat Oncol 2020, 15 (1):156. Noh JM, Lee E, Ahn YC, Oh D, Kim YD, Woo KI, Ko YH, Kim S: Clinical significance of post-surgical residual tumor burden and radiation therapy in treating patients with lacrimal adenoid cystic carcinoma . Oncotarget 2016, 7 (37):60639-60646. Skinner HD, Garden AS, Rosenthal DI, Ang KK, Morrison WH, Esmaeli B, Pinnix CC, Frank SJ: Outcomes of malignant tumors of the lacrimal apparatus: the University of Texas MD Anderson Cancer Center experience . Cancer 2011, 117 (12):2801-2810. Williams MD, Al-Zubidi N, Debnam JM, Shinder R, DeMonte F, Esmaeli B: Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations . Ophthalmic Plast Reconstr Surg 2010, 26 (6):403-408. Holliday EB, Esmaeli B, Pinckard J, Garden AS, Rosenthal DI, Morrison WH, Kies MS, Gunn GB, Fuller CD, Phan J et al : A Multidisciplinary Orbit-Sparing Treatment Approach That Includes Proton Therapy for Epithelial Tumors of the Orbit and Ocular Adnexa . Int J Radiat Oncol Biol Phys 2016, 95 (1):344-352. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5262260","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":366300868,"identity":"67bb1b30-2e93-44b9-b4e2-db6a3d1cd4d0","order_by":0,"name":"Weixu Hu","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Weixu","middleName":"","lastName":"Hu","suffix":""},{"id":366300869,"identity":"e2c070ab-3d39-4c2e-8ef4-d57d5c8a0e3b","order_by":1,"name":"Qiong Cai","email":"","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":false,"prefix":"","firstName":"Qiong","middleName":"","lastName":"Cai","suffix":""},{"id":366300870,"identity":"84303265-ebb0-429f-b112-9deab8462ec9","order_by":2,"name":"Jing Gao","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Gao","suffix":""},{"id":366300871,"identity":"bdd891ee-a5cc-45a3-88be-7967ed266b3f","order_by":3,"name":"Jiyi Hu","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Jiyi","middleName":"","lastName":"Hu","suffix":""},{"id":366300872,"identity":"1b6d4607-563e-4d96-9469-e24ff46eca94","order_by":4,"name":"Qingting Huang","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Qingting","middleName":"","lastName":"Huang","suffix":""},{"id":366300873,"identity":"d912494a-7c89-4060-a23f-4760c3faafdc","order_by":5,"name":"Haojiong Zhang","email":"","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":false,"prefix":"","firstName":"Haojiong","middleName":"","lastName":"Zhang","suffix":""},{"id":366300874,"identity":"5e7acf63-8e42-458e-949d-5b668c0e5e64","order_by":6,"name":"Lin Kong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIie3PsQrCMBCA4UDgXK7NGrHYV6gUOgm+SkPBTXDsUMVB0kHEuW/h2LFSiEvcO+ojdHOUYnG0GQXzL5fhPrgQYrP9YC4ltJsIfn25x2k2TKAnnsshCe5aGRDyJvMpx2j82FMDMnLqoC03CJNdlIodEJYf4oHD3EQU+orgVctGlB7h+nYeIBjWjlQIJFaN0EACvjImQq6FpGYkcWSGwJNOGZJZISsEVJTHWuHgXxjTIW/lduHnp7Z9ptmU5cfvpK/+vNBkvWtrumiz2Wz/2AsgQT5464TGUQAAAABJRU5ErkJggg==","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Lin","middleName":"","lastName":"Kong","suffix":""}],"badges":[],"createdAt":"2024-10-14 15:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5262260/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5262260/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67292284,"identity":"7dcecc78-83f3-4d85-984d-0af35f2a35ce","added_by":"auto","created_at":"2024-10-23 10:29:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":698505,"visible":true,"origin":"","legend":"\u003cp\u003eFor patients with R2 resection or biopsy, the CTV-HR (yellow line) encompassed GTV (red line) with a margin. For R1 or close margin cases, the tumor bed (pink line) and operative bed were included in the CTV-IR (blue line). For R0 cases, only CTV-LR (green line) was treated. Unless the cavernous sinus is involved, it is not routinely irradiated.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5262260/v1/98d457628748d0a57533eaf0.jpg"},{"id":67292281,"identity":"ba895cc4-6b89-4dc5-87a9-8857ab7c83a7","added_by":"auto","created_at":"2024-10-23 10:29:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":298914,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curves of DSS (A), PFS (B), LC (C), and DMC (D) rates for the orbital malignancies.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5262260/v1/c4e5a7a434c5fae74269ef74.jpg"},{"id":67292282,"identity":"8a5e437a-7e11-46c3-b5f8-713fa35a6164","added_by":"auto","created_at":"2024-10-23 10:29:14","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":327105,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curves compare the DSS (A) and DMC (B) rates of patients with larger tumor. Tumors size ≥4 cm was significantly decreased DM control (p=0.014) and DSS (p=0.001) rates. Survival curves compare the DSS (C) rate of patients with extraorbital disease. Extraorbital extension significantly decreased DSS (p=0.001) rate. Survival curves compare the DSS (D) rate of patients with recurrent disease. Recurrent disease significantly decreased DSS (p=0.014) rate.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5262260/v1/1add994a422cbb487e861a18.jpg"},{"id":67292283,"identity":"0e641fca-3cac-44d8-b283-9f92b7cf9c4d","added_by":"auto","created_at":"2024-10-23 10:29:14","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":294609,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curves of DSS (A), PFS (B), LC (C), and DMC (D) rates for the lacrimal tumors.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5262260/v1/e81957c6d61b1c375d665e42.jpg"},{"id":67292285,"identity":"1f09f6d8-8b9c-491d-be2b-364db0bfd7b4","added_by":"auto","created_at":"2024-10-23 10:29:15","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":460373,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival curves compare the DSS (A), PFS (B), LC (C), and DMC (D) rates of patients with advanced T category. Advanced T category was significantly decreased DSS (p=0.001), PFS (p=0.004) and DMC (p=0) rates, but not LC (p=0.258) rate. Survival curves compare the DSS (E), PFS (F), LC (G), and DMC (H) rates of patients with large tumors. Tumors size ≥4 cm was significantly decreased DSS (p=0.001), PFS (p=0), LC (p=0.008) and DMC (p=0) rates. Survival curves compare the DSS (I), PFS (J), LC (K), and DMC (L) rates of patients with bone involvement. Bone involvement significantly decreased PFS (p=0), LC (p=0.04) and DMC (p=0) rates, but not DSS (p=0.081) rate. Survival curves compare the DSS (M), PFS (N), LC (O), and DMC (P) rates of patients with extraorbital disease. Extraorbital extension significantly decreased DSS (p=0), PFS (p=0.012) and DMC (p=0.001) rates, but not LC (p=0.669) rate.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5262260/v1/55ced05d0f8ca6ae923bb5a0.jpg"},{"id":69679327,"identity":"83cd010d-2131-4a65-9b46-0384cfa3805e","added_by":"auto","created_at":"2024-11-23 05:38:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3808006,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5262260/v1/858a453a-0487-4a07-83d5-ff5d64268ee8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term Outcomes and Prognostic Factors of Eye-preserving Treatment with Particle Beam Radiotherapy for Orbital Malignancies","fulltext":[{"header":"Background","content":"\u003cp\u003ePrimary malignant orbital tumors are rare and histologically diverse due to the orbit's complex anatomy, which include the globe, muscles, adipose tissue, blood vessels, lymphatics, and nerves. Lymphoma is the most common type. Lacrimal gland malignancies account for approximately 20% of orbital tumors, with adenoid cystic carcinoma (ACC) being the most prevalent subtype[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe management is challenging due to the critical structures and the limited space within the orbit, which complicates achieving both tumor control and vision preservation. Eye-sparing surgery (ESS) combined with adjuvant radiotherapy has become as the standard treatment approach, offering survival outcomes comparable to orbital exenteration (OE)[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eProton and heavy ion radiotherapy, leveraging the Bragg peak effect, allow precise tumor targeting while minimizing damage to normal tissues[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, carbon ions, as high-linear energy transfer (LET) radiation, possess greater biological efficacy compared to photons or protons[\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], making them particularly effective in treating radioresistant tumors such as adenoid cystic carcinoma, malignant melanoma, and sarcomas. Particle radiotherapy (PBRT) has been increasingly used in head and neck malignancies[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e This study reports updated results on the long-term efficacy and safety of proton beam (PBT) and carbon ion radiotherapy (CIRT) for malignant orbital tumors, analyzing prognostic factors for local control (LC), distant metastasis control (DMC), and disease-specific survival (DSS).\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eFrom November 2015 to November 2021, data from 62 consecutive patients with non-metastatic orbital malignancies were retrospectively reviewed. Excluding one patient whose pathological diagnosis changed mid-treatment. The study received approval from the Institutional Review Board (IRB) of our center. Prior to PBRT, all patients underwent a comprehensive assessment and imaging (MRI or CT) of the orbital region, with staging according to the AJCC 8th edition.\u003c/p\u003e \u003cp\u003ePatients were immobilized in a supine position using a dual-component polyurethane foam and thermoplastic mask. Planning CT scan without contrast. MRI-CT fusion imaging guided target contouring. The gross tumor volume (GTV-p) was defined from imaging, with a 1\u0026ndash;3 mm margin (dependent on OARs) added to create the high-risk clinical target volume (CTV-HR). The intermediate-risk CTV (CTV-IR) encompassed the tumor bed with a 1\u0026ndash;3 mm margin and operative bed for cases with R1 or close surgical margins. The low-risk CTV (CTV-LR) included the orbital wall region within 1-1.5 cm of the primary tumor or its resection bed, and the periosteum. Orbital apex, superior and inferior orbital fissures, and foramen rotundum also included in CTV-LR in ACC, SCC, adenocarcinoma cases. Unless the cavernous sinus is involved, it is not routinely irradiated. An extra 3\u0026ndash;6 mm margin created the planning target volume (PTV), accounting for setup errors and dose distribution uncertainties. The PBRT dose was expressed in Gy-equivalents (GyE). Both intensity-modulated proton therapy (IMPT) and CIRT were delivered using pencil beam scanning (PBS) technology.\u003c/p\u003e \u003cp\u003eDSS was defined as the time from diagnosis to death from disease or the last follow-up. LC and DMC were calculated from the date of diagnosis to recurrence or metastasis. Acute toxicities occurred within 90 days of PBRT initiation and late toxicities arose after 3 months. Survival curves were generated using the Kaplan-Meier method, and differences assessed with log-rank tests. Prognostic factors were evaluated through univariate and multivariate Cox regression analyses. All statistical analyses were performed using SPSS (Version 26.0) and R (Version 3.4.2).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of Patients\u003c/h2\u003e \u003cp\u003eBetween 11/2015 and 11/2021, 61 eligible patients were treated at SPHIC. All patients underwent ESS or biopsy before PBRT. The median follow-up of all cohort was 40.7 months (range 7.7\u0026ndash;91.8), and 44.3 months (range 11.6\u0026ndash;91.8) for surviving patients.\u003c/p\u003e \u003cp\u003eOf the entire cohort, 36 patients (59%) had lacrimal malignancies. The median tumor diameter was 3 cm, and 82% had primary disease. Visible lesions (gross lesions) were detected in 39 patients (63.9%) before PBRT\u003c/p\u003e \u003cp\u003eACC was the most common histology (28 patients, 45.9%) in lacrimal tumors, with 72.2% presenting with T2-stage disease. Gross lesions were detected in 23 patients (63.9%). In 7 patients (19.4%), the lesions extended beyond the orbit. Bone involvement in 44.4% of patients. Perineural invasion (PNI) occurred in 26 patients (72.2%). Detailed characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003echaracteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of patients (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age (orbital tumor, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (14\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age (lacrimal tumor, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (16\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (orbital tumor, n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (54.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (45.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLacrimal gland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLacrimal sac\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInside orbit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (24.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor histology (orbital tumor, n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoid cystic carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (45.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChondrosarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSquamous cells carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyoepithelial carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUndifferentiated carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucoepidermoid carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor histology (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoid cystic carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (72.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyoepithelial carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT category (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (72.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (13.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Tumor diameter\u003c/p\u003e \u003cp\u003e(orbital tumor range, cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.1\u0026ndash;7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Tumor diameter\u003c/p\u003e \u003cp\u003e(lacrimal tumor range, cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.2\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eExtension beyond orbit (orbital tumor, n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (21,3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (78.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtension beyond orbit (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (80.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone involvement (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerineural invasion (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (72.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor status (orbital tumor, n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (82.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (18.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor status (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation course (orbital tumor, n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst course\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (95.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRe-irradiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation course (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst course\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (97.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRe-irradiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin status (orbital tumor, n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR1/close margin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR2/biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin status (lacrimal tumor, n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR1/close margin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR2/biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy technique (orbital tumor, n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProton\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbon Ion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (91.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProton \u0026amp; Carbon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent chemotherapy (orbital tumor)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (91.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticle Radiotherapy Modalities\u003c/h3\u003e\n\u003cp\u003eIn patients receiving PBRT, 91.8% were received CIRT alone, using 63-73.5 GyE in 18\u0026ndash;22 fractions for primary or residual tumors and 54\u0026ndash;60 GyE in 18\u0026ndash;20 fractions for low-risk regions. Four patients received both IMPT and CIRT, with IMPT 56 GyE in 28 fractions to low-risk regions followed by a 15 GyE CIRT boost in 3 fractions for gross lesions. One patient who achieved R0 resection received IMPT alone (56 GyE in 28 fractions). Elective nodal irradiation was not performed. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the target delineation for ACC.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eSurvival Outcomes and Prognostic Factors\u003c/h3\u003e\n\u003cp\u003eFor the entire group, the 3- and 5-year DSS rates were 88.1%, LC rates were 69.9%, DMC rates were 77.5%, and 74.2%, and PFS rates were 58.1% and 55.2%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The tumor size was a critical prognostic factor. Tumors\u0026thinsp;\u0026ge;\u0026thinsp;4 cm was associated with poorer DSS, DMC rates, but not LC rate (Fig.\u0026nbsp;3AB, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Extraorbital extension significantly associated with worse DSS in univariate analysis and a higher risk of DM in multivariate analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Patients with recurrent disease and those undergoing re-irradiation had lower 5-year DSS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). Multivariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) identified melanoma patients, elderly, and females had a higher DM risk, while intraorbital malignancies had a lower PFS rate.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors of orbital malignancies (multivariate analysis)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eDisease specific\u003c/p\u003e \u003cp\u003esurvival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eLocal control\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eDistance metastasis\u003c/p\u003e \u003cp\u003econtrol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eProgression-free\u003c/p\u003e \u003cp\u003esurvival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.942\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.639\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.936\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.339\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.552\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e21.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.356\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLacrimal gland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLacrimal sac\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.987\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.526\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.509\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInside orbit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.839\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.546\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor histology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpithelial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.973\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.547\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMelanoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.989\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e83.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.2222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.542\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.832\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.6647\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.694\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation course\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst course\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRe-irradiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.712\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.476\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.878\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.783\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.343\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.946\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u0026thinsp;+\u0026thinsp;R1/close margin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR2/biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.737\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.861\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.734\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.776\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11.342\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Tumor diameter*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;4cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;4cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.768\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e25.4406\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.532\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtension beyond orbit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.946\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.598\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9.744\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.319\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e* One patient primary tumor diameter was unknow\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA subgroup analysis of patients with lacrimal tumors showed 5-year DSS, LC, DMC, and PFS rates of 83.3%, 64.8%, 66.8%, and 53.4%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). ACC, the most common type (72.2%), with 5-year DSS, LC, DMC, PFS rates were 89.3%, 60.1%, 66.3%, 52.9%. Univariate analysis indicated worse DSS in adenocarcinoma patients, but this requires further validation due to the small sample size. Patients with T1/T2 disease had significantly better outcomes. However, LC rates between early and advanced stages were not significantly different (5-year LC rates: 67% vs. 56.3%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA-D). Tumors\u0026thinsp;\u0026gt;\u0026thinsp;3 cm had a higher risk of metastasis and progression. When tumors\u0026thinsp;\u0026ge;\u0026thinsp;4 cm not only showed worse DSS and DMC, but also a lower LC rate(Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eE-H). Multivariate analysis confirmed that larger tumors were associated with a higher rate of disease progression (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Bone involvement was also a negative prognostic factor associated with lower LC, DMC, and PFS rates in both univariate and multivariate analyses, although DSS was not significantly affected (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eI-L, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Extraorbital extension was correlated to worse DSS, DMC, and PFS, though LC rate was unaffected (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eM-P). PNI was observed in 72.2% of patients, with those without PNI showing worse DSS, although LC, DMC and PFS rates was unaffected. Given that the 4 patients without PNI had other poor prognostic factors (2 had bone invasion and 2 had T4-stage disease), this finding may be subject to bias. Additionally, Recurrent disease was associated with lower 5-year DSS and DMC rates.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors of lacrimal gland tumor (multivariate analysis)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eDisease specific\u003c/p\u003e \u003cp\u003esurvival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eLocal control\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eDistance metastasis\u003c/p\u003e \u003cp\u003econtrol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eProgression-free\u003c/p\u003e \u003cp\u003esurvival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e297.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.902\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.884\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.539\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e126.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.899\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e117.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.881\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor histology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoid cystic carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e157.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.712\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e81.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.652\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyoepithelial carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.979\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.976\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.985\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT category\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.949\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.922\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.953\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e158.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7.044\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u0026thinsp;+\u0026thinsp;R1/close margin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR2/biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.974\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.968\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.957\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.776\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.804\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.426\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.506\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Tumor diameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;4cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;4cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e111.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e157.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e120.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone involvement*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.555\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.515\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.465\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e147.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20.485\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtension beyond orbit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.914\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e832.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.582\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.238\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e55.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.809\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.654\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e* Two patients bone involvement status were unknow\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003ePatterns of failure\u003c/h3\u003e\n\u003cp\u003eSisteen patients (26.2%) experienced local recurrence, with 6 also presenting DM, and 10 were single relapse. Seven recurrences occurred within the CTV-HR, three at the margin of the GTV or tumor bed or within the CTV-IR. Of the 6 local recurrence outside the CTV, most involved inferior or medial orbital wall, or the orbital parietal bone, with none in the cavernous sinus.\u003c/p\u003e \u003cp\u003eA total of 13 patients experienced DM, the most common site was lung (4 patients), followed by skeletal (3 patients), brain (2 patients), parotid gland (2 patients), liver (1 patient), cerebral falx (1 patient), Frontal meninges (1 patient). No patients experienced regional lymph node recurrence.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eToxicity\u003c/h2\u003e \u003cp\u003eAcute and late toxicities were detailed in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Normal function of the contralateral eye was preserved in all patients. No grade 3 or higher acute toxicities were observed, with most patients developing grade 1 toxicities. Two patients experienced grade 2 conjunctival congestion, which fully resolved within a month post-treatment. Late toxicities were observed in 24 patients including two cases of cataracts (1 grade 1, 1 grade 2), two cases of grade 3 glaucoma, and three cases of retinopathy (2 grade 2, 1 grade 3). Three patients developed brain injury one year post-treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of toxicities\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eAcute Toxicities\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"8\" nameend=\"c14\" namest=\"c7\"\u003e \u003cp\u003eLate Toxicities\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpiphora\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDry eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConjunctival congestion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriorbital edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased vision\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCataract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlaucoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRetinopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding visual status. Three patients developed grade 1 visual impairment during acute phase. Two of these patients received CIRT (63GyE/18Fx and 70GyE/20Fx). One maintained grade 1 decreased vision at last follow-up of 6 years, while the other progressed to grade 3 two years post-treatment. The third patient, re-irradiation with CIRT (70GyE/20Fx) experienced worsening vision and eventually vision loss 4 months post-treatment. In the late phase, 13 patients experienced vision decline. Five patients had grade 1\u0026ndash;2 deceased vision, while 8 had grade 3 or 4 (CIRT dose of 60-70GyE/18-20Fx). The median time to serve decreased vision (grade 3/4) was 11.5 months (4\u0026ndash;24 months).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e Our retrospective study analyzed 61 patients with malignant orbital tumors treated with ESS or biopsy followed by PBRT. With a median follow-up of 40.7 months (44.3 months for surviving patients), the 3- and 5-year DSS and LC rates were 88.1% and 69.9%, respectively, and the 3- and 5-year DMC rates were 77.5% and 74.2%. For lacrimal gland carcinoma, the 5-year DSS, LC, DMC, and PFS rates were 83.3%, 64.8%, 66.8%, and 53.4%. Tumor size, T stage, extraorbital invasion, and bone invasion influenced survival, as detailed in the following sections.\u003c/p\u003e \u003cp\u003eA multidisciplinary approach involving ESS and postoperative radiotherapy is gaining favor for malignant orbital tumors[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In 2019, studies by Jie Yang et al.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and Hung JY et al.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] on lacrimal ACC treated with photon radiotherapy after ESS reported a 5-year LC rate of 20%, with 50\u0026ndash;70% local recurrence. PBRT, with its superior dose distribution and biological effectiveness, has since been increasingly adopted. For patients with biopsy or residual disease, higher doses can enhance local control. Paul Lesueur et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reported 5-year OS and LC rates of 78% and 60% for PBT, exceeding photon therapy outcomes.\u003c/p\u003e \u003cp\u003eCarbon ion radiation (CIRT) offers superior dose distribution and higher biological efficacy, though reports on its use for malignant orbital tumors are limited. In 2019, we reported early outcomes, and this study extends the follow-up to a median of 40.7 months[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The 3- and 5-year DSS rates were 88.1%, while the LC rates were 69.9%. DMC rates were 77.5% and 74.2%, with PFS rates of 58.1% and 55.2%, respectively. For patients without radiologically detectable gross lesions (36.1%), the 5-year LC and DSS rates were 82.9% and 86.1%. Patients with gross lesions (63.9%) received high-dose radiotherapy (CIRT of 70\u0026ndash;72 GyE/18\u0026ndash;20 fractions or IMPT 56 GyE/28 fractions combined with CIRT 15 GyE/5 fractions), with 5-year LC and DSS rates of 64.1% and 71.8%. However, both univariate and multivariate analyses showed the presence of gross lesions did not a significant prognostic factor for survivals. Therefore, high-dose PBRT may contribute to disease control. Tumor size\u0026thinsp;\u0026ge;\u0026thinsp;4 cm increased DM incidence and reduced DSS rates, however there was no significant impact on LC rates. These findings may underscore adequate dosing to the gross tumor is critical for local control. In univariate analysis, extraorbital invasion decreased 5-year DSS rates (61.9% vs. 97.7%), but no significant differences in LC or DM rates, and multivariate analysis also showed a significantly increased risk of DM, which may partially explain the lower DSS rate. In a retrospective study, Randa Tao et al.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] included multiple types such as ACC, SCC, and adenocarcinoma and found that the pathological type did not affect OS. In our study, we categorized all patients into three groups: epithelial tumors, sarcomas, and melanoma. Multivariate analysis indicated a higher risk of DM in melanoma. Given the limited sample size, this conclusion may be biased. Generally, the efficacy of treatment for recurrent or re-irradiated diseases is unsatisfactory. In our cohort, recurrence or re-irradiation was associated with lower DSS in univariate analysis. Intraorbital tumors showed a tendency for disease progression in multivariate analysis, but pathological type may influence outcomes (93.3% of these patients had sarcomas or chondrosarcomas), this conclusion requiring further validation.\u003c/p\u003e \u003cp\u003eLacrimal tumors made up 59% of the cohort. The 5-year DSS, LC, DMC, and PFS rates were 83.3%, 64.8%, 66.8%, and 53.4%, respectively. Previous studies reported 5-year OS rate of photon radiotherapy after ESS ranging from 37\u0026ndash;65% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. While a study by Ford JR et al. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], with 49% of patients received PBT showed 5-year DSS and LC rates of 81% and 71%. Sati Akbaba et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] reported outcomes of combination of photon and CIRT, with 5-year OS and LC rates of 68% and 44%. Japanese researchers use CIRT alone for locally advanced lacrimal tumors, with 5-year OS, LC, and DFS rates of 65%, 62%, and 34% [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In our cohort, 36.1% had R0-R1 margins with 5-year DSS, LC and DMC rates of 72.7%, 80.8% and 76.9%. For patients with gross lesions (63.9%), the 5-year DSS, LC, DMC, and PFS rates were 87%, 58.2%, 63%, and 48.4%. Although no significant differences in survivals between patients with or without gross lesions, we advocate high-dose treatment for those with gross lesions.\u003c/p\u003e \u003cp\u003eACC was the most common histological type in lacrimal tumor, accounting for 72.2%, consistent with data from MD Anderson[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], Moorfields Eye Hospital[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], Samsung Medical Center[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and Heidelberg Ion-Beam Therapy Center[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Due to its radioresistance, local recurrence of photon radiotherapy is around 50%[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Studies by Natalie Wolkow et al.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and Paul Lesueur et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] on lacrimal ACC treated with photon and PBT or PBT alone reported lower local recurrence rates of 22% and 20%, with 5-year LC and OS rates of 60% and 78%. Sati Akbaba et al.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] reported 5-year LC and OS rate of 21% and 71% for lacrimal ACC treated with photon and CIRT or CIRT alone. Among our patients with lacrimal ACC, 65.4% had gross lesions, and 5-year DSS, LC, DMC, and PFS rates of 89.3%, 60.1%, 66.3%, and 52.9%, respectively. These outcomes suggest PBRT may offer a survival advantage over photon radiotherapy for ACC, supporting its prioritization in treatment. Our univariate analysis showed a worse DSS rate for adenocarcinoma compared to ACC, but with only 7 cases of adenocarcinoma, this requires validation with a larger sample.\u003c/p\u003e \u003cp\u003eMultiple studies have shown that advanced T-stage is linked to poorer OS[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and higher DM rates[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In our univariate analysis, T3/4 disease correlated with increased DM and reduced DSS, though LC rates were unaffected. Since T-stage is associated with tumor size, bone invasion, and extraconal extension, we analyzed these factors individually. Tumor size\u0026thinsp;\u0026ge;\u0026thinsp;3 cm was associated with a higher risk of DM, although LC rate remained unaffected. When the tumors\u0026thinsp;\u0026ge;\u0026thinsp;4 cm, not only an increased risk of DM and reduced DSS, but also reduced LC rates. Multivariate analysis confirmed larger tumors were more prone to disease progression. Skinner HD et al.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] also reported the incidence of DM was higher when tumors\u0026thinsp;\u0026ge;\u0026thinsp;3.5 cm. The lacrimal gland is firmly anchored to the orbital periosteum and lacrimal tumors may directly invade the orbital bone. Bone invasion was reported common in tumors\u0026thinsp;\u0026gt;\u0026thinsp;2 cm[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and significantly reduced DSS rates[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Our analysis also showed bone invasion not only reduced LC rate but also increased metastasis risk. Therefore, High-dose irradiation is recommended for bone-involved areas. The study by Noh JM et al.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] found that the 5-year survivals were poor in lacrimal ACC with extraorbital extension. Similarly in our study, extraorbital invasion linked to reduced DSS and higher DM rates, though LC was unaffected.\u003c/p\u003e \u003cp\u003eAlthough some reported PNI as a negative factor for survivals[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], others suggested it has no significant impact[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Our analysis showed better DSS rate in patients with PNI, likely due to bias. Since all 4 PNI-negative patients had adverse factors like bone invasion, T4 stage, or re-irradiation. Thus, we excluded PNI from our multivariate analysis.\u003c/p\u003e \u003cp\u003eDespite advancements in ocular preservation through ESS and adjuvant radiotherapy, managing radiation-induced toxicities remains challenging. In a study by Holliday EB et al.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], after a median dose of 60 GyE, 35% of patients experienced Grade 3 acute dermatitis, and 30% developed chronic Grade 3 toxicities. Paul Lesueur et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reported no Grade 3 or higher acute toxicities with 73.8 GyE of PBT, but chronic toxicities included brain injury (27%), hyperprolactinemia (40%), and rare cases of cataracts, keratitis, and osteitis. Japanese study[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] on high-dose CIRT did not result in Grade 3 or higher acute toxicities, however significant late toxicities were observed such as Grade 4 optic nerve injury (36.4%), brain injury (6%), and Grade 3 keratitis (9%). In our center, most toxicities were mild, such as Grade 1 edema, epiphora, dry eye, or conjunctivitis. Among late toxicities, aside from vision deterioration, the common symptom was Grade 1 dry eye (9.8%) and brain injury (4.9%). Regarding visual outcomes, three patients (4.9%) experienced Grade 1 vision impairment during the acute phase. Vision decline occurred in 10 patients during the late phase. Four patients experienced vision deterioration 4 to 7 months post-treatment, two patients around 1 year, and two patients at 2 years. Grade 3\u0026ndash;4 vision loss emerging at a median of 11.5 months post-treatment.\u003c/p\u003e \u003cp\u003eOur study has several limitations. The low incidence of orbital tumors and varying biological behaviors of different pathological types introduce bias. Future studies should aim to increase the number of patients and analyze specific pathological types for greater accuracy. Additionally, no cases of cavernous sinus recurrence were observed. Therefore, for patients with lesions confined to the orbit, the cavernous sinus was excluded form irradiation field, though this warrants further study and longer follow-up. Lastly, currently studies are single-institution and focus on either proton or CIRT. In the future, prospective randomized studies are needed to optimize treatment strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDespite the retrospective nature and modest number of patients, we can still come to the conclusion that proton and carbon ion beam radiation provided a favorable local control and survivals after eye-preserving treatment, and even in patients with unresectable disease. No severe acute PBRT induced toxicity was observed, and severe late toxicity was observed in \u0026lt;\u0026thinsp;15% of cases. Particle radiotherapy was a promising strategy for management of orbital tumors.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIMPT: Intensity-modulated proton therapy\u003c/p\u003e\n\u003cp\u003ePBT: Proton beam therapy\u003c/p\u003e\n\u003cp\u003eCIRT: Carbon-ion radiotherapy\u003c/p\u003e\n\u003cp\u003ePBRT: Particle radiotherapy\u003c/p\u003e\n\u003cp\u003ePBS: Pencil beam scanning\u003c/p\u003e\n\u003cp\u003eACC: Adenoid cystic carcinoma\u003c/p\u003e\n\u003cp\u003eSCC: Squamous cells carcinoma\u003c/p\u003e\n\u003cp\u003eESS: Eye-sparing surgery\u003c/p\u003e\n\u003cp\u003ePNI: Perineural invasion\u003c/p\u003e\n\u003cp\u003eOE: Orbital exenteration\u003c/p\u003e\n\u003cp\u003eLET: High-linear energy transfer\u003c/p\u003e\n\u003cp\u003eLC: Local control\u003c/p\u003e\n\u003cp\u003eDMC: Distant metastasis control\u003c/p\u003e\n\u003cp\u003eDSS: Disease-specific survival\u003c/p\u003e\n\u003cp\u003ePFS: Progression free survival\u003c/p\u003e\n\u003cp\u003eDFS: Disease free survival\u003c/p\u003e\n\u003cp\u003eGTV: Gross tumor volume\u003c/p\u003e\n\u003cp\u003eCTV: clinical target volume\u003c/p\u003e\n\u003cp\u003ePTV: Planning target volume\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been granted an exemption form the requirement of written informed consent and human participants in this study were reviewed and approved by institutional review board (IRB) of Shanghai Proton and Heavy Ion Center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare there is no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Shanghai Municipal Commission of Health (Grants No. 202040280); Pudong New Area Science and Technology Development Fund (Grants No. PKJ2022-Y52); Key Research and Development Program of the Ministry of Science and Technology (Grants No. 2022YFC2401505)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWeixu Hu and Qiong Cai contributed equally as co-first authors. Weixu Hu: design the study, collect data and analysis, interpretation, drafting, revising the article and final approval. Qiong Cai: collect data and analysis, drafting, revising the article and final approval. Jiyi Hu: data collection, data analysis, revision and final approval. Qingting Huang: collect data, drafting, revision and approve of the version. Jing Gao: collect data, revision and approve of the version. Haojiong Zhang: collect patient\u0026rsquo;s data, and approve of the version. Lin Kong: Conceptualization and design study, supervision, data analysis and results interpretation, revising the article, funding acquisition, final approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKim JS, Al-Lozi A, Leyngold IM: \u003cstrong\u003eMalignant Orbital Tumors: Current Approach to Diagnosis and Management\u003c/strong\u003e. \u003cem\u003eCurrent Ophthalmology Reports \u003c/em\u003e2021, \u003cstrong\u003e9\u003c/strong\u003e(1):16-24.\u003c/li\u003e\n\u003cli\u003eFord JR, Rubin ML, Frank SJ, Ning J, Debnam JM, Bell D, El-Naggar A, Ferrarotto R, Esmaeli B: \u003cstrong\u003ePrognostic factors for local recurrence and survival and impact of local treatments on survival in lacrimal gland carcinoma\u003c/strong\u003e. \u003cem\u003eBr J Ophthalmol \u003c/em\u003e2021, \u003cstrong\u003e105\u003c/strong\u003e(6):768-774.\u003c/li\u003e\n\u003cli\u003eBonavolonta P, Esmaeli B, Donna P, Tranfa F, Iuliano A, Abbate V, Fossataro F, Attanasi F, Bonavolonta G: \u003cstrong\u003eOutcomes after eye-sparing surgery vs orbital exenteration in patients with lacrimal gland carcinoma\u003c/strong\u003e. \u003cem\u003eHead Neck \u003c/em\u003e2020, \u003cstrong\u003e42\u003c/strong\u003e(5):988-993.\u003c/li\u003e\n\u003cli\u003eRose GE, Gore SK, Plowman NP: \u003cstrong\u003eCranio-orbital Resection Does Not Appear to Improve Survival of Patients With Lacrimal Gland Carcinoma\u003c/strong\u003e. \u003cem\u003eOphthalmic Plast Reconstr Surg \u003c/em\u003e2019, \u003cstrong\u003e35\u003c/strong\u003e(1):77-84.\u003c/li\u003e\n\u003cli\u003evan de Water TA, Bijl HP, Schilstra C, Pijls-Johannesma M, Langendijk JA: \u003cstrong\u003eThe potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: a systematic review of literature\u003c/strong\u003e. \u003cem\u003eOncologist \u003c/em\u003e2011, \u003cstrong\u003e16\u003c/strong\u003e(3):366-377.\u003c/li\u003e\n\u003cli\u003eKhan FM: \u003cstrong\u003eThe Physics of Radiation Therapy\u003c/strong\u003e: Lippincott Williams \u0026amp; Wilkins; 2009.\u003c/li\u003e\n\u003cli\u003eHirohiko Tsujii TK, Masayuki Baba, Hiroshi Tsuji, Hirotoshi Kato, Shingo Kato, Shigeru Yamada, Shigeo Yasuda, Takeshi Yanagi, Hiroyuki Kato, Ryusuke Hara, Naotaka Yamamoto, Junetsu Mizoe: \u003cstrong\u003eClinical advantages of carbon-ion radiotherapy\u003c/strong\u003e. \u003cem\u003eNew Journal of Physics \u003c/em\u003e2008, \u003cstrong\u003e10\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eKanai T, Endo M, Minohara S, Miyahara N, Koyama-ito H, Tomura H, Matsufuji N, Futami Y, Fukumura A, Hiraoka T\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eBiophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy\u003c/strong\u003e. \u003cem\u003eInt J Radiat Oncol Biol Phys \u003c/em\u003e1999, \u003cstrong\u003e44\u003c/strong\u003e(1):201-210.\u003c/li\u003e\n\u003cli\u003eElsasser T, Kramer M, Scholz M: \u003cstrong\u003eAccuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo\u003c/strong\u003e. \u003cem\u003eInt J Radiat Oncol Biol Phys \u003c/em\u003e2008, \u003cstrong\u003e71\u003c/strong\u003e(3):866-872.\u003c/li\u003e\n\u003cli\u003eJones B: \u003cstrong\u003eA Simpler Energy Transfer Efficiency Model to Predict Relative Biological Effect for Protons and Heavier Ions\u003c/strong\u003e. \u003cem\u003eFront Oncol \u003c/em\u003e2015, \u003cstrong\u003e5\u003c/strong\u003e:184.\u003c/li\u003e\n\u003cli\u003eKarcioglu ZA, Hadjistilianou D, Rozans M, DeFrancesco S: \u003cstrong\u003eOrbital rhabdomyosarcoma\u003c/strong\u003e. \u003cem\u003eCancer Control \u003c/em\u003e2004, \u003cstrong\u003e11\u003c/strong\u003e(5):328-333.\u003c/li\u003e\n\u003cli\u003eWoo KI, Kim YD, Sa HS, Esmaeli B: \u003cstrong\u003eCurrent treatment of lacrimal gland carcinoma\u003c/strong\u003e. \u003cem\u003eCurr Opin Ophthalmol \u003c/em\u003e2016, \u003cstrong\u003e27\u003c/strong\u003e(5):449-456.\u003c/li\u003e\n\u003cli\u003eHan J, Kim YD, Woo KI, Sobti D: \u003cstrong\u003eLong-Term Outcomes of Eye-Sparing Surgery for Adenoid Cystic Carcinoma of Lacrimal Gland\u003c/strong\u003e. \u003cem\u003eOphthalmic Plast Reconstr Surg \u003c/em\u003e2018, \u003cstrong\u003e34\u003c/strong\u003e(1):74-78.\u003c/li\u003e\n\u003cli\u003eEsmaeli B, Yin VT, Hanna EY, Kies MS, William WN, Jr., Bell D, Frank SJ: \u003cstrong\u003eEye-sparing multidisciplinary approach for the management of lacrimal gland carcinoma\u003c/strong\u003e. \u003cem\u003eHead Neck \u003c/em\u003e2016, \u003cstrong\u003e38\u003c/strong\u003e(8):1258-1262.\u003c/li\u003e\n\u003cli\u003eWoo KI, Yeom A, Esmaeli B: \u003cstrong\u003eManagement of Lacrimal Gland Carcinoma: Lessons From the Literature in the Past 40 Years\u003c/strong\u003e. \u003cem\u003eOphthalmic Plast Reconstr Surg \u003c/em\u003e2016, \u003cstrong\u003e32\u003c/strong\u003e(1):1-10.\u003c/li\u003e\n\u003cli\u003eYang J, Zhou C, Wang Y, Fan X, Jia R: \u003cstrong\u003eMultimodal therapy in the management of lacrimal gland adenoid cystic carcinoma\u003c/strong\u003e. \u003cem\u003eBMC Ophthalmol \u003c/em\u003e2019, \u003cstrong\u003e19\u003c/strong\u003e(1):125.\u003c/li\u003e\n\u003cli\u003eHung JY, Wei YH, Huang CH, Chen LW, Fuh CS, Liao SL: \u003cstrong\u003eSurvival outcomes of eye-sparing surgery for adenoid cystic carcinoma of lacrimal gland\u003c/strong\u003e. \u003cem\u003eJpn J Ophthalmol \u003c/em\u003e2019, \u003cstrong\u003e63\u003c/strong\u003e(4):344-351.\u003c/li\u003e\n\u003cli\u003eLesueur P, Rapeaud E, De Marzi L, Goudjil F, Levy C, Galatoire O, Jacomet PV, Dendale R, Calugaru V: \u003cstrong\u003eAdenoid Cystic Carcinoma of the Lacrimal Gland: High Dose Adjuvant Proton Therapy to Improve Patients Outcomes\u003c/strong\u003e. \u003cem\u003eFront Oncol \u003c/em\u003e2020, \u003cstrong\u003e10\u003c/strong\u003e:135.\u003c/li\u003e\n\u003cli\u003eHu W, Hu J, Gao J, Yang J, Qiu X, Kong L, Lu JJ: \u003cstrong\u003eOutcomes of orbital malignancies treated with eye-sparing surgery and adjuvant particle radiotherapy: a retrospective study\u003c/strong\u003e. \u003cem\u003eBMC Cancer \u003c/em\u003e2019, \u003cstrong\u003e19\u003c/strong\u003e(1):776.\u003c/li\u003e\n\u003cli\u003eTao R, Ma D, Takiar V, Frank SJ, Fuller CD, Gunn GB, Beadle BM, Morrison WH, Rosenthal DI, Edson MA\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eOrbital carcinomas treated with adjuvant intensity-modulated radiation therapy\u003c/strong\u003e. \u003cem\u003eHead Neck \u003c/em\u003e2016, \u003cstrong\u003e38 Suppl 1\u003c/strong\u003e:E580-587.\u003c/li\u003e\n\u003cli\u003eAkbaba S, Lang K, Held T, Herfarth K, Rieber J, Plinkert P, Auffarth GU, Rieken S, Debus J, Adeberg S: \u003cstrong\u003eCarbon-ion radiotherapy in accelerated hypofractionated active raster-scanning technique for malignant lacrimal gland tumors: feasibility and safety\u003c/strong\u003e. \u003cem\u003eCancer Manag Res \u003c/em\u003e2019, \u003cstrong\u003e11\u003c/strong\u003e:1155-1166.\u003c/li\u003e\n\u003cli\u003eHayashi K, Koto M, Ikawa H, Ogawa K, Kamada T: \u003cstrong\u003eEfficacy and safety of carbon-ion radiotherapy for lacrimal gland carcinomas with extraorbital extension: a retrospective cohort study\u003c/strong\u003e. \u003cem\u003eOncotarget \u003c/em\u003e2018, \u003cstrong\u003e9\u003c/strong\u003e(16):12932-12940.\u003c/li\u003e\n\u003cli\u003eWoo KI, Sagiv O, Han J, Frank SJ, Kim YD, Esmaeli B: \u003cstrong\u003eEye-Preserving Surgery Followed by Adjuvant Radiotherapy for Lacrimal Gland Carcinoma: Outcomes in 37 Patients\u003c/strong\u003e. \u003cem\u003eOphthalmic Plast Reconstr Surg \u003c/em\u003e2018, \u003cstrong\u003e34\u003c/strong\u003e(6):570-574.\u003c/li\u003e\n\u003cli\u003eWolkow N, Jakobiec FA, Lee H, Sutula FC: \u003cstrong\u003eLong-term Outcomes of Globe-Preserving Surgery With Proton Beam Radiation for Adenoid Cystic Carcinoma of the Lacrimal Gland\u003c/strong\u003e. \u003cem\u003eAm J Ophthalmol \u003c/em\u003e2018, \u003cstrong\u003e195\u003c/strong\u003e:43-62.\u003c/li\u003e\n\u003cli\u003eLin YH, Huang SM, Yap WK, Yang JW, Yeung L, Tsan DL, Chang JT, Chen LC: \u003cstrong\u003eOutcomes in patients with lacrimal gland carcinoma treated with definitive radiotherapy or eye-sparing surgery followed by adjuvant radiotherapy\u003c/strong\u003e. \u003cem\u003eRadiat Oncol \u003c/em\u003e2020, \u003cstrong\u003e15\u003c/strong\u003e(1):156.\u003c/li\u003e\n\u003cli\u003eNoh JM, Lee E, Ahn YC, Oh D, Kim YD, Woo KI, Ko YH, Kim S: \u003cstrong\u003eClinical significance of post-surgical residual tumor burden and radiation therapy in treating patients with lacrimal adenoid cystic carcinoma\u003c/strong\u003e. \u003cem\u003eOncotarget \u003c/em\u003e2016, \u003cstrong\u003e7\u003c/strong\u003e(37):60639-60646.\u003c/li\u003e\n\u003cli\u003eSkinner HD, Garden AS, Rosenthal DI, Ang KK, Morrison WH, Esmaeli B, Pinnix CC, Frank SJ: \u003cstrong\u003eOutcomes of malignant tumors of the lacrimal apparatus: the University of Texas MD Anderson Cancer Center experience\u003c/strong\u003e. \u003cem\u003eCancer \u003c/em\u003e2011, \u003cstrong\u003e117\u003c/strong\u003e(12):2801-2810.\u003c/li\u003e\n\u003cli\u003eWilliams MD, Al-Zubidi N, Debnam JM, Shinder R, DeMonte F, Esmaeli B: \u003cstrong\u003eBone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations\u003c/strong\u003e. \u003cem\u003eOphthalmic Plast Reconstr Surg \u003c/em\u003e2010, \u003cstrong\u003e26\u003c/strong\u003e(6):403-408.\u003c/li\u003e\n\u003cli\u003eHolliday EB, Esmaeli B, Pinckard J, Garden AS, Rosenthal DI, Morrison WH, Kies MS, Gunn GB, Fuller CD, Phan J\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eA Multidisciplinary Orbit-Sparing Treatment Approach That Includes Proton Therapy for Epithelial Tumors of the Orbit and Ocular Adnexa\u003c/strong\u003e. \u003cem\u003eInt J Radiat Oncol Biol Phys \u003c/em\u003e2016, \u003cstrong\u003e95\u003c/strong\u003e(1):344-352.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Orbital tumors, lacrimal gland tumors, proton beam radiation, carbon ion beam radiation, eye-preserving, survival","lastPublishedDoi":"10.21203/rs.3.rs-5262260/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5262260/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis retrospective study report the clinical experience of eye-preserving treatment follow by particle beam radiotherapy (IMPT or CIRT) for orbital malignancies. And to evaluate prognostic factors for orbital and lacrimal gland tumors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSixty-two patients with orbital malignancies were identified in the records of a single center between 2015 and 2021. Sixty-one patients met inclusion criteria. All of the patients received eye-preserving treatment before PBRT. Majority of the patients (91.8%) were treatment with CIRT. Clinical data, treatment modality, local control, metastases and survivals and visual outcomes, as well as associated prognostic indicators were were assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSixty-one patients were followed with a median of 40.7 months (44.3 months for surviving patients). The 3- and 5-year DSS and LC rates were 88.1% and 69.9%, and the 3- and 5-year DMC rates were 77.5% and 74.2% for entire orbital malignancies. For lacrimal gland carcinoma, the 5-year DSS, LC, DMC, and PFS rates were 83.3%, 64.8%, 66.8%, and 53.4%. Tumor size, T stage, extraorbital invasion, and bone invasion influenced survivals. No grade 3 or higher acute toxicities were observed. A total of 8 patients experienced grade 3\u0026ndash;4 visual impairment.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eParticle radiotherapy following eye-preserving treatment provided a favorable local control and survivals with moderate acute and late toxicities, even in patients with unresectable disease. Particle radiotherapy was a promising strategy for management of orbital tumors.\u003c/p\u003e","manuscriptTitle":"Long-term Outcomes and Prognostic Factors of Eye-preserving Treatment with Particle Beam Radiotherapy for Orbital Malignancies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-23 10:29:09","doi":"10.21203/rs.3.rs-5262260/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c9d39e1a-93b9-4668-97a5-88e68dbe661f","owner":[],"postedDate":"October 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-26T11:53:30+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-23 10:29:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5262260","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5262260","identity":"rs-5262260","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}