Outcomes in patients with lacrimal gland carcinoma treated with definitive radiotherapy or eye-sparing surgery followed by adjuvant radiotherapy

Eye-sparing surgery with adjuvant radiotherapy can achieve satisfactory results in patients with T1–2 lacrimal gland carcinoma. Disease stage T3 and above was associated with poor outcomes even with post-operative RT, likely due to distant metastasis.

Lacrimal gland tumors are among the rarest types of head and neck cancers, accounting for approximately 10% of all orbital tumors [1]. Previous studies have estimated annual incidence for these tumors at 0.19–1 per 1,000,000 people [1‐3]. Epithelial lesions, including benign pleomorphic adenoma and malignant tumors, account for 20–30% of all lacrimal gland tumors. Malignant epithelial tumors include adenoid cystic carcinoma (ACC) (60%), carcinoma ex pleomorphic adenoma or adenocarcinoma (20–30%), and mucoepidermoid carcinoma (5%) [1, 4, 5]. In contrast, non-epithelial lesions, such as inflammation, lymphoid tumors, plasmacytoma, histiocytoma, lipoma, and hemangioma account for 70–80% of all lacrimal gland tumors [2, 4, 6‐8].

Lacrimal gland carcinomas are associated with poor local control and significant morbidity and mortality rates [9]. To date, no guidelines on standard treatment for lacrimal gland carcinomas have been developed due to the rarity of these diseases, which are conventionally treated with orbital exenteration followed by radiotherapy (RT) [5, 10]. However, locoregional recurrence, distant relapse, and cancer-related mortality risks are high after orbital exenteration [5, 11, 12]. Thus, eye-preserving surgery followed by adjuvant RT has recently gained popularity, but the optimal approaches to surgery and RT in these patients remain subject to debate [5, 9, 13, 14].

In this study, we examined clinical outcomes associated with either eye-preserving surgery followed by adjuvant RT, or needle biopsy followed by definitive RT, in a cohort of 18 patients with lacrimal gland carcinoma. Clinical outcomes such as local control, survival, and ocular complications were considered. The clinical and pathological factors that affected the outcomes were also examined.

This study protocol was reviewed and approved by the institutional review board of Chang Gung Memorial Hospital (Reference No.: 202000138B0). All data were stored in the hospital database and extracted for research. The participants’ informed consent requirement was waived due to the retrospective nature of this study.

This study reported outcomes in patients with lacrimal gland carcinoma who underwent either needle biopsy followed by definitive radiotherapy with or without chemotherapy due to inoperable tumor, or eye-preserving surgical treatment followed by adjuvant radiotherapy with or without chemotherapy. In the present cohort, 2-year OS, LPFS, and DMFS rates were 69.0, 76.7, and 71.4%, respectively. These outcomes were inferior to those reported in previously, which was probably due to differences in patient characteristics. Esmaeli et al. [15] studied the eye-sparing approach to treating lacrimal gland carcinoma in 11 patients during 2007–2014. All 11 patients were disease-free at the last follow-up visit after the eye-sparing surgery, with a median follow-up time of 33 months (range, 14–64 months). A significant proportion of patients recruited by Esmaeli et al. had early-stage disease (one patient with T1, six patients with T2, one with T3, and three with T4). In addition, Han et al. [16] reported outcomes following eye-sparing surgery and adjuvant radiotherapy in 10 patients with adenoid cystic carcinoma of the lacrimal gland, treated during 1998–2012 (one patient with T1, seven with T2, and two with T3 stage disease), at a median follow-up time of 89.5 months (range 37–217 months). Reported OS was 90%, with a single patient who died 58 months after surgery. Moreover, DMFS was 100%, while local recurrence occurred in one patient. In our series, almost half of the patients had advanced-stage lacrimal gland carcinoma (three patients with T3 [16.7%], and five patients with T4 [27.7%]). In addition, the majority of patients were at high risk of locoregional or distant recurrence, with a positive surgical margin in 72.2% of the patients, and confirmed LVSI and PNI in 33.3 and 44.4% of patients, respectively. The differences in patient baseline characteristics may explain the relatively lower OS, LPFS, and DMFS rates reported in our study.

The present study is among a small number that have examined factors affecting outcomes in patients with lacrimal gland carcinoma, which is an aim that is difficult to achieve due to the rarity of this disease. In a previous report by Woo et al., the only tumor characteristic associated with outcome was T stage. In the same study, adjuvant radiotherapy was strongly associated with a better 5-year recurrence-free survival rate [17]. Friedrich and Bleckmann also found that lower T stage was associated with a better prognosis [18]. Among factors reported as negatively affecting patient outcomes were older age, basaloid or solid pattern ACC, perineural invasion, and the presence of a macroscopic tumor on imaging scans before RT. [12, 19‐22] In the present study, among patients who had received adjuvant radiotherapy, T stage and tumor size emerged as the most important factors that determined patient outcome. Specifically, patients with tumor at stage T1–2 treated with eye-sparing surgery followed by adjuvant radiotherapy achieved 100% 2-year LPFS, DMFS, and OS rates. However, tumor stage T3 and higher was associated with poor outcomes even when treated with surgical resection followed by adjuvant RT, which occurred most likely due to distant metastasis. Adding neoadjuvant chemotherapy or adjuvant chemotherapy to current treatment strategies might be a suitable choice for this group of patients to improve the control of distant disease.

Proton therapy or even heavy ion therapy applied to lacrimal gland cancer is considered promising for reducing low dose delivered outside the treated fields [3]. We have observed better dosimetry associated with the proton plan compared to the photon plan. At a high dose (> 70% dose), proton beam dosimetry is equivalent to photon therapy; however, low-dose distribution is better for proton therapy, whereby the 20% isodose line can spare the opposite eye. Ensuring low dose spread to the nearby healthy tissue is critical in certain cases. Lower dose delivered to the regional organ at risk can reduce the likelihood of secondary malignancy and long-term complications, and therefore should be considered for patients with early-stage lacrimal gland cancer who are likely to achieve good local control and long-term survival after the treatment.

Several ocular toxicities were recorded among our patients. These complications were expected as the radiation doses used were mostly above the dose that is well tolerated by ocular structures other than the sclera. Sensitivity to radiation of the ocular structures has been shown to vary [23‐25]. The lens has been reported as the most radiosensitive ocular structure, with a minimum cataractogenic dose of 5.5 Gy. The lacrimal gland, cornea, and conjunctiva can each tolerate up to 50 Gy of radiation. The retina tolerates doses > 55 Gy. The sclera is the most resistant ocular structure and is believed to tolerate doses > 1000 Gy. The majority of ocular complications reported in the present study were effectively managed by ophthalmologists. Only one patient received a punctal plug due to intolerable dry eye and another patient required intravitreous injection of Avastin (bevacizumab) at 1.25 mg due to radiation-associated retinopathy with retinal neovascularization. Therefore, we recommend that all patients who have received RT for lacrimal gland carcinoma visit an ophthalmologic clinic regularly.

This study has some limitations. First, this was a retrospective study based on medical records, which makes selection bias inevitable. Moreover, some of the patients did not attend the ophthalmologic clinic as recommended, making it likely that the rate of ocular complications was underestimated. Second, due to the rarity of lacrimal gland cancer, the small sample size meant that the analysis was unlikely to yield statistically significant results. Finally, the patients receiving proton treatment were only followed for 1–2 years, as our hospital began proton beam therapy in 2017. A longer follow-up period is required to evaluate the effects of proton therapy on patient survival.

In conclusion, eye-sparing surgery with adjuvant RT can achieve satisfactory results in patients with T1–2 lacrimal gland carcinoma. Disease stage T3 and above was associated with poor outcomes even with post-operative RT, probably due to distant metastasis. Adding neoadjuvant or adjuvant chemotherapy to current treatment strategies may be a suitable choice for this group of patients.