Chapter 26

Lacrimal and Canalicular Toxicity

M. Amir Ahmadi and Bita Esmaeli

Abstract The lacrimal drainage system, which is covered by a highly proliferative epithelium, is susceptible to the side effects of chemotherapy drugs, which are secreted in tears. Docetaxel, an antineoplastic agent widely used to treat patients with advanced breast cancer as well as other malignancies, is secreted in tears almost immediately after intravenous administration and thus may cause canalicular inflammation and tear drainage obstructions. 5-Fluorouracil (5-FU), another frequently used chemotherapeutic agent, commonly causes increased lacrimation. Stenosis of the punctum and canaliculi is a less common side effect of systemic 5-FU therapy. To prevent the need for dacryocystorhinostomy or placement of permanent Pyrex glass lacrimal drainage tubes, patients undergoing treatment with docetaxel or 5-FU should be closely monitored for punctal and canalicular stenosis.

26.1 Introduction

Chemotherapeutic agents work primarily by interfering with DNA synthesis and mitosis, thereby leading to cell death and a reduction in the number of tumor cells. For this reason, chemotherapy’s major side effects are on normal, highly proliferative tissues like the epithelium of skin and internal organs. The lacrimal drainage system is covered by a highly proliferative epithelium; therefore, it is susceptible to chemotherapeutic agents’ side effects. Furthermore, several studies have shown that systemic chemotherapeutic agents are secreted in tears by the lacrimal glands. This explains the direct effects of systemic chemotherapy on the lacrimal secretory and drainage system.

M.A. Ahmadi (B)

Department of Ophthalmology, University of Illinois at Chicago, Chicago, IL, USA e-mail: mamirahmadi@yahoo.com

Oncology Series 6, DOI 10.1007/978-1-4419-0374-7_26,

C Springer Science+Business Media, LLC 2011

26.2 5-Fluorouracil

5-Fluorouracil (5-FU) was first used as a chemotherapeutic agent for gastrointestinal carcinomas in 1958 [1]. It is now widely used in the treatment of gastrointestinal, breast, and head and neck malignancies. 5-FU inhibits thymidylate synthetase and causes DNA strand breakage [2]. Like many other chemotherapeutic agents, it has its greatest effect on rapidly dividing cells, such as epithelial cells.

Increased lacrimation, which resolves after chemotherapy is completed, is common with 5-FU and has been widely documented in the literature [3, 4]. Stenosis of the punctum and canaliculi is a less common side effect of systemic 5-FU therapy. Stenosis of the lacrimal system in patients treated with intravenous administration of 5-FU was first described by Caravella et al. [5] in a report of four patients in 1981. Several subsequent studies have suggested that 5-FU administered intravenously can cause inflammation of the canalicular mucosa, which can lead to fibrosis of the canaliculi and resultant lacrimal outflow obstruction [6–8]. In a study of 58 patients who received systemic 5-FU, Eiseman et al. [9] reported a prevalence of tearing of 24.1% (14 patients). The average time to onset of tearing after treatment with 5-FU in those patients who experienced excessive tearing was 3 weeks (standard deviation, 0.9 weeks). Three of 14 patients with excessive tearing (5.2%) had punctal and/or canalicular abnormalities [9]. Other studies reported a similar prevalence of tearing associated with systemic 5-FU [4, 10].

Despite multiple reports of the ocular side effects of 5-FU, it has been difficult to prove that those effects have been solely related to the use of 5-FU since most patients studied in the published reports were receiving multiple chemotherapeutic medications at the same time.

Several factors have been suggested as being responsible for excessive tearing in patients receiving 5-FU treatment. One theory is that tearing is a reflex phenomenon secondary to the irritation caused by the ocular surface disturbance. Two studies have shown that 5-FU is secreted in tears after intravenous administration and can thus bathe the ocular surface in the toxic substance [10, 11]. This would explain punctal and canalicular stenosis in patients receiving intravenous 5-FU. Evidence that topically applied 5-FU causes ocular surface toxicity, which can lead to excessive tearing, can be found in the results of several other studies [12, 13]. One of these studies found that the application of topical 5-FU in a rabbit model decreased the mitotic rate of both corneal and conjunctival epithelial cells to 1% of the normal rate [12]. In another study, over half the patients who had glaucoma-filtering surgery and were treated with postoperative subconjunctival 5-FU injections developed corneal epithelial defects and often took several weeks to resolve [13]. Finally, eyelid malposition from dermatitis and cicatricial changes, with subsequent punctal eversion and compromise of the lacrimal pump, could also be a cause of excessive tearing [9].

26.3 S-1

S-1 is a prodrug that consists of the 5-FU prodrug tegafur combined with two modulators: 5-chloro-2,4-dihydroxypyridine and potassium oxonate [14]. S-1 is an oral medication and is reportedly less toxic, with fewer gastrointestinal side effects, than 5-FU administered intravenously [15, 16]. Although it is expected that S-1 will have the same lacrimal side effects as 5-FU, there are only a few reported cases of punctal or canalicular stenosis linked to S-1 in the literature [17]. This could be a result of the medication’s novelty, and more cases will be reported as more patients are treated with this new chemotherapeutic agent. S-1 is approved for use in gastrointestinal cancer in Japan, but it is not yet approved by the United States Food and Drug Administration.

26.4 Docetaxel

Docetaxel (Taxotere) is an antineoplastic agent widely used for treatment of patients with advanced breast cancer as well as for treatment of patients with other malignancies [18–20]. Docetaxel belongs to a class of antineoplastic agents known as taxanes, which act by causing apoptotic cell death. Esmaeli et al. [21] initially reported three patients with metastatic breast carcinoma in whom epiphora and canalicular stenosis developed while the patients were undergoing weekly docetaxel treatment.

Subsequent studies showed evidence of secretion of docetaxel in tears almost immediately after intravenous administration of the medication [22]. The secretion of docetaxel in tears may be a mechanism for canalicular inflammation and tear drainage obstructions.

Docetaxel tends to cause more ocular side effects when administered every week versus every 3 weeks. In a prospective study, epiphora occurred in 64% of patients who received weekly docetaxel versus 39% of patients who received docetaxel every 3 weeks, even when the cumulative dose was the same as in the weekly group [23]. The mean interval between initiation of docetaxel and onset of epiphora was 2 months in patients who received docetaxel weekly and 3 months in patients who received docetaxel every 3 weeks. The median cumulative docetaxel dose at the onset of epiphora was 496.5 mg for patients in the weekly group and 420 mg for patients in the every-3-weeks group [23].

In patients who developed epiphora because of weekly docetaxel, half had mild symptoms that improved with the administration of topical steroids, but the other half developed moderate or severe canalicular stenosis. Two-thirds of the patients with moderate or severe canalicular stenosis needed surgical intervention. At the time of surgery, the median cumulative docetaxel dose was 889.5 mg, and the median duration of treatment was 16 weeks. All the patients in the every-3-weeks group who developed epiphora had mild disease, and the epiphora improved with probing and irrigation and administration of topical steroids [23].

Patients who needed surgical repair in the early stages of canalicular stenosis benefited from temporary silicone intubation. The silicone tube was removed after the end of the chemotherapy course, leaving behind no residual stenosis of the canaliculi. Patients with more severe forms of stenosis needed permanent Pyrex glass tube placement. The study showed that early temporary silicone intubation in symptomatic patients receiving weekly docetaxel can prevent further closure of the lacrimal drainage apparatus and obviate the more involved surgical intervention of permanent Pyrex glass tube placement [23, 24].

26.5 Epiphora Associated with Other Chemotherapeutic Drugs

We have observed temporary and mild epiphora in association with paclitaxel (Taxol) and capecitabine (Xeloda) but have not observed the anatomic correlate of punctal or canalicular stenosis associated with these drugs. To our knowledge, there has been one reported case of nasolacrimal duct blockage and canalicular stenosis in a patient who received paclitaxel, but this patient also received head and neck radiation therapy, which is by itself a risk factor for canalicular stenosis and nasolacrimal duct blockage; thus, it is unlikely that paclitaxel causes anatomic closure of canaliculi and nasolacrimal ducts [25, 26].

Similarly, imatinib mesylate can be associated with the onset of epiphora in patients with gastrointestinal stromal tumors or chronic myelogenous leukemia who take this drug on a long-term basis. However, in our experience, the epiphora from imatinib is not associated with the anatomic correlate of punctal and/or canalicular stenosis or nasolacrimal duct blockage [27]. We believe that epiphora in these patients is caused by fluid retention in the periorbital soft tissues and conjunctival chemosis, causing an inefficient blink and lacrimal pump. It can be treated with nonsurgical measures such as the use of systemic diuretics or topical steroids.

26.6 Conclusions

It is important to look for and recognize significant punctal and canalicular stenosis as side effects of treatment with 5-FU, S-1, and docetaxel in early stages so that the judicious use of topical steroids and silicone intubation can prevent the need for a more involved surgery, such as dacryocystorhinostomy or placement of permanent Pyrex glass lacrimal drainage tubes.

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