Blockage of the lacrimal drainage apparatus as a side effect of docetaxel therapy

Authors


Abstract

BACKGROUND

The current study was conducted to report the severity and management of canalicular and nasolacrimal duct stenosis as a side effect of docetaxel therapy and to report the outcomes of surgical intervention for this condition.

METHODS

The records of 148 patients with epiphora associated with docetaxel therapy who were evaluated at the Ophthalmology Service at The University of Texas M. D. Anderson Cancer Center were reviewed. The frequency of docetaxel administration, the dose intensity, the cumulative dose of docetaxel, and any concomitant chemotherapeutic agents were recorded. Each patient underwent an ophthalmologic examination and in-office probing and irrigation. The patients either were treated with topical steroids or offered a surgical procedure for canalicular stenosis– (silicone intubation, dacryocystorhinostomy [DCR] with the placement of silicone tubes, or DCR with the placement of Pyrex glass tubes), depending on the severity of the canalicular stenosis.

RESULTS

Docetaxel was given weekly in 71 patients, every 2 weeks in 5 patients, and every 3 weeks in 72 patients. Thirty patients (59 eyes) who received weekly docetaxel underwent surgery to correct epiphora. Twenty-three patients (39 eyes) were treated with temporary silicone tube placement, 9 patients (13 eyes) were treated with DCR with temporary silicone tube placement, and 4 patients (7 eyes) were treated with DCR with permanent Pyrex glass tube placement. Twenty-nine of the 30 patients who underwent surgery reported improvement or total resolution of epiphora after the procedure. Ten additional patients (20 eyes) who received weekly docetaxel had complete closure of their canaliculi but elected not to undergo surgery. Of special note were two patients who received weekly docetaxel in the neoadjuvant setting and developed complete closure of the canaliculi. Of the patients who received docetaxel every 2 or 3 weeks, only 3 required a surgical intervention to correct epiphora; none required Pyrex glass tube placement.

CONCLUSIONS

Canalicular and nasolacrimal duct obstruction is a common side effect of weekly docetaxel therapy and can occur even when this drug is used in the neoadjuvant setting. The results of the current study indicate that early temporary silicone intubation in symptomatic patients receiving weekly docetaxel can prevent further closure of the lacrimal drainage apparatus and obviate more involved surgical interventions and permanent Pyrex glass tube placement. Cancer 2003;98:504–7. © 2003 American Cancer Society.

DOI 10.1002/cncr.11527

We have previously reported several patients with irreversible blockage of the lacrimal drainage apparatus as a side effect of the weekly administration of docetaxel.1–4 We have demonstrated that docetaxel is secreted into the tears5 and that the early insertion of temporary silicone tubes may prevent permanent scarring and closure of the canaliculi due to weekly docetaxel treatment.3 In patients with advanced stages of canalicular stenosis, silicone intubation is no longer possible and more complicated surgery (such as dacryocystorhinostomy [DCR] with the placement of a permanent Pyrex® [Corning Consumer Product Co., Elmira, NY] glass tube may be necessary to relieve epiphora (excessive tearing). In patients receiving weekly docetaxel, the early recognition and treatment of epiphora and its underlying anatomic correlate, canalicular stenosis, is crucial so that appropriate and timely insertion of silicone tubes can at least be considered. We herein report on our expanded experience with epiphora and canalicular and nasolacrimal duct blockage resulting from docetaxel therapy in all patients treated for this condition since our discovery of this ocular side effect approximately 3 years ago.

MATERIALS AND METHODS

We reviewed the records of all patients evaluated because of epiphora associated with docetaxel use by the Ophthalmology Service at The University of Texas M. D. Anderson Cancer Center between December 1999 and September 2002. In each case, the hospital chart was reviewed for demographic and clinical information (including age, gender, and cancer diagnosis), and the pharmacy records were reviewed to determine the frequency of docetaxel administration, the dose intensity, and the cumulative dose of docetaxel at the time of presentation to the Ophthalmology Service, as well as any concomitant chemotherapeutic agents that the patient may have received.

Each patient underwent a comprehensive ophthalmologic examination including a formal evaluation of the nasolacrimal ducts and all four canaliculi by in-office probing and irrigation. In each case, the presence or absence of canalicular stenosis and the condition of the nasolacrimal ducts (patent or partially or completely obstructed) were recorded. After in-office probing and irrigation, each patient was treated with a topical steroid (a combination of tobramycin (0.3%) and dexamethasone (0.1%) [Tobradex®; Alcon, Fort Worth, TX]) solution at a dose of 1 drop 4 times a day for 1 week with a tapering dose over the next 4 weeks. The follow-up visits occurred at a frequency of every 4–6 weeks while the patients received docetaxel for as long as they remained symptomatic. If epiphora progressed despite this treatment or if the findings on probing and irrigation suggested progressive narrowing of the canaliculi during the follow-up visit 4 weeks after the initiation of topical steroid therapy, silicone intubation was offered as an option. In patients in whom the placement of silicone tubes was impossible because of total closure of the canaliculi, DCR with placement of a Pyrex glass tube was offered to relieve epiphora. In patients in whom silicone intubation without DCR was not possible but the distal portions of the canaliculi were open enough to permit silicone tube placement, DCR with silicone tube placement was offered. In patients who underwent surgery to correct epiphora, surgery was performed between chemotherapy treatments, and chemotherapy was delivered as planned, without interruption.

RESULTS

A total of 148 patients were evaluated for epiphora associated with docetaxel therapy during the study period. The patients ranged in age from 28–83 years (mean, 54.3 years). There were 21 men and 127 women. The cancer diagnoses included breast carcinoma (123 patients), prostate carcinoma (12 patients), lung carcinoma (9 patients), ovarian carcinoma (2 patients), esophageal carcinoma (1 patient), and squamous cell carcinoma of the tongue (1 patient). All but two patients received docetaxel for the treatment of metastatic disease; the other two received docetaxel in the neoadjuvant setting for breast carcinoma. Docetaxel was given weekly in 71 patients, every 2 weeks in 5 patients, and every 3 weeks in 72 patients. Sixty-nine patients received other concomitant drugs with docetaxel (36 patients received herceptin, 25 patients received doxorubicin, 4 patients received estramustine, and 4 patients received imatinib mesylate).

Thirty patients (59 eyes) who received weekly docetaxel underwent surgery to correct epiphora. Thirty-nine eyes (of 23 patients) were treated with temporary tube placement, 13 eyes (of 9 patients) were treated with DCR with temporary silicone tube placement, and 7 eyes (of 4 patients) were treated with DCR with permanent Pyrex glass tube placement. In the patients who underwent surgery, the median duration of weekly docetaxel therapy at the time of surgery was 24 weeks (range, 11–48 weeks). The median cumulative dose of docetaxel at the time of surgery was 1080 mg (range, 168–2116 mg). In the 30 patients who underwent surgery for lacrimal drainage blockage as a side effect of docetaxel, 29 experienced either total resolution or improvement of their epiphora. In all 29 patients, the lacrimal drainage apparatus remained patent with a follow-up time ranging from 1–22 months (median, 5.5 months). In one patient, the nasolacrimal duct and canaliculi scarred around the inserted silicone tube after DCR and silicone intubation, and thus the patient continued to have epiphora. This individual most likely would have benefited from the placement of a Pyrex glass tube but elected not to undergo additional surgery.

Ten additional patients (20 eyes) who received weekly docetaxel had complete closure of their canaliculi with persistent epiphora but did not undergo the recommended DCR and Pyrex glass tube placement either because of a lack of willingness to live with a permanent Pyrex glass tube or because of other ongoing medical problems.

Eleven additional patients who received weekly docetaxel had moderately severe canalicular stenosis and persistent epiphora but elected not to pursue the recommended surgical intervention of silicone intubation or DCR with silicone tube placement. In 8 of these 11 patients, the docetaxel treatment course was administered near the end at the time of the patient's visit to the Ophthalmology Service; thus, the surgery was recommended for the relief of symptoms rather than prevention of further closure of the canaliculi. Follow-up telephone calls in these 11 patients confirmed that 7 of them continued to have persistent epiphora after discontinuation of docetaxel therapy; all 7 had been off docetaxel therapy for at least 6 months at the time of the follow-up telephone call. One of these 11 patients had resolution of epiphora, and the other 3 patients were not able to be reached.

The remaining 20 patients who received weekly docetaxel reported mild epiphora and mild canalicular stenosis. In these patients, symptoms were mild enough or the anticipated remaining treatment duration was short enough that no surgical intervention was recommended. They were treated with a topical steroid (the combination of tobramycin and dexamethasone) solution at a dose of 1 drop 4 times a day for 1 week with a tapering dose over the next 4 weeks. Five of these 20 patients had much lower than average Schirmer test values (< 5 mm), suggesting a lack of tear production and dry eye syndrome. None of these patients underwent surgery.

Of special note among the patients treated with weekly docetaxel are 2 patients (4 eyes) with nonmetastatic breast carcinoma who received weekly docetaxel for 10 weeks and 18 weeks, respectively, in the neoadjuvant setting and developed complete closure of all four canaliculi. One patient underwent bilateral DCR and permanent Pyrex glass tube placement to relieve her incessant epiphora. The other patient elected not to undergo surgery despite her symptoms.

Of the patients who received docetaxel every 2 or 3 weeks, 1 patient (2 eyes) underwent silicone intubation, 1 patient (2 eyes) underwent DCR with silicone tube placement, and 1 patient underwent punctoplasty to relieve epiphora. All three patients experienced either total resolution or improvement of their epiphora. In all three patients, the lacrimal drainage apparatus remained patent at the time of last follow-up. The remaining patients who received docetaxel every 2–3 weeks had resolution of their epiphora after in-office probing and irrigation and a short pulse (4 weeks) of topical steroids (tobramycin and dexamethasone).

Among patients who received docetaxel weekly, the mean cumulative dose of docetaxel at the time of presentation to the Ophthalmology Service was significantly higher in patients who had complete closure of the canaliculi (regardless of whether they had the recommended Pyrex glass tube placement) compared with patients who did not have complete closure (1145 mg vs. 937 mg) (P = 0.05). The duration of therapy at the time of presentation to the Ophthalmology Service was also longer in patients with complete closure of the canaliculi compared with the rest of the patients receiving weekly docetaxel, but this difference was not statistically significant (P = 0.08).

DISCUSSION

The findings in this large cohort confirm our earlier observations that blockage of the lacrimal drainage apparatus is a common and important side effect of weekly docetaxel therapy. Greater than half of the patients who developed epiphora while receiving weekly docetaxel had significant anatomic narrowing of their lacrimal drainage apparatus to the point that surgery was recommended and in many patients was performed to relieve epiphora. We also found that this ocular complication can occur even in the neoadjuvant setting when the drug is used for a limited time, as evidenced by the finding of severe end-stage canalicular stenosis in two individuals with breast carcinoma who received adjuvant docetaxel. The role of weekly taxanes in the neoadjuvant setting is becoming better established.6 Because patients receiving adjuvant docetaxel have a longer life expectancy than patients receiving docetaxel in the metastatic setting, it is especially crucial to recognize canalicular obstruction early and offer the appropriate therapy in patients receiving adjuvant docetaxel. Failure to recognize canalicular obstruction early can leave patients with no options except DCR with Pyrex glass tube placement, an inferior option because Pyrex glass tubes are left in place indefinitely, are associated with problems (e.g., migration and extrusion), and require special daily care.

We found that the severity of canalicular stenosis resulting from weekly docetaxel increased with higher cumulative doses of this drug and longer duration of therapy as evidenced by a higher cumulative dose of docetaxel and longer duration of therapy in patients with complete closure of the canaliculi compared with the rest of the patients who received weekly docetaxel.

Only 3 of the patients who received docetaxel every 2–3 weeks (4%) required a surgical intervention and none of these patients needed placement of a permanent Pyrex glass tube to overcome epiphora.

The current updated series confirms our previously reported experience that the surgical treatment of canalicular stenosis is successful in relieving epiphora in the overwhelming majority of patients who develop anatomic narrowing or total closure of the canaliculi and nasolacrimal duct blockage due to treatment with docetaxel. Ideally, however, all patients should be evaluated and treated early enough in their course so that minimal surgery comprised of the placement of temporary silicone tubes can be performed instead of more invasive surgery such as DCR or the placement of a permanent Pyrex glass tube. Our experience also suggests that in patients treated with weekly administration of docetaxel, a regimen rarely associated with neutropenia and thrombocytopenia, it is safe to perform surgery while the patient continues to receive the previously planned chemotherapy regimen.

Despite the previous publication of several articles by our group regarding canalicular and lacrimal obstruction resulting from docetaxel therapy, we still frequently encounter advanced cases of this condition because of delayed diagnosis. Thus, it appears that oncologists need to become better educated regarding this side effect. Weekly docetaxel has definite advantages over less frequent administration schedules in terms of a lower likelihood of neutropenia or thrombocytopenia, but it is associated with a unique toxicity profile.7–10 In our opinion, canalicular stenosis may be the most important side effect of weekly docetaxel. Nail changes due to weekly taxane administration also are well recognized as an undesirable side effect.11 Arguably, epiphora due to canalicular stenosis can negatively impact the quality of life for patients receiving weekly docetaxel and should be considered when choosing the chemotherapy regimen. Several studies have shown that untreated nasolacrimal duct blockage has a negative impact on visual function.12 Our experience with cancer patients who develop epiphora as a side effect of therapy suggests that they view epiphora as one of the worst side effects of weekly docetaxel therapy because of their inability to read, drive, or wear make-up. Another common and disturbing aspect of epiphora for cancer patients is the mistaken impression of emotional tearing by others.

All patients receiving weekly docetaxel should be monitored closely by an ophthalmologist so that the timely management of canalicular stenosis can be offered. Patients should have a baseline examination followed by monthly visits (which should include probing and irrigation of the nasolacrimal duct, a Schirmer test, and slit-lamp biomicroscopy) during treatment with weekly docetaxel so that timely management, including possible silicone intubation, can be offered in symptomatic patients. With mild early cases of canalicular stenosis, a short course of topical steroids can be attempted. However, the safest approach for patients with progressive epiphora who are to continue receiving weekly docetaxel is to perform outpatient silicone intubation of the nasolacrimal ducts so that further closure is prevented. We recommend silicone intubation in all symptomatic patients who are receiving weekly docetaxel if they are to continue receiving the drug. For symptomatic patients who are receiving docetaxel at a dose of every 3 weeks, we recommend in-office probing and irrigation followed by the administration of a short pulse of topical steroids and reevaluation within 6 weeks. In the majority of patients receiving every-3-weeks docetaxel, this approach relieves symptoms. In patients receiving prolonged courses of every-3-weeks docetaxel who remain symptomatic despite the above regimen, silicone intubation can be considered.

Acknowledgements

The authors wish to thank Stephanie Deming for her invaluable editorial help with this article.

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