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Prospective Study of Incidence and Severity of Epiphora and Canalicular Stenosis in Patients With Metastatic Breast Cancer Receiving Docetaxel

Bita Esmaeli, Sapna Amin, Vicente Valero, Rosnie Adinin, Rebecca Arbuckle, Roberto Banay, Kim-Anh Do, Edgardo Rivera

From the Section of Ophthalmology, Division of Pharmacy, Department of Breast Medical Oncology, and Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Bita Esmaeli, MD, Section of Ophthalmology, Unit 441, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: besmaeli{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To determine the incidence and severity of epiphora and canalicular stenosis in patients receiving docetaxel weekly or every 3 weeks.

PATIENTS AND METHODS: In this prospective trial, each patient underwent an ophthalmologic examination and probing and irrigation of the lacrimal drainage apparatus at baseline and every 4 to 6 weeks after initiation of docetaxel. During each visit, epiphora and canalicular stenosis were graded. Patients with epiphora were treated with tobramycin and dexamethasone drops. If epiphora worsened or if findings on probing and irrigation suggested further canalicular narrowing, silicone intubation was offered.

RESULTS: Twenty-eight patients received docetaxel weekly, and 28 patients received docetaxel every 3 weeks. Eighteen patients (64%) who received weekly docetaxel developed epiphora. Epiphora was mild in seven patients, moderate in five, and severe in six. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Nine patients had worsened canalicular stenosis; six underwent surgery. The median cumulative docetaxel dose was 496.5 mg at onset of epiphora and 889.5 mg at surgery. Eleven patients (39%) who received docetaxel every 3 weeks developed epiphora. The median cumulative docetaxel dose at onset of epiphora in this group was 420 mg. Epiphora was mild in nine patients, moderate in one, and severe in one. Nine patients had resolution of epiphora with tobramycin and dexamethasone administration. Two patients underwent surgery.

CONCLUSION: Epiphora occurred in 64% of patients in the weekly group and in 39% of patients in the every-3-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and in none of the patients in the every-3-weeks group.

	INTRODUCTION

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Epiphora (excessive tearing) and canalicular fibrosis as its anatomic correlate have been reported as adverse effects of many chemotherapeutic drugs, including fluorouracil, some of its derivatives, and docetaxel.^1-4 We have previously reported on more than 160 patients with epiphora and irreversible blockage of the lacrimal drainage apparatus as adverse effects of docetaxel.^4-9 We have also reported that severe canalicular stenosis seems more common in patients who receive weekly docetaxel than in those who receive docetaxel every 3 weeks.^8,9 We have demonstrated that docetaxel is secreted into the tears¹⁰ and that the early insertion of temporary silicone tubes may prevent permanent scarring and closure of the canaliculi in this setting.⁷ Because advanced stages of canalicular stenosis necessitate more complicated surgery, such as dacryocystorhinostomy (DCR) with placement of a permanent Pyrex glass tube, to relieve epiphora, the early recognition and treatment of epiphora and canalicular stenosis is crucial so that appropriate and timely insertion of silicone tubes can be considered.

Despite substantial literature documenting canalicular stenosis as an adverse effect of docetaxel, the exact incidence of this important adverse effect is unknown. All previous publications were based on retrospective studies at tertiary ophthalmology practices, and only patients who had symptoms of epiphora were evaluated.^4-10 We report the findings of a prospective, single-center study designed to determine the incidence and severity of epiphora and its anatomic correlate, canalicular stenosis, in patients receiving docetaxel weekly or every 3 weeks. A second goal was to determine whether the incidence of these adverse effects is associated with the frequency of docetaxel administration.

	PATIENTS AND METHODS

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This prospective, observational trial was approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center (Houston, TX).

Patient Accrual
To be eligible, patients had to be older than 18 years of age. Forty-three of the 56 patients enrolled in this trial were simultaneously enrolled in a prospective, phase III clinical trial at our institution that compared the response rates of docetaxel weekly and every 3 weeks in patients with metastatic breast cancer. Patients who had previously received paclitaxel were excluded from the phase III trial unless the last dose was given as adjuvant therapy at least 12 months before enrollment. Patients were allowed a total of two prior chemotherapy regimens but no more than one for metastatic disease. Patients with uncontrolled brain metastasis were excluded. Patients were randomly assigned to receive docetaxel 75 mg/m² every 21 days or docetaxel 35 mg/m² on days 1, 8, and 15 every 28 days. The other 13 patients received docetaxel either weekly or every 3 weeks; the weekly group received docetaxel on days 1, 8, and 15 every 28 days.

Statistical Considerations and Sample Size
Previous retrospective studies and our clinical experience suggested that the incidence of epiphora might be as high as 50% in patients treated with weekly docetaxel and less than 10% in patients who receive docetaxel every 3 weeks.^8,9 Therefore, a two-group, continuity-corrected ² test with a .05 one-sided significance level would have 90% power to detect a difference between the two groups if they each contained 26 patients. We aimed to accrue 33 patients in each group to account for early drop-outs secondary to toxicity or ineffectiveness of chemotherapy. The follow-up period ended 1 month after discontinuation of docetaxel therapy, when the patient failed to return for a scheduled follow-up visit, or at patient death, whichever occurred first.

Patient Evaluations
Before treatment with docetaxel, patients were evaluated by the same ophthalmologist (B.E.) and underwent a comprehensive ophthalmologic examination, including slit-lamp biomicroscopy, a Schirmer's test, and probing of the canaliculi and irrigation of the nasolacrimal ducts. Patients who had pre-existent epiphora or canalicular or nasolacrimal duct blockage on probing and irrigation were excluded. Patients were evaluated by the same ophthalmologist every 4 to 6 weeks after initiation of docetaxel. During each follow-up visit, patients were asked about epiphora, which was graded on a scale of 0 to 4; 0 represented no epiphora; 1 represented mild epiphora, requiring occasional wiping of tears; 2 represented moderate epiphora, requiring wiping of tears regularly every day; 3 represented more severe epiphora, requiring wiping of tears most of the awake hours; limiting the patient's ability to read, drive, or carry out other activities of daily living. At each visit, patients underwent probing of canaliculi and irrigation of the nasolacrimal ducts. Canalicular stenosis was graded by the ophthalmologist as follows: 0, no stenosis; 1, mild stenosis—puncta were small but could be probed after dilation, and the probe came to a bony stop; 2, moderate stenosis—canaliculi could be only partially probed, the probe did not come to a bony stop, and insertion of the probe was associated with pain; or 3, severe canalicular stenosis—canaliculi could not be probed, probing was associated with severe pain or bleeding, or the nasolacrimal duct was not patent to irrigation through the upper or lower canaliculi.

Management of Epiphora and Canalicular Stenosis
If a patient developed epiphora, topical tobramycin and dexamethasone (Tobradex; Alcon Inc, Fort Worth, TX) drops were started in the affected eye at a frequency of four times a day. The tobramycin and dexamethasone daily dose was tapered by one drop each week until the patient was seen by the opthalmologist again. If epiphora improved, the patient was simply observed and re-evaluated in 4 to 6 weeks. If epiphora worsened or did not improve with tobramycin and dexamethasone, or if findings on probing and irrigation suggested further narrowing of the canaliculi, the patient was counseled regarding the option of bicanalicular silicone intubation. If the principal investigator and the patient agreed to silicone intubation of the affected nasolacrimal duct, this procedure was performed as outpatient surgery under general anesthesia. In patients whose canalicular stenosis was so severe that silicone intubation was not possible, a DCR was performed, with silicone tube placement as a first option. If the canaliculi were completely closed or narrowed so much that silicone tube placement was not possible even with a DCR technique, a Pyrex glass tube was inserted through the caruncle at the time of DCR to bypass the entire canalicular system and allow for direct drainage of tears.

In patients who underwent silicone tube placement, the tubes were left in place for at least 3 months after cessation of docetaxel to allow for clearance of any residual docetaxel from the tears and for resolution of any persistent inflammation of the tear drainage apparatus. Patients were evaluated to determine whether epiphora resolved after the surgical intervention. For patients with epiphora, the cumulative doses of docetaxel at the time of onset and at the time of surgical intervention were recorded.

	RESULTS

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Sixty patients were enrolled on this trial between August 2001 and March 2005. Four patients were not included in the final analysis because of inadequate follow-up data. Twenty-eight patients received docetaxel weekly, and 28 received docetaxel every 3 weeks. The mean age was 55 years (range, 33 to 77 years); two patients were men and 54 were women.

Weekly Docetaxel Group
Among the 28 patients who received weekly docetaxel, 18 (64%) developed bilateral epiphora. Epiphora was graded as mild (grade 1) in seven patients, moderate (grade 2) in five patients, and severe (grade 3) in six patients. The mean interval between initiation of docetaxel and onset of epiphora was 2 months (range, 1 to 3 months. All patients who developed epiphora were treated with tobramycin and dexamethasone for at least 6 weeks. Nine patients had resolution of epiphora in response to tobramycin and dexamethasone. Nine patients had worsening of canalicular stenosis despite tobramycin and dexamethasone (to grade 2 in eight patients and to grade 3 in one patient), so surgery was recommended. Six of these patients underwent surgery to correct epiphora and prevent further stenosis. Two had bilateral temporary silicone tube placement, three had bilateral DCR with temporary silicone tube placement, and one had DCR and silicone tube on one side and temporary silicone tube placement on the other side. Three patients did not undergo the recommended surgery because of fear of surgery or other ongoing medical problems. None of the patients in this study required Pyrex glass tube placement.

The median cumulative docetaxel dose at onset of epiphora was 496.5 mg (range, 140 to 843 mg). The median cumulative docetaxel dose at the time of surgery was 889.5 mg (range, 606 to 993 mg). In the six patients who underwent surgery, the median duration of weekly docetaxel therapy at the time of surgery was 16 weeks (range, 9 to 24 weeks). All six patients experienced either total resolution or improvement of epiphora. In all six patients, the lacrimal drainage apparatus remained patent on probing and irrigation, and the median follow-up time was 27 months (range, 6 to 36 months).

Docetaxel Every-3-Weeks Group
Among the 28 patients who received docetaxel every 3 weeks, 11 (39%) developed bilateral epiphora. Epiphora was mild (grade 1) in nine patients, moderate (grade 2) in one, and severe (grade 3) in one. The mean interval between initiation of docetaxel and onset of epiphora was 3 months (range, 1 to 5 months). The median cumulative docetaxel dose at onset of epiphora was 420 mg (range, 162 to 1,438 mg). All 11 patients who developed epiphora were treated with tobramycin and dexamethasone for at least 6 weeks. Nine patients had resolution of epiphora in response to tobramycin and dexamethasone. Two patients had persistent epiphora and grade 1 canalicular stenosis and underwent bilateral DCR with temporary silicone tube placement. The cumulative docetaxel doses for the respective patients at the time of surgery were 658 mg and 3,086 mg. Both patients experienced complete resolution of epiphora.

The overall incidence of epiphora in the weekly docetaxel group (18 of 28) was greater than in the docetaxel every 3 weeks group (11 of 28; P = .10, Fisher's exact test). Grade 2 or 3 epiphora occurred at a significantly greater frequency in the weekly docetaxel group (11 of 28; 40%) than in the docetaxel every 3 weeks group (2 of 28; 7%; P = .00095, Fisher's exact test). The frequency of recommended surgical intervention was significantly greater in the weekly docetaxel group (9 of 28; 32%) than in the docetaxel every 3 weeks group (2 of 28, 7%; P = 0.04, Fisher's exact test).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
In this prospective, observational study, epiphora was seen in 64% of patients in the weekly docetaxel group and in 39% of patients in the docetaxel every 3 weeks group. Grade 2 or 3 epiphora was seen in approximately 40% of patients in the weekly group compared with only 7% in the every-3-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and in none of the patients in the every-3-weeks group. Thus, this trial confirms our previous observations from retrospective studies that epiphora as a symptom and canalicular stenosis as its anatomic correlate are more severe and occur more frequently in patients who receive weekly docetaxel than in those who receive docetaxel every 3 weeks.^4-10

This study also confirms that judicious use of topical steroids, along with repeated probing and irrigation performed by a skilled ophthalmologist as an office procedure, can resolve epiphora in a subset of patients and eliminate the need for silicone intubation or any other surgical intervention.¹¹ The resolution of epiphora observed in some patients was most likely attributable to the combination of topical steroids and repeat probing of the canaliculi and irrigation of the nasolacrimal duct (including dilation of the puncta and irrigation of fluid through each canaliculus) rather than to topical steroids alone. None of the patients enrolled onto this study required placement of permanent Pyrex glass tubes, supporting our recommendation that close prospective follow-up, repeat probing and irrigation, and judicious use of topical steroids can eliminate the need for Pyrex glass tube placement.

Which docetaxel schedule (weekly vs every 3 weeks) is more effective for treatment of metastatic breast cancer is outside the scope of the current study but will be addressed in the final analysis of the companion, prospective, multicenter, randomized trial that was the source of accrual for the majority of patients in this study. Each schedule of docetaxel administration has a unique adverse effects profile; the every-3-weeks regimen has the disadvantage of being associated with more profound neutropenia. The weekly regimen is more often associated with nail and skin changes and (as demonstrated in the current study and in previous retrospective studies) is more frequently associated with canalicular stenosis occurrence and severity.¹² Our study suggests that administration of docetaxel every 3 weeks may be safer in terms of ophthalmologic adverse effects.

In our clinical experience, we have seen no untoward effects from leaving the silicone tubes in for prolonged periods in patients receiving docetaxel. Silicone tubes have been left in place in some patients as long as 36 months after insertion without associated ocular adverse effects. This period is much longer than the usual period that silicone tubes are left in place after a DCR in other situations. Our experience suggests that, in patients with metastatic breast cancer who remain stable in response to docetaxel, the silicone lacrimal stents can safely be left in place for the duration of docetaxel therapy.

Patients who experience epiphora associated with docetaxel should be promptly referred to an ophthalmologist familiar with this adverse effect. Frequent (approximately every 4-6 weeks) probing and irrigation in the office and judicious use of topical steroids on a tapering dose can eliminate the need for silicone intubation or other lacrimal procedures in approximately 80% of patients taking docetaxel every 3 weeks and in approximately 50% of patients taking docetaxel weekly. However, in about one-third of patients who develop epiphora associated with weekly docetaxel, progressive canalicular stenosis dictates insertion of lacrimal stents to prevent further closure of the canaliculi and nasolacrimal ducts and to avoid involved lacrimal surgery, such as placement of permanent Pyrex glass tubes.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Bita Esmaeli sanofi-aventis (C) Vicente Valero sanofi-aventis (C) Rebecca Arbuckle Sanofi Pharmacy Advisory Board (A) Edgardo Rivera sanofi-aventis (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Bita Esmaeli Financial support: Bita Esmaeli Administrative support: Bita Esmaeli, Rosnie Adinin, Roberto Banay Provision of study materials or patients: Bita Esmaeli, Vicente Valero, Rosnie Adinin, Edgardo Rivera Collection and assembly of data: Bita Esmaeli, Sapna Amin, Vicente Valero, Rosnie Adinin, Rebecca Arbuckle, Roberto Banay, Edgardo Rivera Data analysis and interpretation: Bita Esmaeli, Sapna Amin, Vicente Valero, Roberto Banay, Kim-Anh Do Manuscript writing: Bita Esmaeli, Edgardo Rivera Final approval of manuscript: Bita Esmaeli, Sapna Amin, Vicente Valero, Rosnie Adinin, Rebecca Arbuckle, Kim-Anh Do, Edgardo Rivera

 

	NOTES

 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Fezza JP, Wesley RE, Klippenstein KA: The treatment of punctal and canalicular stenosis in patients on systemic 5-FU. Ophthalmic Surg Lasers 30:105-108, 1999[Medline]

2. Seiff SR, Shorr N, Adams T: Surgical treatment of punctal and canalicular fibrosis from 5-fluorouracil therapy. Cancer 56:2148-2149, 1985[CrossRef][Medline]

3. Esmaeli B, Golio D, Lubecki L, et al: Canalicular and nasolacrimal duct blockage: An ocular side effect associated with the anti-neoplastic drug S-1. Am J Ophthalmol 140:325-327, 2005[CrossRef][Medline]

4. Esmaeli B, Valero V, Ahmadi MA, et al: Canalicular stenosis secondary to docetaxel (Taxotere): A newly recognized side effect. Ophthalmology 108:994-995, 2001[CrossRef]

5. Esmaeli B, Burnstine MA, Ahmadi MA, et al: Docetaxel-induced histologic changes in the lacrimal sac and the nasal mucosa. Ophthal Plast Reconstr Surg 19:305-308, 2003[Medline]

6. Esmaeli B, Hortobagyi G, Esteva F, et al: Canalicular stenosis secondary to weekly docetaxel: A potentially preventable side effect. Ann Oncol 13:218-221, 2002[Abstract/Free Full Text]

7. Ahmadi MA, Esmaeli B: Surgical treatment of canalicular stenosis in patients receiving weekly docetaxel. Arch Ophthalmol 119:1802-1804, 2001[Abstract/Free Full Text]

8. Esmaeli B, Hortobagyi GN, Esteva FJ, et al: Canalicular stenosis secondary to weekly versus every-three-weeks docetaxel in patients with metastatic breast cancer. Ophthalmology 109:1188-1191, 2002[CrossRef]

9. Esmaeli B, Hidaji L, Adnin RB, et al: Blockage of the lacrimal drainage apparatus as a side effect of docetaxel. Cancer 98:504-507, 2003[CrossRef][Medline]

10. Esmaeli B, Ahmadi MA, Rivera E, et al: Docetaxel secretion in tears: Association with lacrimal drainage obstruction. Arch Ophthalmol 120:1180-1182, 2002[Abstract/Free Full Text]

11. Esmaeli B: Management of excessive tearing as a side effect of docetaxel. Clin Breast Cancer 5:455-457, 2005[Medline]

12. Engels FK, Verweij J: Docetaxel administration schedule: From fever to tears? A review of randomized studies. Eur J Cancer 41:1117-1126, 2005[CrossRef][Medline]

Submitted October 25, 2005; accepted January 18, 2006.

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