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Canalicular stenosis secondary to docetaxel (taxotere)
Canalicular Stenosis Secondary to Docetaxel (Taxotere) A Newly Recognized Side Effect Bita Esmaeli, MD,1 Vicente Valero, MD,2 M. Amir Ahmadi, MD,1 Daniel Booser, MD2 Objective: To report a newly recognized side effect of a commonly used antineoplastic agent, docetaxel, in three patients with metastatic breast cancer. Design: Observational case reports. Participants: Three patients with metastatic breast cancer who received weekly docetaxel chemotherapy. Main Outcome Measures: Occurrence of epiphora and severity of punctal and canalicular fibrosis secondary to docetaxel. Results: In three patients receiving weekly docetaxel, canalicular stenosis and resultant epiphora developed shortly after start of their treatment. Discontinuation of drug several months after initiation of therapy did not lead to resolution of symptoms in two of the three patients. Conclusions: Epiphora is a newly recognized side effect of docetaxel and may occur more frequently with weekly cycles of this drug. The mechanism for epiphora seems to be punctal and canalicular stenosis. This side effect, in advanced cases, is not reversible with discontinuation of the drug. Patients being administered weekly cycles of docetaxel should be screened for epiphora and canalicular stenosis, and treatment in the form of silicone intubation or punctoplasty should be considered in early stages to prevent the need for conjunctivodacryocystorhinostomy. Ophthalmology 2001;108:994 –995 © 2001 by the American Academy of Ophthalmology. Docetaxel (Taxotere, Aventis, Collegeville, PA) is an effective, relatively new antineoplastic agent widely used for advanced breast cancer as well as for treatment of other malignancies.1–3 Docetaxel belongs to a class of antineoplastic agents known as taxanes. Paclitaxel was the first member of this class of drugs to be used for the treatment of metastatic breast carcinoma. Docetaxel is more potent than paclitaxel in causing apoptotic cell death and has significant activity in previously untreated as well as previously treated metastatic breast cancer, including that which may have been unresponsive to paclitaxel.4 Common side effects of docetaxel include neutropenic fever, anemia, fluid retention, hypersensitivity reactions, anorexia, myalgias, mucositis, mild alopecia, skin and nail toxicity, and peripheral neuropathy.5,6 We report three patients with metastatic breast carcinoma in whom epiphora and canalicular stenosis developed while the patients were being administered weekly docetaxel. To our knowledge, this side effect of docetaxel has not been previously reported.
Originally received: June 6, 2000. Accepted: November 28, 2000. Manuscript no. 200334. 1 Ophthalmology Section, Department of Plastic Surgery, University of Texas, M.D. Anderson Cancer Center, Houston, Texas. 2 Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Correspondence to Bita Esmaeli, MD, Assistant Professor and Director of Ophthalmology Section, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 443, Houston, TX 77030.
994
© 2001 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
Patients and Methods Patient A, a 37-year-old woman, was treated for metastatic breast cancer with docetaxel. She received weekly docetaxel, 40 mg/m2 (75 mg) intravenously, with dexamethasone coverage, in combination with trastuzumab (Herceptin, Genentech, San Francisco, CA) for a total of 20 doses. She experienced fluid retention secondary to docetaxel, and the cancer worsened on treatment. She was referred to the ophthalmology clinic approximately 2 months after discontinuation of docetaxel with a chief complaint of excessive tearing. She recalled that her symptoms of tearing began a few weeks after docetaxel was started and had not improved after discontinuation of this drug. On examination, she was found to have quiet globes. The ocular adnexal examination was normal, but there was an obvious increase in the tear lake in both eyes. Her best-corrected visual acuity was 20/20 in each eye. Extraocular motility, confrontation visual fields, pupillary examination, slitlamp examination, applanation tonometry, and a dilated funduscopic examination were all within the normal limits. Inspection of the tear drainage system revealed complete closure of all four puncta. Dilation of the puncta was not possible with a punctal dilator under topical anesthesia. She was advised to consider snip punctoplasty plus bicanalicular silicone intubation to improve her symptoms. At the time of this report, she was reluctant to undergo any procedures. Patient B, a 63-year-old woman with metastatic breast carcinoma, received weekly docetaxel, 35 mg/m2 (70 mg), with dexamethasone coverage, for 15 weeks. Her treatment was stopped after the fifteenth cycle secondary to excessive fluid retention. She was referred to the ophthalmology clinic for evaluation of her epiphora 4 months after discontinuation of docetaxel therapy. She stated that excessive tearing began around the time she began docetaxel therapy, and, despite discontinuation of this drug, her ISSN 0161-6420/00/$–see front matter PII S0161-6420(00)00640-0
Esmaeli et al 䡠 Canalicular Fibrosis Secondary to Docetaxel symptoms persisted. Her past ocular history was negative for previous episodes of epiphora, nasolacrimal duct blockage, or ocular surface disease. On examination, her best-corrected visual acuity was 20/30 in each eye. The external examination revealed quiet globes. The results of the ocular adnexal examination were normal except for the presence of increased tear lakes in both eyes. The extraocular motility examination results, confrontation visual fields, pupillary examination results, slit-lamp examination results, tonometry measurements, and results of a careful dilated fundus examination were essentially normal. A careful assessment of the lacrimal drainage apparatus revealed moderate punctal and canalicular stenosis involving all four eyelids. The patient underwent snip punctoplasty of each lower punctum with partial resolution of her symptoms of epiphora. Because she is not scheduled to receive more docetaxel at the present time and she is not bothered by the residual symptoms of epiphora, bicanalicular silicone intubation is not planned. However, she may require silicone intubation of her nasolacrimal ducts in the future, if she receives more docetaxel or if her symptoms worsen. Patient C, a 43-year-old woman with metastatic breast carcinoma, was referred to the ophthalmology clinic for evaluation of excessive tearing, which began approximately 1 month after she started weekly intravenous docetaxel 35 mg/m2 (67 mg), with dexamethasone coverage, in combination with trastuzumab for 3 weeks followed by 1 week without treatment. At the time of her presentation, she had finished 14 weekly cycles of docetaxel. She reported no previous history of epiphora or any other eye problems. On examination, her best-corrected visual acuity was 20/25 in each eye. The external examination revealed quiet globes. There was obvious increase in the tear lake in both eyes. The ocular adnexal examination results, extraocular motility examination results, confrontation visual fields, and applanation tonometry measurements were within the normal limits. The results of a dilated fundus examination were normal. The results of a slit-lamp examination were essentially normal, except for the finding of punctal stenosis involving all four puncta. Irrigation of the nasolacrimal ducts revealed smaller than average puncta and moderate stenosis of all four canaliculi. She underwent bicanalicular silicone intubation of each nasolacrimal duct to prevent further stenosis of the canaliculi, while she continued on her weekly regimen of docetaxel and trastuzumab. The patient’s symptoms of epiphora improved immediately after silicone intubation. We anticipate keeping the silicone tubes in place until she is finished with her docetaxel regimen.
Discussion Excessive tearing, presumably as a result of conjunctivitis, has been described as a side effect of docetaxel treatment.7 We described three patients in whom epiphora developed secondary to punctal or canalicular stenosis during treatment with docetaxel. Canalicular stenosis has been described in association with other chemotherapeutic agents such as 5-fluorouracil,8,9 but, to our knowledge, it has not been reported as a side effect of docetaxel. The mechanism of canalicular stenosis could be secondary to secretion of the chemotherapeutic agent in the tear film and fibrosis of the canaliculi from direct contact with the drug. It is also possible that the mucous membrane lining of the puncta and canaliculi undergoes fibrosis secondary to the systemic effects of the drug, similar to the widespread edema and fibrosis seen with docetaxel elsewhere in the body. In two of our three patients, complete punctal closure or canalicular stenosis persisted even after docetaxel was discontinued. Given the recent widespread use of docetaxel as an
effective first- or second-line antineoplastic agent for the treatment of breast and prostate cancer, it is important for ophthalmologists and oncologists to be aware of this newly recognized side effect. Timely diagnosis and management of punctal and canalicular stenosis secondary to docetaxel can prevent complete closure of the canaliculi. Early stages of canalicular stenosis can be managed with punctoplasty and silicone intubation, whereas complete fibrosis of the canaliculi requires conjunctivodacryocystorhinostomy and placement of a Jones tube. We recommend referral to an ophthalmologist as soon as symptoms of epiphora develop in patients receiving docetaxel. Depending on the severity of symptoms and findings on probing and irrigation of the nasolacrimal ducts, silicone intubation and punctoplasty should be considered to prevent complete closure of the canaliculi while the patient is receiving this antineoplastic agent. Punctoplasty alone may be appropriate for patients with punctal stenosis but with normal canaliculi who have completed their treatment with docetaxel. For patients who need to continue with docetaxel treatment or those with canalicular stenosis, bicanalicular silicone intubation of the nasolacrimal ducts is more appropriate. Current initiatives in the management of metastatic breast carcinoma involve the development of weekly schedules of docetaxel administration in combination with other agents. All three of our patients received weekly docetaxel. It is possible that weekly administration of docetaxel is associated with a greater incidence of canalicular stenosis. This hypothesis needs to be evaluated further in a prospective study of a large number of patients. A prospective study is currently underway at our institution to evaluate the incidence of canalicular stenosis secondary to docetaxel and the relationship between dosing and frequency of administration of this drug and the incidence of this form of toxicity.
References 1. Valero V. Docetaxel as single-agent therapy in metastatic breast cancer: clinical efficacy. Semin Oncol 1997;24(Suppl 13):11– 8. 2. Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999;26(Suppl 17):14 – 8. 3. Burris HA III. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol 1999;26(Suppl 9):1– 6. 4. Hortobagyi GN. Recent progress in the clinical development of docetaxel (Taxotere). Semin Oncol 1999;26(Suppl 9):32– 6. 5. Valero V, Holmes FA, Walters RS, et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 1995;13:2886 –94. 6. Ferraresi V, Milella M, Vaccaro A, et al. Toxicity and activity of docetaxel in anthracycline-pretreated breast cancer patients: a phase II study. Am J Clin Oncol 2000;23:132–9. 7. Burstein HJ, Manola J, Younger J, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000;18:1212–19. 8. Haidak DJ, Hurwitz BS, Yeung KY. Tear-duct fibrosis (dacryostenosis) due to 5-fluorouracil. Ann Intern Med 1978;88:657. 9. Fezza JP, Wesley RE, Klippenstein KA. The treatment of punctal and canalicular stenosis in patients on systemic 5-FU. Ophthalmic Surg Lasers 1999;30:105– 8.
995
Originally received: June 6, 2000. Accepted: November 28, 2000. Manuscript no. 200334. 1 Ophthalmology Section, Department of Plastic Surgery, University of Texas, M.D. Anderson Cancer Center, Houston, Texas. 2 Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Correspondence to Bita Esmaeli, MD, Assistant Professor and Director of Ophthalmology Section, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 443, Houston, TX 77030.
994
© 2001 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
Patients and Methods Patient A, a 37-year-old woman, was treated for metastatic breast cancer with docetaxel. She received weekly docetaxel, 40 mg/m2 (75 mg) intravenously, with dexamethasone coverage, in combination with trastuzumab (Herceptin, Genentech, San Francisco, CA) for a total of 20 doses. She experienced fluid retention secondary to docetaxel, and the cancer worsened on treatment. She was referred to the ophthalmology clinic approximately 2 months after discontinuation of docetaxel with a chief complaint of excessive tearing. She recalled that her symptoms of tearing began a few weeks after docetaxel was started and had not improved after discontinuation of this drug. On examination, she was found to have quiet globes. The ocular adnexal examination was normal, but there was an obvious increase in the tear lake in both eyes. Her best-corrected visual acuity was 20/20 in each eye. Extraocular motility, confrontation visual fields, pupillary examination, slitlamp examination, applanation tonometry, and a dilated funduscopic examination were all within the normal limits. Inspection of the tear drainage system revealed complete closure of all four puncta. Dilation of the puncta was not possible with a punctal dilator under topical anesthesia. She was advised to consider snip punctoplasty plus bicanalicular silicone intubation to improve her symptoms. At the time of this report, she was reluctant to undergo any procedures. Patient B, a 63-year-old woman with metastatic breast carcinoma, received weekly docetaxel, 35 mg/m2 (70 mg), with dexamethasone coverage, for 15 weeks. Her treatment was stopped after the fifteenth cycle secondary to excessive fluid retention. She was referred to the ophthalmology clinic for evaluation of her epiphora 4 months after discontinuation of docetaxel therapy. She stated that excessive tearing began around the time she began docetaxel therapy, and, despite discontinuation of this drug, her ISSN 0161-6420/00/$–see front matter PII S0161-6420(00)00640-0
Esmaeli et al 䡠 Canalicular Fibrosis Secondary to Docetaxel symptoms persisted. Her past ocular history was negative for previous episodes of epiphora, nasolacrimal duct blockage, or ocular surface disease. On examination, her best-corrected visual acuity was 20/30 in each eye. The external examination revealed quiet globes. The results of the ocular adnexal examination were normal except for the presence of increased tear lakes in both eyes. The extraocular motility examination results, confrontation visual fields, pupillary examination results, slit-lamp examination results, tonometry measurements, and results of a careful dilated fundus examination were essentially normal. A careful assessment of the lacrimal drainage apparatus revealed moderate punctal and canalicular stenosis involving all four eyelids. The patient underwent snip punctoplasty of each lower punctum with partial resolution of her symptoms of epiphora. Because she is not scheduled to receive more docetaxel at the present time and she is not bothered by the residual symptoms of epiphora, bicanalicular silicone intubation is not planned. However, she may require silicone intubation of her nasolacrimal ducts in the future, if she receives more docetaxel or if her symptoms worsen. Patient C, a 43-year-old woman with metastatic breast carcinoma, was referred to the ophthalmology clinic for evaluation of excessive tearing, which began approximately 1 month after she started weekly intravenous docetaxel 35 mg/m2 (67 mg), with dexamethasone coverage, in combination with trastuzumab for 3 weeks followed by 1 week without treatment. At the time of her presentation, she had finished 14 weekly cycles of docetaxel. She reported no previous history of epiphora or any other eye problems. On examination, her best-corrected visual acuity was 20/25 in each eye. The external examination revealed quiet globes. There was obvious increase in the tear lake in both eyes. The ocular adnexal examination results, extraocular motility examination results, confrontation visual fields, and applanation tonometry measurements were within the normal limits. The results of a dilated fundus examination were normal. The results of a slit-lamp examination were essentially normal, except for the finding of punctal stenosis involving all four puncta. Irrigation of the nasolacrimal ducts revealed smaller than average puncta and moderate stenosis of all four canaliculi. She underwent bicanalicular silicone intubation of each nasolacrimal duct to prevent further stenosis of the canaliculi, while she continued on her weekly regimen of docetaxel and trastuzumab. The patient’s symptoms of epiphora improved immediately after silicone intubation. We anticipate keeping the silicone tubes in place until she is finished with her docetaxel regimen.
Discussion Excessive tearing, presumably as a result of conjunctivitis, has been described as a side effect of docetaxel treatment.7 We described three patients in whom epiphora developed secondary to punctal or canalicular stenosis during treatment with docetaxel. Canalicular stenosis has been described in association with other chemotherapeutic agents such as 5-fluorouracil,8,9 but, to our knowledge, it has not been reported as a side effect of docetaxel. The mechanism of canalicular stenosis could be secondary to secretion of the chemotherapeutic agent in the tear film and fibrosis of the canaliculi from direct contact with the drug. It is also possible that the mucous membrane lining of the puncta and canaliculi undergoes fibrosis secondary to the systemic effects of the drug, similar to the widespread edema and fibrosis seen with docetaxel elsewhere in the body. In two of our three patients, complete punctal closure or canalicular stenosis persisted even after docetaxel was discontinued. Given the recent widespread use of docetaxel as an
effective first- or second-line antineoplastic agent for the treatment of breast and prostate cancer, it is important for ophthalmologists and oncologists to be aware of this newly recognized side effect. Timely diagnosis and management of punctal and canalicular stenosis secondary to docetaxel can prevent complete closure of the canaliculi. Early stages of canalicular stenosis can be managed with punctoplasty and silicone intubation, whereas complete fibrosis of the canaliculi requires conjunctivodacryocystorhinostomy and placement of a Jones tube. We recommend referral to an ophthalmologist as soon as symptoms of epiphora develop in patients receiving docetaxel. Depending on the severity of symptoms and findings on probing and irrigation of the nasolacrimal ducts, silicone intubation and punctoplasty should be considered to prevent complete closure of the canaliculi while the patient is receiving this antineoplastic agent. Punctoplasty alone may be appropriate for patients with punctal stenosis but with normal canaliculi who have completed their treatment with docetaxel. For patients who need to continue with docetaxel treatment or those with canalicular stenosis, bicanalicular silicone intubation of the nasolacrimal ducts is more appropriate. Current initiatives in the management of metastatic breast carcinoma involve the development of weekly schedules of docetaxel administration in combination with other agents. All three of our patients received weekly docetaxel. It is possible that weekly administration of docetaxel is associated with a greater incidence of canalicular stenosis. This hypothesis needs to be evaluated further in a prospective study of a large number of patients. A prospective study is currently underway at our institution to evaluate the incidence of canalicular stenosis secondary to docetaxel and the relationship between dosing and frequency of administration of this drug and the incidence of this form of toxicity.
References 1. Valero V. Docetaxel as single-agent therapy in metastatic breast cancer: clinical efficacy. Semin Oncol 1997;24(Suppl 13):11– 8. 2. Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999;26(Suppl 17):14 – 8. 3. Burris HA III. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol 1999;26(Suppl 9):1– 6. 4. Hortobagyi GN. Recent progress in the clinical development of docetaxel (Taxotere). Semin Oncol 1999;26(Suppl 9):32– 6. 5. Valero V, Holmes FA, Walters RS, et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 1995;13:2886 –94. 6. Ferraresi V, Milella M, Vaccaro A, et al. Toxicity and activity of docetaxel in anthracycline-pretreated breast cancer patients: a phase II study. Am J Clin Oncol 2000;23:132–9. 7. Burstein HJ, Manola J, Younger J, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000;18:1212–19. 8. Haidak DJ, Hurwitz BS, Yeung KY. Tear-duct fibrosis (dacryostenosis) due to 5-fluorouracil. Ann Intern Med 1978;88:657. 9. Fezza JP, Wesley RE, Klippenstein KA. The treatment of punctal and canalicular stenosis in patients on systemic 5-FU. Ophthalmic Surg Lasers 1999;30:105– 8.
995