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Canalicular stenosis secondary to weekly docetaxel: a potentially preventable side effect
Annals of Oncology 13: 218–221, 2002 DOI: 10.1093/annonc/mdf036
Original article
Canalicular stenosis secondary to weekly docetaxel: a potentially preventable side effect
1
Ophthalmology Section, Department of Plastic Surgery; 2 Department of Breast Medical Oncology; 3Department of Nuclear Medicine; and Department of Pharmacoeconomics, UT M.D. Anderson Cancer Center, Houston, TX, USA
4
Received 16 August 2001; accepted 27 August 2001
Background: The purpose of this study was to describe canalicular stenosis as a mechanism for epiphora (excessive tearing) secondary to weekly docetaxel.
Patients and methods: Fourteen patients with metastatic breast cancer who developed epiphora during weekly docetaxel therapy underwent an ophthalmologic examination, and probing and irrigation of the nasolacrimal ducts. The total duration of docetaxel therapy, the duration of treatment at the time of onset of epiphora, the number of infusions, the cumulative dose of docetaxel and the severity of canalicular stenosis were recorded. Results: All 14 patients had anatomic narrowing of the canaliculi as the underlying mechanism for epiphora. Bicanalicular silicone intubation or dacryocystorhinostomy (DCR) was recommended for all 14 patients. Eleven patients underwent surgery and experienced resolution of their symptoms. The three patients who declined surgery continue to have epiphora at the time of this report. Conclusions: Canalicular stenosis is an underlying mechanism for epiphora in patients receiving weekly docetaxel. Bicanalicular silicone intubation should be considered early in the course of weekly docetaxel therapy to prevent complete closure of the canaliculi. Once complete or near complete stenosis of the canaliculi occurs, DCR with a permanent pyrex glass tube placement may become necessary to overcome the blockage of tear outflow. Key words: bicanalicular silicone intubation, breast neoplasms, canalicular stenosis, docetaxel, epiphora, lacrimal apparatus diseases
Introduction Docetaxel (Taxotere; Aventis, Collegeville, PA, USA) is an effective chemotherapeutic agent for advanced breast cancer, as both first- and second-line therapy in patients previously treated with anthracyclines [1, 2]. Docetaxel is usually administered as a 1 h intravenous infusion every 21 days in women with metastatic breast cancer. With this standard administration schedule, the dose-limiting toxicity is myelosuppression [3]. Alternative schedules of administration—in particular weekly administration of docetaxel—have been studied in phase I and II clinical trials [4, 5]. Weekly docetaxel has a significantly different toxicity profile from docetaxel administered every 3 weeks. Weekly docetaxel causes only mild myelosuppression [6]. Fatigue and asthenia have proven to be the dose-limiting toxicity, with other reported mild side
*Correspondence to: Ophthalmology Section, Department of Plastic Surgery, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA Tel: +1-713-794-1247; Fax: +1-713-794-5492; E-mail: [email protected] © 2002 European Society for Medical Oncology
effects including alopecia, nail changes, and peripheral neuropathy. The symptom of epiphora (excessive tearing) has been reported in up to 50% of patients receiving weekly docetaxel [5]. However, the mechanism for epiphora has not been well established. We report 14 patients with metastatic breast cancer receiving weekly docetaxel who had significant canalicular stenosis as the underlying mechanism for epiphora.
Patients and methods Between March and August of 2000, 14 patients with metastatic breast cancer who were being treated with weekly docetaxel were referred to the Ophthalmology Clinic at the University of Texas M. D. Anderson Cancer Center for evaluation of excessive tearing. In each patient, epiphora was severe enough to interfere with daily activities such as driving and reading. A comprehensive ophthalmologic examination, including evaluation of the tear drainage apparatus by probing and irrigation, was performed in each patient. In each patient, the severity of canalicular stenosis as an anatomic finding was determined by one of us (B.E.) during in-office probing and irrigation using standard, previously published techniques and criteria [7].
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015
B. Esmaeli1*, G. Hortobagyi2, F. Esteva2, V. Valero2, M. A. Ahmadi 1, D. Booser2, N. Ibrahim 2, E. Delpassand3 & R. Arbuckle4
219 All four canaliculi were evaluated in each patient. Moderate canalicular stenosis was defined as the presence of definite resistance when the probe was introduced into the canaliculi, but when the probe could be inserted all the way to a bony stop in the medial canthus. Severe canalicular stenosis was defined as inability to insert the metallic probe for the entire length of the canaliculus, in many instances, associated with severe pain or bleeding, or with total regurgitation of the irrigation fluid back through the canaliculus.
Clinical characteristics of the 14 patients in this study are shown in Table 1. All 14 patients were found to have stenosis of the canaliculi as the underlying mechanism for their excessive tearing. Seven patients had moderate canalicular stenosis, and seven patients had severe canalicular stenosis. For all patients in this series, each cycle of docetaxel treatment was composed of 3 weekly infusions followed by a 1 week break. Table 2 summarizes the details of docetaxel treatment for the patients reported in this study. Patients received a mean of 20 infusions over a mean time of 25.5 weeks, corresponding to a mean cumulative dose of 690 mg/m2. Every patient Table 1. Patient characteristics (n = 14) Age (years) Mean
45
Range
28–60
Discussion
Race White
12
Black
1
Hispanic
1
Concomitant chemotherapy in addition to docetaxel Yes (trastuzumab)
12
No
2
Table 2. Patterns of weekly docetaxel treatment
We identified canalicular stenosis as an underlying mechanism for epiphora in 14 patients with metastatic breast cancer
Table 3. Relationship between cumulative dose of docetaxel and severity of canalicular stenosis at the time of diagnosis Type of stenosis
Cumulative dose of docetaxel Mean (± SD)
Median
Mode
Moderate stenosis
399 (± 129)
420
420
Severe stenosis
501 (± 143)
420
420
Duration of treatment (weeks) Mean
25.5
Range
15–40
Table 4. Surgical intervention
Number of infusions Mean
20
Range
12–30
Dose intensity (mg/m2/week)
Number of patients/number of eyes Bicanalicular silicone intubation
6/11
DCR plus silicone tube
3/5
Mean
35
DCR plus Jones tube
2/4
Range
25–40
Attempted silicone intubation
1a/2
Surgery recommended
3/6
2
Cumulative dose (mg/m ) Mean
690
Range
420–1050
a
In this patient, silicone intubation was attempted, but due to severe canalicular stenosis it was not successful.
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015
Results
received dexamethasone prior to each infusion; the average dose was 16 mg (range 5–24 mg, median 16 mg). The docetaxel dose was not adjusted or stopped due to epiphora in any of the patients in this report. The length of time from commencement of weekly docetaxel therapy to onset of epiphora ranged from 4 to 16 weeks (mean 7 weeks). Two patients received docetaxel as a single agent; the rest received docetaxel in combination with trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA, USA). In five patients, the anatomic finding of canalicular stenosis was first diagnosed after cessation of docetaxel (median 6 weeks after discontinuation of docetaxel, range 3–30 weeks). The mean cumulative dose of docetaxel at the time of diagnosis of epiphora was higher in patients with severe canalicular stenosis than in patients with moderate canalicular stenosis (P = 0.09; Table 3). For all 14 patients, either bicanalicular silicone intubation or dacryocystorhinostomy (DCR) was recommended to overcome the blockage of lacrimal outflow. Eleven patients agreed to have surgery. The frequency and type of surgical procedures performed are listed in Table 4. All patients who underwent surgery experienced complete or near complete resolution of their symptoms of epiphora after silicone intubation or DCR. In the remaining three patients who elected not to have surgery, the symptom of epiphora persisted at the time of this publication.
220 complained of inability to see because of excessive tearing and dissatisfaction with the misleading appearance of ‘emotional tears’ secondary to canalicular obstruction. An analysis of quality of life measures in this cohort will be reported in a separate publication. Although it is not possible to draw any conclusions from this retrospective case series with respect to the frequency of canalicular stenosis secondary to weekly docetaxel, our observations so far suggest that this side effect is fairly common in patients receiving weekly docetaxel for metastatic breast cancer. Burstein et al. [5] reported epiphora in 50% of 29 patients enrolled in a phase II trial of weekly docetaxel, although these authors were not aware of the underlying mechanism for this symptom. Future prospective studies are necessary to better define the frequency and timing of this side effect in patients receiving weekly docetaxel. Given the recent widespread use of weekly docetaxel as an effective first- or second-line antineoplastic treatment for breast cancer and other common malignancies [4, 6, 9–12], it is crucial for ophthalmologists and oncologists to be aware of canalicular stenosis as a possible side effect of weekly docetaxel. Timely diagnosis of canalicular stenosis secondary to docetaxel and insertion of bicanalicular silicone stents can prevent complete closure of the canaliculi. Silicone tubes can be left in place until the patient is no longer exposed to docetaxel. Once complete closure of the canaliculi occurs, conjunctivodacryocystorhinostomy and placement of a permanent pyrex glass tube (Jones tube) is required to overcome the blockage of lacrimal outflow. We recommend referral to an ophthalmologist (ideally a lacrimal surgeon) at the earliest possible time after initiation of weekly docetaxel so that bicanalicular silicone intubation can be considered as soon as symptoms of epiphora are noted by the patient. Future prospective studies should focus on determining the frequency and timing of canalicular stenosis secondary to various schedules of administration of docetaxel and other taxanes.
References 1. Hudis CA, Seidman AD, Crown JP et al. Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14: 58–65. 2. 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: 2886–2894. 3. Cortes JE, Pazdur R. Docetaxel. J Clin Oncol 1995; 13: 2643–2655. 4. Hainsworth JD, Burris HA 3rd, Erland JB et al. Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 1998; 16: 2164–2168. 5. Burstein HJ, Manola J, Younger J et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18: 1212–1219. 6. Hortobagyi GN. Recent progress in the clinical development of docetaxel (taxotere). Semin Oncol 1999; 26 (3 Suppl 9): 32–36.
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015
receiving docetaxel. The present report confirms our previous report of the first three cases of punctal/canalicular stenosis secondary to weekly docetaxel [8] and is the first study to analyze the relationship between the severity of canalicular stenosis and the cumulative dose of weekly docetaxel. Canalicular stenosis associated with weekly docetaxel is most likely caused by secretion of docetaxel in the tear film and resultant chronic inflammation of the canaliculi due to direct contact with the drug as the tears travel through the canaliculi and the nasolacrimal duct to drain into the nose. Alternatively, the mucous membrane lining the canaliculi may become chronically inflamed and eventually fibrotic as part of the widespread mucositis caused by systemic absorption of docetaxel. Although many patients who receive docetaxel once every 3 weeks experience transient symptoms of epiphora, we have not observed significant anatomic narrowing of the canaliculi in these patients (unpublished data). It is possible that administration of docetaxel on a sustained weekly schedule leads to more chronic exposure of the canaliculi to this drug. Furthermore, canalicular stenosis has not been reported with weekly administration of other taxanes. This raises the possibility that structural differences between docetaxel and other taxanes may make docetaxel more likely to be secreted in the tear film or more toxic to the canaliculi. Five patients in our series were first diagnosed with canalicular stenosis as late as 30 weeks after cessation of therapy. It appears that once anatomic narrowing of the canaliculi secondary to docetaxel reaches a critical threshold, it is irreversible without appropriate surgical intervention. Although most of the patients in this study received concurrent trastuzumab, we also observed canalicular stenosis in two patients who received weekly docetaxel as a single agent. Furthermore, the fact that docetaxel is associated with epiphora, albeit transient and mild, even when given every 3 weeks supports the notion that docetaxel and not trastuzumab is the causative agent for canalicular stenosis in patients reported in the current study. We are unaware of any previous reports of epiphora or canalicular stenosis secondary to the use of trastuzumab as a single agent. The mean cumulative dose of docetaxel at the time of diagnosis was higher for patients with severe canalicular stenosis than for patients with moderate stenosis, although this difference was not statistically significant. This finding suggests that patients with advanced metastatic disease, who are likely to receive a longer course of weekly docetaxel and a higher cumulative dose, are at a greater risk of developing canalicular stenosis than patients who are exposed to a shorter course of this drug in the neoadjuvant setting. Our study was not designed to assess quality of life issues in patients receiving weekly docetaxel. Nevertheless, it is important to note that every patient in this study sought consultation with an ophthalmologist because of epiphora, which they perceived as a visually disabling and bothersome symptom. They
221 7. Hurwitz JJ. The Lacrimal System. Philadelphia, PA: LippincottRaven Publishers 1996; 47–59. 8. Esmaeli B, Valero V, Ahmadi MA, Booser D. Canalicular stenosis secondary to docetaxel (taxotere): a newly recognized side effect. Ophthalmology 2001; 108: 994–995. 9. Hainsworth JD, Burris HA, Yardley DA et al. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl cancer research network phase II trial. J Clin Oncol 2001; 19: 3500–3505.
10. Baselga J, Tabernero JM. Weekly docetaxel in breast cancer: applying clinical data to patient therapy. Oncologist 2001; 6 (Suppl): 26–29. 11. Loffler TM. Is there a place for “dose-dense” weekly schedules of the taxoids? Semin Oncol 1998; 25 (5 Suppl 12): 32–34. 12. Tomiak E, Piccart MJ, Kerger J et al. Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis. J Clin Oncol 1994; 12: 1458–1467.
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015
Original article
Canalicular stenosis secondary to weekly docetaxel: a potentially preventable side effect
1
Ophthalmology Section, Department of Plastic Surgery; 2 Department of Breast Medical Oncology; 3Department of Nuclear Medicine; and Department of Pharmacoeconomics, UT M.D. Anderson Cancer Center, Houston, TX, USA
4
Received 16 August 2001; accepted 27 August 2001
Background: The purpose of this study was to describe canalicular stenosis as a mechanism for epiphora (excessive tearing) secondary to weekly docetaxel.
Patients and methods: Fourteen patients with metastatic breast cancer who developed epiphora during weekly docetaxel therapy underwent an ophthalmologic examination, and probing and irrigation of the nasolacrimal ducts. The total duration of docetaxel therapy, the duration of treatment at the time of onset of epiphora, the number of infusions, the cumulative dose of docetaxel and the severity of canalicular stenosis were recorded. Results: All 14 patients had anatomic narrowing of the canaliculi as the underlying mechanism for epiphora. Bicanalicular silicone intubation or dacryocystorhinostomy (DCR) was recommended for all 14 patients. Eleven patients underwent surgery and experienced resolution of their symptoms. The three patients who declined surgery continue to have epiphora at the time of this report. Conclusions: Canalicular stenosis is an underlying mechanism for epiphora in patients receiving weekly docetaxel. Bicanalicular silicone intubation should be considered early in the course of weekly docetaxel therapy to prevent complete closure of the canaliculi. Once complete or near complete stenosis of the canaliculi occurs, DCR with a permanent pyrex glass tube placement may become necessary to overcome the blockage of tear outflow. Key words: bicanalicular silicone intubation, breast neoplasms, canalicular stenosis, docetaxel, epiphora, lacrimal apparatus diseases
Introduction Docetaxel (Taxotere; Aventis, Collegeville, PA, USA) is an effective chemotherapeutic agent for advanced breast cancer, as both first- and second-line therapy in patients previously treated with anthracyclines [1, 2]. Docetaxel is usually administered as a 1 h intravenous infusion every 21 days in women with metastatic breast cancer. With this standard administration schedule, the dose-limiting toxicity is myelosuppression [3]. Alternative schedules of administration—in particular weekly administration of docetaxel—have been studied in phase I and II clinical trials [4, 5]. Weekly docetaxel has a significantly different toxicity profile from docetaxel administered every 3 weeks. Weekly docetaxel causes only mild myelosuppression [6]. Fatigue and asthenia have proven to be the dose-limiting toxicity, with other reported mild side
*Correspondence to: Ophthalmology Section, Department of Plastic Surgery, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA Tel: +1-713-794-1247; Fax: +1-713-794-5492; E-mail: [email protected] © 2002 European Society for Medical Oncology
effects including alopecia, nail changes, and peripheral neuropathy. The symptom of epiphora (excessive tearing) has been reported in up to 50% of patients receiving weekly docetaxel [5]. However, the mechanism for epiphora has not been well established. We report 14 patients with metastatic breast cancer receiving weekly docetaxel who had significant canalicular stenosis as the underlying mechanism for epiphora.
Patients and methods Between March and August of 2000, 14 patients with metastatic breast cancer who were being treated with weekly docetaxel were referred to the Ophthalmology Clinic at the University of Texas M. D. Anderson Cancer Center for evaluation of excessive tearing. In each patient, epiphora was severe enough to interfere with daily activities such as driving and reading. A comprehensive ophthalmologic examination, including evaluation of the tear drainage apparatus by probing and irrigation, was performed in each patient. In each patient, the severity of canalicular stenosis as an anatomic finding was determined by one of us (B.E.) during in-office probing and irrigation using standard, previously published techniques and criteria [7].
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015
B. Esmaeli1*, G. Hortobagyi2, F. Esteva2, V. Valero2, M. A. Ahmadi 1, D. Booser2, N. Ibrahim 2, E. Delpassand3 & R. Arbuckle4
219 All four canaliculi were evaluated in each patient. Moderate canalicular stenosis was defined as the presence of definite resistance when the probe was introduced into the canaliculi, but when the probe could be inserted all the way to a bony stop in the medial canthus. Severe canalicular stenosis was defined as inability to insert the metallic probe for the entire length of the canaliculus, in many instances, associated with severe pain or bleeding, or with total regurgitation of the irrigation fluid back through the canaliculus.
Clinical characteristics of the 14 patients in this study are shown in Table 1. All 14 patients were found to have stenosis of the canaliculi as the underlying mechanism for their excessive tearing. Seven patients had moderate canalicular stenosis, and seven patients had severe canalicular stenosis. For all patients in this series, each cycle of docetaxel treatment was composed of 3 weekly infusions followed by a 1 week break. Table 2 summarizes the details of docetaxel treatment for the patients reported in this study. Patients received a mean of 20 infusions over a mean time of 25.5 weeks, corresponding to a mean cumulative dose of 690 mg/m2. Every patient Table 1. Patient characteristics (n = 14) Age (years) Mean
45
Range
28–60
Discussion
Race White
12
Black
1
Hispanic
1
Concomitant chemotherapy in addition to docetaxel Yes (trastuzumab)
12
No
2
Table 2. Patterns of weekly docetaxel treatment
We identified canalicular stenosis as an underlying mechanism for epiphora in 14 patients with metastatic breast cancer
Table 3. Relationship between cumulative dose of docetaxel and severity of canalicular stenosis at the time of diagnosis Type of stenosis
Cumulative dose of docetaxel Mean (± SD)
Median
Mode
Moderate stenosis
399 (± 129)
420
420
Severe stenosis
501 (± 143)
420
420
Duration of treatment (weeks) Mean
25.5
Range
15–40
Table 4. Surgical intervention
Number of infusions Mean
20
Range
12–30
Dose intensity (mg/m2/week)
Number of patients/number of eyes Bicanalicular silicone intubation
6/11
DCR plus silicone tube
3/5
Mean
35
DCR plus Jones tube
2/4
Range
25–40
Attempted silicone intubation
1a/2
Surgery recommended
3/6
2
Cumulative dose (mg/m ) Mean
690
Range
420–1050
a
In this patient, silicone intubation was attempted, but due to severe canalicular stenosis it was not successful.
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015
Results
received dexamethasone prior to each infusion; the average dose was 16 mg (range 5–24 mg, median 16 mg). The docetaxel dose was not adjusted or stopped due to epiphora in any of the patients in this report. The length of time from commencement of weekly docetaxel therapy to onset of epiphora ranged from 4 to 16 weeks (mean 7 weeks). Two patients received docetaxel as a single agent; the rest received docetaxel in combination with trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA, USA). In five patients, the anatomic finding of canalicular stenosis was first diagnosed after cessation of docetaxel (median 6 weeks after discontinuation of docetaxel, range 3–30 weeks). The mean cumulative dose of docetaxel at the time of diagnosis of epiphora was higher in patients with severe canalicular stenosis than in patients with moderate canalicular stenosis (P = 0.09; Table 3). For all 14 patients, either bicanalicular silicone intubation or dacryocystorhinostomy (DCR) was recommended to overcome the blockage of lacrimal outflow. Eleven patients agreed to have surgery. The frequency and type of surgical procedures performed are listed in Table 4. All patients who underwent surgery experienced complete or near complete resolution of their symptoms of epiphora after silicone intubation or DCR. In the remaining three patients who elected not to have surgery, the symptom of epiphora persisted at the time of this publication.
220 complained of inability to see because of excessive tearing and dissatisfaction with the misleading appearance of ‘emotional tears’ secondary to canalicular obstruction. An analysis of quality of life measures in this cohort will be reported in a separate publication. Although it is not possible to draw any conclusions from this retrospective case series with respect to the frequency of canalicular stenosis secondary to weekly docetaxel, our observations so far suggest that this side effect is fairly common in patients receiving weekly docetaxel for metastatic breast cancer. Burstein et al. [5] reported epiphora in 50% of 29 patients enrolled in a phase II trial of weekly docetaxel, although these authors were not aware of the underlying mechanism for this symptom. Future prospective studies are necessary to better define the frequency and timing of this side effect in patients receiving weekly docetaxel. Given the recent widespread use of weekly docetaxel as an effective first- or second-line antineoplastic treatment for breast cancer and other common malignancies [4, 6, 9–12], it is crucial for ophthalmologists and oncologists to be aware of canalicular stenosis as a possible side effect of weekly docetaxel. Timely diagnosis of canalicular stenosis secondary to docetaxel and insertion of bicanalicular silicone stents can prevent complete closure of the canaliculi. Silicone tubes can be left in place until the patient is no longer exposed to docetaxel. Once complete closure of the canaliculi occurs, conjunctivodacryocystorhinostomy and placement of a permanent pyrex glass tube (Jones tube) is required to overcome the blockage of lacrimal outflow. We recommend referral to an ophthalmologist (ideally a lacrimal surgeon) at the earliest possible time after initiation of weekly docetaxel so that bicanalicular silicone intubation can be considered as soon as symptoms of epiphora are noted by the patient. Future prospective studies should focus on determining the frequency and timing of canalicular stenosis secondary to various schedules of administration of docetaxel and other taxanes.
References 1. Hudis CA, Seidman AD, Crown JP et al. Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14: 58–65. 2. 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: 2886–2894. 3. Cortes JE, Pazdur R. Docetaxel. J Clin Oncol 1995; 13: 2643–2655. 4. Hainsworth JD, Burris HA 3rd, Erland JB et al. Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 1998; 16: 2164–2168. 5. Burstein HJ, Manola J, Younger J et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18: 1212–1219. 6. Hortobagyi GN. Recent progress in the clinical development of docetaxel (taxotere). Semin Oncol 1999; 26 (3 Suppl 9): 32–36.
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015
receiving docetaxel. The present report confirms our previous report of the first three cases of punctal/canalicular stenosis secondary to weekly docetaxel [8] and is the first study to analyze the relationship between the severity of canalicular stenosis and the cumulative dose of weekly docetaxel. Canalicular stenosis associated with weekly docetaxel is most likely caused by secretion of docetaxel in the tear film and resultant chronic inflammation of the canaliculi due to direct contact with the drug as the tears travel through the canaliculi and the nasolacrimal duct to drain into the nose. Alternatively, the mucous membrane lining the canaliculi may become chronically inflamed and eventually fibrotic as part of the widespread mucositis caused by systemic absorption of docetaxel. Although many patients who receive docetaxel once every 3 weeks experience transient symptoms of epiphora, we have not observed significant anatomic narrowing of the canaliculi in these patients (unpublished data). It is possible that administration of docetaxel on a sustained weekly schedule leads to more chronic exposure of the canaliculi to this drug. Furthermore, canalicular stenosis has not been reported with weekly administration of other taxanes. This raises the possibility that structural differences between docetaxel and other taxanes may make docetaxel more likely to be secreted in the tear film or more toxic to the canaliculi. Five patients in our series were first diagnosed with canalicular stenosis as late as 30 weeks after cessation of therapy. It appears that once anatomic narrowing of the canaliculi secondary to docetaxel reaches a critical threshold, it is irreversible without appropriate surgical intervention. Although most of the patients in this study received concurrent trastuzumab, we also observed canalicular stenosis in two patients who received weekly docetaxel as a single agent. Furthermore, the fact that docetaxel is associated with epiphora, albeit transient and mild, even when given every 3 weeks supports the notion that docetaxel and not trastuzumab is the causative agent for canalicular stenosis in patients reported in the current study. We are unaware of any previous reports of epiphora or canalicular stenosis secondary to the use of trastuzumab as a single agent. The mean cumulative dose of docetaxel at the time of diagnosis was higher for patients with severe canalicular stenosis than for patients with moderate stenosis, although this difference was not statistically significant. This finding suggests that patients with advanced metastatic disease, who are likely to receive a longer course of weekly docetaxel and a higher cumulative dose, are at a greater risk of developing canalicular stenosis than patients who are exposed to a shorter course of this drug in the neoadjuvant setting. Our study was not designed to assess quality of life issues in patients receiving weekly docetaxel. Nevertheless, it is important to note that every patient in this study sought consultation with an ophthalmologist because of epiphora, which they perceived as a visually disabling and bothersome symptom. They
221 7. Hurwitz JJ. The Lacrimal System. Philadelphia, PA: LippincottRaven Publishers 1996; 47–59. 8. Esmaeli B, Valero V, Ahmadi MA, Booser D. Canalicular stenosis secondary to docetaxel (taxotere): a newly recognized side effect. Ophthalmology 2001; 108: 994–995. 9. Hainsworth JD, Burris HA, Yardley DA et al. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl cancer research network phase II trial. J Clin Oncol 2001; 19: 3500–3505.
10. Baselga J, Tabernero JM. Weekly docetaxel in breast cancer: applying clinical data to patient therapy. Oncologist 2001; 6 (Suppl): 26–29. 11. Loffler TM. Is there a place for “dose-dense” weekly schedules of the taxoids? Semin Oncol 1998; 25 (5 Suppl 12): 32–34. 12. Tomiak E, Piccart MJ, Kerger J et al. Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis. J Clin Oncol 1994; 12: 1458–1467.
Downloaded from http://annonc.oxfordjournals.org/ at Ernst Mayr Library of the Museum Comp Zoology, Harvard University on July 4, 2015