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Canalicular stenosis secondary to weekly versus every-3-weeks docetaxel in patients with metastatic breast cancer
Canalicular Stenosis Secondary to Weekly Versus Every-3-Weeks Docetaxel in Patients with Metastatic Breast Cancer Bita Esmaeli, MD,1 Gabriel N. Hortobagyi, MD,2 Francisco J. Esteva, MD,2 Daniel Booser, MD,2 M. Amir Ahmadi, MD,1 Edgardo Rivera, MD,2 Rebecca Arbuckle, MS,3 Ebrahim Delpassand, MD,4 Laura Guerra, RN,2 Vicente Valero, MD2 Purpose: To compare the frequency of canalicular stenosis as a side effect of weekly versus every-3-weeks docetaxel in patients with metastatic breast cancer. Design: Retrospective nonrandomized comparative trial. Patients and Methods: Eighteen patients enrolled in a phase II study of weekly docetaxel plus trastuzumab and 18 patients enrolled in a phase II study of every-3-weeks docetaxel plus doxorubicin were evaluated. Each patient underwent a comprehensive ophthalmologic examination, probing and irrigation of the nasolacrimal duct, and, in some instances, a nuclear lacrimal scan. Main Outcome Measures: If epiphora (excessive tearing) was reported by the patient, its time of onset was documented. In patients with epiphora, presence or absence of canalicular stenosis was evaluated on the basis of the findings on probing and irrigation. The duration of treatment with docetaxel, the dose frequency, and the cumulative dose of docetaxel were recorded in each case. Results: Fourteen patients (77%) receiving weekly docetaxel plus trastuzumab had epiphora. Nine of these patients had significant anatomic narrowing of the canaliculi. Bicanalicular silicone intubation or dacryocystorhinostomy was recommended in all nine patients. Eight patients underwent surgery and experienced complete or near complete resolution of epiphora. Although two patients (11%) receiving every-3-weeks docetaxel plus doxorubicin reported transient symptoms of epiphora, neither patient was found to have narrowing of the canaliculi, and the epiphora was not severe enough to justify surgical intervention. The mean duration of docetaxel therapy for the patients in this study was 19 weeks. The mean cumulative dose of docetaxel was higher in patients with canalicular stenosis than in patients without this side effect. Conclusions: Canalicular stenosis was more common in patients receiving weekly docetaxel than in those receiving every-3-weeks docetaxel for metastatic breast cancer. Bicanalicular silicone intubation early in the course of weekly docetaxel therapy should be considered, because this intervention can prevent complete closure of the canaliculi. Once complete or near complete stenosis of the canaliculi occurs, placement of a permanent Pyrex glass tube may become necessary to overcome the blockage of tear outflow. Ophthalmology 2002;109:1188 –1191 © 2002 by the American Academy of Ophthalmology. Docetaxel (Taxotere; Aventis, Bridgewater, New Jersey) is one of the most effective chemotherapeutic agents for advanced breast cancer, both as first-line therapy and as secOriginally received: April 10, 2001. Accepted: July 13, 2001. Manuscript no. 210242. 1 Ophthalmology Section, Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 2 Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 3 Department of Pharmacoeconomics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 4 Department of Nuclear Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Supported in part by grant no. K23-CA82119 from the National Cancer Institute (FJE), Bethesda, Maryland. Reprint requests to Bita Esmaeli, MD, Ophthalmology Section, Department of Plastic Surgery, Box 443, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
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© 2002 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
ond-line therapy in patients previously treated with anthracyclines.1,2 In women with metastatic breast cancer, docetaxel is usually administered as a 1-hour intravenous infusion every 21 days. With this standard administration schedule, the dose-limiting side effect is myelosuppression.3 An alternative schedule—weekly administration of docetaxel— has been studied in phase I and II trials.4,5 Unlike docetaxel administered every 3 weeks, weekly docetaxel causes only mild myelosuppression.6 Fatigue and asthenia are the dose-limiting side effects; other reported mild side effects include alopecia, nail changes, and peripheral neuropathy. Epiphora (excessive tearing) has been reported in up to 50% of patients receiving weekly docetaxel.5 We recently reported that canalicular stenosis is the underlying mechanism for epiphora secondary to weekly docetaxel.7 In this report, we compared the frequency and severity of canalicular stenosis in patients receiving docetaxel weekly versus every 3 weeks. ISSN 0161-6420/02/$–see front matter PII S0161-6420(02)00989-2
Esmaeli et al 䡠 Canalicular Stenosis Secondary to Docetaxel in Metastatic Breast Cancer Table 2. Pattern of Docetaxel Administration
Table 1. Patient Characteristics
Number of patients Age, years Mean Range Race White Black Hispanic Concomitant chemotherapy Trastuzumab Doxorubicin
Weekly Group
Every-3-Weeks Group
18
18
48 36–78
52.5 35–73
15 (83%) 2 (11%) 1 (6%)
13 (72%) 4 (22%) 1 (6%)
18 0
0 18
Patients and Methods Between March 2000 and October 2000, all 18 patients with metastatic breast cancer enrolled in a phase II study of weekly docetaxel plus trastuzumab (Herceptin; Genentech Inc., South San Francisco, CA), and all 18 patients with locally advanced breast cancer enrolled in a phase II study of every-3-weeks docetaxel plus doxorubicin were evaluated in the Ophthalmology Clinic at The University of Texas M. D. Anderson Cancer Center. Each patient underwent a comprehensive ophthalmologic examination, probing and irrigation of the nasolacrimal duct, and, in some instances, a nuclear lacrimal scan. In most patients, the ophthalmologic evaluation and the probing and irrigation of the nasolacrimal duct were done only after docetaxel therapy began. A baseline ophthalmologic examination was not a requirement of either of these two protocols. After we diagnosed canalicular stenosis in a few symptomatic patients, we contacted all patients enrolled in these two protocols and subsequently performed a complete ophthalmologic evaluation, including probing and irrigation of the nasolacrimal duct in each patient. The duration of treatment with docetaxel, the dose frequency, and the cumulative dose of docetaxel were recorded for each patient. If epiphora was reported by the patient, the time of onset of epiphora was documented. In patients with epiphora, the presence or absence of canalicular stenosis was evaluated by one of us (BE) during in-office probing and irrigation using the standard techniques.8 A nuclear lacrimal scan was obtained in patients with equivocal findings on probing and irrigation. The frequency of epiphora was compared between the two groups using a Pearson chi-square test. Similarly, the frequency of canalicular stenosis was compared between patients receiving weekly docetaxel versus those receiving every-3-weeks docetaxel using a Pearson chisquare test.
Results Table 1 lists the clinical characteristics of the patients enrolled in the two protocols. In the group receiving weekly docetaxel plus trastuzumab: 14 patients (77%) reported epiphora that was severe enough to interfere with reading and driving. Nine of these patients had significant anatomic narrowing of the canaliculi. The length of time from beginning of weekly docetaxel therapy to onset of epiphora ranged from 4 to 16 weeks (mean, 7 weeks). In two patients, epiphora and canalicular stenosis persisted after cessation of docetaxel (3 and 4 weeks after discontinuation of docetaxel).
Duration of treatment (weeks) Mean Range Number of infusions Mean Range Dose intensity Dose Cumulative dose Mean Range
Weekly Group
Every-3-Weeks Group
22.5 8–40
15.2 7–25
17 6–30
5 3–6
35 mg/m2
60 mg/m2
595 mg/m2 210–1050 mg/m2
302 mg/m2 180–360 mg/m2
In the group receiving every-3-weeks docetaxel plus doxorubicin, two patients (11%) reported transient symptoms of epiphora. Neither of these patients was found to have anatomic narrowing of the canaliculi. The intervals from beginning of every-3-weeks docetaxel therapy to onset of epiphora were 6 and 15 weeks in these two patients. The frequency of epiphora was significantly greater in the weekly docetaxel/trastuzumab group than in the every-3-weeks docetaxel/doxorubicin group (P ⬍ 0.001, Pearson chi-square test). The frequency of canalicular stenosis as an anatomic finding was also significantly higher in the weekly docetaxel/trastuzumab group than in the every-3-weeks docetaxel/doxorubicin group (P ⬍ 0.001, Pearson chi-square test). For patients enrolled in the docetaxel/trastuzumab protocol, each cycle of docetaxel treatment was composed of three weekly infusions followed by a 1-week break. Docetaxel, 35 mg/m2, and trastuzumab, 4 mg/kg bolus, was given during the first week. For the subsequent 2 weeks docetaxel, 35 mg/m2, was given along with trastuzumab, 2 mg/kg. For patients enrolled in the docetaxel/ doxorubicin protocol, the docetaxel infusions were given once every 3 weeks. Each patient in the every-three-weeks docetaxel/ doxorubicin group received docetaxel, 60 mg/m2, plus doxorubicin, 60 mg/m2, for a maximum of six cycles. In both protocols, therapy was continued until progression of disease, maximal benefit, or development of unacceptable toxicity. Table 2 summarizes the patterns of docetaxel administration for the patients enrolled in the two protocols. Patients in the weekly docetaxel/trastuzumab protocol received a mean of 17 infusions over a mean time of 22.5 weeks, corresponding to a mean cumulative dose of 595 mg/m2 at the time of diagnosis of canalicular stenosis. Every patient received dexamethasone (12 mg), 4 mg the night before, 4 mg just prior to the infusion, and 4 mg 12 hours after the infusion. Patients in the every-3-weeks docetaxel/doxorubicin protocol received a mean of five infusions over a mean time of 15.2 weeks, corresponding to a mean cumulative dose of 302 mg/m2. Each patient received a total of 48 mg of dexamethasone with the first cycle; the total dose of dexamethasone was then decreased to 8 mg for the future cycles. The mean duration of docetaxel therapy for all the patients in this study was 19 weeks. Table 3 shows the relationship between the cumulative dose of docetaxel and the presence or absence of canalicular stenosis for the entire study group. The mean cumulative dose of docetaxel was higher in patients with canalicular stenosis than in patients without canalicular stenosis (P ⫽ 0.0002). Bicanalicular silicone intubation or dacryocystorhinostomy was recommended for all nine patients with significant canalicular stenosis secondary to weekly docetaxel. Eight patients underwent
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Ophthalmology Volume 109, Number 6, June 2002 Table 3. Total Cumulative Dose of Docetaxel in Patients with and without Canalicular Stenosis Cumulative Dose of Docetaxel (mg/m2) Mean (⫾ Standard Deviation)
Median
Mode
712 (⫾201) 361 (⫾172)
735 360
840 360
With stenosis Without stenosis
surgery. The frequency and type of surgical procedures performed are listed in Table 4. In two patients (three eyes), the degree of canalicular blockage was such that insertion of a silicone tube was impossible; thus a canaliculo-dacryocystorhinostomy and silicone intubation was necessary to overcome the lacrimal outflow blockage. One patient declined surgery. All patients who underwent bicanalicular silicone intubation experienced complete or near complete resolution of epiphora. None of the patients enrolled in the every-3-weeks docetaxel protocol had epiphora severe enough to justify surgical intervention. The two patients with transient epiphora were treated with in-office probing and irrigation followed by the use of a combination of topical antibiotics and steroid drops. This approach resulted in resolution of the symptoms in both patients.
Discussion We found that canalicular stenosis and epiphora were more common in patients receiving weekly docetaxel than in patients receiving every-3-weeks docetaxel. We previously reported that canalicular stenosis is the underlying anatomic mechanism for epiphora in patients treated with weekly docetaxel.7 Burstein et al5 reported epiphora in 50% of 29 patients enrolled in a phase II trial of weekly docetaxel as a single agent, although these authors did not describe the underlying mechanism for this symptom. Epiphora and canalicular stenosis have not previously been reported in patients receiving every-3-weeks docetaxel. However, “conjunctivitis” has been reported as a relatively infrequent side effect of every-3-weeks docetaxel. Personal communica-
Table 4. Types of Surgical Treatment Intervention
Number of Patients/ Number of Eyes
Bicanalicular silicone intubation DCR plus silicone intubation Attempted silicone intubation Surgery recommended but not performed Total
6/11 2/3* 1/2† 1/2 9/18
DCR ⫽ dacryocystorhinostomy. *One patient required DCR on one side and silicone intubation on the other side; therefore, this patient is listed twice (both in the silicone intubation and the DCR line). †
In one patient (two eyes), because of severe canalicular stenosis, silicone intubation was not possible, although it was attempted under general anesthesia. Adequate informed consent was not available in this patient’s medical records to allow the surgeon to convert to a DCR.
1190
tions with the investigators of phase II trials of every-3weeks docetaxel for metastatic breast cancer suggest that some investigators assumed patients with excessive tearing had conjunctivitis (Vicente Valero, personal communication January 2001). Thus, the reports of “conjunctivitis” in up to 11% of patients in phase II trials of every-3-weeks docetaxel may actually refer to epiphora associated with mild canalicular stenosis.2 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 caused by direct contact with the drug as the tears travel through these structures to enter the nasolacrimal duct and drain into the nose. It is possible that administration of docetaxel on a sustained weekly schedule leads to more chronic exposure of the canaliculi to this drug compared with the every-3weeks regimen. Although two patients receiving every-3-weeks docetaxel plus doxorubicin experienced transient symptoms of epiphora, these patients had no significant anatomic narrowing of the canaliculi. In-office probing and irrigation followed by administration of topical steroids was very effective in treating the transient symptoms of epiphora in these patients. The only case of significant canalicular stenosis that we have ever observed in a patient receiving every-3weeks docetaxel occurred in a patient who was treated off protocol. In this patient, canalicular stenosis developed after 12 cycles of therapy, and surgical intervention was required to overcome the blockage of tear outflow (unpublished data). In this study the patients enrolled in the every-3weeks docetaxel/doxorubicin protocol received a maximum of only six cycles. It is possible that using every-3-weeks docetaxel at a higher dose and for a longer duration could also lead to symptomatic canalicular stenosis. In this report, there was a significant relationship between the cumulative dose of docetaxel and the presence of canalicular stenosis. Thus, it seems that not only continuous exposure to docetaxel caused by weekly administration of the drug but also the total dose of docetaxel plays a role in the development of canalicular stenosis. This 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 greater risk for the development of canalicular stenosis than patients who are exposed to a shorter course of this drug in the adjuvant or neoadjuvant settings. Although the patients enrolled in this study did not receive docetaxel as a single agent, our experience with other patients receiving weekly docetaxel as a single agent suggests that canalicular stenosis occurs as a side effect of weekly docetaxel (unpublished data), not trastuzumab. Furthermore, the fact that epiphora was also seen, albeit transiently, in some patients receiving every-3-weeks docetaxel supports the notion that docetaxel is the cause of this side effect. Future prospective studies are needed to confirm the frequency and timing of canalicular stenosis in patients receiving weekly docetaxel as a single agent. 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 receiving weekly
Esmaeli et al 䡠 Canalicular Stenosis Secondary to Docetaxel in Metastatic Breast Cancer docetaxel who had epiphora perceived this side effect as a visually disabling and bothersome symptom and was dissatisfied with the misleading appearance of “emotional tears.” Because weekly docetaxel is now widely used as an effective first-line or second-line antineoplastic treatment for breast cancer and other common malignancies,4,6,9,10 it is crucial that ophthalmologists and oncologists be aware of canalicular stenosis as a relatively common side effect of weekly docetaxel. Timely diagnosis of this side effect and timely insertion of bicanalicular silicone stents can prevent permanent and complete closure of the canaliculi. Silicone tubes can be left in place until the patient is no longer exposed to docetaxel. Once significant closure of the canaliculi occurs, conjunctivo-DCR and placement of a permanent Pyrex glass tube (Jones tube) may be required to overcome the blockage of lacrimal outflow. We recommend referral to an ophthalmologist (ideally an oculoplastic surgeon) at the earliest possible time after initiation of weekly docetaxel and at frequent intervals thereafter so that bicanalicular silicone intubation can be considered as soon as symptoms of epiphora are noted. For patients receiving every-three-weeks docetaxel who develop epiphora, we recommend a thorough evaluation of the tear drainage apparatus and in-office probing and irrigation followed by a short course of topical steroids. Surgical intervention may become necessary in patients who have received a high dose or an unusually long course of every-3-weeks docetaxel.
References 1. Hudis CA, Seidman AD, Crown JPA, 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 –94. 3. Cortes JE, Pazdur R. Docetaxel [review]. J Clin Oncol 1995; 13:2643–55. 4. Hainsworth JD, Burris HA III, 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 – 8. 5. Burstein HJ, Manola, J, Younger J, et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18:1212–9. 6. Hortobagyi GN. Recent progress in the clinical development of docetaxel (Taxotere). Semin Oncol 1999;26:32– 6. 7. Esmaeli B, Valero V, Ahmadi MA, Booser D. Canalicular stenosis secondary to docetaxel (taxotere): a newly recognized side effect. Ophthalmology 2001;108:994 –5. 8. Hurwitz JJ, ed. The Lacrimal System. Philadelphia: Lippincott-Raven, 1996;47–59. 9. Loffler TM. Is there a place for “dose-dense” weekly schedules of the taxoids? Semin Oncol 1998;25:32– 4. 10. 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 – 67.
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© 2002 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
ond-line therapy in patients previously treated with anthracyclines.1,2 In women with metastatic breast cancer, docetaxel is usually administered as a 1-hour intravenous infusion every 21 days. With this standard administration schedule, the dose-limiting side effect is myelosuppression.3 An alternative schedule—weekly administration of docetaxel— has been studied in phase I and II trials.4,5 Unlike docetaxel administered every 3 weeks, weekly docetaxel causes only mild myelosuppression.6 Fatigue and asthenia are the dose-limiting side effects; other reported mild side effects include alopecia, nail changes, and peripheral neuropathy. Epiphora (excessive tearing) has been reported in up to 50% of patients receiving weekly docetaxel.5 We recently reported that canalicular stenosis is the underlying mechanism for epiphora secondary to weekly docetaxel.7 In this report, we compared the frequency and severity of canalicular stenosis in patients receiving docetaxel weekly versus every 3 weeks. ISSN 0161-6420/02/$–see front matter PII S0161-6420(02)00989-2
Esmaeli et al 䡠 Canalicular Stenosis Secondary to Docetaxel in Metastatic Breast Cancer Table 2. Pattern of Docetaxel Administration
Table 1. Patient Characteristics
Number of patients Age, years Mean Range Race White Black Hispanic Concomitant chemotherapy Trastuzumab Doxorubicin
Weekly Group
Every-3-Weeks Group
18
18
48 36–78
52.5 35–73
15 (83%) 2 (11%) 1 (6%)
13 (72%) 4 (22%) 1 (6%)
18 0
0 18
Patients and Methods Between March 2000 and October 2000, all 18 patients with metastatic breast cancer enrolled in a phase II study of weekly docetaxel plus trastuzumab (Herceptin; Genentech Inc., South San Francisco, CA), and all 18 patients with locally advanced breast cancer enrolled in a phase II study of every-3-weeks docetaxel plus doxorubicin were evaluated in the Ophthalmology Clinic at The University of Texas M. D. Anderson Cancer Center. Each patient underwent a comprehensive ophthalmologic examination, probing and irrigation of the nasolacrimal duct, and, in some instances, a nuclear lacrimal scan. In most patients, the ophthalmologic evaluation and the probing and irrigation of the nasolacrimal duct were done only after docetaxel therapy began. A baseline ophthalmologic examination was not a requirement of either of these two protocols. After we diagnosed canalicular stenosis in a few symptomatic patients, we contacted all patients enrolled in these two protocols and subsequently performed a complete ophthalmologic evaluation, including probing and irrigation of the nasolacrimal duct in each patient. The duration of treatment with docetaxel, the dose frequency, and the cumulative dose of docetaxel were recorded for each patient. If epiphora was reported by the patient, the time of onset of epiphora was documented. In patients with epiphora, the presence or absence of canalicular stenosis was evaluated by one of us (BE) during in-office probing and irrigation using the standard techniques.8 A nuclear lacrimal scan was obtained in patients with equivocal findings on probing and irrigation. The frequency of epiphora was compared between the two groups using a Pearson chi-square test. Similarly, the frequency of canalicular stenosis was compared between patients receiving weekly docetaxel versus those receiving every-3-weeks docetaxel using a Pearson chisquare test.
Results Table 1 lists the clinical characteristics of the patients enrolled in the two protocols. In the group receiving weekly docetaxel plus trastuzumab: 14 patients (77%) reported epiphora that was severe enough to interfere with reading and driving. Nine of these patients had significant anatomic narrowing of the canaliculi. The length of time from beginning of weekly docetaxel therapy to onset of epiphora ranged from 4 to 16 weeks (mean, 7 weeks). In two patients, epiphora and canalicular stenosis persisted after cessation of docetaxel (3 and 4 weeks after discontinuation of docetaxel).
Duration of treatment (weeks) Mean Range Number of infusions Mean Range Dose intensity Dose Cumulative dose Mean Range
Weekly Group
Every-3-Weeks Group
22.5 8–40
15.2 7–25
17 6–30
5 3–6
35 mg/m2
60 mg/m2
595 mg/m2 210–1050 mg/m2
302 mg/m2 180–360 mg/m2
In the group receiving every-3-weeks docetaxel plus doxorubicin, two patients (11%) reported transient symptoms of epiphora. Neither of these patients was found to have anatomic narrowing of the canaliculi. The intervals from beginning of every-3-weeks docetaxel therapy to onset of epiphora were 6 and 15 weeks in these two patients. The frequency of epiphora was significantly greater in the weekly docetaxel/trastuzumab group than in the every-3-weeks docetaxel/doxorubicin group (P ⬍ 0.001, Pearson chi-square test). The frequency of canalicular stenosis as an anatomic finding was also significantly higher in the weekly docetaxel/trastuzumab group than in the every-3-weeks docetaxel/doxorubicin group (P ⬍ 0.001, Pearson chi-square test). For patients enrolled in the docetaxel/trastuzumab protocol, each cycle of docetaxel treatment was composed of three weekly infusions followed by a 1-week break. Docetaxel, 35 mg/m2, and trastuzumab, 4 mg/kg bolus, was given during the first week. For the subsequent 2 weeks docetaxel, 35 mg/m2, was given along with trastuzumab, 2 mg/kg. For patients enrolled in the docetaxel/ doxorubicin protocol, the docetaxel infusions were given once every 3 weeks. Each patient in the every-three-weeks docetaxel/ doxorubicin group received docetaxel, 60 mg/m2, plus doxorubicin, 60 mg/m2, for a maximum of six cycles. In both protocols, therapy was continued until progression of disease, maximal benefit, or development of unacceptable toxicity. Table 2 summarizes the patterns of docetaxel administration for the patients enrolled in the two protocols. Patients in the weekly docetaxel/trastuzumab protocol received a mean of 17 infusions over a mean time of 22.5 weeks, corresponding to a mean cumulative dose of 595 mg/m2 at the time of diagnosis of canalicular stenosis. Every patient received dexamethasone (12 mg), 4 mg the night before, 4 mg just prior to the infusion, and 4 mg 12 hours after the infusion. Patients in the every-3-weeks docetaxel/doxorubicin protocol received a mean of five infusions over a mean time of 15.2 weeks, corresponding to a mean cumulative dose of 302 mg/m2. Each patient received a total of 48 mg of dexamethasone with the first cycle; the total dose of dexamethasone was then decreased to 8 mg for the future cycles. The mean duration of docetaxel therapy for all the patients in this study was 19 weeks. Table 3 shows the relationship between the cumulative dose of docetaxel and the presence or absence of canalicular stenosis for the entire study group. The mean cumulative dose of docetaxel was higher in patients with canalicular stenosis than in patients without canalicular stenosis (P ⫽ 0.0002). Bicanalicular silicone intubation or dacryocystorhinostomy was recommended for all nine patients with significant canalicular stenosis secondary to weekly docetaxel. Eight patients underwent
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Ophthalmology Volume 109, Number 6, June 2002 Table 3. Total Cumulative Dose of Docetaxel in Patients with and without Canalicular Stenosis Cumulative Dose of Docetaxel (mg/m2) Mean (⫾ Standard Deviation)
Median
Mode
712 (⫾201) 361 (⫾172)
735 360
840 360
With stenosis Without stenosis
surgery. The frequency and type of surgical procedures performed are listed in Table 4. In two patients (three eyes), the degree of canalicular blockage was such that insertion of a silicone tube was impossible; thus a canaliculo-dacryocystorhinostomy and silicone intubation was necessary to overcome the lacrimal outflow blockage. One patient declined surgery. All patients who underwent bicanalicular silicone intubation experienced complete or near complete resolution of epiphora. None of the patients enrolled in the every-3-weeks docetaxel protocol had epiphora severe enough to justify surgical intervention. The two patients with transient epiphora were treated with in-office probing and irrigation followed by the use of a combination of topical antibiotics and steroid drops. This approach resulted in resolution of the symptoms in both patients.
Discussion We found that canalicular stenosis and epiphora were more common in patients receiving weekly docetaxel than in patients receiving every-3-weeks docetaxel. We previously reported that canalicular stenosis is the underlying anatomic mechanism for epiphora in patients treated with weekly docetaxel.7 Burstein et al5 reported epiphora in 50% of 29 patients enrolled in a phase II trial of weekly docetaxel as a single agent, although these authors did not describe the underlying mechanism for this symptom. Epiphora and canalicular stenosis have not previously been reported in patients receiving every-3-weeks docetaxel. However, “conjunctivitis” has been reported as a relatively infrequent side effect of every-3-weeks docetaxel. Personal communica-
Table 4. Types of Surgical Treatment Intervention
Number of Patients/ Number of Eyes
Bicanalicular silicone intubation DCR plus silicone intubation Attempted silicone intubation Surgery recommended but not performed Total
6/11 2/3* 1/2† 1/2 9/18
DCR ⫽ dacryocystorhinostomy. *One patient required DCR on one side and silicone intubation on the other side; therefore, this patient is listed twice (both in the silicone intubation and the DCR line). †
In one patient (two eyes), because of severe canalicular stenosis, silicone intubation was not possible, although it was attempted under general anesthesia. Adequate informed consent was not available in this patient’s medical records to allow the surgeon to convert to a DCR.
1190
tions with the investigators of phase II trials of every-3weeks docetaxel for metastatic breast cancer suggest that some investigators assumed patients with excessive tearing had conjunctivitis (Vicente Valero, personal communication January 2001). Thus, the reports of “conjunctivitis” in up to 11% of patients in phase II trials of every-3-weeks docetaxel may actually refer to epiphora associated with mild canalicular stenosis.2 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 caused by direct contact with the drug as the tears travel through these structures to enter the nasolacrimal duct and drain into the nose. It is possible that administration of docetaxel on a sustained weekly schedule leads to more chronic exposure of the canaliculi to this drug compared with the every-3weeks regimen. Although two patients receiving every-3-weeks docetaxel plus doxorubicin experienced transient symptoms of epiphora, these patients had no significant anatomic narrowing of the canaliculi. In-office probing and irrigation followed by administration of topical steroids was very effective in treating the transient symptoms of epiphora in these patients. The only case of significant canalicular stenosis that we have ever observed in a patient receiving every-3weeks docetaxel occurred in a patient who was treated off protocol. In this patient, canalicular stenosis developed after 12 cycles of therapy, and surgical intervention was required to overcome the blockage of tear outflow (unpublished data). In this study the patients enrolled in the every-3weeks docetaxel/doxorubicin protocol received a maximum of only six cycles. It is possible that using every-3-weeks docetaxel at a higher dose and for a longer duration could also lead to symptomatic canalicular stenosis. In this report, there was a significant relationship between the cumulative dose of docetaxel and the presence of canalicular stenosis. Thus, it seems that not only continuous exposure to docetaxel caused by weekly administration of the drug but also the total dose of docetaxel plays a role in the development of canalicular stenosis. This 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 greater risk for the development of canalicular stenosis than patients who are exposed to a shorter course of this drug in the adjuvant or neoadjuvant settings. Although the patients enrolled in this study did not receive docetaxel as a single agent, our experience with other patients receiving weekly docetaxel as a single agent suggests that canalicular stenosis occurs as a side effect of weekly docetaxel (unpublished data), not trastuzumab. Furthermore, the fact that epiphora was also seen, albeit transiently, in some patients receiving every-3-weeks docetaxel supports the notion that docetaxel is the cause of this side effect. Future prospective studies are needed to confirm the frequency and timing of canalicular stenosis in patients receiving weekly docetaxel as a single agent. 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 receiving weekly
Esmaeli et al 䡠 Canalicular Stenosis Secondary to Docetaxel in Metastatic Breast Cancer docetaxel who had epiphora perceived this side effect as a visually disabling and bothersome symptom and was dissatisfied with the misleading appearance of “emotional tears.” Because weekly docetaxel is now widely used as an effective first-line or second-line antineoplastic treatment for breast cancer and other common malignancies,4,6,9,10 it is crucial that ophthalmologists and oncologists be aware of canalicular stenosis as a relatively common side effect of weekly docetaxel. Timely diagnosis of this side effect and timely insertion of bicanalicular silicone stents can prevent permanent and complete closure of the canaliculi. Silicone tubes can be left in place until the patient is no longer exposed to docetaxel. Once significant closure of the canaliculi occurs, conjunctivo-DCR and placement of a permanent Pyrex glass tube (Jones tube) may be required to overcome the blockage of lacrimal outflow. We recommend referral to an ophthalmologist (ideally an oculoplastic surgeon) at the earliest possible time after initiation of weekly docetaxel and at frequent intervals thereafter so that bicanalicular silicone intubation can be considered as soon as symptoms of epiphora are noted. For patients receiving every-three-weeks docetaxel who develop epiphora, we recommend a thorough evaluation of the tear drainage apparatus and in-office probing and irrigation followed by a short course of topical steroids. Surgical intervention may become necessary in patients who have received a high dose or an unusually long course of every-3-weeks docetaxel.
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