Epiphora and Canalicular Stenosis Associated With Adjuvant Docetaxel in Early Breast Cancer: Is Excessive Tearing Clinically Important?

Docetaxel, as a single agent or in combination, is widely used in the palliative treatment of many common solid tumors, including breast, lung, and prostate cancers. Docetaxel is also used in many of the adjuvant regimens in early breast cancer, including the docetaxel, carboplatin, and trastuzumab regimen, the docetaxel and cyclophosphamide combination, and those with or without an anthracycline or trastuzumab (docetaxel/doxorubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide followed by docetaxel, doxorubicin/cyclophosphamide followed by docetaxel, and doxorubicin/cyclophosphamide followed by docetaxel plus trastuzumab). Adjuvant-based docetaxel may lead to well-known acute and chronic adverse events including neutropenic fever or infection, stomatitis, hypersensitive reaction, rash, fluid retention, peripheral neuropathy, and fatigue. The safety profile of docetaxel is schedule and dose dependent. Excessive tearing (epiphora) is a common adverse event reported in patients who receive docetaxel for metastatic disease. However, there is little published information about ocular toxicity, including epiphora, in the adjuvant setting. Two large docetaxel-based adjuvant phase III studies briefly reported docetaxel-related ocular toxicity. In the Breast Cancer International Research Group (BCIRG) trial 001, lacrimal disorder was reported in 11.3% versus 7.1% of patients who received TAC versus those who received fluorouracil/doxorubicin/ cyclophosphamide, respectively. In the Eastern Cooperative Oncology Group study 1199, grade 3 and 4 lacrimation was reported in 5% of patients who received weekly adjuvant docetaxel versus less than 1% of patients who received adjuvant paclitaxel once per week, paclitaxel once every 3 weeks, or docetaxel once every 3 weeks. Other ocular symptoms such as conjunctivitis were also reported in less than 1% in patients in this trial, including those who received docetaxel once per week. In the article that accompanies this editorial, Chan et al studied the prevalence of epiphora, canalicular stenosis, and nasolacrimal duct obstruction in patients with early-stage breast carcinoma who received adjuvant docetaxel-based combination chemotherapy. This is a large prospective report evaluating ocular toxicity in patients with early breast cancer receiving adjuvant therapy, although several previous studies have reported the association between docetaxel and epiphora and its anatomic correlates, canalicular stenosis and nasolacrimal duct obstruction, in patients with metastatic breast carcinoma. Our group published several reports, some dating back to 2001, on the incidence and severity of epiphora and its anatomic correlates in patients treated with docetaxel, initially in patients treated with docetaxel once every 3 weeks, and later in patients treated with docetaxel once per week. In a prospective randomized clinical trial in patients with metastatic breast cancer, we clearly demonstrated a higher incidence of canalicular stenosis and nasolacrimal duct obstruction in patients receiving docetaxel once per week compared with those receiving docetaxel once every 3 weeks. We also showed that a delay in intervention for patients receiving docetaxel once per week leads to a need for more complicated surgery and worse outcomes. In contrast to the metastatic setting, epiphora and its anatomic correlates, canalicular stenosis and nasolacrimal duct obstruction, have not been well studied previously in patients with early breast cancer. However, it has been recognized that docetaxel given every 3 weeks (not weekly), for a short overall treatment duration (9 to 18 weeks) in patients with metastatic breast cancer is associated with only mild to occasionally moderate ocular symptoms that resolve quickly. Thus, the prospective observations reported by Chan et al using similar docetaxel dosing schedules now confirm previous results that have been observed in the metastatic setting, but in a larger number of patients with early breast cancer. Chan et al reported several important clinical observations. They described rapid onset and high incidence of epiphora (86%). Nearly 70% of patients experienced epiphora before the third cycle. However, only six patients had short-lasting grade 3 epiphora. The authors did not observe any difference between short versus long regimens. However, the majority of patient received six cycles of adjuvant therapy, and we have clearly established that it is not the patients who receive docetaxel once every 3 weeks for short periods who are the subject of greatest concern. Rather, it is the patients who receive docetaxel once per week, or once every 3 weeks for extended periods (ie, patients receiving docetaxel for metastatic disease) who are at greatest risk of canalicular stenosis. In the study by Chan et al, nearly 20% of patients had asymptomatic partial lacrimal duct obstruction at baseline according to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 17 JUNE 1