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© 2000 American Society for Clinical Oncology Docetaxel Administered on a Weekly Basis for Metastatic Breast CancerFrom the Breast Oncology Center; Departments of Adult Oncology and Biostatistical Science, Dana-Farber Cancer Institute; Department of Medicine, Brigham & Women’s Hospital; Division of Hematology/Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA. Address reprint requests to Eric P. Winer, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email ewiner{at}partners.org
PURPOSE: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m2/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m2. There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.
DOCETAXEL (TAXOTERE; Rhône-Poulenc Rorer, Collegeville, PA) is an effective chemotherapeutic agent for advanced breast cancer, with significant activity as both first-line therapy1-3 and as second-line therapy in patients previously treated with anthracyclines.4,5 The standard dose and administration schedule for docetaxel in treating women with metastatic breast cancer is 75 to 100 mg/m2 as a 1-hour intravenous infusion every 21 days. The dose-limiting toxicity is myelosuppression, which is dose- but not schedule-dependent.6 In most published studies, there is a 90% to 95% incidence of grade 3 or 4 neutropenia when docetaxel is administered every 3 weeks at 100 mg/m2. Other toxicities include asthenia/fatigue, alopecia, skin reactions, stomatitis, hypersensitivity reactions, and a fluid-retention syndrome characterized by pedal edema and/or serous effusions. The fluid retention syndrome is related to cumulative dose, is generally reversible with cessation of therapy, and can be attenuated by administration of corticosteroids with docetaxel.7 Docetaxel activity extends over a range of doses. Response rates of 33% to 52% have been observed with doses of 75 mg/m2 every 21 days3,8,9; slightly higher responses rates (40% to 68%) have been observed at the 100-mg/m2 dose. In clinical practice, many patients are treated at lower doses because of decreased performance status, toxicity, liver function test abnormalities, or prior treatment with chemotherapy.3,9-11 The dose-response relationship for the taxanes remains unclear. For paclitaxel, randomized trials using higher doses or more dose-intensive schedules have not demonstrated significantly greater response rates in women with metastatic breast cancer, although higher doses have been associated with improved time to progression and greater degrees of toxicity.12,13 Administration of paclitaxel on a sustained weekly schedule has been shown to be effective in the treatment of advanced breast cancer.14 The delivery of lower, more frequent doses of paclitaxel also alters the toxicity profile. Sensory neuropathy has proven to be the dose-limiting toxicity, whereas myelosuppression is modest.14-16 Phase I studies have examined docetaxel administered on a weekly basis.17-20 This schedule of docetaxel significantly changed the toxicity profile of the drug, causing only mild myelosuppression. Fatigue/asthenia proved to be the dose-limiting toxicity, with other mild side effects including alopecia, nail changes, and peripheral neuropathy. The recommended phase II dose ranged from 36 to 40 mg/m2/wk. Because chemotherapy plays a significant role in the treatment of women with advanced breast cancer, it is important to define regimens that preserve quality of life while retaining clinical activity. In addition, a well-tolerated treatment lends itself to combinations with other chemotherapeutic agents or novel biologically active agents. Based on the favorable side effect profile of weekly docetaxel, a phase II study was conducted to examine the efficacy of this regimen among women with metastatic breast cancer and to explore the side effects that might arise during prolonged therapy.
Eligibility Women with histologically confirmed metastatic breast cancer were eligible for enrollment. Patients were required to be at least 18 years of age and to provide written informed consent. Patients could have received prior systemic adjuvant therapy (chemotherapy and/or hormonal therapy) and/or therapy for metastatic breast cancer (hormonal therapy and/or up to one prior chemotherapy regimen). No prior therapy was required. Patients previously treated with either paclitaxel or docetaxel in the metastatic setting were excluded. Patients were required to have bidimensionally measurable disease, including lytic bone lesions. Adequate general health status (Eastern Cooperative Oncology Group [ECOG] performance status  2; absence of active comorbid illness such as uncontrolled infection, cardiopulmonary disease, or diabetes) and laboratory evaluation (absolute neutrophil count [ANC] > 1,500/µL, platelet count > 100,000/µL, bilirubin level < upper limits of normal, AST < 1.5 x upper limits of normal, creatinine concentration < 1.5 x upper limit of normal, fasting glucose < 200 mg/dL) were required. Patients with neuropathy exceeding grade 1 according to the National Cancer Institute Common Toxicity Criteria (version 1) were excluded. The study was conducted in accordance with guidelines established by the United States Department of Health and Human Services. The Scientific Review and Human Protection Committees of Dana-Farber/Partners Cancer Care approved the study. Patients were enrolled between May and December 1998.
Treatment Plan Patients were assessed weekly for toxicity, which was reported according to the National Cancer Institute toxicity scale. Laboratory evaluation included weekly complete blood count and differential, and bilirubin/AST every other week. Docetaxel dose was reduced by 25% (to 30 mg/m2) for grade 2 neurologic toxicity, febrile neutropenia, grade 4 thrombocytopenia (platelet count < 25,000/µL), or for any grade 3 nonhematologic toxicity. Dose re-escalation after dose reduction was not permitted. Patients were to be taken off protocol for any grade 4 nonhematologic toxicity. Treatment was delayed 1 to 3 weeks for ANC less than 1,000/µL, platelet count less than 100,000/µL, bilirubin level greater than the upper limit of normal, or AST greater than 1.5 times the upper limit of normal. Patients could resume treatment as soon as laboratory evaluation permitted. Patients who experienced ANC less than 1,000/µL for more than 2 weeks were eligible to receive granuloctye colony-stimulating factor. Patients who missed one or two weekly treatments in a cycle but remained eligible for treatment could be treated with docetaxel in week 7 of that cycle. Patients who were ineligible to receive treatment on 3 consecutive weeks were taken off protocol. No patient received more than six docetaxel treatments within each 8-week cycle.
Study Analysis A response rate of 35% was believed to be of clinical interest, and patients were accrued in a two-stage study design. If fewer than three responses were observed among the first 17 eligible patients, accrual would be halted. Because responses were observed, additional patients were enrolled, to a final accrual of 29 women, to estimate better the response rate and characterize the toxicity profile. With this study design, the trial had an 81% chance of positive findings if the true response rate was 35% (at least 10 responses among 29 patients) and a 7% chance of positive findings if the true response rate was 15% (ie, study had a power of 81% and type I error of 7%).
Patient and Treatment Characteristics A total of 29 patients were enrolled onto the study. Table 1 lists the clinical characteristics of patients in the study. Median age was 57 years. All patients but one had a performance status of 0 or 1. Patients on this study had a substantial tumor burden. Seventy percent of patients had at least three organ sites of metastatic cancer. Twenty-three patients (79%) had visceral metastases, including 66% with liver metastases and 48% with lung metastases. Bone, lymph node, and chest wall/breast were other common sites of disease. Two thirds of patients had received prior chemotherapy; 31% of patients had received prior anthracyclines in either the adjuvant or metastatic setting.
Each 8-week cycle was composed of six weekly infusions, followed by a 2-week break in treatment. Patients who did not receive one treatment in a cycle for any reason (eg, travel, toxicity) could receive a "make-up" treatment in week 7. Treatment delays or omissions were uncommon and were usually a result of patient scheduling conflicts. Table 2 lists the patterns of weekly docetaxel treatment for patients enrolled onto the study. At the time of analysis, more than 500 infusions had been administered. Patients received a median of 18 infusions over a median time of 22 weeks on protocol. Median dose-intensity was 30 mg/m2/wk; mean dose-intensity was 27 mg/m2/wk. The median cumulative dose administered was 720 mg/m2.
A total of eight patients (28%) received a dose reduction to 30 mg/m2 after a median of 16 infusions. The actuarial likelihood of a dose reduction is shown in Fig 1. Among patients who received 18 to 20 infusions, the likelihood of a dose reduction was approximately 50%. The most common reason for dose reduction was patient fatigue (n = 5); two patients had dose reductions for neuropathy.
Toxicity All 29 patients were assessable for toxicity. Treatment was generally well tolerated. Table 3 lists toxicities encountered among patients enrolled onto the study. There was no grade 4 toxicity of any type. Only 28% of patients experienced any grade 3 toxicity. Myelosuppression was mild; 14% of patients had grade 3 neutropenia, which was of short duration. No growth factor support was required for neutropenia. Cumulative myelosuppression was not observed. Other hematologic toxicity included mild anemia; there was no thrombocytopenia.
Fatigue was a principal toxicity and the most common reason for dose reduction. Grade 3 fatigue/asthenia (corresponding to an ECOG performance status of 3) was reported by 14% of patients, and grade 2 (ECOG performance status of 2) was reported by 17%. Fatigue did not seem to be related to anemia, other neurologic side effects, or musculoskeletal complaints, but was more common after extensive treatment. In general, fatigue improved after dose reduction. Significant alopecia was reported by 41% of patients and was more likely to occur with increased number of infusions. One patient developed grade 3 neurologic toxicity with neurosensory and neuromotor changes in her fingers. Other skin or nail changes, hypersensitivity reactions, and gastrointestinal side effects were infrequent. Patients were treated with dexamethasone (8 mg orally bid for three doses with each weekly infusion) to minimize risk of fluid retention. Grade 2 fluid retention (requiring initiation of diuretics) developed in four patients (14%), three of whom had pleural effusions. Six other patients developed small pleural effusions believed to be related to treatment; one patient developed a pericardial effusion. Fluid retention appeared after a median dose of 480 mg/m2 and was related to the cumulative dose of docetaxel received (Fig 2). Although most fluid retention toxicities were minor, among patients receiving a cumulative dose of 600 mg/m2 docetaxel, the proportion that developed pleural effusions or pedal edema was 40% and approached 60% at 800 mg/m2. Diuretics seemed to have little effect on the pleural effusions.
An unexpected toxicity was the onset of excessive tearing/lacrimation, which was reported by half of the patients on study. Patients reported increased tearing and, in some cases, mild conjunctivitis or eye irritation. Formal ophthalmologic examination of several patients revealed no abnormalities. As with fluid retention, the onset of tearing seemed to be related to cumulative dose and occurred after a median of 400 mg/m2 (range, 120 to 960 mg/m2). Ten patients developed both tearing/conjunctivitis and some degree of fluid retention. Treatment with artificial tears or other ocular moisturizers ameliorated symptoms in some patients. Eye irritation led to a dose reduction in one patient.
Efficacy
The actuarial plot of time on study is shown in Fig 3. This plot underestimates the actual time to treatment failure or time to progression because it includes patients removed from protocol for progressive disease or toxicity, as well as patient or physician preference and transfers of care. Median time on study was 5 months.
The 29 women in this phase II study received a median of 18 treatments with weekly docetaxel administered over a span of 22 weeks, corresponding to a median cumulative dose of 720 mg/m2. Most side effects were related to cumulative dose; the tolerability of a given weekly dose was high. Toxicities such as fatigue, alopecia, fluid retention syndrome, and tearing developed with extended treatment on study. Acute toxicities related to any given infusion, such as neutropenia, skin reactions, stomatitis, or hypersensitivity reactions, were uncommon. Docetaxel was used as first-line metastatic therapy for 80% of the patients, and 31% of patients had previously been treated with anthracyclines in either the adjuvant or metastatic setting. Clinical response was observed in 41% of women. An additional 17% of patients had stabilization of their disease that lasted more than 6 months and that was often associated with improvement in nonmeasurable tumor burden. Thus, weekly docetaxel altered the side effect profile of docetaxel administration while retaining significant activity against metastatic breast cancer. In treating women with metastatic breast cancer, docetaxel is usually administered every 3 weeks, typically at 75 to 100 mg/m2. With such treatment, the incidence of grade 3 or 4 toxicity is considerable (neutropenia, 90% to 95%; anemia, 0% to 11%; sensory neuropathy, 5% to 14%; nail changes, 3% to 5%; stomatitis, 5% to 20%), and large fractions of patients will also have grade 1 or 2 symptoms.1-5,22-28 In comparison to this collective experience, weekly docetaxel at 40 mg/m2 was associated with less hematologic toxicity (myelosuppression and anemia), less stomatitis, fewer nail changes and other dermatologic events, and less neurologic toxicity. Toxicities related to cumulative dose—in particular, serous effusions and pedal edema—did develop with protracted administration of weekly docetaxel, despite administration of dexamethasone 8 mg orally for three doses with each weekly treatment. It is not known if a different corticosteroid schedule might have altered the incidence of fluid retention. In prior studies with docetaxel administered on an every-3-week schedule, fluid retention developed with an actuarial risk of 50% at 400 mg/m2 (Table 5). Onset is typically noted at a median cumulative dose of 300 to 400 mg/m2 among affected patients. In the present trial of weekly docetaxel, median dose to fluid retention was 480 mg/m2, and actuarial risk of 50% was noted at approximately 720 mg/m2.
An unexpected common side effect was excessive tearing or mild eye irritation. This was bothersome to many patients but only affected dosing in one. Conjunctivitis has been reported as a side effect of every-3-week docetaxel.5 In other phase I/II studies of weekly docetaxel, conjunctival or tearing problems have been reported in 19% to 29% of patients.20,29 Weekly administration enabled relatively high cumulative docetaxel administration (median dose, 720 mg/m2). Cumulative dose is affected by clinical practice patterns and the extent of prior therapy, making comparisons between studies difficult. However, cumulative levels administered with weekly docetaxel compare favorably to other trials of docetaxel given every 3 weeks, in which median doses of 350 to 500 mg/m2 have been typical (Table 5). It is not known if the different administration schedules, and presumably different pharmacokinetic curves, change the clinical efficacy of the drug. Preclinical studies suggested that docetaxel activity was not dependent on the schedule of administration.30 The response rate observed with weekly administration is within the range of responses reported in other trials of docetaxel (Table 5) or paclitaxel31 for metastatic breast cancer, including weekly paclitaxel.14,32 As in other studies of docetaxel, the efficacy observed with a weekly treatment schedule extended to all sites of metastatic disease, including hepatic metastases. Similarly, the response rate was consistent regardless of prior chemotherapy, including prior anthracycline exposure. Are weekly taxane schedules preferable to every-3-week schedules? There are theoretical reasons for believing that "dose-dense" therapy consisting of frequent drug treatments with maintained dose may have superior antitumor efficacy in metastatic breast cancer.33 However, empirical evidence from ongoing randomized trials will be needed to determine if weekly taxane treatment affords response rate, survival, or quality-of-life superiority to every-3-week treatment plans. For instance, the lack of acute toxicity must be considered alongside the more frequent visits to the clinic for treatment. In the meantime, it is clear that patients seem to tolerate weekly taxane infusions well, with fewer acute toxicities. Treatment-limiting side effects are related to extended therapy rather than weekly dose, and they emerge over time. There are particular instances when regular sustained chemotherapy exposure with weekly docetaxel may be advantageous: (1) when clinicians and patients are seeking to avoid acute side effects, and (2) when chemotherapy is being administered concurrently with other treatments such as radiation therapy or biologic therapies. In the latter instance, reliable, steady dosing of chemotherapy with frequent exposure may be desirable to obtain clinical synergy between the two modalities. Under such circumstances, weekly docetaxel administration may prove to be a useful foundation for treatment.
Supported in part by a grant-in-aid from Rhône-Poulenc Rorer, Collegeville, PA.
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Nabholtz JM, Gelman K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858-1867, 1996 13. Winer E, Berry D, Duggan D, et al: Failure of higher dose paclitaxel to improve outcome in patients with metastatic breast cancer: Results from CALGB 9342. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 388) 14. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16:3353-3361, 1998[Abstract] 15. Klaasen U, Wilke H, Strumberg D, et al: Phase I study with a weekly 1-h infusion of paclitaxel in heavily pretreated patients with metastatic breast and ovarian cancer. Eur J Cancer 32A:547-549, 1996
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Perez EA: Paclitaxel in breast cancer. The Oncologist 3:373-389, 1998 32. Perez EA, Irwin DH, Patel R, et al: A large phase II trial of paclitaxel administered as a weekly one hour infusion to patients with metastatic breast cancer. Proc Am Soc Clin Oncol 18:126a, 1999 (abstr 480) 33. Norton L: Kinetic concepts in the systemic drug therapy of breast cancer. Oncol 26:11-20, 1999 (suppl 2) Submitted July 1, 1999; accepted November 29, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
80% reductions in serum tumor marker (CA 27.29) levels. Considering these patients with stable disease, the clinical activity rate among all patients was 59% (17 of 29). 
